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Adam and Eve in the Garden of Viagra® Bruce R. Gilbert, M.D., Ph.D. Associate Clinical Professor of Urology Associate Clinical Professor of Male Reproductive.

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Presentation on theme: "Adam and Eve in the Garden of Viagra® Bruce R. Gilbert, M.D., Ph.D. Associate Clinical Professor of Urology Associate Clinical Professor of Male Reproductive."— Presentation transcript:

1 Adam and Eve in the Garden of Viagra® Bruce R. Gilbert, M.D., Ph.D. Associate Clinical Professor of Urology Associate Clinical Professor of Male Reproductive Medicine and Surgery Weill Cornell Medical College

2 Disclosure  Member of the Speakers Bureau for Pfizer –Sildenafil Citrate (Viagra®)  Clinical Investigator for Johnson and Johnson –Investigational Drug for Rapid Ejaculation  Clinical Investigator for GlaxoSmithKlein PLC –Investigational drug affecting sexual function

3 March 1998




7 To Provide an Overview of Male and Female Sexual Dysfunction  Part I –Prevalence –Classification –Risk Factors –Effects of Psychotropic Medications  Part II –Physiological Correlates –Treatment Options

8 How Common is Sexual Dysfunction?


10 Prevalence of Sexual Dysfunction  10% to 52% of men  25% to 63% of women Frank et al, 1978, Spector et al,1990 Rosen et al,1993

11 Sexual Dysfunction in Women: Office Based Survey of Women in Both Urologic and Gynecologic Practice Wellman W. Cheung 1, Nabet G. Kasabian 2, Stanton C. Honig 3, Mary J. Minkin 3, Bruce R. Gilbert 1,2, 1 SUNY at Stony Brook, 2 North Shore University Hospital, 3 Yale University AUA 2000

12 Introduction  In this survey we attempted to define the prevalence of and identify the interest in, treatment for sexual dysfunction in women in our community.

13 Methods  102 women who presented for routine urologic (26) or gynecologic (76) care were asked to complete a questionnaire (anonymous).

14 Results  Age 42.9 + 11.8 –range 24.9 to 78.5  Medical History –73% excellent health –6% hypertension –1% smoking –No patients with diabetes or neurologic disease

15 Results (con’t)  Social History –5.8% used antidepressants –Alcohol (65.4%) 5.5% < 1 drink/week 49% 1-2 drinks/week 38% 3-5 drinks/week 7.5% > 5 drinks/week –Bicycling 28.4% ( 1.75 hours/week )

16 Most Common Complaints

17 Other Complaints

18 Results (con’t)  81% described impairment of sexual function  55% would seek treatment if effective treatment available

19 National 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 age Lauman et al, 1994  In 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, 281,537,1999  43% of Women (and 31% of Men) had sexual dysfunction


21 Global Study of Sexual Attitudes and Behaviors (GSSAB)  An International survey of adults aged 40 to 80 years  13,882 Women, 13,618 Men Most 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

22 How is Sexual Dysfunction Classified?

23 Classification 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 responses –Male: Persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate erection Basson 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

24 Classification of Sexual Dysfunction  ORGASMIC DISORDER –Female (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)

25 Risk Factors for Sexual Dysfunction

26  ED may indicate the presence of serious medical disorder  Massachusetts Male Aging Study (MMAS) reports* 1 –Cardiovascular39% incidence of ED disease –Diabetes 29% in men with good control; 46% in men with poor control 2 –Depression Up to 90% have some sexual complaints –Hyperlipidemia16% association with ED  90% demonstrate penile arterial disease on Doppler ultrasound 2 *Impotence probability pattern after adjusting for age. 1. Feldman HA et al. J Urol. 1994;151:54-61. 2. Billups K. Presented at: 95th Annual Meeting of the American Urological Association; April 29-May 4, 2000; Atlanta, Ga. Abstract. *Impotence probability pattern after adjusting for age. 1. Feldman HA et al. J Urol. 1994;151:54-61. 2. Billups K. Presented at: 95th Annual Meeting of the American Urological Association; April 29-May 4, 2000; Atlanta, Ga. Abstract. Sexual Dysfunction is an Important Health Concern

