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Adam and Eve in the Garden of Viagra®

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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

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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?

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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. Cheung1, Nabet G. Kasabian2, Stanton C. Honig3, Mary J. Minkin3, Bruce R. Gilbert1,2, 1SUNY at Stony Brook, 2North Shore University Hospital, 3Yale 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 Medical History range 24.9 to 78.5
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% drinks/week 38% 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

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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 Sexual Dysfunction is an Important Health Concern
ED may indicate the presence of serious medical disorder Massachusetts Male Aging Study (MMAS) reports*1 Cardiovascular 39% incidence of ED disease Diabetes 29% in men with good control; % in men with poor control2 Depression Up to 90% have some sexual complaints Hyperlipidemia 16% association with ED 90% 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.

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 H2 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): , 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 Giving drug “holidays”
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? What group of women are most at risk?
What are the anatomic correlates Are the same treatment options used for men effective in women?

50 Population 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.

51 The 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.

52 Due 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.

53 Population 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.

54 Keshavarz 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.

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

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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 ) 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

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71 Estrogen 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.

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

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76 Etiologies of FSD Vasculogenic Neurogenic Hormonal/Endocrine
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

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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 Clitoral Therapy Device
EROS Clitoral Therapy Device

90 Results of EROS–CTD Clinical Study: Efficacy
Changes in Sensation After Using the EROS–CTD Device Changes in Ability to Achieve Orgasm After Using the EROS–CTD Device After 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 12 Changes in Sexual Satisfaction After Using the EROS–CTD Device Changes in Lubrication After Using the EROS–CTD Device After 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 12 After 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

91 Complementary Approaches
Acupuncture Herbal Therapy Biofeedback Nutritional Supplementation Vitamins DHEA

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

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

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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. www. brucegilbertmd. com bruce
Bruce R. Gilbert, M.D., Ph.D.


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