Female Sexual Dysfunction
Androgens and Female Sexuality
By By Susan R. Davis, MBBS, FRACP, PhD
Nov 15, 2002, 10:34pm

An accumulating body of data indicates that many women experience a cluster of symptoms that are responsive to testosterone treatment and may be due to androgen deficiency. Characteristically, affected women complain of low libido, persistent fatigue, and diminished well-being and are found to have low circulating bioavailable testosterone. Whether the apparent therapeutic effects of testosterone are mediated via the androgen receptor or as a consequence of metabolism to estrogen is not known. Despite the lack of understanding of the mechanism(s) by which testosterone may enhance libido, the prescription of testosterone to women in a variety of formulations is becoming increasingly popular. This article provides an overview of the rationale for testosterone therapy in women, offers a broad definition of androgen deficiency in women based on the clinical experience of the author, and outlines the currently available options and potential risks of testosterone replacement in women.(The Journal of Gender-Specific Medicine 2000;3[1]36-40)

There are multiple modulators of sexual desire in women. They include level of knowledge, past experiences, expectations, cultural and religious beliefs, availability of a partner, and the individual's hormonal milieu. The aim of this article is to consider the influence of hormones, particularly androgens, on female sexuality and to address the rationale for androgen replacement therapy.

Hormones that may influence female sexuality include estrogens, androgens, oxytocin, and progesterone and its metabolites. Perimenopausal and postmenopausal women may experience vasomotor symptoms (hot flushes and night sweats) and urogenital atrophy secondary to estrogen deficiency. Such symptoms may significantly contribute to loss of sexual desire as a consequence of diminished well-being and atrophic vaginitis. Other frequently reported menopausal symptoms include anxiety, emotional lability, depression, decline in short-term memory and concentration, myalgia, arthralgia, formication, and aversion to touch. The extent to which these symptoms are a primary consequence of estrogen deficiency remains controversial. Nonetheless, such symptoms may impact significantly on sexual desire. Because estrogen replacement will alleviate vasomotor symptoms, vaginal atrophy, and often many of the other symptoms listed above, estrogen therapy alone may result in restoration of the libido in a significant proportion of perimenopausal and postmenopausal women.

However, many postmenopausal women continue to experience diminished libido despite adequate estrogen replacement therapy. The theory that this phenomenon may be due to androgen deficiency is becoming increasingly accepted. Currently, there are no formal definitions of either clinical or biochemical androgen deficiency in women. Therefore, the prevalence of so-called androgen deficiency among women is not known. As the practice of prescribing androgen therapy, most commonly testosterone, to postmenopausal women complaining of loss of libido becomes more widespread, it is essential that the rationale for such treatment be evaluated objectively. Guidelines on what constitutes androgen deficiency and a clinical profile of the patient most likely to respond to therapy must be established. Finally, any risks associated with androgen replacement for women should be considered.

DEFINING HYPOANDROGENISM IN WOMEN

A biochemical definition of androgen deficiency in women has been hampered by the insensitivity of most assays for testosterone at the lower end of the normal female reproductive range. There is no consensus clinical definition of androgen deficiency in women, and certainly many physicians and researchers remain highly skeptical about whether such a condition actually exists. It is the author's cumulative experience that the clinical profile that characterizes the women most likely to respond to androgen therapy includes low libido, decreased motivation, fatigue, and lack of well-being in an estrogen-replete woman with low bioavailiable testosterone (either total testosterone:sex hormone–binding globulin [SHGB] ratio, or free testosterone in the lowest third of the normal reproductive female range). At present, this appears to be a reasonable working definition of androgen deficiency in terms of sexual dysfunction.

The basis of each of these symptoms is likely to be multifactorial; thus it is important for the treating physician to evaluate the extent to which other factors contribute to these symptoms. Any identified factors should be dealt with before prescription of testosterone therapy for low libido. This may involve commencement of estrogen replacement for vaginal dryness, psychiatric referral, counseling, or referral to a sex therapist.

