Female sexual disorders: Treatment options in the pipeline
Female sexual problems are best conceptualized from a biopsychosocial perspective that includes biological, psychological, sociocultural, and interpersonal factors. Treatment also follows a biopsychosocial model and options include psychotherapy, pharmacotherapy, physical therapy, and complementary approaches alone or in combination.
This article focuses on emerging treatment options for female sexual disorders. Currently, only 2 treatment options for female sexual complaints are approved by FDA: 1) The Eros clitoral stimulator, approved in 2000 for female sexual arousal disorder (FSAD); and 2) conjugated equine estrogen, approved in 2008 for treatment of moderate to severe dyspareunia.
Most of the research and development currently under way in this area is focused on pharmacologic options for treatment of hypoactive sexual desire disorder (HSDD)—the most prevalent female sexual disorder. Treatments primarily involve both steroid hormone and neurohormone mediators. The table provides a glossary of terminology related to female sexual disorders discussed in this article.
Central brain studies have shown that serotonin, norepinephrine, and dopamine are implicated in sexual function. Dopamine agonists and central melanocyte-stimulating hormone (MSH) analogs also are currently being investigated as possible mediators of female sexual function. In addition, estrogen therapy (ET) and testosterone replacement continue to be common treatments in female sexual medicine for vulvovaginal health and HSDD in postmenopausal women, respectively.
Clinicians and patients, however, are still somewhat hesitant to use ET, even locally, because of concerns about systemic risks of local ET. Off-label use of systemic testosterone for HSDD is associated with similar concerns. The following is an overview of investigational treatments of female sexual disorders, including drugs currently in phase 2 or 3 clinical trials and a thermal therapy.
Flibanserin is a 5-HT(1A) agonist/5-HT2 antagonist for treatment of HSDD. Phase 3 pivotal trials have shown it to be effective, with mild adverse effects including nausea, dizziness, fatigue, and sleeplessness.
In a recent phase 3 trial in premenopausal women with HSDD, Katz and colleagues found that flibanserin 100 mg at bedtime was associated with clinically meaningful and significant improvement in the number of satisfying sexual events (SSE) and the sexual desire domain of the female sexual function index (FSFI).1 Significant differences also were demonstrated between treatment and placebo on the secondary end points of the Female Sexual Distress Scale-Revised total (FSDS-R total) and distress associated with low desire (FSDS-R item 13). In a trial of postmenopausal women with HSDD, flibanserin 100 mg at bedtime also was associated with clinically meaningful and significant improvement. The coprimary end points were SSE and sexual desire (FSFI-desire domain). Secondary end points for distress (FSDS-R total) and distress associated with low sexual desire (FSDS-R item 13) improved compared with placebo.2–4 To date, flibanserin has been studied in trials involving approximately 11,000 women.
Lybrido and Lybridos
Lybrido and Lybridos are novel combination drugs that are in development for treatment of HSDD. Lybrido combines testosterone with a phosphodiesterase inhibitor (PDE5 inhibitor) and Lybridos combines testosterone with a 5HT(1A) agonist (buspirone). Lybrido is designed for women with HSDD and low motivation, theorized to be a result of a relatively insensitive system for sexual cues. Testosterone is believed to improve desire, whereas the PDE5 inhibitor works to increase genital sensitivity. Because Lybrido is administered sublingually, the time of peak concentration of the PDE5 inhibitor coincides with the 4-hour delay in behavioral effect of testosterone.
Lybridos is designed for women with HSDD who also have sexual inhibition. Testosterone increases sexual motivation, and buspirone counters the sexual inhibition mechanism in the prefrontal area of the brain. As with Lybrido, administration of Lybridos is sublingual. The time frame for the pharmacologic effects of the buspirone coincide with the behavioral window for testosterone administration.5,6
LibiGel is a low-dose (300 µg) gel formulation of topical testosterone in development for treatment of HSDD in postmenopausal women. In recent phase 3 clinical trials, it did not demonstrate efficacy in primary end points, and the sponsor has announced plans to repeat this pivotal research.7
Coprimary end points of the efficacy trials were the change in the total number of days with a satisfying sexual event from baseline and the change in mean sexual desire from baseline. The Data Safety and Monitoring Board also made 9 “unblinded” reviews of all the data in the safety study and allowed the research to continue without changes. No specific safety signal has been observed with respect to cardiovascular disease or breast cancer.8
TBS-2 is an intranasal low-dose nasal gel formulation of testosterone. It is being developed to offer women with female orgasmic disorder (inability to achieve orgasm despite adequate sexual stimulation) an on-demand treatment option.
