10.1177/0897190003253959 HEATHER FEMALE SEXUAL B. MILLER DYSFUNCTION and JACQUELYN S.

HUNT

ARTICLE

Female Sexual Dysfunction: Review of the Disorder and Evidence for Available Treatment Alternatives
Heather B. Miller, PharmD, and Jacquelyn S. Hunt, PharmD, BCPS

With the introduction and marketing of sildenafil, national attention has focused on sexual dysfunction in men. However, strides are being made to focus more effort on evaluation and treatment of female sexual disorder (FSD) since a 1999 national survey reported prevalence rates as high as 43% in women. Evaluation and assessment of FSD requires a comprehensive history and physical examination. Understanding of FSD requires knowledge and understanding of sexual anatomy, physiology, and pathophysiology. Nonpharmacologic treatment may include sex therapy or re-

lationship counseling. Pharmacologic treatment of FSD has focused mainly on hormonal therapies, including estrogen and testosterone, with the majority of studies being done in postmenopausal and hysterectomized women. However, recent studies indicate a more prudent and careful use of hormonal therapies. Research is also moving toward evaluation of bupropion and sildenafil as options for women who suffer from FSD. Available evidence for treatment alternatives is scant and in some cases inconclusive.

KEY WORDS: Female sexual dysfunction, libido, female sexual arousal disorder.

ITH THE INTRODUCTION AND MARKETING of sildenafil, national attention was focused on sexual dysfunction in men. The success of sildenafil for treatment of male erectile dysfunction has set the stage for more open discussion of female sexual dysfunction (FSD). In 1999, a probability sample study was published analyzing data from the 1992 US National Health and Social Life Survey for the purpose of determining sexual behavior among 1749 women and 1410 men. The survey demonstrated that sexual dysfunction of some form was reported more commonly among females (43%) as compared to males (31%).1-3 The majority of complaints noted by women related to emotional problems and stress, particularly in women reporting arousal disorder.
To whom correspondence should be addressed: Heather B. Miller, Clinical Pharmacy Specialist, Providence Health System, Department of Primary Care Pharmacy, 3601 SW Murray Blvd., Suite 45, Beaverton, OR 97005; e-mail: heatherb.miller@providence.org. Jacquelyn S. Hunt, PharmD, BCPS, Director of Primary Care Pharmacy and Research, Providence Health System. JOURNAL OF PHARMACY PRACTICE 2003.16;3:200208 2003 Sage Publications DOI: 10.1177/0897190003253959

To date, much of the research on FSD has focused on hormonal therapy, including estrogen and testosterone therapy. Based on recent publications clarifying the risks and benefits of estrogen, the use of hormonal therapy for every indication, including FSD, must be scrutinized.4-7 This review will provide background on the pathophysiology and diagnosis of FSD and evaluate the current evidence supporting available treatment alternatives. ANATOMY OF FEMALE SEXUAL FUNCTION Clinicians and educators must be comfortable in the knowledge and discussion of the female anatomy as it pertains to sexual function, dysfunction, and treatment. Female genitalia are differentiated into external and internal structures (see Figure 1). Each of these structures plays an integral role in the sexual response cycle. The outermost genital structure is the vulva, composed of the labia majora and minora. The labia majora cover and protect the labia minora. The labia minora enfold and protect the clitoris, urethral orifice, and vaginal opening, collectively termed the vestibule. The prepuce, the portion of the labia minora covering the clitoris, is also known as the clitoral hood. The cli-

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Figure 1. Anatomy of female sex organs. 2003 A.D.A.M., Inc. Reprinted by permission.

toris, an erectile tissue analogous to the male penis and sharing embryonic origin, has three main parts: the glans (head) and, moving inward, the middle corpus (body) and the crura.8 The internal genitalia consist of the uterus, fallopian tubes, ovaries, and vagina. The vagina is a vertical cylinder connecting the uterus with the external genitalia, the distal portion of which is highly innervated. Three layers form the walls of the vagina. Innermost is a layer of aglandular epithelial mucous membrane. Underneath the inner layer lies the vascular muscularis, incorporating smooth muscle and a large network of blood vessels providing engorgement during arousal. Structural support is provided by the fibrosa layer, which resides beneath the vascular muscularis. Multiple rugae throughout the lower third of the vagina allow for expansion and frictional tension during intercourse.8 Pathophysiology The sexual response cycle consists of three phases: desire, arousal, and orgasm. Desire is the initial phase that sets the stage for arousal. Without desire, many women have difficulty becoming aroused and if arousal is incomplete, there can be difficulty in achieving orgasm. Arousal is marked by engorgement of the clitoris and labia minora. The vagina, clitoris, and labia minora undergo a 2- to 3fold increase in length and diameter, becoming everted and exposing the inner surface. The smooth muscles of the vaginal wall relax to aid in the