In general, the concept of androgen deficiency has been most widely accepted for women who have had bilateral ovariectomy. Women who have undergone a natural menopause may also experience androgen deficiency symptoms, as do a subset of women in their late reproductive years. Young women who have suffered either primary or secondary ovarian failure may also experience low libido in association with low blood androgen levels.

CAUSES OF HYPOANDROGENISM IN WOMEN

The ovaries produce androstenedione (A), testosterone, and a small amount of dehydroepiandrosterone (DHEA). The adrenals produce A and DHEA-sulfate (DHEA-S). The latter can be metabolized peripherally to testosterone or to estrogens. In turn, testosterone is converted by 5 *-reductase to the potent androgen 5*-dihydrotestosterone (DHT) or aromatized to estradiol-17ß (E2).

Circulating androgen levels have been shown to fall continuously with age in women.1 This decrease appears to be a consequence of the age-related decline in adrenal androgen production and the loss of the midcycle surge in ovarian testosterone production during the late reproductive years.2,3 Bilateral ovariectomy results in reductions in testosterone and A of approximately 50%.4 Chemical ovariectomy (chemotherapy or gonadotropin-releasing hormone agonist treatment), radiotherapy, glucocorticosteroid treatment, and administration of exogenous estrogens are other causes of low circulating androgens. Both oral postmenopausal estrogen therapy and the oral contraceptive pill suppress free testosterone by increasing SHBG levels and suppressing pituitary luteinizing hormone secretion.5,6 Oral glucocorticosteroids suppress pituitary secretion of adrenocorticotropic hormone and, therefore, adrenal androgen production.7 These mechanisms probably contribute to the bone loss that typifies long-term glucocorticosteroid treatment.

Hypothalamic amenorrhea and hyperprolactinemia may also be associated with low testosterone, and many women with premature ovarian failure have low testosterone levels. Thus, prescription of the oral contraceptive pill to older reproductive women or women with hypothalamic amenorrhea or premature ovarian failure may significantly exacerbate androgen insufficiency.

DOES TESTOSTERONE THERAPY IMPROVE PARAMETERS OF FEMALE SEXUALITY?

The mechanisms underlying the physiologic effects of androgens in women are not well-understood. Androgens may act directly via the androgen receptor; as precursor hormones for estrogen production in extragonadal tissues such as adipose, bone, brain and vascular tissues; or by lowering SHBG and increasing free circulating levels of multiple sex steroids. It is most likely that each of these mechanisms is physiologically important.

Few blind, randomized studies have specifically addressed the effects of testosterone therapy on libido and other aspects of sexuality in postmenopausal women. Androgens appear to be important in female sexuality, with reduced androgen levels in the late reproductive years and beyond contributing to the decline in sexual interest experienced by many women. In a study of sexagenarian women, the only hormone positively correlated with sexual desire was circulating free testosterone.8 Both oral methyltestosterone and parenteral testosterone administration to postmenopausal women have been reported to have enhancing effects on various measures of sexuality.

The author and others have demonstrated improvement in several aspects of sexuality in postmenopausal women treated with testosterone that are over and above the effects of estrogen replacement alone.9-13 Sustained improvements in the intensity of sexual drive, arousal, frequency of sexual fantasies, satisfaction, pleasure, and relevancy to daily life were observed in a cohort of postmenopausal women.11 Enhanced sexuality as observed in this and other studies is subtle. Notably, increased sexual activity in women is a poor index of response to therapy, since frequency of intercourse is often dictated by established patterns and interest of the partner. Our results11 may differ from other reports because we conducted one of the very few blind, randomized studies designed specifically to address the effects of testosterone on sexuality, and our protocol involved a two-year observation period with six monthly evaluations to minimize the confounding effects of a placebo response.

Whether premenopausal women who complain of loss of libido and who have low bioavailable testosterone levels should be offered androgen replacement is controversial. To date, no studies have evaluated the use of testosterone replacement in premenopausal women. Therefore, management of such women needs to be very open-minded and therapy completely individualized. It is the clinical experience of the author that a subset of premenopausal women with sexual dysfunction and reduced circulating androgen levels significantly benefits from judicious parenteral testosterone replacement. However, testosterone replacement is unlikely to benefit women at any age in whom other factors play a dominant role in sexual dysfunction. Thus, a thorough psychosocial and sexual history is essential when evaluating the appropriateness of testosterone therapy in a woman.

