Presentation on theme: "Adam and Eve in the Garden of Viagra®"— Presentation transcript:
1Adam and Eve in the Garden of Viagra® Bruce R. Gilbert, M.D., Ph.D.Associate Clinical Professor of UrologyAssociate Clinical Professor of Male Reproductive Medicine and SurgeryWeill Cornell Medical College
2Disclosure Member of the Speakers Bureau for Pfizer Sildenafil Citrate (Viagra®)Clinical Investigator for Johnson and JohnsonInvestigational Drug for Rapid EjaculationClinical Investigator for GlaxoSmithKlein PLCInvestigational drug affecting sexual function
10Prevalence of Sexual Dysfunction 10% to 52% of men25% to 63% of womenFrank et al, 1978,Spector et al,1990Rosen et al,1993
11Sexual Dysfunction in Women: Office Based Survey of Women in Both Urologic and Gynecologic Practice Wellman W. Cheung1, Nabet G. Kasabian2, Stanton C. Honig3, Mary J. Minkin3, Bruce R. Gilbert1,2, 1SUNY at Stony Brook, 2North Shore University Hospital, 3Yale UniversityAUA 2000
12IntroductionIn this survey we attempted to define the prevalence of and identify the interest in, treatment for sexual dysfunction in women in our community.
13Methods102 women who presented for routine urologic (26) or gynecologic (76) care were asked to complete a questionnaire (anonymous).
14Results Age 42.9 + 11.8 Medical History range 24.9 to 78.5 73% excellent health6% hypertension1% smokingNo patients with diabetes or neurologic disease
15Results (con’t) Social History 5.8% used antidepressants Alcohol (65.4%)5.5% < 1 drink/week49% drinks/week38% drinks/week7.5% > 5 drinks/weekBicycling28.4% (1.75 hours/week)
18Results (con’t) 81% described impairment of sexual function 55% would seek treatment if effective treatment available
19National Prevalence of FSD National Health and Social Life Survey (NHSLS): a study (90 minute personal interview by trained/experienced interviewer) of adult sexual behavior in the United States: 1410 men and 1749 women between 18 and 59 years of ageLauman et al, 1994In 1999 data from the NHSLS was re-evaluated using multivariate techniques to estimate the relative risk (RR) of sexual dysfunction for each demographic characteristic as well as for key risk factors.Lauman et al, Sexual Dysfunction in The United States, JAMA, 281,537,199943% of Women (and 31% of Men) had sexual dysfunction
21Global Study of Sexual Attitudes and Behaviors (GSSAB) An International survey of adults aged 40 to 80 years13,882 Women, 13,618 MenMost Common Complaints:Women:lack of interest (26 to 43%), inability to reach orgasm (18 to 41%), difficulty with lubrication (16 to 37%)Men:rapid ejaculation (12 to 30%), erectile dysfunction (13 to 28%)Lauman,ED et al, Int J Impot Res, 17(1):39-57, 2005
23Classification of Sexual Dysfunction SEXUAL DESIRE DISORDER The persistent or recurring deficiency (or absence) of sexual fantasies, thoughts and/or receptivity to sexual activity which causes personal distress.Hypoactive sexual desire disorder (302.71)Sexual aversion disorder (302.79)SEXUAL AROUSAL DISORDER (302.72)Female: The persistent or recurring inability to attain or maintain adequate sexual excitement causing personal distress. (e.g., lack of genital lubrication/swelling) or other somatic responsesMale: Persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate erectionBasson et al, Report of the International Consensus Development Conference on Female Sexual Dysfunction: Definitions and Classifications, J. Urol., 163:888,2000* Not included: sexual satisfaction disorder, substance-induced FSD
24Classification of Sexual Dysfunction ORGASMIC DISORDERFemale (302.73): The persistent or recurring difficulty, delay in, or absence of attaining orgasm following sufficient stimulation and arousal that causes personal distress.Male (302.74): Persistent or recurrent delay in, or absence of orgasm following a normal sexual excitement phase during sexual activity.Male (302.75): Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration and before the person wishes.SEXUAL PAIN DISORDER (recurrent or persistent)Dyspareunia (302.76) Recurrent or persistent genital pain associated with sexual intercourse.Vaginismus (306.51) Recurrent or persistent involuntary spasms of the muscles of the outer third of the vagina that interferes with vaginal penetration, and which causes personal distress.Other (non-coital) Recurrent or persistent genital pain induced by non-coital sexual stimulation (e.g., infections, vestibulitis, trauma,endometriosis)
26Sexual Dysfunction is an Important Health Concern ED may indicate the presence of serious medical disorderMassachusetts Male Aging Study (MMAS) reports*1Cardiovascular 39% incidence of ED diseaseDiabetes 29% in men with good control; % in men with poor control2Depression Up to 90% have some sexual complaintsHyperlipidemia 16% association with ED90% demonstrate penile arterial disease on Doppler ultrasound2*Impotence probability pattern after adjusting for age.1. Feldman HA et al. J Urol. 1994;151: Billups K. Presented at: 95th Annual Meeting of the American Urological Association; April 29-May 4, 2000; Atlanta, Ga. Abstract.
