US Pharm. 2015;40(9):46-49.
ABSTRACT: Many women will likely experience a sexual problem in their lifetimes. Female sexual dysfunction (FSD) is a broad term used to describe three categories of disorders of a multifactorial nature. Efficacious but limited pharmacotherapeutic options exist to address FSD. The FDA recently approved the first agent for treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. Off-label use of hormonal therapies, particularly estrogen and testosterone, are the most widely employed for FSD, particularly in postmenopausal women. Other drugs currently under investigation include phosphodiesterase inhibitors and agents that modulate dopamine or melanocortin receptors. Pharmacists should be aware of the classifications of FSD and the options that are currently available for treatment.
Many women will likely experience a sexual problem in their lifetimes. The Prevalence of Female Sexual Problems Associated with Distress and Determinants of Treatment Seeking (PRESIDE) study surveyed more than 30,000 U.S. women aged ³18 years regarding sexual function.1 Results from this study estimated that 12% of women experience a diagnosable sexual disorder that causes personal distress, with lack of sexual desire being the most prevalent.
Female sexual dysfunction (FSD) is a complex interplay of biological, hormonal, and psychological factors that can have a significant negative effect on female sexual health and quality of life.2 FSD can be influenced by several dynamics, including advancing age, social factors, psycho-social stress, and trauma.2
Classifications and Causes of FSD
The latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published in May 2013, describes revised classifications for sexual dysfunction (TABLE 1).3 Female hypoactive sexual desire disorder and female arousal disorder have been combined into one category; dyspareunia and vaginismus have been merged into one category as well. Sexual aversion disorder has been deleted. Female orgasmic disorder is unchanged. Several criteria, including personal distress and duration and severity of symptoms, contribute to an accurate diagnosis and recommended treatment.
Declining estrogen and androgen levels associated with aging can significantly contribute to the occurrence of FSD. Estrogen withdrawal can have marked effects on the vagina such as atrophy and dryness, which may lead to impaired sexual desire.4 Declining androgen levels are also associated with decreasing sexual desire.4 Thus, female sexual health in postmenopausal women should be addressed by healthcare providers, particularly in women who report symptoms of FSD. Other possible biological influences on FSD are medical conditions. Hypertension and diabetes mellitus have been linked to FSD, as well as psychiatric conditions such as depression and anxiety. Cultural norms and religious beliefs may also impact FSD and women’s communication with their healthcare providers. Furthermore, past abuse or trauma can adversely affect a woman’s sexual health and lead to the manifestation of FSD.4 It is important to note that sexual dysfunction in females can also be drug-induced. See TABLE 2 for drugs that may induce sexual dysfunction in women.4-9
There are several agents used for the treatment of FSD (TABLE 3); however, most drugs have off-label indications. Use of hormonal therapies for FSD is most prominently documented in postmenopausal women. Controlled studies of hormonal therapies for FSD in premenopausal women are virtually absent. There have been some studies that have examined use of specific nonhormonal agents in premenopausal women with selective serotonin reuptake inhibitor (SSRI)–induced sexual dysfunction. SSRIs have been reported to negatively impact desire, arousal, and/or orgasm.10 The addition of bupropion sustained-release 150 mg twice daily to the SSRI regimen has helped to improve sexual dysfunction, as reported in a Cochrane Database Systematic Review.11
Flibanserin: The FDA recently approved flibanserin (Addyi) 100-mg tablets for treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women.12 It is the first and only FDA-approved treatment for this condition. Flibanserin, described as a multifunctional serotonin agonist antagonist (MSAA), is a serotonin1A receptor agonist and a serotonin2A receptor antagonist. The reported mechanism of action is to increase the release of norepinephrine and dopamine and decrease the release of serotonin in the cortex of the brain. The balance of neurotransmitters is believed to improve sexual functioning.13