Tefina is expected to have an attractive safety profile, with virtually no androgen-related adverse effects such as acne, growth of facial and body hair, or deepening of the voice that may be associated with other chronic regimens. Moreover, there is no expected risk of skin-to-skin transfer of testosterone to family members with the unit-dose nasal applicator currently under development. A phase 2 trial of Tefina is under way in the United States, Canada, and Australia.9,10
Alprostadil (prostaglandin E1-PGE1) is a naturally occurring, potent vasodilator that has an important role in regulating blood flow to the female reproductive tract. Alprostadil also potentiates the activity of sensory afferent nerves. Femprox is an alprostadil-based cream intended for treatment of FSAD. Nine clinical studies of Femprox have been completed to date, including a 98-patient, phase 2 US study and a 400-patient, phase 3 study in China. In a randomized clinical phase 3 trial of topical alprostadil 0.4% cream with a skin penetration enhancer, an ester of N,N-dimethylalanine and dodecanol (DDAIP), a 900-µg dose showed significant and clinically relevant improvements in primary arousal success and secondary efficacy outcomes (FSFI) and Global Assessment Questionnaire (GAQ) and FSDS.11
Apomorphine is a dopamine agonist that has been used as a subcutaneous (SQ) injection for treatment of Parkinson disease and researched in oral form for treatment of arousal disorder. Research findings have been inconclusive, and apomorphine can be associated with emesis. In a small study of subjective or objective arousal in women with arousal complaints, changes in peak velocity of clitoral hemodynamics were significantly higher in patients given 3 mg apomorphine than in controls.12 This translated into changes in arousal and lubrication that were also significantly improved in the apomorphine group. The researchers concluded that the medication was beneficial in women with orgasmic problems or difficulties in the domains of subjective and objective complaints. Incidence of adverse events, which were mostly mild and transient, was low.
MSH Analog: Bremelanotide
Bremelanotide is a melanocortin receptor 4 agonist (MCR4 agonist) for treatment of HSDD and FSAD. It is a synthetic analog of a MSH and an agonist that activates the melanocortin receptors MC3-R and MC4-R in the central nervous system. Bremelanotide was initially delivered as a nasal spray. Phase 2 results with that formulation were promising, but development was stopped because of adverse effects on blood pressure.13 The drug has recently been reformulated in a lower dose for SQ injection and a phase 2b study is under way in premenopausal women with HSDD and FSAD.
Intravaginal DHEA suppositories
Intravaginal dehydroepiandrosterone (DHEA) is currently under investigation for treatment of vulvovaginal atrophic changes. Preliminary data are encouraging and suggest that this drug can reverse atrophic effects without increasing systemic estradiol levels. Intravaginal DHEA suppositories also may have an effect on HSDD. Phase 3 clinical trials of DHEA are under way, and more data
Ospemifene is a novel estrogen agonist and antagonist that has been studied as an oral agent for treatment of vulvovaginal atrophy (VVA) and, therefore, would be effective for VVA-related sexual pain. In phase 3 clinical trials, 826 women were randomized to 30 mg or 60 mg of this unique compound or to placebo for 12 weeks. The 60-mg dose was shown to be effective, well tolerated, and efficacious for vaginal dryness and dyspareunia.15 No proliferative effects on endometrium were seen, and adverse effects were minimal. The most commonly reported complaint was an increase in hot flashes.15
The Viveve procedure
Viveve (Sunnyvale, Calif.) has developed a monopolar radiofrequency (RF) thermal therapy to improve laxity of the vaginal introitus and sexual satisfaction in women after vaginal deliveries. To assess sexual satisfaction, sexual function, and distress associated with sexual activity, the FSFI and the FSDS-R scales were used in the clinical design. In addition, to discern effectiveness, patient-reported outcome questionnaires (Vaginal Laxity Questionnaire and Sexual Satisfaction Questionnaire) were used. In a pilot study in 24 women aged 25 to 44 years, reverse-gradient RF (energy range, 60 joules [n=3], 75 joules [n=3], and 90 joules [n=18]) was delivered through the vaginal mucosa. No adverse events were reported, and no topical anesthetics were required. Self-reported vaginal tightness improved in 67% of patients at 1 month posttreatment and in 87% at 6 months (P<0.001). Mean sexual function scores improved, and FSDS-R score before treatment was 13.6 ± 8.7, declining to 4.3 ± 5.0 at month 6 posttreatment (P< 0.001). The office-based procedure is well tolerated and has shown excellent preliminary results.16
Only 2 FDA-approved treatments currently exist for female sexual disorders, but a wide range of oral, topical, and SQ formulations are being investigated. The etiologies of female sexual disorders are multifactorial, and a variety of treatment options are necessary to individualize treatment. Development of effective therapies is 1 important step for improving the sexual health of women. â
1. Katz M, DeRogatis L, Ackerman R, et al. Efficacy of flibanserin as a potential treatment for hypoactive sexual desire disorder in North American premenopausal women: results of the Begonia Trial. J Sex Med. 2011; 3(suppl 1):153.