27Risk Factors for Sexual Dysfunction HypertensionHyperlipidemiaHypogonadismEndocrine disordersSmokingAlcohol abuseDrug abuseAnemiaTrauma or surgery to the pelvis or spineCoronary artery or peripheral vascular diseasePeyronie’s diseaseVascular surgeryDepressionMedications
28Drugs Associated with Sexual Dysfunction AlcoholEstrogensAntiandrogensH2 receptor blockersAnticholinergicsKetoconazoleAntidepressantsMarijuanaAntihypertensivesNarcotics-blockersPsychotropicsCigarettesCocaineSpironolactoneLipid-lowering agentsNSAIDsCytotoxic drugsDiuretics
29Psychotropics and Sexual Dysfunction Key HormonesDHEAOxytocinPhenylethylamaine (PEA)EstrogenTestosteroneProgesteroneProlactinVasopressinDopamineSerotoninAcetylcholineGutierrez,M et al, Pharmacotherapy:19(7): , 1999
30DHEA (dehydroepiandrosterone) Precursor of Testosterone and EstrogenExcitatory role in limbic arousalDecrease DHEA: carbamazebine, phenytoin, cytochrome P450, 3A4 inhibitors, alcoholIncrease DHEA: bupropion, digoxin,diltiazem, cigarette smoking
31Oxytocin Facilitates attraction and touch sensation. Levels increase with touch and spike with orgasmResponsible for postorgasm inertia and refractory periodIncreased by estrogen and yohimbineDecreased by alcohol, catecholamines
32ProlactinDirectly inhibits sexual desire, arousal and orgasm and erectile functionLevels increased by dopamine-blocking drugs (most antipsychotic drugs) and opiatesLevels decreased by bromocriptine, testosterone, dopamine and bupropion
33Dopamine (DA) Neurotransmitter in the mesolimbic “pleasure center” Increasing DA activity may enhance sexual response whereas blocking it may compromise itMany antipsychotic agents are DA blockersBupropion has mild DA agonist activity
34Serotonin Reciprocal relationship with Dopamine (DA) Serotonin decreases the release of DA in the mesolimbic area decreasing sexual responseDrugs increasing Serotonin (serotonin agonists,SSRI’s) commonly result in delayed ejaculation and anorgasmiaThe serotonin 5-HT receptor may block descending pathways from the brain stem to spinal neurons and interfere with spinal reflex centers necessary for delayed ejaculation and anorgasmia. This may explain why some antidepressants with 5-HT blocking effects (nefazodone, mirtazapine) do not cause anorgasmia
36Decreased Libido30-60% of both men and women taking “typical” antipsychotic drugs (chlorpromazine, thioridazine, haloperidol, fluphenazine,thiothizene) experience adverse sexual effects due to increased prolactin levels.Anticholinergic agents given to treat extrapyramidal effects further contribute to the dysfunction.
37Delayed Ejaculation and Anorgasmia Serotonergic antidepressants are the most common causeMany patients treated for a major depression are not aware of SSRI induced anorgasmia until the episode is effectively treated. Thus pre-marketing clinical trials underestimate the true frequency (14-96%)Clomipramine has the greatest potential to cause delayed ejaculation and anorgasmia. Usually disappears within several days after the drug is stopped.
38Premature Ejaculation Although viewed as an adverse effect of SSRIs, this “adverse effect” is often used as a treatment for men with rapid ejaculation.Most SSRI’s require several weeks of use to prolong ejaculatory latency timeClomipramine is the only agent (thus far…) to be effective for rapid ejaculation with a single dose.
39Priapism…sustained, painful erection that cannot be relieved by intercourse or masturbation.Usually subsides within a few days….but 50-80% of these patients have significant erectile dysfunction afterwards…must be treated within 4 hoursTrazodone most common agent (<0.1% of patients)Most antipsychotic agents (risperidone, SSRIs,bupropion, phenelzine, prazosin, intracavernosal injectable agents) have also been associated with this condition.Clitoral priapism has also been reported and associated with pain/discomfort or increased libido/orgasmic response.
