bionyt-118-kilder

Ref.93:

Andropause, the male menopause

Treatment for Andropause consists of replacing lost hormones with natural hormones that are molecularly equal to those occurring naturally within the body. Andropause also refers to sexual regression in men over 40 due to dropping male hormone levels.
For more information on andropause click here

Ref.92a:

Taurin – Taurine
Tilhører aminosyrerne. Nøgleord: Epilepsi, migræne, diabetes, depression, nervekramper, højt blodtryk, højt blodkolesterol, lav skjoldbruskkirtelaktivitet, galdesten, podagra, nedsat sædkvalitet og nyrelidelser.

Beskrivelse:
Anvendes til så forskelligartede lidelser som epilepsi, migræne, diabetes, depression, nervekramper, højt blodtryk, højt blodcholesterol, lav skjoldbruskkirtelaktivitet, galdesten, podagra, nedsat sædkvalitet og nyrelidelser.

Denne usædvanlige aminosyre er svovlholdig – ligesom L-Methionine, L-Cysteine og L-Cystin samt tripeptidet L-Glutathione – og udfylder en lang række forskellige biokemiske roller. Som elektrokemisk stabilisator er den involveret i transporten af ioner – natrium, kalium, kalcium, magnesium og måske andre – gennem cellevægge og andre membraner. Den er derfor af vital betydning for hjerne, hjerte, øjne, galdeblære og kredsløb.

Taurin er en ikke særlig kendt og strukturelt meget simpel aminosyre, vandopløselig og med ringe molekylstørrelse. Dens enkle opbygning gør, at den – ligesom glycin – ikke har nogen L-eller D-form, og derfor altså heller ikke findes i en racemisk syntetisk udgave. Den indgår heller ikke i dannelsen af peptider og derfor heller ikke strukturelt i opbygningen af proteiner, men optræder i kroppen som et frit molekyle, især i hjernevævet og centralnervesystemet iøvrigt, i hjertet og skeletmuskulaturen. Taurin findes i alle kroppens membraner.

Taurin dannes i organismen ud fra L-Cysteine under forudsætning af tilstedeværelsen af aktivt B6-vitamin – pyridoxalfosfat – og de nødvendige enzymer. Skønt voksne mennesker kan fremstille en del taurin i organismen, er det tvivlsomt om de i almindelighed vil kunne dække deres egne behov gennem denne biosyntese. Meget tyder på, at de er afhængige af tilførsel gennem kosten, og derfor også afhængige af kostsammensætningen.

Taurin findes ikke i nævneværdig mængde i planteproteiner eller mejeriprodukter. Derimod findes det ret udbredt i kød og fisk. Men den rigeste fødekilde, når det gælder taurin, står normalt ikke højt på ønskemenuen i vor del af verden. Det er nemlig hjerne.

Når det gælder behandlingen af de her omtalte lidelser, vil taurin fra fødekilder næppe slå til. Målene vil også være for usikre til at kunne benyttes effektivt i sygdomsbehandling. Denne kræver specificerede kosttilskud. Den nyfødte er ikke i stand til selv at danne taurin i organismen, men er helt afhængig af tilførsel gennem modermælken. Babyer på modermælkserstatning, der ikke trives, lider ofte af mangel på taurin.

Mange kødædende husdyr, især hunde og katte, lider ikke sjældent af mangel på taurin, da kommerciel dyremad ofte mangler denne faktor. Denne mangel kan føre til lidelser i øjne, nyrer og hjerte og til stendannelser. Giv regelmæssigt dyrene organkød – nyrer, hjerne, lever, hjerte – for at beskytte dem mod disse degenerative lidelser.

Migræne og epilepsi er blandt de superlukrative sygdomme, der indtjener millioner til medicinalindustrien. De mediciner lægerne bruger i behandlingen af disse lidelser har deres egne skadevirkninger, der på længere sigt kræver behandling med andre mediciner, hvilket betyder en yderligere indtægt for industrien og en yderligere forarmelse af patienter, skatteborgere og sundhedsvæsen bortset fra smerte og invalidering.

Denne groteske situation sættes i endnu grummere relief af den kendsgerning, at disse to lidelser oftest er ganske simple mangelreaktioner, der billigt og nemt kan lindres og helbredes. Lidt kosttilskud, livsstilssanering, zoneterapi eller akupunktur er i talrige tilfælde alt, hvad der kræves. Uden enorme omkostninger, uden forkrøblende bivirkninger.

For at begynde med det enkleste og mest basale. Megen migræne og epilepsi skyldes simpel magnesiummangel. Så start her med et tilskud! Er det ikke tilstrækkeligt, så tilfør B6-vitamin – pyridoxin. Så er problemet i mange tilfælde løst. Men er det ikke det, så giv yderligere aminosyren taurin. Denne tretrinsraket har helbredt tusinder.

Vi ved allerede, at taurin fortrinsvis findes i områder med høj elektrokemisk aktivitet – for eksempel hjerne og øjne. I disse områder er taurines vigtigste opgave at stabilisere nervecellernes membraner. Disse membraner modtager og overfører til stadighed elektriske impulser opstået som følge af ionbevægelser – ioniserede, altså elektrisk ladede atomer som natrium, kalium, magnesium, kalcium og andre – som flintrer frem og tilbage over cellemembranerne og ud og ind ad cellerne. Hvis cellemembranen bliver elektrisk ustabil – for eksempel på grund af mangel på taurin – begynder cellen at affyre elektriske salver på må og få, i forvirring mod det omkringliggende væv. Dette er årsagen til nogen former for epilepsi.

Vi ved, at stress tapper os for taurin og dramatisk øger vore behov for denne aminosyre i en grad, som vor egen biosyntese ikke kan hamle op med. Stress er ofte den umiddelbare forløber for epileptiske anfald eller migræne. Et massivt tilskud af taurin har en ofte forbløffende hurtig virkning og også en bemærkelsesværdig langtidseffekt.

Et andet elektrokemisk følsomt organ er hjertet. Forstyrret hjerterytme er ofte et elektrofænomen, ikke sjældent forårsaget af ionmangel – for eksempel underskud af magnesium. Andre faktorer kan selvfølgelig også komme i betragtning: For eksempel den elektrokemisk stabiliserende membranfaktor taurin – mest mærkbar når den mangler!

Taurin forbinder sig med galdesalte, holder derved fedtstoffer og kolesterol flydende og modvirker derved galdestensdannelse. Har med held været brugt i visse former for epilepsi, især i samvirkende terapi med vitamin B6 (pyridoxin) og magnesiumsalte. Modvirker kaliummangel og beskytter derved hjertemuskulaturen. Støtter insulinaktiviteten og er derfor gavnlig for diabetikere. Har vist god virkning mod uregelmæssig hjerterytme.

Terapeutisk dosering
50 – 500 mg dagligt. Tages formiddag og eftermiddag imellem måltider.

Til epileptikere: Begynd med 1 g dagligt og reducer om muligt til en vedligeholdelsesdosering på 50 mg dagligt. Vær opmærksom på, at højere doser i dette tilfælde ofte er mindre effektive end lave. Supplér med vitamin B6 og magnesium.

Se også "Aminosyrer" her og "Aminosyrekomplekser" her

Aminosyrer i Shop Vitaviva:

Produkt:
Kort beskrivelse:

Taurin "L-Taurine"
100 kpsl. 500 mg aminosyre L-Taurin. Andre ingredienser: Cellulose og vegetabilsk stearat. Gelatinekapsler.

Ref.92: Hvad er Taurin?
Taurin blev opdaget i 1827 i tyren, deraf navnet. Det er en aminosyre der er sammensat af de svovlbundne aminosyrer: methionin og cystein.
Modsat klassiske aminosyrer, der er bundne i komplekse proteinsammensætninger, forbliver Taurin ubundet. Følgende væv er meget rigt på Taurin: muskelvæv, hjerte, centralnervesystemet, nethinden i øjet.
Den første kendte betydning af Taurin

I katte er Taurin essentiel for dannelsen af galden, der har betydning for optagelsen af fedtstoffer i tyndtarmen.
Modsat andre pattedyr, kan katten ikke bruge en anden aminosyre end Taurin til at udføre denne funktion. Derfor kan kattens behov for Taurin ikke imødekommes med andre svovlbundne aminosyrer i foderet. Katten skal have tilført Taurin direkte gennem sit daglige foder.
Dette betyder at katten er afhængig af et animalsk baseret foder, da Taurin ikke findes i vegetabilske råvarer.
Andre fysiologiske betydninger af Taurin
Taurin og synet

Taurin er uundværligt for opretholdelsen af nethinden i øjet (nethinden er den membran der dækker selve øjet). I nethinden er Taurinkoncentrationen 100 til 400 gange større end den er i blodet. Siden 1975 har man vidst, at hos en kat der udsættes for en kronisk mangel på Taurin, nedbrydes nethinden systematisk og dette vil føre til total blindhed indenfor 2 år. Tilføres katten Taurin undervejs i forløbet, kan processen standses, men skader der allerede er opstået, kan ikke helbredes.
Taurin og hjertefunktionen

Taurin udgør 50% af de frie aminosyrer i hjertemuskulaturen. Det er ikke så længe siden (1987) at forholdet mellem Taurinmangel og hjerteproblemer blev bekræftet. De berørte dyr havde en markant udvidelse af den venstre del af hjertet. Ved at tilsætte Taurin til foderet, kan problemet afhjælpes.
Taurin og reproduktion

Taurinmangel kan give flere forskellige problemer i forbindelse med kattens reproduktion: manglende fertilitet, aborter, abnormiteter hos nyfødte killinger, vækstproblemer hos killinger.
Diverse

Taurin er essentielt for udviklingen af nervesystemet. Der er også kendt at Taurin har en beskyttende effekt på cellemembranerne. Det har betydning for blodets evne til at størkne, immunforsvaret, beskyttelse af lungevævet.
Diagnosticering af Taurinmangel hos katte

Hvis der er opstået Taurinmangel hos katten, vil nedbrydningen af nethinden og hjerteproblemerne være meget forskellige fra kat til kat. Nogle katte viser overhovedet ingen tegn på problemer. Når der er mistanke om Taurinmangel hos katten, kan dette kun konstateres ved at kontrollere Taurinindholdet i blodet. Hvis niveauet her er for lavt, har katten Taurinmangel.
Forebyggelse af Taurinmangel hos katte

Efter at have konstateret en sammenhæng mellem hjertesygdomme og Taurinmangel, har man hævet grænsen for det optimale Taurinindhold i kattens foder. I dag er videnskaben enig om at anbefale minimum 1000 mg Taurin pr. kg tørstof i tørfoder, eller 0,1%. Niveauet i dåsefoder skal være dobbelt så højt, eller 0,2%. Effektiviteten af Taurinen i foderet er afhængig af foderets kvalitet og de råvarer der er brugt.
Der er ikke tilsat Taurin til hundefoder, da hunde ikke har det samme behov for Taurin. Dette er en af grundene til, at det ikke er optimalt at fodre katte med hundefoder gennem en længere periode.

Taurinkilder||~ Ingredienser
Taurin (mg/kg)
Kyllingekød
337
Lammekød
473
Oksekød
362
Svinekød
496
Torsk
314
Østers
698
Muslinger
2400

Ref.91: http://www.guarana.com/
Ref.90: https://www.google.dk/search?q=Saw+Palmetto+for+Benign+Prostatic+Hyperplasia+(BPH)&rlz=1C1AOHY_enDK708DK708&oq=Saw+Palmetto+for+Benign+Prostatic+Hyperplasia+(BPH)&aqs=chrome..69i57.1163j0j7&sourceid=chrome&ie=UTF-8

Ref.89: https://www.medicinenet.com/script/main/art.asp?articlekey=8229

Ref.88: https://www.viagra.com/
Ref.87: https://www.google.dk/search?newwindow=1&hl=da&source=hp&ei=50noWov2E8yfsAHzmLHoDw&q=Sigra+is+een+supplement&oq=Sigra+is+een+supplement&gs_l=psy-ab.3..33i160k1.3121.3121.0.4397.2.1.0.0.0.0.123.123.0j1.1.0….0…1c.1.64.psy-ab..1.1.123.0…0.RiPrZr3P0i0
Ref.84:

MAINTAINING AN ERECTION

Phosphodiesterase-5 (PDE-5) Inhibition

Overview: Sexual stimulation initiates the release of nitric oxide from nerve endings and cells inside the penis.
Nitric Oxide then activates specific enzymes which result in increased levels of cyclic guanosine monophosphate (cGMP).
cGMP causes the tissue around the penile arteries to relax, allowing the underlying arteries to dilate … allowing for increased blood flow … and ultimately a firm erection.

Introducing Phosphodiesterase-V (PDE-5)

PDE-5 is an enzyme that binds to and digests cGMP.
If cGMP is digested too quickly, its "relaxing" affect on penile smooth muscle tissue will be reversed, causing the erection to weaken (in many cases this will happen so rapidly, it will appear as if no erection was ever present).

Enter the PDE-5 Inhibitor

Sildenafil citrate (VIAGRA®) is classified as a PDE-5 inhibitor … meaning it blocks the activity of PDE-5, allowing the cGMP to remain an active part of the erection process!
The active components: 4-Methylpiperazine and Pyrazolo pyrimidin-7-1 play a critical role in sildenafil citrate’s ability to inhibit PDE-5 activity.

Enter CyclovarTM … an O.T.C. Option!

CyclovarTM utilizes xanthoparmelia scabrosa and cnidium monnier, the natural sources for 4-Methylpiperazine and Pyrazolo pyrimidin-7-1 (sildenafil citrate’s components largely responsible for PDE-5 inhibition).

Ref.83:
Fysisk aktivitet gir bedre sexliv for menn Att skriva ut utan menyn, logan eller banner
Moderat mosjon minsker risikoen for impotens
Det som er bra for hjertet er også bra for sexlivet. Moderat og regelmessig mosjon forebygger impotens, mener amerikanske forskere i en stor undersøkelse.
Kilde: PrimaVi
external image pv_bild143.jpe Menn som forbrenner mist 200 kalorier om dagen gjennom å mosjonere har lavere risiko for å rammes av impotens enn menn som er inaktive. Det viser en omfattende forskningsundersøkelse som er gjort av Boston University School of Medicine og som nylig ble offentliggjort i det ansette amerikanske tidsskriftet "Urology".

Livsstilsfaktorer i fokus

I en periode på mer enn ni år fulgte forskerne nærmere 600 menn som til å begynne med ikke hadde noen problemer med impotens. Forskerne konsentrerte seg om å undersøke hvordan livsstilfaktorer som f. eks. røyking, alkoholforbruk, inaktivitet og overvekt påvirket mannens potens. Resultaten viste at de menn som mosjonerte regelmessig allerede før undersøkelsen startet, og de menn som begynte å mosjonere mens undersøkelsen pågikk, betydelig minsket risikoen for å rammes av impotens.

Bedre sent enn aldri

Den viktigste sluttsatsene som forskerne trekker av denne undersøkelsen er at menn kan minske risikoen for impotens selv om de ikke begynner å mosjonere før i middelalderen. Det er deriomot ikke nok å slutte og røyke, drikke mindre eller gå ned i vekt, mener forskerne.

Regelmessig mosjon later til å forhindre impotensproblemer samtidig som det forebygger hjerte-karproblemer. Begge tilstander bunner i forverret blodstrømming til organene, og mosjon gjør det lettere for blodet å strømme fritt gjennom blodkarene. Impotens kan til og med være en tidlig advarsel om at noe ikke står helt bra til med hjertet, ettersom penis er mer følsom for forstyrrelser i blodsirkulasjonen.

Ola Blomqvist
Ola Blomqvist ola@medicallink.se

Ref.82:
Hormoninjektioner kan höja livskvaliteten hos äldre män
Friskt och sjukt åldrande Del 3
Med stigande ålder påverkas mannen av hormonella förändringar. Det är främst sköldkörteln och testiklarnas produktivitet som minskar och ger effekter på de flesta av kroppens organ. Med hjälp av hormoninjektioner kan de negativa följderna begränsas och livskvaliteten hos den drabbade öka.

external image annons.gif

Äldre män drabbas ofta av hormonella brister. De vanligast hormonrubbningarna hänger samman med minskad effektivitet i sköldkörteln och testiklarna, så kallad hypotyreos och hypogonadism. De både bristtillstånden ger många gånger symtom som lätt kan förväxlas med normalt åldrande beroende på att hormonbrist i de flesta fall utvecklas långsamt och den drabbade anpassar sig successivt till en lägre funktionsgrad.

Ämnesomsättingen sjunker
När sköldkörtelns funktion avtar kan symtomen var påtagliga och lätta att känna igen. De kan till exempel yttra sig i form av viktuppgång, torr hud, förstoppning och frusenhet. Men det förekommer även att symtomen är betydligt mer diffusa, vilket förstås också gör dem svåra att diagnostisera. Vidare ger sköldkörtelns nedsatta funktion upphov till en högre kolesterolnivå samt att kroppens ämnesomsättning sjunker i sin tur vilket leder till att alla processer i kroppen går långsammare.

Den testosteronbrist som den äldre mannen ofta drabbas av påverkar de flesta organsystem i kroppen och ger symtom i såväl det centrala nervsystemet som i perifera vävnader. Den förändrande kroppssammansättningen gör att fettupplagringen ökar, inte minst kring buken. Som en följd av att det centrala nervsystemet påverkas av hormonbristen kan den åldrande mannen drabbas av nedsatt psykisk energi, nedstämdhet och libidoförlust.

Musklerna och blodvärdena stärks
Flera undersökningar har visat att genom att tillföra testosteron kan såväl muskelstyrka och blodvärde som psykisk energi och libido förbättras hos äldre män. Även styrkan och täthet i skelettet påverkas positivt av testosterontillförsel. Nedsatt funktion i könskörtlarna utgör en väsentlig riskfaktor för att benskörhet drabbar mannen med stigande ålder.

Kunskaperna är dock fortfarande begränsade om hur effektiv behandlingar med testosteron är. Det saknas fortfarande studier med många deltagare som sträcker sig över lång tid. De behandlingar med testosteron som syftat till att höja potensen har visat mindre lyckade resultat. Detta talar för att erektionsstörningar hos äldre många gånger påverkas av andra faktorer än brist på testosteron. Emellertid finns det fakta som pekar på att den sexuella aktiviteten och de sexuella fantasierna kan påverkas positivt hos äldre män som tillförs testosteron och det finns ett klarlagt samband mellan testosteronnivåer och sexuell aktivitet.

Få biverkningar
Testosteronbehandlingar utförs antingen genom att man injicerar hormonet, tar det i tablettform eller får det i sig via ett depåplåster. Effektmässigt skiljer sig de olika sätten att ta hormonet åt. Genom att injicera testosteronet nås den maximala hormonnivån efter cirka ett dygn för att därefter successivt gå tillbaka till ursprungsnivån efter några veckor. I tablettform nås kortlivade toppar av hormonet och med hjälp av depåplåstret nås hormonnivåer som efterliknar de som hittas hos friska män. Biverkningar av testosteronbehandling är ovanliga. Hos vissa män kan behandlingen ge en överdriven ökning av de röda blodkropparna. Det är därför viktigt att hela tiden ha kontakt med sin läkare medan behandlingen pågår.

Stefan Arver, Andrologenheten, Karolinska Sjukhuset, Stockholm

Bearbetad av Ola Blomqvist

Ola Blomqvist Källa: PrimaVi Datum: 2000-01-04

Ref.81:

Debat: Drømmen om evig potens

Af Preben Hertoft,, professor i sexologi

"For jeg er så ked af, den hænger neda", sang Lille Palle engang. Og sangen fortsætter: "For i min lille have der skal alting gerne stå". Han vil naturligvis være potent.

Potens betyder ordret styrke, mægtig, indflydelsesrig. Selv små drenge promenerer stolt deres rejste penis indtil en vis alder og de er uhyre optagede af den.

Mange, måske alle mænd kommer nu og da ud for erektionsvanskeligheder, uanset alder og livsforhold. Er det blot forbigående, lader de fleste sig ikke varigt anfægte af det, men vedvarende erektiv dysfunktion påvirker antagelig alle mænds selvfølelse. Ikke tilfældigt har ordet impotens – kraftesløshed – karakter af et skældsord. Impotens truer ikke blot en mands seksuelle funktionsevne, men opleves som et generelt statustab, en svækkelse af den mandlige kønsrolle. Kan han ikke længere få rejsning, føler han sig ikke som mand, hverken seksuelt eller alment.

Det kan man så harcelere over, kalde primitivt, trække på skulderen ad. Det bliver det ikke mindre en realitet af. Det er interessant, at antallet af videnskabelige artikler, hvori ordet impotens forekommer, er vokset dramatisk siden 1970. Mens artikler om såkaldt frigiditet næsten er forsvundet. Er det mon et udtryk for en ændret balance mellem kønnene? I hvert fald har det været lettere at få udryddet det nedvurderende begreb frigiditet end skældsordet impotens.

Den magiske betydning mænd helt fra barndommen tillægger deres penis, får man bekræftet i Bo Green Jensens anmeldelse i Weekendavisen af filmen Boogie Nights. Filmen tager sit udgangspunkt i pornostjernen John Holmes, hvis kvalifikation især var en penis på hele 33 cm. I filmen hedder han Dirk Diggler. Ved filmens slutning er det gået ned ad bakke for ham, men han håber på et comeback. Forinden sidder han foran et spejl "og prøver at booste sit selvværd op med en peptalk" , hvorefter han, i en scene, der ifølge anmelderen virker "mærkeligt gribende", "lyner bukserne ned og kærtegner sit køn, som også vi længe gransker i spejlet. Han taler til det. Han mander sig op, og han har bogstavelig talt ikke anden identitet tilbage, end den der sidder i hans "særlige ting"." Det er klart, at hvis man har det sådan, selv når man er så veludstyret som Dirk, hvilken tiltrækning vil det så ikke have for talrige mænd, at der nu kommer et middel på markedet, som én gang for alle kan befri dem for den evige potens-angst. På mere end én måde vil de føle sig afstivet.

Den amerikanske feminist og sexolog Leonore Tiefer taler om at vi ligger under for "jagten på den perfekte penis", og at det er mænd i langt højere grad end kvinder, der tror, at dermed er lykken gjort og næsten alle samlivsproblemer løst.

Samtidig lægges der, individuelt såvel som af massemedierne, i tiltagende grad vægt på livslang seksuel aktivitet. Og dette følges nu op af en ny medicinsk teknologi, der lover at opfylde utopien om stabil, uforstyrret erektion fra vugge til grav.

At der tilbydes nye muligheder og håb for mange, mænd såvel som kvinder, der har behov for hjælp, er naturligvis i orden. Men når man betænker, hvor let mænds angst for impotens vækkes, øges sideordnet en stor risiko for en unødig medikamentalisering af seksuallivet. Der fokuseres så meget på penis, at vi glemmer, at sex er andet og mere end kaffe og kage, frem og tilbage. For selv for mænd handler sex jo også om nærhed, intimitet, sommetider endog om kærlighed.

Midler, der kan stimulere mænds seksualkraft – herunder såkaldte elskovsmidler, afrodisiaka – har været efterstræbt til alle tider.

Mange påståede midler var ineffektive, men troen kan som bekendt flytte bjerge – somme tider også give rejsning. Blandt midler fra vore dage kan nævnes vibratorer (massageapparater), pubesringe, erektionspumper, penisimplantater (stavproteser, pumpeproteser), yohimbin, nitroglycerinplastre påsat penis og alprostadil (Prostataglandin E 1), mere kendt under fabriksnavnet Caverject – det indsprøjtes i penis" svulmelegeme.

Viagra er det sidste skud på stammen, hvis man kan bruge denne metafor, tages som en pille, angives at have få bivirkninger og kan effektivt styrke erektion. Især vil det være indiceret til mænd med beskadiget nerveforsyning til penis – for eksempel efter rygmarvsskade, operationer på kønsorganerne, på grund af mangeårig diabetes – eller hvis blodforsyningen til penis er utilstrækkelig.

Men er det også indiceret ved såkaldt psykogen erektiv dysfunktion? Medicinfirmaet Pfizer, der fremstiller Viagra, fremhæver i hvert fald, at også psykogen impotens er en indikation for brugen af midlet. Og det er naturligvis der, jeg har mine betænkeligheder. Hvorfor, skal jeg prøve at begrunde.

Mange mænd lider af præstationsangst – angst for fiasko, for at blive til grin, for at penis ikke er stor nok, for at andre skal få kendskab til deres manglende formåen og så videre. Det, vi kalder impotens, er næsten altid bundet til bestemte situationer – fra fortiden eller i nutiden. Det er et signal om at noget ikke er som det skal være.

Men ironisk nok er de fleste mænd mere tilbøjelige til at tro, at der er noget fysisk i vejen med dem, end at overveje, hvad det er, kroppen, deres uregerlige penis, vil fortælle dem, hvis erektionen udebliver. Den manglende erektion burde måske i stedet vække til eftertanke. Manglende rejsning kan faktisk være en sandere, om man vil: sundere reaktion, på ugunstige vilkår, end at penis stereotypt og automatisk reagerer med erektion uanset omstændighederne.

Den amerikanske psykolog Herb Goldberg hævder, at rejsning ikke for enhver pris er et gode, heller ikke hvis den for en stund kan dulme en mands angst. For en mands penis er ikke blot et stykke isenkram, men et udtryk for hele hans person. Og derfor bør han lytte til og lære af sin krops reaktioner frem for kun at anskue dem mekanisk. Ofte vil penis nemlig, førend hans bevidste erkendelse, have registreret, at alt ikke er som det bør være. Derfor gør manden – og hans partner – klogere i at spørge: Hvilken betydning har dette signal? Hvad er årsag og virkning? Er mandens forstemning, nervøsitet og uligevægt en reaktion på impotensen eller en årsag til den? Er kvindens reaktioner overvejende en følgetilstand eller en årsagsfaktor? Hvilken rolle spiller vanskeligheder i parforholdet? Og så videre.

For nogen vil en sådan søgeproces være en farbar vej til både øget selvforståelse og gensidig indsigt – især hvis parret får lidt kvalificeret hjælp. For at citere Goldberg: "Hvis manden tager ansvaret for sine egne følelser og impulser og opfordrer sin partner til at gøre det samme, baner han vejen for en nedbrydning af den falske forestilling om, at impotens ene og alene er mandens problem. Bliv ikke skræmt, hvis du ikke får erektion. Spørg i stedet dig selv, hvad det mon er, din krop vil fortælle dig, og som du ikke er dig bevidst. Og vigtigst af alt: respekter penisvisdommen. Dit mål er ikke at være potent, men at være tro mod dine egne seksuelle reaktioner, derfor må du lære at tage det fulde ansvar for den sandhed, dine følelser indeholder."

Naturligvis ved jeg, at man ofte vil tale for døve øren, når man kommer med sådan et forslag, at mange vil vige tilbage for denne selvgranskning. Især nu, hvor de straks kan gribe til flasken med de dyrebare – og dyre – Viagra-piller. Og lad os håbe, at det så hjælper dem over problemet, hvis det kun er rejsning, det drejer sig om. Men erektion er jo ikke løsningen på alle samlivsproblemer. Som det hedder i en artikel i Time Magazine: "Man kan give et vredt par Viagra, og så har vi et vredt par med en erektion." Sådanne par har jeg selv mødt mange af førend Viagra blev lanceret, og jeg er sikker på, at endnu flere vil følge.

Den tyske sexolog Gunter Schmidt anfører, at mænd med psykogen impotens "overrumples" af Viagras virkning, men blot med den følge "at han antagelig fortsat, ganske som med sin impotens, vil holde sig sin kone fra livet, på afstand, men nu med fallos som distancevåben. Kærlighedsløst, hjerteløst, hensynsløst vil han degradere hende til kulisse, fuld af beundring for hans sprængklare penis. Han har udlevet sit symptom uden at skulle stå ved den skændsel, der knytter sig til impotens."

Schmidt mener, at mange mænd utvivlsomt vil afprøve Viagra, både som potensmiddel og som afrodisiakum. Ikke fordi midlet i sig selv øger lysten, men fordi den erigerede penis fremmer mandens selvfølelse og derigennem hans lyst. Derfor antager Schmidt, at kvinder endnu oftere end før vil møde den selvoptagede, narcissistiske variant af mandlig seksualitet, uanset om manden har et potensproblem eller blot sluger en pille for at kunne stråle endnu kraftigere i al sin narcissistiske glans.

Det er ikke noget, der siger de fleste kvinder ret meget, tværtimod opleves det som ret enerverende. For piller fører ikke til løsning af parproblemer. Hjælper ikke manden til at tale og lytte bedre, giver ham ikke større indlevelsesevne, gør ham ikke mere fantasifuld eller erotisk. Ifølge Schmidt vil brugen af Viagra især være tillokkende for mænd med "en traditionel opfattelse af mandlig seksualitet samt dem, der gerne designer deres liv med farmaka – Viagra til sex, speed til arbejde, spiritus til afspænding. Men måske opdager mange af disse mænd senere, at Viagra-fri sex var noget særligt attraktivt og vender så tilbage til det."

Som bekendt skelner man sædvanligvis mellem legemlige og psykiske årsager til utilstrækkelig penisrejsning. Psykiske årsager til impotens er ofte angst – for eksempel præstationsangst, frygt for at blive til grin, mindreværdsfølelse (psykisk eller fysisk), frygt for ikke at kunne tilfredsstille partneren, frygt for seksuel nydelse, frygt for kønssygdomme, dårlig samvittighed og så videre. Men det kan også være aggression, bevidst eller ubevidst. Aggression rettet mod partneren, eventuelt mod hele kvindekønnet, eller selvhad. Sex og aggression er som bekendt tæt forbundet. Impotens kan være et aspekt af en magtkamp mellem parterne. For eksempel at han, bevidst eller ubevidst, straffer hende, ikke under hende sin potens, eller at hun gang på gang bringer ham i situationer, hvor erektionen svigter, så hun atter kan føle sig ovenpå.

Ofte er alt dette forbundet med kommunikationsproblemer – parterne misforstår hinanden, kommer ikke med klare meldinger, fortæller hverken hinanden hvad de foretrækker eller afviser. Ofte er det hele pakket ind i en dyne af falske hensyn. Måske tror de at de elsker hinanden så højt, at de ikke tør være sig selv. Måske passer de slet ikke sammen. Endelig kan seksuelle særtræk spille forstyrrende ind – fetichisme, transvestisme, sadomasochisme, homoseksuelle komponenter med mere. I stedet for hele denne opremsning kunne jeg nøjes med at sige: Sex er noget af det mest ulogiske og uforudsigelige der findes. Har vi ikke alle undret os over, hvem der kan finde ud af det sammen, næsten på tværs af alle spilleregler, mens andre slet ikke kan, skønt betingelserne tilsyneladende er de bedste. Eros er en spøgefugl, sagde allerede Platon for mere end 2000 år siden.

Og så påstår medicinalindustrien, at Viagra kan lænke den rebelske Eros, at her er midlet mod hele dette sammensurium af fortid og nutid, angst og aggression, magi og snusfornuft, det ubevidste og det dagsklare. Og sandelig om ikke mænd og kvinder agter sig selv så lidt, at mange uden videre hopper på forestillingen om, at her ligger løsningen. Når pengene i kassen klinger, straks sjælen ud af skærsilden springer. Eller som professor Tribini sagde foran teltet på Dyrehavsbakken: "Hvis De ikke morer Dem, er pengene spildt."

De tal, der opgives, varierer meget, bland andet afhængigt af lægens uddannelse – for eksempel om han er urolog eller psykiater – vedkommendes subjektive indstilling og det klientel, der søger ham. I det hele taget er adskillelsen mellem fysisk og psykisk impotens alt for firkantet. Selv hvor der foreligger en udtalt fysisk impotens, er der altid en psykisk.

Men lad os se på nogle tal fra USA: På et stort New York-hospitals urologiske afdeling Beth Israel Medical Center, henvistes fra 1981 mere end 800 mænd gennem en tiårs periode. Knap 10 procent kunne umiddelbart rubriceres som psykogene og blev henvist til samlivsterapi. Resten, over 90 procent, mente selv, at deres impotens helt eller overvejende var fysisk betinget. Men yderligere undersøgelser viste, at kun 45 procent kunne rubriceres i den gruppe, mens 55 procent helt eller overvejende blev rubriceret som psykogene.

I en anden undersøgelse fra Johns Hopkins Hospital i Baltimore af 105 mænd henvist for erektiv dysfunktion, alle over 50 år, ansås kun cirka 30 procent for at være fysisk betingede.

I Chicago fandt en urologisk klinik, at 43 procent af dens klientel, i hvert fald delvis, havde en fysisk årsag til impotensen, mod kun 11 procent fra en psykiatrisk afdeling.

Meget tyder altså på, at antallet af psykogene problemer underestimeres. Mange tror, at ældre mænd uvægerlig vil blive impotente, men for eksempel i Danmark er cirka 80 procent af mænd langt op i 70erne fortsat i stand til at gennemføre samleje.

Mange mænd søger først behandling for rejsningsproblemer, når deres forhold truer med at gå i stykker. Det gælder for mænd i alle aldre, men der kan gå både halve og hele år førend de søger hjælp. Enhver, der klager over et seksuelt problem, har selvfølgelig krav på, at lægen tager dem alvorligt. En forudsætning for det er, at lægen giver sig tid til at tale ordentligt med begge parter og foretager en dækkende undersøgelse. for eksempel ikke blot hurtigt spiser dem af med en recept.

Farmaka mod potensproblemer bør primært anvendes ved fysisk betingede erektionsforstyrrelser suppleret med rådgivning, for medicin alene er sjældent tilstrækkeligt. Ved psykogen erektiv dysfunktion bør rådgivning og samlivsterapi fortsat være det primære valg – eventuelt kombineret med visse farmaka. Begge former for rådgivning kan foregå i almen praksis, hvis lægen er indstillet på det, hvad mange heldigvis er. Hvis lægen ikke selv vil påtage sig opgaven, eller hvis hans patient ikke responderer på rådgivningen, bør patienten henvises til en speciallæge med sexologisk træning, ofte enten en urolog eller en psykiater. Med frigivelsen af Viagra kan lægen imidlertid blive presset til, hurtigst muligt, at skrive recept på Viagra. Forhåbentlig vil de fleste læger modstå presset.

Ét er i hvert fald givet: Hvis man tror, at samlivsterapeuterne bliver arbejdsløse, når Viagra holder sit indtog, tager man fejl.
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Sidst opdateret 01.02.2000
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Ref.80:

Hvordan virker det?

Viagra virker ved at øge blodtilstrømningen i penis ved seksuel stimulation, så naturlig rejsning eventuelt opnås. Virkningen indtræder efter cirka en halv time. En enkeltdosis kan give erektion ved seksuel stimulation op til fem timer efter indtagelse.

Hvad bruges det imod?

Lægemidlet anvendes mod impotens.

Hvordan og hvor meget?

Viagra findes som tabletter á 25, 50 og 100 mg.

Normalt tages 50 mg cirka en time før ønsket virkning. Eventuelt kan dosis sænkes til 25 mg eller øges til 100 mg. Anbefalet maksimaldosis er 100 mg en gang dagligt. Hos ældre prøves først med 25 mg, og eventuelt øges dosis senere til 50 eller 100 mg. Virkningen forsinkes ved indtagelse sammen med mad. Dosis nedsættes hos personer med dårlige nyrer eller lever.

Graviditet

Anvendes ikke.

Amning

Anvendes ikke.

Advarsel!

Lægemidlet må ikke anvendes af personer med alvorlige hjerte-karlidelser, lavt blodtryk, stærkt nedsat leverfunktion eller arveligt betingede sygdomme i øjets nethinde.
Forsigtighed tilrådes ved bilkørsel og betjening af maskiner.

Mulige bivirkninger

Lægemidlet kan forårsage lavt blodtryk, hvilket kan medføre svimmelhed, hurtig puls og eventuelt besvimelse hvis man rejser sig hurtigt op.
Der kan desuden forekomme hovedpine, fordøjelsesbesvær, tilstoppet næse og synsforstyrrelser.

Må man samtidig indtage anden medicin?

Viagra må ikke tages sammen med nitratprodukter.
Virkningen og bivirkningerne kan øges ved samtidig indtagelse afcimetidin eller erythromycin, hvorfor doseringen bør nedsættes.
Hvis du er i tvivl så kontakt din læge eller spørg på apoteket.

Sidst opdateret 02.05.2001
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Ref.8:
Dette er en tekstkopi af:
http://www.newscientist.com/news/news.jsp?id=ns99992667

Short women more successful with men

14 August 02 NewScientist.com news service

Shorter women are more likely to have long-term relationships with men, and more likely to have children, according to a study of 10,000 people born in the UK in 1958.

The average height for a British woman is 1.62 metres (5 feet, 4 inches). But those who were between 1.51 and 1.58 metres were most likely to be married and to have children by the age of 42. This relationship held true even after accounting for social class.

The study also found that women prefer men who are taller than average. A man of 1.83 metres (6 feet exactly) was more likely to have a partner and children than a man standing at the average height of 1.77 metres (5 feet, 10 inches).

But why men should prefer smaller women is unclear, says Daniel Nettle of the Open University, who led the research. "There is no evidence that shorter women conceive more quickly or are more fertile in a contemporary population," he says. In fact, previous studies have found that smaller women are more likely to die in childbirth.