lengthening and dilation of the vaginal canal. The first noticeable sign of arousal is lubrication, which occurs simultaneously with genital vasocongestion. Lubrication originates from uterine gland secretions and formation of a transudate from subepithelial vascular beds. The transudate is forced into the vaginal canal by increased capillary pressure. The Bartholins glands also contribute to vaginal lubrication during intercourse.8 Vaginal pH increases from the normal 4.5 to between 6.0 and 6.5 during the aroused state. As arousal and engorgement continue, eventually uterine elevation occurs.9 Sexual sensory signals travel, via the pudendal nerve and sacral plexus, through the spinal cord to the cerebrum. Female orgasm is the result of maximal physical stimulation and appropriate psychic conditioning signals from the cerebrum culminating in a spinal cord reflex, which drives multiple (315) 0.8-second rhythmic contractions of the perineal muscles, anus, orgasmic platform, and in some women the uterus.10,11 Since this is a cycle with each phase dependent on and often overlapping with the others, dysfunction in one component of the cycle can lead to global sexual dysfunction. Much of what is accepted about the pathophysiology of FSD has been extrapolated from investigations into male physiologic sexual response.9 Several mechanisms have been associated with the pathophysiology of sexual dysfunction specific to females, including vasogenic, neurogenic, hormonal, psychogenic, musculogenic, and iatrogenic factors (see Table 1).1,12 Dysfunction can result from any one of these mechanisms alone or in combination.

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Table 1 Mechanisms of Female Sexual Dysfunction13-15 Mechanism Psychogenic Description Relationship issues Depression Anxiety Emotional issues Self-esteem and body image Performance pressure Control issues Personal loss History of abuse History of female sexual disorder of other etiology Medications: psychotropic agents, chronic oral contraceptives, progesterones, blockers, central nervous system depressants, anticholinergic agents Gynecologic surgery Perineal trauma during delivery Cardiovascular disease Diabetes mellitus Hypertension Atherosclerosis Hyperlipidemia Smoking Traumatic injury to iliohypogastric pudendal arterial bedpelvic fractures, blunt trauma, chronic perineal pressure from bicycle riding Spinal cord injury Disease of central nervous system or peripheral nervous systemmultiple sclerosis, peripheral neuropathy, lumbar radiculopathy Neurotransmitter dysfunctionserotonin, norepinephrine, nitric oxide, dopamine, epinephrine, opioids, oxytocin, prolactin, acetylcholine, histamine, GABA Hypothalamic-pituitary axis dysfunction Premature ovarian failure Estrogen deficiencynatural (menopause), surgical (hysterectomy) Androgen deficiency Hypertonic pelvic floor musclesvaginismusdyspareunia Hypotonic pelvic floor musclesvaginal hypoanesthesia, coital anorgasmia, urinary incontinence during intercourse or orgasm

Iatrogenic

Vascular

Neurogenic

Hormonal

Musculogenic

DIAGNOSIS The Diagnostic Statistical Manual of Mental Disorders (DSM-IV) classifies FSD as a disturbance in the processes that characterize the sexual response cycle or by pain associated with sexual intercourse.2,16,17 The frequency of these sexual disorders is relatively unknown. A 1999 international expert consensus panel has further delineated the diagnostic categories of FSD. The four categories of sexual dysfunction are the following:
1. sexual desire disorders: hypoactive sexual desire disorder: persistent or recurrent deficiency/absence of sexual fantasies/

thoughts and/or desire for or receptivity to sexual activity, which causes personal distress sexual aversion disorder: the persistent or recurrent phobic aversion to and avoidance of sexual contact with a sexual partner, which causes personal distress 2. sexual arousal disorder: the persistent or recurrent inability to attain or maintain sufficient sexual excitement, causing personal distress, which may be expressed as a lack of subjective excitement, or genital or other somatic responses 3. orgasmic disorder: persistent or recurrent difficulty, delay in, or absence of attaining orgasm following sufficient sexual stimulation and arousal, which causes personal distress 4. sexual pain disorders:

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dyspareunia: recurrent or persistent genital pain associated with sexual intercourse vaginismus: recurrent or persistent involuntary spasm of the musculature of the outer third of the vagina that interferes with vaginal penetration, which causes personal distress other sexual pain disorders.

ital and perineal sensation should be evaluated for abnormalities, which could indicate need for further neurologic evaluation. NONPHARMACOLOGIC TREATMENT Once FSD is uncovered, determination of potential etiologies will help guide selection of nonpharmacologic or pharmacologic treatment alternatives. The appropriateness of nonpharmacologic interventions will vary depending on patient preference and etiology of the disorder. Patients can be encouraged to eliminate routine from sexual activity. When desire and arousal issues are identified, it may be appropriate to suggest erotica or sexual paraphernalia. For a woman who reports that stress or time constraints interfere with intimacy, an option may be to schedule dates with her partner for sexual activity. Pelvic muscle exercises (Kegels) can be done during intercourse and as routine therapy to improve muscle tone, orgasmic intensity, correction of orgasmic urine leakage, and improvement in personal sexual response.21 Several books are available for couples facing issues of sexual dysfunction. Getting both the patient and her partner involved in the treatment also serves to heighten the partners awareness of issues. The EROS Clitoral Therapy Device (UroMetrics, Inc.) was FDA approved in May 2000 for the treatment of female arousal and orgasmic disorders. The device provides suction over the clitoris to enhance blood flow and engorgement and can be used to promote stimulation prior to intercourse or for self-stimulation. Clinical trials show significant improvement in arousal and orgasm, although numbers of patients in all studies were small.22 Since the device may be misconstrued as a replacement for intimacy, there exists a possible drawback for patients with underlying relationship issues. Referral to a sex therapist may be considered for patients who do not respond to therapy and have longstanding dysfunction, multiple dysfunctions, abuse, or psychologic disorders. PHARMACOLOGIC TREATMENT Studies evaluating therapies for FSD are generally limited by small sample size; lack of standardized, objective outcome measures; populations with undifferentiated sexual disorders; and short duration of treatment. With that in mind, the following will review currently available evidence.

Diagnosis of FSD is difficult and confounded by the lack of readily available objective measures of female sexual response and arousal. Accordingly, evaluation relies heavily on subjective patient report pertaining to the three phases of the sexual response cycle. A careful history and exam is used to uncover mechanisms and classify the nature of the sexual disorder. The medical history should include a sexual history with the intent of eliciting five key items: (1) nature of the sexual problem, (2) onset and course, (3) why the patient thinks she has the problem, (4) how the patient has previously attempted to solve the problem, and (5) what kind of help the patient would like from the clinician, if any (see Table 2).12 An emotional evaluation should consider the patients ability to communicate her sexual needs to her partner. Additional factors that would predispose a woman to FSD should be evaluated, including history of pregnancy and surgeries. The evaluation of sexual desire should include physical sensation, fantasies, thoughts and images, interest in other sexual partners, and interest in genital and nongenital stimulation.2 When hormone deficiency or abnormality is suspected, a hormone profile should be obtained (ie, follicle stimulating hormone, luteinizing hormone, total and free testosterone, estradiol). Testosterone levels in females are still somewhat arbitrary, as a normal range is not yet agreed upon. Textbook reference for normal levels of serum testosterone and free testosterone are 20 to 80 ng/dL (69-277 nmol/L) and 0.3 to 1.9 ng/dL (1.06.6 nmol/L), respectively.18 However, studies have used a range of 14 to 58 ng/dL (0.5-2.0 nmol/L) for reference of total testosterone, while others suggest a cutoff of 30 ng/dL (1.0 nmol/L) total and 0.35 ng/dL (0.0121 nmol/L) free testosterone to define testosterone deficiency.19,20 A complete physical and pelvic exam should include evaluation of muscular tone, Kegel strength, and determination of bulbocavernosus reflex.1 External genitalia should be examined for atrophy, vaginismus, dermatitis, vulvar dystrophy and/or vestibulitis, clitoral adhesions, herpetic ulcers, Bartholinitis, and episiotomy scars, which can cause dyspareunia.19 Gen-