40The Best Antidepressants… Bupropion has no significant effect on serotonin and as a mild dopamine agonist has potential positive effect on sexual desire and arousal.Nefazodone and Mirtazapine are serotonin agonists but have postsynaptic 5-HT blocking effects that maintain the ability to have an orgasm.
41Management Options…. Decreasing the dose Giving drug “holidays” Rarely possible without compromising efficacyGiving drug “holidays”concern about withdrawal syndromeWaiting for tolerance to develop…..most evidence suggests that tolerance does not developAdding another agente.g. PDE5 inhibitorSwitching to an alternative
42Summary (Part 1)Sexual dysfunction is extremely prevalent among our patients and has a significant impact on the quality of their life.We need to know how to identify risk factors for sexual dysfunction and the effects of the medications we use to treat our patients.Most importantly we need to evaluate our patients’ sexual function throughout the course of their treatment and make adjustments, when possible, to their treatment regime.
46Intracavernosal Correlates of Erectile Dysfunction
47Intracavernosal Mediators of Erectile Dysfunction Neurogenic MediatorsNon-adrenergic/Non-cholinergicVIP(?NANC neurotransmitter) and NO modulate smooth muscle relaxationPDE V is inhibited by PDE V Inhibitors (Sildenafil, Tadalafil and Vardenafil)
48Diagnostic Overview of Erectile Dysfunction Nickel et al: J. Urol.: 132:40, 1984
49What about Women? What group of women are most at risk? What are the anatomic correlatesAre the same treatment options used for men effective in women?
50Population demographics were based on the 1993 World Development Report by the World Bank. Projections were made on a regional basis, using assumed levels and age patterns for fertility, mortality, and migration.Age 50 was used as a proxy for menopause as there are a paucity of data on the exact age of menopause onset across regions.In 1990, there were approximately 467 million women aged 50 years and older (defined as post menopausal) with an average age of 60 years.It is projected that an additional 47 million women each year will be over the age of 50 years with a projected increase to 1.2 billion postmenopausal women in 2030.The majority of growth will be in the developing world where the population of menopausal women is expected to triple between 1990 and 2030.Main point: The menopausal population is growing and will continue to grow with the aging population.
51The baby boomers are growing older, popularly referred to as the “graying of America.” Based on the 2000 US census data, approximately 2 million women turn 50 years of age each year.In the 2000 census count, there were more than 42 million women age 50 and over in the United States. In other words, 1 out of 3 women are older than 50 years.Main point: The menopausal population in the United States is growing and will continue to grow with the aging population.
52Due to improvements in public health and medicine over the past 150 years, the life expectancy for women in the United States has increased into the late 70s.The age of menopause onset has not changed.Main point: It is expected that women will spend approximately one third of their life in post menopause.
53Population data were derived from the US Census. Hysterectomy rates (a hysterectomy with or without a bilateral oophorectomy) were determined from the National Hospital Discharge Survey, a national probability sample of short-stay (<30 days) patients discharged from nonfederal hospitals in the United States.From , an estimated 3.5 million hysterectomies were performed among US women aged 15 years or older.After Cesarean section, hysterectomy is the most frequently performed major surgery among reproductive-age women in the United States.The highest rates of hysterectomy are in women aged 30 to 54 years.Frequent reasons for a hysterectomy prior to menopause include uterine prolapse, uterine leiomyoma, and endometriosis. Additional reasons include pelvic pain and benign uterine bleeding problems.Main point: Approximately one-half million US women undergo hysterectomy each year.
54Keshavarz et al also analyzed the frequency of hysterectomies with bilateral oophorectomy. Fifty-five percent of women who had a hysterectomy during the study period had concomitant bilateral oophorectomy.Most bilateral oophorectomies are elective for ovarian cancer prophylaxis.The highest percentage (75%) was in the 45 to 54 age group.Main point: Approximately one half of women who have a hysterectomy also have a bilateral oophorectomy.
