A New Frontiers Program on Women s Health Emerging

A New Frontiers Program on Women’s Health Emerging Perspectives on the Science and Medicine of Hypoactive Sexual Desire Disorder (HSDD) The Internal Medicine and Primary Care Perspective Program Chairman and Moderator Anita H. Clayton, MD David C Wilson Professor Department of Psychiatry & Neurobehavioral Sciences Professor of Clinical Obstetrics & Gynecology University of Virginia Charlottesville, VA

Program Faculty PROGRAM CHAIRPERSON Anita H. Clayton, MD David C Wilson Professor Department of Psychiatry & Neurobehavioral Sciences Professor of Clinical Obstetrics & Gynecology University of Virginia Charlottesville, VA Jennifer E. Frank, MD, FAAFP Assistant Professor Department of Family Medicine University of Wisconsin School of Medicine and Public Health Appleton, Wisconsin Sheryl Kingsberg, Ph. D Division Chief, Behavioral Medicine Program University Hospitals Associate Professor of Medicine Case Western Reserve University Cleveland, Ohio Lori Brotto, Ph. D Assistant Professor Department of Obstetrics and Gynecology University of British Columbia Vancouver, BC

A New Frontiers Program on Women’s Health Addressing Current Challenges in Female Sexual Disorders What Internal Medicine Specialists Need to Know about HSDD Program Chairman and Moderator Anita H. Clayton, MD David C Wilson Professor Department of Psychiatry & Neurobehavioral Sciences Professor of Clinical Obstetrics & Gynecology University of Virginia Charlottesville, VA

A New Frontiers Program on Women’s Health ► Clinical focus ► Prevalence and pathophysiology of HSDD ► Communication strategies ► Differential diagnoses ► Intervention and management

Case Example ► 26 -year-old MWF presents with 1 year history of decreased libido, some problems with vaginal lubrication, and diminished orgasmic capacity. No pain with intercourse. § § Change in sexual function since marriage 4 years ago, but relationship still strong 1 year post-partum with mild depressive symptoms since delivery No general health problems On oral contraceptives for birth control

A New Frontiers Program on Women’s Health Hypoactive Sexual Desire Disorder Prevalence and Barriers to Recognition in the Primary Care Setting Sheryl A. Kingsberg, Ph. D Chief, Division of Behavioral Medicine University Hospitals Case Medical Center Professor, Department of Reproductive Biology Case Western Reserve University School of Medicine Cleveland OH

“Normal” Female Sexuality Defined by Cultural Norms ► Historically given little attention ► Victorian era: discovery that female orgasm irrelevant to conception ► 2008: women’s sexuality hits ‘Primetime’ but not quite its ‘Prime’

Human Sexual Response: Classic Models ►Excitement Divided ►Plateau Desire Arousal ►Orgasm ►Resolution Linear progression Masters WH, Johnson VE. Human Sexual Response. Boston, Mass: Little Brown; 1966. Kaplan HS. The New Sex Therapy. 1974.

Female Sexual Response Cycle Orgasm Plateau (C) t on utiion Resoll Reso A BC n Resollutiio n Reso ut o Excitement Re so lu tio n (A) Adapted from Masters WH, Johnson VE. Human Sexual Inadequacy. Little Brown; 1970. (B)

Female Sexual Response Cycle Emotional Intimacy Seeking Out and Being Receptive to Emotional and Physical Satisfaction Spontaneous Sexual Drive Sexual Stimuli Sexual Arousal Biologic Arousal and Sexual Desire Psychological Basson R. Med Aspects Hum Sex. 2001; 1: 41 -42.

Women’s Endorsement of Models of Female Sexual Response ► The Nurses’ Sexuality Study, N=133 ► Equal proportions of women endorsed the Masters and Johnson, Kaplan, and Basson models of female sexual response as representing their own sexual experience. ► Women endorsing the Basson model had significantly lower FSFI domain scores than women who endorsed either the Masters and Johnson or Kaplan models. Michael Sand, Ph. D, MPH, and William A. Fisher, Ph. D, JSM, 2007 4: 708 -719

Biopsychosocial Model of Female Sexual Response (e. g. , physical health, neurobiology, endocrine function) (e. g. , upbringing, cultural norms and expectations) Biology Psychology Sociocultural Interpersonal 1. Rosen RC, Barsky JL. Obstet Gynecol Clin North Am. 2006; 334: 515 -526. (e. g. , performance anxiety, depression) (e. g. , quality of current and past relationships, intervals of abstinence, life stressors, finances)

US Adult Women Are Sexually Active* Random Digital Dialing Survey of Women 18 -94 Years Old (N=2000) † 100 US Women Sexually Active (%) 70 66 70 65 60 50 46 40 30 20 20 10 0 18 -29 30 -39 40 -49 (n=362) (n=451) (n=473) 50 -59 (n=271) 60 -94 (n=443) Age Ranges *Sexually active was defined as oral (active or receptive), vaginal, or anal intercourse in the past 3 months. †Age-adjusted percentages. Patel D, et al. Sex Trans Dis. 2003; 30(3): 216 -220.

DSM-IV-TR Classification of FSDs Sexual Desire Disorders Hypoactive Sexual Desire Disorder Absence or deficiency of sexual interest and/or desire Sexual Aversion Disorder Aversion to and avoidance of genital contact with a sexual partner Sexual Arousal Disorders Female Sexual Arousal Disorder Inability to attain or maintain adequate lubrication-swelling response of sexual excitement Orgasmic Disorders Female Orgasmic Disorder Delay in or absence of orgasm after a normal sexual excitement phase Pain Disorders Dyspareunia Genital pain associated with sexual intercourse Vaginismus Involuntary contraction of the perineal muscles preventing vaginal penetration

DSM-IV TR Criteria for FSD ► Sexual complaint or problem in desire, arousal, orgasm, or sexual pain: ● Judgment of severity of sexual symptom is made by the clinician, talking into account factors that affect sexual functioning, such as age and the context of the person’s life ► The disturbance causes marked distress or interpersonal difficulty ► The sexual dysfunction is not: ● ● Better accounted for by another primary psychiatric disorder (except another Sexual Dysfunction) Due exclusively to the direct physiological effects of a substance (eg, drug of abuse, medication) or a general medical condition American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4 th Ed, text revision (DSM-IV-TR). Washington, DC: American Psychiatric Association; 2000.

