Androgen Therapy in Women

US Pharm. 2014;39(8):42-46.

ABSTRACT: Approximately 43% of women in the United States between the ages of 18 and 59 years experience sexual dysfunction. Hypoactive sexual desire disorder (HSDD) is characterized by the absence of sexual fantasies and desire for sexual activity. Male sexual dysfunction has been extensively researched, but there is less evidence addressing the treatment of HSDD in women, particularly with regard to the use of androgen therapy. There are no FDA-approved testosterone treatments for women, despite the fact that 4 million prescriptions have been written off-label for HSDD. This highlights the need for more research on safety, efficacy, side effects, and transference issues.

In 2011, the FDA Reproductive and Urologic Drug Products Advisory Committee stated that hypoactive sexual desire disorder (HSDD) is a significant medical condition for women. HSDD, which is considered to be a form of sexual dysfunction, is characterized by the absence of sexual fantasies and desire for sexual activity, as judged by a clinician. In 1999, it was reported that the proportion of U.S. women aged 18 to 59 years with sexual dysfunction was 43%.¹ HSDD in women cannot be diagnosed by assessing the level of circulating sex hormones, such as testosterone; some women with low testosterone levels do not experience desire problems, and most women with HSDD have normal testosterone levels. Male sexual dysfunction has been extensively researched, but there is less evidence addressing the treatment of HSDD in women, particularly with regard to the use of androgen therapy. The complexity of factors involved in HSDD and the lack of awareness that low desire associated with distress is a medical condition have slowed the development of drugs specifically designed for women.

Testosterone is considered to be the main hormone underlying sexual desire in both men and women. In healthy women, free testosterone levels have been linked to sexual desire and antiandrogen therapy has been linked to loss of sexual desire.² Combinations of oral esterified estrogens and methyltestosterone, including Estratest and Estratest HS (half-strength), have been marketed in the U.S. since 1964. These products are for the treatment of moderate-to-severe vasomotor symptoms associated with menopause in female patients whose symptoms have not been relieved by estrogens alone. There are no testosterone pills, patches, or gels currently approved by the FDA for treating sexual dysfunction in women.

Transdermal testosterone gels were introduced in the U.S. in 2000. Two gels are approved in the U.S. for men: AndroGel and Testim (1%). These topically applied products are a favorable and popular mode of testosterone replacement therapy. The usual starting dose for testosterone gels in men is 50 to 60 mg per day. Survey data on the prescribing of testosterone by U.S. physicians in 2009 found that approximately 4 million prescriptions for estrogen/androgen oral medications, compounded testosterone, or brand testosterone approved for use in men were written off-label for women.³ Since the commercially available dosages are too strong for women, female patients typically are treated with testosterone compounded at a dosage of 0.5 to 2 mg per day.

For postmenopausal women with secondary HSDD, the administration of androgens, testosterone patches, or a combination of estrogen and methyltestosterone was reported to be moderately beneficial.⁴ Manufacturers have tried to gain FDA approval of two testosterone products for HSDD; both were denied, however. The first product, Intrinsa—a 300-mcg/24-hour testosterone patch developed by Procter & Gamble—failed to receive approval following phase III trials because of long-term safety issues.⁵ However, the product was licensed by the European Medicines Agency for the treatment of HSDD in women undergoing bilateral oophorectomy and hysterectomy (i.e., surgically induced menopause) who receive concomitant estrogen therapy. The second product, LibiGel, was a 1% testosterone hydroalcoholic gel applied in pea-sized amounts to a small area of skin on the upper arm. Administered once daily, LibiGel increased serum free testosterone levels in postmenopausal women to the testosterone range of younger, premenopausal women.⁶ The FDA ended BioSante Pharmaceuticals’ trials of LibiGel based on an initial analysis of trial data showing nonsignificant differences between the treatment and placebo arms for the secondary endpoints.⁷

Testosterone Production and Metabolism in Women

Testosterone is important for women since it is a major precursor of estradiol production. In premenopausal women, circulating testosterone levels are approximately 10-fold greater than estradiol levels.² The normal range for testosterone in women is 15 to 70 ng/dL, and by the time women reach their 40s, their blood testosterone levels are approximately one-half less than in their 20s.²

Approximately one-third of circulating testosterone comes directly from the ovaries; the remaining two-thirds derives from peripheral conversion of precursors from the ovaries and the adrenal gland. Because the ovaries account for roughly 50% of circulating testosterone, bilateral oophorectomy significantly reduces testosterone levels.^8,9 In contrast, spontaneous menopause is not associated with a significant change in circulating testosterone levels. The postmenopausal ovary appears to produce testosterone throughout life, although not all studies are in agreement.^8,9

A number of factors can lead to reduced testosterone levels in women. See TABLE 1 for a summary.¹⁰

Advantages and Disadvantages of Testosterone Use in Women

Several randomized, controlled trials of exogenous testosterone therapy in postmenopausal women suggested improvements in sexual desire, sexual responsiveness, and frequency of sexual activity.^11-14 With the exception of a particular testosterone-alone arm in one study that included no data on adverse events, these trials combined testosterone with either estrogen therapy or, for women with an intact uterus, estrogen-progestin therapy.^11-15 However, despite findings of short-term efficacy for testosterone therapy in women, reviews of safety in long-term studies are lacking.

