UpdatE

SEXUAL DYSFUNCTION A dearth of approved drugs for desire and arousal disorders frustrates women and clinicians alike. The good news? Several products are in the pipeline.

›› Barbara S. Levy, MD Dr. Levy is Medical Director of the Women’s Health Center, Franciscan Health System, in Federal Way, Wash. She serves on the OBG Management Board of Editors.

Dr. Levy reports no financial relationships relevant to this article.

ince sildenafil (Viagra) was approved by tial increases in the risks of coronary artery Sthe US Food and Drug Administration disease and breast cancer. Pivotal trial data to treat erectile dysfunction, women have did not demonstrate enhanced risk, but the In this numbers were too small and the timeframe Article been calling for research and development of treatments for female sexual dysfunction. too short (a maximum follow-up of 2 years) Intravaginal DHEA Despite considerable research docu- to establish an effect, so the FDA asked for improves post- menting improvement in sexual responsive- long-term studies. In 2006, European regu- menopausal sexual ness, genital sensation, and overall well-being lators approved Intrinsa to treat low sexual function among women who were given testosterone desire in surgically menopausal women. after undergoing bilateral oophorectomy, Then there’s flibanserin, which also page 25 there remains only one testosterone formula- failed to win approval from an FDA advisory tion for women. A combination of synthetic committee after numerous concerns were What can you offer estrogen and methyl testosterone (Estratest; raised about its safety and efficacy in pre- to patients who report Abbott) is indicated for management of mod- menopausal women (see more about this sexual dysfunction? erate to severe vasomotor symptoms associ- on page 22). page 26 ated with menopause in patients who do not The lack of approved drugs leaves gyne- respond to estrogens alone. cologists and women’s health providers with In the testing stage from BioSante is little to offer our patients who are distressed Dr. Levy talks about LibiGel, a transdermal testosterone prod- by sexual dysfunction. how to talk about sex uct. Acrux is developing Luramist, a daily In this Update, I discuss: with patients testosterone spray. Proctor & Gamble’s • the complexity of female sexual function at obgmanagement.com efforts to gain approval of a testosterone- • what derailed flibanserin containing transdermal patch (Intrinsa) for • recent findings that suggest dehydroepi- treatment of low libido were unsuccessful, androsterone (DHEA) may be beneficial largely because of concern about poten- • recommendations for clinical practice.

continued on page 21

20 OBG Management | September 2010 | Vol. 22 No. 9 obgmanagement.com UpdatE sexual dysfunction

As understanding of female sexual dysfunction evolves, so do its labels

he fourth edition of the Diagnostic and subsumed into a new category, “sexual inter- TStatistical Manual of Mental Disorders est/arousal disorder in women”.1 (DSM-IV) divides female sexual dysfunction into four categories: The female response • hypoactive sexual desire disorder to sexual stimuli is complex (HSDD)—a persistent or recurrent defi- The complexity of sexual arousal disorders in ciency or absence of sexual fantasies and women complicates research into the patho- desire for sexual activity physiology and potential pharmacologic • female sexual arousal disorder—a per- treatment of these conditions. Conflicting sistent or recurrent inability to achieve or evidence for any benefit of the phosphodies- maintain adequate vaginal lubrication or terase type-5 (PDE5) inhibitors, such as silde- vulvar swelling (i.e., sexual excitement) nafil, in the treatment of sexual dysfunction in • female orgasmic disorder—persis- women likely arises from a lack of precision in tent or recurrent delay in or absence of defining the conditions in which and patients orgasm following a normal sexual excite- for whom these interventions are appropriate. ment phase Functional magnetic resonance imaging • dyspareunia—persistent or recurrent (MRI) studies of men and women reveal dif- genital pain that is associated with sexual ferences in areas of brain activity related to intercourse. sexual arousal. The neurophysiology of sex- These categories were revised in 2003 by ual desire and response is complex, involv- an international consensus committee spon- ing multiple neurotransmitters, peptides, In the fifth edition sored by the American Urological Associa- and hormones as well as multiple structural of DSM, hypoactive tion Foundation; arousal disorder has been regions within the brain. Dopamine, nor- sexual desire subdivided into: epinephrine, melanocortin, oxytocin, and disorder and female • combined arousal disorder—absent serotonin (at some of its receptors) promote sexual arousal feelings of sexual arousal from any type of sexual activity, whereas prolactin, gamma disorder may be stimulation, as well as absent or impaired amino butyric acid (GABA), and serotonin subsumed in a new genital sexual arousal (vulvar swelling (at most of its receptors) are inhibitory. category: “Sexual and vaginal lubrication) In animal studies, both an increase in interest/arousal • subjective arousal disorder—absent dopamine and a change in social environ- disorder in women” feelings of sexual excitement and plea- ment can trigger increased sexual behavior. sure from any type of stimulation in the In women, a dopaminergic drug such as presence of genital sexual arousal (vulvar buproprion may increase arousability and swelling and vaginal lubrication) pleasure—but so can a new partner. • genital arousal disorder—subjective All these bits of the “big picture” con- sexual excitement from nongenital sex- tinue to complicate research in female sexual ual stimuli with reduced sensation from function. genital touching and an absence of geni- It is imperative that we begin to under- tal sexual arousal from any type of sexual stand the nuances of our patients’ sexual stimulation. problems if we are to offer effective sugges- These updated definitions will be incorpo- tions for treatment and management. Objec- rated into DSM-V, to be published in 2013. tively determined genital arousal disorder Also likely to change in DSM-V: HSDD very likely derives from neurovascular causes and female sexual arousal disorder may be and is likely to respond to PDE5 inhibitors,