Overlap of FSDs Sexual Desire Disorders Sexual Arousal Disorder Orgasmic Disorder Dyspareunia Vaginismus Basson R, et al. J Urol. 2000; 163: 888 -893.

Prevalence of FSD: A Historical Perspective Sexual Dysfunction in the United States* ► OBJECTIVES: Assess the prevalence and risk of experiencing sexual dysfunction in men and women ► NOT ASSESSED: Distress or interpersonal difficulty ► POPULATION: 1749 women and 1410 men 18 -59 years of age ► RESULTS: 43% of women reported sexual dysfunction 100 50 43 Prevalence of Sexual Dysfunction in Women by Latent Class Women (%) 40 30 22 20 14 7 10 0 Total for Sexual Low Sexual Dysfunctions Desire Assessed Arousal Pain Subsets for Sexual Dysfunctions Assessed *Sexual problems were measured in this study. NHLHS data on critical symptoms do not connote a clinical definition of sexual dysfunction. Laumann E, et al. JAMA. 1999; 281(6): 537 -544.

Prevalence of FSD: PRESIDE ► OBJECTIVES: Estimate the prevalence of self-reported sexual problems (any, desire, arousal, and orgasm), the prevalence of problems accompanied by personal distress, and describe related correlates ► NOT DETERMINED: Whether low desire with sexually related personal distress was primary or secondary to another illness; pain was not assessed ► POPULATION: 31, 581 US female respondents ≥ 18 years of age from 50, 002 households ► RESULTS*: Response rate was 63% (n=31, 581 / 50, 002) Prevalence of Female Sexual Problems Associated With Distress 100 50 43. 1 US Women (%) 45 40 35 30 Sexual Problems 25. 3 25 Distressing Sexual Problems 21. 1 20 15 10 *All results are US population ageadjusted. 37. 7 11. 5 9. 5 5. 1 5 4. 6 0 Desire Arousal Shifren JL, et al. Obstet Gynecol. 2008; 112(5): 970 -978. Orgasm Any

Prevalence of Sexual Problems Associated with Distress (PRESIDE) Age-stratified prevalence Desire Arousal Orgasm Any 2868/28, 447 1556/28, 461 1315/27, 854 3456/28, 403 18 -44 8. 9 3. 3 3. 4 10. 8 45 -64 12. 3 7. 5 5. 7 14. 8 65 or older 7. 4 6. 0 5. 8 8. 9 Shifren J et al Obstetrics & Gynecology, 2008, 112(5).

Prevalence of Low Sexual Desire and Hypoactive Sexual Desire Disorder Nationally Representative Sample of US Women Low Desire N Low Desire % HSDD N HSDD % All 1936 36. 2 1920 8. 3 Age 30 -39 453 30. 8 453 8. 3 Age 40 -49 542 25. 3 539 9. 0 Age 50 -59 824 37. 8 814 9. 4 Age 60 -70 117 60. 7 114 5. 8 Surgical Menopausal 635 39. 7 631 12. 5 Natural Menopausal 551 52. 4 541 6. 6 Premenopausal 750 26. 7 748 7. 7 Category West SL et al Archives of Internal Medicine, 2008

Decreased Sexual Desire With Distress Negatively Impacts Women’s Lives ► Decreased sexual desire is associated with negative effects including: 1, 2 ● ● Poor self-image Mood instability Depression Strained relationships with partners 1. Shifren JL, et al. Obstet Gynecol. 2008; 112(5): 970 -978. 2. Leiblum SR. Menopause. 2006; 13(1): 46 -56.

Hypoactive Sexual Desire Disorder (HSDD) ► Persistent or recurrent deficiency or absence of sexual thoughts, fantasies and/or desire for, or receptivity to, sexual activity ● Causes marked personal distress or interpersonal difficulties ● Not better accounted for by another primary disorder, drug/medication, or general medical condition

Components of Sexual Desire ► Drive: ● Sex steroids and neurotransmitters play a role in modulating sexual desire, drive, and excitement ► Expectations, beliefs, and values ► Motivation Hull EM, et al. Behav Brain Res. 1999; 105: 105– 116. Levine S. Sexual Life, 1994

Social Psychology Theories: Understanding Psychosocial Aspects of Female Sexual Desire ► Self-Perception Theory ● People make attributions about their own attitudes by relying on observations of external behaviors (Bem, 1965) ► Wundt's schema of sensory affect (aka Kingsberg’s Ice. Cream Analogy) ● Increases of stimulus intensity above threshold are felt as increasingly pleasant up to a peak value beyond which pleasantness falls off through indifference to increasing unpleasantness.

Prevention and Treatment of Sexual Problems ASK! You cannot treat a problem if you don’t know it exists

In PRESIDE About One-Third of Women With a Distressing Sexual Problem Sought Formal Care Type of Help-Seeking (n=3239) 14. 5% Did not seek help Formal 34. 5% 9. 1% Anonymous Informal 41. 9% Formal=HCP; informal=anyone other than an HCP. Shifren JL, et al. J Women’s Health. 2009; 18(4)461 -468.

