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Should Postmenopausal Women Receive Testosterone Therapy?

YES Glenn D. Braunstein, MD   Lack of sexual desire sufficient to cause distress is a common problem, occurring in approximately 14% of US women aged 50 to 70 years. Once depression, marital discord, adverse drug reactions, estrogen-deficient dyspareunia, and systemic illness are ruled out as causes, a therapeutic trial of testosterone is a reasonable option. The majority of postmenopausal women who meet the criteria for hypoactive sexual desire disorder (HSDD) have free testosterone levels that are near or below the lower limits for younger, reproductive-age women. This is not surprising, as testosterone levels are known to decline from the early 20s until about age 50, and most studies have shown neither a further decline in testosterone during the menopausal transition nor a relationship between serum testosterone concentrations and libido. Nevertheless, numerous double-blind, placebo-controlled trials of testosterone therapy in surgically or naturally menopausal women (receiving concomitant estrogens or not) show that when the free testosterone level is raised to high-normal, there is increased sexual desire, frequency of satisfying sexual events, and decreased distress.1 In addition, androgen treatment of women with hypopituitarism or hypoadrenalism (conditions also associated with low androgen levels) likewise improves sexual function. Although less well studied, data demonstrate a similar salutatory effect of testosterone on sexual desire in premenopausal women with low libido. Thus, testosterone is not used for replacement therapy alone, but also as a drug for treating HSDD. In December 2004, a New Drug Application was presented to an FDA advisory committee for a transdermal testosterone system to treat HSDD in surgically menopausal women receiving estrogen. In a 14-3 vote, the committee decided that the treatment was efficacious and represented a clinically meaningful benefit above that of placebo. However, because the studies provided only 6 months of double-blind safety data, there were concerns about the long-term safety of testosterone with regard to metabolic syndrome, cardiovascular disease, and breast cancer. In this respect, the members neglected to consider the substantial clinical experience garnered over more than 50 years in which testosterone has been used to treat women with low libido and female-to-male transsexuals. These data indicate that the only adverse effects at the doses used to treat women with HSDD are hirsutism and acne, while female-to-male transsexuals also develop deepening of the voice, temporal hair recession, and clitoral enlargement. By contrast, there was no increase in cardiovascular disease, insulin resistance, or uterine/breast cancer.2 Therefore, it would seem that many of the safety concerns are unfounded and that testosterone therapy should be considered at least for hyposexual postmenopausal women and those with hypopituitarism or adrenal insufficiency and HSDD. Glenn D. Braunstein, MD, is chairman, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA. References Shifren JL, Davis SR, Dennerstein L, Heiman JR, Lobo RA, Simon JA. The role of testosterone therapy in postmenopausal women: position statement of The North American Menopause Society. Menopause. 2005;12(5):497-511. Braunstein GD. Safety of testosterone treatment in postmenopausal women. Fertil Steril. 2007;88(1):1-17.

NO William Rosner, MD   This discussion concerns testosterone (T) treatment of the hypoactive sexual desire disorder (HSDD) in women. The influences that play on sexual desire in women are too numerous to reproduce here, but include psychosocial, psychological, and medical factors as well as a host of prescription and non-prescription pharmacologic agents. After addressing these etiologies, there is a group of women with HSDD who might have an “androgen deficiency” that might be related to their complaint. How can one know? There is no correlation between plasma T and sexual desire in women. Even that is moot; most methods for plasma T in women are so flawed that they are all but useless.1 Let’s look at the data. The clearest studies are in ovariectomized women in whom both T and estrogen were replaced. Four to six weeks after initiation of therapy, there is a semiquantifiable increase in desire persisting for the 6 months of most trials, but there are almost no data on the meaningfulness of the changes to the T-treated or placebo-treated women. If one treats patients in the USA, what is one to use? The single available product, Estratest, contains esterified estrogens and methyltestosterone. The successful clinical trials, however, have used T implants or transdermal preparations. These are not FDA-approved for women in the USA. However, there are a variety of T–containing products available from “prescribing pharmacies.” They are subject to no kind of governmental quality control. Caveat emptor. How about adverse effects? The obvious androgenizing effects of T — acne, hirsutism, alopecia, oily skin, etc are unimportant because they are immediately apparent to the patient who can then make an informed decision as to the risk versus benefit of treatment. Of greatest concern are the potential serious health consequences remaining to become apparent. Most importantly, in terms of both benefit and risk, there are almost no data on what happens to women receiving T for more than six months. Not only do benefits wane when therapy stops, it is not proven that treatment beyond six months confers continuing benefit. Thus, there is an indefinite commitment to use a powerful pharmacologic agent with unknown consequences. The arguments that the potential consequences will not be serious are all indirect. There has been no direct study of the long term consequences of androgen administration on women’s health. The most serious concerns involve the cardiovascular system, components of the metabolic syndrome, and malignancies involving the breast and uterus. In regard to the latter, increased plasma T is associated with double the risk of breast cancer, an increase as great as that associated with increased estrogens.2 Thus, we are left with treating a complex psychosocial/medical syndrome with an entity of questionable safety, doubtful composition (in the USA), and whose measurement in plasma is, at best, seriously problematic. You choose. William Rosner, MD, is professor of medicine, Columbia University, College of Physicians and Surgeons, and director, Institute of Health Sciences, St. Luke’s Roosevelt Hospital, New York, NY. References Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society Position Statement. J Clin Endocrinol Metab. 2007;92(2):405-413. Tamimi RM, Byrne C, Colditz GA, Hankinson SE. Endogenous hormone levels, mammographic density, and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2007;99(15):1178-1187.