Female sexual dysfunction (FSD) is a common disorder in the United States but is often overlooked and undertreated. FSD impacts approximately 43% of women and causes personal distress in up to 12% . The prevalence of this distress increases with age and peaks among women at age 45–64 years. The 2019 American College of Gynecologists practice bulletin highlights several different types of FSD, including female sexual interest/arousal disorder (FSIAD), female orgasmic disorder, genito-pelvic pain/penetration disorder, substance/medication-induced sexual dysfunction, and other specified sexual dysfunctions that include pregnancy-related FSD and menopause-related FSD [2▪▪]. The focus of this review will be to discuss the current evidence for the use of testosterone therapy (TTh) in females with FSIAD and other available and emerging options.
FSIAD is defined by The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition; DSM-V) as a lack of, or significant decrease in, at least three of the following: first, interest in sexual activity; second, sexual or erotic thoughts or fantasies; third, initiation of sexual activity and responsiveness to a partner's initiation; fourth, excitement or pleasure during all or almost all sexual activities; fifth, interest or arousal in response to internal or external sexual or erotic cues (e.g., written, verbal, visual); sixth, genital or nongenital sensations during sexual activity in almost all or all sexual encounters. In addition, these symptoms must persist for a minimum of 6 months and cause clinically significant distress in the individual. Here we discuss the role of androgens in FSD and highlight the current approach to treating women with FSIAD, including TTh.
THE ROLE OF ANDROGENS IN FEMALE SEXUAL DYSFUNCTION
To assess the potential efficacy that TTh may have on improving symptoms of FSD, it is important to identify the role that endogenous testosterone plays in supporting normal female sexual function. We know that testosterone is a precursor for estrogen biosynthesis and that androgens play a complex and critical role in female physiology. In the female there are several androgens present, including dehydroepiandrosterone (DHEA), DHEA-sulfate, androstenedione, testosterone, and dihydrotestosterone, which are produced in the ovaries, adrenal glands, and peripheral conversion in target tissues. Androgen receptors have been identified all over the body including the brain, bone, and genitourinary tract . Numerous studies have confirmed the presence of androgen and estrogen receptors in the genitourinary tissues, further validating their effects on genital blood flow, arousal, vaginal lengthening, lubrication, and sensation [4▪,5,6▪▪,7–9]. Testosterone levels are known to decline beginning in the mid reproductive years but appear to be maintained in women beyond the age of 64 [5,8,9,10▪▪].
Due to the many factors and variables that may impact female sexual function, it is extremely difficult to quantify the effects of androgens on female sexual function, but it is clear that they play an important role. The prevalence of low sexual desire in women varies and has been estimated at 27% in premenopausal women and 52% in naturally menopausal women . Although numerous studies have shown a positive correlation between testosterone levels and sexual desire, motivation, initiation of sexual activity, and masturbation frequency in women, other studies have failed to find any association between low testosterone levels and diminished sexual function in women [12–18]. Between 2000 and 2008, a series of large multicenter trials looking at the effect of transdermal testosterone (300 μg/day patch) on surgically and naturally menopausal women were conducted. All showed favorable results and increases in sexual activity and desire, including those on concomitant estrogen therapy and those not receiving estrogen therapy [19–23]. However, following that, two large randomized controlled studies published in 2012 involved postmenopausal women with hypoactive sexual desire disorder (HSDD) who used a transdermal testosterone gel for 6 months; these did not show any improvements in any measures of sexual function as compared with placebo .
Despite all of the conflicting information and data, the majority of clinical trials still support the use of systemic TTh in women. This has been validated by the most recent meta-analysis published in The Lancet Diabetes & Endocrinology, which evaluated a total of 36 randomized control trials (RCTs) spanning 1990–2018 and included 8480 subjects. Results showed that TTh did significantly increase female sexual function across all indices when compared with either a placebo or drug-control (e.g., estrogen ± progestogen) in postmenopausal women. Minor side effects that were noted included weight gain, acne, and hair growth, but no increase in serious adverse events was recorded [25▪▪].
TESTOSTERONE TO TREAT FEMALE SEXUAL INTEREST/AROUSAL DISORDER
In October 2019, a Global Consensus Position on the use of Testosterone Therapy for Women was published simultaneously in several journals and supported by 12 international societies including The International Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The International Society for Sexual Medicine, The International Society for the Study of Women's Sexual Health, The North American Menopause Society, The Federación Latinoamericana de Sociedades de Climaterio y Menopausia, The Royal College of Obstetricians and Gynecologists, The International Society of Endocrinology, The Endocrine Society of Australia, and The Royal Australian and New Zealand College of Obstetricians and Gynecologists (Fig. 1) [10▪▪]. This important position statement was driven primarily by the performance of a meta-analysis of RCTs evaluating the safety and efficacy of TTh to treat FSIAD [25▪▪].