Fertility cues

"But we know that men are drawn to things that in our evolutionary past would have been a cue for fertility. And in one sense tallness is a negative cue – tall women reach puberty later and probably their secondary sexual characteristics develop somewhat later," he says.

Nettle thinks the finding that men prefer mates who are smaller than average, but women prefer the opposite, also suggests the height disparity between the sexes is likely to continue.

The genetics of height is poorly understood, he stresses. "Oddly enough, we know that the heights of mother and son and of father and daughter correlate. So it would seem that a woman choosing a tall husband is also choosing tall daughters."

However, Nettle says this choice must also select a factor linked to the sex of the child, which maintains the difference in height between men and women.

Journal reference: Proceedings of the Royal Society B (DOI: rspb.2002.211)

Emma Young

Ref.79:
Nya potensläkemedel i kö för godkännande external image pl_bild1754.gif
Flera nya potensläkemedel som verkar på liknande sätt som Viagra, men med längre verkningstid, är nu på väg. Ett kanske blir godkänt i Sverige redan i september. Genterapeutiska metoder och användande av stamceller för reparation av svällkroppsvävnaden är andra möjligheter i framtiden.

external image annons.gif

Bakgrund
Efter introduktionen av Viagra blev plötsligt potensläkemedel tillgängliga för den stora grupp män som drabbats av erektionssvårigheter (erektil dysfunktion, impotens). Merparten av män med erektionsproblem har fått dessa som en komplikation till andra sjukdomar eller behandling av dessa. Viagra skapade en ny medvetenhet om erektionsproblem och hjälpte till att bryta barriären av skam och andra känslor som hindrat saklig diskussion kring en viktig livskvalitetsfråga. Det är dock fortfarande långt kvar innan frågor kring potensproblem blir en lika naturlig del av den medicinska uppföljningen av t ex hjärtkärl- sjukdomar som frågor om njurfunktion eller kranskärlsförträngning. Intresset för terapiområdet är fortfarande stort, inte minst från kommersiell sida även om de ekonomiska förväntningarna skruvats ned betydligt. De stora summor som betalades för rätten till marknadsföring av läkemedel för behandling av potensproblem i slutet av 90-talet har i de flesta fall inte givit önskad återbäring.

Det började med Papaverin
Den verkliga utvecklingen av farmakologisk behandling av erektionsstörningar tog fart efter den franske kärlkirurgen Virag´s observation att lokal injektion av ett kärlvidgande medel (papaverin) i peniscirkulationen gav upphov till erektion. Den PR-begåvade neurofysiologen Brindley fick den urologiska världen att häpna efter en demonstration av effekten av penisinjektion på sig själv i ett framträdande inför en galaklädd publik av kongressande urologer i Las Vegas. Injektionsbehandling var under hela 80-talet en läkardriven verksamhet utanför läkemedelsverkens godkännande och kontroll. Inte förrän Upjohn lät registrera Caverject (prostaglandin E1) 1994 blev behandlingen tillgänglig för en större grupp patienter. Sveriges läkemedelsverk gick här i bräschen för att garantera en medicinskt säkrare och bättre dokumenterad behandling.

Socialministerns hjältemodiga ingrepp
Sverige var länge ett föregångsland i utveckling av erektionsbehandling och var först med att godkänna Caverject (Prostaglandin E1 för injektion i penis) för behandling av erektionsproblem. Sveriges som ett framsynt land upphörde när socialministern med sitt hjältemodiga tillslag satte stopp för rabattering av potensläkemedel. I ett hastigt påkommet beslut togs grundvalen bort genom att med ekonomiska medel hindra de svagaste grupperna i samhället att få effektiv läkemedelsbehandling. Idag framstår det i andra sammanhang så bigotta USA som ett föregångsland genom att acceptera människors behov av sexuell samvaro och subventionera kostnaden för exempelvis
Viagra. Till och med England godtar det medicinska och mänskliga behovet hos män som på grund av sjukdom inte kan få erektion och ger läkemedelsrabatt för behandling.

Mindre kända preparat
Utöver Viagra och Caverject finns idag i Sverige även Uprima och Bondil som alternativa terapier. Bondil innehåller samma aktiva substans som Caverject men ges i form av en gelplugg som förs in i urinröret. Bondil har nått blygsam framgång bland patienter mest beroende på bristande effekt och relativt hög frekvens av biverkningar – särskilt smärta i penis.

Uprima har som aktiv substans apomorfin, vilket har använts medicinskt sedan länge i högre dosering. Apomorfin är en dopaminagonist och verkar sannolikt både på centralnivå men även på ryggmärgsnivå genom aktivering av erektionsnerver. För närvarande finns en beredningsform registrerad, en sugtablett, medan andra är under klinisk testning. Uprima ger snabb effekt men tycks inte vara tillnärmelsevis så effektivt som Viagra. Det snabba tillslaget och avsaknad av interaktion med nitroglycerin framförs som fördelar med Uprima.

Nya hämmare av PDE-5
Viagra verkar genom hämning av enzymet fosfodiesteras och åstadkommer därmed en förstärkning av den NO- (kväveoxid) effekt som förmedlas av erektionsnerverna. I penis svällkroppar finns uteslutande en specifik variant av fosfodiesteras kallat typ 5 (PDE-5) och Viagra är relativt specifikt för just den varianten av fosfodiesteras-enzym. Av någon anledning finns PDE-5 uteslutande i svällkroppsvävnad vilket gör att effekten av PDE-5- hämmare huvudsakligen lokaliseras till svällkropparna.

Under de senaste åren har fler PDE-5 hämmare tagits fram och testats kliniskt. Två av dessa, vardenafil och tadalafil, är nu nära att bli godkända och kan bli tillgängliga hösten 2002 eller i början av 2003.

Vardenafil har längre halveringtid än Viagra
Vardenafil (utvecklat av Bayer AG) har genomgått klinisk prövning runt om i världen och är liksom Viagra effektivt som erektionsstärkande drog. Några resultat från jämförande studier mellan Vardenafil och Viagra (Sildenafil) är dock inte kända .. Farmkologiskt noteras att vardenafil har längre halveringstid än Viagra vilket möjligen kan översättas i längre verkanstid. Tiden för tillslag från intag av tabletten är jämförbar med Viagra. Vardenafil kommera att marknadsföras av Bayer i samarbete med GSK (GlaxoSmithKline). Preparatet kan bli tillgängligt på den svenska marknaden i början av 2003.

Tadalafil (Cialis) har betydligt längre effekt än Viagra
Tadalafil (utvecklat av Lilly-ICOS) har också genomgått omfattande klinisk prövning runt om i världen. Preparatet kommer att ha det kommersiella namnet Cialis och kan bli tillgängligt i Sverige under hösten 2002, kanske redan i september. Cialis är en mer specifik hämmare av PDE-5 än Viagra och har en avsevärt längre halveringstid. Verkan av drogen sitter således i betydligt längre och efter intag av läkemedlet kan den erektionsstärkande effekten kvarstå mer än ett dygn. Förutsatt att detta inte är kopplat till ökad biverkningsrisk kan det upplevas som en fördel bland patienter. Den ökade specificiteten för svällkroppsformen av PDE, PDE-5, är kanske en förutsättning för reduktion av biverkningsrisken. Hittills tillgängliga studier antyder att Cialis ger endast hälften så mycket biverkningar i form av huvudvärk, flushning och magtarmbesvär som Viagra. Genom att Cialis har högre selektivitet för PDE-5, särskilt i relation till PDE-6, har detta medfört att inga synrubbningar hittills rapporterats. En studie med Cialis visar upp till 93 procent lyckosamt genomförda samlag med dosen 50 mg vid mild-måttlig erektil dysfunktion. En annan studie visar positiv effekt i 64 procent hos diabetiker med dosen 20 mg.

Genterapeutiska metoder under utveckling
Genterapeutiska modeller för behandling av bristande erektionsförmåga finns. Två utvecklingslinjer kan skönjas, dels insertion (tillägg av gensekvens) av den gen som kodar för det kväveoxid-producerande enzymet NO-syntas (NOS). Detta leder till ökning av kapaciteten att producera NO. Den andra genterapimodellen bygger på ökning av kaliumkanal-aktiviteten i svällkropparnas glatta muskler. Ökad kaliumkanalaktivitet hämmar kontraktionen av de glatta musklerna och underlättar därmed erektion (kärlvidgning). Dessa metoder är fortfarande på djurmodellstadiet men med ökad kunskap om genterapi kan de mycket snart komma över i klinisk forskning på människa.

Användande av stamceller ny möjlighet
Lyckade försök att skapa ny svällkroppsvävnad med stamceller har rapporterats. Detta kan bli en enkel terapeutisk princip med utgångsmaterial redan tillgängligt hos den som skall behandlas. Metoden kan bara användas när erektionsproblematiken har sin orsak i bristande relaxationsförmåga i svällkropparna, vilket i sig är den vanligaste orsaken till åldrandets potensproblematik.

Stefan Arver
Överläkare och klinikchef vid Andrologiskt Centrum, Karolinska sjukhuset, Stockholm.

– Källa: Medical Link Datum: 2002-06-15

Ref.78:
Sex på dåse Att skriva ut utan menyn, logan eller banner
Den nye generation af sexpiller er beregnet til både mænd og kvinder
For nogle år siden revolutionerede Viagra behandlingen af impotens hos mænd. Pillen var det første afprøvede lægemiddel mod erektionsproblemer, hvormed det lykkedes at stimulere den naturlige erektion. Tidligere havde mænd med disse problemer været henvist til forskellige måder, som ad 'kunstig' vej, f.eks. ved hjælp af vakuumpumper, kunne frembringe erektion, eller behandlinger i form af ofte smertefulde operationer eller injektioner.
Source: PrimaVi
external image pl_bild1627.jpe Kort tid efter fik Viagra konkurrence af en anden generation af sexpiller, som et stor antal klinikker især i USA netop nu er ved at undersøge til bunds.

Den største forskel på de nye sexpiller og Viagra er, at de øger sexlysten. Viagra kan kun råde bod på de fysiske mekanismer – sexlysten skal være til stede i forvejen. Flere af de nye sexpiller kan tages af kvinder, som har problemer med sexlysten, eller som har svært ved at få orgasme ved samleje.

Tvivlsomt om Viagra hjælper kvinder

Hidtil er Viagra kun blevet anvendt som et middel mod impotens. Men allerede da Viagra kom på markedet, forlød det, at pillen også kunne hjælpe kvinder. Især de kvinder, der har tørre slimhinder i skeden og problemer med at få orgasme. Medicinalfirmaet, som har fremstillet præparatet, har studeret dets virkning på 800 kvinder i USA, hvor op imod fyrre procent af alle kvinder menes at have seksuelle problemer. De senest fremlagte resultater fra forsøget tyder dog på, at den forventede virkning hos kvinder er udeblevet.

Nogle af de nye sexpiller virker på samme måde som Viagra, det vil sige, at blodkarrene udvides, og der sker en omfordeling af blodet til penis. Men forskerne forsøger at finde et stof, som giver en hurtigere og mere vedvarende virkning. Det tager ca. en time, før Viagra giver maksimal effekt, mens flere nye midler viser sig at virke inden for 15-30 minutter.

– Formålet med flere af de Viagra-lignende præparater, som er under udvikling, er, at de skal have færre bivirkninger end Viagra og virke i længere tid. Man skal kunne tage tabletten om morgenen, og derefter skal den virke hele døgnet, siger Stefan Arver, overlæge og klinikchef ved afdelingen for andrologi, af reproduktionsmedicinsk center ved Karolinska Sjukhuset i Stockholm.

Apomorfin aktiverer erektionscentret i hjernen

Mange af de stoffer, som giver den ønskede udvidelse af blodkarrene, anvendes inden for andre medicinske områder. Viagras aktive stof, sildenafil, blev til at begynde med udviklet for at afhjælpe forkalkning i hjertet. Et nyt stof i sexpillesammenhæng er apomorfin, som i mange år blev anvendt til at afhjælpe rystelser hos Parkinson-patienter.

Det var også Parkinson-patienter, som satte sexpilleforskerne på sporet af apomorfinets evne til at fremme erektionen hos mænd. Mange mandlige Parkinson-patienter har i årenes løb ikke blot kunnet berette om, hvordan apomorfinet har afhjalp de typiske rystelser, som sygdommen giver, men også at det gjorde det meget lettere at få erektion.

– Apomorfin aktiverer hjernens erektionscenter ved at stimulere de såkaldte dopaminreceptorer. Denne stimulation gør, at man reagerer ved først at gabe og strække sig, for derefter at få erektion og til sidst at kaste op. Men ved at give præparatet i form af sugetabletter, der virker hurtigt uden at give så høj en koncentration i blodet, er det muligt at finde et niveau, hvor de negative bivirkninger kan undgås, så man kun opnår erektionseffekten, siger Stefan Arver.

Eftersom apomorfin aktiverer bestemte hjernecentre, håber forskerne, at præparatet også kan påvirke sexlysten positivt.

–Hvis dette er tilfældet, går man, ifølge Stefan Arver, også ud fra, at præparatet har en god virkning på kvinder.

Godkendt i USA

Sexpiller som indeholder apomorfin er foreløbig godkendt i USA og ventes snart at blive sendt på det amerikanske marked. Dette betyder, at præparatet kommer til Europa og Sverige om ca. seks måneder.

Forskerne har længe diskuteret, hvordan den kvindelige seksualitet fungerer. Samt hvilket præparat, der måske kan påvirke sexlysten i positiv retning. Man ved, at hormoner spiller en afgørende rolle for sexlysten, men en del af forskningsresultaterne peger i retning af, at det mandlige kønshormon, testosteron, bidrager til at øge sexlysten.

– Kvinder har normalt små mængder af det mandlige kønshormon, testosteron, i kroppen. Og det har vist sig, at variationer inden for disse lave niveauer påvirker en del psykoseksuelle funktioner hos kvinder, siger Stefan Arver.

Allerede de gamle…

Der er intet nyt i, at mandlige kønshormoner har en gavnlig virknig på kvinders sexlyst.De gamle romere og romerinder anvendte testosteron til at øge sexlysten. Indsamlingen af testosteron foregik på følgende måde:Efter en hård dag på kamparenaen tog gladiatorerne ofte et bad i olivenolie.Efter badet blev olivenolien, som nu udover gladiatorernes sved også indeholdt små mængder testosteron, opsamlet og hældt på små krus.Disse blev solgt til kvinder, som smurte sig med den sved- og testosteronholdige olivenolie.Dette øgede testosteronværdierne lidt og dermed også sexlysten.

Romerindernes brug af testosteronholdige olivenolier har en slående lighed med de testosteronplastre, som mænd, der ikke selv kan producere tilstrækkelige mængder, anvender i dag.

– Der udføres ligeledes fremskredne forsøg med testosteronplaster, der afgiver små doser, og som er beregnet til at øge kvinders sexlyst. Stefan Arver siger, at man forventer, at resultaterne fra disse forsøg inden længe bliver offentliggjorte.
Ola Blomqvist ola@medicallink.se

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Erectile Dysfunction : "THE" Book

Introduction

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Forewords

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American Family Physician July 1, 2000

Published by the American Academy of Family Physicians

Female Sexual Dysfunction: Evaluation and Treatment

NANCY A. PHILLIPS, M.D.

Wellington School of Medicine, University of Otago, Wellington, New Zealand

Sexual dysfunction includes desire, arousal, orgasmic and sex pain disorders (dyspareunia and vaginismus). Primary care physicians must assume a proactive role in the diagnosis and treatment of these disorders. Long-term medical diseases, minor ailments, medications and psychosocial difficulties, including prior physical or sexual abuse, are etiologic factors. Gynecologic maladies and cancers (including breast cancer) are also frequent sources of sexual dysfunction. Patient education and reassurance, with early diagnosis and intervention, are essential for effective treatment. Patient history and physical examination techniques, normal sexual responses and the factors that influence these responses, and the application of medical and gynecologic treatments to sexual issues are discussed. Basic treatment strategies, which may be successfully provided by primary care physicians for most sexual dysfunctions, are outlined. Referral can be reserved for patients who do not respond to therapy. (Am Fam Physician 2000;62:127-36,141-2.)

Sexuality is a complex process, coordinated by the neurologic, vascular and endocrine systems.1 Individually, sexuality incorporates family, societal and religious beliefs, and is altered with aging, health status and personal experience. In addition, sexual activity incorporates interpersonal relationships, each partner bringing unique attitudes, needs and responses into the coupling. A breakdown in any of these areas may lead to sexual dysfunction.

Primary care physicians, skilled in the treatment of medical and psychologic disorders, often feel unqualified to treat patients with sexual dysfunction. However, with an understanding of sexual functioning and application of general medical and gynecologic treatments to sexual issues, sexual dysfunction may be effectively approached with the same skills. The latter includes obtaining a complete patient history, conducting a physical examination, application of basic treatment strategies, providing patient education and reassurance, and recommending appropriate referral when indicated.

Diagnosis

Female sexual dysfunction can be subdivided into desire, arousal, orgasmic and sexual pain disorders. Sexual pain disorders include dyspareunia and vaginismus.2

Estimates of the number of women who have sexual dysfunction range from 19 to 50 percent in "normal" outpatient populations3-6 and increase to 68 to 75 percent when sexual dissatisfaction or problems (not dysfunctional in nature) are included.5,7 Yet, one review of physicians' chart notes revealed a recorded sexual problem in only 2 percent.5 In another review, physician inquiry of patients in a gynecologic office setting about sexual problems increased reported complaints about sexual dysfunction sixfold.3 This discrepancy demonstrates a need for physician education in this area.

FIGURE 1.Cycle of sexual dysfunction. Example showing how a patient can enter the cycle of sexual dysfunction in one area (i.e., decreased orgasm) and proceed to another area (i.e., decreased desire) so that the presenting complaint may not represent the problem that actually requires evaluation and treatment. Adapted with permission from Phillips NA. The clinical evaluation of dyspareunia. Int J Impot Res 1998;10(suppl 2):S117-20.

The diagnosis of female sexual dysfunction requires the physician to obtain a detailed patient history that defines the dysfunction, identifies causative or confounding medical or gynecologic conditions, and elicits psychosocial information.8 Preappointment questionnaires or appointments at which only the history is taken allow patient-physician communication to be unhindered by time constraints or patient fears of an upcoming physical examination.

Establishment of the patient's sexual orientation is necessary for appropriate evaluation and management. Nonjudgmental, direct questions best achieve this goal. Because gender identity conflicts are often a cause of sexual dysfunction, the mode and type of questions asked by physicians should create an environment where patients may openly express their concerns. Specialized counseling is important for these patients.

The sexual dysfunction should be defined in terms of onset and duration and situational versus global effect. A situational dysfunction occurs with a specific partner, in a certain setting or in a definable circumstance.

The presence of more than one dysfunction should be ascertained, because considerable interdependence may exist. For example, a patient complaining about decreased desire might have a primary orgasmic disorder from insufficient stimulation, with decreased desire developing secondarily as a result of unsatisfying sexual encounters (Figure 1).8 Thus, treating the orgasmic disorder would indirectly enhance desire; whereas, treating a desire disorder would be unsuccessful and perhaps add to patient frustration and perpetuate the cycle of dysfunction.

Questioning the patient about what she thinks is causing the problem may add insight. She may reveal fear of redeveloping an abnormal Papanicolaou smear from penile penetration, or she may admit that she is not attracted to her partner. Obtaining this information early in the evaluation process will expedite diagnosis and initiation of treatment.

TABLE 1

Medical Causes of Female Sexual Dysfunction

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

Medical conditions are a frequent source of direct or indirect sexual difficulties. Vascular disease associated with diabetes might preclude adequate arousal; cardiovascular disease may inhibit intercourse secondary to dyspnea (Table 1).1 Arthritis or urinary incontinence may cause discomfort or embarrassment, leading to dysfunction or decreased sexual activity.2 Aggressive treatment of long-term disease and minor ailments, with attention to their sexual implications, will help enhance sexuality.

Prescription and over-the-counter medications, illicit drugs and alcohol abuse contribute to sexual dysfunction9,10 (Table 2).10 Medication changes, drug discontinuation, or dosage or schedule alterations may provide relief. Cigarette smoking, known to cause erectile dysfunction in men, may have a similar negative effect on arousal in women.

Gynecologic conditions contribute physically to sexual difficulties (Table 3),8 and treatment must address both of these issues. For example, treatment of a patient with recurrent cystitis as a cause of dyspareunia should include the use of lubricants and distraction techniques at first intercourse to assure adequate lubrication and relaxation, respectively. These steps help resolve any secondary difficulties that may have developed (e.g., an arousal disorder or mild vaginismus). For patients with a female partner, details concerning sexual habits and objects of penetration, if any, are necessary. In these instances, hygienic use of vibrators may result in fewer episodes of cystitis.

Hysterectomy, gynecologic malignancies and breast cancer present medical and mortality concerns, and alter or remove physical and psychologic symbols of femininity that may result in feelings of decreased sexuality. In one study,11 74 percent of patients who underwent surgery for gynecologic malignancy reported decreased desire, and 40 percent reported dyspareunia. In another study12 of patients who had undergone hysterectomy for benign disease, a decrease in sexual responsiveness of up to 30 percent was noted. Breast cancer survivors report a 21 to 39 percent incidence of sexual dysfunction,13 although a recent study14 suggests that this may be related to chemotherapy or hypoestrogenism secondary to ovarian failure. Preoperative counseling, including explanations of postoperative anatomy and potential effects on sexuality, is essential in these patient populations. Continued postoperative counseling and early recognition and treatment of sexual difficulties may also help these patients maintain satisfying sexual relationships.

TABLE 2Medications and Female Sexual Dysfunction

Medications that cause disorders of desire Psychoactive medications Antipsychotics Barbiturates Benzodiazepines Selective serotonin reuptake inhibitors Lithium Tricyclic antidepressants Cardiovascular and antihypertensive medications Antilipid medications Beta blockers Clonidine (Catapres) Digoxin Spironolactone (Aldactone) Hormonal preparations Danazol (Danocrine) GnRh agonists (e.g., Lupron, Synarel) Oral contraceptives Other Histamine H2-receptor blockers and promotility agents Indomethacin (Indocin) Ketoconazole (Nizoral) Phenytoin sodium (Dilantin) Medications that cause disorders of arousal Anticholinergics Antihistamines Antihypertensives Psychoactive medications Benzodiazepines Selective serotonin reuptake inhibitors Monoamine oxidase inhibitors Tricyclic antidepressants Medications that cause orgasmic dysfunction Methyldopa (Aldomet) Amphetamines and related anorexic drugs Antipsychotics Benzodiazepines Selective serotonin reuptake inhibitors Narcotics Trazadone (Desyrel) Tricyclic antidepressants*

*–Also associated with painful orgasm Adapted with permission from Drugs that cause sexual dysfunction: an update. Med Lett Drugs Ther 1992;34:73-8.

TABLE 3

Gynecologic Causes of Female Sexual Dysfunction and Method of Gynecologic Examination

Examination Condition

External genitalia

Assess muscle tone Vaginismus

Assess skin color and texture Vulvar dystrophy, dermatitis

Assess skin turgor and thickness Atrophy

Assess pubic hair amount and distribution Atrophy

Expose clitoris Clitoral adhesions

Assess for ulcers Herpes simplex virus

Perform cotton swab test of vestibule Vulvar vestibulitis

Palpate Bartholin glands Bartholinitis

Assess posterior forchette and hymenal ring Episiotomy scars, strictures

Monomanual

Palpate rectovaginal surface Rectal disease

Palpate levator ani Levator ani myalgia, vaginismus

Palpate bladder/urethra Urethritis, interstitial cystitis, urinary tract infection

Assess for cervical motion tenderness Infection, peritonitis

Assess vaginal depth Postoperative changes, postradiation changes, stricture

Bimanual

Palpate uterus Retrogression, fibroids, endometritis

Palpate adnexa Masses, cysts, endometriosis, tenderness

Perform rectovaginal examination Rule out endometriosis

Obtain guaiac test Bowel disease

Speculum

Evaluate discharge, pH Vaginitis, atrophy

Evaluate vaginal mucosa Atrophy

Perform Papanicolaou smear Human papillomavirus infection, cancer

Assess for prolapse Cystocele, rectocele, uterine prolapse

Adapted with permission from Phillips NA. The clinical evaluation of dyspareunia. Int J Impot Res 1998;(suppl 2):S117-20.

Gynecologic changes related to a woman's reproductive life (e.g., puberty, pregnancy, the postpartum period and menopause) present unique problems and potential obstacles to sexuality. Puberty may lead to concerns regarding sexual identity. Pregnancy and the postpartum period are often associated with a decrease in sexual activity, desire and satisfaction, which may be prolonged with lactation.15

For patients with dyspareunia, a "monomanual" examination is appropriate, with the physician inserting one or two fingers into the vagina and the other hand held away from the abdomen so as not to confuse the source of discomfort.

The hypoestrogenic state of menopause may cause significant physical changes16,17 (Table 4)17 and alterations in mood or a diminished sense of well-being, which have been found to have a significant, negative impact on sexuality.18 A decline in desire, arousal and frequency of intercourse and an increase in dyspareunia have been associated with menopause,19-21 although these findings are not universal.18

The final goal is to elicit psychosocial information. Previous experiences and current intra- and interpersonal factors should be explored (Table 5).

Physical Examination

Each patient should undergo a thorough examination, with the gynecologic examination individually guided by and tailored to patient comfort. The goal of the examination is detection of disease; however, the examination also provides an opportunity to educate the patient about normal anatomy and sexual function, and to reproduce and localize pain encountered during sexual activity.

TABLE 4

Physiologic Changes of Menopause

Skin Decreased activity of sweat and sebaceous glands, decreased tactile stimulation Breasts Decreased fat content, decreased breast swelling and nipple erectile response with sexual arousal Vagina Shortening and loss of elasticity of vaginal barrel, diminished physiologic secretions, rise in vaginal pH from 3.5 to 4.5 to greater than 5, thinning of epithelial layers Internal reproductive organs Ovaries and fallopian tubes diminish in size, ovarian follicles undergo atresia, ovarian stroma becomes fibrotic, uterine body weight decreases 30 to 50 percent, cervix atrophies and decreases mucous production Bladder Urethra and bladder trigone atrophy

Reproduced with permission from Phillips NA, Rosen RC. Menopause and sexuality. In: Lobo RA, ed. Treatment of the postmenopausal woman. 2d ed. Phildelphia: Lippincott Williams and Wilkins, 1999:437-43.

TABLE 5

Psychosocial Factors of Female Sexual Dysfunction

Intrapersonal conflicts Religious taboos, social restrictions, sexual identity conflicts, guilt (i.e., widow with new partner) Historical factors Past or current abuse (sexual, verbal, physical), rape, sexual inexperience Interpersonal conflicts Relationship conflicts; extra-marital affairs; current physical, verbal or sexual abuse; sexual libido; desire or practices different from partner; poor sexual communication Life stressors Financial, family or job problems, family illness or death, depression

A routine examination seeks signs of general medical conditions. The gynecologic examination is comprehensive (Table 3),8 beginning with inspection of the external genitalia, including a cotton swab test if indicated (gently touching the vestibule of the vagina with a cotton swab will elicit moderate to severe pain in patients with vulvar vestibulitis). For patients with dyspareunia, a "mono-manual" examination should follow, with one or two fingers in the vagina (proceeding from posterior to anterior), and the other hand held away from the abdomen so as not to confuse the source of discomfort (Table 3).8 Bimanual and rectovaginal examinations are then performed. The timing of the speculum examination is guided by patient symptoms. In patients with deep dyspareunia, the speculum examination should follow the bimanual examination because localization of pain is crucial in these patients. In patients in whom vaginitis, cervical cancer or a sexually transmitted disease is suspected, cultures and vaginal samples should be obtained first.

Laboratory testing should be guided by patient symptoms and examination findings. No specific tests are universally recommended for patients with sexual dysfunction. Attention to routine screening tests must not be overlooked.

General Treatment Guidelines

Following the patient history and physical examination, a suspected etiology may be treated.

If no etiology is discovered, basic treatment strategies are applied (Table 6). The patient's (and partner's) personal tastes and comfort must be considered. Physicians should respect a patient's choice to decline treatment, because studies show that sexual activity is not correlated with overall sexual satisfaction or intimacy in all persons.18,22 In general, treatments are similar despite sexual orientations.

TABLE 6

Basic Treatment Strategies for Female Sexual Dysfunction

Provide education Provide information and education (e.g., about normal anatomy, sexual function, normal changes of aging, pregnancy, menopause). Provide booklets, encourage reading; discuss sexual issues when a medical condition is diagnosed, a new medication is started, and during pre- and postoperative periods; give permission for sexual experimentation. Enhance stimulation and eliminate routine Encourage use of erotic materials (videos, books); suggest masturbation to maximize familiarity with pleasurable sensations; encourage communication during sexual activity; recommend use of vibrators*; discuss varying positions, times of day or places; suggest making a "date" for sexual activity. Provide distraction techniques Encourage erotic or nonerotic fantasy; recommend pelvic muscle contraction and relaxation (similar to Kegel exercise) exercises with intercourse; recommend use of background music, videos or television. Encourage noncoital behaviors* Recommend sensual massage, sensate-focus exercises (sensual massage with no involvement of sexual areas, where one partner provides the massage and the receiving partner provides feedback as to what feels good; aimed to promote comfort and communication between partners); oral or noncoital stimulation, with or without orgasm. Minimize dyspareunia Superficial: female astride for control of penetration, topical lidocaine, warm baths before intercourse, biofeedback. Vaginal: same as for superficial dyspareunia but with the addition of lubricants. Deep: position changes so that force is away from pain and deep thrusts are minimized, nonsteroidal anti-inflammatory drugs before intercourse.

NOTE: For a review, see Striar S, Bartlik B. Stimulation of the libido: the use of erotica in sex therapy. Psych Annals 1999;29:60-2. *–Provide information for obtaining one discreetly.–Helpful in eliminating anxiety, increasing relaxation and diminishing spectatoring.*–Also helpful if partner has erectile dysfunction.

Disorders of Desire

Women with disorders of desire are difficult to treat. Occasionally, decreased desire in patients is secondary to boredom with sexual routines. Suggesting changes in positions or venues, or the addition of erotic materials is helpful.

Disorders of desire in premenopausal patients may be secondary to lifestyle factors (e.g., careers, children), medications or another sexual dysfunction (e.g., pain or orgasmic disorder). No medical treatment is available specific to patients with disorders of desire. If no underlying medical or hormonal etiology is discovered, individual or couple counseling may be helpful.

Estrogen replacement therapy has been shown to correlate positively with sexual activity, enjoyment and desire, although the findings are not universal.

In peri- and postmenopausal women, the relationship between hormones and sexuality is unclear.18-21 Nonetheless, estrogen replacement therapy has been shown to correlate positively with sexual activity, enjoyment and fantasies–the latter thought to represent desire.23,24 The mechanism of estrogen's effect on desire is indirect and occurs through improvement in urogenital atrophy, vasomotor symptoms and menopausal mood disorders (i.e., depression). This relationship helps predict which patients are likely to respond to estrogen replacement therapy (i.e., those with symptoms of hypoestrogenism) and may explain why some studies do not show estrogen-mediated improvement in sexual functioning.25

The role of progesterone therapy, which is necessary in estrogen-treated patients with an intact uterus, has not been widely studied in terms of sexuality, but one study24 suggests that it exhibits a negative impact by dampening mood and decreasing available androgens. The addition of estrogen for several weeks before progesterone therapy is initiated, or taking into account monthly symptom calendars, will help determine each hormone's influence and guide dosage and schedule adjustments.

TABLE 7

Testosterone Therapy for Treatment of Disorders of Desire*

Screening Baseline testosterone levels (free and total), baseline lipid profile, baseline liver enzyme levels, mammography, Papanicolaou smear Initiate therapy* Combination product (Estratest or Estratest hs) Methyltestosterone (Android), 1.25 to 2.5 mg daily Micronized oral testosterone, 5 mg twice daily Testosterone proprionate 2 percent in petroleum applied daily to every other day Testosterone injectables/pellets Reevaluation at three to four months Repeat testosterone levels, lipid profile, liver enzyme levels Monitor symptoms, side effects Continued therapy Taper to lowest effective dosage Monitor lipid levels, liver enzyme levels once or twice yearly Routine Papanicolaou smear and mammography schedules

*–These are recommendations; no evidence-based protocols are available on testosterone therapy for the treatment of women with desire disorders.–Many authors recommend that total levels remain in "normal" range for premenopausal women.*–None of these medications are labeled by the U.S. Food and Drug Administration for treatment of desire disorders. –Alternate daily combined with estrogen-only pill, take testosterone pill every other day, 5 days a week, etc. (not shown in studies to be safer or have fewer side effects).

Testosterone appears to have a direct role in sexual desire.20 However, because studies evaluate mostly testosterone-deficient, oophorectomized women or women who develop supraphysiologic levels secondary to testosterone treatment, clinical applications are limited. No guidelines for testosterone replacement therapy for women with disorders of desire and no consensus of "normal" or "therapeutic" levels of testosterone therapy exist. Many physicians are concerned about the lack of safety data on the role of testosterone in breast cancer and on hepatic side effects; however, hepatocellular damage or carcinoma is rare at prescribed dosages,26 and the development of breast cancer has not been reported clinically.27

The side effects of testosterone, which occur in 5 to 35 percent of patients, include lower levels of high-density lipoprotein, acne, hirsutism, clitorimegaly and voice deepening.27 However, these side effects on lipoprotein levels are rarely significant if estrogen and testosterone are coadministered; moreover, most other side effects are reversible with discontinuation of testosterone or a dosage adjustment.26

A role for testosterone treatment exists in selected patients (Table 7). Coadministration with estrogen therapy should be provided to prevent deleterious effects on lipoprotein levels. Before initiating testosterone treatment, physicians should discuss the potential and theoretic risks, and individual risk and benefit assessments with the patient. In general, patients with current or previous breast cancer, uncontrolled hyperlipidemia, liver disease, acne or hirsutism should not receive testosterone therapy.

Arousal Disorders

Current treatment of patients with arousal disorders is limited to the use of commercial lubricants, although vitamin E and mineral oils are also options. Arousal disorders may be secondary to inadequate stimulation, especially in older women who require more stimulation to reach a level of arousal that was more easily attained at a younger age. Encouraging adequate foreplay or the use of vibrators to increase stimulation may be helpful. Taking a warm bath before intercourse may also increase arousal. Anxiety may inhibit arousal, and strategies to alleviate anxiety by employing distraction techniques are helpful.

Urogenital atrophy is the most common cause of arousal disorders in postmenopausal women, and estrogen replacement, when appropriate, is usually effective therapy. However, women taking systemic estrogens occasionally require supplementation with local therapy. Long-term use of estrogen-containing vaginal creams is considered an unopposed-estrogen treatment in women with an intact uterus, requiring progesterone opposition. An oral progesterone such as medroxyprogesterone 5 mg daily for 10 days every one to three months (or equivalent) may be used initially, with frequency or dosage increased if withdrawal bleeding occurs. Estring (an estradiol-containing vaginal ring) has little systemic absorption and does not require the addition of progesterone. Patients who are uncomfortable wearing the ring during the day often achieve relief with night use only.

Premenopausal women with arousal disorders, women who do not respond to estrogen therapy and women who are unable or unwilling to take estrogen represent difficult patient groups because few treatment options are available.

TABLE 8

Kegel Exercises

Potential uses Increased pubococcygeal tone Improved orgasmic intensity Correction of orgasmic urine leakage Distraction technique during intercourse Improved patient awareness of sexual response Teaching Kegel exercises Instructional examination with examiner's finger in vagina Initial patient home exercise with patient's finger in vagina Slow count to 10, with movement directed "in and up" Hold for count of 3 Slow release to count of 10 Repeat 10 to 15 times daily Consider vaginal weights, biofeedback clinics Maintaining Kegel exercises Advise repetitions during routine activities (standing in line, at stop lights, etc.) Schedule follow-up appointments to discuss progress

Investigators recognize that small-vessel atherosclerotic disease of the vagina and clitoris may contribute to arousal disorders and are exploring vasoactive medications as treatment.28 Small studies29,30 have been conducted with favorable results, but larger studies are needed. Currently, treatment of arousal disorder in women who are taking these medications, including sildenafil (Viagra), is not recommended, although anecdotal success has been reported.30

Orgasmic Disorders

Anorgasmia is quite responsive to therapy. This condition is caused by sexual inexperience or the lack of sufficient stimulation and is common in women who have never experienced orgasm. Orgasmic disorders may also be psychologic ("involuntary inhibition" of the orgasmic reflex) or caused by medications or chronic disease.

Treatment relies on maximizing stimulation and minimizing inhibition.31 Stimulation may include masturbation with prolonged stimulation (initially up to one hour) and/or the use of a vibrator as needed, and muscular control of sexual tension (alternating contraction and relaxation of the pelvic muscles during high sexual arousal). The latter is similar to Kegel exercises (Table 8). Methods to minimize inhibition include distraction by "spectatoring" (observing oneself from a third-party perspective), fantasizing or listening to music. Women who do not respond to therapy should be referred to an appropriate therapist.

Sex Pain Disorders

Dyspareunia can be divided into three types of pain: superficial, vaginal and deep (Table 6). Superficial dyspareunia occurs with attempted penetration, usually secondary to anatomic or irritative conditions, or vaginismus. Vaginal dyspareunia is pain related to friction (i.e., lubrication problems), including arousal disorders. Deep dyspareunia is pain related to thrusting, often associated with pelvic disease or relaxation.7

Treatment of orgasmic disorders relies on maximizing stimulation and minimizing inhibition.

