Female Sexual Dysfunction: From Causality to Cure

US Pharm.2008;33(11):Epub.

Female sexual dysfunction (FSD) is a highly prevalent disorder affecting women's quality of life across the lifespan and around the world. In the United States, according to results of the National Health and Social Life Survey, nearly 43% of women younger than age 60 experience some type of sexual dysfunction.¹ Disorders of sexual function are known to increase with age, subsequent to the onset of menopause. Approximately 52.4% of naturally menopausal women--an estimated 16 million women aged 50 and older--are likely to be affected by low sexual desire and symptoms of FSD.² Other medical comorbidities that may be involved include diabetes, hypertension, cardiovascular disease, cancer, surgical procedures (particularly pelvic-floor surgery), and the use of certain medications.³ A complete understanding of the continuum of FSD's manifestations is essential for comprehending the functions of the various treatment options pharmacists can recommend to patients with this complex condition.

Classification of Female Sexual Disorders
According to the American Foundation for Urologic Disease and the American Psychiatric Association, female sexual disorders can be categorized into four broad classifications: disorders of decreased desire and sexual aversion, arousal, orgasm, and sexual pain resulting in personal distress.^4,5 Persistent absence of sexual ideation, fantasy, and receptivity, or avoidance of sexual activity altogether, characterizes disorders of decreased desire and sexual aversion. Inability to attain or maintain sexual excitement (symptoms such as decreased or absent vaginal lubrication, sensation, and vaginal-muscle relaxation) are associated with disorders of sexual arousal. Recurrent or persistent delay of, or inability to attain, orgasm despite sufficient stimulation defines orgasmic disorders. Dyspareunia (genital pain associated with intercourse) and vaginismus (involuntary muscle spasms of the vagina that interfere with penetration) are hallmarks of disorders of sexual pain in some women. Importantly, these manifestations of FSD are attributable to various psychological, physical, and medical causes that must be identified before effective treatment can occur.

Causes of FSD
The etiology of FSD is multifactorial. General physical and mental status; prior sexual experiences; levels of stress, education, and employment; socioeconomic status; cultural and ethnic identity; relationship dynamics; and the presence and health status of a partner all contribute to a woman's sexual identity and define usual sexual behavior. An abbreviated list of factors associated with each of the various types of FSD is given in TABLE 1.^6,20

Psychological factors related to emotional or relationship issues; depression and the use of antidepressants; and poor self-esteem and self-perception are the most prevalent, and often the most difficult to treat, causes of FSD.^6,7 These psychogenic triggers can be associated with any of the manifestations of FSD. Additionally, psychiatric illness and adverse effects of antipsychotic medications may sometimes manifest as symptoms of FSD.

A woman's body is subject to hormonal influences and imbalances throughout her lifespan that affect her sexual physiology, most notably pregnancy and menopause. While pregnancy itself is generally associated with a diminished interest in sex, 23% to 57% of women report decreased libido at three months postpartum and nearly 40% report this at six months.^8,9 Women who breast-feed often report increased vaginal dryness secondary to diminished estrogen production during this time, and dyspareunia may be associated with the natural childbirth process itself.¹⁰ As a woman's body transitions through menopause, cessation of ovarian estrogen production is associated with urogenital atrophy and diminished sexual response.¹¹ These physical changes are often accompanied by vasomotor symptoms, mood alterations, emotional lability, and diminished sense of well-being, which negatively impact sexual function and quality of life.¹²

Vascular diseases like diabetes, hypertension, hyperlipidemia, kidney disease, atherosclerosis, and traumatic injury are associated with diminished vaginal and clitoral blood flow and impaired sexual functioning.^13,14 Smoking is associated with diminished genital blood flow in both men and women.¹⁵ Sexual dysfunction is a common manifestation in women suffering from urologic infections and conditions such as interstitial cystitis, urinary incontinence, disorders of bladder-emptying, sexually transmitted diseases, and pelvic inflammatory disease.¹⁶ Physiologic disorders of the vagina and uterus such as vaginal fissures and endometriosis are associated with sexual-pain disorders.¹⁷ Pelvic surgery, diseases of the central nervous system, and spinal-cord injury cause autonomic nerve dysfunction and have been associated with disorders of arousal and orgasm.^18,19

Numerous medications have been identified as causing sexual dysfunction. Some of the most common such agents are listed in TABLE 2.²⁰ Information from female patients experiencing sexual adverse effects related to medication is sparse and is often based on case reports and anecdotal evidence. Further, underlying disease manifestation and progression cannot be distinguished from an adverse consequence of drug therapy, as is the case with antihypertensive agents and coronary artery disease.