Possible beneficial effects of testosterone therapy, such as reduced fracture risk and improved cognitive function, require further research. It is difficult to know which route of administration is more advantageous; however, transdermal application has several advantages over other forms of administration. When testosterone is taken orally, there is extensive first-pass metabolism in the liver that would be prevented with topical application. IM injections are invasive, but topical gels are painless and easy to apply. There are peaks and troughs associated with injections, whereas the topical method remains constant. With patches, there is a limited amount of exposure to the medication, but this modality is often associated with application-site reactions, and the patch is visible on the skin.¹⁶

Limitations of testosterone treatment in women include the variety of side effects, contraindications, and concerns about long-term use. These factors have delayed the development of an effective, safe treatment option for HSDD and other female disorders, including primary ovarian insufficiency (POI). POI is a disorder accompanied by infertility, depression, an increased risk of osteoporosis, and cardiovascular disease. Compared with women with normal ovarian function, those with POI have reduced ovarian production of estradiol and progesterone and decreased circulating levels of androgens.¹⁷ Testosterone production is insufficient in this disorder, so testosterone therapy would be a sensible method for restoring circulating testosterone levels to a normal range.

Although studies have shown benefits from testosterone use, there are contraindications to its use in women. Women who could become pregnant should avoid testosterone therapy, because its use during pregnancy introduces the risk of the development of male traits in a female fetus. Testosterone therapy should also be avoided in women who have or have had breast or uterine cancer, have high cholesterol or heart disease, or have liver disease.²

A study using combined estrogen and testosterone preparations for treatment showed uncommon side effects of alopecia, acne, and hirsutism, although these side effects are dependent on dosage and duration.¹⁵ Low incidence rates of deep voice, oily skin, acne, and male-pattern hair loss were found in a few controlled studies. Virilization can occur with higher-than-normal dosing of testosterone, but it is uncommon and reversible.¹⁸ Women using the lowest effective dosage of testosterone have not been shown to experience side effects or adverse events. Increased dosages inevitably result in the aforementioned adverse effects, as well as increased hair growth.^11-15

Testosterone Transference

Transference is the direct or indirect displacement of testosterone from the skin of the patient to someone or something else. Transference issues have been extensively studied in men, which led to the FDA issuing a black box warning for testosterone products regarding the threat of virilization from topical dosage forms.^19,20 In contrast, transference has not undergone in-depth study in women. Transference to partners, family members, friends, children, or animals could be an issue. There are documented cases of transference in men, but there are no studies documenting transference from women undergoing testosterone treatment.

In order to prevent transference, it is best to avoid all contact until the drug is either completely absorbed or washed clean. The time necessary for absorption varies per product; however, each product comes with a medication guide that should be read fully before use. If skin-to-skin contact with another person or an animal cannot be avoided, covering the application site with clothing decreases risk of transfer. If accidental contact occurs, immediately wash the affected areas with soap and water. It is important to note that skin-to-skin contact is not the sole method of transference. Caution should be taken with regard to shared inanimate objects, as well as residue on furniture, sheets, and clothing. Key prevention methods include washing the hands immediately after application, applying the drug only to indicated areas, covering the area with clothing once dry, cleansing the area before sleeping on bedding, and washing all fabrics that have come in contact with the application site.²¹

It is important for pharmacists to instruct patients on safe storage of all their medications and educate them about the signs and symptoms of transference. Enlarged genitalia, early development of pubic hair, increased erections or libido, and aggressive behavior are signs and symptoms of early puberty and accidental exposure. Women will develop changes in body hair or a noticeable increase in acne, which are also signs and symptoms of exposure. In such cases, the testosterone product should be discontinued and the primary healthcare provider should be contacted.²¹

Conclusion

Since the emergence of testosterone products in the 1990s and transdermal gels in 2000, there have been several approved products on the market for testosterone replacement therapy in men, but there are currently no FDA-approved products for women. Although androgen insufficiency is a clinical symptom of multiple disease states in men, androgen is considered to be the primary hormone underlying sexual desire in both men and women. Testosterone, along with estrogen and progesterone, is elemental in the development of increased libido in females.

Decreased libido is a common complaint among women and is the leading cause of several sexual-dysfunction disorders, such as HSDD. Coupled with the dearth of approved treatments and the lack of knowledge and clinical research on the disease states themselves, a wide gap has been left in the care of female patients. Despite testosterone’s apparent benefits, it is contraindicated in certain female populations. In addition, unconfirmed doses lead to many unwanted potential adverse effects, and transference issues still pose an issue. Measures can be taken to prevent transference, as with men, and it is crucial that women receiving testosterone therapy receive appropriate and necessary counseling.

Androgen therapy in women is an important topic and has been recognized as such by several groups in the past few years.²² Even in the absence of FDA approval, it is apparent that testosterone therapy has some use in certain female populations; however, extensive clinical research on all aspects of the subject is needed in order to formulate guidelines on appropriate indications, dosages, and safety. It is recommend that the medical community delve deeper into not only androgen therapy, but also the conditions requiring it. Additional information on normal laboratory values and assessments of the safety and efficacy of testosterone therapy in all populations of women will greatly improve our knowledge base.

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