What are the challenges in prescribing pharmacotherapy for female sexual dysfunctions?

KEYWORDS:

• Sexual education
• female sexual dysfunctions (FSDs)
• vulvovaginal atrophy/genitourinary syndrome of menopause (VVA/GSM)
• hypoactive sexual desire disorder (HSDD)
• ospemifene
• DHEA
• flibanserin
• bremelanotide

1. Background

Sexual symptoms are common, affecting nearly half of all women in their lifetime. However, personal or relationship distress, which is a key element to diagnose female sexual dysfunctions (FSD), is much less prevalent, especially in the elderly [1]. Despite intensive research over the last two decades, we are far away from having an effective management of FSDs in clinical practice. Sexual health is an important quality-of-life issue, but age, education, and marital and socioeconomic status, including a gender-equal sexual regime, are significant deterrents to discussing this topic. Women should consult anytime they do not feel satisfied by their sexual response due to either difficulties with drive, arousal, or orgasm or with painful intercourse. Sadly, embarrassment, poor awareness, misconceptions, and fears of social stigma are still barriers to effective communication with health-care providers (HCPs). Thus, sexual problems may remain untreated [2]. In most cases, women expect to discuss sexual health in routine family planning, antenatal, and menopause care programs. Provision of individualized care has the aim to prevent, diagnose, and treat a broad range of conditions with a significant impact on the well-being associated with sexual and reproductive function. Unfortunately, HCPs face the challenge of making a diagnosis that revolves around a very sensitive issue in a short timeframe, even though these dysfunctions usually involve a multitude of factors, ranging from organic determinants to intrapersonal and interpersonal components. Knowledge and confidence are key elements for conducting a proactive assessment of clinically significant sexual dysfunctions [3]. Given the multifactorial origin of FSDs and the frequent overlapping of sexual symptoms, HCPs may find it hard to formulate a treatment plan from a biopsychosocial perspective. This step is rather complex, and it may be time consuming, resulting in low-profit margins. It requires a multidisciplinary approach or the ability to refer to another specialist when appropriate. Nonetheless, HCPs must rule out any underlying medical conditions, recognize situations in which it may be normal to have a sexual impairment, and select the most effective strategy to reach the therapeutic goal [4].

Reproductive stages and hormonal interventions (hormonal contraception, fertility treatment, and menopausal hormone therapy) are strong influencers in FSD because sex hormones play a role in the physical, emotional, and cognitive domains of the sexual response. They modulate neural, vascular, muscular, and other organic substrates of desire, arousal, and orgasm. In postmenopausal women, pharmacotherapy has the primary aim to reverse hormonal deficiency associated with FSDs. Other biological and psychosocial causes can be treated with nonhormonal compounds and cognitive and behavioral strategies. In premenopausal women, instead, the main organic therapeutic target is the vast array of substances such as neuromodulators and vasoactive molecules likely involved in the occurrence of FSDs [2].