Flibanserin can cause severe hypotension and syncope and has a potentially serious interaction with alcohol.12 It has a boxed warning to highlight these risks and will only be available with a risk evaluation and mitigation strategy (REMS). The FDA has also required the manufacturer to conduct three well-designed studies in women to better understand the known serious risks of the alcohol interaction. Other common adverse effects reported with flibanserin include dizziness, somnolence, nausea, fatigue, insomnia, and dry mouth.12
Testosterone: Testosterone is used off-label in postmenopausal women. Evidence from randomized, controlled trials supports the improvement of decreased sexual desire in postmenopausal women using various testosterone formulations.2 For example, transdermal patches that delivered 300 mcg/day showed beneficial effects. A 1%-strength compounded transdermal cream can also be applied to the arms, abdomen, or legs. Dose-dependent effects of testosterone include acne, hirsutism, and alopecia.2 Oral testosterone has also been associated with altered lipids and liver functions. The Endocrine Society issued a clinical practice guideline reappraisal of androgen therapy for FSD in 2014, recommending short-term treatment of testosterone due to the lack of long-term safety data for its use.14
Currently, there are no FDA-approved testosterone therapies for FSD. However, in 2014 the FDA approved an intranasal metered-dose pump formulation of testosterone for the treatment of hypogonadism. Studies are investigating the use of the intranasal gel for the treatment of FSD in the dosage range from 0.6 to 1.8 mg. The intranasal formulation may have the advantage of not producing androgen-related side effects and be void of the skin-to-skin transfer that occurs with other testosterone formulations such as topical gels.15
Estrogen: Local estrogen therapy (LET), rather than systemic hormone therapy, is generally used to treat specific symptoms of FSD in postmenopausal women who do not have other underlying reproductive conditions such as breast cancer.16,17 LET treats symptoms of vaginal atrophy and can improve dyspareunia in postmenopausal women.18 LET may indirectly improve sexual desire and arousal by increasing vaginal lubrication and blood flow.19 This therapy is recommended for severe symptoms or if OTC products do not work. Formulations of LET include a conjugated estrogen cream (Premarin 0.625 mg/g), an estradiol cream (Estrace 100 mcg/g), and a vaginal tablet (Vagifem 10 mcg). These formulations may be initiated nightly for 2 weeks and then twice weekly for maintenance.10 A vaginal estradiol ring (Estring) placed vaginally every 3 months is also available.10 Efficacy, safety, and tolerability have been established in postmenopausal women using LET.18 In addition, augmenting estrogen therapy with testosterone has been shown to improve sexual function in postmenopausal women.20
Ospemifene: Ospemifene is a selective estrogen receptor modulator (SERM) with the indication to treat moderate-to-severe dyspareunia. Ospemifene mimics the effects of estrogen on vaginal tissue and appears to be as effective as vaginal estrogen for dyspareunia.16 Ospemifene is available as a 60-mg oral daily tablet. The agent is an alternative to estrogen if estrogen should be avoided or is contraindicated. Ospemifene is more expensive than most estrogen formulations and is associated with adverse effects of hot flashes, increased risk of thromboembolism, vaginal discharge, leg cramps, and sweating.21
Vaginal Moisturizers and Lubricants: For treatment of mild dyspareunia, nonhormonal OTC agents can be effective.16 Vaginal agents are formulated as moisturizers or lubricants. Moisturizers are applied daily in the form of gel or liquid and replenish vaginal moisture. One popular moisturizer is formulated to adhere to the vaginal lining to provide relief for 3 to 5 days. Moisturizers are more effective if used on a regular basis. Lubricants are used as needed with the water-based products being the most popular. Lubricants that contain menthol are marketed as “warming agents.”22
Alprostadil: The prostaglandin alprostadil has been studied in a topical formulation for treatment of FSD.23 Alprostadil is indicated for male erectile dysfunction as an intracavernous injection or urethral suppository. In females, topical alprostadil has been shown to increase blood flow to the vaginal area by producing smooth muscle relaxation and vasodilation. Adverse reactions of vaginal burning and irritation have been reported.23