The meta-analysis, recently published in The Lancet Diabetes & Endocrinology, evaluated a total of 36 RCTs spanning 1990–2018 and includes a total of 8480 subjects [25▪▪]. The primary findings were that TTh increased sexual function, including satisfactory sexual event frequency, sexual desire, pleasure, arousal, orgasm, responsiveness, and self-image, when compared with either a placebo or drug-control (e.g., estrogen ± progestogen). TTh was effective regardless of testosterone level, as the current position does not support using a testosterone cutoff to initiate therapy. Testosterone cutoffs in women have yet to be broadly accepted due to the variability of testosterone effects at different levels between different women. A trial of efficacy was the approach used, therefore, in the included RCTs, and these focused on symptom resolution rather than testosterone level changes. In addition, TTh reduced sexual concerns and distress in postmenopausal women. Side effects included an increase in weight, acne, and hair growth, but there was no increase in serious adverse events. Importantly, TTh duration was greater than 12 weeks in all RCTs included in this meta-analysis.
In addition to these findings, the Global Consensus Position offers guidance that a complete clinical assessment should be performed and all other factors or causes of FSD should be addressed prior to considering TTh. A diagnosis of HSDD/FSIAD should be made based on the Biopsychosocial Model and current assessment tools. Although there is no testosterone cutoff for the diagnosis or initiation of therapy, some signs of testosterone insufficiency in women include decreased lean body mass, increased body fat, thinning or loss of hair, osteopenia or osteoporosis. Symptoms that women with androgen insufficiency may describe include decline in libido, fatigue and lack of energy, lack of sense of well being, lack of concentration, orgasmic dysfunction, arousal disorder, and depression . In addition, systemic TTh may be recommended in naturally or surgically postmenopausal women only with HSDD, with/or without concurrent estrogen therapy. The statement recommends against the use of a serum testosterone cut-off to diagnose and begin treatment for FSIAD and supports a treatment goal of physiologic testosterone levels as present in premenopausal women. Although no baseline testosterone should be used to initiate therapy, a starting testosterone level should be obtained and followed every 3–6 months after beginning treatment. If no benefit is achieved with TTh by 6 months, treatment should be discontinued. The position statement does not support the use of oral testosterone preparations due to the adverse impact on lipid profiles. In addition to TTh, multimodal therapies including other pharmacologic options, psychotherapy, and/or behavioral/lifestyle modifications should be continued.
It is important to note that the Global Consensus Position identified limitations in which current data is insufficient to guide decision-making. These areas include the use of TTh in premenopausal women, the effect of testosterone on adverse cardiac events, as well as the impact of testosterone on cognitive function, mood, well being, and musculoskeletal tissues in women. In addition, there remains insufficient data to understand the long-term effects of TTh on breast cancer risk or the safety of TTh in physiologic doses beyond 24 months. Another area lacking sufficient data is the use of systemic DHEA treatment in postmenopausal women with normal adrenal function. Finally, the safety and efficacy of compounded testosterone preparations remains largely unknown.
Currently there are no Food and Drug Administration-approved TTh preparations for women. The Global Consensus Position Statement clearly states, ‘Compounded ‘bioidentical’ testosterone therapy cannot be recommended for the treatment of HSDD, due to the lack of evidence for efficacy and safety, unless an authorized equivalent preparation is not available (Expert Opinion).’ It is possible to prescribe the FDA-approved formulations for men (Androgel, Testim) ‘off-label’ for women with dose modifications, but most practitioners have reservations given the risk of dosing variability. Given the current situation, practitioners have little choice but to prescribe compounded formulations available in different forms, including creams, gels, subcutaneous implants or pellets, intramuscular or subcutaneous injections, sublingual troches, and oral administration. With this, a huge multimillion dollar compounding pharmacy industry has developed. It is up to the practitioner to select an industry compliant and accredited compounding pharmacy when prescribing TTh to women in these forms.
THE USE OF TESTOSTERONE IN COMBINATION WITH OTHER AGENTS TO TREAT FEMALE SEXUAL INTEREST/AROUSAL DISORDER
Recent work has explored combining testosterone with sildenafil or buspirone to treat women with FSIAD based on the excitatory-inhibitory model of sexual dysfunction [27▪,28▪▪,29,30]. This approach provides a simpler treatment regimen allowing for as-needed dosing several hours before sexual activity [28▪▪]. This compares favorably to filbanserin which requires daily treatment.
