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Sexual Health & Intimacy

Hypoactive Sexual Desire Disorder in the Reproductive-Aged Woman

Bonita Westwood, APN; Cynthia Frazier, MD; Rebecca Lancaster, APN, PhD

It has been estimated that 40 million American women are affected by female sexual dysfunction (FSD).¹ Low sexual desire has been reported repeatedly as the most common form of FSD, particularly among reproductive-aged women.² For many years, FSD was thought to be caused mainly by emotional conflict, whereas male sexual dysfunction was attributed to pathophysiologic changes.^3,4 In fact, the two main determinants of FSD are biologic and psychological, but they generally interact.¹ Many women are embarrassed to discuss sexual issues with their primary care physician, or believe their physician would dismiss sexual concerns.² There is a strong association between low sexual desire and decreased physical, emotional, and overall life satisfaction. These physical and emotional aspects can have a "ripple" effect on other relationships with family, work, or spouse. However, even though there is a strong relationship be-tween quality of life and sexual dysfunction, there is a lack of adequate research regarding low sexual desire and its treatment in women. Although a testosterone patch is under development, no androgen therapies are currently approved by the US Food and Drug Administration (FDA) for the treatment of any form of FSD. This article discusses the prevalence of female hypoactive sexual desire disorder (HSDD), describes HSDD as it applies to reproductive-aged women, identifies potential causes and influencing factors, and introduces guidelines for clinical evaluation and treatment.

DEFINITION

The American Psychiatric Association has defined HSDD as "the persistent or recurring deficiency or absence of sexual fantasies/ thoughts and/or desire for receptivity to sexual activity which causes personal distress."⁵ This definition does not apply to women who lack desire due to situational or temporary circumstances. As a woman with HSDD can function sexually in terms of arousal and orgasm,¹ personal distress is a significant part of this definition. Addressing such distress requires the patient to seek treatment, but they are often reluctant to do so. Finally, this definition leaves some questions, as levels of sexual interest can differ significantly, and there are no clear, acceptable norms in this area.

PREVALENCE

It has been estimated that 40 million American women are affected by FSD.⁶ Data analyzed from the National Health and Social Life Survey involving 1,749 women and 1,410 men showed that 31% of women were affected by low sexual desire.⁷ This population-based study was representative of US adults aged 18 to 59 years. Women reported a higher incidence of sexual dysfunction (43%) than men (31%). The incidence of women reporting low sexual desire increased with age from 30% at age 30 years to about 50% at age 50 years, and then declined to 27% at age 50 to 59 years. Luteinizing hormone (LH) continues to stimulate the ovarian hilar cells and the interstitial cells after menopause to produce androgens, and this may be why many women have adequate sexual desire at age 50 years and after. Of the women affected with low sexual desire, 64% were under 39 years of age. The National Health and Social Life Survey is one of the largest surveys conducted to date, and is extremely relevant due to the age of the study population.

In a related study conducted on the Internet, Berman et al⁸ also reported that the most common sexual complaint was low desire, affecting 77% of the women surveyed; 67% of the subjects were premeno-pausal. A survey by Kadri et al⁹ of 728 premenopausal women revealed HSDD as the most common sexual disorder. Nusbaum et al¹⁰ mailed a survey to 1,500 women seeking routine gynecologic care; 90% of these respondents were aged 18 to 87 years, with an average age of 44 years. One or more sexual concerns were reported by 98.8% of subjects, with lack of interest noted most often at 87.2%. Thus, the high prevalence of this condition warrants attention from health care providers.

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CAUSES

There are several etiologies of low sexual desire. The two main determinants are biologic and psychological, which then interact. Only recently has low sexual desire been recognized as arising from psychological issues as well as from multiple organic etiologies.¹It is well known that certain diseases and medications can affect sexual desire. The most common medical conditions are dysfunction of the hypothalamic/pituitary axis, surgical or medical menopause, and premature ovarian failure.⁴

The hormone that controls sexual desire in women and men is testosterone. There is little dispute that testosterone directly influences female sexual desire, but controversy mpersists regarding androgen therapy in reproductive-aged women. Androgens include testosterone, 5 α-dihydrotestosterone (DHT), andro- stenedione, androstenediol, and dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S). Reproductive-aged women produce androgens in the peripheral tissues, ovaries, and adrenal gland (Figure 1). Only 1% of testosterone circulates freely in women, as opposed to 3% in men.^11,12

Organic Etiologies

Gracia et al¹³ conducted a prospective cohort study involving 436 women aged 35 to 47 years, and followed them over a 4-year period. A fluctuation in total testosterone levels in the late reproductive years was found to be associated with low libido, even after adjusting for vaginal dryness, living with children, and depression. In a related study, Goldstat et al¹² conducted a double-blind, randomized, placebo-controlled crossover study on the effects of transdermal testosterone, 1% cream, self-administered to the thigh daily in 31 healthy premenopausal women (mean age 39.7 years) with low libido. The 12-week treatment periods were separated by a single-blind, 4-week washout period. Each woman began with a normal baseline testosterone level, and by the end of the 12-week period the mean values for total testosterone remained within the normal female reproductive range. However, the free androgen index (FAI) rose above the upper limit of normal. Statistically significant improvements were reported in the sexual function of the 31 subjects, with no reported side effects.