The chronic progressive condition formerly known as vulvovaginal atrophy (VVA) was recently renamed genitourinary syndrome of menopause (GSM) to indicate the constellation of urogenital signs and symptoms associated with aging and hormonal changes. It is a clear example of the beneficial role hormone therapy can play in reversing FSDs. Local estrogen therapy is a first-line and well-established strategy to relieve VVA/GSM symptoms, whereas ospemifene oral tablets (Osphena/Senshio, Shionogi & Co, Ltd., London, UK), an estrogen selective receptor modulator, and dehydroepiandrosterone (DHEA) vaginal inserts (Intrarosa, Endoceutics, Inc., MSH, Québec Canada), a prohormone with both estrogenic and androgenic activity, were approved only recently for the treatment of dyspareunia and other symptoms associated with VVA/GSM [5]. These drugs effectively ameliorate sexual function in postmenopausal women, when treating sexual pain associated with VVA/GSM. Their positive effect against placebo is evident during the first three months of treatment, and it is supported by a significant improvement in objective parameters, such as vaginal pH and maturation index. Safety data are currently available for the first year of therapy [5–7]. Differently from VVA/GSM, in which signs associated with symptoms are visible and can be monitored through a gynecological examination, the assessment and management of hypoactive desire disorder (HSDD) require screener questions and/or inquiring about a history of modifiable biopsychosocial factors influencing sexual health [8]. When low desire presents simultaneously with VVA/GSM, the former may resolve following the adequate treatment of dyspareunia and other urogenital symptoms. HSDD may result from low androgens due to age, iatrogenic menopause, or any other factor impairing ovarian or adrenal function. By using subjective validated psychometric scales, high-quality studies demonstrated that transdermal testosterone (300 µg/twice a week) improves sexual desire, arousal, orgasm frequency, pleasure, and overall satisfaction. In addition, it decreases distress in a clinically relevant manner in the majority of women with HSDD. On the other hand, transdermal testosterone has been approved only in Europe, and its indication has been limited to treating postmenopausal women receiving concomitant estrogen therapy following bilateral ovariectomy plus hysterectomy. As a matter of fact, there is no blood androgen level below which women can be diagnosed with hypoandrogenism, and HCPs should exclude other treatable conditions associated with HSDD, before prescribing testosterone therapy. There were no major safety issues, but transdermal testosterone is no longer available because of the lack of adequately powered studies on the risk of breast cancer. Women still use testosterone either off-label or as compounded therapy. Intravaginal administration may be also effective to improve sexual satisfaction [9].

Evidence-based solutions should be implemented to address FSDs in a more comprehensive manner. Even though women of any age may benefit from new options, younger patients seem to be more challenging because they report higher distress associated with sexual symptoms while expecting greater treatment efficacy. In addition, women of childbearing age introduce potential confounders such as the use of hormonal contraception, which may interfere with some domains of sexual response. On the other hand, HCPs tend to prioritize safety when treating not life-threatening conditions such as FSDs. A clear understanding of the clinical relevance is fundamental for the appropriate prescription of chronic pharmacotherapies. In this context, the current DSM-5 diagnostic nosology causes confusion for prescribers by replacing HSDD with female sexual interest/arousal disorder, a combination of desire and arousal disorders (HSDD and FSAD) [10]. These are some reasons why the availability of flibanserin (brand name ADDYI® [Sprout Pharmaceuticals Inc., North Carolina, USA]), the sole product approved by the Food and Drug Administration (FDA) for the treatment of acquired generalized HSDD in premenopausal women, stimulated an intense debate both in the scientific community and in the general public. This centrally acting, multifunctional serotonin agonist and antagonist, a nonhormonal oral agent, exerts its effect in the interplay between excitatory and inhibitory neuromodulatory processes influencing sexual responsiveness. Flibanserin (100 mg daily at bedtime) is effective over placebo in approximately 50% of the women with HSDD showing an improvement in the level of sexual desire and the number of sexually satisfying events and a decrease in sexual distress. Similar results were evident in postmenopausal women with HSDD, but flibanserin has not yet been approved in this population. Like many other psychoactive agents, flibanserin requires long-term treatment. Its onset of action is delayed, and it may cause central nervous system side effects. In addition, a high placebo response rate has been documented. Its interaction with some very common drugs such as moderate or strong cytochrome P-4503A4 inhibitors must be taken into account, and concomitant alcohol consumption should be avoided [11]. Several drugs to treat FSDs are under investigation including bremelanotide (BMT), a novel melanocortin-receptor agonist with high affinity for the type-4 receptor, which acts by modulating brain pathways involved in sexual responsiveness [12]. The US FDA has accepted the New Drug Application (NDA) filing for BMT, which is presently still under review.