Tuiten et al. performed a study of 497 women with FSIAD who were categorized on the basis of distinct causes. The two subtypes into which the women were grouped were having ‘low sensitivity for sexual cues’ or ‘dysfunctional over-activation of sexual inhibition.’ The authors used a demarcation formula based on both psychological and biological factors to stratify the subjects. Those participants with decreased excitation received a tablet containing testosterone + sildenafil, while those women with over-inhibition were given testosterone + buspirone. The authors found that both combinations significantly increased the number of satisfying sexual events (SSEs) in the respective groups [28▪▪].
OTHER OPTIONS FOR TREATMENT FOR WOMEN WITH SEXUAL DYSFUNCTION
FSD is determined based on a multifactorial biopsychosocial model and a physician's treatment plan be led by the unique etiologic factors predisposing female patients to this disease . Patients can be evaluated using the Decreased Sexual Desire Screener and the Female Sexual Function Index (FSFI) questionnaires. Patients who are postmenopausal with low libido are candidates for TTh as well as treatment for vulvovaginal atrophy and genitourinary syndrome and menopause (GSM). Premenopausal women need individualized based on a complete evaluation, assessment, and patient preference for a specific delivery system or modality. Treatment requires extensive counseling and a thorough discussion of possible side effects of each treatment. Usually more than one visit and most treatment will need at least a 3-month trial. It is important for the clinician to recognize that some patients will respond to one treatment, whereas others will not.
In addition to testosterone, an array of pharmacologic and nonpharmacologic interventions exist for the treatment of FSIAD (Table 1). FSIAD is multifactorial in cause, with physical, emotional, and psychological well being all contributing to the overall sexual experience. Recognizing and treating underlying medical comorbidities such as mood disorders or pelvic pain syndromes can result in significant improvements in FSIAD . Female sexual desire has been closely linked to physical health, psycho-emotional health, cultural factors, and lifestyle factors, such as overall stress levels, exercise patterns, perceived body image, and relationship satisfaction [33▪,34▪,35–38]. Addressing these issues in an interdisciplinary manner with the aid of trained sexual therapists, physical therapists, couples therapists, and cognitive behavioral therapies forms the foundation for treatment of FSIAD.
The hormone estrogen, like testosterone, has been shown to act centrally and peripherally to promote sexual desire. Surgically menopausal women and women experiencing menopause prematurely or early, who experience vasomotor symptoms, sleep disruption, and reduced quality of life have been shown to benefit from systemic hormone therapy . Local vaginal hormone therapies have also shown to affect and improve female sexual function. It is estimated that over 50% of postmenopausal women experience bothersome genitourinary symptoms including dryness, burning, itching, odor, urinary frequency, urgency, and pain with sex. These symptoms can have a clear effect on emotional well being, sexual function, relationships, and daily function. Fortunately, many FDA-approved treatments are now available for genital atrophy and GSM. These include estrogen vaginal creams (Estrace, Premarin), estrogen vaginal tablets (Vagifem - Novo Nordisk - Plainsboro, NJ, USA) and soft gel inserts (Imvexxy - TherapeuticsMD, Inc, Boca Raton, FL, USA), vaginal DHEA ovules (Intrarosa - AMAG Pharmaceuticals, Inc, Waltham, MA, US), and the oral agent Ospemifene (Osphena - Duschesnay USA, Bryn Mawr, PA, USA), an estrogen agonist and antagonist selective for the vulvovaginal area. The choice and duration of treatment should be individualized based on the woman's symptoms, medical and gynecologic history, and preference. Providers knowledgeable and experienced in prescribing these important therapies should be consulted.
Given the success of the phosphodiesterase-5 inhibitors (PDE-5i) in the treatment of male sexual dysfunction, several researchers have explored PDE-5i as a therapeutic option for females with sexual dysfunction. PDE-5i have been primarily studied in FSIAD, a condition characterized by appropriate sexual motivation with lack of physiologic sexual response. In these patients, some studies have shown that sildenafil effectively enhances vaginal blood flow and clitoral engorgement, resulting in increased genital sensation and overall intercourse satisfaction [40,41]. Other data has shown that although a physiologic response is observed, this does not correspond to measurable improvements in overall sexual function [42,43].