55What is Female Sexual Dysfunction (FSD)? “A multicausal and multidimensional problem combining biological, psychological and interpersonal determinants”Multiple etiologies and manifestationsAge related, progressive and highly prevalentBasson et al, Report of the International Consensus Development Conference on Female Sexual Dysfunction: Definitions and Classifications, J. Urol., 163:888,2000
59Anatomic Correlates of FSD Vaginamucosa undergoes hormonal related cyclic changesmuscularis layer w/ extensive vascular network that engorges during sexual arousal (pH increase from a normal of 4.5 to )Adventitia provides structural support and contributes to increased friction with coitus
60Anatomic Correlates of FSD ClitorisAn erectile organ derived from the genital tubercle3 Parts: outermost glans, middle corpus, innermost cruraGlans and body: 2-4 cmCrura: 9-11 cmNo method for venous trapping;tumescence w/o rigidity
61Anatomic Correlates of FSD Vestibular bulbHomologous to the c. spongiosum of penis, yet separate from clitoris, urethra and vaginal vestibuleUterusUterine and cervical glands secrete mucous during sexual arousal to lubricate the vaginaPelvic floor musclesFunctional group of muscles that serve to pull the rectum, vagina and urethra anteriorly toward the pubic bones, compressing the lumens
62Anatomic Correlates of FSD Neurogenic MediatorsNon-adrenergic/Non-cholinergicVIP(?NANC neurotransmitter) and NO appear to modulate vaginal relaxation and secretionPDE V has been isolated in human clitoral,vestibular bulb and vaginal smooth muscle culture and is inhibited by Sildenafil Citrate
69Estrogen and FSD Low Estrogen (<50pg/ml) Thinning of vaginal mucosal epitheliumAtrophy of vaginal smooth muscleDecreased vaginal acidityDecreased clitoral and vaginal blood flow due to both vasoprotective and vasodilatory effectsDecreased vaginal and clitoral nitric oxide synthetase expression and apoptosis of vaginal smooth muscle and mucosal epitheliumJP Sarrell,1990,1998JR Berman,1998
71Estrogen deficiency, as a result of natural or surgical menopause, is often associated with altered sexual function.Data are from 93 women enrolled in the Yale Midlife study.When levels of estradiol were <50 pg/mL, women reported greater levels of vaginal dryness, dyspareunia, pain from intercourse, and burning. When estradiol levels were increased to >50 pg/mL, these symptoms abated.Main point: The presence of sexual problems was related to low levels of estradiol.
72Testosterone and FSD Low testosterone (<20pg/ml) Associated with decreased sexual arousal, genital sensation, libido and orgasm (Sherwin et al,1995; Rako,1998)Presently no FDA approved testosterone preparations for womenAll androgens carry the risk of inducing virilization in women: acne, hirsutism, menstrual irregularitiesLong term side effects: male pattern baldness, worsening of hirsutism, voice changes, clitoral hypertrophySupplementation decreases HDL and increases triglyceridesConversion to estradiol may be contraindicated in women with a history of breast cancer
76Etiologies of FSD Vasculogenic Neurogenic Hormonal/Endocrine BP, cholesterol, smoking, heart diseaseNeurogenicSpinal cord injury and diseaseHormonal/EndocrineH/P axis, surgical or medical castration, menopause and premature ovarian failure, chronic birth control use
77Etiologies of FSD (con’t) MusculogenicPelvic floor muscles; levator ani and perineal membrane (bulbocavernosus and ischiocavernosus muscles)Hypertonicity: vaginismus leading to dyspareunia and other sexual pain disordersHypotonicity: coital anorgasmia and urinary incontinencePsychogenicAbility to respond sexually is interrelated; Self-esteem, body image, quality of relationshipDepression and other disorders and medications used to treat themSSRI (serotonin re-uptake inhibitors): decreased desire, arousal, genital stimulation and difficulty achieving orgasm
81Clinical Evaluation (Female Sexual Response) Physiologic changes during female sexual arousal are difficult to evaluate in the clinical setting and are often not recognizable by the patientTherefore, previous techniques have focused on vaginal engorgement (photoplethsmography) and hormonal evaluation (FSH, LH, Prolactin, estradiol, Testosterone (free and total), SHBG)
82Clinical Evaluation (Female Sexual Response) Techniques presently being investigated include assessment of:Genital Blood Flow: Duplex dopplerVaginal lubrication: pH measurement during sexual arousal using a vaginal probeVaginal compliance/elasticity: pressure/volume measurementsGenital sensation: recorded pre and post stimulation