27 Risk Factors for Sexual Dysfunction  Hypertension  Hyperlipidemia  Hypogonadism  Endocrine disorders  Smoking  Alcohol abuse  Drug abuse  Anemia  Trauma or surgery to the pelvis or spine  Coronary artery or peripheral vascular disease  Peyronie’s disease  Vascular surgery  Depression  Medications

28 Drugs Associated with Sexual Dysfunction  Alcohol  Estrogens  Antiandrogens  H 2 receptor blockers  Anticholinergics  Ketoconazole  Antidepressants  Marijuana  Antihypertensives  Narcotics  -blockers  Psychotropics  Cigarettes  Cocaine  Spironolactone  Lipid-lowering agents  NSAIDs  Cytotoxic drugs  Diuretics

29 Psychotropics and Sexual Dysfunction  Key Hormones –DHEA –Oxytocin –Phenylethylamaine (PEA) –Estrogen –Testosterone –Progesterone –Prolactin –Vasopressin –Dopamine –Serotonin –Acetylcholine Gutierrez,M et al, Pharmacotherapy:19(7):823-831, 1999

30 DHEA (dehydroepiandrosterone)  Precursor of Testosterone and Estrogen  Excitatory role in limbic arousal  Decrease DHEA: carbamazebine, phenytoin, cytochrome P450, 3A4 inhibitors, alcohol  Increase DHEA: bupropion, digoxin,diltiazem, cigarette smoking

31 Oxytocin  Facilitates attraction and touch sensation.  Levels increase with touch and spike with orgasm  Responsible for postorgasm inertia and refractory period  Increased by estrogen and yohimbine  Decreased by alcohol, catecholamines

32 Prolactin  Directly inhibits sexual desire, arousal and orgasm and erectile function  Levels increased by dopamine-blocking drugs (most antipsychotic drugs) and opiates  Levels decreased by bromocriptine, testosterone, dopamine and bupropion

33 Dopamine (DA)  Neurotransmitter in the mesolimbic “pleasure center”  Increasing DA activity may enhance sexual response whereas blocking it may compromise it  Many antipsychotic agents are DA blockers  Bupropion has mild DA agonist activity

34 Serotonin  Reciprocal relationship with Dopamine (DA)  Serotonin decreases the release of DA in the mesolimbic area decreasing sexual response  Drugs increasing Serotonin (serotonin agonists,SSRI’s) commonly result in delayed ejaculation and anorgasmia  The 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

35 Clinical Correlation

36 Decreased Libido  30-60% 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.

37 Delayed Ejaculation and Anorgasmia  Serotonergic antidepressants are the most common cause  Many 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.

38 Premature 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 time –Clomipramine is the only agent (thus far…) to be effective for rapid ejaculation with a single dose.

39 Priapism  …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 hours  Trazodone 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.

40 The 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.

41 Management Options….  Decreasing the dose –Rarely possible without compromising efficacy  Giving drug “holidays” –concern about withdrawal syndrome  Waiting for tolerance to develop…..most evidence suggests that tolerance does not develop  Adding another agent –e.g. PDE5 inhibitor  Switching to an alternative

42 Summary (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.

43 Physiological Correlates

44 Vascular Correlates of Erectile Dysfunction

45 Neurologic Correlates of Erectile Dysfunction

46 Intracavernosal Correlates of Erectile Dysfunction

47 Intracavernosal Mediators of Erectile Dysfunction  Neurogenic Mediators –Non-adrenergic/Non- cholinergic VIP(?NANC neurotransmitter) and NO modulate smooth muscle relaxation –PDE V is inhibited by PDE V Inhibitors (Sildenafil, Tadalafil and Vardenafil)

48 Diagnostic Overview of Erectile Dysfunction Nickel et al: J. Urol.: 132:40, 1984

49 What about Women? 1. What group of women are most at risk? 2. What are the anatomic correlates 3. Are the same treatment options used for men effective in women?