In the absence of regular, cyclic menses, assessment of follicle-stimulating hormone (FSH) and LH values can help determine primary or secondary hypogonadism that may cause low sexual desire. Low levels of FSH and LH suggest impairment of the hypothalamic-pituitary axis, whereas an elevation may suggest primary gonadal failure. Pathologic processes may affect adrenal and ovarian function, decreasing available testosterone.¹⁴ Hyperprolactinemia may result from pituitary tumors, hypothyroidism, stress, hepatic disease, or pharmacologic therapy, and can produce low sexual desire as well.¹⁵The Princeton Consensus Conference on Androgen Insufficiency in Women concluded that there is an urgent need for research to determine the normal values of various androgens in women.¹⁶To date, no specific laboratory tests have been universally recommended for the diagnosis of low sexual desire, but some experts advocate assessing baseline hormone levels.

Pharmacologic Etiologies

Reproductive-aged women with regular menses can also have decreased testosterone levels that may lead to low sexual desire.¹⁷ A serum testosterone reduction of 42% has been associated with various forms of oral estrogen therapy.¹⁸ An increase in estrogen values decreases stimulation of the androgen-producing cells in the ovary by inhibiting pituitary LH. Oral contraceptives (OCs), lactation, anorexia nervosa, and decreased ovarian function may result in subnormal levels of testosterone.11 With the use of OCs, the liver increases production of sex hormone-binding globulin (SHBG), thus increasing the binding of free testosterone. Adams et al19 concluded that there is a peak in female-initiated sexual activity during the ovulatory phase, as opposed to no peak in OC users. A 20% increase in testosterone has been shown to occur with ovulation,20 leading to the conclusion that inhibition of ovulation by OCs may contribute to decreased libido due to increased SHBG levels.²⁰

Other medications that may contribute to low sexual desire are corticosteroids, anticancer drugs, anticonvulsants, antidepressants, antihypertensives, histamine-2 receptor antagonists, neuroleptics, and sedatives.¹⁴ Many women experience HSDD with normal testosterone levels, though, so that multiple factors must be considered in the patient's history.

Psychological Etiologies

Emotional and relational issues have a clear impact on sexual desire in women. Some of these issues include depression, stress, drug or alcohol abuse, body image, and relationship problems. The most common psychogenic causes of HSDD are depression, substance abuse, and fatigue.²¹ Interpersonal problems such as relationship conflicts with a partner affect the sexual response as well.⁴Intrapersonal conflicts have a primary influence on a woman's sexuality. Families often provide the basis for sexual responses, including values, beliefs, and expectations regarding fertility, virginity, marriage, social restrictions, and monogamy. A history of physical, sexual, or emotional abuse, or pain during intercourse, can also inhibit a woman's interest in sexual activity. Social and environmental exposures—including media images of women, religion, daily events, and personal experiences with violence—also impose a direct influence. Some women experience distress in the pursuit of cultural expectations regarding attractiveness and sexual response. Finally, early learning also directly influences what women view as normal or abnormal sexual behavior.²²

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MEASUREMENT TOOLS

Low sexual desire is measured both psychologically and biologically. To qualify for a diagnosis of low sexual desire, the female patient must show evidence of significant personal distress. Therefore, it is imperative that physicians utilize psychological measurement tools that exhibit a high degree of sensitivity and reliability to detect problems and evaluate interventions. Biologic assessment enables the provider to identify and treat organic etiologies. Although objective findings play a lesser role in the evaluation of low sexual desire, they must not be overlooked. Routine administration of scales or questionnaires is not recommended for reproductive-aged women²³; rather, testing should be reserved for those with an observed or proclaimed sexual dysfunction.

Psychological Measurements

There are several brief, self-report sexual function tests that have been developed over the past decade and used as primary endpoints and for screening in clinical trials. Establishing the presence of personal distress is essential to meet the diagnostic criteria for HSDD. One useful scale for evaluating this component is the Female Sexual Distress Scale. It has been shown to be sensitive to treatment effects, and has been used repeatedly in the evaluation and establishment of overall distress. This 12-item scale assesses subjective distress, and exhibits a high test-retest reliability and internal consistency.²⁴ Diaries and event logs do not provide the multidimensional approach afforded by this questionnaire. However, they are key in providing the subjective and quantitative data that are important in both the assessment and treatment phases of low sexual desire.