obgmanagement.com Vol. 22 No. 9 | September 2010 | OBG Management 21 UpdatE sexual dysfunction

but subjective arousal disorder with normal This is the state of our basic science vulvar and vaginal engorgement and lubrica- knowledge in 2010. What’s out there and on tion is not likely to respond to these agents. the horizon for us to offer our patients?

Flibanserin gets an unequivocal thumbs down

Phase-3 Trial 511.71. A twenty-four week, random- Sexual desire was rated daily by the par- ized, double-blind, placebo-controlled, safety and ef- ticipants using an eDiary. ficacy trial of flibanserin 50 milligrams every evening In North American phase-3 trials, 2,462 and flibanserin 100 mg every evening in women with premenopausal women with acquired HSDD hypoactive sexual desire disorder in North America. in stable, monogamous, functionally hetero- NCT00360529. sexual, communicative relationships for at least 1 year were enrolled. Comorbid arousal Phase-3 Trial 511.75. Best tolerability: 50 mg twice and orgasmic disorders were allowed if they daily versus 100 mg in the evening versus 25 mg twice were secondary to decreased desire. Mean daily versus placebo in younger women in North Amer- age of the participants was 35 to 36 years, ica. NCT00360555. and they were predominantly white, highly educated women in long-term relationships. Two important exclusions worth noting: libanserin is a 5HT 1A agonist, 2A antag- • women who had depression, breast or In phase 2 trials, Fonist, and weak dopamine agonist. It other cancers (except skin cancer), or flibanserin proved was originally studied as a treatment for any major medical condition to be superior major depressive disorder. In phase-2 trials, • women who were taking any of the med- to placebo in it was ineffective for management of depres- ications on a five-page list of excluded improving sex drive sion but superior to placebo and an active drugs (due to metabolism with the in women comparator in improving sex drive (based enzyme cytochrome P3A4). on validated questionnaires). These results Once they were screened, women com- formed the basis for studying flibanserin pleted a 4-week baseline assessment of sex- as a treatment for HSDD. More than 5,000 ual activity and desire, followed by a 24-week women have been involved in phase-2 and study period. They were randomized to phase-3 trials in the United States, Canada, receive 50 mg or 100 mg of flibanserin or pla- and Europe. cebo daily. Improvements in sexual function, Following FDA guidance for spon- compared with the 4-week baseline, had to sors developing treatments for HSDD, drug be both statistically and clinically significant maker Boehringer Ingelheim defined the for the studies to be successful. primary endpoints for the pivotal trials as an increase in the number of sexually satisfying Flibanserin’s effects events (SSEs) and sexual desire, as measured were clinically unimpressive by a daily diary. Sexual events included: At a daily dosage of 100 mg, flibanserin was • genital touching by the partner associated with a significant increase in the • masturbation number of SSEs, compared with placebo. • oral sex However, the co-primary endpoint of an • intercourse increase in desire, as assessed by the eDiary,­ • orgasm. was not achieved in the active treatment