Recently, a meta-analysis including 24 randomized controlled trials with a placebo arm documented a strong placebo effect of 67% in the treatment of FSD. These findings support the idea that pharmacological interventions in pre- and postmenopausal women have little clinical efficacy. However, results were obtained by calculating the rate of improvement only on one of the validated end points in clinical trials, the female sexual function index (FSFI), which is unable to capture the full range of sexual behaviors specifically related to HSDD [13]. Moreover, the statistical methodology did not consider the effect size, which measures the magnitude of a given intervention in comparison with placebo and other treatments, without confounding by sample size. The comparison of effect size for medications and placebo by using the main measures of sexual desire and distress indicated that the median differential effect size was almost double for medications (flibanserin,BMT, and transdermal testosterone) when compared to placebo [14]. These results are in line with patient-reported outcomes on meaningful clinical benefits with drugs over placebo and collectively suggest reconsidering study design, validated end points, and instruments to assess clinical significance. Interestingly, the two identical Phase 3 (RECONNECT) studies with BMT, self-injected subcutaneously on-demand, at the dose of 1.75 mg, included a 1-month no-intervention qualification period, a 1-month single-blind placebo treatment period, a 24-week double-blind treatment period, and an ongoing 52-week open-label extension. By using psychometric instruments specifically designed to better explore differences between responders versus nonresponders, BMT provided a clinically meaningful and statistically significant improvement in the key aspects of generalized, acquired HSDD in premenopausal women [15].

In conclusion, the field of sexual medicine is constantly evolving. The possibility that new scientific requirements to investigate potential pharmacotherapies for FSDs will result in less controversial data is of great hope for clinicians and researchers.

2. Expert opinion

Best practices for treating women with FSDs are challenged both by the ongoing debate on nomenclature and by the paucity of medications approved by medical agencies for specific sexual disorders. There is still controversy over the criteria to diagnose HSDD in light of the difficulties in differentiating mental and physical factors that contribute to low desire and poor arousal. In addition, the placebo effect of pharmacotherapy for FSDs indicates that the methodology to investigate the effectiveness of drugs is likely to be inadequate because sexual problems do not occur in a vacuum, and intrapersonal and interpersonal components are very important. The impact of a given treatment may exceed its real biological effect due to expectations and other placebo effects. On the other hand, subclinical mood disorders, life-stressors, discrepant desire levels between partners, and other psychosocial factors may dampen the therapeutic power of potential drugs. Therefore, measures to assess whether changes in validated scores are clinically meaningful are mandatory. Indeed, from a safety perspective, placebo separation should guide the prescription practice of drugs on either a regular basis or on-demand. This would be desirable in both genders. However, even in well-designed clinical trials, it is unlikely that investigators will be able to fully control for the myriad of potential biases involved in FSDs. The identification of factors associated with non-responding to a candidate drug may shed light on the etiology of FSDs. Only the availability of several effective drugs will ultimately allow HCPs to routinely tailor treatment to individual patients and to identify those situations requiring sex therapy or other psychosocial approaches either alone or in conjunction with medications.

Being aware that the treatment of FSDs is multifactorial is the key element to meet the challenges in prescribing pharmacotherapy. Education of women and HCPs is a fundamental step in sexual medicine to dispel myths, overcome barriers, and acquire skills. Sexual history and sexual counseling should be part of every consultation across specialties for an effective management of sexual problems in women and in their partners.

Declaration of interest

RE Nappi has had a past financial relationship (lecturer, member of advisory boards and/or consultant) with Boehringer Ingelheim, Ely Lilly and Company, Gedeon Richter, HRA Pharma, Pfizer Inc, Procter & Gamble Co, TEVA Women’s Health Inc and Zambon SpA. At present, she has on-going relationships with Bayer HealthCare AG, Endoceutics, Exceltis, Merck Sharpe & Dohme, Novo Nordisk, Palatin Technologies, Shionogi Limited and Theramex. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One referee acts as a consultant to all of the sponsors of drugs mentioned in this editorial including Sprout (flibanerin), Palatin (Bremelanotide) Duchesnay (ospemefine) Endoceutics/Amag (Prasterone/vaginal dhea) as well as TX004 (TherapeuticsMD) and premarin vaginal cream (Pfizer). Furthermore, one referee is consultant for Eli Lilly and Company and Palatin while another is a shareholder in S1 Biopharma. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Acknowledgments

The authors are very grateful to Dr Carmela Quatrale, University of Pavia, Italy, for her helpful literature search and to Dr Giorgio Tarchini, Westside Regional Hospital Plantation Florida, for his careful linguistic revision.

Additional information

Funding

This manuscript has not been funded.