ADMINISTERING TESTOSTERONE TO WOMEN

The majority of available testosterone preparations for human use have been formulated for use in men. Few countries have officially approved the use of testosterone for hormone replacement therapy in women, and clinical guidelines for safe use are lacking. Testosterone is available as oral methyltestosterone in the United States, and testosterone implants have been approved for replacement therapy for postmenopausal women in the United Kingdom. It is the author's clinical experience that, even for postmenopausal women, testosterone levels often need to be restored to at least the upper end of the normal physiologic range for young ovulating women in order to achieve a good therapeutic response in terms of improved libido. The aim, however, should be to administer a dose of testosterone that achieves circulating levels as close to physiologic as possible in order to avoid adverse side effects.

Oral methyltestosterone in combination with esterified estrogen (EE) (either 0.625 mg EE plus 1.25 mg methyltestosterone or 1.25 mg EE plus 2.5 mg methyltestosterone) is available in North America for use in women. Androgenic side effects may occur with these EE/methyltestosterone preparations,14 and treating physicians should warn patients of this possibility and monitor for androgenic side effects. Because this compound cannot be measured in the serum in a clinical setting, it is impossible to recommend biochemical treatment guidelines.

Oral therapy may negate some of the beneficial lipid effects of estrogen, with reductions in high-density lipoprotein–cholesterol and apolipoprotein A-I with 0.625 mg EE plus 1.25 mg methyltestosterone.14 This therapy does not appear to attenuate the favorable effects of EE on vascular reactivity,15 and it is associated with reduced concentrations of apolipoprotein B14,16 and increased total body low-density lipoprotein–cholesterol catabolism.16 Although long-term therapy with large doses of this compound has adverse hepatic effects, these effects have not been seen with lower doses.14

Oral testosterone undecanoate has not been as well-studied in women. However, a recent pharmacokinetic study indicates undesirable supraphysiologic peaks of circulating testosterone with doses of testosterone undecanoate as low as 20 mg.17 Therefore, with the limited data available, its use in women cannot be recommended.

Subcutaneous testosterone implants have been used for many years in postmenopausal women in Australia and the United Kingdom. These fused crystalline implants are 4.5 mm in diameter and contain testosterone BP (British Pharmacopoeia) as the active ingredient. The author's clinical experience, corroborated by published data, suggests that a dose of 50 mg is extremely effective in enhancing libido and improving bone mineral density without unwanted virilizing side effects.9-11 The 50-mg implant, which is inserted subcutaneously (usually in the lower anterior abdominal wall) using local anesthesia, is effective for three to six months. There is, however, marked individual variation in the time frame over which the pellet breaks down. Therefore, testosterone levels should be carefully monitored and serum testosterone measured prior to the administration of each subsequent implant. Rarely are testosterone implants of 100 mg necessary to achieve adequate therapeutic effects. Indeed, Buckler et al17 and others have reported circulating testosterone levels approximately three times the upper limit of normal four weeks after insertion of a 100-mg testosterone pellet. Unfortunately, the impact of these levels on sexuality and other clinical parameters was not reported.17 In contrast, six weeks after insertion of a 50-mg testosterone implant, mean circulating testosterone levels have been shown to be just above the upper limit of the normal range for ovulating women.11

Although there are no published studies to support their use in women, 50 mg to 100 mg of mixed testosterone esters are occasionally administered every four to six weeks as an intramuscular injection in women with androgen-deficiency symptoms. Clinical experience suggests that this therapy results in a more rapid onset of effects, such that women report enhanced libido within two to three days of treatment. In contrast, women generally report a delay in restoration of libido 10 to 14 days after insertion of a testosterone implant. The pharmacokinetics of mixed testosterone esters administered intramuscularly in women has not been studied; however, many women report increased acne and occasional clitorimegaly with this therapy.