Diagnosis of an underlying etiology should be aggressively sought, even if surgical investigation (laparoscopy) is required. The physical examination must include meticulous detail, with the physician's focus on recreating the pain. Treatment of the underlying etiology is fundamental, but as in long-term pain disorders, counseling and pain control strategies are essential. General recommendations for improved sexual function are discussed in Table 6 and are similar despite sexual orientation.

TABLE 9

Female Sexual Dysfunction: When to Refer

Longstanding dysfunctionMultiple dysfunctionsCurrent or past abusePsychologic disorder or acute psychologic eventUnknown etiologyNo response to therapy

Vaginismus, the involuntary contraction of the muscles of the outer one third of the vagina, is often related to sexual phobias or past abuse or trauma.10,32 Vaginismus may be complete or situational, so that a pelvic examination might be possible while intercourse is not. Therapy for and counseling of women with vaginismus can be initiated and often successfully completed by primary care physicians.

Treatment of women with vaginismus consists of progressive muscle relaxation and vaginal dilatation (actually a misnomer because the vagina is not physically stretched). Progressive muscle relaxation can be taught during an instructional examination by having the patient alternate contracting and relaxing the pelvic muscles around the examiner's finger. Women with vaginismus can achieve vaginal dilatation with the use of commercial dilators or tampons of increasing diameter, placed into the vagina for 15 minutes twice daily. Once the patient can easily accept an equivalent-sized dilator into the vagina, penile penetration by the partner can occur. Success rates approach 90 percent.31,32 Patients who do not respond to this therapy should be referred to a sex therapist who specializes in the treatment of women with this disorder (Table 9).

The Author

NANCY A. PHILLIPS, M.D.,

is a senior lecturer and consultant in the Department of Obstetrics and Gynecology at the Wellington School of Medicine, University of Otago, Wellington, New Zealand. Dr. Phillips earned her medical degree from the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway and completed her obstetrics and gynecology residency at George Washington University Hospital, Washington, D.C.

Address correspondence to Nancy Phillips, M.D., 119 Mitchell St., Brooklyn, Wellington, New Zealand. Reprints are not available from the author.

REFERENCES

1. Bachmann GA, Phillips NA. Sexual dysfunction. In: Steege JF, Metzger DA, Levy BS, eds. Chronic pelvic pain: an integrated approach. Philadelphia: Saunders, 1998:77-90.

2. ACOG technical bulletin. Sexual dysfunction. No. 211. Washington, D.C.: American College of Obstetricians and Gynecologists, September 1995.

3. Bachmann GA, Leiblum S, Grill J. Brief sexual inquiry in gynecologic practice. Obstet Gynecol 1989;73(3 pt 1):425-7.

4. Angst J. Sexual problems in healthy and depressed persons. Int Clin Psychopharmacol 1998;13(suppl 6): S1-4.

5. Read S, King M, Watson J. Sexual dysfunction in primary medical care: prevalence, characteristics and detection by the general practitioner. J Public Health Med 1997;19:387-91.

6. Michael RT. Sex in America: a definitive survey. Boston: Little, Brown, 1994:111-31.

7. Schein M, Zyzanski SJ, Levine S, Medalie JH, Dickman RL, Alemagno SA. The frequency of sexual problems among family practice patients. Fam Pract Res J 1988;7:122-34.

8. Phillips NA. The clinical evaluation of dyspareunia. Int J Impot Res 1998;10(suppl 2):S117-20.

9. Weiner DN, Rosen RC. Medications and their impact. In: Sipski ML, Alexander CJ, eds. Sexual function in people with disability and chronic illness: a health professional's guide. Gaithersburg, Md.: Aspen, 1997.

10. Drugs that cause sexual dysfunction: an update. Med Lett Drugs Ther 1992;34:73-8.

11. Thranov I, Klee M. Sexuality among gynecologic cancer patients–a cross-sectional study. Gynecol Oncol 1994;52:14-19.

12. Virtanen H, Makinen J, Tenho T, Kiilholma P, Pitkanen Y, Hirvonen T. Effects of hysterectomy on urinary and sexual symptoms. Br J Urol 1993;72:868-72.

13. Goldstein MK, Teng NN. Gynecologic factors in sexual dysfunction of the older woman. Clin Geriatr Med 1991;7:41-61.

14. Ganz PA, Rowland JH, Desmond K, Meyerowitz BE, Wyatt GE. Life after breast cancer: understanding women's health-related quality of life and sexual functioning. J Clin Oncol 1998;16:501-14.

15. Byrd JE, Hyde JS, DeLamater JD, Plant EA. Sexuality during pregnancy and the year postpartum. J Fam Pract 1998;47:305-8.

16. Bachmann GA. Influence of menopause on sexuality. Int J Fertil Menopausal Stud 1995;40(suppl 1): 16-22.

17. Phillips NA, Rosen RC. Menopause and sexuality: basic and clinical aspects. In: Lobo RA, ed. Treatment of the postmenopausal woman. 2d ed. Philadelphia: Lippincott Williams and Wilkins, 1999:437-43.

18. Cawood EH, Bancroft J. Steroid hormones, the menopause, sexuality and well-being of women. Psychol Med 1996;26:925-36.

19. Laan E, van Lunsen RH. Hormones and sexuality in postmenopausal women: a psychophysiological study. J Psychosom Obstet Gynecol 1997;18:126-33.

20. Davis SR, Burger HG. Clinical review 82: androgens and the postmenopausal woman. J Clin Endocrinol Metab 1996;81:2759-63.

21. Bachmann GA, Leiblum SR. Sexuality in sexagenarian women. Maturitas 1991;13:43-50.

22. Rosen RC, Taylor JF, Leiblum SR, Bachmann GA. Prevalence of sexual dysfunction in women: results of a survey study of 329 women in an outpatient gynecological clinic. J Sex Marital Ther 1993;19: 171-88.

23. Nathorst-Boos J, Wiklund I, Mattsson LA, Sandin K, von Schoultz B. Is sexual life influenced by transdermal estrogen therapy? A double blind placebo controlled study in postmenopausal women. Acta Obstet Gynecol Scand 1993;72:656-60.

24. Sherwin BB. The impact of different doses of estrogen and progestin on mood and sexual behavior in postmenopausal women. J Clin Endocrinol Metab 1991;72:336-43.

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30. Fava M, Rankin MA, Alpert JE, Nierenberg AA, Worthington JJ. An open trial of oral sildenafil in antidepressant-induced sexual dysfunction. Psychther Psychosom 1998;67:328-31.

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http://www.postgradmed.com/issues/2001/11_01/khouzam.htm

Posttraumatic stress disorder

Safe, effective management in the primary care setting

Hani Raoul Khouzam, MD, MPH; Nancy J. Donnelly, MS, ARNP

VOL 110 / NO 5 / NOVEMBER 2001 / POSTGRADUATE MEDICINE Online

CME learning objectives

· To define posttraumatic stress disorder (PTSD) and describe its causes, key symptoms, and diagnostic criteria

· To identify the symptom clusters in PTSD that may respond to pharmacologic intervention

· To discuss the benefits and side effects of the pharmacologic agents used in PTSD treatment

The authors disclose no financial interest in this article.

Preview: The terrorist attacks on the United States on September 11 had far-reaching effects as onlookers witnessed the violent death, threatened death, or serious injury of thousands. Such unprecedented violence can have severe psychological repercussions, including posttraumatic stress disorder (PTSD). This article describes this complicated condition and focuses on a symptom-based, often multisystem approach to treatment of PTSD in the primary care setting.

Khouzam HR, Donnelly NJ. Posttraumatic stress disorder: safe, effective management in the primary care setting. Postgrad Med 2001:110(5):60-78

Often considered primarily a disorder of military combat veterans, PTSD is now known to affect people in all walks of life. Natural disasters, violent crimes, massacres, school shootings, terrorism, and the unprecedented exodus of refugees from ethnic wars are expanding the number of psychologically traumatized people who are at increased risk for PTSD (1,2). The condition is gaining increasing recognition as a complex and chronic psychiatric disorder (1). Lifetime prevalence worldwide is 1% to 4%. In the United States, PTSD affects 5% of men and 10% of women (1,2).

A comprehensive, multidisciplinary approach to management combines psychological, social, spiritual, and pharmacologic interventions. This article reviews the clues to diagnosis of PTSD in the primary care setting and focuses on the various pharmacologic agents that can be used for symptomatic treatment.

Causes and symptoms

PTSD is an anxiety disorder that may develop in a person who has experienced, witnessed, or learned about a physically or psychologically distressing event (1-5). The event may involve death, threatened death, serious injury, or other threat to a person's physical integrity. The immediate cause of PTSD appears to be the specific stressors associated with the event or events (1,2). The severity of the event appears to be a primary factor: it must be extreme (not just severe) and cause powerful subjective feelings of intense fear, helplessness, and horror (2,5) (table 1). Table 1. Stressors that can cause posttraumatic stress disorder Criminal assault

Hostage taking

Imprisonment

Military duties

Natural disaster

Serious accident

Sexual or physical abuse

Torture

Terrorist attack

Witnessing or learning about such events

Why some people are vulnerable to PTSD and others are not is unknown (2,3). Factors that may influence the development of PTSD include childhood trauma; borderline, paranoid, dependent, or antisocial personality traits; predisposition to psychiatric conditions; low educational status; alcohol or drug abuse; recent stressful life-changing events; and lack of or inadequate social support network (3,4).

PTSD is characterized by the persistence of separate symptom clusters with varying degrees of severity, including the following (5):

· Reexperiencing the event through intrusive thoughts, nightmares, or flashbacks that recollect traumatic images and memories

· Avoidance and emotional numbing expressed as flattening of affect, detachment from others, loss of interest, lack of motivation, and constant avoidance of any activity, place, person, or event associated with the traumatic experience

· Increased arousal usually accompanied by startle reaction, poor concentration, irritability, jumpiness, insomnia, and hypervigilance

PTSD is considered acute when symptoms last less than 3 months and chronic when symptoms last 3 months or more. Symptoms occurring immediately after the stressor and lasting less than 1 month may be transient and self-limited (5); severe symptoms during this time increase the risk of PTSD (3,4). When symptoms last 1 to 3 months, active treatment may help reduce the otherwise high risk of chronic PTSD (3-5). With chronic PTSD, the incidence of comorbid psychiatric disorders increases (4-6).

Psychiatric comorbidity

Persons with chronic PTSD have unusually high rates of associated psychiatric conditions throughout life, including substance abuse and dependence (23%), major depression (20%), alcohol dependence (75%), and personality disorder (20%) (4-6). Other comorbid psychiatric conditions include panic disorder, agoraphobia, generalized anxiety disorder, social phobia, and bipolar disorder (5,6). When such conditions are identified and treated, the intensity of PTSD symptoms usually decreases (4,7).

Differential diagnosis

PTSD can be easily misdiagnosed and inappropriately treated (5,7). Findings on history taking, including onset of symptoms as they relate to traumatic experiences, can help distinguish PTSD from other conditions. Traumatic head injury, concussion, delirium, and seizure disorders must be ruled out. Alcohol and substance abuse, along with acute intoxication or withdrawal, must also be considered. PTSD must be delineated from factitious disorders, personality disorders, and malingering (3,7). In some cases, the distinction between comorbid psychiatric conditions and clinical differential diagnostic considerations becomes blurred, and psychiatric consultation may be required.

Prognosis

Prognosis is usually good when symptoms begin within 6 months of the traumatic event, the patient was previously psychologically stable, and the patient has a good social support network. Absence of comorbid medical, psychiatric, or substance-related disorders is also important in predicting the course and prognosis of PTSD.

Pharmacologic treatment

Duration of pharmacologic treatment generally is longer for PTSD than for other psychiatric conditions (3). High doses and a combination of agents may be needed to target the complex symptoms of PTSD (3). Drug selection depends on specific symptoms and coexisting psychiatric conditions (4). Symptoms of PTSD that may respond to medications include anger, hostility, violent impulses, anxiety, poor concentration, sleep disturbances, nightmares, violent dreams, depressed mood, recurrent intrusive recollections (flashbacks), and avoidance behaviors (5). Pharmacologic therapy for comorbid psychiatric conditions must be carefully selected to complement therapy targeted at PTSD symptoms (1,3).

Antidepressants

Selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), trazodone hydrochloride (Desyrel), and various atypical (novel) antidepressants are used to treat PTSD. The majority of these medications can be safely prescribed and monitored by primary care physicians.

SSRIs: In general, SSRIs effectively target PTSD symptoms such as intrusive thoughts, flashbacks, hyperarousal, irritability, angry outbursts, difficulty concentrating, and associated depression and anxiety. SSRIs are also used to treat dissociative symptoms (8,9). Table 2 outlines the dosages. Use of SSRIs can be encouraged because of their relatively simple dosage regimen, safety, and favorable outcomes in many patients. The US Food and Drug Administration approved sertraline hydrochloride (Zoloft) for treatment of PTSD in 1999 (6). Table 2. SSRI therapy for posttraumatic stress disorder Agent Dose (mg/day) Starting Average Maximum Citalopram HBr (Celexa) 20 20-40 60 Fluoxetine HCl (Prozac) 10-20 20-50 80 Fluvoxamine maleate (Luvox) 50 100-250 300 Paroxetine HCl (Paxil) 10-20 20-50 60 Sertraline HCl (Zoloft) 25-50 50-150 200 SSRI, selective serotonin reuptake inhibitor. About 50% of patients experience adverse effects common to SSRIs, including gastrointestinal (GI) disturbances, nausea, diarrhea, headache, restlessness, and sexual dysfunction. Also, individual SSRIs have distinct side effects (10). GI disturbances are more common with sertraline, somnolence and dry mouth with paroxetine hydrochloride (Paxil), initial restlessness with fluoxetine hydrochloride (Prozac), sedation with fluvoxamine maleate (Luvox), and nausea with citalopram hydrobromide (Celexa).

TCAs: These drugs have some documented efficacy in treating several PTSD symptoms, including intrusive thoughts, flashbacks, anxiety and panic-related hyperarousal, loss of interest, sleep disturbances, irritability, and depressed mood affecting concentration and contributing to feelings of shame and guilt (11). Average daily doses are as follows: amitriptyline hydrochloride (Elavil), 150 mg; nortriptyline hydrochloride (Aventyl HCl, Pamelor), 100 mg; and doxepin hydrochloride (Sinequan) and imipramine hydrochloride (Tofranil), 200 mg.

TCAs inhibit reuptake of norepinephrine and serotonin in the central nervous system (CNS). They also exert effects on other neurotransmitter systems, including adrenergic, histaminergic, muscarinic, and cholinergic receptors. Adverse effects include sedation, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, cognitive dysfunction, and weight gain (11,12). Interaction with other sedating and anticholinergic medications potentiates these effects (12). TCAs were first-line agents in treating PTSD but are now considered secondary agents because of their potentially life-threatening cardiotoxicity, especially after overdose attempts.

Trazodone: This agent has anxiolytic properties and is chemically unrelated to the TCAs. Although the mechanism of action is not fully understood, it is believed that trazodone inhibits serotonin reuptake and acts as a partial antagonist of serotonin 5-HT2 receptors. It can ameliorate chronic insomnia and decrease the intensity of nightmares. It also is effective in managing aggressive behavior (13). Dosage depends on response; maximum daily dose is 600 mg.

Trazodone has minor anticholinergic effects but is quite sedating, can cause orthostatic hypotension, and in a small percentage of male patients causes priapism requiring surgical intervention. Overdose attempts are not lethal if trazodone is ingested without alcohol or other drugs.

Atypical antidepressants: Antidepressants with atypical modes of action can be considered for treatment of PTSD in patients who cannot tolerate the adverse effects of TCAs, trazodone, and SSRIs, although the role of these newer agents has not been fully studied. Agents include nefazodone hydrochloride (Serzone), venlafaxine (Effexor), mirtazapine (Remeron), and bupropion hydrochloride (Wellbutrin), as well as the older class of antidepressants, monoamine oxidase inhibitors (MAOIs).

Nefazodone: This drug is structurally related to trazodone and acts as a 5-HT2 antagonist, inhibiting reuptake of both norepinephrine and serotonin (14). Nefazodone is useful for decreasing intrusive thoughts, flashbacks, depression, anxiety, panic symptoms, avoidance behaviors, irritability, and angry outbursts. It can also decrease hyperarousal, hypervigilance, and startle reactions. Maximum daily dose is 400 mg. Common adverse effects are asthenia, somnolence, nausea, constipation, and dry mouth. Nefazodone is less likely than trazodone to cause orthostatic hypotension or priapism (13,14). Nefazodone increases plasma levels of alprazolam (Xanax), triazolam (Halcion), haloperidol (Haldol), and digoxin (Lanoxin) and can decrease plasma levels of propranolol (14).

Venlafaxine: This drug inhibits both norepinephrine and serotonin uptake and is a weak inhibitor of dopamine reuptake (15). It can be used for symptomatic relief of severe depressive symptoms associated with PTSD, anxiety, phobic reactions, and panic symptoms. Maximum daily dose is 225 mg. Side effects include nausea, headache, nervousness, anxiety, anorexia, sweating, and insomnia. At high doses, a small percentage of patients experience increased diastolic blood pressure; a smaller percentage may have increased heart rate and serum cholesterol levels. When used as recommended, venlafaxine has no effect on cytochrome P-450 isoenzymes (14).

Mirtazapine: This tetracyclic compound acts as a potent antagonist of 5-HT2 and 5-HT3 receptors (16). It is also a potent antagonist of histamine1 receptors and a moderate antagonist of muscarinic receptors. Although use of mirtazapine in treatment of PTSD has not yet been systematically studied, its sedating properties can be beneficial in sleep disturbances and in decreasing hyperarousal. It is also an alternative medication for comorbid treatment-resistant depression. Maximum daily dose is 60 mg. Somnolence, dizziness, and increased appetite with weight gain are the main side effects. Sedating effects can interfere with cognitive and motor performance. Agranulocytosis is a risk, so patients should pay particular attention to flulike or other symptoms that suggest infection (16).

Bupropion: The precise neurochemical mechanism of action of bupropion is not fully understood, but it affects noradrenergic and dopaminergic systems (17). Its effects on PTSD symptoms are not well known, but it has shown some benefits in patients with comorbid depression and anxiety who cannot tolerate adverse effects of other antidepressants. The main adverse effects are headache, nausea, agitation, and insomnia. Maximum daily dose is 300 mg; with higher doses, seizures are a risk. Bupropion is absolutely contraindicated in patients with seizure disorders or anorexia and bulimia (17).

MAOIs: It is advised that MAOIs be prescribed by, or in consultation with, a psychiatrist. MAOIs block the degradation of dopamine, norepinephrine, and serotonin. Phenelzine sulfate (Nardil) was found to be effective in decreasing intrusive thoughts and avoidance behaviors (17). It also has efficacy in treating atypical depressive symptoms characterized by hypersomnia, hyperphagia, and anxiety. Maximum daily dose is 60 mg, although some patients may tolerate up to 90 mg daily.

MAOIs can cause anticholinergic side effects (dry mouth, urinary retention, constipation, blurred vision), orthostatic hypotension, and sexual dysfunction. Patients should adhere to a tyramine-free diet, because the irreversible inhibition of MAO can cause a fatal hypertensive crisis if tyramine-containing food is ingested (17). The potential for drug-drug and alcohol interactions precludes use of MAOIs by substance abusers (7).

Mood stabilizers

Lithium (Eskalith, Lithonate, Lithotabs), carbamazepine (Atretol, Epitol, Tegretol), and valproic acid (Depakene) have been used in patients with prominent symptoms of hyperarousal, hyperactivity, hostility, irritability, and angry outbursts (3,17,18). These agents can be added to an antidepressant regimen in cases of partial response or used as first-line therapy for patients with PTSD and bipolar disorder (3).

Lithium: This salt alters sodium transport in the nerve and muscle cells, resulting in a shift toward intraneuronal catecholamine metabolism (17). It decreases norepinephrine reuptake and increases serotonin receptor sensitivity.

Side effects include fine hand tremor, polydipsia, polyuria, nausea, vomiting, drowsiness, muscle weakness, poor coordination, giddiness, ringing or buzzing in the ears, and blurred vision. Thyroid function should be monitored. Lithium interacts with haloperidol, chlorpromazine hydrochloride (Thorazine), TCAs, and calcium channel blockers. Concomitant use of angiotensin-converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs can increase serum lithium levels, leading to toxicity. Because of its effects on the kidneys, lithium should be judiciously administered with loop diuretics. It should not be given with a salt-free diet because of the risk of hyponatremia (17). The difference between therapeutic and toxic lithium levels is narrow, so serum levels should be monitored often.

Carbamazepine: This anti-convulsant appears to reduce polysynaptic responses and block posttetanic potentiation (17). It may be useful in sleep disturbance because it decreases sleep latency and does not disrupt rapid eye movement sleep (13). It is effective in treating agitation, rage attacks, poor impulse control, violent behavior, and angry outbursts.

According to the kindling model, periodic brain stimuli that are initially too low to stimulate the limbic system may progressively induce bioelectrical changes, which ultimately lead to abnormal limbic sensitization manifested by periodic mood swings, agitation, and violence. Carbamazepine has been reported to modulate the kindling effects documented in PTSD (18).

Side effects include drowsiness, dizziness, and blurred vision. Carbamazepine is a hepatic enzyme inducer that can initially decrease its own plasma levels and influence plasma levels of other drugs affected by the same hepatic pathways. Periodic monitoring of liver enzyme levels and blood counts is necessary to avoid hepatotoxicity and blood dyscrasias. Serum carbamazepine levels must be monitored every 3 to 6 months regardless of the patient's stability and the absence of adverse effects (17).

Valproic acid and derivatives: This group includes valproic acid, sodium valproate (the sodium salt), and divalproex sodium (17). An anticonvulsant, valproic acid increases g-aminobutyric acid (GABA) levels as well as the sensitivity of GABA receptor sites. The rationale for using valproic acid is similar to that for using carbamazepine–limbic kindling. Increased GABA levels are thought to interfere with the kindling process, diminishing the symptoms of flashbacks, nightmares, and hyperarousal.

Side effects include GI upset and throat or mouth irritation (from chewing the tablets or capsules). Patients who have difficulty swallowing may use the syrup or sprinkle forms. Indigestion, sedation, sleepiness, weakness, fatigue, skin rash, diarrhea, stomach cramps, constipation, weight gain, and problems with muscle coordination also can occur. Liver enzyme levels should be monitored regularly to avoid elevation (17).

Other anticonvulsants: The use of newly approved antiseizure medications gabapentin (Neurontin), lamotrigine (Lamictal), and topiramate (Topamax) in the treatment of PTSD has been documented in case studies. However, no large case-controlled studies have been completed.

Antianxiety agents

Antidepressants have useful anxiolytic properties (19), but some patients require adjunctive anti-anxiety therapy for acute, severe, and debilitating symptoms of fear, panic, avoidance, hyperarousal, hypervigilance, startle reactions, and sleep disturbances (17). This section focuses on the benzodiazepines and buspirone hydrochloride (BuSpar).

Benzodiazepines: The benzodiazepines are widely used anxiolytic agents. Their use in treatment of PTSD warrants careful consideration, but routine use should be discouraged because of the risks of physiologic dependence, interdose rebound, and breakthrough anxiety symptoms. Abuse potential, along with exacerbation of PTSD symptoms during withdrawal, limits their long-term use.

Physicians prescribing a benzodiazepine need to be aware of comorbid substance abuse by the patient and consider the possibility of paradoxical disinhibition, which can precipitate impulsive and hostile behaviors. Depressive symptoms that often emerge during PTSD treatment have been associated with benzodiazepines. Considerable research is needed to discern the role and impact of benzodiazepines on the overall pharmacologic treatment of PTSD (17).

Buspirone: This nonbenzodiazepine anxiolytic has high affinity for serotonin 5-HT1A receptors. It has no significant affinity for benzodiazepine receptors and does not affect GABA binding. Buspirone has moderate affinity for D2 dopamine receptors and appears to act as a presynaptic dopamine agonist. Because of its efficacy in management of anxiety disorders, it has a role in treatment of hyperarousal and startle reactions. Buspirone can cause dizziness, nausea, headache, fatigue, nervousness, light-headedness, and excitement. Patients need to be alerted to the possibility of these side effects early in treatment so the effects are not interpreted as an aggravation of preexisting symptoms. Buspirone has been effective in the management of SSRI-induced sexual dysfunction in men (17).

Antipsychotic agents

Because of their adverse effects and potential for inducing tardive dyskinesia, conventional anti-psychotic agents have generally not been used in treatment of PTSD (13,17). However, newer, atypical antipsychotics pose a much lower risk of side effects; these agents are useful adjunctive therapy for PTSD, especially for comorbid hallucinations and delusions (associated with suspiciousness and paranoia) (20).

Irritability, nightmares, and vivid sensory flashbacks with auditory, visual, olfactory, and tactile hallucinations (although possibly related to episodes of dissociation and reexperiencing of actual traumatic events) might respond to a short course of anti-psychotic treatment (13). The association between PTSD and bipolar disorder also may indicate the need for adjunctive antipsychotic therapy (17).

In the past, risks of extrapyramidal side effects, tardive dyskinesia, and worsening anhedonia were major obstacles to use of antipsychotics in PTSD. With the advancement of atypical anti-psychotic agents, however, these risks have markedly decreased (20). These agents can be considered for brief low-dose therapy targeting specific symptoms (15). They should be prescribed by a psychiatrist, when possible, or in conjunction with psychiatric consultation.

Adrenergic and antiadrenergic agents

These agents decrease autonomic hyperactivity in general anxiety, hyperarousal, hypervigilance, and startle reactions. These symptoms may respond to judicious use of adrenergic agents such as clonidine hydrochloride (Catapres) and antiadrenergic agents such as propranolol hydrochloride (Inderal) (13,17).

Clonidine: This alpha2-adrenergic agonist has been shown to reduce symptoms of hyperarousal and to sometimes potentiate the effects of TCAs. Common side effects are dry mouth, drowsiness, and sedation. Constipation, dizziness, headache, and fatigue are also common but usually diminish within 6 weeks (13,17). Guanfacine hydrochloride, a centrally acting alpha2-adrenoceptor agonist, also has been studied as an alternative for patients who do not tolerate the side effects of clonidine. Results of these studies are pending (17,18).

Propranolol: This beta-blocker has demonstrated anxiolytic effects in decreasing symptoms of hyperarousal, restlessness, startle reactions, and autonomic hyperactivity. It is usually given in a daily divided dose of 120 to 160 mg. Other beta-blockers, such as atenolol (Tenormin) and nadolol (Corgard), also have been reported to be beneficial. Long-acting propranolol (Inderal LA) offers convenient once-daily dosing, resulting in better compliance. The chief side effects of beta-blockers are tiredness, weakness, bradycardia, dizziness, breathing difficulty, bronchospasm, sleeplessness, and male impotence (13,17). Frequent monitoring of blood pressure and pulse rate is necessary to detect hypotension and bradycardia.

Sedative hypnotics

Antihistamines and hypnotic agents can be used as adjunctive hypnotic therapy in managing chronic sleep disturbances associated with PTSD.

Antihistamines: Hydroxyzine (Atarax, Vistaril), diphenhydramine hydrochloride, and cyproheptadine hydrochloride (Periactin) can be used temporarily to induce drowsiness and sleep (17). The main side effects are drowsiness, anticholinergic effects (dry mouth, urinary retention, constipation), exacerbation of asthma, and breathing difficulties. Additive CNS depressant effects may occur when antihistamines are combined with other sedating agents (17). Some reports, however, suggest that antihistamines might cause stimulation and hyperexcitability in the PTSD population (17,21).

Hypnotic agents: Zolpidem tartrate (Ambien) is an imidazopyridine chemically unrelated to benzodiazepines, barbiturates, or other hypnotic agents. The usual dose is 10 mg taken at bedtime. Downward dose adjustment may be necessary when zolpidem is given with other CNS depressants (15).

Zaleplon (Sonata), a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class, differentially binds to the benzodiazepine type I site (22). It exerts sedative, anxiolytic, muscle-relaxing, and anticonvulsant properties (22). A 10-mg dose is recommended for adults and a 5-mg dose for geriatric patients. Both zolpidem and zaleplon have shown efficacy in treating short-term insomnia; however, efficacy in long-term insomnia and other PTSD symptoms has not been studied (17,22).

Summary and conclusion

PTSD is a severe and chronic psychiatric condition (1,2). Because of the complex symptoms, no single treatment is effective. Pharmacologic treatment is an integral component of a multidisciplinary approach that addresses the psychological, social (22), and spiritual (23) dimensions of PTSD. Psychopharmacologic agents provide symptomatic relief and are beneficial in managing other comorbid psychiatric conditions. Primary care physicians can base treatment decisions on the patient's prevailing symptoms. Specialized psychiatric consultation may be needed in difficult and complicated cases.

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21. Clark RD, Calais LA, Qualls C, et al. Cyproheptadine treatment of nightmares associated with posttraumatic stress disorder. (Letter) J Clin Psychopharmacol 1999;19(5):486-7

22. Elie R, Ruther E, Farr I, et al. Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic. J Clin Psychiatry 1999;60(8):536-44

23. Khouzam HR, Kissmeyer P. Antidepressant treatment, posttraumatic stress disorder, survivor guilt, and spiritual awakening. J Trauma Stress 1997;10(4):691-6

The authors thank Nancy Berry, MSW, and Mark Gilbertson, PhD, for their clinical input; Robert Hierholzer, MD, for his support; Robert West for his administrative assistance; and Cynthia K. Meyer, Patricia Kangas, and Daphne Perry for their literature search.

Dr Khouzam is staff psychiatrist, Veterans Affairs Central California Health Care System, Fresno; clinical instructor in medicine, Harvard Medical School, Boston; and visiting lecturer, department of psychiatry and behavioral sciences, University of Oklahoma College of Medicine, Oklahoma City. Ms Donnelly is a clinical nurse specialist, Veterans Affairs Medical Center, Manchester, New Hampshire. Correspondence: Hani Raoul Khouzam, MD, MPH, VA Central California Health Care System, 2615 E Clinton Ave, Fresno, CA 93703. E-mail: hani.khouzam2@med.va.gov.

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Sexual dysfunction

The roles of yohimbine hydrochloride and intracavernosal vasoactive drugs in the treatment of erectile dysfunction, the effect of transurethral resection of prostate on sexual functions and the impact of dihydrotestosterone on andropausal symptoms

Pekka Kunelius

Department of Surgery, University of Oulu

Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in Auditorium 1 of the University Hospital of Oulu, on November 26th, 1999, at 12 noon.

University of Oulu

Manuscript received 20 September 1999

Manuscript accepted 6 October 1999

Communicated by

Docent Martti Ala-Opas

Docent Martti Talja

UNIVERSITY OF OULU, OULU FINLAND 1999

ISBN 951-42-5386-8

URN:ISBN:9514253868

Abstract

Altogether 406 patients were included in five studies, and all patients were examined and controlled in the Oulu University Hospital during the years 1991 – 1998.

Twenty-nine patients with mixed-type erectile dysfunction (ED) were recruited into a randomized, controlled, double-blind crossover comparison of placebo and high-dose yohimbine hydrochloride (36 mg per day orally). Positive clinical responses were obtained in 44% of the patients during yohimbine treatment and in 48% during placebo treatment.

Thirty patients with ED underwent an intracavernosal injection test (ICI) using three different active agents (prostaglandin E1(PGE1), papaverine hydrochloride (PV), moxisylyte (MS)) and physiological saline. PGE1 produced significantly better rigidity than either PV or MS.

The sexual functions of 155 patients with benign prostatic hyperplasia (BPH) were evaluated before TURP and 6 and 12 months afterwards with questionnaires. Only 26% of the patients had completely satisfactory erections before TURP, while 22% had satisfactory erections 6 months later and 24% 12 months later. The majority of patients (about 70%) were satisfied with their sexual life both before and after the procedure.

123 men with symptoms of andropause participated in a randomized, placebo-controlled study to assess the effects of dihydrotestosterone (DHT) gel in men with andropausal symptoms. The drug was administered transdermally once a day during six months. Early morning erections improved significantly (p < 0.003) in the DHT group by the three-month control, the ability to maintain erections was better, and there was also a positive effect on libido. In the patients with a elevated (> 12) international index of the prostatic symptoms score (I-PSS) before DHT treatment, I-PSS decreased from 17.7 to 12.3 points.

As a conclusion yohimbine hydrochloride is no better than placebo in the treatment of patients with mixed-type ED. PGE1, PV and MS are well tolerated, and PGE1 was shown to be the most effective drug of the three. ICI therapy with PGE1 in long-term use is safe and effective. Sexual functions in men did not change after TURP, and this group of aging men were fairly satisfied with their sexual life despite of the fact that they had some ED and one third of the patients had not had intercourse during the previous year. Transdermal administration of DHT in aging men improves sexual function.

Keywords: erectile dysfunction, intracavernous injection (ICI) test, andropause, dihydrotestosterone

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Acta Universitatis Ouluensis

Medica

D 550

ISBN 951-42-5385-X

ISSN 0355-3221

————————–

SEXUAL DYSFUNCTION:

THE ROLES OF YOHIMBINE HYDROCHORIDE AND INTRACAVERNOSAL VASOACTIVE DRUGS IN THE TREATMENT OF ERECTILE DYSFUNCTION, THE EFFECT OF TRANSURETHRAL RESECTION OF PROSTATE ON SEXUAL FUNCTIONS AND THE IMPACT OF DIHYDROTESTOSTERONE ON ANDROPAUSAL SYMPTOMS

Pekka Kunelius

Department of Surgery, University of Oulu, FIN-90401, Oulu, Finland

Abstract

The aim of this study was to clarify the effects of yohimbine hydrochloride and three intracavernosal vasoactive agents in patients with erectile dysfunction and the effect of dihydrotestosterone gel in men with andropausal symptoms. The effect of transurethral resection of prostate (TURP) on sexual functions was also examined.

Altogether 406 patients were included in five studies, and all patients were examined and controlled in the Oulu University Hospital during the years 1991-1998.

Sixty-nine patients with ED who had started ICI therapy with PGE1 at least three years previously were invited to a control examination to find out the long-term outcome of this treatment and to evaluate the patients' overall satisfaction with their sexual life.46.4% of the patients had discontinued PGE1 therapy, the mean time of using PGE1 having been 23.3 months (range 0-48 months). 34.8% of the patients reported that their own spontaneous erections had improved during the PGE1 therapy.The sexual functions of 155 patients with benign prostatic hyperplasia (BPH) were evaluated before TURP and 6 and 12 months afterwards with questionnaires. Only 26% of the patients had completely satisfactory erections before TURP, while 22% had satisfactory erections 6 months later and 24% 12 months later. The majority of patients (about 70%) were satisfied with their sexual life both before and after the procedure.

Dedicated to my family

Table of Contents

Acknowledgements

Abbrevations

List of original publications

1. Introduction

2. Review of the literature

2.1. Prevalence and epidemiology of erectile dysfunction

2.2. Physiology of penile erection

2.3. Evaluation of erectile dysfunction

2.3.1. Patient history and use of questionnaires

2.3.2. Laboratory tests

2.3.3. Functional studies of ED

2.3.4. Pharmacotest

2.3.5. Vascular evaluation of ED

2.3.6. Neurogenic evaluation of ED

2.4. Conservative treatment options

2.4.1. Psychosexual therapy

2.4.2. Vacuum devices

2.4.3. Hormonal treatment

2.4.4. Oral drug therapy

2.4.5. Topical drug therapy

2.4.6. Transurethral drug therapy

2.4.7. Intracavernosal therapy

3. Outlines of present research

4. Patients and methods

4.1. High-dose yohimbine hydrochloride in the treatment of mixed-type impotence (I)

4.2. Intracavernous injection test in the evaluation of patients with erectile dysfunction (II)

4.3. Intracavernous self-injection of prostaglandin E1 in the treatment of erectile dysfunction (III)

4.4. Effect of transurethral resection of the prostate on sexual functions (IV)

4.5. Effects of transdermal dihydrotestosterone on andropausal symptoms (V)

5. Results

5.1. High-dose yohimbine hydrochloride in the treatment of mixed-type impotence (I)

5.2. Intracavernous injection test in the evaluation of patients with erectile dysfunction (II)

5.3. Intracavernous self-injection of prostaglandin E1 in the treatment of erectile dysfunction (III)

5.4. Effect of transurethral resection of the prostate on sexual functions (IV)

5.5. Effects of transdermal dihydrotestosterone on andropausal symptoms (V)

6. Discussion

6.1. General

6.2. High-dose yohimbine hydrochloride in the treatment of mixed-type impotence(I)

6.3. Intracavernous injection test in the evaluation of patients with erectile dysfunction (II)

6.4. Intracavernous self-injection of prostaglandin E1 in the treatment of erectile dysfunction (III)

6.5. Effect of transurethral resection of prostate on sexual functions (IV)

6.6. Effects of transdermal dihydrotestosterone on andropausal symptoms (V)

7. Conclusions

References

List of Tables

2-1. Drugs that may produce erectile dysfunction (from Benet & Melman1995).