Physician Questioning Increases Patient Reporting of Sexual Dysfunction 40 Patients (%) 30 19% 20 10 3% 0 Spontaneous Reporting N=887. Bachmann GA, et al. Obstet Gynecol. 1989: 73: 425 -427. Reporting After Direct Inquiry

Physician-Based Barriers ► Lack of training/Inadequate knowledge or skills 1 ► Lack of awareness of associated comorbid conditions ► “Improving quality of life” may not be considered a high priority 2 ► Time constraints 3 ► Underestimation of prevalence ► No FDA approved treatments for female sexual dysfunction 1 Broekman CPM, et al. Int J Impot Res. 1994; 6: 67 -72. to Erectile Dysfunction. Lawrence Della. Corte Publications, Inc; 2001. 3 Baum N, et al. Patient Care. Spring 1998(suppl): 17 -21. 2 Eid JF, et al. Cliniguide®

Training Is Not Preparing HCPs To Be Informed in the Area of FSD Curriculum Time (Hours) Dedicated to Human Sexual Health Education (N=101)* *Human sexual health education was not specifically defined in the survey but included: type of educational experiences, disciplines, subject and topics areas, clinical program, continuing medical education, total number of hours, amongst others. Solursh DS, et al. Int J Impot Res. 2003; 15(suppl 5): S 41 -S 45.

Most HCPs Have Little or No Confidence in Screening for or Diagnosing HSDD Web-Based Survey Consisting of Residents and Faculty in an Academic Primary Care Clinic (N=53; 41. 5% women, 58. 5% men) Respondents who had not screened or diagnosed patients with HSDD 90 HCPs who felt little or no confidence in diagnosing HSDD 91 HCPs who had little confidence in ability to manage HSDD 57 0 20 40 60 HCPs (%) Harsh V, et al. J Sex Med. 2008; 5(3): 640 -645. 80 100

HCPs Perceive Patients as Reluctant to Bring Up Sexual Issues Patient Barriers Identified by HCPs in the Management of Sexual Dysfunction (n=133 HCPs) Doesn't want to waste doctors' time 2. 2 Difficult area to discuss 4. 3 Indirect presentation (hidden by other symptoms) 5. 4 Patient thinks it's “normal”/lack of knowledge and awareness 15 Patients‘ reluctance/ reticence/embarrassment 73. 1 0 20 40 60 80 Total Number of Barriers (%)* *Total number of patient barriers=93; most HCPs identified more than one barrier. Humphrey S, et al. Fam Pract. 2001; 18(5): 516 -518.

HCP Comfort Level Impacted by Patient Gender Differences in Physician Comfort Level Influenced by Gender (N=69) 50* Physician self-report of discomfort with male patients 19 Female physicians (n=29) Male physicians (n=40) 12* Physician self-report of discomfort with female patients 35 45 Physician perception of male patient discomfort 40 24* Physician perception of female patient discomfort 53 0 10 *P<0. 05. Burd ID, et al. J Sex Med. 2006; 3(2): 194 -200. 20 30 40 Physicians (%) 50 60 70

Open-Ended Questions ► Require narrative elaboration, not yes/no or short response ● Directive open-ended questions focus the topic Open the door to context, understanding, & feelings ► Doctors ask ≈1 question/min; >90% are closed-ended ► Physicians can increase use open-ended questions & improve ● ● ● ► Assessment of functional impairment Adherence Patient satisfaction Open-ended dialog is efficient (≈ 90 seconds for impairment dialog)4 & effectively reveals syndromal symptoms Lipton et al. JGIM 2008; 23: 1145 -1151. Hahn et al. Curr Med Res Opin 2008; 24: 1711 -1718.

The Challenges of the Differential Diagnosis • Ensure that sexual dysfunction IS NOT due exclusively to the – Physiological effects of a specified general medical condition (eg, neurological, hormonal, metabolic abnormalities)* In Order to Meet the Diagnostic Criteria for HSDD: • Ensure that sexual dysfunction IS NOT due exclusively to the – Physiological effects of substance (prescribed or illicit) abuse† • HSDD and concomitant sexual dysfunctions (both should be noted) ● Also, additional diagnosis of HSDD IS NOT made if low sexual desire is better accounted for by another Axis I disorder (eg, major depressive disorder, obsessive-compulsive disorder, posttraumatic stress disorder) – HSDD diagnosis may be appropriate if low desire predates the Axis I diagnosis *If it is, refer to the diagnosis: Sexual Dysfunction Due to a General Medical Condition. †If it is, refer to the diagnosis is Substance-Induced Sexual Dysfunction. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition, Text Revision, Washington, DC: American Psychiatric Press; 2000.

The Challenges of Differential Diagnosis Psychiatric Illnesses and General Health Factors May Affect Sexual Function ► Mood disorders 1 ● ● Major depression Bipolar illness ► Anxiety disorders 2, 3 ► Psychotic illness 4 ► Hypertension ► Neurological disorders 6 ● Urological problems 8 ● Sexually transmitted infections 9 ● Gynecological problems — Post-partum 10 ● Other chronic illness — Rheumatoid arthritis 11 — Psoriasis 12 — Breast cancer 13 ► Endocrine disorders 7 ● Diabetes, thyroid disorders, hyperprolactinemia 7 1. Casper RC, et al. Arch Gen Psychiatry. 1985; 42: 1098 -1104. 2. van Lankveld JJ, Grotjohann Y. Arch 1. Casper RC, et al. Arch Psychiatry. 1985; 42: 1098 -1104. 2. van Lankveld JJ, Grotjohann Y. Arch Sex Behav. 2000; 29: 479 -498. 3. Shifren J, et al. Obstet Gynecol. 2008; 112: 970 -978. 4. Friedman S, Harrison G. Arch Sex Behav. 1984; 13: 555 -567. 5. Okeahialam BN, Obeka NC. J Natl Med al. Obstet Gynecol. 2008; 112: 970 -978. 4. Friedman S, Harrison G. Arch Behav. 1984; 13: 555 -567. 5. Okeahialam BN, Obeka NC. J Assoc. 2006; 98: 638 -640. 6. Rees PM, et al. Lancet. 2007; 369(9560): 512 -525. 7. Bhasin S, et al. Lancet. 2007; 369(9561): 597 -611. 8. Aslan G, et al. Int J Impot Res. 2005; 17: 248 -251. 9. Smith EM, et al. Infect Dis Obstet Gynecol. 2002; 10(4): 193 -202. 10. Baksu B, et al. Int Urogynecol J. Res. 2005; 17: 248 -251. 9. Smith EM, et al. Infect Gynecol. 2002; 10(4): 193 -202. 10. Baksu B, et al. Int J. 2007; 18: 401 -406. 11. Abdel-Nasser A, Ali E. Clin Rheumatol. 2006; 25: 822 -830. 12. Sampogna F, et al. Dermatology. 2007; 214: 144 -150.