Biologic Measurements

While no specific laboratory tests are universally recommended for the diagnosis of low sexual desire, baseline hormone testing may be indicated. If warranted, it is best to measure hormone levels at midcycle and in the absence of OC or other hormone therapy (HT).²⁵ Testosterone measurements in women are problematic. Researchers have explored the C19 sex steroids to determine which can be measured most accurately, and found a lack of sensitivity and reliability in the current assays for measuring testosterone in the lower ranges.¹⁵ Therefore, the most frequently recommended measurement is the FAI. This calculation should not be used in women with abnormal liver or kidney disease. Most laboratories do not calculate the FAI, but rather offer free testosterone values. The FAI is calculated using the total testosterone and SHBG levels. The SHBG level will help to determine the free biologically active testosterone level. This is calculated by multiplying the total testosterone level (ng/mL) by 3.47, and dividing the result by the SHBG value. The Table summarizes the normal FAI ranges, which vary by age.¹⁷

Although there are new methods for objectively measuring FSDs such as decreased arousal, dyspareunia, or inability/difficulty achieving orgasm, there are currently no such tests to measure low sexual desire.²³ Thus, objectivity plays a lesser role in the assessment of low sexual desire.

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TREATMENT

Most physicians perform detailed comprehensive clinical assessment, medical and psychosocial histories, physical examination, and laboratory testing prior to initiating a trial of androgen therapy.²⁶ For the treatment of sexual dysfunction, there are no national guidelines or FDA labeling for testosterone therapy in women.^27,28 Some physicians have expressed concern regarding the safety of testosterone therapy. Side effects of androgen therapy may occur in up to 35% of patients, including lower levels of high-density lipoproteins, weight gain, acne, hirsutism, clitoromegaly, and deepening of the voice.²⁶ Homeostatic control of androgens in women has not been clearly defined.

Pharmacologic Options

There is a lack of androgen preparations that consistently produce normal ranges of testosterone in women.¹⁴ Intramuscular testosterone results in peak serum levels above the therapeutic range. For women with sexual dysfunction and total testosterone in the lower 25% of the normal reproductive range, the two most common recommendations for androgen therapy are DHEA or testosterone.²⁹ Replacement of DHEA at 50 mg results in androgenic side effects in more than 20% of women, despite normal serum ranges of DHEA and DHEA-S.³⁰In the United States, DHEA is available without a prescription, and is not FDA-regulated. Thus, the quantity and quality of DHEA in various preparations is not monitored or tested for contaminants. Recently, FDA investigators found that approximately 45 over-the-counter DHEA products contained from 0% to 109.5% of the declared amount.³¹Therefore, monitoring a woman's serum DHEA level is extremely important if she is using a DHEA preparation.

Estrogen/testosterone HT combinations are available for postmenopausal women, but these are not indicated for treating sexual dysfunction/low desire. A new testosterone matrix patch for women is currently in phase III trials. This preparation, which is similar to the second generation of transdermal estradiol patches, is smaller, thinner, and better tolerated during wear for multiple days. This method of administration reduces the first-pass effects that occur with oral administration. Reported clinical trial data have shown no virilizing effects or adverse effects on lipids or liver enzymes.³² Other modes of testosterone administration are currently being explored, including vaginal, buccal, and sublingual.³³ Administration of a testosterone lozenge by buccal absorption has been shown to produce rapid and brief elevation of testosterone levels.³⁴

Although not FDA-approved, compounded topical androgen preparations are used to treat some women with low testosterone values and low sexual desire.³⁵ Testosterone is available via patches, creams, or depot preparations. Transdermal therapy may provide the best balance, without the peaks and valleys seen with oral and intramuscular methods, plus offering a favorable safety profile in regard to liver effects and lipid profiles.³⁶ Price ranges for compounded forms of testosterone range from $25 to $70 per month. Some physicians begin with testosterone, 5mg/g cream, 1 g applied three times per week, in women with low levels. Women must be instructed that fine hair growth may occur at the site of application.³⁷

Total testosterone and SHBG or free testosterone hormone levels should be re-evaluated every 3 months by the same laboratory and at the same point in the menstrual cycle. This monitoring should include estradiol levels as well, as testosterone can be converted to estrogen.⁴ Testosterone therapy is contraindicated in patients with a history of breast cancer, liver disease, pregnancy, lactation, acne, or hirsuitism.²⁸ Many experts feel that androgen therapy should only be considered as adjuvant therapy to psychological counseling.³⁸