Apomorphine: Apomorphine is a nonselective dopamine receptor agonist that works in the central nervous system (CNS) and is thought to enhance sexual response due to stimuli. For the treatment of FSD, a sublingual dose of 2 to 3 mg is being studied. Reported adverse reactions include nausea, vomiting, headache, and dizziness.24
Bremelanotide: Bremelanotide stimulates melanocortin-4 receptors in the CNS, which increases sexual arousal and desire.25 Bremelanotide is a synthetic analogue of melanocyte stimulation hormone (MSH). MSH is commonly associated with development of skin pigmentation, protecting the dermis from ultraviolet radiation, and appetite control. The agent is being tested in dosages of 1.25 and 1.75 mg for SC injection. Originally, it was formulated as a nasal spray but in clinical trials was found to increase blood pressure. Adverse reactions associated with SC use include nausea, headache, and flushing.25
Bupropion: Bupropion has been shown to improve sexual function in premenopausal women with HSDD, as reported in two studies.26,27 Bupropion sustained-release 150 mg daily and 300 to 400 mg daily yielded satisfactory responses in these studies. Women reported that they were satisfied with the treatment27 and that bupropion increased sexual arousal, orgasm completion, and sexual satisfaction.26 The mechanism of action of bupropion has not been clearly defined, but it is thought to facilitate dopamine and norepinephrine neuro-transmission, possibly by inhibiting the reuptake of neurotransmitters.28
Dehydroepiandrosterone (DHEA): DHEA and its sulfate ester DHEA-S are steroid hormones produced in the adrenal glands, liver, and testes in men. DHEA is metabolized to androstenedione, the precursor to androgen and estrogen. Levels of DHEA usually decline with age. DHEA is available as an OTC supplement and has been reported to increase libido in postmenopausal women. DHEA supplementation is believed to change the circulating androgen-estrogen ratio in a gender-specific manner.29 Therefore, the supplementation of DHEA in women increases the concentration of testosterone more than estrogen.
Oral administration of DHEA has been studied with variable results for the treatment of vaginal atrophy and HSDD. An oral dosage of 50 to 1,600 mg daily has been studied with mixed results.30 An intravaginal 0.25% to 1% cream is being evaluated because oral dosages have been linked with acne and hirsutism.31
Pharmacists should be aware of adverse effects associated with DHEA, especially since it is available as an OTC supplement as tablets or capsules in strengths of 25 and 50 mg. A daily dosage of 50 mg is associated with mild-to-low side effects. Dosages of 200 mg per day or greater are linked to various adverse effects such as acne, hirsutism, hair loss, voice deepening, insulin resistance, changes in menstrual pattern, hepatic dysfunction, abdominal pain, and hypertension.29
Phosphodiesterase Type 5 (PDE5) Inhibitors: PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil have been successful for treatment of male erectile dysfunction. The use of PDE5s for treatment of sexual dysfunction in women has not been as favorable. PDE5s may be efficacious in women with FSD secondary to the use of SSRIs and may additionally be effective in women diagnosed with sexual interest/arousal disorder.32
There are established and efficacious pharmacotherapeutic options for treating specific aspects of FSD. However, additional options are desirable in order to effectively address the multifactorial disorders of this condition and improve female sexual health.
1. Shifren J, Monz B, Russo P, et al. Sexual problems and distress in United States women: prevalence and correlates. Obstet Gynecol. 2008;112(5):970-978.
2. Kingsberg S, Woodard T. Female sexual dysfunction: focus on low desire. Obstet Gynecol. 2015;125(2):477-486.
3. American Psychiatric Association. Diagnostic and Statis-tical Manual of Mental Disorders, 5th Edition (DSM-5). Arlington, VA: American Psychiatric Press; 2013.
4. Buster JE. Managing female sexual dysfunction. Fertil Steril. 2013;100(4):905-915.
5. Association of Reproductive Health Professionals. Women’s sexual health in midlife and beyond. ARHP Clin Proc. 2005;5:8-12.
6. Conaglen HM, Conaglen JV. Drug-induced sexual dysfunction in men and women. Aust Prescr. 2013;36: 42-45.
7. Drugs that cause sexual dysfunction: an update. Med Lett Drugs Ther. 1992;34:73-78.
8. Drug facts and comparisons. Facts & Comparisons [online database]. St. Louis, MO: Wolters Kluwer Health, Inc. www.wolterskluwercdi.com. Accessed March 22, 2015.
9. Morphine and tramadol. Lexicomp Online. Hudson, Ohio: Lexi-Comp, Inc. www.wolterskluwercdi.com. Accessed March 27, 2015.