The Challenges of Differential Diagnosis Numerous Medications are Associated with Female Sexual Problems Psychotropic drug classes/agents Other drug classes ● ● ● ● Antipsychotics 1 SSRIs 2 Lithium 3 SNRIs 4 Tricyclic antidepressants 5 Chemotherapeutic agents 6 Aromatase Inhibitors 7 Triglyceride-lowering agents 8 Histamine receptors (H 2) blockers 9 Weight loss agents 10 Antiepileptics 11 Immunosuppresants 12 Central alpha-adrenergic agonists 13 Opioid antagonists 14 1. Liu-Seifert H, et al. Neuropsychiatr Dis Treat. 2009; 5: 47 -54. 2. Serretti A, Chiesa A. J Clin Psychopharmacol. 2009; 29: 259 -266. 3. Lithium 1. Liu-Seifert H, et al. Neuropsychiatr Treat. 2009; 5: 47 -54. 2. Serretti A, Chiesa A. J Psychopharmacol. 2009; 29: 259 -266. 3. Lithium carbonate [package insert]. 2003. 4. Venlafaxine hydrochloride [package insert]. 2003. 5. Imipramine hydrochloride [package insert]. 2007. 6. Fobair P, Spiegel D. Cancer J. 2009; 15(1): 19 -26. 7. Mok K, et al. Breast. 2008; 17(5): 436 -440. 8. Fenofibrate [package insert]. 2008. 9. Ranitidine 6. Fobair P, Spiegel D. Cancer J. 2009; 15(1): 19 -26. 7. Mok K, et al. Breast. 2008; 17(5): 436 -440. 8. Fenofibrate [package insert]. 2008. 9. Ranitidine hydrochloride [package insert]. 2009. 10. Sibutramine hydrochloride monohydrate [package insert]. 2009. 11. Rees PM, et al. Lancet. 2007; 369: 512525. 12. Muehrer RJ, et al. West J Nurs Res. 2006; 28: 137 -150. 13. Clonidine [package insert]. 2009. 14. Naltrexone hydrochloride [package insert]. 525. 12. Muehrer RJ, et al. West Res. 2006; 28: 137 -150. 13. Clonidine [package insert]. 2009. 14. Naltrexone hydrochloride [package insert]. 2003.

Thank you Sheryl. kingsberg@uhhospitals. org

A New Frontiers Program on Women’s Health Pathophysiology of Decreased Desire in Premenopausal Women Psychological, Pharmacologic, and Neurobiological Mechanisms Program Chairman and Moderator Anita H. Clayton, MD David C Wilson Professor Department of Psychiatry & Neurobehavioral Sciences Professor of Clinical Obstetrics & Gynecology University of Virginia Charlottesville, VA

Objectives At the conclusion of this activity, participants should be able to: ► Describe the psychological, pharmacological and neurobiological factors affecting desire in premenopausal women

What’s it all about anyhow? ► Psychological/social/emotional ► Physiological/biological: interactions of sex steroids and neurotransmitters ► Cognitive: thoughts, fantasies, satisfaction ► Cultural American Psychiatric Association, DSM IV, 1994

Central Effects on Sexual Function + - 5 -HT testosterone +/- progesterone + + estrogen + + dopamine (DA) - DESIRE + 5 -HT prolactin oxytocin - SUBJECTIVE EXCITEMENT + norepinephrine (NE) + ORGASM Modified from Clayton AH. Psych Clin NA 2003; 26: 673 -682 Cohen AJ. AD-induced SD associated with low serum free testosterone 2000. http: //www. mental-healthtoday. com/rx/testos. htm

Peripheral Effects on Sexual Function gonads adrenals } • Estrogen • Testosterone • Progestin 5 -HT - maintain genital structure and function Nitric Oxide (NO) + - Clitoral and penile tissue SENSATION VASOCONGESTION 5 -HT 2 A + + NE Prostaglandin E + Cholinergic fibers Clayton AH. Psychiatric Clinics of North America 2003; 26: 673 -682 +

Physiology of Sexual Function ► Desire: ● ● ► Excitatory: dopamine, norepinephrine, testosterone, estrogen Inhibitory: serotonin, prolactin Arousal: ● ● Excitatory: dopamine, norepinephrine, nitric oxide, acetylcholine, estrogen, testosterone Inhibitory: serotonin, prolactin Pfaus JG. J Sex Med 2009; 6: 1506 -1533.

Influences on Sexual Functioning ► Neurobiological ● ● ● ► Reproductive endocrinology (ie. anything that lowers testosterone such as hyperprolactinemia, opiates, menopause) General health status/illness (e. g. fatigue)1 and comorbidities Medication/substance use Psychological ● ● ● Body image (e. g. obesity) Psychological/relationship issues, partner availability/aging 1 Fears (e. g. pregnancy, infertility, STD, history of sexual abuse/trauma, cultural practices) 1 Meston C. Western Journal of Medicine 1997; 167(4): 285 -290

DSM-IV TR Criteria for HSDD ► Sexual complaint or problem in sexual desire and/or fantasies ● ► ► The judgement of severity of the sexual symptom is made by the clinician, taking into account factors that affect sexual functioning, such as age and the context of the person’s life The disturbance causes marked distress or interpersonal difficulty The sexual dysfunction is not: ● ● Better accounted for by another primary psychiatric disorder (except another Sexual Dysfunction) Due exclusively to the direct physiological effects of a substance (e. g. , a drug of abuse, a medication) or a general medical condition American Psychiatric Association. DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, 4 th ed. , text revision. Washington, DC: American Psychiatric Press; 2000