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Table 2 Components of a Psychodynamic Sexual History12 Early development What kinds of early messages did the patient receive about sex while growing up? Was her family environment a nurturing or a hostile one? Was touching acceptable and comfortable? Did the patient experience any touching that was too much, too soon? Is the patients sociocultural/ethnic background warm/expressive or aloof/stoic? What did she learn during childhood about what it means to be a woman? What principles did she glean about moral issues like monogamy or sex outside of marriage? What attitudes and beliefs about sex were advocated by the patients religion? What concern does the patient have about her physical appearance? What features about her body does she like? What does she dislike? How does the patient feel about her femininity? How important is having an intimate relationship? How many intimate relationships has she had? How long did each one last? Which was the most important intimate relationship? If the relationship has ended, under what circumstances did it end? What is the nature of the patients friendships with same-sex individuals? With opposite-sex individuals? What is the nature of the patients current relationship? What first drew the patient to her current partner? What first seemed attractive about the partner? When and how did things go wrong? If the patient were to be given a magic wand, what 3 things would she change about the partner? What does the patient foresee for the future of this relationship?

Social, cultural, and religious factors

Body issues

Relationships

Current relationship

Source: Saks BR. Identifying and discussing sexual dysfunction. J Clin Psychiatry. 1999;17:4-8. Copyright 1999, Physicians Postgraduate Press. Reprinted by permission.

Hormone Therapy Estrogen Therapy A study by Sarrell23,24 at Yale University demonstrated a correlation between female sexual problems (vaginal dryness, dyspareunia, and pain) and low serum estradiol levels (<50 pg/mL) as compared to normal levels (>50 pg/mL). Observational data from this study also suggest that menopausal women receiving estrogen therapy had less pain and higher vaginal lubrication and vulvar blood flow. Only 2 studies investigating the effects of estrogen therapy on sexual function met criteria of randomization and double-blinding. Ethinyl estradiol was studied in 49 women who had undergone total abdominal hysterectomy and bilateral salpingoophorectomy.25 This 12-month, double-blind, placebo-controlled study randomized patients to 1 of 4 arms: estradiol (50 mcg/d), levonorgestrel (250 mcg/d), combination, or placebo. Patients were crossed over in 3-month intervals so that each woman received each drug. Measurement was based on patient self-report by interview and written analogue scale assessing sexual desire, enjoyment, lubrication, fantasies, and coital frequency. At 3 months, verbal reports of sexual desire and enjoyment were significantly greater only with estradiol monotherapy compared to placebo. Based on insufficient reporting of results, differences between

groups by written analogue scores could not be quantitatively determined. Estradiol in the transdermal formulation (50 mcg patch twice weekly) was compared to oral conjugated estrogens (0.625 mg/d) in 87 naturally postmenopausal women.26 At 16 weeks, both groups showed improvement in the sexual-function-specific items from the Menopause-Specific Quality of Life Questionnaire. However, there was no significant difference noted between the 2 arms. Conclusions about the efficacy of estrogens are difficult to make based on study limitations of poor study design, heterogeneous populations, small sample sizes, high withdrawal rates (27%), and nonstandardized assessment tools. Furthermore, a conservative approach for selecting estrogen therapy for sexual dysfunction is warranted in light of new evidence weighing the risks and benefits.4-7 Progesterone Therapy Results from the Yale study also showed that addition of medroxyprogesterone to estrogen therapy caused decreased vulvar blood flow and increased pain with intercourse.23,24 The effect of progesterone on sexual function has only been studied in 1 randomized, double-blind, placebo-controlled trial.25 In contrast to the early observational study, the results of this study