55 What is Female Sexual Dysfunction (FSD)?  “A multicausal and multidimensional problem combining biological, psychological and interpersonal determinants” –Multiple etiologies and manifestations –Age related, progressive and highly prevalent Basson et al, Report of the International Consensus Development Conference on Female Sexual Dysfunction: Definitions and Classifications, J. Urol., 163:888,2000




59 Anatomic Correlates of FSD  Vagina –mucosa undergoes hormonal related cyclic changes –muscularis layer w/ extensive vascular network that engorges during sexual arousal (pH increase from a normal of 4.5 to 6.0-6.5) –Adventitia provides structural support and contributes to increased friction with coitus

60 Anatomic Correlates of FSD  Clitoris –An erectile organ derived from the genital tubercle –3 Parts: outermost glans, middle corpus, innermost crura Glans and body: 2-4 cm Crura: 9-11 cm –No method for venous trapping;tumescence w/o rigidity

61 Anatomic Correlates of FSD  Vestibular bulb –Homologous to the c. spongiosum of penis, yet separate from clitoris, urethra and vaginal vestibule  Uterus –Uterine and cervical glands secrete mucous during sexual arousal to lubricate the vagina  Pelvic floor muscles –Functional group of muscles that serve to pull the rectum, vagina and urethra anteriorly toward the pubic bones, compressing the lumens

62 Anatomic Correlates of FSD  Neurogenic Mediators –Non-adrenergic/Non- cholinergic VIP(?NANC neurotransmitter) and NO appear to modulate vaginal relaxation and secretion –PDE V has been isolated in human clitoral,vestibular bulb and vaginal smooth muscle culture and is inhibited by Sildenafil Citrate

63 What Treatment Options are Available ?

64 Available Treatment Options for Erectile Dysfunction  Sex Therapy - Psychotherapy  Oral Drug Therapy –Sildenafil, Tadalafil, Vardenafil  Intracorporal Injection Therapy

65 Treatment of Erectile Dysfunction  Intraurethral Therapy –Alprostadil (Prostaglandin E1)  Vacuum Constriction Devices

66 Treatment of Erectile Dysfunction  Surgical Therapy –Arterial revascularization –Venous Ligation –Correction of Penile Angulation –Penile Prostheses

67 Are there available treatment options for Women?

68 Diagnostic Groups for ED

69 Estrogen and FSD  Low Estrogen (<50pg/ml) –Thinning of vaginal mucosal epithelium –Atrophy of vaginal smooth muscle –Decreased vaginal acidity –Decreased clitoral and vaginal blood flow due to both vasoprotective and vasodilatory effects –Decreased vaginal and clitoral nitric oxide synthetase expression and apoptosis of vaginal smooth muscle and mucosal epithelium JP Sarrell,1990,1998 JR Berman,1998



72 Testosterone 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 women –All androgens carry the risk of inducing virilization in women: acne, hirsutism, menstrual irregularities –Long term side effects: male pattern baldness, worsening of hirsutism, voice changes, clitoral hypertrophy –Supplementation decreases HDL and increases triglycerides –Conversion to estradiol may be contraindicated in women with a history of breast cancer




76 Etiologies of FSD  Vasculogenic –BP, cholesterol, smoking, heart disease  Neurogenic –Spinal cord injury and disease  Hormonal/Endocrine –H/P axis, surgical or medical castration, menopause and premature ovarian failure, chronic birth control use

77 Etiologies of FSD (con’t)  Musculogenic –Pelvic floor muscles; levator ani and perineal membrane (bulbocavernosus and ischiocavernosus muscles) Hypertonicity: vaginismus leading to dyspareunia and other sexual pain disorders Hypotonicity: coital anorgasmia and urinary incontinence  Psychogenic –Ability to respond sexually is interrelated; Self-esteem, body image, quality of relationship –Depression and other disorders and medications used to treat them SSRI (serotonin re-uptake inhibitors): decreased desire, arousal, genital stimulation and difficulty achieving orgasm