The recent development of a transdermal testosterone matrix patch intended specifically for use in women will provide a new therapeutic option for androgen replacement for women. The patch is designed to deliver 150 µg of testosterone per day with a twice-weekly application. This results in an average increase in circulating testosterone levels of approximately 25 ng/dL (about 1 nmol/L). The availability of such a patch will have some obvious advantages over both oral and implant therapy; however, some women may experience skin irritation or may simply prefer a less conspicuous mode of therapy. Much-higher-dose transdermal patches in women have been reported to produce supraphysiologic circulating testosterone levels in women, and their use cannot be advocated.17

Nandrolone decanoate is a very weakly aromatizable androgen that is available in some countries for the treatment of postmenopausal osteoporosis18 and is administered intramuscularly. There is no evidence that this therapy significantly enhances sexuality in women using dosages that do not cause virilization.

Other alternatives that are not currently generally available but are still in widespread use are transdermal testosterone as a cream or gel or delivery of testosterone by a transvaginal ring. Such preparations may be regionally available on specific prescription from compounding pharmacists; however, to date there are no pharmocokinetic data or published clinical studies regarding the use of such preparations.

As a general rule, testosterone replacement should not be administered to postmenopausal women who are not on concurrent estrogen replacement therapy. Estrogen alone may improve other postmenopausal symptoms, alleviate vaginal dryness, and enhance sexuality, obviating the need for androgen therapy. Furthermore, suppression of SHBG with testosterone alone may increase the possibility of adverse side effects, although this may be less relevant for methyltestosterone, which binds poorly to SHBG.14

Relatively strong contraindications to testosterone therapy include moderate-to-severe acne, clinical hirsutism, androgenic alopecia, and circumstances in which enhanced libido would be undesirable. Absolute contraindications include pregnancy and lactation, as well as known or suspected androgen-dependent neoplasia.

Side effects from excessive dosage include virilization, fluid retention, and potentially adverse lipoprotein-lipid effects, which are more likely with oral administration. Available clinical data indicate that parenteral testosterone therapy resulting in testosterone levels close to and within the normal physiologic range for women has no undesirable metabolic consequences.11,19,20 It is not known whether there is any relationship between exogenous androgen therapy and the incidence of breast cancer, since epidemiologic studies have shown both positive and negative associations between endogenous androgen levels and breast cancer risk. Androgen receptors are found in more than 50% of breast tumors21 and are associated with longer survival in women with operable breast cancer and a favorable response to hormone treatment in advanced disease.22 There are also some data to suggest that the mechanism by which high-dose medroxyprogesterone acetate has a therapeutic effect on breast cancer is mediated via the androgen receptor.23

CONCLUSION

It is increasingly becoming accepted that androgen deficiency in women underpins a variety of symptoms, particularly loss of sexual desire and pathophysiologic conditions, and that in certain subsets of women, androgen replacement therapy is of clinical benefit. The inclusion of testosterone therapy in postmenopausal hormone therapy regimens is increasing but is still limited by the lack of availability of preparations and formulations designed specifically for use in women. Although more controversial, it is also warranted to consider androgen replacement in premenopausal women complaining of loss of libido who experience either spontaneous or iatrogenic androgen deficiency.

Many women are not comfortable discussing their loss of sexual desire, particularly those who have undergone chemotherapy, who often comment that they feel that the issue will be viewed by their physician as trivial relative to their recovery or remission. Additionally, the symptoms of iatrogenic menopause can easily be attributed to side effects of chemotherapy or to other psychosocial factors in premenopausal women or those who have undergone a premature menopause. Therefore, it is the treating physician's responsibility to facilitate discussion of sexuality in all "at risk" women and to address the possibility that low circulating androgen levels are an underlying cause in those with positive symptomatology.

Acknowledgment

The author's research on the testosterone patch was funded by a grant from TheraTech, Inc.

About he Author

Dr. Davis is Director of Research at the Jean Hailes Foundation, Clayton, Victoria, Australia. Address for correspondence: Susan R. Davis, MBBS, FRACP, PhD, Director of Research, Jean Hailes Foundation, 173 Carinish Rd, Clayton, Victoria 3168, Australia. E-mail: suedavis@netlink.com.au.

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