83Clinical Evaluation (Psychosocial/Psychosexual Assessment) Emotional and/or relational issues are thought to play a large role in female sexual dysfunction.Intervention is not considered successful unless the women is subjectively able to experience sexual arousal, pleasure and satisfactionUse of validated instruments are proposed:Brief Index of Sexual Function Inventory (BISF-W): discriminates between depressed, sexually dysfunctional and healthy patients. (Rosen,Taylor,Leiblum &Bachmann,Archives of Sexual Behavior, 23:627, 1994)Index of Female Sexual Function (IFSF): 19 questions, desire, arousal, lubrication, orgasm, satisfaction pain (Rosen et al, J Sex and Marital Therapy, 2000)
84Approaches to the Treatment of Female Sexual Dysfunction PsychologicalSurgicalUrologicGynecologicMedicalConventionalComplementary
85Medical Approaches to the Treatment of FSD ConventionalDrug optionsHormonal: estrogen, testosteroneLubricantsInvestigational:Sildenafil, Tadalafil, Vardenafil, L-arginine, Yohimbine (presynaptic a-2 blocker), PGE1, apomorphineDHEA (dehydroepiandrosterone) Genazzani et al, Fert Steril, 76:241, 2001Devices
86Medical Approaches: DHEA DHEA (dehydroepiandrosterone) Genazzani et al, Fert Steril, 76:241, 200131 postmenopausal women divided into 4 groups based on age (50 -55; 60-65) and body mass (20-24; 25-30). All patients were given 50 mg DHEA daily. Endocrine and neuroendocrine blood tests were done prior to and after 3 and 6 months on DHEALH, FSH decreasedE2, E1 increasedAndrostenedione, testosterone, GH (but not GHRH induced release), IGF-1, osteocalcin (marker of bone turnover) increased
87Medical Approaches: Lubricants Replaces/supplements normal vaginal secretionsCan increase Arousal by increasing sensitivityCan decrease Pain by decreasing frictionProtects vaginal mucosa from drynessCompensates for erectile dysfunction
88Vacuum Induced Clitoral Engorgement for Treatment of Female Sexual Dysfunction Kevin L. Billups, M.D.Laura Berman, Ph.D.Jennifer Berman, M.D.Michael E. Metz, Ph.D.Margaret E. Glennon, P.A.C.Irwin Goldstein, M.D.
90Results of EROS–CTD Clinical Study: Efficacy Changes in Sensation After Using the EROS–CTD DeviceChanges in Ability to Achieve Orgasm After Using the EROS–CTD DeviceAfter using the Device Women w/ FSD Women w/o FSD (%) More than Before 86% 67% Less than Before 0% 0% Same as Before 14% 33% n =After using the Device Women w/ FSD (%) Women w/o FSD (%) More than Before 55% 50% Less than Before 0% 0% Same as Before 45% 50% n = 22 12Changes in Sexual Satisfaction After Using the EROS–CTD DeviceChanges in Lubrication After Using the EROS–CTD DeviceAfter using the Device Women w/ FSD (%) Women w/o FSD (%) More than Before 77% 33% Less than Before 0% 0% Same as Before 23% 67% n = 22 12After using the Device Women w/ FSD (%) Women w/o FSD (%) More than Before 73% 50% Less than Before 0% 0% Same as Before 27% 42% I couldn’t tell, partner yes 0% 8% n = 22 12
93Use of TCM in Male Sexual Dysfunction Stress associated sexual dysfunctionDecreased LibidoPremature EjaculationPsychogenic erectile dysfunctionNeed better wording
94Use of TCM in Female Sexual Dysfunction Hormonal irregularities (Lin et al 1988;, Stener-Victorin et al 2000)Menopausal related symptoms :insomnia, hot flushes, memory problems, anxiety (Lin 1995, Wyon et al 1994, Sher 1998, Deng et al 1995, Sher 1998)Dysmenorrhea (Coco 1999, Helms 1987, Wang 1987)Pelvic pain (Rapkin and , Kames 1987, Ercolani et al. 1983)Stress associated sexual dysfunctionDecreased LibidoImpaired orgasm
95Complementary Approaches Nutritional SupplementationMalnutrition and GI disease have a well documented effect on sexual functionRostami et al, 2001, Kulin et al, 1982Stress ReductionValidated testing instruments for anxiety have documented a consistent and direct association between stress and sexual performanceTherapies have included:Biofeedback:Massage TherapyExercise Therapy
97Summary and Conclusions Sexual dysfunction is extremely prevalent among our patients and has a significant impact on their quality of lifeWe need to know,what to ask, how to evaluate and what to offer our patients suffering from this distressing disorder.
98Bruce R. Gilbert, M. D. , Ph. D. www. brucegilbertmd. com bruce Bruce R. Gilbert, M.D., Ph.D.