10. Wright J, O’Connor K. Female sexual dysfunction. Med Clin North Am. 2015;99(3):607-628.
11. Taylor M, Rudkin L, Bullemor-Day P, et al. Strategies for managing sexual dysfunction induced by antidepressant medication. Cochrane Database Syst Rev. 2013;31(5):CD003382.
12. FDA approves first treatment for sexual desire disorder. FDA news release. August 18, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm. Accessed August 20, 2015.
13. Stahl S. Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in hypo-active sexual desire disorder. CNS Spectr. 2015;20(1):1-6.
14. Wierman M, Arlt W, Basson R, et al. Androgen therapy in women: a reappraisal: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(10):3489-3510.
15. Tkachenko N, Dickstein J, Kreppner W. An open-labeled, single and multiple-application of intranasal testosterone gel in healthy premenopausal female subjects at three dose levels. J Sex Med. 2013;10(suppl 2):165.
16. Suckling JA, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev. 2006;(4):CD001500.
17. Schmidt P. The 2012 hormone therapy position statement of the North American Menopause Society. Menopause. 2012;19(3):257-271.
18. Utian W, Maamari R. Attitudes and approaches to vaginal atrophy in postmenopausal women: a focus group qualitative study. Climacteric. 2014;17(1):29-36.
19. Goldstein I, Alexander JL. Practical aspects in the management of vaginal atrophy and sexual dysfunction in perimenopausal and postmenopausal women. J Sex Med. 2005;2(suppl 3):154-165.
20. Nappi R, Cucinella L. Advances in pharmacotherapy for treating female sexual dysfunction. Expert Opin Pharmacother. 2015;16(6):875-887.
21. Portman DJ, Bachmann GA, Simon JA, et al. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause. 2013;20(6):623-630.
22. Lodise NM. Chapter 8. Vaginal and vulvovaginal disorders. In: Krinsky DL, Berardi RB, Ferreri SP, et al, eds. Handbook of Nonprescription Drugs. 17th ed. Washington, DC: American Pharmacists Association; 2012.
23. Goldstein I, Qinping L, Damaj B, et al. Phase 3 clin-ical trial results with Femprox treatment in FSAD patients show correlation of arousal with both lubrication and orgasm but not with desire. J Sex Med. 2013;10(1):58-73.
24. Caruso S, Agnello C, Intelisano G, et al. Placebo-controlled study of efficacy and safety of daily apomorphine SL intake in premenopausal women affected by hypoactive sexual desire disorder and sexual arousal disorder. Urology. 2004;63(5):955-959.
25. Portman DJ, Edelson J, Jordan R, et al. Bremelanotide for hypoactive sexual disorder: analyses from a phase 2B dose-ranging study. Obstet Gyneol. 2014;123(suppl):131S.
26. Segraves R, Clayton A, Croft H, et al. Bupropion sustained release for the treatment of hypoactive sexual desire disorder in premenopausal women. J Clin Psychopharmacol. 2004;24(3):339-342.
27. Safarinejad MR, Hosseini SY, Asgari MA, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of bupropion for treating hypoactive sexual desire disorder in ovulating women. BJU Int. 2010;106(6):832-839.28. Carroll F, Blough B, Mascarella S, et al. Bupropion and bupropion analogs as treatments for CNS disorders. Adv Pharmacol. 2014;69:177-216.
29. DHEA monograph. Natural Medicines Comprehensive Database. http://naturaldatabase.therapeuticresearch.com. Accessed March 22, 2105.30. Panjari M, Davis SR. DHEA for postmenopausal women: a review of the evidence. Maturitas. 2010;66(2): 172-179.
31. Labrie F, Archer D, Bouchard C, et al. Effect of intravaginal dehydroepiandrosterone (pasterone) on libido and sexual dysfunction in postmenopausal women. Menopause. 2009;15(5):923-931.32. Chivers ML, Rosen RC. Phosphodiesterase type 5 inhibitors and female sexual response: faulty protocols or paradigms? J Sex Med. 2010;7(2 pt 2):858-872.
To comment on this article, contact email@example.com.