5-1. The patients` subjective visual analogue scale (0-100) assessments of libido, rigidity of the penis, duration of erection, and sensation of orgasm before and during placebo and yohimbine treatments¤

5-2. Grade 3-5 erection and the duration of erection (grades 4-5) achieved with physiological saline (NaCl), papaverine hydrochloride (PV), prostaglandin E1 (PGE1) and moxisylyte (MS) at 15 minutes after the injection. The results are expressed as arithmetic means.

5-3. Reasons for dropping out among 69 patients who began intracavernosal home therapy with PGE1.

List of Figures

2-1. The three pathways that regulate penile smooth muscle relaxation: cGMP, cAMP and hyperpolarization. (NA = noradrenaline, AD = adrenaline, ß -ADR = ß 2-adrenergic receptor, EP-P = prostaglandin E receptor, VIP-R = vasoactive intestinal peptide receptor, Na+-pump = Na+-K+-ATPase, NO nitric oxide) (From Saenz de Tejada & Moncada 1996).

2-2. Rigiscan ambulatory penile tumescence and rigidity monitoring device.

5-1. Coital frequency in the study group before and after TURP.

5-2. Effect of DHT on the hemoglobin level during the treatment.

Abbrevations

AVSST

audiovisual sexual stimulation test

BCRL

bulbocavernous reflex

BMI

body mass index

BPH

benign prostatic hyperplasia

cc-EMG

corpus cavernosum electromyography

CVD

cardiovascular disease

duplex-Doppler color sonography

DHEA

dehydroepiandrosterone

DHT

dihydrotestosterone

erectile dysfunction

estradiol

FSD

female sexual dysfunction

FSH

follicle stimulating hormone

GTP

guanosine-5"-triphosphate

HDL

high-density lipoprotein

ICI

intracavernosal injection

IIEF

international index of erectile function

luteinizing hormone

moxisylyte

nitric oxide

NPT

nocturnal penile tumescence

NPTR

nocturnal penile tumescence and rigidity

PGE1

prostaglandin E1

PSA

prostate-specific antigen

papaverine hydrochloride

REM

rapid eye movement

SHBG

sex-hormone binding globulin

testosterone

TRUS

transrectal ultrasound

TURP

transurethral resection of prostate

VAS

visual analogue scale

VCD

vacuum/constriction device

List of original publications

This thesis is based on the following articles, which are referred to in the text by their Roman numerals:

I Kunelius P, Häkkinen J & Lukkarinen O (1997) Is high-dose yohimbin hydrochloride effective in treatment of mixed-type impotence? A prospective randomized, controlled double-blind crossover study. Urology: 49:441-444.

II Kunelius P & Lukkarinen O (1998) Intracavernous injection test in the evaluation of patients with erectile dysfunction: a blind, cross-over placebo-controlled study between three different vasoactive agents in 30 impotent patients. Sexual Dysfunction 1:35-38.

III Kunelius P & Lukkarinen O (1999) Intracavernous self-injection therapy of prostaglandin E1 in the treatment of erectile dysfunction. Int J Impot Res 11:21-24.

IV Kunelius P, Häkkinen J & Lukkarinen O (1998) Sexual functions in patients with benign prostatic hyperplasia before and after transurethral resection of the prostate. Urol Res 26:7-9.

V Kunelius P, Lukkarinen O & Tapanainen J (1999) The effects of transdermal dihydrotestosterone on andropause symptoms: a prospective, randomized, double-blind study. Submitted for publication.

1. Introduction

The inability of a male to attain and maintain an erection sufficient to allow sexual intercourse is called erectile dysfunction (ED). It is a part of the general male sexual dysfunction called impotence, which also includes libidinal, orgasmic and ejaculatory dysfunction. Until the 1990's, "impotence" was the term used in clinical work to refer to erectile dysfunction.

The most usual sexual dysfunction of man is weakness of erections. Erectile dysfunction affects millions of men, and although it may not mean a total loss of sexual satisfaction, it often creates a mental stress that affects the man's quality of life. Erectile dysfunction goes hand in hand with aging. The prevalence of complete ED is estimated to be approximately 5% among 40-year-olds, 10% among men in their 60s, 15% in men in their 70s, and 30-40% in men in their 80s (Feldman et al. 1994).

Erectile dysfunction is a common problem. In the 1970s it was believed that most of the problems causing erectile dysfunction were psychological. Nowadays, about 50-85% of ED patients can be shown to have a somatic cause by modern methods of examination (Mulligan & Katz 1989). One must, however, recognise that there are always some psychological factors at the background. Erectile dysfunction may also occur as a result of a specific illness or medical treatment. Various operations may similarly cause erectile dysfunction (Quinlan et al. 1991).

Knowledge of erectile dysfunction has increased remarkably over the past decade: the most striking finding was the possibility to use intracavernosal (papaverine hydrochloride) treatment, which was reported by Dr. Virag in the early 1980s (Virag 1982). Since that time, many other injectable vasoactive medicines have been introduced (Buvat J et al. 1989, Lue 1990, Chao & Clowers 1994). The other important finding was sildenafil, which enables the use of effective oral medication for ED (Goldstein et al. 1998).

The mechanism of erection is also better understood now when the new drugs have been investigated (Hedlund & Andersson 1985, Goldstein et al. 1998). The clinical investigations of erectile dysfunction have become more sophisticated: color duplex Doppler (DD) sonography, audiovisual sexual stimulation tests (AVSST), and computer-aided programs area available for the analysis of erections and nocturnal penile tumescence (NPT) (Rigiscan device). It is also possible to examine the etiology of erectile dysfunction with intracavernosal injection tests (ICI) (Stackl et al. 1990).

Nowadays the most important contemporary treatments of ED are peroral sildenafil and intracavernosal pharmacotherapy using vasoactive medicines. 70%-90% of all patients with ED are able to restore their erections with these treatments (Benard et al. 1990, Virag et al. 1991, Goldstein et al. 1998). However, these drugs are not suitable to every patient. More nonivasive methods to treat erectile dysfunction, such as oral medication or locally applicable preparations are needed.

2. Review of the literature

Table of Contents

2.1. Prevalence and epidemiology of erectile dysfunction

2.2. Physiology of penile erection

2.3. Evaluation of erectile dysfunction

2.4. Conservative treatment options

2.1. Prevalence and epidemiology of erectile dysfunction

Until the 1970s, sex was a private matter and publications about sexual behaviour were rare. Erectile dysfunction was a non-threatening disorder, and only a minority of the patients suffering from it consulted a doctor.

The first thorough epidemiologic study in the United States was published by Kinsey and associates in 1948. According to Kinsey`s survey, which covered 4108 adult males, less than 1% of the population were affected before the age of 30 years, while 6.7 % of men were affected between 45 and 55 years, 25% at the age of 65 years, and up to 75% of men at the age of 80 years. One should notice, however that only a minority of these patients, namely 306, were aged above 55; it is therefore difficult to draw very definite conclusions concerning elderly men`s prevalence of erectile dysfunction on the basis of Kinsey's report. Spector and Carey (1990) reviewed 23 studies on sexual dysfunction in males and females carried out between 1948 and 1988 in different settings, among the general population and in different clinical settings, reporting that the prevalence of ED was 4% to 9%. The most recent epidemiologic study is the the Massachusetts Male Aging Study (MMAS) reported by Feldman and colleagues (1994), where 1290 males aged 40-70 years filled in a sexual questionnaire with 9 items between the years 1987 and 1989. This study reports a combined 52 % prevalence of minimal, moderate and complete impotence. Age was the variable most strongly associated with impotence. The authors concluded that erectile dysfunction increases with age, and the probability of complete impotence tripled from 5 to 15 % between the ages of 40 and 70 years. Prior studies have shown similar relationships between impotence and aging (Kinsley et al. 1948, Pearlman & Kopashi 1972, Frank et al. 1978, Mulligan et al. 1988). The MMAS study could concluded, based on these figures, that impotence is a major health concern in view of its high prevalence. It has been noticed in various investigations that 80-90% of men over 60 years of age continue their sexual activity (Brecher 1984).

Erectile dysfunction is often multifactorial in etiology. When the patient is diagnosed as having organic ED, it means that organic factors are the main contributors to his ED. For didactic purposes, ED has been divided into organic and psychogenic types. Atherosclerotic vascular disease accounts for nearly half of all ED in men more than 50 years of age (Mulligan & Katz 1989). Heart disease and two associated risk factors, hypertension and low serum high-density lipoprotein, significantly correlated with impotence in the MMAS sample (Feldman et al. 1994). Several studies on impotent men have shown that the number of abnormal penile vascular findings significantly increases when the patient history includes myocardial infarction or vascular risk factors, such as hypertension and cigarette smoking (Shabsigh et al. 1991).

Diabetes is known to be associated with impotence. The prevalence of ED in the diabetic population ranges from 15% to 55%, depending on the age and extent of the disease (Smith 1981). In the MMAS sample, the age-adjusted probability of complete impotence was 3-fold in subjects reporting treated diabetes compared to those without diabetes (Feldman et al. 1994).

Of the many other diseases causing ED, chronic renal failure induces ED in up to 40% of the men affected (Abrams et al. 1975). Several neurological diseases have also been associated with ED. Multiple sclerosis is associated with a high incidence of ED (Lilius et al. 1976). Loss of erection was reported in 53% of 55 male Alzheimer`s disease patients (Zeiss et al. 1990).

Endocrine disorders are commonly associated with ED, and hypopituitarism, non-functioning pituitary tumors, prolactin-secreting pituitary tumors and hyperthyroidism may cause ED (Braunstein 1983). The effect of androgens on libido and sexual behavior is well established, but their contribution to the erectile mechanism remains unclear (Korenman 1990). In the MMAS survey, of the 17 hormones measured, only dehydroepiandrosterone was strongly associated with impotence (Feldman et al. 1994).

Psychogenic ED is more prevalent in young men, but its prevalence in older men cannot be ignored, especially not the widower`s syndrome (Morley 1985).

Men suffering from depression may have organic ED due to the decreased testosterone levels caused by elevated levels of corticotropin-releasing factor (CRF) (Ono et al. 1984). Several chronic infectious diseases are associated with ED. The outcome of prolonged priapism is usually ED, while many conditons are associated with priapism and are often drug-induced and are caused by or sickle cell disease, trauma, neoplasia, leukemia, intracavernosal injections and total parenteral alimentation.

Cigarette smoking has been shown to be an independent risk factor for vasculogenic impotence (Rosen et al. 1991). The roles of excessive alcohol consumption, obesity and physical inactivity are unclear (Fried et al. 1986, Friedman et al. 1986, Kosch et al. 1988).

Trauma to the pelvic structures may cause ED in a significant number of men affected, and urologic surgery is also closely associated with ED. Radical prostatectomy using the retropubic approach and a nerve-sparing procedure causes ED in 15 % to 30% (Quinlan et al. 1991). Transurethral resection of prostate (TURP) has resulted in a high incidence of ED in many studies, but the incidence varies from none to 40% (Holtgrave & Valk 1964, Finkle & Prian 1966, Hargreave & Stephensen 1977, Bolt et al. 1987, Libman & Fichten 1987, Mebust et al. 1989).

Drug-induced erectile dysfunction is common. The data available on this topic are based on empirical observations, case reports and pre- or post-marketing drug surveys. Most of the studies have been uncontrolled. Slag and collegues (1983) found a 25 % prevalence of drug-associated impotence in a medical outpatient population. Most of the drugs causing male erectile dysfunction have been associated with the available antihypertensive agents, including symphatolytics, ß -adrenoceptor blocking agents, vasodilatators and diuretics (Wein et al. 1988). Many drugs that produce central nervous system sedation or depression, such as opiates, are also associated with ED by causing elevation of plasma prolactin levels (von Graffenreid et al. 1978), as are also drugs that lower plasma testosterone levels, such as estrogen, ketokonazole and digoxin (Pont et al. 1982, Przybilla & Schill 1985). There are numerous drugs and many different mechanisms that could also cause ED (Table 2-1). More and more drugs are being identified as causing ED, but consideration should also be given to the natural occurrence of ED.

Table 2-1. Drugs that may produce erectile dysfunction (from Benet & Melman1995). Drug type Drugs Diuretics Thiazides

Spironolactone Antihypertensives Methyldopa

Clonidine

Reserpine

ß -Blockers

Guanethidine

Verapamil Cardiac Clofibrate

Gemfibrozil

Digoxin Tranquilizers Phenothiazines

Butyrophenones Antidepressants Tricyclic antidepressants

Monoamine oxidase inhibitors

Lithium

Prozac H2 antagonists Cimetidine

Ranitidine Hormones Estrogens

Progesterone

Corticosteroids

Cyproterone acetate

Eulexin

Proscar

Gonadotropin-releasing hormone agonists Cytotoxic agents Cyclophosphamide

Methotrexate

Roferon-A Anticholinergics Disopyramide

Anticonvulsants Miscellaneous Metoclopramide

Baclofen

Carbonic anhydrase inhibitors

Nonsteroidal anti-inflammatory

Tobacco

Alcohol

Amphetamines

Opiates 2.2. Physiology of penile erection

The central sensory psychogenic stimuli or penile stimulation or both increase parasympathetic activity, resulting in relaxation of the penile smooth muscle (Saenz de Tejada & Moncada 1996). This phenomenon is mediated by activation of the NO/cGMP pathway and by additional activation of the cAMP pathway, which result in increased blood flow through the penile arteries.

NO exerts a significant impact on the penis, operating as the princial mediator of ED (Burnett 1997). NO is a free radical and therefore a highly reactive and chemically unstable molecule. NO crosses the plasma membrane of cells targeting on the guanylate cyclase enzyme, producing a conformational change in the molecule that increases its activity. Activated guanylate cyclase catalyzes the conversion of guanosine-5"-triphosphate (GTP) to 3`,5`cyclic guanosine monophosphate (cGMP). The accumulation of cGMP sets in motion a cascade of events at the intracellular level which induce a loss of contractile tone of penile smooth muscle and increase of bood flow in cavernous body (Saenz de Tejada & Moncada 1996, Figure 2-1).

The other pathway for inducing relaxation and erection is mediated by vasoactive intestinal peptide (VIP) (Ehmke et al. 1995). The VIP receptors in the cavernous body are coupled to specific proteins that stimulate the catalytic activity of adenylate cyclase with the formation of cAMP (Figure 2-1). Endogenous prostanoids participate in the regulation of penile smooth muscle contractility. The receptor that mediates relaxation to PGE is designated "EP receptor" (prostaglandin E receptor, Figure 2-1). The stimulation of beta-adrenergic receptors by catecholamines causes relaxation of the arterial and trabecular smooth muscle. The beta-2 subtype is probably the most important receptor mediating these effects (Dhabuwala et al. 1985). Adrenaline has high affinity for this receptor, whose stimulation partly counteracts the constrictor effects of this catecholamine, which are mediated by alpha-adrenergic receptors.

One of the mechanisms by which cyclic nucleotides induce the relaxation of smooth muscle is through the opening of potassium channels, which hyperpolarize the cell. The activation of potassium channels by PGE1 action, an effect mediated by AMPc, has been demonstrated (Christ et al. 1996).

The termination of erection takes place via increased adrenergic activity, and it has two components: a direct constrictor effect on the smooth muscle mediated by the alpha1- and alpha2-receptors and an indirect effect, whereby the vasodilatator effect of noncholinergic neurotransmitter nerves is inhibited by a prejunctional, alpha2-adrenergic-mediated mechanism (Saenz de Tajada & Moncada 1996).

Figure 2-1. The three pathways that regulate penile smooth muscle relaxation: cGMP, cAMP and hyperpolarization. (NA = noradrenaline, AD = adrenaline, ß -ADR = ß 2-adrenergic receptor, EP-P = prostaglandin E receptor, VIP-R = vasoactive intestinal peptide receptor, Na+-pump = Na+-K+-ATPase, NO nitric oxide) (From Saenz de Tejada & Moncada 1996).

2.3. Evaluation of erectile dysfunction

2.3.1. Patient history and use of questionnaires

The evaluation of ED begins with a comprehensive patient history and physical examination. A careful sexual history and knowledge of current illnesses and medications are essential. In the study by Davis-Joseph and colleagues (1995), history and physical examination had 95 % sensivity, but only 50% specificity in diagnosing organic ED. The accuracy rates of history and physical examination in diagnosing ED were 80% and 60%, respectively.

The history of sexual function is best obtained through self-reporting by the patient. In an effort to improve the way in which men communicate about their sexual function, O`Leary and colleagues (1995) developed and validated a self-administered questionnaire, which they found useful in practice and research. The goal of the analysis was to identify the minimum number of questions that would reliably and validly describe the four main domains of male sexuality: sexual drive or libido, erection, ejaculation and overall satisfaction. The resulting 11-item index captures the key areas of male sexuality as clearly and concisely as possible.

Visual analogue scale analysis has seldom used for assessment of ED, mainly it is used in evaluating pain in clinical studies (Gillam et al. 1997, Yalcin et al. 1998) also concerning pain after intracavernosal injections (Kim et al. 1997, Sato et al. 1998).

Recently, several international questionnaires have been developed. The International Index of Erectile Function (IIEF) has been used widely, and it has been validated in several languages (Rosen et al. 1997, Goldstein et al. 1998). According to Goldstein and colleagues (1998), the efficacy of sildenafil was assessed on the basis of the scores for the five separate response domains concerning male sexual function on IIEF: erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction.

2.3.2. Laboratory tests

The laboratory tests of an impotent patient aim to identify treatable conditions or previously undetected medical illnesses that may contribute to ED (Carroll et al. 1992). The value of routine endocrinologic testing in the evaluation of impotent men is controversial, as the overall incidence of endocrinopathy in impotent patients varies from 1.7% to 35%, with most large series reporting incidences closer to 1.7% (Johnson & Jarow 1992). The effectiveness of hormonal replacement in the treatment of hypogonadal impotence has also been rather disappointing. Morales and associates (1994) reported a total response rate of only 9% among patients treated with oral androgen replacement. Up to 20% of elderly men who undergo estrogen therapy or surgical castration for prostate cancer are able to maintain erections adequate for intercourse despite the castrate levels of testosterone (Ellis & Grayhack 1963). Therefore, some investigators have suggested that an evaluation of endocrinopathy is only necessary in men who demonstrate clinical evidence of hypogonadism (bilateral testicular atrophy) or report decreased libido (Johnson & Jarow 1992, Friedman et al. 1986). If hormonal evaluation is done, it is enough to assess serum testosterone. The National Institutes of Health (NIH) suggested the use of an a.m. serum testosterone value (NIH Consensus Conference 1993). Serum testosterone levels, however, vary widely in normal men and are related to the episodic secretion of LH (Spratt et al. 1988).

2.3.3. Functional studies of ED

Evaluation of nocturnal penile tumescence (NPT) was one of the earliest tests devised to study erectile dysfunction. The association between sleep and erections was documented as early as 1940 by Halverson. Aserinsky and Kleitman (1953) first described rapid eye movement (REM) sleep and later recognized that nocturnal erections seemed to correspond to the REM periods during normal sleep. Fischer (1965) found the association between REM sleep and erections. In 1970, Karacan suggested that NPT could be used to evaluate ED. NPT testing might be a useful method for differentiating between organic and psychogenic impotence: the mechanism of NPT is presumed to rely on neurovascular response mechanisms similar to those seen in erotically induced erections. The basic assumption is that the relevant psychologic factors which may inhibit sexually induced erection while awake would be inoperative during sleep. The truth of this assumption has not been proven. Some investigators have reported that NPT studies correlate poorly with patient-reported sexual performance (Condra et al. 1986). At least two consecutive nights of recording NPT are necessary to evaluate nocturnal penile tumescence and rigidity; in addition, sexual intercourse seems to decrease nocturnal penile tumescence and rigidity, although not statistically significantly (Hatzichristou et al. 1998).

The validity and usefulness of NPT studies in the evaluation of ED have been questioned, and the normative values and the standardized technique available for determining such parameters as the number of episodes, the degree of tumescence and rigidity, have not been well established. Nor has it been determined what constitutes a normal NPT study (Wein et al. 1981, Sohn et al. 1993).

In 1985, Bradley and Timm described the Rigiscan monitoring device (Dacomed Corporation, Minneapolis, MN) used by patients at home to provide continuous recording of penile tumescence and rigidity (NPTR)(Figure 2-2). It has been used widely in NPT studies (Karadeniz et al. 1997) and also for monitoring during audiovisual sexual stimulation (AVSS) (Martins & Reis 1997).

AVSS tests have been used for the initial screening of psychogenic erectile dysfunction: a positive response to visual erotic stimulation is strongly indicative of a predominantly psychogenic cause of erectile dysfunction (Martins & Reis 1997). The use of vibrotactile stimulation and visual sexual stimulation together may assist in determining the potential sexual potency of men experiencing erection problems during the process of differential diagnosis (Rowland et al. 1994).

Figure 2-2. Rigiscan ambulatory penile tumescence and rigidity monitoring device.

2.3.4. Pharmacotest

Intracorporeal injection of vasoactive agents, which was first introduced by Virag and associates, was found to be useful as a diagnostic tool in patients with suspected vasculogenic impotence (Virag et al. 1984, Abber et al. 1986). Theoretically, vasoactive substances substitute for the neurotransmitter to activate arterial and sinusoidal mechanisms. Initially, a positive erectile response, defined as rigid erection, has been presumed to signify normal vascular status. If only short-lived, partial or no response resulted from the injection, vascular ED was presumed (Lue & Tanagho 1987). In 1994, Pescatori and co-workers demonstrated that a positive erectile response implies normal veno-occlusive function, but not necessarily normal arterial function. A negative erectile response may be due to excessive adrenergic constrictor tone as a result of anxiety (Buvat et al. 1986). It has also been noticed that the level of norepinephrine in penile blood during a pharmacotest is higher in patients with psychogenic ED than in healthy controls or patients with vascular ED (Kim & Oh 1992).

There are many vasoactive agents that can be used for pharmacotesting and administered as therapy for ED (Junemann & Alken 1989, Stackl et al. 1990). In a multicenter study comparing papaverine, papaverine-phentolamine and PGE1, PGE1 emerged as the most reliable diagnostic drug with an overall erection rate of 74% and a prolonged erection rate of only 0.1% (Porst 1990). Nisen & Cormio (1993) concluded in their study that pharmacotesting with a high dose of prostaglandin is a useful screening test for vasculogenic impotence. There have been several methods to enhance the diagnostic accuracy of pharmacotesting: it has been used with initial high doses or re-dosing or combined with genital self-stimulation or vibratory stimulation (Donatucci & Lue 1992, Janssen et al. 1994, Incrocci et al. 1996). Visual erotic stimulation (VES) or AVSS have also been used with pharmacotesting to improve its accuracy (Katlowitz et al. 1993, Janssen et al. 1994, Vruggink et al. 1995). Montorsi and associates (1996) showed that a combination of injection and genital plus audiovisual sexual stimulation caused a significantly greater erectile response than re-dosing.

The most feared complication of pharmacotesting is prolonged erection (Fouda et al. 1989). Younger patients with nonvascular ED are most prone to prolonged erection (Lomas & Jarow 1994). Therefore, the dose used for testing should be adapted to the history of the patient and reduced in the presence of suspected neurogenic or psychological ED (Witjes et al. 1992).

2.3.5. Vascular evaluation of ED

Color duplex Doppler ultrasound is a minimally invasive method for studying the arterial blood supply to the penis (Lue et al. 1985, Gall et al. 1989, Lewis & Mauda 1994). It assesses the integrity of the arterial supply to the penis and provides some useful information on the veno-occlusive mechanism (Nisen et al. 1993). Because the arterial diameter and the flow rate change during the different phases of erection, duplex Doppler ultrasound is performed after pharmacostimulation and, if necessary, after self-stimulation (Lue 1990). Montorsi and associates (1996) suggested that color Doppler sonography should be performed after an injection plus genital and audiovisual sexual stimulation: when the erectile response does not equal the maximal physiological erection reported by the patient, a second injection with stimulation should be given. Ultrasonic and pulsed Doppler scanning after pharmacostimulation can only be done on the area distal to the pubic bone. When the study suggests an arterial disease and medical treatment is unsuccessful, further visualization with internal pudendal arteriography may be indicated (Lue & Tanagho 1987). It is recommended that all pudendal angiographies should be done after an intracavernosal injection, which gives good visulialization of the penile arterial tree (Lue & Tanagho 1987).

A more precise assessment of this mechanism requires a specialised invasive test: the alternatives for diagnosing veno-occlusive dysfunction are cavernosography and pharmacologic cavernosometry (Wagner 1981, Wespes et al. 1986, Shabsigh et al. 1991). These tests should be done if patient history supports congenital venous leakage or arterial supply of cavernous body has been shown to be normal and intracavernosal injection test is negative.

Although many impotent men who underwent cavernosography were found to have a venous leak, the initial enthusiasm for venous ligation procedures has waned due to the poor long-term outcome seen in many patients (Kim & McVary 1995). The finding of venous leakage is often related to other abnormalities in the erectile mechanism, such as intrinsic sinusoidal disease (Aboseif et al. 1992).

Over the past few years, attention has been focused on structural investigation of cavernous tissue obtained by needle biopsy as a tool in the diagnosis of diseases of the cavernous body (Wespes et al. 1992).

2.3.6. Neurogenic evaluation of ED

The diagnosis of neurogenic ED is problematic, as there is no test available to examine the autonomic nervous system (Weiske 1997). The measurement of the latency of the bulbocavernous reflex (BCRL) is probably the most widely used neurophysiologic test. It can reveal only lesions of the somatic penile innervation (pudendal nerve), but not of the autonomic innervation (parasympathetic and sympathetic nerves). Wagner and Gerstenberg (1988) reported measurement of electric potentials in the cavernous body. Unfortunately, corpus cavernosum EMG (cc-EMG) does not meet the demand to detect reliably autonomic neuropathy of the cavernous body and smooth muscle dysfunction as a result of degeneration because of artifacts; there is, however, some hope that intelligent software will be capable of identifying and eliminating these artifacts in the future (Stief et al. 1994).

2.4. Conservative treatment options

2.4.1. Psychosexual therapy

Psychosexual therapy for ED problems was introduced in the early part of this century with Freudian-style psychoanalysis. In 1970, a treatment programme involving a combination of behavioral and psychotherapeutic elements was described, and a 70% success rate after 5 years of follow-up was reported (Barnes 1991). Nowadays, these methods have mostly been replaced by more behaviorally oriented therapy, which aims to reduce performance anxiety via programmed relearning of sexual behavior. Hartman (1998) concluded that psychosexual therapy is a feasible treatment option, with significant improvements in 50 to 80% of cases, but its long-term outcome is less favorable.

Surridge and co-workers (1998) concluded that men with ED want to have a rigid penis, while they and their partners are less interested in having help with relationship issues, general sexual issues and life style issues.

2.4.2. Vacuum devices

The vacuum constriction device (VCD) works by a combination of the twin principles of vacuum and tension: the negative pressure (vacuum) device increases corporeal blood flow, thereby inducing an erection, which is maintained by a constriction ring (tension) around the base of the penis that decreases corporeal venous drainage. VCD was developed over 100 years ago. Dr. John King introduced the first device in 1874, and the first patent was issued for the device to Dr. Otto Lederer in 1917. It took over 100 years before the device was approved as a legal treatment option; Osbon`s device (ErecAidTM) was granted FDA permission in 1982 (Osbon 1983).

It has been reported that erections have succeeded in 84-95% of cases (Nadig et al. 1986, Cookson & Nadig 1993, Baltaci et al. 1995) and overall satisfaction with the device has been slightly lower, 72-94% (Turner et al. 1991, Price et al. 1991, Vrijhof et al. 1994).

Complications are generally of minor nature: pain, either during the suction (20-40%) or caused by the ring (45%), is the commonest complaint, which is most frequently presented at the beginning of treatment (Turner et al. 1990). Pain on ejaculation has been reported by 3-16% of users, and an inability to ejaculate by 12-30% (Witherington 1989, Turner et al. 1991, Cookson & Nadig 1993). Petechiae on the penis have been reported by 25-39%, concurrent bruising by 6-20% (Cookson & Nadig 1993, Baltaci et al. 1995), and numbness as a major problem during erection by 5% (Cookson & Nadig 1993). Few serious complications have been reported, usually due to misuse of the device, such as skin necrosis (Meinhardt et al. 1990), Peyronie`s disease (Kim & Carson 1993) and Fournier`s gangrene (Theiss et al. 1995). Many find the main disadvantage of the VCD to be the lack of spontaneity in the production of effective erection and some men complain that the rings act as a reminder of their inadequacy (Turner et al. 1992).

In patients who fail to respond both subjectively and objectively to either intracavernosal injection or VCD, a combination of these options should be tested (Chen et al. 1995).

2.4.3. Hormonal treatment

Testicular function of both the exo- and endocrine compartments decreases at old age, causing a series of clinical symptoms that are analogous to, although less pronounced than, the menopausal syndrome: these symptoms are considered to represent the male climacterium or andropause (Vermeulen 1993, Swerdloff & Wang 1993). With age, an increase of sex hormone-binding globulin (SHBG) occurs in plasma and a corresponding decrease is seen in non-SHBG-bound testosterone, which is believed to be the only effectively bioavailable agent for target tissues (Nahoy & Roger 1990, Gray et al. 1991). The circadian rhythmicity in blood testosterone decreases in healthy aging men compared to healthy young men (Bremner et al. 1983). Long-term androgen deficiency in aging men may lead to asthenia, a decrease of muscle mass, osteoporosis, decreased sexual activity and, in some cases, changes in mood and cognitive functions (Swerdloff & Wang 1993).

Androgen substitution may improve ED in some patients with diagnosed hypogonadism (Krane et al. 1989). Improvements in mood and sexual function can be elicited in hypogonadic men by increasing the plasma concentrations of either testosterone (T) or dihydrotestosterone (DHT) (Kuhn et al. 1986). However, it has been demonstrated that, in hypogonadal men with impotence, the administration of testosterone alone results in improvement of erection in only approximately 60% of patients (Morales et al. 1997). Androgens facilitate erection, and their absence does not necessarily preclude good erectile function. Furthermore, there are some hypogonadal men in whom ED is more dependent on vascular risk factors than low testosterone levels (Morales et al. 1997). In elderly men, short-term studies on a small number of patients have been performed and have shown favorable effects on sexuality, well-being and muscular strength (Morley et al. 1993, Tenover 1992). However, its well known that a great majority of prostatic carcinomas are androgen-dependent, and it is reasonable to believe, until proved otherwise, that androgen substitution might accelarate the growth and evolution of prostatic carcinoma, which is why androgen substitution should only be performed under strictly controlled conditions (Vermeulen 1993). Kirby (1994) proposed that testosterone should not be used in eugonadal men with ED because it may enhance prostatic hyperplasia or promote the growth of prostate cancer.

Which hormonal changes could be implied in the pathophysiology of prostatic anomalies in men aged over 50 years remains to be debated: testosterone (T) and dihydrotestosterone (DHT) are two potent androgens with opposite effects regarding aromatase activity, which presents in prostatic stroma and is suspected to have a pathogenic influence through local estradiol synthesis. Testosterone is the main substrate for aromatase and estradiol synthesis, while dihydrotestosterone is not aromatizable and, at a sufficient concentration, lowers the testosterone and estradiol levels (de Lignieres 1993). In a 1.8-year survey of 37 men aged 55-70 years, daily percutaneous DHT treatment (>8.5 nmol/l) effectively induced clinical benefits while slightly but significantly reducing prostatic size. DHT may therefore be considered an attractive alternative for long-term treatment of andropause (de Lignieres 1993).

Because of the poor bioavailability of the drug, oral therapy with testosterone is less effective than parenteral testosterone in achieving normal serum testosterone levels and has a higher incidence of hepatotoxicity and adverse serum lipid effects (Krane et al. 1989, Morley & Kaiser 1989). New transdermal formulations of testosterone and dihydrotestoterone as well as oral formulations without associated liver toxity have been developed (Wagner & Tejada 1998).

Bromocriptine has been used successfully in men with hyperprolactinaemia-associated hypogonadism, with subsequent improvements in erectile dysfunction (Leonard et al. 1989).

2.4.4. Oral drug therapy

Yohimbine is an indole alkaloid derived from the bark of the Central African Paysinystalin yohimbe tree. It has been classified as an aphrodisiac for over a century, but it was only recently investigated in controlled trials. Yohimbine is a centrally and peripherally acting alpha-2-adrenoceptor antagonist (Grunhaus et al. 1989); it produces a rise in sympathetic drive by increasing noradrenaline release and the firing rate of cells located in noradrenergic nuclei of the central nervous system. It is 50 to 100 times more active at presynaptic compared to postsynaptic receptors (Brown et al. 1980). Many studies have failed to demonstrate any statistically significant benefit of yohimbine over placebo in the treatment of erectile failure (Morales et al. 1982, Susset et al. 1989). Otherwise, several placebo-controlled, non-randomized trials have suggested the efficacy of yohimbine (Miller 1968, Sobotka 1969, Sonda et al. 1990). A promising effect of yohimbine on psychogenic impotence was reported by Reid and associates (1987): a 62% response rate versus a 16% rate for placebo. Many studies have supported the original assessment of yohimbine as an erectogenic agent, although the optimal dose remains undetermined (Susset et al. 1989). Yohimbine has no effect on erectility when given intracavernosally (Brindley 1986). The adverse effects of yohimbine hydrochloride include anxiety, nausea, palpitations, fine tremor and elevation of diastolic blood pressure (Morales et al. 1995), but serious adverse reactions are infrequent and reversible (Ernst & Pittler 1998).

In association with testosterone and strychnine, yohimbine contributed to a 80 % improvement or cure rate in a series of 10,000 impotent men reported by Margolis and associates (1971). Clark and co-workers (1985) concluded that testosterone is not required for the enhancement of sexual motivation by yohimbine and supported the suggestion that alpha-2-adrenoceptors are involved in the modulation of sexual arousal. Recent studies have attributed a synergistic effect to a combination of yohimbine and trazodone (Montorsi et al. 1994).

Trazodone is an a antidepressant that has been used empirically for the treatment of erectile dysfunction. In addition to its serotonergic activity, trazodone has also been demonstrated to have alpha-blocking properties. Its activity was initially found incidentally through anecdotal observations of improved libido and the development of priapism in men (Saenz de Tejada et al. 1991) and a woman taking trazodone for its antidepressant properties (Pescatori et al. 1993). The mechanism of trazodone has not been elucidated, but it is recognized that the drug acts centrally by increasing serotonin at the 5-HT1c receptor through reuptake inhibition (Abber et al. 1987). Some studies have reported that trazodone used as a single agent is effective in a about 60% of patients (Abber et al. 1987). Meinhardt and co-workers (1997) concluded recently that in a group of patients not selected on the basis of the etiology of ED, the efficacy of trazodone could not been demonstrated over placebo. When injected intracavernosally to patients with impotence, trazodone causes tumescence, but not full erection (Azadzoi et al. 1990).

Phentolamine, which is an alpha1/alpha-2-receptor antagonist, was suggested to be effective in an initial study by Gwinup (1988). Zorgniotti reported a 42% positive response in men with psychogenic or mild vascular impotence in 1993. In an trial by Becker and associates (1998), the drug was found to be free of major systemic side effects. Phentolamine mesylate is now being examined in large multicenter studies in men with ED, and it will also be examined in women with female sexual dysfunction (FSD) (Goldstein et al. 1998).

Apomorphine is a dopaminergic agonist with direct central D2 receptor agonist activity. It has long been known to induce bouts of yawning and penile erections in animals and humans when administred by subcutaneus injection (Morales et al. 1995). Morales and co-workers (1995) developed a buccal tablet of apomorphine that appears to be effective in many patients with minimal vascular impotence; 67% of patients with psychogenic impotence experienced durable erections with apomorphine. The adverse effects of apomorphine include persistent yawning, nausea, vomiting and hypotension, but recent formulations (a sublingual, sustained-release tablet) minimise these side effects (Heaton et al. 1995).

L-Arginine is a precursor of nitric oxide.The only study reported in the literature is a placebo-controlled trial in which large oral doses of L-arginine (2800 mg) were given daily for a short period (2 weeks). 40% of the patients experienced improvement in their erections (Zorgniotti & Lizza 1994).

Sildenafil is a competetive and selective inhibitor of cGMP type V phosphodiesterase, the predominant isozyme metabolizing cyclic GMP in the corpus cavernosum (Boolell et al. 1996). Normal penile erection depends on the relaxation of smooth muscles in the corpora cavernosa. In response to sexual stimuli, cavernous nerves and endothelial cells release nitric oxide, which stimulates the formation of cyclic guanosine monophosphate (GMP) by guanylate cyclase (Burnett 1995). In a large study of patients with erectile dysfunction of organic, psychogenic or mixed causes, it was found that 69 percent of all attempts at sexual intercourse were successful among men receiving sildenafil as compared to 22 percent of those receiving placebo (Goldstein et al. 1998). Headache, flushing and dyspepsia were the most common adverse effects of sildenafil, occuring in 6 to 18 % of the men (Goldstein et al. 1998).

2.4.5. Topical drug therapy

Nitroglycerin (glyceryl trinitrate), a nitric oxide donor, applied topically to the penis or the perineum has been shown to induce some degree of penile erection (Claes & Baert 1989). Side effects include hypotension and severe headache, which may also be experienced by the partner; this can be avoided by applying the pasta to the perineum.