FSD may be Multi-faceted ► Biological/Pharmacological ● ● ● ► Medical diagnoses Psychiatric conditions Other sexual disorders Medications/substances Hormonal changes Socio-cultural ● ● Lower education Religious restrictions Social taboos Cultural conflict ► Psychological ● ● ● Prior sexual or physical abuse Relational (conflict, lack of partner, partner SD) Body image, sexual self -esteem Negative emotional states Stress

Relational Problems (not HSDD) ► Sexual dysfunction in partner ► Interpersonal conflict ► Extra-marital affair by either partner ► Desire discrepancy ► Cultural differences ► Reproductive concerns ► History of sexual abuse

Prevalence of Sexual Dysfunction SEXUAL COMPLAIN T SEXUAL PROBLEM PLUS DISTRESS FSD WITHOUT DEPRESSION Desire 38. 7% 10% 6. 3 – 8. 8% Arousal 26. 1% 5. 4% 3. 3 – 4. 7% Orgasm 20. 5% 4. 7% 2. 8 – 4. 1% Any Dysfunctio 44. 2% 12% 7. 6 – 10. 7% N=31, 581. Definition of depression: Self-reported depressive n sx’s + AD use; AD use without current depressive sx’s; Depressive symptoms without AD use Shifren J et al. Sexual problems and distress in United States women: Prevalence and correlates. Obstet Gynecol 2008; 112: 970 -978; Johannes CB et al. Distressing Sexual Problems in United States Women Revisited: Prevalence after Accounting for Depression. J Clin Psychiatry 2009; 70(12): 1698 -1706

Proportion of Partnered Women with HSDD By Age and Menopausal Status 30 P=0. 002 % of Patients 25 20 P=0. 067 15 10 5 0 Premenopausal Surgically postmenopausal Age 20 -49 years Naturally Surgically postmenopausal Age 50 -70 years Leiblum SR et al. Hypoactive sexual desire disorder in postmenopausal women: US results from the Women’s International Study of Health and Sexuality (WISHe. S).

Medical Conditions that may Impact Sexual Function Neurologic Genitourinary Endocrine Systemic Illness Vascular Psychiatric Spinal cord injury, neuropathy, herniated disc, MS, epilepsy Hypothyroidism, adrenal dysfunction, hypogonadism, diabetes mellitus, menopause Hypertension, arteriosclerosis, stroke, venous insufficiency, sickle cell disorder Urinary incontinence, vaginitis, PID, endometriosis Renal, pulmonary, hepatic diseases, advanced malignancies, infections Depression, anxiety disorders, psychotic illness, eating disorders, PTSD Clayton & Ramamurthy in Sexual Dysfunction: The Brain-Body Connection. Ed: R Balon, Karger, Basel, Switzerland, 2008; Basson R, Schultz WW. Lancet. 2007; 369: 409 -424; Kingsberg SA, Janata JW. Urol Clin North Am. 2007; 34: 497 -506; Zemishlany & Weizman in Sexual Dysfunction: The Brain-Body Connection. Ed: R Balon, Karger Basel, Swithzerland 2008

Pharmacotherapies and Risk of FSD PSYCHOTROPIC MEDICATIONS SSRIs/SNRIs/TCAs Mood stabilizers Antipsychotics ANTIHYPERTENSIVES Beta-blockers Alpha-blockers CARDIOVASCULAR AGENTS Lipid-lowering agents Digoxin HORMONES Oral contraceptives Estrogens Progestins Benzodiazepines Antiepileptic drugs OTHER Diuretics Ant-iandrogens Gn. RH agonists Histamine H 2 -receptor blockers Narcotics NSAIDs Clayton & Ramamurthy in Sexual Dysfunction: The Brain-Body Connection. Ed: R Balon, Karger, Basel, Switzerland, 2008; Basson R, Schultz WW. Lancet. 2007; 369: 409 -424; Kingsberg SA, Janata JW. Urol Clin North Am. 2007; 34: 497 -506.

Correlates of Distress with HSDD: PRESIDE ►Psychological • Having a partner (OR 4. 63) • Demographics: Greatest age < 45 years; to lesser degree < 65 years; white race ►Neurobiological • • Untreated depression > treated depression Presence of anxiety Urinary incontinence Use of hormonal contraceptives or HRT Rosen RC, et al. Correlates of sexually related personal distress in women with low sexual desire. J Sex Med 2009; 6: 1549 -1560.

Decreased Sexual Desire Screener (DSDS) ©Boehringer Ingelheim International Gmb. H 2005. All rights reserved. Sensitivity 0. 836, 0. 946, 0. 956, and specificity 0. 878 Goldfischer ER et al. Obstet Gynecol 2008; 111: 109 S Clayton A et al. J Sex Med 2009; 6: 730– 738 Nappi R et al. J Sex Med 2009; 6(suppl 2): 46

Conclusions ► Multiple factors may affect sexual functioning in women across the life cycle ► Appropriate assessment is important in management

A New Frontiers Program on Women’s Health Addressing Current Challenges in Female Sexual Disorders What Internal Medicine Specialists Need to Know About HSDD Lori Brotto, Ph. D Assistant Professor Department of Obstetrics and Gynecology University of British Columbia Vancouver, BC

Outline ► Physician-patient communication ► Screening strategies ► Differential diagnosis ► Interview techniques ► PLISSIT / ALLOW

Why is inquiry about sexual function difficult? ► Topic not important enough ► It is a private experience ► Embarrassment ► “I don’t exactly know why I am asking” ► Lack of training ► Absence of norms ► Sexual behaviour is a topic only when it is deviant or when others are at risk ► Incorrect beliefs about the benefit of asking

Is Marriage Good for Your Health? New York Times Magazine, April 12, 2010

Complicating factors: Symptom or disorder? ► ► Lutfey et al. , 2008, Arch Sex Behav n = 3, 205; Black, Hispanic, White Factoring in distress, rates of low desire drop by half in all studies Note, DSM-IV-TR criteria for HSDD and all sexual dysfunctions require distress