For OC users with low sexual desire, changing to a preparation with stronger androgenic or estrogenic effects may be beneficial.⁴ Another option may be a 2-month drug "holiday" from OCs, followed by reevaluation of sexual desire.⁴ However, this approach may place the patient at risk for unintended pregnancy, so the physician should ensure that she is using an alternative, nonhormonal form of contraception. Estrogen administration via a transdermal patch may have a less negative effect on sexual desire than oral therapy.³⁵

Bupropion, sustained-release (SR) 150 mg/d, has been evaluated recently in the treatment of low sexual desire. It has been reported to increase sexual desire in 29% of 51 nondepressed subjects aged 23 to 65 years, the majority of whom were white and premenopausal. Increases were shown in the number of episodes of sexual arousal, fantasy, and interest. Response was reported as early as 2 weeks, and by the end of the 8-week treatment phase. The response rate indicated a 2-fold increase in frequency, interest, and sexual activity. The cost of bupropion ranges from $50 to $65 per month and it was generally well tolerated, with no significant changes in vital signs or weight.³⁹

There are many other agents available through alternative medicine. One is the herbal supplement Avlimil, which is promoted for FSD and packaged much like OCs. It is recommended as a daily supplement, and costs $34.75 per month. This product is not FDA-approved, and does not list quantities of individual ingredients. The manufacturer funded a prospective, randomized, double-blind, placebo- based, parallel-group clinical trial involving 49 women aged 25 to 65 years. The trial lasted 3 months, and resulted in an overall improvement in sexual function. Data were gathered using the Self-Report Assessment of Female Sexual Function and the Brief Index of Sexual Functioning for Women.⁴⁰

The Natural Medicines Comprehensive Database identifies several concerns about the use of Avlimil.⁴¹ It is contraindicated during pregnancy, as some of the ingredients have uterine-stimulant effects. Women with hormone-sensitive conditions such as endometriosis and breast, uterine, or ovarian cancer should also avoid the product. Sage leaf, which is the primary component of Avlimil, contains the neurotoxin thujone; this leaf is safe to use in cooking in small amounts, but higher doses for prolonged periods may result in thujone toxicity. Known side effects include nausea, headache, and abdominal discomfort.

Additional pharmaceutical options for the treatment of FSD are being pursued. These include dopaminergic agonists, melanocortin-stimulating hormones, adrenergic receptor antagonists, nitric oxide delivery systems, prostaglandins, and androgens.⁴²

Counseling

Psychological therapy may help women experiencing low sexual desire. Initially, women with this complaint should be screened for physical and psychological illness, and current relationships investigated to exclude interpersonal conflicts.² This can be achieved with or without the partner. The therapist can be beneficial in clarifying relationship dynamics and background issues that may be influencing the problem, such as body image, roles, view of the partner, outside pressures, depression, or substance abuse.^43,44Couples therapy has been shown to reduce relationship distress, and can provide substantial benefits in the presence of a supportive partner.^38,45

Sex therapy involves education regarding the sexual responses of self and partner. This therapy is best performed by a therapist with specific training in sexual problems and the exploration of conflict-management issues as well.^38,46 Even if the lack of desire is found to have a physiologic cause, the concurrent emotional and relationship issues must be addressed.⁶

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CONCLUSION

Current literature suggests that the majority of women who complain of low sexual desire are in the reproductive age group. However, it is difficult to find studies that include pharmacologic therapy for this group. While no recommendations can be made at this time for testosterone therapy in the presence of normal levels, calculation of the FAI often reveals abnormal free androgen levels in women with normal total testosterone values. The testosterone patch, which has completed phase III clinical trial, shows promise, as has bupropion SR. Some alternative therapies may be helpful as well. However, use of bupropion SR for HSDD is currently considered off-label.

A thorough history and physical examination should be the initial components in assessing low sexual desire, followed by a review of medication, alcohol, and/or drug use, with any positive findings addressed. Women with psychological problems or interpersonal conflicts should be referred for single or couples counseling. If indicated, appropriate laboratory tests should be ordered, and abnormal results addressed. Follow-up should include monitoring of hormone levels, as well as the use of a validated scale to evaluate treatment interventions. It is important to assess each component to identify the appropriate treatment. This same comprehensive approach is useful in evaluating treatment efficacy.

When presented with a complaint of low sexual desire from a reproductive-aged woman, many physicians fail to consider a hormonal cause. Clinicians should take the sexual health of a woman as a serious and important aspect of her life that requires evaluation of all potential causes.

Mitchell Tepper, PhD, MPH, is founder and president of The Sexual Health Network and www.SexualHealth.com.

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