Papaverine gel applied topically to the penis has been shown to increase penile blood flow (Kim et al. 1995): it appears to augment reflex erections in patients with spinal cord injuries and may be of benefit in this population.

Minoxidil is a vasodilator widely known for its capacity to reverse alopecia androgenetica, and it has also been investigated in the management of erectile dysfunction. In a direct comparison with nitroglycerin, minoxidil was shown to be more effective in producing erectile rigidity (Cavallini 1991). It has further been shown that the addition of capsacain may increase the efficacy of minoxidil (Cavallini 1994).

Topical prostaglandin E1 has also been investigated in the treatment of ED. Kim and McVary (1995) concluded, in a phase I placebo-controlled, non-blinded investigation, that topical prostaglandin E1 appears to be safe and well tolerated after application to the genitals and significantly increases blood flow to the penis.

2.4.6. Transurethral drug therapy

Padma-Nathan and co-workers (1994) reported that intraurethral administration of alprostadil 500 µg elicits marked cavernosal smooth muscle relaxation. Alprostadil pellets measuring 1 x 1 mm are placed 2 to 3cm into the distal urethra after voiding followed by massaging of the distal shaft. Approximately 20% of the medication absorbs into the corpus cavernosum via intercommunicating veins. The remaining 80% of the drug is absorbed into the systemic circulation, although 99% of it is metabolized on the first pass through the lungs (Padma-Nathan et al. 1994).

In 1997, Padma-Nathan and associates reported a double-blind, placebo-controlled multicenter phase II study including 1511 men with chronic erectile dysfunction due to various organic causes. The men were first tested in the clinic with up to four doses of the drug (125, 250, 500 and 1000 µg), and those with sufficient responses were randomly assigned to treatment with either an effective dose of alprostadil or placebo for three months at home. 64.9% of the patients showed responses sufficient to enter the "at home phase" of the study. 62% of the patients who used this system at home had, on at least one occasion, an erection sufficient for intercourse. The most common side effect was mild penile pain, which occured after 10.8% of alprostadil treatments. Hypotension occured in the clinic in 3.3% of men receiving alprostadil. None of them had priapism or penile fibrosis. Porst (1996) concluded in his study that, due to the superior efficacy and fewer side-effects, intracavernosal self-injection therapy with alprostadil remains the gold standard in the management of male impotence.

2.4.7. Intracavernosal therapy

In 1982, Virag reported incidental findings of penile erection induced by an intracavernous injection of papaverine. One year later, Brindley reported the induction of erection with phenoxybenzamine (Brindley 1983a). 1984 Virag and co-workers suggested that intracavernous injection of papaverine could be used diagnostically to differentiate between vasculogenic and nonvasculogenic impotence. Since then, a number of agents have been utilised for diagnostic and treament purposes, most commonly papaverine and phentolamine and later alprostadil (PGE1). Zorgniotti and Lefleur (1985) began teaching patients autoinjection of a mixture of papaverin and phentolamine in home use.These drugs have been administered alone or in a variety of combinations with good results.

2.4.7.1. Papaverine hydrochloride

Papaverine is an opium derivative that increases intracellular cAMP via nonselective inhibition of phosphodiesterases. In this way, papaverine alters the membrane calcium channel function and increases the efflux from cells, resulting in a decline of intracellular calcium levels and subsequent smooth muscle cell relaxation (Wang & Large 1991). Papaverine relaxes all components of the penile erectile system, i.e. the penile arteries, the cavernous sinusoids and the penile veins (Kirkeby et al. 1990). Papaverine is acidic in solution (pH 3 to 4) and may precipitate at pH higher than 5. Papaverine has relatively short plasma life (1-2 h), and it is extensively metabolized in the liver. High concentrations are obtained following intracavernosal injection, and the drug is relatively slow to clear from the corpora (Hakenberg et al. 1990).

Various doses of papaverine have been used in the diagnosis and treatment of ED. At the University of Iowa, from 1986 to 1989, papaverine alone was used for test injections, and 55% of 232 patients achieved satisfactory erectile response at initial doses of 5 to 60 mg (Fallon 1995). Only 35% of 356 patients combined from five studies using papaverine alone achieved full erection (Juneman & Alken 1989). In Virag and associates' follow-up study in 1980-1988, the average doses were 20+12 mg of papaverine for the psychogenic type and 40+25 mg of papaverine for the organic type of erectile dysfunction (Virag et al. 1991).

Because corporal clearance of papaverine is relatively slow, papaverine tends to predispose to priapism (Fouda et al. 1989, Hwang et al. 1991). According to a literature review of agents, papaverine alone produced priapism in 9.5% of 2,134 patients, papaverine-phentolamine in 5.3% of 2,914 patients, and PGE1 in 2.4% of 1,284 patients (Juneman & Alken 1989). A lethal complication of papaverine-induced priapism has also been reported: when papaverine and phentolamine failed to produce adequate erection, the patient injected a second dose, which resulted in priapism and death from massive pulmonary embolism (Hashmat et al. 1991).

Fibrotic nodules were reported in 5.4% of 1,573 patients collected from different series using papaverine monotherapy and papaverine-phentolamine combinations (Juneman & Alken 1989). In a prospective study, Levine and coworkers (1989) reported that the percentange of men with painless nodules almost consistently doubled from one follow-up examination to the next, being 8% at 1 month, 17% at 3 months, 32% at 6 months, and 57% at 12 months. Aboseif and coworkers (1989) studied monkeys which were given 75 intracavernous injections of papaverine over a nine-month period and found significant histologic changes with a loss of normal architecture in both light and electron microscopy.

The solution of papaverine hydrochloride is acidic (pH 3 to 4), and the importance of this for the production of intracavernous fibrosis has been discussed (Seidmon & Samaha 1989). It was suggested that an intracavernosal injection buffered by blood will lead to precipitation of the drug, which may cause primary intracorporeal scarring. After all, rabbit studies have shown that intracorporeal scarring is related to the drug itself rather than the pH or osmolarity of the solution (Stackl et al. 1989). Papaverine is extensively metabolized in the liver and some elevation of liver transaminases may therefore take place, but the hepatotoxicity of papaverine is less well known (Andersson et al. 1991). Prolonged pain after intracavernous papaverine monotherapy or papaverine in combination with phentolamine is rare (Levine et al. 1989).

2.4.7.2. Prostaglandin E1 (alprostadil)

PGE1 is a natural constituent of many mammalian tissues (Piper 1973), and human cavernous tissue generates prostaglandins (Roy et al. 1984). PGE1 is known to have a variety of pharmacological effects: it produces systemic vasodilatation, prevents platelet aggregation and stimulates intestinal activity. Administered systemically, the drug has been used clinically to a limited extent. It has been given to keep the ductus arteriosus patent in congenital heart disorders and also as a treatment of peripheral vascular disease. It is of interest that it has a short duration of action and is extensively metabolized; as much as 80% may be metabolized upon one pass through the lungs, which may partly explain why PGE1 seldom causes circulatory side-effects when injected intracavernosally (Stackl et al. 1988, Andersson et al. 1991).

PGE1 relaxes the isolated penile smooth muscle contracted by noradrenaline and PGF 2-alpha (Hedlund & Andersson 1985). It exerts its effect by activating adenylate cyclase via G-protein cleavage. When administered intracavernosally, PGE1 has a half-life of 5 to 10 minutes (Stackl et al. 1988) and is almost completely metabolized in the corporal tissue.

The published reports on intracavernosal use of PGE1 since 1986 (Ischii et al. 1986, Virag & Adaikan 1987) consist primarily of data derived from uncontrolled retrospective studies with different formulations. PGE1 has been used as monotherapy for erectile dysfunction in doses typically ranging from 1 to 40 ug. Earle and associates (1990) reported that patients with spinal cord injury are very sensitive and may respond to as little 1 or 2 µg. Hwang and co-workers (1989) treated 80 impotent men with a single 20 µg injection of prostaglandin E1, and their overall positive response rate was 79%, while in patients with psychogenic and neurogenic impotence the response rate was 100%. The assumption that intracavernous injections of vasoactive drugs, including PGE1, are most successful in patients with neurogenic, psychogenic and mild arteriogenic impotence was supported by Gerber and Levine's findings in 1991. Men with psychogenic and neurogenic impotence and those with ED following a radical pelvic operation required significantly lower doses of prostaglandin E1 to achieve tumescence. PGE1 was increasingly effective as the doses increased from 2.5 to 20 µg (Schramek & Waldhauser 1989). A dose-response relation was also found in another trial of alprostadil by von Heyden and collegues (1993). Fallon (1995) has concluded several studies of PGE1 with an overall response rate of 71%, but the erectile dysfunction in these studies has been of mixed origin. The most frequently used initial dose was 20 µg. Typically, a latency of about 10 minutes was noted before the onset of erection, and the duration of erection ranged from 30 minutes to 6 hours with an average of about 2 hours. Several studies have confirmed the efficacy of PGE1 to induce erections sufficient for intercourse, and in one meta-analysis PGE1 proved to be the most efficient monotherapeutic intracavernosal drug with an overall success rate of 75% (Juneman & Alken 1989).

Prolonged erection or priapism is seldom seen in PGE1 users. In a literature review of different agents, PGE1 produced priapism in 2.4% of 1,284 patients (Juneman & Alken 1989). Linet and Ogrinc (1996) reported, in their three separate multi-institutional prospective studies, prolonged erection (4 to 6 h) in 5% of men and priapism (> 6 h) in 1 %. Many large studies have reported no priapism at all (Stackl et al. 1988, Ishii et al. 1989, Sarosdy et al. 1989, Gerber & Levine 1991). Gerber and Levine (1991) conclude that, while prolonged erections may still occur with prostaglandin E1, their likelihood is extremely small once the proper PGE1 dose has been determined.

PGE1 monotherapy seems to result in a very low incidence of fibrosis (Ravnik-Oblak et al. 1990, Gerber & Levine 1991, Linet & Ogrinc 1996, Porst 1996). Chen and associates (1996) compared PGE1 users with or without penile scarring and did not find any significant differences between the groups with regard to the duration of follow-up, the injection frequency, the PGE1 dose per injection, the total number of injections or the total PGE1 dose: penile scarring and fibrosis are sporadic and unpredictable. Support for the lack of side-effects in cavernous tissue associated with PGE1 has also been derived from animal studies (Aboseif et al. 1989, Stack et al. 1989, Hwang et al. 1991): Aboseif and collegues (1989) found that monkeys injected with 20 µg of prostaglandin E1 twice weekly until a total of 75 injections was reached showed few pathological changes in cavernous tissue. The changes were similar to those caused with intracavernosally injected saline alone.

Prolonged pain, which is variously described by patients as occurring through the shaft of the penis, in the perineum or both (Fallon 1995) or an aching sensation along the ventral surface of the penis lasting for 30 minutes to 3 hours (Gerber & Levine 1991) after the injection is quite common with PGE1 alone. The incidence of penile pain after the injection of PGE1 has varied in different series from 0 to 91% (Stackl et al. 1988, Hwang et al. 1989, Ishii et al. 1989, Lee et al. 1989, Earle et al. 1990, Schramek et al. 1990, Linet & Ogrinc 1996, Kim et al. 1997). In most cases, however, the pain is mild. Gerber and Levine (1991) did not find any difference in pain incidence based upon the etiology. The etiology of pain has not been fully elucidated. The pain is probably induced by alprostadil itself, because PGE1 can sensitize the peripheral terminals of primary afferent nociceptors and, consequently, produce hyperalgesia (Ferreira 1983, Capetola 1983). Alkalinization of the injected solution from pH 4.17 to 7.05 by the addition of sodium bicarbonate was found to produce significant alleviation of penile pain in a randomized study of patients injected with a mixture containing 10 µg of PGE (Moriel & Rajfer 1993). The addition of procaine has also been experimentally used as a method of reducing PGE1-associated pain (Schramek et al. 1994): a combination of 20 µg of PGE1 with 20 mg of procaine decreased the incidence of local pain significantly. Multidrug combinations including PGE1 have resulted in a lower incidence of pain (Govier et al.U1993, Montorsi et al. 1993).

2.4.7.3. Phentolamine

Phentolamine is a competetive alpha-adrenoceptor antagonist with similar affinity for alpha1- and alpha2-adrenoceptors (Andersson et al. 1991). In addition, the drug may have a direct non-specific, relaxant effect on vessels (Taylor et al. 1965). Its plasma half-life is 30 minutes. Since a single intravenous phentolamine injection does not result in a satisfactory erectile response in most cases, the drug has been used in combination with other agents, primarily papaverine (Zorgniotti & Lefleur 1985, Juneman & Alken 1989).

2.4.7.4. Phenoxybenzamine

Phenoxybenzamine is a potent alpha1- and alpha2-blocker. It also blocks the receptors for acetylcholine, histamine, and 5-HT. The adrenergic blockade is prolonged and the serum half-life is 24 hours, and prolonged effects of phenoxybenzamine may be demonstrable for 3-4 days (Andersson et al. 1991). Systemic side effects are common, including postural hypotension, which may be associated with reflex tachycardia and cardiac arrhythmias. Local pain at the injection site, prolonged erections and cavernous fibrosis may occur, and the agent has also been demonstrated to have carcinogenic effects in rodents (Flind 1984).

2.4.7.5. Vasoactive intestinal peptide (VIP)

VIP is a potent vasodilatator that inhibits contractile activity in many types of smooth muscle and stimulates cardiac contractility and many exocrine secretions (Fahrenkrug 1989). Gu and associates (1984) suggested that VIP not only was the principal neurotransmitter involved in penile erection, but that the depletion of peptide may also play a key role in the development of impotence. In animals works, VIP was later shown to be the most important noncholinergic transmitter involved in penile erection (Juenemann et al. 1987, Aoki et al. 1990). Later, however, the weak intracavernosal erectile response suggested that it cannot be the only noncholinergic mediator for the relaxation of penile erectile tissues (Roy et al. 1990). Combination with phentolamine has resulted in a better erectile response (McMahon 1996).

2.4.7.6. Moxisylyte (thymoxamine)

Thymoxamine has a competetive and relatively selective blocking action on alpha1-adrenoceptors and may also have antihistaminic actions (Andersson 1991). Brindley (1986) showed that moxisylyte produces erection when injected intracavernosally. It has been shown that moxisylyte is less active than papaverine, but its main advantage is its safety (Buvat et al. 1989). Navratil and co-workers (1995) concluded that there was no instances of priapism and no pain was experienced on injection. Moxisylyte is able to induce an erectile response at a minimum dose of 10 mg. Costa and co-workers (1993) found out in their double-blind study that, compared to placebo, intracavernous injection of 10, 20 and 30 mg of moxisylyte is efficient at inducing pharmacological penile erection without any side effects: a majority of the patients had predominantly psychogenic ED (Costa et al. 1993). Buvat and associates (1991) also found out that there is a reduced rate of fibrotic nodules in the cavernous bodies following intracavernous injections of moxisylyte compared to papaverine.

2.4.7.7. Multidrug combinations

The first combination used was papaverine combined with phentolamine, which has been extensively used since 1985 (Zorgniotti & Lefleur 1985). This combination has been more effective, especially for older men, than papaverine alone (Richter et al. 1990). A combination of three drugs, papaverine-phentolamine-PGE1 (Trimix), was introduced in 1991 by Bennet and associates. They concluded that the synergism of agents reduces the amounts of individual drugs needed while improving erectile quality and reducing side effects. A randomized crossover study of 228 patients comparing the efficacy of Trimix with that of PGE1 alone and with a mixture of papaverine and phentolamine also revealed the superiority of Trimix (McMahon 1991). A long-term follow-up also showed a low incidence of priapism (1.7%), pain (3.5%) and scarring (4.2%) (Govier et al. 1993). It has further been shown that the total dose and volume of the injected drugs is reduced when several vasoactive drugs are combined (Bennet et al. 1991, McMahon 1991, Govier et al. 1993, Montorsi et al. 1993, Fallon 1995). Montorsi and co-workers used (1993) a four-drug vasoactive mixture (papaverine hydrochloride, PGE1, phentolamine mesylate, atropine sulphate) for intracavernous injection therapy in 94 patients with vasculogenic impotence with good results, the total response rate being over 90%. A mixture of six vasoactive substances has been described, which is called Ceritine (contains papaverine hydrochloride, ifenprodil tartrate, atropine sulphate, yohimbine, dipyridamole, piribedil), which is equally effective as a three-drug combination (Virag et al. 1991).

2.4.7.8. Miscellaneous agents

Linsidomine, a nitric oxide donor (SIN-1), has been used to treat ED, but it has not been shown to be of significant benefit (Wegner et al. 1994). Calsitonin Gene-Related Peptide (CGRP) is a potent vasodilator, as it has been shown in bladder and penis smooth muscle: a combination of CGRP to alprostadil allowed the use of subthreshold dosage of the latter (Stief et al. 1990).

2.4.7.9. Long-term results and acceptance of intracavernosal therapy

Many reports do not mention the initial acceptance rates, but after a trial injection at the office, some of the responders normally refuse injection treatment because of pain, inconvenience, lack of regular partner, etc. (Cooper 1991). Long-term follow-up has shown that the proportion of drop-outs varies from 11% to over 50 % (Virag et al. 1991, Gerber & Levine 1991, Montorsi et al. 1993, Govier et al. 1993, Valdevenito & Melman 1994): most reports do not have cover periods beyond 2 or 3 years, but those which have longer-term information show the retention rate of patients to be high (Virag et al. 1991). Many reasons for dropping out in the long term have been described: recovery of spontaneous erections, loss of interest, complications, disacceptance of the injection technique, etc. (Fallon 1995). There have been several reports in the literature of transient, partial or complete restoration of spontaneous coital or nocturnal erections in patients using self-injection (Virag et al. 1984, Aravena & Bustamente 1986, Buvat et al. 1987, McMahon 1991). In conclusion, intracavernous injection therapy is often associated with the restoration of spontaneous erections in patients with psychogenic impotence, but is rarely seen in patients with organic impotence.

3. Outlines of present research

Erectile dysfunction, i.e. a persistent inability to achieve and maintain an erection sufficient for satisfactory sexual activity, is known to be a common condition, which increases with age. This study had the following aims: First, we wanted to use the modern investigation modalities (AVSST, questionnaires, VAS, Rigiscan) in the evaluation of ED. Second, we wanted to learn more about erectile dysfunction and sexuality in men (I-V), especially aging men (IV, V), and third, we wanted to obtain more knowledge about specific questions related to the modern conservative treatment options.

The purposes of the present research were:

1. to determine the effectiveness and safety of high-dose yohimbine for the treatment of mixed-type impotence (I).

2. to test the effectiveness and safety of prostaglandin E1 (PGE1), papaverine hydrochloride (PV) and moxisylyte (MS) and to evaluate the suitability of these three agents for intracavernosal injection tests (ICI test) (II).

3. to assess the long-term outcome of PGE1 treatment and the patients` overall satisfaction with their sexual life (III).

4. to evaluate the sexual functions of aging men with benign prostatic hyperplasia (BPH) before and after transurethral resection of the prostate (TURP) (IV).

5. to study the effect and tolerance of transdermal dihydrotestosterone (DHT) in men with andropausal symptoms (V).

4. Patients and methods

Table of Contents

4.1. High-dose yohimbine hydrochloride in the treatment of mixed-type impotence (I)

4.2. Intracavernous injection test in the evaluation of patients with erectile dysfunction (II)

4.3. Intracavernous self-injection of prostaglandin E1 in the treatment of erectile dysfunction (III)

4.4. Effect of transurethral resection of the prostate on sexual functions (IV)

4.5. Effects of transdermal dihydrotestosterone on andropausal symptoms (V)

The present work was carried out at the Department of Surgery, Urological Unit, Oulu University Hospital during the years 1991-1998. More detailed descriptions of the materials and methods have been given in the original papers (I-V).

4.1. High-dose yohimbine hydrochloride in the treatment of mixed-type impotence (I)

The series of patients consisted of 29 men with mixed-type erectile dysfunction. Two patients did not complete the whole treatment schedule. Purely psychogenic or organic causes were excluded including patients having a definite arterial or venous cause for impotence. The mean age of the patients was 51 years, the youngest subject being 25 years old and the oldest 69.

The patients underwent the following tests and examinations before the beginning of the treatment: filling in an anamnestic form, physical examination, blood pressure, pulse rate, weight, laboratory tests (hemoglobin, white and red blood cells, platelets, creatinine, testosterone, prolactin, thyroxine, thyroid-stimulating hormone, prostate-specific antigen, urine analysis), assessment of the sensory pain threshold of the dorsal nerve of the penis, bulbocavernous reflex, prostaglandin E1 injection test, AVSST, visual analogue scale (VAS, a 0- to 100-point scale), assessments of libido, rigidity of the penis, failure of erection, duration of erection, and sensation of orgasm. Duplex Doppler ultrasonography was performed on all patients.

The treatment consisted of two 25-day therapy with a 14-day washout period between courses. Patients therapy was started randomly with yohimbine hydrochloride (36 mg per day orally) or placebo and swithced over to other test medication.

The patients came for a control visit three times: the first took place at the end of the first part of the trial (25 days), the second at the end of the washout period (39 days) and the third at the end of the second part (64 days). The following examinations were made on each occasion: blood pressure, pulse rate and weight, testosterone, assessment of side effects, VAS scales, and AVSST. Penile tumescence and rigidity were tested with a portable monitor (Rigiscan) during the AVSST.

The Mann-Whitney test was used to compare the data of the groups.

4.2. Intracavernous injection test in the evaluation of patients with erectile dysfunction (II)

The study population consisted of 30 consecutive patients with ED at a mean age of 55 years (range 22-71 years). The patients had been referred to our outpatient clinic in the university hospital by primary care physicians. All patients were suspected to have organic erectile dysfunction. Each patient filled in our own questionnaire on sexual disorders. Apart from a clinical examination and hormonal laboratory tests (total testosterone and prolactin), the patient underwent an ICI test with each of the agents: (papaverine hydrochloride (PV), prostaglandin E1(PGE1), moxisylyte (MS) and saline solution (NaCl)) during different visits. Each patient made five visits. Altogether 120 ICI tests were administered.

The order of the ICI test agents was randomized for each patient. A Rigiscan device was used to measure the tumescence and rigidity of cavernous tissue for 15 minutes after each injection. Pulse rate and blood pressure were recorded before the injection and at 5 and 15 minutes afterwards. The degree of erection was estimated clinically (grades 0-5) by the doctor. Grade 0 was no response after the injection, grade 1 was minimal tumescence and no rigidity, grade 2 was moderate tumescence and no rigidity, grade 3 was full tumescence and no rigidity, grade 4 was moderate rigidity, but the penis could be bent, and grade 5 was full rigidity. The grades 4 and 5 are sufficient for penetration. In addition, after each ICI test, the patient evaluated his own satisfaction with the erection and the amount of pain on a visual analogue scale (VAS a 0- to 100-point scale). If the erection persisted for more than two hours, it was released by giving the patient an intracavernous dose of 5 mg of etilephrine before discharge. The ICI tests doses for different test agents were physiological saline 1 ml, papaverine hydrochloride 40 mg (1ml), prostaglandin E1 20 µg (1ml) and moxisylyte 20 mg (1ml). The amounts of PV, PGE1 and MS administered are commonly used in the treatment of impotence.

A statistical comparison of the treatment and control groups in terms of the response to treatment was carried out using the Mann-Whitney U-test.

4.3. Intracavernous self-injection of prostaglandin E1 in the treatment of erectile dysfunction (III)

The primary study population consisted of 95 patients with ED who had been started on intracavernosal PGE1 medication in the Oulu University Hospital at least three years previously. The patients were invited to a control visit after three years. 26 patients did not come, and the final study population hence consisted of 69 patients. The mean age of the patients was 60.5 years (range 44-83 years). All patients had erectile dysfunction: 30 had mainly a vasculogenic etiology, 31 had mainly a psychogenic etiology, and 8 had mainly a neurogenic etiology. The primary examinations consisted of a thorough sexual history with a questionnaire, physical examination, laboratory tests (hemoglobin, white cells, serum creatinine, serum glucose, serum cholesterol, serum total testosterone). Each patient underwent an intracavernous injection test (ICI) with PGE1 (20 µg) and duplex Doppler ultrasonography of the penile vessels.

Before the control visit, all patients filled in a follow-up questionnaire at home, and the responses were checked when the patient came for the control visit. The questionnaire included several items pertaining to various aspects of sexual function at home and possible problems with PGE1 self-injection. Each patient also evaluated his own satisfaction with erection with or without intracavernosal injection as well as his ejaculation, orgasm and libido on a Visual analogue scale (VAS a 0- to 100-point scale). A clinical examination was made, and the penile shaft was examined by ultrasonography (5MHz, Bruel & Kjaer). Apart from the clinical examination, the patients underwent an ICI test with their home dose of PGE1. The tumescence and rigidity of erection were determined with a portable monitor (Rigiscan). The degree of erection was also estimated clinically (grades 0-5) in the same way as in study II. The erection induced in the examination room was compared to the erection attained at home by the patient.

4.4. Effect of transurethral resection of the prostate on sexual functions (IV)

The primary study population consisted of 212 consecutive patients with BPH referred for elective electroresection of the prostate. 57 patients were not included in the analysis because of a lack of data. The mean age of the patients was 69 years (range 49-86). The mean prostatic volume determined by transrectal sonography (Bruel & Kjaer) before TURP was 50.4 cm3 (range 14.0-107.0 cm3). The mean weight of the prostate chips resected in TURP was 27.4 g (range 3-96 g). Incidental malignancies were diagnosed from the chips in only three of the 155 patients (2%).

On the day before TURP, each patient filled in a questionnaire related to this study in our hospital. The questionnaire consisted of 22 items pertaining to various aspects of sexual function, including the patients` life styles and general health, libido, satisfaction with their current sex life, occurrence of early morning erections, coital frequency, sexual potency, satisfaction with erection and ejaculation, percentage of successful intercourses, and the possible detrimental effect of the procedure on potency. When necessary, the staff helped the patient to fill in the questionnaire. The patients completed the same questionnaire 6 and 12 months after TURP.

The Prat test was used to compare the different sexual functions before and after TURP.

4.5. Effects of transdermal dihydrotestosterone on andropausal symptoms (V)

A total of 123 males aged 50 to 70 years (mean age 58) participated in this mono-center, double-blind, randomized, placebo-controlled, parallel group study. The subjects were randomized into a DHT (61) and a placebo (62) group.

The patients included were to have had rarefaction of nocturnal penile tumescence (< 1 time/week) and at least one of the following symptoms of andropause: astenia, depressive mood, erectile dysfunction, decreased libido and urinary disorders. In addition, the subjects were to have total serum testosterone < 15nmol/l and/or SHBG over 30nmol/l.

The patients were excluded from the study if they had neurogenic impotence, major depression, significant psychiatric pathology, suspected prostatic pathology (PSA over 10 ng/ml), prostatectomy, known diabetes, other known endocrinological pathology, polyglobulia (Hb over 170 g/l and/or hematocrit over 50%), clinically significant hepatic dysfunction, renal dysfunction, lipid profile out of the normal age-adjusted range, coronary heart disease, incompensated heart failure, unstable hypertension, thromboembolic disease, alcohol or narcotics abuse. Other reasons for exclusion were androgenic or other hormonal therapy or therapy with inhibitors of 5-alpha-reductase, anticoagulants or platelet antiaggregants. Significant obesity (BMI > 30) was also an exclusion criteria.

The patients were treated for 6 months with DHT or placebo, and the drug was applied transdermally to the shoulders once a day. The doses of DHT varied within 125-250mg daily; for all patients with a DHT level < 5.8 nmol/l the daily dose was 250 mg of gel, for patients with a DHT level between 5.8 and 11.6 nmol/l the daily dose was 187.5 mg of gel, and for patients with a DHT level > 11.6 nmol/l the daily dose of 125 mg was maintained. The gel was applied to both forearms, arms and shoulders.

The study findings were evaluated with the Quality of Life questionnaire, which also includes sexual questions, with the International Prostate Symptoms Score (I-PSS), with transrectal ultrasonography (TRUS) and with laboratory tests (PSA, total testosterone, SHBG, FSH, LH, hemoglobin, hematocrit, platelets, liver function tests, creatinine, cholesterol, triglycerides). The patients came for a control visit at one, three and six months after the randomization.

All the parameters were analyzed using the ANOVA test for the main efficacy criteria analysis and Student's t-test for the analysis of quantitives variables.

5. Results

Table of Contents

5.1. High-dose yohimbine hydrochloride in the treatment of mixed-type impotence (I)

5.2. Intracavernous injection test in the evaluation of patients with erectile dysfunction (II)

5.3. Intracavernous self-injection of prostaglandin E1 in the treatment of erectile dysfunction (III)

5.4. Effect of transurethral resection of the prostate on sexual functions (IV)

5.5. Effects of transdermal dihydrotestosterone on andropausal symptoms (V)

A summary of the results is presented here. More detailed results have been given in the appropriate papers (I-V).

5.1. High-dose yohimbine hydrochloride in the treatment of mixed-type impotence (I)

The average weight, pulse rate, and systolic and diastolic blood pressure of the patients during each treatment did not differ statistically significantly between the two groups.The patients` subjective assessments of libido, rigidity of the penis, duration of erection, and sensation of orgasm on the VAS scale (0 to 100) are shown in Table 5-1.

Table 5-1. The patients` subjective visual analogue scale (0-100) assessments of libido, rigidity of the penis, duration of erection, and sensation of orgasm before and during placebo and yohimbine treatments¤ Period Libido Rigidity of penis Duration of erection Orgasm Before treatments 74 (0-100) 49 (0-100) 60 (0-100) 79 (0-100) During placebo treatment 72 (14-100) 58 (0-99) 40 (0-91) 79 (0-99) During yohimbine treatment 75 (27-98) 59 (0-96) 47 (2-100) 82 (17-100) ¤ The results are given as arithmetic means and ranges. Orgasm was achieved slightly more frequently in the yohimbine group, but the difference was not significant. The results of the audiovisual sexual stimulation test with Rigiscan device measurements of rigidity and tumescence showed that rigidity at the base of the penis was slightly, but not significantly, better in the yohimbine group. On the whole, none of the parameters revealed a statistical significance between the control group and the yohimbine group. Only 3 of the 27 (11%) patients on yohimbine hydrochloride and 2 of the 27 (7%) on placebo reported having received adequate help for their impotence. 33% of the patients in the yohimbine group and 41% in the placebo group reported some help, while 56% in the yohimbine group and 52% of those on placebo felt no effect at all.

High-dose yohimbine hydrochloride (36 mg/day) was tolerated moderately well, but there were two serious side effects, one hypertensive crisis and one severe palpitation. Both patients discontinued the trial after the episode.

5.2. Intracavernous injection test in the evaluation of patients with erectile dysfunction (II)

There was no difference in the amount of tumescence between the three vasoactive agents. Measured with the Rigiscan device, PGE1 produced significantly (p < 0.05-0.01) better rigidity both at the base and at the tip of the penis than papaverine hydrochloride or moxisylyte. 15 minutes after the ICI, the physician estimated the grade of erection. The results are presented in Table 5-2. As it can be seen, PGE1 produced much better erections even when estimated clinically.

Table 5-2. Grade 3-5 erection and the duration of erection (grades 4-5) achieved with physiological saline (NaCl), papaverine hydrochloride (PV), prostaglandin E1 (PGE1) and moxisylyte (MS) at 15 minutes after the injection. The results are expressed as arithmetic means. Injected agent Patients with grade 3-5 erection (no.) Duration of erection (min) NaCl 0% 0 PV 37% (11) 13.4 PGE1 77% (23) 40.2 MS 27% (8) 6.5 The patients` satisfaction with the erection in the ICI test was measured with VAS: overall, it was quite low, being mean 33% (range 0-86 %) in the PGE1 group and 18% (0-98%) in the PV, 12% (0-96%) in the MS and 3% (0-15%) in the NaCl groups, respectively. VAS was also used to identify the amount of pain just after the injection and when the erection began. The pain score was 22% ( 0-76%) for PGE1, 22% (0-100%) for PV, 13% (0-50%) for MS and 5% (0-38%) for NaCl. There were no statistically significant changes in the pulse rate and blood pressure values 5 and 15 minutes after the injection in correlation to preinjection values. The erection lasted for two hours in three patients given PGE1, two patients given PV and one patient given MS, and all of those was given etilephrine (5 mg) which ceased the erections effectively.

After the ICI tests with every study medicine, the patients were presented the treatment options. Nine patients (30%) started intracavernosal treatment: seven patients selected PGE1, one PV and one MS according to their preference in blind testing. In addition, nine patients (30%) wished primarily to try oral medication before the use of intracavernosal injection. Twelve patients (40%) underwent further investigations.

5.3. Intracavernous self-injection of prostaglandin E1 in the treatment of erectile dysfunction (III)

The mean home dose of PGE1 was 17.5 µg (4-40 µg). The most common dose of PGE1 was between 10-15 µg (33%). 25% of the patients used 15-20 µg, 20% 5-10 µg, 16% 20-30 µg, 3% under 5 µg and 3% over 30 µg. 13% of the patients had changed the home dose of PGE1 after they had first been precsribed it three years ago. Nearly half (46.4%) of the patients had discontinued PGE1 therapy. Most of the patients (84.1%) had found it easy to learn the injection technique, and the rest (15.9%) had only had difficulties in the beginning. The mean time of using PGE1 was 23.3 months (0-48). The mean coital frequency with ICI therapy was 2.8 times per month (0-8). Erection began after the injection within 9.4 minutes (2-20), and the duration of erection at home was 58.7 minutes (0-240). The injections failed to produce a sufficient erection in 2% of the patients after at least ten attempts. 34.8% of the patients reported that their own erections improved after the introduction of ICI therapy: most of the patients who reported improvement of their own erections had a psychogenic etiology (54.2%), while 37.5% had a vasculogenic dysfunction and 8.3% a neurogenic etiology.

Table 5-3 shows the reasons for the discontinuation of therapy, loss of efficacy and spontaneous erections being prominent. The dropout rate was highest among the patients with vasculogenic dysfunction (56.3%) compared to the other etiologies.

Table 5-3. Reasons for dropping out among 69 patients who began intracavernosal home therapy with PGE1. Reasons for dropping out Number Loss of efficacy 9 (13%) ICI therapy too expensive 2 (2.9%) Illness of wife 2 (2.9%) Wife disapproved of treatment 2 (2.9%) Spontaneous erections 8 (11.6%) Did not get a new prescription 2 (2.9%) Fibrosis in the penile shaft 3 (4.3%) Pain after injection 4 (5.8%) Total 32 (46.4%) All the complications within the use of PGE1 were slight, and the most common problem was hematomas, which occurred in 10.1% of the patients, but were small and did not cause discontinuation of the therapy. Three instances of priapism (4.3%) occurred at the beginning of the therapy, but after an adjustment of the amount of PGE1, there were no further problems. 7.2% of the patients reported some kind of pain immediately after the injection, which did not, however, cause discontinuation of therapy. Four patients (5.8%) had fibrosis in the penile shaft at the control visit, which was also detected by ultrasound, the mean size being 1.75 cm (1-2cm).

The mean value of libido estimated on a VAS scale at the time of the control checkup was 65.3% (5-97). The patients` satisfaction with their erections at home without injections was only 23.5%, but PGE1 therapy increased it up to 67.3%.

The ICI test was done with the home dose of PGE1, and erection was determined with the Rigiscan device. The mean maximal rigidity at the tip and the base of the penis was 56.6% and 53.3%. The degree of erection was estimated as in study II by the doctor, and there was grade 3-5 erection in 85.9% of the cases. About half of the patients estimated their erection at the control visit worsen than in a "real situation" at home, while 40.4% said their erection was the same as at home. Only 7% considered their erection better at the office than at home.

5.4. Effect of transurethral resection of the prostate on sexual functions (IV)

In this study population, only 7% of the 155 patients had been treated by pharmacotherapy for impotence before TURP. 60% of the patients reported good libido before TURP, while 59% did so at 6 months and 54 % at 12 months. Before TURP, 56% of the patients reported failure of intercouse on half or more than half of occasions, while after the procedure the corresponding percentages were 51% at 6 months and 43% at 12 months. The patients estimated their erections, and 26% of the patients had completely satisfactory erections before TURP, while 11% had no erections at all before the procedure. After the operation, 22% of the patients had completely satisfactory erections at 6 months and 24% at 12 months. No erection was reported by 13% of the patients at 6 months and 16% at 12 months. Orgasm was experienced during intercourse on half or more than half of the occasions by 76% of the patients before the procedure, and by 70% at 6 months and 74% at 12 months. 12% of the patients did not have ejaculation before TURP, and 84% of the patients did not have it after the operation. Early morning erections were reported by 53% of the patients before the procedure, and 83% at 6 months and 72% at 12 months, the difference before and after TURP was significant (p < 0.01).

A majority of the patients, i.e. 68%, were satisfied with their sex life before TURP despite of the fact they had some ED. Satisfaction did not change notably after the procedure, being 67% after 12 months. There were no diffrences in coital frequency before and after the procedure, and 32% of the patients reported not having had intercourse during the previous year (Figure 5-1)

Figure 5-1. Coital frequency in the study group before and after TURP.