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showed that the addition of levonorgestrel to ethinyl estradiol did not negatively affect female sexual function as compared to placebo. Women who require progesterone therapy and experience decreased sexual desire or dryness and pain may benefit from cycling of hormones to achieve a progesterone-free period.19 A trade-off to this option is increased risk of breakthrough bleeding. Testosterone Replacement/Supplementation Five randomized, double-blind, controlled trials27-31 have evaluated testosterone supplementation (alone or in combination with estrogen) in women experiencing menopausal symptoms and sexual dysfunction. Among the studies, testosterone was administered by transdermal patch, intramuscular injection, oral, and sublingual routes. Although there has been public interest in the testosterone gel and cream, no controlled studies were found evaluating these formulations. Study sample sizes are generally small, ranging from 9 to 81 patients per treatment arm. Outcome measures varied from subjective patient ratings to serum hormone levels. These study results show split outcomes, with 3 of the 5 studies showing significant benefit. The positive studies were all conducted in postmenopausal women. Formulations of testosterone studied included transdermal patch (150 and 300 mcg/d; not yet available commercially), oral methyltestosterone (2.5 mg/d), and monthly depo-injections (150-200 mg testosterone enanthate).27,29,30 Two studies showed no significant benefit. In 1 case, a lower dose of methyltestosterone was studied (1.25 mg), and in the other case androstenedione was studied in younger women with FSD induced by oral contraceptives. Evidence shows that testosterone may be an option for postmenopausal women with sexual dysfunction and premenopausal women with lower than expected testosterone values for premenopausal women. Practically, the oral and depo-injection formulations are currently available. The only transdermal patches marketed deliver testosterone at doses of 2.5 and 5 mg (Androderm, Testoderm), far above the 150 and 300 mcg/d studied. Potential for sexual benefit of testosterone supplementation must be weighed against the unknown long-term risks. Known side effects include masculinization, acne, facial and body hair growth, voice changes, fluid retention, and bloating. High-dose testosterone can increase risk of cardiovascular disease, hepatocellular damage, and cancer. Other issues include the correlation between testosterone and some breast tumors and concern of teratogenicity.32

Dehydroepiandrosterone (DHEA) Testosterone is derived, in part, as a result of peripheral conversion of DHEA and DHEA sulfate, adrenal androgen precursors.33 The role of adrenal androgens in sexual function in men and women has recently become a topic of investigation. Controlled evaluation of DHEA supplementation is limited to 1 study in women with adrenal insufficiency and low DHEA levels.34 This double-blind, placebo-controlled, crossover study randomized patients (N = 24) to DHEA 50 mg/d or placebo for 4 months with a 1-month washout period. Mean scores for 4 separate visual-analogue scales for sexuality significantly improved following active treatment. Side effects of DHEA included a significant decrease in HDL and total cholesterol. No studies were found that evaluate the effect of DHEA in women with sexual dysfunction and normal adrenal function with or without low DHEA levels. Antidepressants Studies have demonstrated an association between depression and diminished libido in addition to sexual dysfunction that can occur as a side effect of many antidepressants.21,35 Treatment of depression often leads to improved sexual function regardless of which agent is used. For patients whose depression is successfully treated but side effects are interfering with normal sexual function, the following are options: (1) titrate the antidepressant to the minimum effective dose, potentially blunting sexual side effects; (2) attempt a weekend drug holiday for selective serotonin reuptake inhibitors (SSRIs) with shorter half-lives;36 (3) switch to an antidepressant associated with less adverse sexual effects;37 and (4) consider the addition of an SSRI antidote to temporarily increase serotonin (eg, yohimbine, amantadine, cyproheptadine). For further information regarding available evidence for treatment of SSRI-induced sexual dysfunction and antidotes, the reader is referred to more focused reviews of this indication.35,38 Bupropion Bupropion has been suggested to have sex-enhancing properties. Bupropion has been evaluated as adjunctive therapy with SSRIs to blunt sexual side effects, as alternative antidepressant therapy in patients with SSRIinduced sexual dysfunction, and for nondepressed patients with sexual dysfunction. Two small, open-label studies suggest benefit with addition of bupropion to SSRI therapy, but results from a prospective, randomized, placebo-controlled trial (N = 31) are less convincJOURNAL OF PHARMACY PRACTICE 2003(16.3) 205