Bupropion is an antidepressant medication that functions by inhibiting the reuptake of dopamine and norepinephrine at the neural synapse . Although not FDA-approved for the treatment of HSDD/FSIAD, several large RCTs studying the drug in premenopausal women with HSDD/FSIAD and no underlying depression have demonstrated increased scores across several scales of sexual function [45,46]. In addition, a combination treatment with bupropion and trazodone has been recently studied in a combined phase 1b/2a RCT, showing a 38% increased efficacy in FSIAD over bupropion alone [47▪].
Used for the treatment of generalized anxiety disorder, buspirone is a 5-HT1A partial agonist and binds to both the serotonin and dopamine receptors in the brain. Buspirone has been used off-label in patients with generalized anxiety disorder and HSDD and has been shown to increase sexual desire [48,49]. In two separate studies, buspirone was also shown to improve sexual function when used in combination with Selective Serotonin Reuptake Inhibitor treatment for depression [50,51]. Adverse effects of buspirone include dizziness, drowsiness, nausea, and headache.
Flibanserin was the first FDA-approved drug for the treatment of acquired generalized HSDD for premenopausal women, coming on the market in August 2015. It is dosed daily with a median time to onset of 4 weeks and functions as a serotonin receptor agonist/antagonist . Flibanserin's most frequent adverse effects are somnolence, dizziness, nausea, and fatigue, which occurred in approximately 10% of patients and are exacerbated by alcohol or concomitant use with CYP3A4 inhibitors . The FDA recommends that it is not taken within 2 h of ethanol use [54▪]. In double blind randomized trials, it has been shown to have a 0.5–1 increase in monthly SSEs from an average of 2–3 per month, and to have significant improvement over placebo in levels of sexual desire and associated distress in 50% of women with FSIAD [55–57].
Bremalaanotide is a melanocortin receptor agonist approved for use in June 2019 for the treatment of acquired generalized HSDD in premenopausal women. It is self-administered as a subcutaneous injection as needed 45 min before sexual activity. Overall safety data showed it was well tolerated with the most common side effects including nausea and flushing, which the majority of patients reported to be mild to moderate and transient. In two randomized phase 3 trials, bremelanotide was shown to have a significant increase in sexual desire and a decrease in distress, the two coprimary endpoints of the studies [58,59▪▪]. In addition, no significant hypotensive events or drug-related adverse events were observed when combined with alcohol .
In addition to the previously described treatments, several potential pharmacotherapies remain on the horizon for FSIAD. The company Emotional Brain is currently developing two combination testosterone therapies in an on-demand sublingual form: Lybrido and Lybridos. Lybrido is testosterone and sildenafil, and is designed increase sensitivity to sexual cues by increasing blood flow to the genitals . Lybridos is testosterone and buspirone, and is aimed at decreasing sexual inhibition . These medications have shown a modest increase in SSEs in phase 2b trials [28▪▪]. Currently phase 3 studies are being planned.
BP101 is another drug being developed for the potential treatment of FSIAD. It is a synthetic peptide molecule initially studied in female rats, in which it was found to stimulate sexual motivation . A phase 2a placebo-controlled proof of concept study in 110 adult women showed a significant increase in the FSFI score after 4 and 8 weeks of treatment [64▪]. The investigators are currently recruiting for phase 3 studies .
A key debate in the future of drug development for FSIAD will be around the saliency of the FDA's currently preferred primary endpoint: SSEs. Many researchers argue that SSEs do not adequately capture augmentations in desire . Sexual acts may be completed for a variety of reasons outside of sexual desire alone, including meeting a partner's sexual desires or pursuing relationship growth and development [67,68]. Measuring SSEs does little to capture the motivation or desire surrounding an individual event. Even so, it is not obvious how internal sexual desire should be assessed. Future work is needed to establish outcome measures for new therapies that can account for both quantity and quality of sexual desire.
The past decade has produced a significant number of studies on FSD with a greater understanding of HSDD/FSIAD and treatments in women. The recently published meta-analysis on the safety and efficacy of testosterone for women and the Global Consensus Position Statement on the Use of Testosterone Therapy for Women in 2019 have been pivotal at clarifying safety, efficacy, and guidelines for TTh. There is a clear need for more research and long-term safety data on the effects of TTh on cardiovascular health, breast health, cognitive function, and the musculoskeletal system in women with the ultimate goal of an FDA-approved testosterone product for women. Until then, off-label or compounded TTh will likely remain a popular and prescribed option.
Financial support and sponsorship
There was no financial support or sponsorship for this work.
Conflicts of interest
There are no conflicts of interest.
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* Catherine F. Ingram and Kelly S. Payne contributed equally to the article.