5.5. Effects of transdermal dihydrotestosterone on andropausal symptoms (V)

The most common amount of DHT gel used was 187.5mg (44.3% of patients), followed by 250 mg (31.1%) and 125mg (24.6%). Early morning erections improved significantly in DHT group at three months (p < 0.05) and correspondenly the ability to maintain erections improved significantly at six months (p < 0.05). DHT also had a positive effect on libido, which improved in 26.5% of the subjects receiving DHT compared to 8.5% in the placebo group (p < 0,02). There were no differences in positive well-being or vitality in either treatment group.

Among the patients who had high I-PSS-scores initially (over 12 points), the I-PSS score decreased from 17.7 to 12.3 points. Prostatic volume did not change in the DHT group. PSA did not change in either group.There were no major adverse events; three patients (5.6%) had mild headache during the DHT treatment. As regards adverse events, one subject with acute pyelonephritis in the DHT group, and two subjects suffering from worsened angina pectoris plus one subject with skin cancer in the placebo group dropped out: these adverse events were not considered to be related to the treatment. The active medication group showed a significant reduction in serum estradiol, serum testosterone and S-SHBG (p < 0.005). There were no changes in the serum cholesterol and HDL values, but triglycerides were higher in both groups at the end of the study. Hemoglobin (Figure 5-2) and hematocrit increased significantly in the DHT group. Liver function tests did not change in either group.

Figure 5-2. Effect of DHT on the hemoglobin level during the treatment.

6. Discussion

Table of Contents

6.1. General

6.2. High-dose yohimbine hydrochloride in the treatment of mixed-type impotence(I)

6.3. Intracavernous injection test in the evaluation of patients with erectile dysfunction (II)

6.4. Intracavernous self-injection of prostaglandin E1 in the treatment of erectile dysfunction (III)

6.5. Effect of transurethral resection of prostate on sexual functions (IV)

6.6. Effects of transdermal dihydrotestosterone on andropausal symptoms (V)

6.1. General

For the evaluation of erectile dysfunction, there are several modalities available, but all of them suffer from certain weaknesses: the results of objective measurements (ICI test, Rigiscan device, duplex Doppler -ultrasound, etc.) vary from time to time, and the investigator must know that a natural relaxing atmosphere gives the most appropriate values (Buvat et al. 1986). You can get "the right values" only in a real situation with your partner at home. In large series of patients evaluating the efficacy of ED therapy, the most practical method to have answers is a questionnaire, which allows the patients to make their own estimations about their sexual functions (Andersen & Broffitt 1988). Multidimensional scales have been said to be better in the evaluation of treatment efficacy than monodimensional scales (Stewart & Ware 1992). We used both multidimensional questionnaires and VAS scales. When internationally standardized questionnaires are used, the investigators can compare the results of different studies.

When treating aging men, we should first take a careful sexual history, for which purpose questionnaires are helpful, and also notice symptoms other than ED and try to conclude which is the main problem and which symptom is the target for treatment; men older than 50 may also have other symptoms of andropause than ED, e.g. decrease of libido and well-being or depressive mood (IV,V).

The first-line treatment of ED always includes testing of the medicine at home, and before the treatment the patient should have all the available information about the medicine, including how it should be taken and how it works. Before the ICI -program, precise determination of the home dose of PGE1 and counselling concerning the technique are important (I,II,III). At the beginning of androgen therapy, it is necessary to inform the patient that androgens affect mainly libido and well-being (V). Furthermore, it is useful to arrange follow-up to assess the effectiveness of the treatment and, when necessary, change the medication or give more advice concerning the administration of the medicine. Especially when having androgen treatment, one should consider the efficacy of the treatment, because unnecessary treatment should be avoided (V,Vermeulen 1993).

Before surgical procedures, which may have negative consequences on sexual functions, e.g. TURP, the patient must have appropriate information about it: unnecessary fear about a total loss of erection may lead to ED (IV). At the time of the first postoperative control checkup, it would therefore be wise to ask about the patient's sexual functions and give him a possibility for treatment.

During treatment for ED, we should always bear in mind the possibility of side-effects, as there is no totally safe treatment option available (I,II,III,V). Especially in old men with severe heart disease and other concurrent problems, it is not feasible to introduce new treatment modalities for ED and predispose the patient to extreme physical distress.

6.2. High-dose yohimbine hydrochloride in the treatment of mixed-type impotence(I)

Yohimbine has been known for over 100 years: it increases parasympathomimetic or cholinergic activity and reduces sympathetic or adrenergic activity (Murburg et al. 1991). Yohimbine hydrochloride produces a rise in sympathetic drive by increasing noradrenaline release and, theoretically, by blocking the alpha-2-adrenergic receptors and increasing the blood supply to cavernous body tissues (Grunhaus et al. 1989, Murburg et al. 1991). Because erection is dependent on cholinergic activity, yohimbine has long been used to treat impotence. The response rates have varied a lot from no effect to a statistically significant benefit compared to placebo (Reid et al. 1987, Susset et al. 1989, Sonda et al. 1990, Morales et al. 1995). Studies have shown yohimbine to be an erectogenic agent, but the optimal dose remains undetermined (Susset et al. 1989). In cases of impotence, there has not been good assessment of high-dose yohimbine in a complete crossover design using modern treatment modalities with placebo.

Our study showed high-dose yohimbine hydrochloride to have no effect on mixed-type impotence contrary to many other studies (Reid et al. 1987, Susset et al. 1989, Deamer & Thompson 1991, Nessel 1994). Montorsi and co-workers (1994) have noticed in their study that combination treatment with trazodone is clearly better than placebo alone for the treatment of psychogenic impotence (Montorsi et al. 1994).

Reported side-effects have been minimal (Morales et al. 1995). However, two patients in this study had serious side-effects that necessitated an interruption of the trial, one had a hypertensive crisis and the other severe palpitation. Yohimbine may elevate blood pressure and pulse rate by increasing serum noradrenalin (Murburg et al. 1991). High dose treatment with yohimbine hydrochoride should be accepted critically.

Over half of the patients had no effect on sexual function either with placebo or with active medication. Positive clinical results (complete and partial responses) were obtained in 12 cases (44%) at the end of yohimbine phase and 13 (48%) after placebo period. In our study concerning ED, the response rates in the placebo group were high compared to many other studies (Reis et al. 1987, Goldstein et al. 1998).

In this study, yohimbine appeared to be no better than placebo as a first-line treatment for mixed-type impotence.

6.3. Intracavernous injection test in the evaluation of patients with erectile dysfunction (II)

After the finding that penile erection can be induced by intracavernous injection of papaverine in 1982, examinations of various intracavernosal medications were started. Since then, a number of agents have been utilized for both diagnostic and treatment purposes. One year later, Brindley reported the induction of erection with phenoxybentzamine and phentolamine (Brindley 1983a, Brindley 1983b).

In the course of developing treatments for erectile impotence and priapism in 1986, Brindley made, using himself as an object, observations on the actions of a number of other drugs given intracavernosally, including imipramine, verpamil, naftidrofuryl, salbutamol, hydralatzine, lignocaine, bupivacaine, neostigmine, atropine propranolol and idazoxan. He ended up suggesting the use of thymoxamine, phentolamine, verpamile and guanethidine (Brindley 1986). Later in 1988, especially in France, a thymoxamine called moxisylyte was introduced into clinical use. In the same year, the first reports about prostaglandin E1 in intracavernosal use were published (Ischii et al. 1986).

The most widely used agents for ED injected alone are papaverine hydrochloride (PV), prostaglandin E1 (PGE1) and moxisylyte (MS). PGE1 has been claimed to cause occasionally painful erections (Stack et al. 1990), while papaverine has been found to cause prolonged erection, priapism and fibrosis (Levine et al. 1989, Lakin et al. 1989), and moxisylyte has been criticized for its poor effectiveness (Buvat et al. 1989).

We noticed in our study that PGE1 was the most effective of these three vasoactive agents both objectively (Rigiscan measurement) and subjectively (VAS questionnaire). Induced tumescence was about the same in all the three groups. Pain was evaluated to be more intense by the PGE1 and PV users (22 % on a VAS scale in both groups). There were no serious side-effects in the tests, and the pulse rates and blood pressure values were low. The present findings strongly suggest that PGE1 is the most effective drug in the ICI test.

6.4. Intracavernous self-injection of prostaglandin E1 in the treatment of erectile dysfunction (III)

One of the most significant improvements in the treatment of erectile dysfunction took place in 1982, when intracavernosal injection therapy was introduced (Andersson et al. 1991). Most of the impotent patients (70-90%) can be treated by intracavernosal agents (Stackl et al. 1988, Schramek et al. 1989, Ravnik-Oblak et al. 1990). The most common vasoactive agent nowadays is PGE1 (Gerber 1991). Its effectiveness and safety have been proved in several studies (Stackl et al. 1988, Ravnik-Oblat et al. 1990, Hwang et al. 1991). Prolonged pain immediately after the injection has been described with PGE1 (Ravnik-Oblak et al. 1990). There are very few local complications, such as indurations and fibrosis, during long-term use.

The patients were followed up for three years after starting the ICI program. The mean coital frequency with ICI therapy was quite low, 2.8 times per month. Most of the patients did not have problems with giving injection themselves even in the beginning (84.1%). The mean dose of PGE1 used at home was 17.5 micrograms. The most frequently used dose of PGE1 is 20 µg (Stackl et al. 1988, Hwang et al. 1989, Ravnik-Oblak et al. 1990). Erection began within a normal time (9.4 minutes), and its duration was about one hour, which is less than reported previously (Stackl et al. 1988, Ravnik-Oblak et al. 1990, Hwang et al. 1991).

Almost all attemps at intercourse succeeded with PGE1 at home. When measured with Rigiscan at the office, the home dose of PGE1 showed the erection to be fairly good (mean maximal rigidity 53.3% at the base and 56.6% at the tip of the penis). When the patients themselves evaluated the rigidity of the penis in the ICI test situation compared to that at home, the majority did not have equally good erection at the office (52.6%) as at home. This can be explained by sympathoconia or adrenergic constrictor tone due to anxiety (Buvat et al. 1986).

There were no systemic side-effects with PGE1. 7.2% of patients had prolonged pain after the injection, leading to discontinuation by 5.8% of the patients. This is less than in most of other studies where PGE1 has been used alone. When PGE1 is used in combination with other drugs, the incidence of pain could be less (Stackl et al. 1988, Gerber & Levine 1991, Schramek et al. 1994). Priapism occurred in only 3 cases at the beginning of the treatment, but after finding the right dose, no more problems occurred. Priapism used to be a relatively common complication in papaverine users, but after the introduction of PGE1 treatment it has been become rare (Fouda et al. 1989, Hasmat et al. 1991).

Fibrosis was seen in 5.8% of the patients using PGE1 for three years. It led to discontinuation of the drug in 4.3% of the cases. The fibrosis or nodules were small, their mean size being less than 2 cm. In the literature, papaverine users have been reported to have penile scarring and fibrosis more often than PGE1 users (Chen et al. 1994, Hwang et al. 1991).

Many studies have reported improvement of spontaneous erections in men using intracavernous injections (Gerber & Levine 1991, Virag et al. 1991, McMahon 1992, Sharlip 1997). In our study, 34.8% of the patients reported improvement of their own erections after PGE1 therapy. 11.6% of the patients discontinued the ICI therapy for this reason and majority of those patients had a psychogenic etiology. High amount of psychogenic etiology may be one reason for the high dropout percentage up to 49% in some studies (Sister 1990, Gerber & Levine 1991, Govier et al. 1993, Fallon 1995).

The main reasons why many patients do not continue their PGE1 therapy in the long run include the fact that their own erections improve or that there are changes in their life situation. At the baseline, precise determination of the home dose of PGE1 and instruction with the technique are important for treatment acceptance.

6.5. Effect of transurethral resection of prostate on sexual functions (IV)

Transurethral resection of the prostate (TURP) continues to be the commonest and most effective method of treating benign prostatic hyperplasia (BPH) despite the new treatments available. It may, however, have some adverse effects, most commonly disturbances of sexual function, which have been reported to occur in 4-40% of the patients undergoing this procedure (Bolt et al. 1986, Libman & Fichten 1987, Mebust et al. 1989). Our interest was to examine prospectively the effect of TURP on sexual functions. At the same time, we would have a good sample of aging men with BPH to ask about their lifestyles, libido, satisfaction with their current sex life, erection and coital frequency.

Erection is a complex phenomenon that involves neurological, hormonal, arterial, venous and muscular components and is further influenced by psychogenic, cognitive and environmental factors (Lue & Tanagho 1987, Bush et al. 1992). TURP can have an effect on these components, causing erectile dysfunction: ED can be brought about via several different routes, including the psychogenic effect of an invasive procedure in the genital region, injury of the nerve tracts supplying the corpus cavernosum as a result of electrocoagulation, thrombosis of the arteria cavernosa, venous leakage, and injury of nerve tracts resulting from urethral dilatation and uretrotomy before TURP (Walsh & Donker 1982, Handbury & Sethia 1995, Padma-Nathan & Goldstein 1998).

Our patients were rather old, with a mean age of 69 years, and the resected tissue in TURP was quite extensive: TURP did not cause overall changes in the patients' libido, erection, orgasm and sex life in our study. Early morning erections even improved after the operation. No such result has been reported previously. Also the amount of reported failures of intercouse reduced after TURP. This may be explained by that fact that the patients already had some ED before the operation, and they were fairly satisfied with their sex life as a whole both before and after the operation, although one third of them had not had coitus for a year. On the other hand, this may be explained by the fact that after TURP voiding problems diminished and overall condition was better. These results could also be explained by the fact that detailed information was given to the patient on the nature of TURP as well as on the possible risks related to it and their probability, and the study was prospective and the patients` memories did not hence influence the results.

6.6. Effects of transdermal dihydrotestosterone on andropausal symptoms (V)

Serum testosterone is said to decline in aging men, but this process is slow and the clincal picture is therefore difficult to recognize (Gray et al. 1991). This situation has been called "andropause", "male climacterium", "male menopause", "mid-age crisis" or "androgen decline in the aging male (ADAM)".

Androgens stimulate the production of erythropoietin in the kidneys, increasing hemoglobin concentrations (Bagatell et al. 1994) and hematocrit (Tenover 1992). Because older men tend to have slightly lower hematocrits than young adult men, the hematopoietic effects of androgens may only rarely lead to problems with polycythemia (Tenover 1992). In our study, both hemoglobin and hematocrit increased significantly during DHT treatment, however staying in normal value range in all patients. Despite this, in patients using DHT, Hb should be controlled after 3-6 months of treatment.

The administration of androgens decreases plasma HDL cholesterol in adolecent boys with delayed puberty and in men with hypogonadism (Sorva et al. 1988).Treatment with parenteral administration of normal doses of either T or DHT to healthy aged men induce limited changes in circulating lipids with tendency to lower total levels ofThe significance of this finding is that low HDL and high LDL-to-HDL ratios are associated with increased risk for coronary heart disease (Swerdloff & Wang 1993). On the other hand, some authors have reported a favourable effect on HDL cholesterol after moderate doses of natural testosterone (Marin et al. 1992). It has also been concluded that low circulating testosterone levels might be associated with hypercoagulability and could therefore contribute to an increased risk of ischemic heart disease (Bonithon-Kopp et al. 1988). In our study, there were no changes in cholesterol and HDL values in either group, but, for some unknown reason, both the DHT and the placebo groups had an increase in the triglyceride values.

Huge doses of parenteral administration of testosterone may reduce insulin sensitivity (Cohen & Hickman 1987), but normal doses improve insulin sensitivity in middle-aged abdominally obese men (Marin et al. 1992). In our study, there was no changes in plasma glucose level during the medication.

Percutaneus testosterone and DHT have been shown to be equally effective in the treatment of hypogonadal men (Kuhn et al. 1986). Testosterone increases plasma estradiol levels, which DHT does not do, though it has been shown to reduce the estradiol levels (Fiet et al. 1982). In our study, there was a significant reduction in the estradiol and also in serum testosterone and S-SHBG levels.

There were no changes in the liver function tests in either group in this study. Alkylated androgens administered at high doses in long-term use may cause liver dysfunction (Gurakal et al. 1994).

It has been earlier noticed that testosterone administered to elderly men involves the risk of stimulating the growth of sublinical prostatic carcinoma (Vermeulen 1993). Furthermore, it has been recognized in some studies that physiological testosterone enanthate supplementation results in sustained stimulation of PSA (Tenover 1992, Hajjar et al. 1997). Holmäng and associates (1993) reported that testosterone increased the mean prostatic volume in a study where 160 mg/day testosterone undecanoate was used for 8 months. Many other studies have failed to reveal any change in prostatic volume during the treatment (Cooper et al. 1998). It has therefore been recommended that aging should be screened carefully and followed periodically throughout testosterone therapy (Tenover 1992).

It has been noticed that the administration of estradiol both stimulates prostatic growth (Suzuki et al. 1994) and increases the incidence of prostatic carcinoma in rats (Shirai et al. 1994). Rats treated with DHT plus estradiol did not develop tumors (Shirai et al. 1994). In a 1.8-year open survey of 37 men aged 55-70 years treated with daily percutaneus DHT treatment, high plasma levels of DHT (> 8.5 nmol/l) effectively induced clinical benefits in andropausal symptoms, while slighly but significantly reducing prostatic size (de Lignieres 1993). It has been concluded in many studies that estrogens play an important role in the pathogenesis of BPH. Estradiol but not DHT acts in concert with SHBG to produce an 8-fold increase in intracellular cAMP in human BPH tissue, causing growth of the prostate, while DHT, which blocks the binding of estradiol to SHBG, completely negates the effect of estradiol (Nakhla et al. 1994). In our study, the size of the prostate remained the same and serum PSA did not increase, and there was also some relief in the obstructive symptoms in BPH patients with high symptom scores (I-PSS) before the study.

Androgens are expected to have some positive effects on the central nervous system and a stimulating effect on sexual function in men (Burris et al. 1992, Bagatell et al. 1994). There was no clear positive effect on well-being and vitality, which may be because the patients mostly expected the drug to have an effect on their sexual function.

In our study, morning erections improved and libido was better in the DHT group, and the maintenance of erections during the intercourse was also better in the actively medicated group. We found DHT to be a safe option for long-term treatment of andropausal symptoms, it may also have a positive effect on urinating problems.

7. Conclusions

1. This study could not show any benefit from high-dose yohimbine hydrochloride in correlation with placebo in the treatment of mixed type ED. The medication was moderately well tolerated, but two serious side-effects were reported (a hypertensive crisis and a severe palpitation) leading to discontinuation of medication.

2. PGE1 was shown to be the most effective of the three agents (papaverine hydrochloride(PV),prostaglandin E1 (PGE1) and moxisylyte (MS)), both subjectively and objectively. There were no differences in the amount of tumescence produced by these drugs. PGE1 and PV caused more pain than MS, but not significantly. All the vasoactive drugs were well tolerated. When using pharmacotest to evaluate ED, the most effective vasoactive drug is strongly suggested to be the drug of choice, which was PGE1.

3. In long-term use PGE1 is well tolerated and has only minor problems. The patients`satisfaction with their erection at home was good. The high dropout percentage in long term use of PGE1 may be due partly to the fact that spontaneous erections did improve, especially with patients with a psychogenic etiology. Precise determination of home dose of PGE1 and teaching of the technique are important at the beginning of this treatment modality.

4. TURP does not affect the sexual function of patients with BPH, with exception of retrograde ejaculation. Early morning erections even improved after the operation. The majority of patients were satisfied with their sexual life both before and after procedure, although one third of them had not had coitus for a year.

5. Transdermal administration of dihydrotestosterone (DHT) improves sexual function and libido and offers a useful and safe alternative in the treatment of andropause. If oestrogens play a role in prostate growth, as has been suggested, the use of non-aromatize androgens may be beneficial compared with aromatizable androgens. Controlled follow-up trials of androgen replacement therapy in general are needed to clarify the possible long-term benefits and risks.

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Witherington R (1989) Vacuum constriction device for management of erectile dysfunction. J Urol 141: 320-322.

Witjes WP, Meuleman EJ, Lycklama N, Van Driel MF, Leliefeld HH, Kropman RF & Doesburg WH (1992) the efficiacy and acceptance of intracavernous autoinjection therapy with the combination of papaverine/ phentolamine. A prospective multicenter trial. Int J Impot Res 4: 65-71.

Von Graffenreid B, del Pozo E, Roubiceck J, Roubicek J, Krebs E, Pöldinger W, Burmeister P & Kerp L (1978) Effects of synthetic enkephalin analogue FK 33-824 in man. Nature 272: 729-730.

Von Heyden B, Donatucci CF, Marshall GA, Brock GB & Lue TF (1993) A prostaglandin E1 dose-response study in man. J Urol 150: 1825-1828.

Vrijhof HJ & Delaere KP (1994) Vacuum constriction devices in erectile dysfunction vacuum tumescence device: a retrospective analysis of acceptance and satisfaction. Br J Urol 74: 102-105.

Vruggink PA, Diemont WL, Debruyne FM & Meuleman EJ (1995) Enhanced pharmacological testing in patients with erectile dysfunction. J Androl 16(2): 163-168

Yalcin S, Altundag K, Asil M & Tekuzman G (1998) Sublingual piroxicam for cancer pain. Med Oncol 15 (2): 137-139.

Zeiss AM, Davies HD, Wood M & Tinklenberg JR (1990) The incidence and correlates of erectile problems in patients with Alzheimer`s disease. Arch Sex Behav 19: 325-331.

Zorgniotti AW (1992) ´On demand´oral drug for erection in impotent men. J Urol 147: 308A.

Zorgniotti AW & Lefleur RS (1985) Auto-injection of corpus cavernosum with vasoactive drug combination of vasculogenic impotence. J Urol 133: 39-41.

Zorgniotti AW & Lizza AF (1994) Effect of large doses of the nitric oxide precursor, L-arginine, on erectile dysfunction. Int J Impot Res 6: 33-35.

Ref.68:

Dette er en tekstkopi af:
http://www.lu.se/info/forskdag00/09.html

Erektion – varför fungerar det och varför fungerar det inte?

Karl-Erik Andersson

Avdelningen för Klinisk Farmakologi

Lunds universitet, Universitetssjukhuset i Lund

Mannens penis innehåller ett svällkroppsystem som kan variera i storlek. Då penis är slapp är svällkropparna små och har en relativt låg genomblödning. Det låga blodflödet bibehålls genom sammandragning av artärer och deras små grenar, som leder blod in i de håligheter (sinusoider) som finns i svällkropparna. Erektion kan åstadkommas av olika impulser från sinnena – känsel, syn och lukt, men även genom fantasin. Dessa impulser samordnas i hjärnan och ryggmärgen och ger upphov till aktivitet i de nerver som försörjer svällkropparna och som styr deras blodflöde. När nervimpulserna når penis vidgas artärerna varpå blodflödet ökar och sinusoiderna börjar fyllas med blod. Svällkropparna utvidgas vilket leder till att de kärl som leder blod från penis (vener) blir ihopklämda och blodflödet från penis försvåras. Härigenom ökar trycket i svällkropparna som blir hårda och en erektion uppstår.

Vad händer i penis vid erektion?

Kontrollen av blodflödet i penis beror på balansen mellan faktorer som drar samman och faktorer som vidgar artärer och svällkropparnas sinusoider. Den viktigaste sammandragande faktorn är noradrenalin, en signalsubstans som frisätts från nerver och vars effekt dominerar då penis är slapp. Kväveoxid (NO; eng. nitric oxide) är den viktigaste vidgande faktorn och bildas i nerver, men även i endotelceller som bekläder insidan av blodkärlen och sinusoiderna. Vid erektion höjs aktiviteten i nerver som ökar mängden NO i svällkropparna. Inuti artärernas och svällkropparnas sk. glatta muskulatur, stimulerar NO till bildning av en budbärarsubstans som kallas för cykliskt GMP (cGMP). En ökning av mängden cGMP är en förutsättning för att de glatta muskelcellerna ska kunna slappna av och härigenom vidga svällkropparna och ge erektion. Nedbrytningen av cGMP sker genom inverkan av enzymer. Genom att blockera dessa enzym i svällkropparna kan man behandla en sviktande erektionsförmåga. Detta är verkningsmekanismen för Viagra® (sildenafil).

Varför fungerar det inte?

Förekomsten av en sviktande erektionsförmåga, eller erektil dysfunktion (ED), ökar med ökande ålder. Undersökningar har visat att 55% av alla män vid 75 års ålder har ED. Den vanligaste orsaken till ED är kärlförändringar som ger försämrat blodflöde till penis. Detta kan vara ett led i en generell hjärtkärlsjukdom med förhöjt blodtryck och åderförkalkning. Minskad blodförsörjning till penis leder till minskad bildning av NO och därmed även till minskad bildning av cGMP. Vid diabetes, framförallt vid dåligt reglerad sjukdom, kan både kärl och nervförändringar uppkomma i relativt tidig ålder och ED är därför vanligare i denna grupp. Andra orsaker kan vara yttre skador på hjärna, ryggmärg och nerver. Män som opererats för prostatacancer får ofta ED som komplikation på grund av skador på nerver till penis. Psykiska faktorer, t ex prestationsångest, men även depressioner och schizofreni kan bidra till en ED. Stroke, Parkinsons sjukdom och Alzheimers sjukdom kan också ge ED. Läkemedel kan orsaka ED. Antidepressiv medicin och läkemedel vid högt blodtryck ("vätskedrivande" och "betablockare") bör nämnas i detta sammanhang. Hormonrubbningar med låga nivåer av manligt könshormon kan bidraga till ED men är mindre vanligt än vad som skulle kunna förmodas.

De nämnda faktorerna och sjukdomarna kan på olika sätt gripa in i signalkedjan från hjärnan till penis. Oftast blir dock slutresultatet detsamma: en minskad bildning av de nyckelfaktorer som kan vidga artärer och svällkroppsvävnad i penis. Oavsett orsaken kan man i de flesta fall med läkemedel övervinna "hindret" och härigenom behandla patienter med ED på ett effektivt och säkert sätt.

Ref.65:
Dette er en tekstkopi af:
http://www.vivus.com/products_muse.asp

This information is intended for use by our customers, patients and healthcare professionals in the United States only. VIVUS, Inc. recognizes that the Internet is a global communications medium; however, laws, regulatory requirements and medical practices for pharmaceutical products vary from country to country. The information included here may not be appropriate for use outside the United States. MUSE® is available in many countries around the world through our marketing partners, Abbott and Paladin. Please refer to the International Directory of Marketing Partners for information regarding the distribution of MUSE to countries outside the United States.

MUSE OVERVIEW

VIVUS' product MUSE® is a transurethral delivery system for alprostadil to treat erectile dysfunction. A unique approach to treating erectile dysfunction, it works quickly to produce a natural-feeling erection sufficient for sexual intercourse that begins 5-10 minutes after dosing, and should last about 30-60 minutes. MUSE is pre-filled and ready to use, allowing for the spontaneity that both parties desire.

MUSE is based on the discovery that the urethra (the tube in the penis through which urine and semen flow) can absorb certain medications and distribute them into the surrounding tissues. MUSE is a small, medicated pellet that contains alprostadil, a naturally occurring vasodilator, which is identical to a naturally occurring substance in human semen. Alprostadil works by opening blood vessels to increase blood flow into the penis.

DOSING

MUSE is available in four doses: 125 mcg, 250 mcg, 500 mcg, and 1000 mcg. The initial administration of MUSE is performed in the physician's office, where the proper strength can be determined and where the patient can be monitored for certain side effects and educated in proper techniques to achieve maximum results. Subsequent doses can be administered at home. MUSE is available by prescription only and may not be used more than twice in a 24-hour period.

MUSE USE

Several steps must be taken when using MUSE to ensure that MUSE administration is effective, comfortable, and safe. For more detailed information, please consult your physician, or review the detailed instructions provided in the patient instruction leaflet or the patient instruction video(Video contains some adult material). VIVUS also has a toll-free patient information hotline: 1-888-367-6873.

PREPARATION

· Allow MUSE to warm to room temperature prior to use

· Wash hands before handling MUSE

· Urinate immediately prior to administration

· DO NOT touch the applicator stem or tip

· DO NOT apply any additional lubrication

· DO NOT push or pull the button prior to use

· DO NOT administer MUSE while laying down

ADMINISTRATION

· Stand or sit for the administration of MUSE

· Extend the penis in an upright position

· Slowly insert the applicator up to the collar

· Completely depress the button, then keep the MUSE in position, up to the collar, for 5 seconds

· While in position, gently rock the applicator back and forth to dislodge the pellet

· Roll the penis between the hands in the upright position for 10 seconds to distribute the medication

· Stand or walk around for 10 minutes after administration as the erection develops

Nedenstående er en tekstkopi af:
http://www.phoenix5.org/sexaids/injections/musefaqafud.html

MUSE FAQ

The following is from a leaflet produced by the UK division of the American Foundation for Urologic Diseases (AFUD).

Developed in the United States of America, MUSE is the latest addition to the treatments available for erectile dysfunction (impotence). This fact sheet provides basic information on MUSE; for more detailed information you should consult your doctor.

What is MUSE?

What medication is used in MUSE?

What is involved in this form of treatment?

How soon after using MUSE does erection occur?

How long will the erection last?

What side effects may be associated with MUSE?

Are there any side effects in the female partner?

What conditions may prevent a man using MUSE?

How can I obtain MUSE?

What is MUSE?

MUSE is short for "medicated urethral system for erection." This treatment is based on the discovery that the urethra (the tube passing from the bladder to the tip of the penis through which urine is passed and semen ejaculated) can absorb certain medications, which can then pass into the surrounding erectile tissue creating an erection.

What medication is used in MUSE?

The active ingredient in MUSE is alprostadil. This is identical to a naturally occurring substance within the penis which is involved in the development of an erection. Alprostadil has been used in the treatment of impotence for many years. Before the introduction of MUSE it had to be injected into the penis when an erection was wanted. Alprostadil relaxes the muscles in the erectile tissue of the penis allowing increased blood flow, the basis of a normal erection.

What is involved in this form of treatment?

In MUSE, alprostadil is formulated as a small pellet which is supplied in a specially designed applicator. Each MUSE applicator is individually foil wrapped. The applicator has a narrow stem which can be introduced easily into the urethra. After inserting the applicator, the alprostadil pellet is then released into the urethra by depressing a button on the top of the applicator.

The manufacturer recommends that immediately prior to insertion of MUSE, the man urinates and then gently shakes the penis several times to remove excess urine. A moist urethra makes administration of MUSE easier and facilitates the absorption of alprostadil.

How soon after using MUSE does erection occur?

An erection usually occurs within five to ten minutes of administration.

How long will the erection last?

When this form of treatment is effective, an erection generally lasts 30 to 60 minutes. Extremely rarely a prolonged erection may occur. MUSE can be used twice in any 24 hour period, however 2 units should not be used consecutively.

Different doses: MUSE is available in four strengths – 125 mcg, 250 mcg, 500 mcg and 1,000 mcg. The initial dose is selected by the doctor.

What side effects may be associated with MUSE?

Side effects have been reported only infrequently. When first using MUSE, some men experience minor discomfort from insertion but prior urination will reduce the chance of this happening.

Following the first dose of MUSE, fainting has occurred, but only in an extremely small proportion of men. However, for this reason, it is recommended that the first dose of MUSE should be in the doctor's office.

Other side effects that have been reported, albeit extremely rarely, include light-headedness, dizziness, fainting, rapid pulse and swelling of the leg veins. Patients are advised not to drive up to one hour after using MUSE.

Are there any side effects in the female partner?

Mild vaginal itching and burning have been reported.

What conditions may prevent a man using MUSE?

MUSE should not be used in the following conditions:

Known hypersensitivity (allergy) to alprostadil

An abnormally formed penis

Diseases that might result in prolonged erection (e.g. sickle cell anemia or trait, leukemia, multiple myeloma).

MUSE should not be used for sexual intercourse with a pregnant woman unless a condom is used.

How can I obtain MUSE?

MUSE is available only on prescription. You should discuss this form of treatment with your doctor who may prescribe it for you or refer you to a specialist clinic.

Nedenstående er en tekstkopi af:
http://www.vivus.com/fr_set.asp?SECTION=rnd

VIVUS’ goal is to establish a robust pipeline consisting of drug candidates at various stages of development, with a focus on innovative therapies intended to serve large and unsatisfied markets. In addition to the Company’s currently marketed products, MUSE® and ACTIS®, VIVUS is developing products for male erectile dysfunction, female sexual dysfunction, and premature ejaculation. The Company believes that patients with these conditions are not being adequately treated, and VIVUS has the expertise and intellectual property necessary to make meaningful contributions in these areas.

In conjunction with research and development activities, VIVUS is focused on maintaining its Intellectual Property Rights, and continues to aggressively pursue new patents to further strengthen its patent position. Significant progress has been made to identify markets, discover treatments, and create patents, with the ultimate goal of bringing products to the marketplace

Ref.64:
Dette er en tekstkopi af:
http://www.phoenix5.org/sexaids/injections/musefaqafud.html

MUSE FAQ

The following is from a leaflet produced by the UK division of the American Foundation for Urologic Diseases (AFUD).

What is MUSE?

What medication is used in MUSE?

What is involved in this form of treatment?

How soon after using MUSE does erection occur?

How long will the erection last?

What side effects may be associated with MUSE?

Are there any side effects in the female partner?

What conditions may prevent a man using MUSE?

How can I obtain MUSE?

What is MUSE?

What medication is used in MUSE?

What is involved in this form of treatment?

How soon after using MUSE does erection occur?

An erection usually occurs within five to ten minutes of administration.

How long will the erection last?

Different doses: MUSE is available in four strengths – 125 mcg, 250 mcg, 500 mcg and 1,000 mcg. The initial dose is selected by the doctor.

What side effects may be associated with MUSE?

Side effects have been reported only infrequently. When first using MUSE, some men experience minor discomfort from insertion but prior urination will reduce the chance of this happening.

Are there any side effects in the female partner?

Mild vaginal itching and burning have been reported.

What conditions may prevent a man using MUSE?

MUSE should not be used in the following conditions:

Known hypersensitivity (allergy) to alprostadil

An abnormally formed penis

Diseases that might result in prolonged erection (e.g. sickle cell anemia or trait, leukemia, multiple myeloma).

MUSE should not be used for sexual intercourse with a pregnant woman unless a condom is used.

How can I obtain MUSE?

MUSE is available only on prescription. You should discuss this form of treatment with your doctor who may prescribe it for you or refer you to a specialist clinic.

Nedenstående er en tekstkopi af:
http://www.vivus.com/fr_set.asp?SECTION=rnd

Ref.63:
Dette er en tekstkopi af:
http://www.nexmed.com/press/news83.htm

Alprox-TD® Data Presented at Key Meeting

Robbinsville, NJ, December 6, 2001 — NexMed, Inc. (Nasdaq: NEXM), a developer of innovative treatments based on its proprietary drug delivery system, today announced that Dr. Chris Steidle, Director, Northeast Indiana Research Clinic, will present the combined Phase 2 clinical results for Alprox-TD® at the Third Annual Fall Research Meeting of the Sexual Medicine Society of North America, December 7-9, 2001, Charleston Place Hotel, Charleston, SC. Alprox-TD® is NexMed's proprietary treatment for erectile dysfunction ("ED").

Dr. Joseph Mo, the Company's President and C.E.O. commented, "We are pleased that Dr. Steidle, who is one of the lead investigators studying Alprox-TD®, will share these exciting clinical results with his colleagues in Charleston." Dr. Mo further added, "This meeting venue seems most appropriate to further present the data on Alprox-TD® to a prestigious group of physicians who specialize in diagnosing and treating ED."

Alprox-TD® incorporates alprostadil (PGE1) with the patented NexACT transdermal delivery technology. NexMed conducted two U.S. Phase 2 studies for Alprox-TD® at clinical sites throughout the U.S. The studies were randomized, parallel, double-blind, placebo-controlled, and were designed to investigate the dose-response relationships of the efficacy and safety of escalating doses of Alprox-TD® in 300 men with mild, moderate and severe ED. The clinical data indicate that up to 83% of the patients reported satisfaction with treatment. The side-effects observed in the studies were mostly mild to moderate in nature and short in duration.

NexMed has initiated two pivotal Phase 3 clinical trials for Alprox-TD® at clinical sites throughout the U.S. The studies include patients with mild to severe ED and patients who cannot take oral ED medication. NexMed is also conducting a Phase 2 study with FemproxTM cream for the treatment of female sexual arousal disorder ("FSAD").

About NexMed, Inc.

NexMed, Inc., is an emerging pharmaceutical and medical technology company, with a product development pipeline of innovative topical drug treatments based on the NexACT® acute transdermal delivery technology. Its two lead NexACT® products under development are the Alprox-TD® and FemproxTM creams for ED and FSAD, respectively. NexMed is also developing Viratrol®, a hand-held treatment device for herpes simplex lesions.

Statements under the Private Securities Litigation Reform Act: with the exception of the historical information contained in this release, the matters described herein contain forward-looking statements that involve risk and uncertainties that may individually or mutually impact the matters herein described, including but not limited to successful completion of clinical development programs, regulatory review and approval, product development and acceptance, manufacturing, competition, and/or other factors, some of which are outside the control of the Company.

Ref.59:
Dette er en tekstkopi af:
http://www.palatin.com/main.asp?con=5%2E1EP&nav=5 og ledsagende sider

What is PT-141?

