Female patients demand ‘equal time’ in development of sexual dysfunction therapies

Female sexual dysfunction is multifaceted and complex, experts agree. Women seeking solutions are confronted with conflicting beliefs about the biological and psychological aspects of the disorder, and some contend that the FDA holds the pharmaceutical industry to a double standard when reviewing new therapies.

“Unfortunately, we are not very advanced in the field of biological components of female sexual dysfunction,” Rosemary Basson, MD, FRCP, director of the Sexual Medicine Program at University of British Columbia, Canada, told Endocrine Today.

Diagnosis and prevalence

In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), published in 2013, the separate classifications of hypoactive sexual desire disorder (HSDD) and female sexual arousal disorder (FSAD) were merged into a single syndrome: female sexual interest/arousal disorder.

Articles published in Archives of Sexual Behavior and The Journal of Sexual Medicine elucidated “huge difficulties” involved in the transition, Basson said. “[The] DSM-IV [classification] is modeled on the male response, and it just doesn’t work for women,” she said. “Coming up with something everyone can agree on for women is challenging.”

 

DSM-5 lists three sexual dysfunction classifications for women and four for men, according to a review of the diagnostic changes published in Reproductive System & Sexual Disorders. The criteria for all these diagnoses include presence of symptoms 75% to 100% of the time and significant distress.

Women with complaints of low desire expressed this distress during a 2-day meeting in late October, when the FDA brought the condition to the forefront under the Patient-Focused Drug Development initiative to better understand the impact and consider treatment options.

Margery L. S. Gass, MD, NCMP, a gynecologist and executive director of the North American Menopause Society, called this stakeholder focus an “excellent move forward.”

“[Low libido] is a topic that has been neglected, and it’s the No. 1 sexual complaint for women,” Gass told Endocrine Today. “A lot of people would like some medical support for this condition.”

In the PRESIDE study, published in The Journal of Sexual Medicine, Rosen and colleagues showed that 27.5% of more than 10,000 US adult women reporting low sexual desire also reported sexual distress (mean age, 48.6 years; 81% with a current partner).

A second study by Johannesand colleagues published in The Journal of Clinical Psychiatry using the same data and accounting for depression showed the unadjusted population-based prevalence of desire disorder to be 10% of all respondents and 6.3% of those without concurrent depression.

An investigator on both studies, Jan L. Shifren, MD, a gynecologist specializing in clinical reproductive endocrinology and director of the Massachusetts General Hospital Midlife Women’s Health Center, Boston, said clinicians must assess the distress.

“Low libido is probably normative for women at many points in their lives — busy with kids, long-term relationships — but that doesn’t necessarily mean they’re dissatisfied with their sex lives,” Shifren said.

Some women rarely reach orgasm but describe sex as pleasurable and satisfying, she said. They may wish for more frequent or intense orgasms, but because there is no associated distress, no treatment or intervention is required.

“We need to be careful not to pathologize normal differences in female sexual function,” Shifren said.

Psychology and biology, women and men

Female sexual dysfunction generally occurs in a loving relationship in which a sexual need exists on one side and on the other is a partner engaging in something that holds no interest for her, according to Irwin Goldstein, MD, a urologist and president of San Diego Sexual Medicine.

“Doing anything you are not really into is a challenging experience,” Goldstein told Endocrine Today. “Just think of being asked to have sex on a regular basis, and you’re not interested at all, but you’re doing it out of mate-guarding or duty.”

Women become consumed with avoidance strategies, he said.

Without any standardized methodology for the management of the condition, women are barraged with different views, according to Goldstein.

In Basson’s view, a woman’s sexuality is influenced by context; she said it may be evident to clinicians, with patients who report low sexual desire and little sexual response for years but experience improvements upon the decision to leave a relationship.

“Clearly, there’s nothing inherently abnormal with their sexual response, whether it’s their nerves, their hormones or whatever aspect you want to look at,” Basson said.

Rather, the problem lies in how a woman thinks about being sexual with her partner.

“It’s not to say none of this is true for men, but it’s not so markedly obvious,” Basson said. “For men and women, but to different degrees, sexual response is dependent on stimuli that have potential to arouse. Whether those stimuli do lead to arousal is the question.”

Goldstein said women with sexual dysfunction are missing critical biological “hotwiring” — the kind that keeps humans reproducing so the species does not disappear. Biological imbalances in neurochemicals that diminish excitation and elevate inhibition are influencing factors.

“On the excitation side are neurochemicals well-recognized to affect the sexuality responses, such as dopamine, oxytocin, norepinephrine and melanocortins,” Goldstein said. “Serotonin, opioids, endocannabinoids and prolactin are inhibitory neurochemicals.”