22 OBG Management | September 2010 | Vol. 22 No. 9 obgmanagement.com UpdatE sexual dysfunction

When the public got to talk about flibanserin, it had a lot to say

Attendees who spoke during the open public hearing on Web site sponsored by Boehringer Ingelheim that of- flibanserin, held June 8 in Gaithersburg, Md, had mixed fers, among other resources, a “sexual satisfaction opinions of the drug’s utility in premenopausal women checklist.” with hypoactive sexual desire disorder (HSDD). Some Many other attendees had a personal interest in the believe approval of a “female Viagra” is long overdue. issue or represented advocacy groups, and their respons- Others, not so much. es were just as mixed. “In 1920, women were given the right to vote,” said Michelle King Robson, founder and CEO of Empow- Sue Goldstein, clinical trial coordinator at San Diego Sex- Her, a women’s health media company, favored approval ual Medicine in San Diego, Calif. “What we’re asking now of flibanserin. is that women be empowered again, that they be given “Women are struggling to find solutions to their the right to choose to be treated with an FDA-approved sexual dysfunction,” she said. product for HSDD.” She added: “Once again, we are the Liz Canner, director of the feature documentary film forgotten gender.” Orgasm, Inc., which takes as its subject “the strange sci- Leonore Tiefer, PhD, sees things differently. ence of female pleasure,” accused Boehringer Ingelheim “The simple but appealing notion that a new brain of “disease mongering” (and held a viewing of her film in drug can help you with [hypoactive sexual desire dis- a room down the hall). order] because, well, desire is in the brain, has been One of the last to speak was Amy Allina, program di- peddled for the past year as if it were a fancy pair rector of the National Women’s Health Network, who as- of shoes,” said Tiefer, clinical associate professor of serted that flibanserin offers “little benefit for real women psychiatry at New York University School of Medicine. in the real world.” “Flibanserin is not a choice when it’s promoted by There may one day be an effective agent for HSDD, bad science and half-truths and when self-diagnosis she said. checklists are passed off as medical care.” Her last “This drug is not it,” she added. comment was a reference to sexbrainbody.com, a —Janelle Yates, Senior Editor

group. Women who took flibanserin had a flibanserin. However, concomitant use of response rate of 30% to 40%, compared with alcohol, a selective serotonin reuptake inhib- 15% to 30% for women who took placebo. itor (SSRI) or serotonin-norepinephrine Although this difference was significant, it reuptake inhibitor (SNRI), or a triptan was was clinically unimpressive, with fewer than associated with a marked increase in side 50% of participants experiencing significant effects. improvement (Table 1). In addition, women who were predisposed to depression or suicidal ideation were more Frequency of side effects is troubling likely to develop suicidal tendencies while tak- Among women who took the active drug, ing flibanserin, compared with placebo. 34.6% discontinued the medication because Given the long list of prohibited medi- of side effects, compared with 6.8% of women cations (CYP3A4 promoters or inhibitors), who took placebo. Most common side effects many of which are in widespread use, and (and their incidence) were: given the lack of pharmacodynamic assess- • nausea (12%) ment by the sponsor of circulating levels of • dizziness (11%) active drug if used with any of these medi- • fatigue (11%) cations, FDA reviewers and advisory panel • daytime somnolence (9.5%) members grew concerned about the poten- • anxiety (2%). tial for major side effects if flibanserin were In the healthy study population, no to be released for commercial use. major safety issues were associated with Ultimately, the FDA advisory panel

24 OBG Management | September 2010 | Vol. 22 No. 9 obgmanagement.com TABLE 1 Flibanserin increased the mean number of sexually satisfying events—but improvement was modest

Phase-3 trial Measure Placebo Flibanserin P value 511.71 Baseline 2.7 3.0 24 weeks 3.5 4.6 .005 511.75 Baseline 2.7 2.6 24 weeks 2.6 4.4 .024 voted unanimously to withhold approval of company to continue studies in postmeno- flibanserin for treatment of HSDD in pre- pausal women. Recruitment is under way menopausal women but encouraged the for NCT00996372.