PT-141 is a new, nasally administered peptide for the treatment of sexual dysfunction. Palatin research suggests that PT-141 works through a mechanism involving the central nervous system (CNS) rather than directly on the vascular system. As a result, it may offer significant safety and efficacy benefits over currently available products. Palatin began human clinical testing of PT-141 for erectile dysfunction (ED) in the first quarter of 2001. The company has completed a Phase I study, and plans to initiate Phase II efficacy trials later in the year. Palatin also plans to initiate a pilot clinical study in female sexual dysfunction in the fourth quarter of 2001.

How does PT-141 work?

Approximately 30 minutes before intercourse, the patient will take a single nasal dose of PT-141. The rapid onset of PT-141 activity should be preferable to patients when compared to the 1+ hours that current oral ED therapies require. In addition, the nasal formulation of PT-141 is as convenient as oral treatments, and more patient friendly than invasive treatments for ED, such as injections and trans-urethral pellets.

PT-141 offers many potential advantages over current therapies for ED. The intranasal mode of administration is non-invasive, fast acting and consistant. The CNS involvement in the mechanism of action also offers several potential benefits for patients and medical practitioners over currently available PDE (phosphodiesterase) inhibitors like Viagra that work through the body's vascular system on blood flow.

· The CNS activity of PT-141 may give it broader potential to treat both organic (vascular) and psychogenic (no obvious physical cause) male sexual dysfunction. Thus, a larger patient population might benefit from PT-141 than can be served by currently marketed therapies for ED.

· · The CNS mechanism of PT-141 suggests it may also have more potential for treating female sexual dysfunctions including inhibited sexual arousal and response. Women are clearly underserved by current treatments which focus on physical erection, rather than the aspects of sexual desire, response and orgasm that are the predominant concerns in female sexual dysfunction.

· · PT-141 and cardiac (heart) function: Based on pre-clinical data, Palatin does not anticipate that PT-141 will be associated with such cardiovascular side-effects as headache and sudden drop in blood pressure in cardiac patients taking nitroglycerin. Men receiving PT-141 in a Phase I clinical safety study tolerated the drug well at all doses, and investigators reported no safety issues with the treatment.

· PT-141 Pre-Clinical Development Status

In pre-clinical studies PT-141 was a remarkably potent inducer of penile erection. Preclinical toxicity and safety studies indicate that PT-141 is well tolerated with intranasal dosing. Researchers have noted no treatment-related effects on hemodynamic or cardiac functions in these pre-clinical studies.

PT-141 Clinical Development Status

An initial Phase 1 safety study of PT-141 in healthy subjects showed that participants in the study tolerated treatment well at all doses, and investigators reported no safety concerns. Palatin plans to initiate another Phase 1 Study to evaluate multiple dose pharmacokinetics in the 4th quarter 2001.

A Phase 2A efficacy study is planned to begin in mid-2001 in patients with ED. If results support further development of PT-141, a placebo-controlled Phase 2B at-home efficacy study is planned for the 1st quarter 2002.

Palatin also plans to conduct a proof-of-principle study of PT-141 in female patients starting in the 1st quarter of 2002.

The aging of the "baby boom" generation has brought sexual dysfunction into prominence as a medical concern. Men and women who suffer sexual dysfunction are a large and growing market not satisfied with current treatments. According to the Massachusetts Male Aging Study, more than 50% of men aged 40-70 report episodes of ED and more than 30 million men in the US suffer ongoing ED. The current market size in dollars is estimated to be from $1.5-3.0 billion, with several products already competing in the male ED market segment. The statistics for women are not well defined, yet sexual dysfunction is clearly a concern for a large number of women.

For nearly a decade, there have been mechanical methods for treating ED, such as vacuum constriction devices or surgically implanted penile prostheses. However, recent advances in understanding the molecular physiology of penile erection have led to development of pharmaceutical treatments for ED. The first generation of such products mainly focused on the vascular physiology (blood flow) of penile erection. For example, PDE-5 inhibitors and PGE1 prostaglandin hormones induce smooth muscle relaxation to cause penile blood vessels to fill. This initiates erection. These drugs cause similar effects elsewhere in the body as well. In contrast, PT-141 appears to work on the Central Nervous System (CNS), interacting more fundamentally with the underlying brain and nervous system aspects of sexual arousal and response, hence initiating penile erection through a more natural mechanism

Herbert, G.W., Koegler F.G., Cameron J.L. and Shadiack, A.M. Effects of PT-141 on erectile function and other behaviors in adult male sprague-dawley rats and rhesus macaques. (June 2001) American Urological Association meeting transcript.

Wessells, H., Gralnek D., Dorr R., Hruby V., Hadley M. and Levine N. Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction. Urology 2000; 56, 641-646.

Wessells, H., Levine N., Hadley M.E., Dorr R. and Hruby V. Melanocortin receptor agonists, penile erection, and sexual motivation: Human studies with Melanotan II. International Journal of Impotence Research, 2000; 12, (4), 574-579.

Wessells, H., Fuciarelli K., Hansen J., Hadley M., Hruby V., Dorr R. and Levine N. Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: Double-blind crossover placebo-controlled study. Journal of Urology 1998; 160, 389-393.

LeuTech®

Thuakur, M.L., Marcus, C.S., Kipper, S.L., et al. Imaging infection with Leutech® Nucl. Med. Communications 2001; 22, 513-519.

Kipper, S.L., Rypins E.B., Evans, D.G., Thakur, M.L., Smith, T.D., and Rhodes B. Neutrophil-specific 99mTc-labeled anti-CD15 monoclonal antibody imaging for diagnosis of equivocal appendicitis. J. Nucl. Med. 2000; 41: 447-455.

Mozley, P.D., Thakur, M.L., Alavi, A. et al. Effects of a 99mTc-labeled murine immunoglobulin M antibody to CD15 antigens on human granulocyte membranes in healthy volunteers. J. Nucl. Med. 2000; 40, 2107-2114.

Kipper, S.L., Kramer, E.L., Evans, D.G. et al. Tc-99m anti-CD 15 neutrophil monoclonal antibody (LeuTech) scan for diagnosis of equivocal appendicitis: Clinical evaluation of safety, efficacy and patient management. J. Nucl. Med. 1999; 40, (5), p16. (Abst.)

Kipper, S.L. The role of rediolabeled leukocyte imaging in the management of patients with acute appendicitis. Q.J. Nucl. Med. 1999; 43, 83-92.

Mozley, P.D., Stubbs, J.B., Dresel, S.H. et al. Radiation dosimetry of a 99m Tc-labeled IgM murine antibody to CD 15 antigens on human granulocytes. J. Nucl. Med. 1999; 40, 625-630.

Thakur, M.L., Marcus, C.S., Henneman, P. et al. Imaging inflammatory diseases with neutrophil-specific technetium-99m-labeled monoclonal antibody anti-SSEA-1. J. Nucl. Med. 1996; 37, 1789-1795.

MIDAS™ Technology

Sharma, S.D. and Rhodes, B.A. Differential stability of Syn- and Anti-isomers in 99mTc-complexes – Evidence from cycteine challenge studies. Technetium and Rhenium in Chemistry and Nuclear Medicine, 1999; 5, 697-700.

Shi, Y., and Sharma, S.D. Metallopeptide approach to drug design: Synthesis of a specific inhibitor for human neutrphil elastase. BioOrg. Med. Chem. Letter, 1999; Issue 9, 1469-1474

Ref.49: Dette er en tekstkopi af:
http://216.239.35.100/search?q=cache:lD7smjblvuIC:www.free-viagra-information.com/proven.htm+Virility+Max+RETURN&hl=da&ie=UTF-8

Herbal Aphrodisiacs

with Some Evidence of Effectiveness

Before you ever get horizontal, there are some obvious advantages to giving non-prescription sexual stimulants a try: No embarrassing doctor visits (although you may buy Viagra online by completing a brief medical questionnaire); the convenience of ordering from your PC (again available with Viagra as well); reduced concern for side effects (which are mostly comprised of a stuffy head and finding out how out of shape you are). The scares about heart attack and hypertension appear to be mostly unfounded.

There are at least a hundred products sold by purveyors claiming wonderful results. There's about two ways to rise to the ocassion: increased blood flow (which Pfizer has hit on the head) and increased testosterone levels, which is a delicate balance. Not enough and you get a fizzle. Too much – same thing.

There are only a few products listed here which have some reasonable claim to effectiveness. Before spending any money, we would recommend a good diet, exercise, peace with the Maker and your mate, a few bucks in the bank and a fully restored (red) 1981 Corvette Stingray. But, if you want to spend less than a hundred and cut corners, give each of these a try:

Virility Max

Virility Max is repurchased more often than any other 'natural alternative' to Viagra, simply because, for many men, it works. Moreover, it is purchased with a money-back guarantee. If it doesn't work for you, you're welcome to return the unused portion for a refund.

In advance, we apologize for the presentation given at the Virility Max website. The product is good. It is guaranteed to work. So please overlook the slant toward 'sales hype' in gleaning information about Virility Max.

Herbal V – The 'Mark McGuire Drug'

Herbal V was invented by a group of scientists from Harvard, Stanford and Princeton, who wanted to create the ultimate all-natural aphrodisiac. The Herbal V formula resulted, containing a blend of pro-sexual nutrients which increase blood flow, releae stored testosterone and excite key pleasure zones.

Herbal V's primary ingredients are Yohimbe (the only herb listed in The Physicians' Desk Reference Book as a 'natural aphrodisiac') and Avena Sativa which allegedly stimulates the neuro-transmitter pleasure centers.

List of ingredients: Yohimbe extract, Avena Sativa extract, Siberian Ginseng extract, Saw Palmetto extract, Guarana extract, Androstenedione, Taurine, and Tribulus Terrestris extract.

Vasoderm

Vasoderm is a personal lubricant. It is the result of years of development of natural supplement advances, producing the most effective and safe solution for increased sexual prowess and function available today. Vasoderm, is helping couples achieve the most from their sex lives without the side effects and high cost of Viagra.

Vasoderm™ personal lubricant for women – Previously only available in Natural Foods stores, Vasoderm™ is now available directly to you at your home or office via the Internet! Incorporating the latest research in natural sexual supplements, Vasoderm™ is an easy-to-apply squeeze-bottle lubricant which features a bioadhesive delivery system for more effective results than pills. Go here for more information and to order.

Ginseng

Ginseng is widely used in the U.S. as a dietary supplement by consumers seeking to improve general energy and vitality, particularly during times of fatigue or stress. The most commonly used type of ginseng is Asian ginseng (Panax ginseng C.A., Meyer), often sold as Panax, Chinese, or Korean ginseng. Closely related to Asian ginseng is American ginseng (Panax quinquefolius L.), which is sometimes preferred for its milder effects. Siberian ginseng, also called eleuthero (Eleutherococcus senticosus Rupr ex Maxim), is not as closely related to the other two, is often considered somewhat weaker in action, and is a less expensive ingredient.

Tissue and animal studies of one form of ginseng, called panax, give some credence to the root's sexy reputation. A study published in the May 1995 issue of the journal British Pharmacology, for instance, concluded that substances in ginseng extract known as ginsenosides may work in a similar way to Viagra. Viagra enhances the effects of nitric oxide, which helps relax artery walls, allowing more blood flow into the penis. Ginsenosides may encourage the release of more nitric oxide.

Products Containing Ginseng

Yohimbine

Yohimbe bark, taken from a towering evergreen tree, was traditionally used in its native Africa to stimulate erections. A century before Viagra, yohimbine, a substance derived from the bark, was prescribed in Europe for male sexual dysfunction. While yohimbe is available over the counter, it's yohimbine — still available only with a doctor's prescription — that's been the subject of clinical studies.

A combined analysis of more than a dozen studies involving hundreds of subjects, published in the journal Archives of Sexual Behavior in August 1996, concluded that yohimbine can help many men who have problems getting an erection. It appears to work in part by increasing blood flow to the penis and may affect brain chemistry as well.

Products Containing Yohimbe

Ginkgo Biloba

While best known for supposedly aiding mental processes, the modern leaf extract of this ancient species of tree has also been studied for its effects on male erections. Both effects could be caused by ginkgo's encouragement of increased peripheral blood flow.

Ginkgo biloba has become a widely used dietary supplement for increasing cognitive functions in elderly people, delaying the progression of Alzheimer's disease, increasing blood flow to the legs, treating tinnitus (ringing in the ear) of a circulatory origin, as well as treating depression and asthma. It is an extract of the leaf of the Ginkgo biloba tree that is used in dietary supplements.

The Ginkgo biloba extract, or GBE, used in most clinical trials contains specific types of naturally occurring chemicals: Flavonol glycosides, of which there are three, are believed to confer anti-oxidant activity; Terpene lactones, of which there are two categories, may be responsible for the dilatory effect on blood vessels. Each of these chemicals is expected to exist in a specific amount in clinical quality GBE, representing a standard for assessing ginkgo products. Many GBE products now claim to be "standardized" or manufactured to contain specific total amounts of flavonol glycosides and/or total terpene lactones.

Products Containing Ginkgo

L-Arginine

L-arginine is an essential amino acid present in many foods; supplement makers are now offering it in concentrated form to improve sexual performance. The vendors argue that L-arginine might work something like Viagra because the amino acid is necessary for the formation of nitric oxide, the substance central to erections.

Studies of L-arginine supplements have also shown mixed results. A 1999 study of 30 impotent men found that 1,500 milligrams of oral L-arginine worked no better than a placebo. But a study of 21 men with "mild to moderate" impotence taking a supplement called ArginMax (3,000 milligrams per day) found big improvements in erection and sexual satisfaction. ArginMax also contains ginseng and ginkgo biloba.

Products Containing L-Arginine

Alternatives – Research in the Works:

Uprima – TAP Pharmaceutical's Uprima (apomorphine) is a tablet that dissolves under the tongue, acts within 15-25 minutes and uses a different route to trigger brain mechanisms that stimulate an erection. Despite concerns about nausea, this drug may be available soon. Other companies are looking to market this drug as a nasal spray.

Vardenafil and Cialis

Other drugs that may enhance blood flow to the penis but perhaps with fewer side effects include Bayer's Vardenafil (expected in 2002) and Eli Lilly's Cialis (allows more spontaneous sexual activity by acting within 15-20 minutes and lasting up to 24 hours.) These drugs are similar to Viagra, but are more specific to the enzyme in the penis.

Alprox-TD – Clinical trials are underway of Alprox-TD (alprostadil), an alternative to treatment with pills. This drug can be injected or used as a suppository.

Viagra for her – His and hers drugs are on the horizon. Based on the theory that if it works for him it might work for her, researchers are testing Viagra and its ability to increase blood flow to the female genitals. Although the results are inconclusive, some women have reported feeling more aroused.

Ref.48a:

Epimedin A, Epimedin B, Epimedin C, Epimedokoreanoside I, Epimedokoreanoside II, Epimedoside A, I-karisoside A, (quercetin), 4'-methoxy-5-hydroxy-8-3, 3-dimethylallylflavone-3-glucosyl (1–2) rhamnoside-7-glucoside), 4'-methoxy-5-hydroxy-8-3, 3-dimethylallylflavone-3-xylosyl (1–2) rhamnoside-7-glucoside), 4'-methoxy-5-hydroxy-8-3, 3-dimethylallylflavone-3-rham-nosyl (1–2) rhamnoside-7-glucoside.

Isoquercetin, icaritin-3-O-alpha-rhamnoside, hyperin, sagittatoside A, sagittatoside B, sagittatoside C, sagittatin A, sagittatin B, Anhydroicaritin-3-O-alpha-rhamnoside, Icariside E6, Icariside E7, Icaride A1, Icaride A2, Icariside D3, Icariside H1, Icariside B9.

Epimedoside C, baohuoside VI, baohuoside I, rouhuoside.

Wushanicariin.

Dosage: 6-15 g.

Samples of formulae: With wu wei zi, gou qi zi, and sha yuan ji li for deficient Kidney impotence and infertility.

With sang ji sheng for painful obstructions, especially paralysis and pain of the lower extremities, or muscular contraction and numbness of the extremities.

With xian mao, Huang bai, and zhi mu for menopausal symptoms such as facial pallor, lower back pain, nocturia, menstrual irregularity, and dizziness from deficient Liver and Kidney yin and subsequent ascendant Liver yang. This combination is also used for the abovementioned ascendant Liver yang symptoms in men.

Source of above formula: Bensky and Gamble.

Today's Usage: 1. For impotence:

A. Use yin yang herb 15 g. with Tu si zi 15 g. Grind into powder. 5 g a day in 3 servings. To be taken with yellow rice wine. 20 days is one treatment. Take every day first thing in morning and before bed. Massage the perineal area from left to right and right to left about 10 times .

B. Every night use chuan xiong 15 g and xi sin 15 g. Boil a decoction and put in bathtub and sit for 20 minutes. Avoid intercourse for 100 days. Avoid overexertion and getting chilled. 7 days is one treatment.

Total cases: 38. 8 cases got better. 20 cases completely healed. After 2 years, no patients had recurring problems. Total effectiveness: 92 per cent.

2. For white patches of vagina. 3. For neurasthenia . 4. For coronary disease. 5. For viral infections of the heart muscle. 6. For chronic bronchial infection and asthma. 7. For treating the decrease of white cells. 8. For treating inflammation of the gray matter of the spinal cord.

Modern Research: Often steeped in wine for both kidney yang deficiency and painful obstruction. Traditional preparation by stir frying with fat of goat is an effective method. Although stir frying with goat fat does not increase the total saponin in the leaves but the total saponin that dissolves by boiling in water increases; thus , improve the efficacy of the herb.

Cautions: Contraindicated in patients with fire from yin deficiency. This herb should not be taken as a decoction, over prolonged periods. This herb can damage the yin. In some people, ingesting it can lead to dizziness, vomiting, dry mouth, thirst, and nosebleed.

Ref.48b:
Dette er en tekstkopi af:
http://www.thehormoneshop.com/hornygoatweed.htm

Horny Goat Weed

These statements have not been evaluated by the Food & Drug

Administration. These products are not intended to diagnose, cure, treat or prevent

any disease. If pregnant or lactating, consult a physician before using.

Horny Goat Weed is an all-natural botanical sexual enhancer. It is a botanical complex that contains Horny Goat Weed (yes that is the name of the herb), Maca, L-Dopa and other exotic botanicals.

What Does it Do? ( See Clinical Trials )

Horny Goat Weed's combination of botanical ingredients may enhance sexual performance through a variety of mechanisms such as increased testosterone production, increased energy and increased sexual hormone production. ( See Clinical Trials)

Many of the herbs contained in Horny Goat Weed have been used in traditional botanical medicine in China, South America and Ayruveda.

It is a robust all-natural stimulant that can support a more robust life as well as love-life.

How Do I Take it?

Take 2 capsules daily with a meal. For more IMMEDIATE ACTION, take 3-4 capsules 90 minutes before activity.

These statements have not been evaluated by the FDA. This product is not

intended to diagnose, treat, cure or prevent any disease.

Horny Goat Weed (Please note the word "Standardized" it is important)

Each Capsule Provides:

Horny Goat Weed (Epimedium sagittatum, Epimedium brevicornum)…..500 mg

(Standardized 10% icariin)

Maca Pure' (Lepidium meyenii)…………………………………. 250 mg

(Standardized 0.6% macamides & macaenes)

Macuna pruriens……………………………………………………. 33.3 mg

(Standardized 15% l-dopa)

Polypodium vulgare………………………………………………….. 25 mg

(Standardized 8% 20-hydroxyecdysone)

Directions for use: As a dietary supplement, take 2 capsules daily with a meal. For more IMMEDIATE ACTION, take 3-4 capsules 90 minutes before activity.

UNCONDITIONAL, 30 DAY, MONEY-BACK GUARANTEE!

Horny Goat Weed – 60 Tablets – $28.99

Effect of Horny Goat Weed Herbal Complex Supplement on Sexual Satisfaction in Healthy Men and Men Treated with Viagra

Clinical Trial.

Steven Lamm, M.D. and Gerald Secor Couzens

Purpose We examine the effects of an herbal complex product on sexual satisfaction in healthy male volunteers and male volunteers who use Viagra.

Methods In this study, 25 healthy men (HM) and 13 men (VM) who used Viagra were assigned to initially receive daily therapy for 45 days with two capsules (808 mg x 2) of a commercially-prepared herbal complex of epimedium grandiflorum, maca pure (lepidium meyenii), mucuna pruriens, and polypodium vulgare . An additional four capsules (3232 mg) were taken one to two hours prior to sexual activity to determine its effect on sexual interest, sexual performance, and overall sexual satisfaction. After 45 days, the double-blind phase of the study began with a placebo product and active product randomly given to healthy men (HM) who had reported a positive response and taken for two weeks to four weeks. All subjects were evaluated after the first 45 days of treatment and finally after 60 days.

Results 13 of 20 HM had a positive response to the herbal mixture and 6 of the 13 VM had a positive response to the herbal mixture. In the double-blind placebo portion of the study, no HM had a positive response to placebo product; 6 of the 7 HM had a positive response to the active product.

Conclusions Daily use of the herbal complex for a minimum of 45 days resulted in an enhancement of sexual satisfaction in 60 percent of healthy male subjects and 45 percent of men using Viagra. The exact mechanism of action of the herbal mixture is unknown although it may have a testosterone-like effect.

Folk medicine has always been applied whenever a man's virility showed signs of waning. A seemingly endless succession of herbal potions, drugs, and mechanical devices have been employed over the centuries, from crushed rhinoceros horn and pulverized antelope, deer, and horse testicles, to parings of human nails. In times of desperation, a piece of bone was actually eased into the urethra to stiffen the penis.1

The mandrake plant, a member of the nightshade family, was used extensively in medieval Europe, northern Africa, and Asia as both a pain killer and a cure for ED (erectile dysfunction). It is even mentioned in the Old Testament, under the name dudaim, as the stimulant used by Jacob. Stemless, with bell-shaped flowers, the plant's long and thick root, which often divides into two sections, resembles the lower male torso. It contains many alkaloids of medicinal value, making it one of the most discussed plants in medical literature, as well as the subject of myth and superstition. Alkaloids are a diverse group of nitrogen-containing substances produced by plants that have powerful effects on body function; some of the more common alkaloids include atropine, morphine, quinine, and codeine.1

And then there was food. Throughout history, edibles, especially those phallic in shape, were employed as virility boosters. Asparagus, bananas, carrots, and cucumbers stood out in this category. Some indigenous tribes in coastal areas traditionally rubbed long, slender fish against their penises in the hope that they would become similarly long and hard.1

The herbal complex product used in this study is a proprietary combination of plant parts, primarily epimedium grandiflorum, lepidium meyenii, mucuna pruriens, and polypodium vulgare. Epimedium grandiflorum has been used historically as a sexual enhancer by the Chinese for 2,000 years. The herbal product is a combination of epimedium grandiflorum and other plants which are shredded and prepared traditionally as a powder as a supplement for sexual enhancement. Because of its sexual medicine properties, this herbal product has been offered commercially in the USA in preparations of pulverized plant parts.

The most consistent use related of this herbal product by Chinese medical practitioners has been to enhance sexual desire and performance. The mechanism of action is unclear but may be related to androgenic stimulating properties, perhaps working on the hypothalamus or pituitary gland.2

Today, sexual medicine is in its infancy and male sexual enhancement programs are being studied. At least 30 percent of men between the ages of 40 and 70 in the U.S. are dissatisfied with their sexual lives. According to the Massachusetts Male Aging Study a high percentage of the dissatisfaction comes from erectile dysfunction.3 For many, dissatisfaction is related to lack of intimacy or depressed desire.4 (Compared to male dissatisfaction, female sexual dissatisfaction is reported to be at a higher level (42 percent).4 It's obvious that more research is needed in this important and little-studied area.)

Sexual medicine programs are just beginning to come into use. Because of the increased interest in this area, triggered in part by the world-wide approval of the prescription medication Viagra in 1998 and due to anecdotal reports of the beneficial prosexual effect of herbal supplements, we have undertaken to test the hypothesis that a particular herbal supplement has a prosexual effect on healthy men as well as men using Viagra by evaluating it and comparing it to placebo product in volunteers.

Here we report that the HGW herbal complex supplement did enhance sexual satisfaction, and hence these data suggest an important possible clinical application for it.

METHODS

A human intervention study was carried out using male volunteers attending a General Practice Clinic in New York City. The randomization, administration of the herbal complex product in unlabeled bottles and collection of medical data was carried out by Dr. Steven Lamm and his program coordinator located at 12 East 86th Street in New York City between July 2000 and October 2000. Male volunteers between 25 and 66 years with exclusion criteria of no serious untreated sexual dysfunction were included in the study.

Initially, 38 male volunteers were divided into two groups (Table 1): Healthy Male (HM: n = 25; age, 25 to 65 years); and men using Viagra (VM: n = 13; age, 36 to 66 years). HM is defined as sexually active and not needing Viagra for sexual activity. However, he may be using medication for the treatment of other common ailments, including hypertension, depression, asthma, etc. HM and VM were told they were going to receive either a 45-day supply of the commercially-prepared herbal complex of epimedium grandiflorum, maca pure (lepidium meyenii), mucuna pruriens, and polypodium vulgare (Bodyonics, Hicksville, NY) or a placebo that would be taken daily at a dose of 1616 mg orally (2 capsules) with an additional 3232 mg (4 capsules) that would be taken 60 minutes prior to sexual activity with approximately 4 to 6 ounces of water. The capsules were contained in unmarked white plastic bottles.

The 13 VM (Table 2) followed a similar protocol except they took the herbal product two hours prior to a sexual encounter, followed by Viagra, as needed, one hour prior to a sexual encounter. The study participants received a study questionnaire to complete at the beginning of the study which assessed their sexual satisfaction and sexual performance levels. This 16-question questionnaire for HM and 25-question questionnaire for VM was designed by Dr. Steven Lamm and Gerald Secor Couzens, incorporating the key domains as outlined in part in the International Index of Erectile Dysfunction.5

After 45 days, 20 of the 25 HM completed the trial. 5 men did not complete this portion of the trial due to personal reasons; no side effects were reported. In the sildenafil (Viagra) phase, 13 VM completed the trial; no one reported any side effects. Study participants were asked to fill out another questionnaire assessing their impressions of the herbal complex product.

At this time, 13 HM subjects who admitted having a positive response to the product were randomized by the program coordinator to receive either placebo or active product (Active product n = 7; placebo product n = 6) in unmarked white plastic bottles. Neither patients nor study director knew which product patients had received. 6 VM noted enhanced sexual satisfaction from the products after 45 days and they continued taking the active product. They were not subject to the double-blind portion of the study.

RESULTS

The population of men for this trial came from the patients of a clinic in New York City with ages between 25 and 65. There were no documented side effects attributed to the herbal complex supplement during the trial evaluation of 60 days. 20 HM and 13 VM completed the trial.

Sexual Satisfaction

o 13 HM reported a variety of positive effects after taking the herbal complex product.

When the men were specifically asked:

Over the last four weeks, how satisfied have you been with your overall sex life?

Very satisfied

o Moderately satisfied

o About equally satisfied and dissatisfied

o Moderately dissatisfied

o Very dissatisfied

we noted increases of 20% in overall satisfaction with sex life in 4 of the 13 respondents, with 4 reporting a 40% increase in overall satisfaction (Table 3a). 1 respondent went from being very dissatisfied to moderately satisfied with his overall sex life, a gain of 60%.

o Individual satisfaction increased from Day 1 to Day 45, the initial time period the herbal capsules were taken (Table 3b).

When the men were specifically asked:

Over the last four weeks, when you attempted sexual activity, how often was it satisfactory to you?)

o Did not attempt sexual activity

o Almost always or always

o Most times (much more than half the time)

o Sometimes (about half the time)

o A few times (much less than half the time)

o Almost never or never

we noted that of the 13 respondents, 3 said there was an increase in 20% in personal satisfaction in their sexual activity. One man noted an increase of 40%, going from being satisfied much less than half the time to being personally satisfied in sexual activity more than half the time.

o Overall sexual satisfaction has a lot to do with the satisfaction a man feels his partner is experiencing (Table 3c).

When we asked:

Over the last four weeks, how satisfied has your partner been with your overall sex life?

o Very satisfied

o Moderately satisfied

o About equally satisfied and dissatisfied

o Moderately dissatisfied

o Very dissatisfied

5 of the 13 men reported no change in the sexual satisfaction of their partner after taking the capsules. However, 4 men felt there was a 20% jump in sexual satisfaction, going from being moderately satisfied to very satisfied. 2 men noted a jump in their partner's satisfaction, going from being equally satisfied and dissatisfied to very satisfied. 1 man felt his partner's satisfaction went from moderately dissatisfied to moderately satisfied.

Sexual Desire

o Enhanced or increased sexual desire plays a large role in overall sexual satisfaction.

When we asked:

Over the last four weeks, how often have you felt sexual desire?

o Almost always or always (daily)

o Most times (several times a week)

o Sometimes (several times a month)

o A few times (a few times per month)

o Almost never or never

we noted that sexual desire was increased by use of the herbal complex product (Table 4a). While 5 subjects maintained the same level of desire over the course of the study, 6 subjects noted an increase in 20%, with 1 subject noting a boost of 40%, going from feeling sexual desire a few times a month to several times a week.

o Perception of one's sexual desire is critical in overall sexual satisfaction.

When we asked:

Over the last four weeks, how would you rate your level of sexual desire?

o Very high

o High

o Moderate

o Low

o Very low or none at all

we found that most of the men maintained their same level of sexual desire (n = 7). However, after taking the herbal complex product, five noted increases of 20% in their levels of sexual desire. 2 went from low levels of desire to moderate levels; 1 went from moderate to high levels of desire; and 1 went from high to very high levels of sexual desire. 1 man noted a 40% increase, going from very low or no desire to a moderate level of sexual desire.

Sexual Activity

o In an effort to see if the herbal complex product triggered an increase in the amount of sexual activity, we asked:

Over the last four weeks, how many times have you attempted sexual activity? (Sexual activity was defined as masturbation or intercourse.)

o No attempts

o 1-2 attempts

o 3-4 attempts

o 5-6 attempts

o 7-10 attempts

o 11-20 attempts

After taking the product for the allotted time, we noted that there was an increase in sexual activity (Table 5). 5 men in the active group maintained their high levels of sexual activity (3-4 attempts or higher), while 2 men had a decrease in sexual activity; 1 man admitted that he did not have a regular sexual partner, which accounted for his decrease in activity. 6 men noted 20% increases in sexual activity, with 4 men going from 7 to 10 attempts in the time span to 11 to 20 attempts.

The Viagra Trial

o The population of men for this portion of the trial used Viagra (VM) and were patients at a clinic in New York City. They ranged in age from 36 and 66 and over. There were no documented side effects attributed to the herbal complex product during the trial evaluation of 60 days. 13 VM completed the trial. After 45 days, 6 of the 13 men noted a positive effect of the herbal complex product on their overall sexual satisfaction.

Sexual Satisfaction

When the 6 VM men were specifically asked:

Over the last four weeks, how satisfied have you been with your overall sex life?

o Very satisfied

o Moderately satisfied

o About equally satisfied and dissatisfied

o Moderately dissatisfied

o Very dissatisfied

we noted that 5 of the 6 men maintained their same level of satisfaction, perhaps indicating the efficacy of Viagra (Table 6a) . However, one subject noted a jump in his satisfaction, going from moderately dissatisfied to moderately satisfied after using the herbal complex product.

o Individual satisfaction remained the same for 4 of the 6 respondents from Day 1 to Day 45 (Table 6b).

When the 6 VM were specifically asked:

Over the last four weeks, when you attempted sexual activity, how often was it satisfactory to you?)

o Did not attempt sexual activity

o Almost always or always

o Most times (much more than half the time)

o Sometimes (about half the time)

o A few times (much less than half the time)

o Almost never or never

we noted that of the 6 respondents, 2 said there was an increase in 20% in personal satisfaction in their sexual activity.

o In order to find out how much the subject enjoyed sexual intercourse after taking the herbal complex product, we asked:

Over the last month, how much have you enjoyed sexual intercourse?

o No intercourse

o Very highly enjoyable

o Highly enjoyable

o Fairly enjoyable

o Not very enjoyable

o No enjoyment

3 of the 6 subjects noted increases in enjoyment (Table 6c). 1 subject went from feeling very enjoyable to very highly enjoyable. 2 subjects noted 20% increases, going from fairly enjoyable to highly enjoyable and highly enjoyable to very highly enjoyable. 1 subject maintained his highly enjoyable feelings. 1 male went from very highly enjoyable to enjoyable, and 1 man had no sexual intercourse in that period.

o Overall sexual satisfaction has a lot to do with the satisfaction a man feels his partner is experiencing (Table 6d).

When we asked:

Over the last four weeks, how satisfied have you been with your sexual relationship with your partner?

o Very satisfied

o Moderately satisfied

o About equally satisfied and dissatisfied

o Moderately dissatisfied

o Very dissatisfied

2 of the 5 respondents remained moderately and very satisfied, while 1 man went from feeling moderately dissatisfied to very satisfied with his sexual relationship after taking the capsules. Conversely, two men taking Viagra noted a drop in their sexual satisfaction with their partners. 1 man did not have a regular sexual partner.

Sexual Desire

o Enhanced or increased sexual desire plays a large role in overall sexual satisfaction.

When we asked:

Over the last four weeks, how often have you felt sexual desire?

o Almost always or always (daily)

o Most times (several times a week)

o Sometimes (several times a month)

o A few times (a few times per month)

o Almost never or never

we noted that increases in feelings of sexual desire in 3 of the 6 respondents (Table 7a). 2 of the subjects jumped from feeling sexual desire sometimes to almost always. 2 subjects maintained the highest levels of sexual desire; 1 man noted an increase from sometimes to most times, and 1 man dropped from feeling sexual desire almost always to most times.

o Perception of one's sexual desire is critical in overall sexual satisfaction.

When we asked:

Over the last four weeks, how would you rate your level of sexual desire?

o Very high

o High

o Moderate

o Low

o Very low or none at all

we found that there was a marked increase in desire (Table 7b), with 2 men noting that desire increased after taking the herbal complex product from moderate to high, and 1 man noting an increase from moderate to very high. 2 subjects maintained their previous very high and high levels of sexual desire, while 1 man noted a drop in overall desire from high to moderate.

Sexual Activity

o In an effort to see if the herbal complex product triggered an increase in the amount of sexual activity, we asked:

Over the last four weeks, how many times have you attempted sexual activity? (Sexual activity was defined as masturbation or intercourse.)

o No attempts

o 1-2 attempts

o 3-4 attempts

o 5-6 attempts

o 7-10 attempts

o 11-20 attempts

After taking the product along with their Viagra for the allotted time, we noted that there was definitely an increase in sexual activity (Table 8). While 3 men maintained their level of sexual activity, 3 men went from 7-10 attempts at sexual activity per month to 11 to 20 attempts.

Erectogenic Effect

o In an effort to see if the herbal complex product could have an impact on a man's ability to get an erection during sexual activity (Table 9a), we asked,

Over the last month, how often were you able to get an erection during sexual activity?

o No sexual activity

o Almost always or always

o Most times (much more than half the time)

o Sometimes (about half the time)

o A few times (much less than half the time)

o Almost never or never

4 of the 6 subjects maintained the same high level of being able to get an erection. However, 1 man went from sometimes being able to get an erection to almost always or always. Finally, 1 man reported that he went from no sexual activity in the previous month to sometimes being able to get an erection, which was a product of engaging in sexual activity.

o Maintaining an erection suitable enough for penetration is often a problem for men with erectile dysfunction. In order to determine how often their erections were hard enough for penetration (Table 9b), we asked:

Over the last month, when you had erections with sexual stimulation, how often were your erections hard enough for penetration?

o No sexual activity

o Almost always or always

o Most times (much more than half the time)

o Sometimes (about half the time)

o A few times (much less than half the time)

o Almost never or never

In this instance, the herbal complex product seemed to have a positive effect in 5 of the 6 men. Although 1 subject dropped from almost always to most times in being able to maintain his erection and 1 man maintained his high consistency, 4 men noted improvements. 2 men went from most times to almost always being able to maintain their hard erections and 1 man noted going from almost never being able to have an erection suitable for penetration to sometimes being able to have an erection suitable for penetration. Finally, 1 man went from no sexual activity in the previous month to sometimes being able to maintain an erection suitable for penetration.

Sexual Confidence

o Finally, the men were asked if they felt increased confidence in their ability to achieve and maintain an erection (Table 9c). We specifically asked:

Over the last month, how do you rate your confidence that you can get and keep your erection?

o Very high

o High

o Moderate

o Low

o Very low

3 of the 6 respondents maintained their moderate and high levels of confidence after taking the herbal complex product. However 1 man felt that he had increased his confidence from moderate to high and 1 man went from high to a very high level of confidence. 1 man jumped from a low level of confidence at the beginning of the study to a very high level of confidence that he could achieve and maintain his erection by study's end.

The Placebo Phase

o The placebo phase of the study lasted for two weeks. (Table 10) 13 men who had noted a positive effect of the herbal complex product on their sexual satisfaction were randomly selected by the study program coordinator to receive an unlabeled container with active product or an unlabeled container with placebo product. 6 men received the placebo, and 7 men received the active product. The plain white plastic bottles were unlabeled and neither the study participants nor the study director knew which men received which product during this phase of the study.

After two weeks, the study director telephoned the men and asked the participants if they noted any continued positive effect with the product they had been provided. Of the 6 men who received the placebo, no one noted any positive response. Of the 7 men who received the active product, 6 men noted a continuation of the positive response, with 1 noting no effect whatsoever on sexual satisfaction.