Research by Holstege and colleagues, published in 2011 in Hormones and Behavior, demonstrates through scans of blood flow the complex activation occurring in regions of the brain as women approach orgasm.

“This is not a usual reflex, it’s not what happens in speech and hearing and movement,” Goldstein said. “It’s dedicated, much more sophisticated brain activity. Women with sexual dysfunction cannot do this.”

A series of studies in The Journal of Sexual Medicine also demonstrate differences between the brains of women with female sexual dysfunction and those without, Goldstein said.

“This is a genuine sexual health problem,” he said. “Science has to win here, and hopefully it will. Our society — and the FDA as part of that — has to lose the cultural bias that this is in women’s heads and men’s biology. There’s psychology for both, and there’s biology for both.”

Treatment approach

Clinicians should spend a significant amount of time talking to women about their sexual concerns and exploring possible etiologic factors before entering a conversation about treatment, according to Shifren.

Potential underlying causes for female sexual dysfunction are numerous and diverse; they include depression and anxiety, relationship quality or conflict, erectile dysfunction in a male partner, fatigue, and discomfort with intercourse due to vaginal atrophy or genitourinary syndrome of menopause, she said.

“Unless you’ve taken a thorough history, you shouldn’t be pulling out a prescription pad,” Shifren said. After ruling out reasons such as those above, many sexual concerns remain related to lifestyle.

“There are many safe and effective interventions to improve sexual interest and satisfaction, such as building the relationship, increasing novelty, reducing stress and fatigue, and improving body image,” Shifren said.

During the scientific workshop portion of the FDA meeting, some experts suggested that medication is not the route to take but that cognitive therapy should be the initial approach, Gass said.

“The path forward will be to decide whether there is a role for both,” Gass said, noting that she thinks there is. “My hope is for the community to move forward together in recognizing counseling, marital therapy, personal therapy and medication as helpful in treating these women; it would be an ideal way.”

Gass likened female sexual dysfunction to depression — a two-pronged approach has proven successful in treating the latter, and a similar strategy holds potential to address the former.

“It’s great to have counseling that can help people adopt another way of looking at life and their problems and give them other ways of affecting their depressed mood; on the other hand, it’s wonderful that they can get some quick relief from medication,” Gass said. “I view depression as a condition that’s a model for the value of both of those approaches.”

Dearth of drugs

When women with sexual dysfunction require drug therapy, no validated, regulated, approved option is available, Susan Davis, MBBS, PhD, an endocrinologist and chair of women’s health at Monash University School of Public Health and Preventive Medicine, Melbourne, Australia, told Endocrine Today.

“Women in most countries in the world are using either off-label male products or compounded pharmaceuticals that aren’t tested for dose, safety or efficacy — and I don’t think that’s right,” Davis said.

While working in an Australian menopause clinic in the 1980s, Davis recalled first seeing women with low libido being treated with testosterone implants. “As a young doctor, I was horrified,” anticipating side effects.

Davis set up a single blind, randomized controlled trial investigating the effects of implants (estrogen only or estrogen plus testosterone) inserted subcutaneously in the abdominal wall. Every 6 months for 2 years, body composition, bone density and lipids were measured, and the women filled out a sexual function questionnaire.

The data showed improvement in sexual function and bone density and no adverse effect on lipids.

From her early days investigating the efficacy and safety of testosterone patches, Davis said she has dedicated her career to finding help for this population of women.

Studies investigating the Intrinsa testosterone patch, undertaken by Proctor & Gamble, show statistically significant improvements and safety. Investigations by BioSante Pharmaceuticals into testosterone gels using the same protocol showed that blood levels increased, but the therapy was not effective, Davis said.

In Europe, the Intrinsa patch with active ingredient testosterone gained limited approval, but was not embraced by the market, Davis said.

In Australia, clinicians prescribe a testosterone cream (AndroFeme, Lawley Pharmaceuticals), she said. The hormone therapy, available since 2000, has state but not national approval. The medication is manufactured to FDA standards, having undergone a clinical trial and a pharmacokinetics study, both of which were published in Menopause. But Davis said the company is too small to support the funding necessary to undergo the approval process in the United States.

Unable to locate any research investigating women’s expectations of treatment, Fooladi and colleagues conducted a qualitative study published in Climacteric; 17 patients from Davis’ clinic participated.

“We wanted to understand: If women are actually coming for treatment, why do they come? What do they want? What’s bothering them, and what are their expectations?” Davis said.

The women (aged 26 to 70 years), all referred by a primary care provider, were asked upon making an appointment whether discussing sexual concerns was among the reasons for their visit. If yes, they were asked to come in early for an interview. Based on recorded and transcribed sessions, four themes emerged.