HEATHER B. MILLER and JACQUELYN S. HUNT ing.39-41 This blinded trial included men and women with a diagnosis of depression, optimally controlled with SSRI therapy.41 Patients had to be euthymic based on a score of less than 10 on the Hamilton Depression Rating Scale (HAM-D) and have confirmed SSRIinduced sexual dysfunction, as measured by the Arizona Sexual Experiences Scale. Thirty-one patients were randomized to receive 150 mg/d of bupropion-SR or placebo for 3 weeks in addition to SSRI therapy. Efficacy was measured by improvement of 50% or more on the Arizona Sexual Experiences Scale from baseline to 3 weeks. Patients in the treatment group reached only a 25% improvement in scores, although actual scores were not reported. A statistically significant improvement in vaginal lubrication/erection (P = .04) was noted for bupropion-SR over placebo at 2 weeks, but there was no mention of actual scores or improvement from baseline being clinically significant. It is also difficult to extrapolate findings specific to treatment of FSD since results were not reported by gender. Two prospective, open-label studies have evaluated substitution of bupropion for SSRI therapy in patients with SSRI-induced sexual dysfunction.42,43 In the first study (N = 11), sexual function was reported to improve after 4 weeks of bupropion monotherapy. However, 6 of the 11 patients withdrew due to adverse events or recurrence of depressive symptoms. In the second, larger study (N = 39), patients were switched to bupropion at a mean dose of 329 mg/d. Baseline and bimonthly assessment consisted of investigator-rated sexual function scores for orgasm function, libido, and overall sexual satisfaction, based on a 7-point Likerttype scale. At the end of 8 weeks, 88% of the 25 women remaining in the study reported a complete or partial resolution of orgasmic dysfunction, with most patients responding at week 2. In addition, HAM-D scores improved from 16.6 at baseline to 8.4 at study end in 36 evaluated patients. A 12-week, double-blind, placebo-controlled study (N = 60) evaluated bupropion, 225 to 450 mg/d, in nondepressed (HAM-D score <15) patients with psychosexual dysfunction (defined as sexual aversion or inhibited sexual desire, inhibited sexual excitement, and/or inhibited orgasm) for the primary outcomes of improvement in weekly libido self-rating, clinical global impression scores, and weekly frequency of sexual encounters.44 Sexual drive was assessed at baseline and weekly on a 20-point scale from lowest to highest (10 to +10). Following an 8-week, single-blind, placebo lead-in period, bupropion was titrated to a maximum, double-blinded dose of 450 mg/d in the treatment group (range 390-410 mg/d). After 2 weeks of treatment, global improvement ratings became signifi206 JOURNAL OF PHARMACY PRACTICE 2003(16.3)

cantly better for the bupropion group than for placebo (P < .05). The treatment group also showed a greater increase in ratings for sex drive (P < .05). No changes were noted for pleasure or intensity over the duration of the study, and results were not reported separately for men and women. These results are supported by 2 smaller, single-blind, placebo-controlled studies.37,45 Sildenafil Efforts to explore the potential benefits of the phosphodiesterase inhibitor, sildenafil, in female sexual arousal disorder are based on the physiologic similarities of the penis and clitoris. Like the penis, the clitoris becomes engorged during sexual arousal, facilitated by smooth muscle relaxation of the clitoral corpus cavernosum. Sildenafil may enhance this smooth muscle relaxation and promote tumescence of the clitoris and thereby enhance sexual arousal. A double-blind, crossover study recently evaluated sildenafil in 53 premenopausal women (aged 22-28) with sexual arousal disorder.46 Outcome measures included subjective arousal, orgasm, enjoyment, and frequency of sexual fantasies and intercourse. Measures were assessed with baseline and monthly Personal Experiences Questionnaire, which uses a 5-point Likerttype scale. Significant improvement from baseline and placebo in the subjective measure of frequency of arousal (primary outcome) was reported with 25 and 50 mg doses of sildenafil (P < .001). Additional subjective and objective measures, including orgasm (P < .001), enjoyment, satisfaction with frequency, frequency of intercourse, and frequency of fantasies, were all found to have improved significantly between treatment and placebo (P < .05). Greater than 84% of women completed each arm of treatment. There was no significant difference between sildenafil doses for any measure of the study. Results of this study are consistent with similar findings from an open label study of 9 women with antidepressant-induced FSD and a controlled trial in 19 women with spinal cord injury.47,48 Herbals Herbal remedies that patients may find on their own include any combination of the following: quickum, nettle, saw palmetto, damiana, bee pollen, black cohosh, Mexican yam extract, GABA, maca extract, Lhistadine, pregnolone, androstenidione, L-orthinine, and niacin. Little is known about the safety and efficacy of these agents, and randomized controlled trials were not found to support their use in FSD. Many supplements marketed for treatment of sexual dysfunction