Intravaginal DHEA improves postmenopausal sexual function

Labrie F, Archer D, Bouchard C, et al. Effect of intravag- women to placebo or 3.25 mg, 6.5 mg, or 13 inal dehydroepiandrosterone (Prasterone) on libido mg of DHEA daily. Median age of partici- and sexual dysfunction in postmenopausal women. pants was 58. Menopause. 2009;16(5):923–931. The study began with a 4-week base- line screening phase, followed by 12 weeks All aspects of placebo or active treatment. Women were of female sexual HEA has been studied as a treatment for enrolled if they were postmenopausal and function—desire, Dfemale sexual dysfunction in postmeno- experienced vaginal dryness or vulvar or arousal, orgasm, pausal women, in whom it acts as a precursor vaginal irritation or pain. Most women had and pain—improved for both estrogen and androgen synthesis. moderate to severe symptoms. significantly among In this study by Labrie and colleagues, all Topical or systemic hormone therapy postmenopausal aspects of female sexual function—desire, was prohibited, and women who had preex- women using arousal, orgasm, and pain—improved sig- isting cancer (except skin cancer) or endo- intravaginal DHEA nificantly with intravaginal DHEA (Table 2). metrial hyperplasia were excluded. The This phase-3, multicenter, placebo- primary endpoint was improvement in the controlled, randomized clinical trial of 216 four domains of sexual dysfunction. participants—50 in each arm—randomized Although women were not initially

TABLE 2 Women using intravaginal DHEA experienced improvement in all four domains of female sexual function

Domain Improvement after 12 weeks P value of 1% DHEA Desire 49% <.0001 Arousal 68% .0004 Orgasm 75% <.0001 Dryness (pain) 57% .0001

obgmanagement.com Vol. 22 No. 9 | September 2010 | OBG Management 25 UpdatE sexual dysfunction

selected for this trial based on measures they were taking other medications known to of personal distress related to their sexual affect sexual function, with the exception of dysfunction (marked distress or interpersonal systemic or topical hormonal treatment. difficulty is required by DSM-IV for a diagno- The robust results in this study were sis), approximately 50% indicated a desire for achieved without increasing circulating improvement on the intake questionnaire. levels of estrogen, testosterone, or DHEA Women were not excluded from this study if beyond the normal postmenopausal range.

What can we offer to our patients?

emale sexual dysfunction is more difficult paying attention to sexuality increased Fto categorize and certainly more difficult measures of female sexual function by as to measure scientifically than male sexual much as 30% dysfunction. The distinction between desire, • encouragement about a healthy life- arousal, and pain disorders in women is eas- style, such as regular exercise, which ily blurred. Certainly, the ability to declare increases blood flow to the genitalia—as success in clinical trials is straightforward does discontinuation of smoking. Silde- and unequivocal for men. Not so for women. nafil may have a role in managing SSRI- Female sexual dysfunction that causes induced or vascular disease–related distress for our patients is not uncommon. It genital arousal disorder.2 is a source of frustration for our patients and for us as providers. For now, in the absence of Stay tuned In the trials a “little pink pill,” we can offer: Despite recent disappointments in pharmaco- described in this • techniques to eliminate pain such as therapy, our awareness about and knowledge article, simple topical estrogen for atrophy and physical of female sexual dysfunction continues to enrollment and therapy and biofeedback for secondary grow. Safe and effective treatments for HSDD increased focus vaginismus and the other conditions affecting women’s adjustment of medications on sexuality • that may sexual function are in the pipeline. thwart sexual desire, arousal, or orgasm, improved sexual References such as SSRIs and antihypertensive regi- 1. American Psychiatric Association. DSM-5 development. function by Sexual and gender identity disorders.http://www.dsm5.org/ mens as much as 30% ProposedRevisions/Pages/SexualandGenderIdentityDisorders. • counseling and psychotherapy to help aspx. Accessed July 27, 2010. 2. Caruso S, Rugolo S, Agnello C, Intelisano G, Di Mari L, Cianci focus the relationship back to intimacy A. Sildenafil improves sexual functioning in premenopausal and sexuality. Remember that just enroll- women with type 1 diabetes who are affected by sexual arousal disorder: a double-blind, crossover, placebo- ing in the clinical trials I described and controlled pilot study. Fertil Steril. 2006;85(5):1496–1501.

the year concludes with these informative Updates

›› October: Pelvic floor surgery, from Dr. Cindy Amundsen and Dr. Amie Kawasaki ›› November: Osteoporosis, from Dr. Steven Goldstein

›› December: Urinary incontinence, from Dr. Marie Fidela R. Paraiso and Dr. Elena Tunitsky-Bitton

26 OBG Management | September 2010 | Vol. 22 No. 9 obgmanagement.com