Their top concern was personal psychological distress associated with female sexual dysfunction, followed by the adverse effect on the relationship with their sexual partner, belief in an association between their condition and hormone deficiency, and an expectation to be treated and experience positive physical and sexual changes.

“[The study] reinforces the fact that this is not a construct by a pharmaceutical industry to develop a condition and then develop a drug for it,” Davis said. “This is a condition that deeply affects and truly distresses women. They want a treatment option.”

Mechanisms at work

Historically, connecting low sexual desire with androgen deficit has not been straightforward. However, recent research by Wåhlin-Jacobsen and colleagues, published in The Journal of Sexual Medicine, showed a statistically significant correlation between low testosterone and low libido.

The researchers conducted a cross-sectional study of 560 healthy women aged 19 to 65 years to examine the relationship between levels of serum androgens and sexual desire and whether androsterone glucuronide (ADT-G) level better correlated with desire than circulating androgens.

After assigning the women to one of three groups based on age, the investigators used liquid chromatography-mass spectrometry to measure total testosterone, calculated free testosterone, androstenedione, dehydroepiandrosterone sulfate and ADT-G. Sexual desire was based on the domain score of sexual desire in the Female Sexual Function Index (FSFI).

Across all women, sexual desire correlated overall with free testosterone and androstenedione. In women aged 25 to 44 years who did not use systemic hormonal contraception, sexual desire correlated with total testosterone, free testosterone, androstenedione and DHEA sulfate. In women aged 45 to 65 years, androstenedione correlated with sexual desire. No correlations were found between ADT-G and sexual desire.

Sensitivity in androgen receptors is a complicating factor, Basson said. Although a woman may not appear to be in the low range when androgen activity is measured through serum testosterone, she may be deficient if her receptors are relatively resistant.

“We haven’t got anything going for measuring androgen sensitivity in women, nor any studies showing any change in sexual function with change in androgen-receptor sensitivity,” Basson said.

Neurosteroids are another area that warrants further exploration, she said. Similar to the adrenal and the ovary, the brain turns cholesterol into testosterone and estrogen, but clinicians have no way of measuring it.

“Maybe it doesn’t matter very much what’s going around a woman’s bloodstream if we’re talking about sexual desire and arousal and orgasm,” Basson said. “Maybe it matters what hormones the brain is making.”

If this were the case, she said, it would make irrelevant several decades of work.

In the pipeline

Sheryl Kingsberg, PhD, a clinical psychologist and chief of behavioral medicine at University Hospitals Case Medical Center, Cleveland, said she is hopeful that a product to treat female sexual dysfunction will be approved soon, adding that what occurred during the recent FDA workshop fostered a mind shift.

“Up until now, there has been a difficult risk–benefit ratio for the FDA that they didn’t understand,” Kingsberg said. “With the day 1 patient perspective and the day 2 consensus about the impact on patients and their lives, they recognize this cannot be a ‘no-risk’ scenario, and that some risk — and it is a modest risk — makes sense.”

The meeting also seemed to help overturn the agency’s ongoing concern about modest benefit of treatments. “They now understand modest is meaningful,” she said.

Recalling the FDA’s denial of the nonhormonal treatment flibanserin (a serotonin receptor 1A agonist/serotonin receptor 2A antagonist) in 2010, Kingsberg said drug developer Boehringer Ingelheim did not offer enough evidence for efficacy.

“One of their key endpoints was a daily diary, which is a terrible endpoint and not clinically advisable,” she said. “It’s fatiguing and difficult to tease out sexual desire on a daily basis. Desire is a state. Women are much better at recognizing their desire over a month’s time.”

The most recent of the flibanserin pivotal trials, BEGONIA, published in The Journal of Sexual Medicine and conducted by Katz and colleagues, involved more than 1,000 premenopausal women.

The randomized, placebo-controlled trial showed once-daily 100-mg flibanserin at bedtime resulted in a significant increase in the number of satisfying sexual events (SSEs) and sexual desire based on the FSFI desire domain score, along with significant reductions in distress during 24 weeks vs. placebo.

Similar outcomes were seen in the SNOWDROP trial involving postmenopausal women, published in Menopause, which Kingsberg participated in with Simon and colleagues.

The most frequently reported adverse events associated with flibanserin were dizziness, somnolence, nausea and headache.

“SSEs and FSFI for desire are appropriate co-primary endpoints,” Kingsberg said. “At the FDA workshop, there was complete consensus that those are the endpoints that should be used in the clinical trial.”

The current drug owner, Sprout Pharmaceuticals, has since gone back before the FDA with the new data, along with the requested statistically significant global measure of clinical relevance in patients’ lives, but the agency was concerned about day-after driving and potential drug interactions, Kingsberg said.