2. Simon J, DeRogatis L, Dennerstein L, et al. Efficacy of flibanserin as a potential treatment for hypoactive sexual desire disorder in North American post-menopausal women. J Sex Med. 2012;9(suppl 1):23.
3. Goldfischer ER, et al. Continued efficacy and safety of flibanerin in premenopausal women with hypoactive sexual desire disorder (HSDD): results from a randomized withdrawal trial. J Sex Med. 2011;8(11):3160-3172.
4. Derogatis L, et al. Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the VIOLET STUDY. J Sex Med. 2012;9(4):1074-1085.
5. van der Made F, Bloemers J, van Ham D, et al. Childhood sexual abuse, selective attention for sexual cues and the effects of testosterone with or without vardenfil on physiological sexual arousal in women with sexual dysfunction: a pilot study. J Sex Med. 2009;6(2):429-439.
6. van der Made F, Bloemers J, Yassem WE, et al. The influence of testosterone combined with a PDE5-inhibitor on cognitive, affective, and physiological sexual functioning in women suffering from sexual dysfunction. J Sex Med. 2009;6(3):777-790.
7. BioSante rises after ending LibiGel safety study. Businessweek.com Web site. www.businessweek.com/ap/2012-09-04/biosante-rises-after-ending-libigel-s.... Published September 4, 2012. Accessed October 3, 2012.
8. BioSante Pharmaceuticals announces positive LibiGel phase III safety data review and decision to conclude the safety study [press release]. Lincolnshire, IL: BioSante Pharmaceuticals; September 4, 2012.
9. van Gorsel H, Laan E, Tkachenko N, Dickstein J, Kreppner W. Pharmacokinetics and pharmacodynamic efficacy of testosterone intranasal gel in women with hypoactive sexual desire disorder and anorgasmia. Poster presented at: International Society for the Study of Women’s Sexual Health Annual Meeting (ISSWSH); February 19-22, 2012; Jerusalem, Israel.
10. Efficacy and safety of TBS-2 testosterone gel in premenopausal women with acquired female orgasmic disorder. Clinical Trials Identifier: NCT01607658. www.clinicaltrials.gov/ct2/show/NCT01607658.
11. Goldstein I, Bassam D, Frank D, Hachicha M, Fernando Y, Schupp J. Results of a phase 3 clinical trial for female sexual arousal disorder (FSAD) with Femprox, A topical alprostadil 0.4% cream with a novel transdermal delivery technology. J Sex Med. 2012;9(suppl 1):22.
12. Bechara A, Bertolino MV, Casabé A, Fredotovich N. A double blind randomized placebo control study comparing the objective and subjective changes in female sexual response using sublingual apomorphine. J Sex Med. 2004;1(2):209-214.
13. Levine SB, Brown C, Palace E, Fischkoff S, Schnorrbusch C. Bremelanotide study in pre- and post-menopausal women with female sexual arousal disorder. Poster presented at: ACOG 56th Annual Clinical Meeting; May 3-7, 2008; New Orleans, LA.
14. Labrie F, Archer D, Bouchard C, et al. Effect of intravaginal dehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women. Menopause. 2009;16(5);923-931.
15. Bachmann GA, Komi JO. Ospemifene Study Group. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause. 2010;17(3):480-486.
16. Millheiser LS, Pauls RN, Herbst SJ, Chen BH. Radiofrequency treatment of vaginal laxity after vaginal delivery: nonsurgical vaginal tightening. J Sex Med. 2010; Sep;7(9):3088-3095.