Complicating Factors: Low Desire Does Not Always Imply Dissatisfaction ► Oberg et al. (2004) found a prevalence of manifest distress despite the absence of any sexual symptoms of 12. 4% ► Bancroft, Loftus, and Long (2003) found that 8% of women reported distress about the relationship and 5. 4% reported personal distress despite absence of sexual symptoms ► Lutfey, Link, Rosen, Wiegel, and Mc. Kinlay (2008) reported that 5. 5% of women were dissatisfied or very dissatisfied despite not having any sexual symptoms. ► Cain et al. (2003) in the SWAN study found that 70% of women reported thinking about sex less than once/week but 86% remained sexually satisfied. ► King et al. (2007) found that 19% of women did not have an ICD-10 diagnosed sexual dysfunction but still reported significant low sexual satisfaction. ► Dunn et al. (2000) found that 79% of women were very sexually satisfied but 24% had no sexual activity in the past 3 months. ► Laumann et al. (2005) in the GSSAB found that 7. 7% - 17. 4% of women reported not finding sex pleasurable/satisfying.

Why assess sexual function? ► Sexual dysfunction is common ► Integral component of quality of life and general well-being

Lindau et al. , NEJM, 2007

Physician-patient communication

Are physicians asking? ► 53 primary care physicians (or internal medicine residents) at UVA completed questionnaire about their experience asking about HSDD ● ● ● 86. 3% had not screened for HSDD 90% had not diagnosed HSDD 53% felt not confident at all, 38% little confidence Harsh et al. , J Sex Med 2008

Percentage of survey participants providing estimate Survey Participants and Patients who Initiate First Discussion of FSDs Survey participants initiating first discussion of FSD J Sex Med 2006; 3: 639 -645 Patients initiating first discussion of FSD

Who should I ask about sexuality? EVERYONE! ► Legitimizes the patient’s concerns with and interest in sex ► Allows the patient to ask questions ► Identifies the provider as a potential resource for sexual information ► Maximizes the chances that patients will get help for sexual and relationship problems ►

Screening Strategies

Screening questions ► Are you satisfied with your sexual response (sex life)? If not, why not? ► Are you currently active with a sexual partner? ● ● Men, women or both Frequency (activity including masturbation) ► How often do you have difficulty _____? ► What questions or problems related to sex would you like to discuss?

When to ask? 1. During routine inquiry ► ► Include it in a standard set of questions during developmental and psychosocial periods Include it on self-report questionnaire “you were telling me about your male friendships growing up…Do you remember when you first became aware of sexual feelings? ”

When to ask? 2. After direct presentation ► ► Patient directly states problem Ask permission and collect information 3. After indirect presentation ► ► ► Patient is indirect and vague, hoping the clinician will ask about sexual complaints e. g. , medication non-compliance Know about that particular condition and sideeffect profiles of medications

How to ask? 1. Need clinical knowledge, a non- judgmental attitude, and fundamental interviewing skills ► ► ► Observing and monitoring Interpreting skills Responding skills

How to ask? 2. Clarify the problem Patient: I’ve lost my nature Clinician: Tell me what a nature is? I haven’t heard that expression before. 3. Use personalized language ► ► Use the correct term and allow the patient to pick up on it Sometimes may be appropriate to use patient’s language

How to ask? 4. Use open-ended questions ► ► Use: “to what extent…what…how…” Don’t use: “do you…did you…are you…have you…” “What were the circumstances that led you to be sexual with him? ” 5. Be empathic ► ► Is an expression of professional understanding “that must have been really difficult for you…”

How to ask? 6. Facilitate ► Encourage the patient to continue by nodding, leaning forward, using “yes…go on. ” 7. Provide information ► ► Anticipate worries and speculate Confirm understanding of the problem before proceeding

Differential Diagnosis

Comorbidity of Women’s Sexual Difficulties • desire and lubrication – 65% • desire and orgasm - 53% • desire and vaginismus – 75% • lubrication and orgasm – 28% • lubrication and dyspareunia – 61% Basson et al. , 2003 J Psychosom Obstet Gynaecol Desire difficulties Arousal difficulties Orgasm difficulties Pain Vaginismic difficulties

Depression?

Interview Techniques Self-report measures

Use of Validated Questionnaires ► Decreased Sexual Desire Screener (DSDS) Clayton et al. 2009, J Sex Med ► Female Sexual Function Index (FSFI) Rosen et al. 2000, J Sex Marital Ther ► Profile of Female Sexual Function Mc. Horney et al. 2004, Menopause ► Female Sexual Distress Scale (FSDS) Derogatis et al. 2002, J Sex Marital Ther

Decreased Sexual Desire Screener Clayton, Goldfischer, Goldstein, De. Rogatis, Lewis-D’Agostino, Pyke, J Sex Med 2009; 6: 730 -738 1. In the past was your level of sexual desire or interest good and satisfying to you? 2. Has there been a decrease in your level of sexual desire or interest? 3. Are you bothered by your decreased level of sexual desire or interest? 4. Would you like your level of sexual desire or interest to increase? 5. Please check all the factors that you feel may be contributing to you current decrease in sexual desire or interest.