With both additional safety studies now complete, Sprout is poised to reapply. Kingsberg said her patients are “clamoring” for the drug and hopes the company will make the application soon. “They ask me every day: Are we any closer?”

Bremelanotide, a compound under development by Palatin Technologies, is another promising treatment, Kingsberg said, with a phase 3 pivotal trial about to begin.

The novel heptapeptide melanocortin receptor-4 agonist, designed for subcutaneous self-administration, yielded improvements in a phase 2 dose-ranging trial conducted by Portman and colleagues, published in Obstetrics and Gynecology.

Nearly 300 premenopausal women, with confirmed HSDD, FSAD or both, were randomly assigned to double-blind placebo or bremelanotide at 0.75 mg, 1.25 mg or 1.75 mg for 12 weeks after a 1-month placebo run-in. At the end of the study, SSEs, FSFI scores and Female Sexual Distress Scale-Desire/Arousal/Orgasm scores all improved with treatment, with a statistically significant benefit at 1.75 mg.

“What’s nice is this is very different,” Kingsberg said. “These are not one-size-fits-all conditions. Some women will respond to flibanserin, some will respond to testosterone, some will respond to bremelanotide, and some will respond to psychotherapy,” she said.

“It’s not clear who will respond to what, but just like having a dozen or so antidepressants, it’s important to be able to have options,” she said. – by Allegra Tiver

Is there a double standard when it comes to treating female sexual dysfunction?

There is not a sexual bias in the arena of sexual dysfunction. For better or worse, men and women are different. That’s what makes the world go around.

First, you can much more objectively measure what happens in men than women. When evaluating a man with sexual dysfunction, it is easier to count the number of erections or penetrations. In women, you can certainly count the number of times they have intercourse, but many are willing to participate even though they do not have the desire.

Instead, you count the number of satisfying sexual events for women, whether it be intercourse, oral sex, or masturbation, and gauge the decrease in personal distress, through questionnaires or diaries. But it is quantifying subjective measures.

Another challenge is the major placebo effect in the whole field. If the number of events increases by a quarter to a third with a placebo, and 40% or 50% with the active drug, the difference may be as high as 20%. If this translates to one or two more satisfying sexual events per month over placebo, it may be statistically significant, but is it clinically significant? Indeed, for some women it is.

The FDA must balance efficacy vs. safety to approve treatments and tries to be very fair in this analysis, but the bar for safety has to be really high for a quality-of-life drug compared with a life-or-death drug.

You have to approach both sexes on their own accord, with properly validated tools to measure responsiveness, placebo-controlled studies and an excellent drug safety profile. I don’t think that is unreasonable.

Glenn D. Braunstein, MD, Professor of Medicine, Cedars-Sinai Medical Center. Disclosure: Braunstein reports being a consultant for and principal investigator of testosterone studies in women sponsored by BioSante Laboratories and Proctor & Gamble.

The inequality and lack of access, opportunity and options in the field of sexual dysfunction are important to discuss. The advancement of diagnostic evaluation, standardization of tests, financial support for trials and treatment availability has not been as robust for women vs. men.

There are fewer sophisticated methods for assessment and less integration of research and experimental techniques in clinical practice for women, including the assessment of blood hormones and neurologic function related to sexual function.

In men, androgen deficiency, arousal dysfunction and specifically erectile dysfunction have received more research attention and pharmaceutical dollars, resulting in approved treatments; there are limited comparable available treatments for women.

Whether it is a lack of dedicated government-sponsored funding or a lack of interest in developing campaigns to address potential products on an industry level is hard to know.

Some topical and oral therapies, including estrogen and selective estrogen receptor modulators, are available for vulvovaginal symptoms postmenopause; but treatments for female low libido, anorgasmia or arousal dysfunction unrelated to menopause are not.

Despite well-defined syndromes and trial data, there is a lack of similar criterion regarding efficacy and safety by governmental agencies for androgen products for women; therapies for females have not received the same appraisal or opportunity as those for males.

Experimental androgen replacement in the transdermal form has been demonstrated to improve sexual symptoms related to androgen deficiency in women in numerous quality randomized controlled trials; despite that, products presented to the FDA have not been approved.

Similarly, equivalent and even more robust safety data for women as compared to men have been offered and not been deemed sufficient regarding potential risks of androgen therapy.

I don’t know if it is bias, or the composition of the panel at the time, but it appears that therapies to treat female sexual dysfunction have met with more rigorous requirements and have been less likely to get approved.

Sharon J. Parish, MD, Professor of Medicine in Clinical Psychiatry, Weill Cornell Medical College. Disclosure: Parish reports serving on the advisory boards for Emotional Brain, Pfizer Pharmaceuticals, Sprout and Strategic Science Technologies and on the speakers bureau for Pfizer Pharmaceuticals.