Nonpharmacologic Interventions
Currently, there are no treatment guidelines or consensus statements dictating the care of women with FSD. Due to the diversity of causative factors associated with symptoms of FSD, modifying lifestyle, addressing physical and psychological causes, and changing behavioral habits associated with sex are preferential first steps in the treatment of FSD that could result in a reversal of symptoms if addressed appropriately. Smoking and alcohol cessation, dietary modification, incorporation of stress-reducing techniques, routine physical exercise, and treatment of medical conditions such as diabetes and hypertension that may predispose women to FSD are essential lifestyle modifications that have been reported to improve female sexual functioning.^21,22 Identification and discontinuation of medications related to symptomatic complaints may be warranted if therapeutic alternatives exist. Depending on the cause and symptoms of a woman's sexual dysfunction, physical modifications associated with intercourse--including use of vibrators or electrical stimulation devices, lubricants, pelvic-floor strengthening exercises, and varying of sexual position--may help increase satisfaction.^23,24 Significant improvements in arousal, sensation, orgasm, and overall sexual pleasure have been reported by women with physiologic arousal disorders caused by inadequate blood flow to the genitalia who utilized the Eros Clitoral Therapy Device, a nonpharmacologic clitoral-stimulation vacuum apparatus.^25,26 Psychotherapy and counseling by a sex therapist is particularly important for women whose dysfunction is related to relationship conflicts, past sexual experiences, emotional issues, anxiety, or depression.²⁷ In a clinical trial designed to assess the effectiveness of a cognitive-behavioral modification program in FSD patients, women reported improved attitudes, perceived greater sexual enjoyment, and were less likely to report sexual dysfunction after therapy.²⁸ Because of the multiple, complex, and often coexistent factors associated with symptoms of sexual dysfunction in women, nonpharmacologic and pharmacologic interventions are commonly combined to optimize therapeutic outcome.

Pharmacologic Interventions
Historically, women with FSD have been limited to relying on hormone replacement therapy and vaginal lubricants to improve sexual functionality. More recently, medications successfully utilized to treat erectile dysfunction in men, including sildenafil and alprostadil, have been studied in women.^29,30 The clinical efficacy of these agents is generally poor, although they are sometimes used off-label. Until recently,  there were no FDA-approved medications indicated for the treatment of sexual dysfunction in females.  In April 2007, the FDA expanded the indications for synthetic conjugated estrogens, B(Enjuvia) to include the treatment of moderate-to-severe vaginal dryness, dyspareunia, and vulvar and vaginal atrophy associated with menopause.³¹ Newer agents targeting the neurotransmitters dopamine, serotonin, and melanocortin--the neuropeptide responsible for physiologic sexual response in men and women--are currently being investigated in clinical trials.³² A comparison of agents used to treat the various disorders of FSD is provided in TABLE 3.

Hormonal supplementation therapy with either estrogen or testosterone has been utilized to replenish diminished levels thought to be associated with sexual dysfunction, particularly in perimenopausal and postmenopausal women.³³ Estrogen replacement therapy (ERT) is associated with significant improvements in sexual desire, orgasm, symptoms of dyspareunia, and vaginal dryness. In addition to improving vaginal symptoms, vasomotor symptoms including hot flashes also are alleviated by this therapeutic modality.^34,35 Despite its well-described efficacy, ERT generally is not indicated for women whose symptoms are unrelated to vaginal or vasomotor dysfunction. The risks associated with ERT, including venous thrombosis, are well known. As androgen levels also diminish with age, women reporting decreased sexual desire and satisfaction--symptoms related to testosterone deficiency or low serum testosterone levels--may benefit from testosterone replacement therapy, although recent findings suggest that there is no evidence that low serum testosterone levels are, in fact, associated with sexual dysfunction.^36-38 Long-term efficacy and safety data for testosterone replacement therapy are unknown. Estrogen–testosterone combination products, including esterified estrogens and methyltestosterone (Estratest; Estratest HS), have also been utilized and are approved for menopausal symptoms unrelieved by estrogen supplementation alone; they also may be used off-label for certain disorders of sexual dysfunction.

Vasoactive medications, particularly phosphodiesterase inhibitors, have garnered much attention in the realm of male sexual dysfunction. In women, sildenafil works by decreasing cyclic guanosine monophosphate metabolism, resulting in nitric oxide–mediated vasodilation and relaxation of the vaginal smooth muscles and clitoris. Data from clinical trials in premenopausal and postmenopausal women are conflicting, with younger women experiencing improvements in arousal, orgasm, sexual fantasy, and activity and older women experiencing minimal, nonsignificant improvements in satisfaction and overall sexual function.^39,40 Phentolamine, an alpha-adrenergic receptor antagonist with vasodilatory properties, is reported to increase arousal and enhance vaginal lubrication.^41,42 Oral tablets and topical solutions are not available in the U.S.

For women whose sexual dysfunction is related to the use of antidepressants, switching to bupropion--an agent that exerts its effects by blocking the reuptake of norepinephrine and dopamine--may provide relief. Bupropion has been studied in the treatment of selective serotonin reuptake inhibitor–induced sexual dysfunction and has been associated with a statistically significant improvement in arousal and sexual satisfaction.^43,44 Apomorphine, a short-acting, nonselective dopamine agonist, was investigated as a sublingual tablet for the treatment of FSD. The agent was associated with enhanced clitoral blood flow, arousal, lubrication, and orgasm in one small-scale clinical trial; however, its utility is limited by dose-limiting nausea, emesis, and dizziness.^45,46

Alprostadil, a prostaglandin analog available in injectable form for use in men with erectile dysfunction, has been investigated as a topical genital cream for sexual arousal disorder in women. Despite mixed clinical-trial results, the agent is generally well tolerated. It is associated with transient local irritation.³⁰

Conclusion
Sexual dysfunction affects millions of women in the U.S. and worldwide. Pharmacists can help build a working relationship with female patients suffering from this disorder by opening up communication that may be difficult for them to initiate. Pharmacists can also play an important role in educating patients about nonpharmacologic and pharmacologic interventions for FSD.

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