81 Clinical 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 patient  Therefore, previous techniques have focused on vaginal engorgement (photoplethsmography) and hormonal evaluation (FSH, LH, Prolactin, estradiol, Testosterone (free and total), SHBG)

82 Clinical Evaluation (Female Sexual Response)  Techniques presently being investigated include assessment of: –Genital Blood Flow: Duplex doppler –Vaginal lubrication: pH measurement during sexual arousal using a vaginal probe –Vaginal compliance/elasticity: pressure/volume measurements –Genital sensation: recorded pre and post stimulation

83 Clinical 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 satisfaction  Use 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)

84 Approaches to the Treatment of Female Sexual Dysfunction  Psychological  Surgical –Urologic –Gynecologic  Medical –Conventional –Complementary

85 Medical Approaches to the Treatment of FSD  Conventional –Drug options Hormonal: estrogen, testosterone Lubricants Investigational: –Sildenafil, Tadalafil, Vardenafil, L- arginine, Yohimbine (presynaptic a-2 blocker), PGE1, apomorphine –DHEA (dehydroepiandrosterone) Genazzani et al, Fert Steril, 76:241, 2001 –Devices

86 Medical Approaches: DHEA  DHEA (dehydroepiandrosterone) Genazzani et al, Fert Steril, 76:241, 2001 –31 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 DHEA –LH, FSH decreased –E2, E1 increased –Androstenedione, testosterone, GH (but not GHRH induced release), IGF-1, osteocalcin (marker of bone turnover) increased

87 Medical Approaches: Lubricants  Replaces/supplements normal vaginal secretions –Can increase Arousal by increasing sensitivity –Can decrease Pain by decreasing friction  Protects vaginal mucosa from dryness  Compensates for erectile dysfunction

88 Vacuum 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.

89 EROS Clitoral Therapy Device

90 After using the DeviceWomen w/ FSD Women w/o FSD (%) More than Before86%67% Less than Before0%0% Same as Before14%33% n = 22 12 Changes in Sensation After Using the EROS–CTD Device Changes in Ability to Achieve Orgasm After Using the EROS–CTD Device Changes in Sexual Satisfaction After Using the EROS–CTD Device Changes in Lubrication After Using the EROS–CTD Device After using the DeviceWomen w/ FSD (%)Women w/o FSD (%) More than Before55%50% Less than Before0%0% Same as Before45%50% n =2212 After using the DeviceWomen w/ FSD (%)Women w/o FSD (%) More than Before77%33% Less than Before0%0% Same as Before23%67% n =2212 After using the DeviceWomen w/ FSD (%)Women w/o FSD (%) More than Before73%50% Less than Before0%0% Same as Before27%42% I couldn’t tell, partner yes0%8% n =2212 Results of EROS–CTD Clinical Study: Efficacy

91 Complementary Approaches  Acupuncture  Herbal Therapy  Biofeedback  Nutritional Supplementation Vitamins DHEA


93 Use of TCM in Male Sexual Dysfunction  Stress associated sexual dysfunction  Decreased Libido  Premature Ejaculation  Psychogenic erectile dysfunction

94 Use 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 dysfunction  Decreased Libido  Impaired orgasm

95 Complementary Approaches  Nutritional Supplementation –Malnutrition and GI disease have a well documented effect on sexual function Rostami et al, 2001, Kulin et al, 1982  Stress Reduction –Validated testing instruments for anxiety have documented a consistent and direct association between stress and sexual performance –Therapies have included: Biofeedback: Massage Therapy Exercise Therapy


97 Summary and Conclusions  Sexual dysfunction is extremely prevalent among our patients and has a significant impact on their quality of life  We need to know,what to ask, how to evaluate and what to offer our patients suffering from this distressing disorder.

98 Bruce R. Gilbert, M.D., Ph.D.

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