Use of a Validated Structured Interview ►Women’s Sexual Interest Diagnostic Interview De. Rogatis et al. 2008, J Sex Med *39 items assessing desire, arousal, orgasm, pain and distress, partner sexual dysfunction, relationship problems, depression * Permission to use the WSID can be obtained by contacting Solvay Pharmaceuticals, Inc. (+1 -770 -579 - 7374, chun-yuan. guo@solvay. com) ►Sexual Interest and Desire Inventory-Female Version (SIDI) Clayton et al. 2005, J Sex Marital Ther *13 -item clinician administered measure of sexual interest, desire and arousability

Interview Techniques Face-to-face interview

PLISSIT ► Permission ● ● ► Limited Information ● ► Basic education regarding anatomy & sexual response Specific Suggestions ● ● ► Acceptance, empathy “I ask all my patients about sex. Is it OK to do so now? ” Medical-medication, procedures to relieve discomfort Psychological-behavioral strategies, communication skills Intensive Therapy ● ● Individual or couples therapy to manage sexual or relationship issues Surgery (penile implants, vestibulectomy)

ALLOW Sadovsky, 2002

Goals of a Comprehensive Sexual History ► Identify the primary complaint ► Determine patient’s perspective of their problem ► Develop hypotheses about etiology ► Decide on an appropriate course of treatment (including referral)

Elements of a Comprehensive Sexual History ► Assess sexual functioning ► Assess risk behaviours ► Assess medical/organic contributors ► Assess partner status ► Ask about history of childhood sexual or physical abuse ► Assess mood ► Assess relationship satisfaction and functioning

Sample Assessment Questions What is your sexual interest like? What factors enhance and/or inhibit your desire? ► Many people engage in self-stimulation. Is this part of your sexual experiences? ► Some people avoid sexual activity for any variety of reasons? Can you relate to this? ► Many women talk about difficulties with lubrication or sexual activity that is painful. What is your experience with this? ► Most men experience occasional difficulties with their erection. Has this been the case for you? ►

Sample Assessment Questions Do you notice any difference between your erections during sexual intercourse, during masturbation, and those when you wake up? ► When you’re experiencing this difficulty, can you recall what you’re thinking or feeling at the time? How about right before? ► Of your last 10 sexual encounters, on how many of them did you experience this difficulty? ► What do you do in response to this difficulty? What does your partner do? ► Can you describe the sensation of the pain? Is it burning, throbbing, or sharp? When do you experience it? ►

Problems to Avoid During the Sexual Interview ► Meddling: always rationalize your questioning ► Preoccupation: focus on each response ► Identification: consult with a colleague if you’re not able to be objective ► Sexual arousal: be aware of your own feelings

Putting the Sexual History in Context ► What explanations does the patient have (their theory)? ► What have they done to try to resolve the problem? ► Are there problems in multiple areas of sexual functioning? What is the relationship between these? ► What have they discussed with their partner and what was the reaction?

Multi-Factorial Model Maintaining Factors Predisposing Factors Early Development Precipitating Factors Current Functioning

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A New Frontiers Program on Women’s Health Current and Emerging Therapies for Hypoactive Sexual Desire Disorder Jennifer Frank, MD, FAAFP Assistant Professor Department of Family Medicine University of Wisconsin School of Medicine and Public Health

Learning Objectives ► Describe a multimodal treatment approach to HSDD ► Identify components of nonpharmacologic treatment of HSDD ► Describe current pharmacologic treatment options for HSDD in both postmenopausal and premenopausal women ► Identify emerging pharmacologic treatment options for HSDD

HSDD Treatment Starts with Nonpharmacologic Approaches ► Foundation of therapy ► Includes treatment initiated and managed by the primary care physician ► May include treatment by specialist partners ● ● Sex therapist Physical therapist Cognitive behavioral therapist Marital/relationship counselor

Nonpharmacologic Treatment PCP based ► Education ● Dispelling myths Specialist based ► CBT ► Sensate-focus ► Controlled selfstimulation ► Exercise ► Healthy Diet ► Adequate Rest ► Couples counseling ► Stress Reduction ► Physical therapy ● ● Vaginal dilators Biofeedback Bitzer J, Brandenburg U. Psychotherapeutic interventions for female sexual dysfunction. Maturitas 2009; 63: 160 -3.

Sex Therapy for the PCP ► Education What is normal? Basics of anatomy and physiology? ► Lubrication Basic familiarity with 3 or 4 different products ► Maximize intimacy and opportunities for intimacy ► Introduce novelty – different positions, venues, toys, etc. ► Getting into a sexual frame of mind ► ► “Men are like light switches, women are like ovens. ” Patient focused reading T. L. C. Redistribution of childcare and household responsibilities Improving body image Potter JE. A 60 -year-old woman with sexual difficulties. JAMA 2007; 297: 620 -33. Up. To. Date and www. sexedsolutions. com

Barriers to Nonpharmacologic Treatment ► Physician’s unfamiliarity with counseling and recommendations ► Physician’s discomfort with this role ► Patient’s resistance to relationship work ► Patient’s perceived barriers to implementing change ► Patient’s unwillingness to change ► Patient’s belief in a “little blue pill” ► Lack of or paucity of hope ► Reward not worth the work

Current Pharmacologic Treatment Options for FSD ► Hormonal ● ● ► Psychotropic medications ● ► Estrogen Testosterone* Buproprion* Phosphodiesterase inhibitors ● Sildenafil* *Not FDA approved for this indication

Local Estrogen Therapy for Vaginal Atrophy (Level C) ► Postmenopausal women without a history of hormone-dependent breast cancer ► Low dose as long as symptoms persist ► Not indicated for HSDD but can be helpful if pain/dryness is contributing to low desire ► Consider if prescribing testosterone

Consider Testosterone for Post. Menopausal Women with HSDD ► Good evidence (Level A) to support its use in estrogen replete women 1 -3 ► 300 mcg patch for 24 weeks ► Both naturally 4 and surgically 1 -3 menopausal women ► Improvements seen in desire, orgasm frequency and total number of sexually satisfying encounters 1. Braunstein et al. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women. Arch Intern Med 2005; 165: 1582 -9. , 2. Buster et al. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol 2005; 105: 944 -52. , 3. Davis et al. Efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Menopause 2006; 13: 387 -96. 4. Shifren et al. Testosterone patch for the treatment of hypoactive sexual desire disorder in naturally menopausal women: results from the INTIMATE NM 1 study. Menopause 2006; 5: 770 -9. ,

Testosterone’s Role in Postmenopausal Women without ERT ► DBRCT of placebo vs. testosterone patch ► Increase in SSEs/month at 300 mcg daily dose ● 2. 1 (active) vs. 0. 7 (placebo) ► Increase in desire ► Decrease in distress ► Treatment effect similar in naturally and surgically menopausal women ► 4 episodes of breast cancer in study participants (n=537) Davis et al. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med 2008; 359: 2005 -17.