There were no negative side effects noted.

TABLES

Table 1.

Schedule of events for clinical evaluation of an herbal complex product as enhancer of sexual response.

Time Healthy Male Group

Day 1

Complete consent form Complete questionnaire

Distribute herbal capsules

Start taking supplement

Day 45

Return questionnaire #1

Complete second questionnaire

Randomized to placebo group

and active group based on stated

efficacy of product.

Day 60

Phone participants for comments on

product

Table 2.

Schedule of events for clinical evaluation of an herbal complex product as enhancer of sexual response.

Time Viagra Group

Day 1

Complete consent form Complete questionnaire

Distribute herbal capsules

Start supplement

Day 45

Return questionnaire #1

Complete second questionnaire

Continue taking the product

The following three questions ask about sexual satisfaction.

| See Table 3a & 3b |

Day 60 Phone participants for comments on product

| See Tables 3c, 4a, 4b, & 5 |

The following four questions ask about sexual satisfaction.

| See Tables 6a, 6b, 6c, 7a, & 7b |

The following question refers to sexual activity.

| See Tables 8, 9a, 9b, 9c & 10 |

DISCUSSION

Sex, when not intended for procreation, is about having fun. It can have positive value, helping increase one's sense of well being and may even prolong life. Sex is a highly complex issue. Whether one is an adolescent or a senior citizen, sex requires various levels of desire, performance, and communication. We appreciate just how complicated the issue of determining actual sexual satisfaction actually is. We do know, however, that there appears to be a large portion of our population, both male and female, that is not experiencing sex commensurate with their expectation levels. Males and females have similar and dissimilar issues. Dissimilar issues include those of desire, performance, and communication. Biologic issues such as atherosclerosis, neurological difficulties, diabetes, arthritis, and hormonal factors, as well as social and religious factors, early sexual experience, trauma, and medications all contribute to the overall sexual satisfaction of men and women.1

With that in mind, we understand that one single performance medication, such as Viagra, or less powerful agents, such as the herbal complex product, will not be the solution to everyone's overall sexual satisfaction. Still, anecdotal reports of an improvement in sexual satisfaction with a particular herbal complex product prompted us to investigate whether there was a beneficial prosexual effect. There are currently many OTC prosexual products available in pharmacies, health food stores, and via the Internet. We chose a specific herbal complex product supplement and the manufacturer supplied us with unmarked containers of capsules for our study.

Although the pharmacology of each of the four individual prosexual ingredients in the mixture can be found in various texts, we do not know the pharmacological action of this particular mixture. In this two phase, double-blind placebo-controlled study of oral supplementation with a herbal complex product in men, we found no toxic side effects with the two-capsule (1616 mg) daily dose or the additional four-capsule (3232 mg) dose taken prior to sexual activity as judged from medical interviews by the attending physician and questionnaire reports. The mode of action of the herbal complex product has not been clearly defined, although anecdotally it is known to enhance sexual arousal in animal and human subjects.

There were no toxic side effects observed. Statistically significant sexual satisfaction was observed for the individuals taking the herbal complex product. A significant number of healthy men (n = 13) reported that the product enhanced their overall sexual satisfaction. In reviewing patient questionnaires and in telephone interviews, what was clearly noted was that taking the herbal complex product seems to significantly increase sexual satisfaction in healthy men and in men taking Viagra. We hypothesize that the particular ingredients working in concert produce a stimulating effect on most men.

A fulfilling sex life requires a lot more than a pill or a capsule. There are any number of variables and conditions which can affect the attraction, as well as the sexual performance, of two people. Therefore, we must note that sexual satisfaction can't be judged by only one parameter. For some men, enhancing sexual satisfaction requires enhanced sexual performance, while for others it requires enhanced sexual interest. For others, it's a boost in confidence which then leads to an increase in overall sexual activity and satisfaction. Still, in others, enhanced sexual satisfaction is linked with the deep and loving relationship they have established with their partner.

This particular herbal complex product appears to function on multiple levels. What percentage has a placebo effect is unknown. We know there is a placebo effect with every product and there may be one with this one as well. However, we believe that this herbal complex product goes beyond placebo and is worthy of use.

In summary, our Phase 1 study demonstrates that daily supplementation with Horny Goat Weed herbal complex product can lead to increases in overall sexual satisfaction.

REFERENCES

1. Couzens GS, Lamm S. The Virility Solution. New York, NY: Simon & Schuster, 1998

2. Bensky D, Gamble A. Chinese Materia Medica. Vista, CA: Eastland Press. 1993

3. Feldman HA, Goldstein I, Hatzichriston DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151: 54-61.

4. Laumann EO, Paik A, Rosen RC. Sexual Dysfunction in the United States; prevalence and predictors. JAMA 1000; 281, No 6: 537-44.

5. Rosen, RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The International Index of Erectile Dysfunction (IIEF); a multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: 822-30.

Ref.48c:
Dette er en tekstkopi af:
http://earthnotes.tripod.com/barrenwort.htm

BARRENWORT

aka Horny goat weed

(Epimedium spp)

[YIN YANG HUO] CAUTION: Excess causes vomiting, dizziness, thirst and nosebleed. Not to be taken over long periods. CONTRAINDICATIONS: When there is a tendency toward hypersexuality and wet dreams and for those with severe emaciation and weakness. A low-growing herb with underground stems, small compound leaves and small flowers, which is native to temperate regions of Europe and Asia. In Asia the leaves are eaten as food. Its common name means 'friend of the barren'. Or in this case the belief that barreness is caused by a non-existant libido which this herb is believed to cure. Plants of this species have been used as a folk remedy for rheumatism as well as having an anecdotal history as a cure for certain types of cancers (breast and uterus). The species has also been used in folk medicine for impotence, neurasthenia, numbness, and weak knees. Some or all are considered to be analeptic, aphrodisiac, carminative, sudorific and tonic.

Besides the three listed here, related varieties include E. brevicornum and E. Koreanum.

Epimedium acuminatum

CONTAINS: Ceryl alcohol, hentriacontane, oleic acid, linoleic acid, palmitic acid, stearic acid, and phytosterol.

MEDICINAL USES:

Anti-asthmatic, antirheumatic, antitussive, aphrodisiac.

Used for eye ailments and renitis.

Considered tonic for stimulating hormone secretion to cure impotence.

Also used for absentmindedness.

Epimedium grandiflorum

CONTAINS: Glycoside icariin or epimedin, benzene, sterols, tanning, palmitic acid, linolenic acid, oleic acid and vitamin E.

PART USED: Leaves.

MEDICINAL USES:

Antirheumatic and aphrodisiac.

Used in traditional Chinese medicine for impotence, frigidity, spermatorrhea, frequent urination, forgetfulness, withdrawal, feelings of coldness in lower back accompanied by soreness in back and knees, spasms and cramps in hands and feet, numbness in extremities, dizziness and menstrual irregularity associated with high blood pressure.

Chinese research reports effectiveness in stimulating sexual activity and sperm production. Also, stimulating 'sensory nerves'. Has mild androgenic effect on testes, prostate and levator ani. The leaf extract increases frequency of copulation in animals. Injections of epidemin increase seminal secretions in dogs.

Low doses increase urine output while large doses decrease it.

Epimedium sagittatum

PROPAGATION: By seed in late summer and by division in spring and autumn.

NEEDS: Grown as an ornamental. Needs moist, rich, well-draining soil in partial shade. Cut back in late winter before new growth appears. Young shoots can be damaged by frost.

HARVEST: Whole plant during the growing season. Dry for decoctions.

MEDICINAL USES:

Pungent and sweet; liver and kidney tonic; dilates blood vessels, lowers blood pressure, antitussive, expectorant; aphrodisiac, stimulates secretion of hormones.

Used for asthma, bronchitis, cold or numb extremities, arthritis, lumbago, impotence, involuntary or premature ejaculation, high blood pressure, and forgetfulness.

May be useful to stimulate sex drive in women who are androgen deficient.

DOSE:

INFUSION = 1 to 3 tsp steeped in 1 cup of water and taken 1 cup per day.

Ref.45a:
Dette er en tekstkopi af:
http://www.tribestan.com

Tribestan improves sexual activity, and also improves and prolongs penile erection in men. In women it improves sexual activity, stimulates ovogenesis and has other beneficial effects as well. Traditionally used as a dietary supplement to enhance vigor, vitality and stamina.

Naturally Safe for Enhanced Performance

o Improves muscle growth & body strength

o o Reported to enhance libido sexualis & erectile function

o o Reported to increase the number and motility of spermatozoa

o o Reported to increase the body's natural testosterone and LH levels

o o Helps in alleviating some symptoms associated with male menopause

o o No adverse effects

o o No toxicity and side effects

o Why Tribestan and NOT other Tribulus products

The active substance in Tribestan is a proprietary extract and does NOT contain herbal particles that may pose health danger.

o Raw Material vs. The Extract

o o Comparative testing on Tribulus Terrestris products and substances vs. Tribestan

o o Tribulus qualities for an Effective Product

What is Tribestan used for?

Since the body's natural testosterone promotes protein synthesis and positive nitrogen balance, the benefits for the professional or the recreational athlete engaged in active training and workout, are muscle cell growth and increased body strength as well as faster recuperation and recovery from muscular stress.

What is Tribestan?

o Tribestan is a completely natural non-hormonal herbal (phytochemical) biostimulator derived from the plant Tribulus terrestris L., Bulgaricum, which contains predominantly saponins of furostanol type, with prevailing quantity of protodioscin (not less than 45% in Tribestan). It is a natural herbal alternative to synthetic anabolic hormones without any clinically proven toxic effects.

o o Tribestan administration leads to increased muscle mass in active sports by activating the enzyme associated with energy metabolism. At the same time it has also been reported to have the ability to stimulate some functions associated with the increase of the body's natural endogenous testosterone and lutenizing hormone (LH) levels. With the increase of the body's natural endogenous testosterone level, it can help alleviating some symptoms associated with male menopause.

o o Nearly 20 years of experience with natural herbal Tribestan administration has seen no toxicity and negative effects to date.

On muscle growth and body strength

For years, Tribestan has been used by athletes of the Soviet Bloc. The Bulgarian strength athletes have also used it extensively with effectiveness. Tribestan has passed all the drug tests at every competitive level and has been used with significant results by top professional athletes as well as by recreational sport participants with no contraindications, no toxicity and no side effects. With its good safety profile and its natural herbal origin, Tribestan is sold as a dietary supplement in many countries with little restriction on its use

On safety

o Special attention should be given to the harmlessness of the natural herbal product Tribestan.

o o No evidence of acute, sub-acute and chronic toxicity has been found during the experimental behavioral, hematological, functional, biochemical and morphological studies.

o o Absence of carcinogenic and teratogenic effect.

o o No adverse effects were noted in any of the clinical studies and additional research demonstrated no adverse effects on the Central Nervous System and the Cardiovascular System.

A summary on clinical studies on Tribestan

o Tribestan has also been reported to be a popular medicinal herb in Bulgaria and the East, Eastern Europe, China, India, etc. for the treatment of sexual deficiencies. Three major medical centers in Bulgaria have therefore conducted clinical studies on Tribestan effect on reproductive functions. In 1981, Tribestan was incorporated into mainstream medical treatment in much of Eastern Europe for:

o o Improvement of libido and erectile function

o o Increasing serum concentration of testosterone and LH

o o Stimulation of spermatogenesis with increased concentration of spermatozoa, increase in sperm motility and viability

o Report on libido sexualis and erectle dysfunction

o In clinical studies on 212 patients, 85% of patients with reduced libido, demonstrated improved libido after 30 days and 94% after 60 days of treatment with Tribestan.

o o For 36 patients with chronic prostatitis and reduced libido, 75% reported favorable effects at the end of the treatment cycle.

o o In animal studies, libido and sexual reflexes were restored in 71% of subjects with complete absence of libido. In subjects with poor libido and sexual reflexes, recovery was recorded in 100% of cases.

o o Treatment of patients with unilateral and bilateral hypotrophy of the testes, demonstrated enhanced libido and improved spermogram after 60 days.

o o In patients with primary and secondary hypogonadism, 78% reported restored and enhanced libido

o Report on stimulation of spermatogenesis

Tribestan administered to males with idiopathic oligoasthnozoospermia or with spermogram disturbances due to varicocele, has shown increased concentration of spermatozoa, increased percentage of motile spermatozoa. Increased spermatozoa motility rate and, for some cases, increased volume of ejaculate of 1 to 2 ml. In controlled studies the number of Sertoli cells increased by 40% with no change in the number of Leydig cells.

Report on increase of the body's natural testosterone

In patients with testosterone serum levels below the lower limit of the norm, the physiological levels were reached after treatment, whereas in patients with normal initial levels, the testosterone level was not significantly changed after treatment.

Ref.45b:
Dette er en tekstkopi af:
http://www.natur-drogeriet.dk/produkt1203.cfm

Tribulus – godt nyt for sportsfolk!

Tribulus terrestris er en urt, der er blevet brugt i Bulgarien og Østen i århundreder til at øge energi og ydeevne. Særligt interessant er Tribulus for atleter og sportsfolk, og dets virkninger har i årtier været eftertragtet af bulgarske atleter. Tribulus er vital, fordi den spiller en nøglerolle i vores krop, herunder i opbygningen af musklerne og dermed har betydning for deres størrelse og styrke. Atleter bruger Tribulus for at sikre sig bedre resultater på et hvilket som helst tidspunkt! Tribulus kapsler forhandles i Danmark i en styrke af 340 mg Tribulus terrestris ekstrakt pr. kapsel, indeholdende 30% saponiner. Dosis: 1-2 kapsler pr. dag. Bivirkninger: Ikke kendt ved anbefalet dosis. Dåse med 90 kapsler. Præparaterne forhandles af materialister, helsekostforretninger og nogle apoteker.

Ref.45c: Dette er en tekstkopi af:
http://www.urtegartneriet.dk/Korte_Nyheder.htm

Naturens viagra

Januar 99

Rumpetorn (Tribulus terrestris) siges af canadiere, at virke lige så godt som viagra. En 25 årig mand Eric Wicik, tog tinktur og siger at det hjalp i løbet af 2 dage. Rumpetorn, på engelsk Puncture vine, har så skarpe frø at de kan punktere en cykel.

Den vokser vildt i USA og det sydlige Europa.

Den har længe været brugt indenfor naturmedicin mod impotens. I de senere år har den mest været kendt blandt bodybuildere som et naturligt steroid. I følge en undersøgelse fra 1981 på Chemical Pharmaceutical Institute in Sofia, Bulgaria, kan den i løbet af få dage øge testosteron tallet med op til 30 procent.

Sædkvaliteten steg væsentligt, den forbedrede immunforsvaret, øgede selvtilliden, forbedrede humøret og sænkede kolesteroltallet.

Den skulle kunne bruges af begge køn. (dette modsiges af vores ældre urtelitteratur f.eks. 'A Modern Herbal' af Mrs. M. Grieve, 1931 der kun anbefaler den til mænd)

Det må vi nok sige! Den trænger vist til yderligere undersøgelser.

Forøvrigt er det en af de mest omdiskuterede urter i amerikanske urtekredse i år. Derovre markedsføres den allerede som tinktur m.m.

Det kan næppe vare længe før vi ser den i handelen i Europa.

Ref.32: Dette er en tekstkopi af:
http://www.hisandherhealth.com/sms2001/vardenafil_a_new_selective.shtml
VARDENAFIL, A NEW SELECTIVE PDE-5 INHIBITOR, INTERACTS MINIMALLY WITH NITROGLYCERIN IN HEALTHY MIDDLE-AGED MALE SUBJECTS Arthur L. Mazzu, PhD, West Haven, CT; Andrew J. Nicholls, MD, PhD, West Haven, CT and Miguel Zinny, MD, Boston, MA (Presentation by Dr. Mazzu) Funded by Bayer Corp.

The combination of the phosphodesterase-5 (PDE-5) inhibitor sildenafil and an organic nitrate may produce significant hypotension. The population likely to be prescribed a PDE-5 inhibitor for erectile dysfunction (ED) is also at risk of coronary ischemia. The current study was undertaken to evaluate the interaction between nitroglycerin and vardenafil, a selective PDE-5 inhibitor under development. This was a randomized, placebo-controlled cross-over study of vardenafil in healthy males (n=18, age 40-65). The hypotensive effect of single doses of sublingual nitroglycerin (NTG, 400 micro g) was assessed 24, 8, 4 and 1 hour (approximately tmax) after a series of oral doses of vardenafil 10 mg or matching placebo. Subjects' blood pressure (BP) and heart rate (HR) were measured when seated. Immediately prior to NTG administration, BP and HR were comparable following treatment with vardenafil and placebo. BP and HR data over the 90 minutes following NTG for the treatment day in which vardenafil or placebo was administered 1 hour before NTG are provided in the Table. NTG administration 1 hour after vardenafil caused changes in blood pressure and heart rate comparable with those observed following NTG and placebo. Similar data were obtained for larger intervals between vardenafil and NTG dosing. In all cases the combination of agents was well tolerated.

The apparent lack of an interaction between NTG and vardenafil observed in this study should be evaluated in the target patient population.

Table: Mean maximum changes (min, max) in BP and HR following NTG (400 micro g) administered one hour after oral vardenafil (n=18).

……………………………………Vardenafil 10 mg ………..Placebo Change in syst. BP (mm Hg)

-19.2 (-3 to -42) …………….-20.9 (-9 to -37) ……….Change in diast. BP (mm Hg)

-20.1 (-9 to -32) …………….-17.9 (-9 to -33)

Increase in HR (bmp) ………..13.9 (1 to 27) ………….15.6 (6 yo 27)

Ref.31: Dette er en tekstkopi af:
http://www.meerburgpharmacy.com/uprima_information_leaflet.htm
Uprima 2 mg sublingual tablets respectively Uprima 3mg sublingual tablets

apomorphine hydrochloride

Each Uprima 2 mg tablet contains 2 mg of apomorphine hydrochloride, equivalent to 1.71 mg of apomorphine . Each Uprima 3mg tablet contains 3 mg of apomorphine hydrochloride, equivalent to 2,56 mg of apomorphine.

The other ingredients are: microcrystalline cellulose, hypromellose, citric acid, magnesium stearate, ascorbic acid, disodium edetate, silicon dioxide, red iron oxide (E172), acesulfame potassium, Orange mint flavour (WONF WL-28499) and mannitol.

The Marketing Authorisation holder and the manufacturer of Uprima is Abbott Laboratories Ltd, Queenborough, Kent ME11 5EL, United Kingdom

1. WHAT UPRIMA IS AND WHAT IT IS USED FOR

Uprima 2 mg tablets are sub-lingual tablets each containing 2 mg of apomorphine (as hydrochloride). The 2 mg tablet is available in packs of 1, 2, 3, 4 and 8 sublingual tablets. Uprima 2 mg tablets are brick red in colour and are pentagon shaped embossed with 2 on one side and the Abbott logo on the other side.

Uprima tablets are sub-lingual tablets each containing 3 mg of apomorphine (as hydrochloride). The 3 mg tablet is available in packs of 1, 2, 4, 8 and 12 sublingual tablets. Uprima 3 mg tablets are brick red in colour and are triangle shaped embossed with 3 on one side and the Abbott logo on the other side.

Uprima is a medicine known as a dopaminergic agonist which helps men achieve an erection by stimulating the region of the brain, called the hypothalamus, thereby helping to produce the natural signals which start the erection process in the penis. Sexual stimulation is necessary for Uprima to work.

Uprima is different to morphine and has no morphine-like properties.

Uprima is a therapy for the treatment of men with erectile dysfunction (sometimes called ED or impotence). This is a condition in which a man cannot get, or keep, a hard penis (erection) sufficient for satisfactory sexual performance.

2. BEFORE YOU TAKE UPRIMA

Do not take Uprima if:

You have ever had an allergic reaction to apomorphine or any of the ingredients in Uprima. Possible signs of an allergic reaction include rash, itching, swollen face or lips and shortness of breath. Tell your Doctor if you get any of these.

You have severe unstable angina, recent myocardial infarction, severe heart failure or hypotension, and other medical conditions which could make sexual activity dangerous. Always consult your Doctor about your medical history.

Your partner is pregnant or breastfeeding

You should tell your Doctor if:

You have a deformity or disease of the penis as these may require special care when using medicines such as Uprima.

You experience severe dizziness/lightheadedness or feel faint after taking Uprima, especially if you also have severe nausea or vomiting, sweating, become pale or become unusually hot. In these cases you should not attempt to stand up. If you experience these symptoms or feel faint for any reason you should lie down and raise your legs. The feeling of faintness should go away.

You are taking nitrates (often used for the relief of angina or chest pains) or any medicines for hypertension (high blood pressure).

You have liver or kidney problems. Your suitability for Uprima and/or the appropriate dose may need to be considered by your doctor.

You have abnormally high or low blood pressure or are prone to dizzy spells or fainting.

You are taking any other treatment for erectile dysfunction. Uprima should not be used with any other treatment for erectile dysfunction.

Uprima should not be given to children under the age of 18. No dose adjustment is required for the elderly.

Interactions with foot and drink

Taking alcohol with Uprima can increase any undesirable effects, in particular low blood pressure. In addition, taking alcohol can make it more difficult to obtain an erection.

Use by pregnant or breast-feeding women

Not for use in women.

Driving and using machines:

Because some patients can experience dizziness, lightheadedness and, uncommonly fainting, it is recommended that you do not drive or operate machinery for at least 2 hours after taking Uprima or until any such symptoms are fully resolved.

Taking other medicines:

Please inform your doctor if:

You are taking nitrates (often used for the relief of angina or chest pains) or any medicines for hypertension (high blood pressure).

You are taking drugs which affect the dopamine system (often used to treat Parkinson's disease, disturbances of the mind or to prevent vomiting).

You should also inform your doctor or pharmacist if you are taking or have recently taken any other medicines, even those not prescribed.

3. HOW TO TAKE UPRIMA

Your Doctor will decide the dose of Uprima which is suitable for you. Do not take more tablets than your Doctor has prescribed. All patients should begin with the 2 mg tablet. If your erection is not sufficient for satisfactory sexual activity at this dose and you have not experienced side effects, you may increase the dose to the 3 mg tablet following consultation with your doctor. You should not take more than 3 mg in any 8 hour period.

When taking Uprima:

Swallow a small amount of water to help moisten your mouth

Place one tablet of Uprima under your tongue. The tablet will not work if you swallow it.

Let the tablet dissolve under your tongue – this usually takes about 10 minutes (if any tablet residue is left after 20 minutes it may be swallowed).

Sexual activity may begin as soon as the Uprima is placed under your tongue and you may proceed with intercourse when you and your partner are ready.

Typically erections may be achieved in under 20 minutes, although this varies from person to person.

You should not take more than 3 mg Uprima in any 8 hour period.

If Uprima does not help you get a satisfactory erection tell your Doctor as your dose may need adjustment.

You should only take Uprima as directed. If you take too many tablets or the wrong dose, contact your Doctor.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Uprima can have side effects. These are generally mild and transient in nature.

Common undesirable effects are nausea, headache, dizziness, yawning, sleepiness, infection, sore throat, pain, increased cough, rhinitis, flushing, taste disorder and sweating.

Uncommonly, fainting has occurred. If you feel faint, follow the instructions given under 'Do not take Uprima:'

If you have chest pains during intercourse, you should stop immediately and contact your doctor.

If you have any undesirable effect which is severe or prolonged you should tell your Doctor. If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist.

5. STORING UPRIMA

Keep out of the reach and sight of children

Store your Uprima in the original package. Do not use this medicine after the expiry date shown on the pack, or if the pack has been damaged or tampered with.

Ref.27: Dette er en tekstkopi af:
http://www.palatin.com/main.asp?con=5%2E2C&nav=5

PT-141

The aging of the “baby boom” generation has brought sexual dysfunction into prominence as a medical concern. Men and women who suffer sexual dysfunction are a large and growing market not satisfied with current treatments. According to the Massachusetts Male Aging Study, more than 50% of men aged 40-70 report episodes of ED and more than 30 million men in the US suffer ongoing ED. The current market size in dollars is estimated to be from $1.5-3.0 billion, with several products already competing in the male ED market segment. The statistics for women are not well defined, yet sexual dysfunction is clearly a concern for a large number of women.

Ref.18: Dette er en tekstkopi af:
http://dir.salon.com/sex/feature/2000/09/26/wellbutrin/index.html?pn=3

Wonderful Wellbutrin?

Wellbutrin languished both on pharmacy shelves and as a focus of research. But in the mid-1990s, as the predecessors of Viagra demonstrated the market potential of pro-sexual medications, researchers showed renewed interest in Crenshaw's report. In the past few years, several studies published in respected journals — but ignored by the mass media — have confirmed Crenshaw's findings and extended them.

In a 1997 report, published in Clinical Pharmacological Therapies, researchers at the University of Alabama at Birmingham gave 107 depression sufferers one of four antidepressants: Wellbutrin or three SSRIs — Prozac, Paxil or Zoloft. Among those taking the SSRIs, 73 percent complained of sex-impairing side effects. Only 14 percent of the Wellbutrin group reported sex problems, while 77 percent said the drug "heightened sexual function." That same year, in a pilot study at the Medical University of South Carolina in Charleston, eight people who complained of sex-impairing SSRI side effects were told to take a low dose of Wellbutrin in addition. After one month, half reported "marked improvement" in their sex problems. The results were published in Annals of Clinical Psychiatry.

In another 1997 study, reported in Journal of Clinical Psychopharmacology, researchers at Valparaiso University in Indiana gave Wellbutrin to 14 nondepressed diabetic men with erection problems caused by diabetes. After 10 weeks, they showed improved sexual functioning.

In a 1998 study, researchers at the State University of New York at Buffalo repeated the South Carolina study, but on a larger scale. They tested Wellbutrin as an antidote for SSRI-induced sexual impairment in 47 depressed individuals who were told to take the drug an hour or two before sex. Wellbutrin successfully reversed the sex problems in 66 percent of them. The only significant side effect was tremor (in 15 percent).

Wellbutrin watcher Joe Graedon found these studies tantalizing. "There was mounting evidence that Wellbrutrin has a significant pro-sexual effect for people with a variety of conditions. No other drug had ever done that."

But the studies also left him frustrated. "One key question remained unanswered: Is Wellbutrin truly sex enhancing? Or is its ability to improve sexual function simply a result of mood elevation in formerly depressed people taking a drug that didn't kill sexuality? No one had nailed that down."

This year, two studies have focused on this question by testing Wellbutrin as a treatment for sexual dysfunction in people not suffering from depression or any other serious medical condition. Both studies used placebos that looked identical to Wellbutrin pills so subjects could not tell the difference.

At Case Western Reserve University School of Medicine, a team led by R. Taylor Seagraves, M.D., a professor of psychiatry, gave Wellbutrin to 66 women, ages 23 to 65, who had experienced low or no libido for an average of six years. All 66 took a placebo for six weeks, then the drug for eight weeks. At the end of the placebo phase of the study, the group averaged 0.9 sexual encounters. But by the end of treatment with Wellbutrin, the figure had more than doubled to 2.3. Extent of sexual arousal also increased significantly, and number of sexual fantasies more than doubled (0.7 to 1.8). "Before starting treatment," Seagraves says, "100 percent of the women were dissatisfied with their level of sexual desire, but by the end of the [Wellbutrin] treatment phase, 40 percent reported feeling satisfied." The drug's only signficant side effects were insomnia (18 percent), tremor (6 percent) and rash (6 percent).

Ref.1: Dette er en tekstkopi af:
http://www.independent.co.uk/story.jsp?story=319949

Paradise in a pill?

You can't buy it yet, but a drug is being developed in labs in Australia and the US that may prove to be the ultimate lifestyle enhancer – you'd get a fantastic tan and a highly active libido, with a slim figure and clear skin as possible side-effects. It's been tagged 'the Barbie drug', but has serious origins as a treatment for skin cancer and sexual dysfunction.

By David Usborne

31 July 2002

The sun may be shining brightly now, but cast your mind back to winter. Or the dismal British spring. You were pasty, probably a little overweight, and your libido was nowhere to be found, as if washed down the plughole of your shower with what remained of your hair. What were you to do? Take a trip to a tanning-salon, or to Ibiza, perhaps, and pop out the Viagra?

Viagra is all well and good – although possibly not if you have a heart condition. But wouldn't it be fabulous if the medical community could come up with a revved-up version of that blue lozenge? How about a drug that would make you brim over again with sexual desire and simultaneously turn you into an object of desire – by restoring that all-over tan, for instance?

Sounds ridiculous? Well, assorted pharmaceutical companies around the world are quietly conducting trials right now on different versions of a compound called Melanotan, which has the power to do both those things. The press has already dubbed it the "Barbie drug", after that improbably perfect physical specimen; but at the moment it's men, those who would like to look like her boyfriend, Ken, who look set to benefit. This innocent-looking white substance – an artificial version of a naturally occurring hormone – should be able to deliver a rich tan and impressive tumescence all at once. But Barbie and Ken are thin, you may protest. Believe it or not, Melanotan holds promise as an appetite suppressant, too.

What we are speaking of here, in fact, is the lifestyle drug par excellence. The only hurdle in its way is the regulatory authorities around the world. You can see why they might balk. Ageing males donning the skimpiest trunks to parade their new golden hues on Brighton beach might suddenly find themselves also parading that other physiological effect of the drug. Oh, dear. Moreover, sales of Viagra, owned by Pfizer, as well as of plane seats to the Med, might plummet. If you can tan that way, why bother with sand between your toes?

No wonder, then, that those involved in developing Melanotan on two continents have been relatively quiet about it. Johnnie Johnson, spokesman for Competitive Technologies Inc, CTT, the US company that sold the technology to the different drug companies to manufacture and market Melanotan, points to the conservative mindset of the US Food and Drug Agency. "The FDA is always reluctant to license anything that could be called a 'party drug'," he says. (Well, FDA, shape up. We want it! Now!)

Assuming any of us do ever get our hands on the stuff – and, no, sadly, there were no test samples made available for this writer – we will have researchers at the University of Arizona to thank. Interestingly, the multiple characteristics of Melanotan were stumbled upon almost by mistake. Originally, the team in Tucson, headed by Mac Hadley, a professor of cell biology and anatomy, was interested in Melanotan only as a tan inducer and a new weapon against skin cancer. It was only when men among his first guinea-pig patients reported a startling side-effect, namely a raging reaction down under, that attention was paid to the possibility of administering the drug to those of us who suffer from what the medical world coyly calls "erectile dysfunction".

That the substance – a synthetic version of a cell-activating hormone called alpha-MSH – was effective on darkening the skin quickly became evident. In early tests, green frogs turned an ominous inky colour in 40 seconds. It even worked on animal hair. "If you inject it into a golden retriever, its hair comes out black," Professor Hadley reported on those early trials in the mid-1990s. The human subjects started turning a natural-looking brown in about six days, suffering only from occasional flushing of the face as a side-effect. It works by triggering production of the melanin pigment in your skin – the stuff that turns you brown.

But then the erectile issue came up. "It so happens that one very astute observer who took this drug reported to us that he was developing spontaneous erections," recalled Dr Norman Levine, a dermatologist involved in those early trials. And so a urologist at the University of Arizona, Dr Hunter Wessells, was asked to conduct separate trials. He developed a variation on the tanning compound and called it Melanotan II. It instantly seemed to hold promise. Among his subjects at the time was Jim, who had begun to suffer from impotence at 42, when he was dating – with nervousness, he admitted – a new girlfriend. "The Melanotan, the first time, was absolutely amazing," Jim reported. "I knew something was going on. It was a very large effect."

CTT, a firm specialising in investing in innovative technologies, based in Fairfield, Connecticut, subsequently bought the patents from the university and set about awarding licences to interested drug companies. (It expects to get whopping royalty payments when Melanotan, in its different forms, hits the market. Assuming it eventually does.) The licence to manufacture Melanotan I, the tanning compound, went to a company in Australia called EpiTan. Melanotan II was taken on by a New Jersey biotech firm called Palatin.

Remember that, in the interest of winning government approval, the game here is not to stress the vanity aspects of the drug. The FDA must be shuddering now that Botox has become the de rigueur treatment for removing crow's-feet from the faces of America's newsreaders and Upper East Side social flit-abouts. (Where once you might have been invited to a Tupperware soirée in this town, today it is more likely to be a Botox party.) The message attached to Melanotan I is that it will combat skin cancer. It was smart, therefore, to direct that particular licence to Australia, the country with the highest incidence of skin cancer in the world. The beach-loving Aussies suffer from a rate of skin cancer that is 600 per 100,000 of the population. Of all the cancer cases reported in Australia, 80 per cent are skin cancers.

Getting brown to stop the damage seems almost counter-intuitive. But the idea is very simple. As EpiTan points out, the skin turns brown – when the natural alpha-MSH hormone in the body triggers the melanin – precisely to protect you from harmful UVA rays, but always too late. "When the skin is burnt, the body belatedly produces alpha-MSH, racing against the clock – a race it always loses," notes EpiTan's chief executive, Wayne Millen. "We deliver Melanotan to you ahead of your holiday, so that in the absence of sunlight, you are protected in advance." And Melanotan delivers 1,000 times more alpha-MSH than occurs naturally.

EpiTan announced in May this year that it had successfully completed a first round of human trials at the Royal Adelaide Hospital, and that it was on course to bring the drug to the market, barring problems with government bureaucrats, in about three years. While so far, it has been administering the substance via injections, the company hopes to develop a pellet that will be inserted beneath the skin to keep the subject glowing nicely for six months at a time. EpiTan, which has had to raise capital on the markets, boasts of a potential market of $1bn a year.

There is no less a sense of excitement over at the headquarters of Palatin in New Jersey, which is exploring its own variant of Melanotan II, the version that is most effective at stirring desire. It also is well into its cycle of human trials and all is going well, not least because the drug seems to stimulate sexual lust in women as well as men. And while Viagra works in a cardiovascular way, raising the blood flow into the male sexual organ – which is what makes it a no-no for anyone with a dicky heart – this drug works on the central nervous system. More specifically, Melanotan II seems to target receptors in the hypothalamus, the part of the brain where our arousal on-off switches are located. "We are trying to develop a drug that will be safe for men with cardiac problems and have a more natural effect on the pathways to normal sexual arousal," Dr Annette Shadiack, director of biological and preclinical research at Palatin, explained this week.

Talk of a "Barbie drug" makes everyone involved nervous. While EpiTan and Palatin are working on slightly different versions of the Melanotan compound first developed at the University of Arizona, you might ask if they could be recombined to offer both benefits at once, the tan and the tumescence. And don't forget the weight-loss potential of the substance. That is something that Palatin is also exploring with Melanotan, and word is that Merck, the global drug company, is also looking at developing it as an appetite reducer.

In a technical tutorial that had this non-expert reeling, Dr Shadiack explained that Melanotan seems to act on five different categories of cell receptors in the body, both in the brain and in the skin. Indeed, there may be possible applications not yet entirely understood. As if skin colour, levels of libido and numbers on the bathroom scales were not enough, there are indications that it will work to reduce inflammation, combat diabetes and eradicate acne as well. It may be primarily aimed at "Ken", but clearly it wouldn't be bad for "Barbie" either.

"It would be more difficult to get a drug like that approved," Dr Shadiack cautions. "Because what would you call the effect of such a drug and the side-effect?" Never mind that many of us dumpy mortals wouldn't care less what is a side-effect and what isn't. The bare mention in my office of a possible wonderdrug that could answer all of our insecurities of sexual performance and physical appearance in one small dose had everyone drooling. Where can I get it? Is it out yet? Can you get us any?

What about the versions of Melanotan already under development in New Jersey and Melbourne? Everyone, it seems, is striving to develop a strain of the drug that will exhibit only one of its potential characteristics, precisely because of approval worries. But is everyone sure they can do it? Certainly, no one at EpiTan has seen fit yet to explain to the men of Australia that sporting a Melanotan tan on Bondi Beach could bring unexpected erectile embarrassment. Nor has Palatin spoken about the risk that patients looking for renewed libido might also have to explain to co-workers that they have not just spent their weekend in the Caribbean.

"I don't know whether the sexual dysfunction folks have tried to negate the tanning, although I don't think that's possible, nor do I think that the EpiTan folks have disabled the sexual arousal," noted Mr Johnson of CTT. "It's all about what you are allowed to sell it as."

At Palatin, Dr Shadiack is more circumspect. But, adopting a more scientific vocabulary, she almost agrees. "If you have a compound that is triggering one of those receptors and you give enough of it, it could activate other receptors. If you deliver high amounts, it could trigger some cross-reactivity." Isolating one effect from the other may therefore be difficult. She does note that EpiTan may have a particular problem with its ambition of inserting a pellet beneath the skin to keep the Melanotan working for six months in one stretch. None of us, surely, however frustrated, could sustain a high level of sexual arousal for that length of time?

So – to return to the billion-dollar question – would it be possible deliberately to deliver a form of Melanotan that would indeed offer all the promised effects at once? In other words, would it be possible to give us the "Ken-and-Barbie drug" that so many of us would surely crave? "You could," she replied, quickly.

Get ready for bliss-on-Earth, where even the saddest among us will have a chance to be that Mattel doll. Our skins will be bronzed and a new firmness will return to our acne-free complexions – and to other parts. Too good to be true? Hey, welcome to the bright new biotech world.

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