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postmenopausal women: principal results from the womens health initiative randomized controlled trial. JAMA. 2002; 288:321-333. Hulley S, Furberg C, Barrett-Connor E, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: heart and estrogen/progestin replacement study follow-up (HERS II). JAMA. 2002;288:58-66. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: heart and estrogen/progestin replacement study follow-up (HERS II). JAMA. 2002;288:49-57. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605-613. Berman JR, Goldstein I. Female sexual dysfunction. Urol Clin N Am. 2001;28:405-416. Meston CM. The psychophysiological assessment of female sexual dysfunction. J Sex Education & Therapy. 2000;25:6-16. Guyton AC. Pregnancy, reproductive functions of the female, and female hormones. In: Guyton AC, ed. Textbook of Medical Physiology. Philadelphia, Pa: WB Saunders; 1981:1017-1018. Baram DA. Sexuality and sexual function. In: Berek JS, Adashi EY, Hilard PA, eds. Novaks Gynecology. 12th ed. Baltimore, Md: Williams & Wilkins; 1996:281-282. Saks BR. Identifying and discussing sexual dysfunction. J Clin Psychiatry. 1999;17:4-8. Meston CM, Frohlich PF. Update on female sexual function. Curr Opin Urol. 2001;11:603-609. Meston CM, Frohlich PF. The neurobiology of sexual function. Arch Gen Psychiatry. 2000;57:1012-1030. Nusbaum MRH, Hamilton C, Lenahan P. Chronic illness and sexual functioning. Am Fam Physician. 2003;67:347-354. American Psychiatric Association. DSM-IV: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Press; 1994:493-538. Basson R, Berman J, Burnett A, et al. Report of the International Consensus Development Conference on female sexual dysfunction: definitions and classifications. J Urol. 2000;163:888-893. Hershlag A, Peterson CM. Endocrine disorders. In: Berek JS, Adashi EY, Hilard PA, eds. Novaks Gynecology. 12th ed. Baltimore, Md: Williams & Wilkins; 1996:836. Phillips NA. Female sexual dysfunction: evaluation and treatment. Am Fam Physician. 2000;62:127-137. Tuiten A, Van Honk J, Koppeschaar H, Bernaards C, Thijssen J, Verbaten R. Time course of effects of testosterone administration on sexual arousal in women. Arch Gen Psychiatry. 2000;57:149153. Phillips RL, Slaughter J. Depression and sexual desire. Am Fam Physician. 2000;62:782-786. http://www.urometrics.com/products/eros/hcpro.html. Accessed January 15, 2003. Sarrell P. Progestogens and blood flow. Int Proc J. 1989;1:266271. Sarrell PM. Sexuality and menopause. Obstet Gynecol. 1990;75:26S-30S. Dennerstein L, Burrows GD, Wood C, Hyman G. Hormones and sexuality: effect of estrogen and progestogen. Obstet Gynecol. 1980;56:316-322. Hilditch JR, Lewis J, Ross AH. A comparison of the effects of oral conjugated equine estrogen and transdermal estradiol-17-beta combined with an oral progestin on quality of life in postmenopausal women. Maturitas. 1996;24:177-184. Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. 2000;343:682-688.

contain L-arginine, which is a precursor to nitric oxide. Nitric oxide mediates vascular and nonvascular smooth muscle relaxation. Agents Under Investigation Prostaglandin E1 (Alprostadil) Alprostadil causes smooth muscle relaxation and vasodilation to improve blood flow and engorgement of the genitalia. A vaginal preparation for the treatment of FSD is reported to be under investigation; however, no clinical trials could be found at the time of this review.2 Phentolamine (VasoFem) Phentolamine is an -adrenergic blocker that increases blood flow to the genitalia via vasodilation. VasoFem, a vaginal suppository form of phentolamine, is currently in phase 2 clinical trials.2,49 CONCLUSION Despite the high prevalence of FSD, little evidence exists to guide therapeutic decision making. FSD has a complex etiology requiring a thoughtful workup to identify reversible causes. Open and clear dialogue between the provider and patient is necessary to determine optimal and appropriate treatment options where evidence exists. Nonpharmacologic treatment options should be considered first unless clear diagnostic evidence supports use and manipulation of pharmacologic therapy. Due to increased awareness, more research is being conducted to improve available options. Depending on the patients underlying etiology, there is some evidence supporting several pharmacologic agents to improve female sexual arousal, desire and orgasm disorders, and overall quality of life. Results from clinical trials should be interpreted with caution based on the frequent reliance on subjective measures of sexual function and the small sample size of most studies. REFERENCES
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