Testosterone for Premenopausal Women may Have a Role DBRPCT of 261 premenopausal women Not depressed Low serum testosterone Testosterone at 90 microliters/day (spray) daily x 16 weeks Increase of 0. 8 SSEs/month over placebo Strong placebo effect SSE not related to testosterone levels Levels returned to baseline at 20 weeks (4 weeks after study) but SSEs did not Davis et al. Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women. Ann Intern Med 2008; 148: 569 -577.

Testosterone Treatment Limitations ► Androgen levels not clearly associated with decreased desire Difficult to measure testosterone levels accurately ► Role in premenopausal women is not established 1 ► Off label indication ► Long term efficacy/safety not known 1 -3 ► Study population (definition of decreased desire)1 ► Relationship between arousal and desire 1 ► Need for concomitant use of estrogen (? )1 1. Basson R. Pharmacotherapy for women’s sexual dysfunction. Expert Opin Pharmacother 2009; 10: 1631 -48. 2. NAMS. The role of testosterone therapy in postmenopausal women: position statement of the North American Menopause Society. Menopause 2005; 12: 497 -511. 3. Wierman et al. Androgen therapy in women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2006; 91: 3697 -3710.

Buproprion has Limited Data to Demonstrate Efficacy in HSDD (Level B/C) Buproprion (300 mg/day) x 112 days in non-depressed premenopausal women with normal serum testosterone 1 268 women ages 20 -40 diagnosed with HSDD (Level B)2 1. 2. 3. 4. Premenopausal, not depressed, normal testosterone 12 weeks of buproprion SR 150 mg/day Improvement in rating scale of sexual function (globally and specific subsets) Global improvement in sexual functioning and on subsets of arousal, orgasm completion and pleasure on one of the scales used(Level C) No statistically significant improvement in desire Greatest improvement in frequency of sexual activity, thoughts/desire, and pleasure/orgasm Decrease in personal distress score Add-on or substitute therapy for SSRI induced sexual dysfunction(Level B)3, 4 Segraves et al. Buproprion SR for the treatment of HSDD in premenopausal women. J Clin Psychopharm 2004; 24: 339 -42. Safarinejad et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of buproprion for treating hypoactive sexual desire disorder in ovulating women. BJU International Feb 2010 [Epub]. Safarinejad. Reversal of SSRI-induced female sexual dysfunction by adjunctive buproprion in menstruating women: a double-blind, placebocontrolled and randomized study. J Clin Psychopharm Jan 2010 [Epub]. Seretti A, Chiesa A. Treatment-emergent sexual dysfunction and anti-depressants: a meta-analysis. J Clin Psychopharm. 2009; 29: 259 -66.

Phosphodiesterase Inhibitors ► No demonstrable role in the treatment of HSDD ► Use in antidepressant associated FSD 1 ● ► Main effect on orgasmic capacity Potential use in women with neurovascular mediated sexual dysfunction 2 ● Primarily arousal, orgasmic dysfunction 1. Nurnberg et al. Sildenafil treatment of women with antidepressant-associated sexual dysfunction. JAMA 2008; 300: 395 -404. 2. Brown DA et al. Assessing the clinical efficacy of sildenafil for the treatment of female sexual dysfunction. Ann Pharmacother 2009; 43: 1275 -85.

Emerging Pharmacologic Therapies ► Hormonal ● ► Testosterone Centrally acting agents ● Flibanserin ► Phosphodiesterase Inhibitors ► Others ● Prostaglandin gel

Testosterone in the Future 1 ► Premenopausal women ● ► Effects of long term use are unknown Search for an FDA approved preparation ● ● Libi. Gel Intrinsa 2 ► Tibolone 3 - estrogenic, progestogenic, ► Combined with ERT? androgenic synthetic hormone 1. Krapf and Simon. The role of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women. Maturitas 2009; 63: 213 -9. 2. Davis et al. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med 2008; 359: 2005 -17. 3. Wylie and Malik. Review of drug treatment for female sexual dysfunction. Int J STD AIDS 2009; 20: 671 -4.

Centrally Acting Agents 1 ► Bremelanotide 3 ● ● ► Flibanserin 1 ● ● 1. 2. 3. Melanocortin agonist FSAD Acts as a partial serotonin agonist/antagonist Specifically being studied for HSDD Wylie and Malik. Review of drug treatment for female sexual dysfunction. Int J STD AIDS 2009; 20: 671 -4. Baldwin. Agomelatine in the treatment of mood anxiety disorders. Brit J Hospital Med 2010; 71: 153 -6. Safarinejad. Evaluation of the safety and efficacy of bremelanotide, a melanocortin receptor agonist, in female subjects with arousal disorder: a double-blind placebo-controlled, fixed dose, randomized study. J Sex Med 2008; 887 -97.

Other Agents ► Phosphodiesterase inhibitors ● ● Role will likely be focused to specific populations No demonstrable effect on desire ► Alprostadil (Prostaglandin E 1) in trials for FSAD (vasodilatory properties)

Conclusions ► The foundation of HSDD treatment is nonpharmacologic including PCP directed and specialty directed modalities. ► Pharmacotherapeutic options are limited at this time. ► Most promising treatments for HSDD include hormonal (testosterone) and centrally acting agents (buproprion and flibanserin). ► Other medications may have role for different types of FSD.

Case Example ► 26 -year-old MWF presents with 1 year history of decreased libido, some problems with vaginal lubrication, and diminished orgasmic capacity. No pain with intercourse. § Change in sexual function since marriage 4 years ago, but relationship still strong § 1 year post-partum with mild depressive symptoms since delivery § No general health problems § On oral contraceptives for birth control

Differential Diagnosis

Evaluation/Interventions ► Consider labs such as TSH ► Consider change from birth control pills to non -hormonal contraceptive ► Specific suggestions ► Consider adding bupropion to treat depression and enhance sexual functioning ► If no improvement, check testosterone levels before supplementing