Should testosterone therapy be used to treat HSDD in reproductive-aged women?

PRO: In some circumstances testosterone therapy is warranted in this population.

John E. Buster, MD

Dr. Buster is Professor of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence.

He has no conflict of interest to disclose with respect to the contents of this article.

Sexual desire is at the center of the human sexual cycle, and hypoactive sexual desire disorder (HSDD) is a common female sexual dysfunction. Diagnosis of HSDD is made when lost sexual desire causes personal distress and the patient complains. HSDD is consequential to genetically linked declines in circulating androgens from adrenal reticularis zone atrophy and ovulatory failure from menopause.^1-3

In older women, whose androgen production is at a lifetime low, HSDD is diagnosed frequently as an isolated event, with prevalence approaching 50% in this population. Transdermal testosterone, even in modest doses, is highly effective in randomized prospective trials that involve older (postmenopausal) women who normally have low levels of circulating testosterone (< 20 ng/dL).²

In reproductive-aged women, whose androgen production is at a lifetime high, HSDD is diagnosed infrequently as an isolated event.. Rather, HSDD in younger women is often linked to situational circumstances, dysfunctional interpersonal relationships, chronic disease, depression, drugs, gynecologic disorders, or other mitigating factors. In general, treatment of these mitigating factors is the best strategy for treating HSDD in the reproductive-aged group.

Testosterone, unless administered in pharmacologic doses, is not usually effective in treating HSDD in reproductive-aged women. In one exception-oophorectomized women-the response to testosterone is similar to the postmenopausal population.^1,3

When to prescribe for reproductive-aged women

There is little information on transdermal testosterone in reproductive-aged women and it is generally considered ineffective. In my experience, however, transdermal testosterone is more likely be effective in patients who are testosterone-depleted (ie, whose total serum testosterone is under
20 ng/dl). Based on this experience, there are 3 circumstances in which I recommend transdermal testosterone to reproductive-aged women complaining of HSDD.

1. After oophorectomy: In this setting, in addition to menopausal symptoms from estrogen withdrawal, HSDD is common. I customarily offer transdermal testosterone if HSDD is a complaint following surgery.

2. Low serum testosterone: In reproductive-aged women who complain of HSDD, I normally measure early-follicular-phase serum testosterone as part of the evaluation for HSDD. In my experience, some younger women have testosterone levels < 20 ng/dL, and in general, they are responsive to treatment. There is no information available on the cause of hypotestosteronemia in these women.

3. Psychotropic drugs: SSRIs and major antidepressants are a common cause of HSDD in reproductive-aged women. In circumstances in which depression is severe and antidepressant doses cannot be cut, I will prescribe transdermal testosterone in superphysiologic doses to overcome this effect.

A major adverse effect of superphysiologic testosterone is clinical hyperandrogenization. In desperation, patients will tolerate this. Because the testosterone is administered transdermally and there is no first-pass hepatic effect, the metabolic adverse consequences are minimal.

References

1. Buster JE, Kingsberg SA, Aguirre O, et al. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol. 2005;105(5 Pt 1):944–952.

2. Buster JE. Managing female sexual dysfunction. Fertil Steril. 2013;100(4):905–915.

3. Buster JE. Sex and the 50-something woman: strategies for restoring satisfaction. Contemporary OB/GYN. 2012;57(8):32–39.

NEXT: The 'CON' position:  Testosterone has not been proven to increase desire and is not worth the risk >>

Con: Testosterone has not been proven to increase desire and is not worth the risk.

Leslie R. Schover, PhD

Dr. Schover is Professor of Behavioral Science at the University of Texas MD Anderson Cancer Center, Houston.

She has no conflict of interest to disclose with respect to the contents of this article.

Hypoactive sexual desire disorder (HSDD) is the most complex and poorly understood sexual dysfunction. Some women have never felt sexual desire or excitement. Others have had normal desire for sex in the past but no longer do. A debate continues about whether a lack of desire to have sex is inextricably linked with difficulty feeling erotic sensations and thoughts once sexual stimulation begins, or if there are many women who have no spontaneous lust, but can get “turned on” fairly easily by an erotic video or the right kind of genital caressing.¹

When a woman complains about low desire, clinicians may assume that the problem occurs across all situations in her life, yet I find that a careful interview often reveals that the right sexual partner or fantasy can evoke desire.

Until the recent wider use of liquid chromatography-tandem mass spectrometry to measure androgens in women, available assays were not accurate enough to compare women with normal desire to those with low desire. A recent cohort study using mass spectrometry failed to find any significant hormonal differences between normal- and low-desire women.¹

However, psychosocial factors including anxiety, depression, and negative sexual experiences in childhood are clearly linked to women’s desire.¹ Among more than 1000 premenopausal women with HSDD in a large registry, dissatisfaction with appearance, stress, fatigue, and dyspareunia were commonly cited as contributing to the problem.²

Many years and millions of dollars have been spent to find a pill that would increase women’s desire for sex. Most clinical trials of testosterone replacement for women with low desire have focused on naturally or surgically postmenopausal women, but in a few studies, testosterone was administered to premenopausal women.³

Double-blinded randomized trials of testosterone as a treatment for low desire in women generally have 4 fatal flaws: 1) Women in the trial have very mild problems with sexual desire compared to clinical populations; 2) Only the highest doses of testosterone are better than placebo, but these doses also raise serum testosterone to supranormal levels; 3) The placebo effect is strikingly large; and 4) Women are never debriefed about their confidence that they are in the active drug versus placebo arm, yet are repeatedly asked to fill out checklists highlighting symptoms such as acne or clitoral enlargement that might indicate that they are taking testosterone.

If women can guess their treatment group correctly, their different expectations probably account for the small gap in efficacy between active drug and placebo.⁴ A recent trial of the antidepressant flibanserin in premenopausal women with low desire suffers from very similar methodology limitations.⁵

I not only strongly doubt that testosterone deficiency accounts for desire problems in healthy, premenopausal women, but I also worry that testosterone therapy could increase their risk of breast cancer.⁴ Since I wrote about my concern in 2008, it has become increasingly clear that androgens are not always antiproliferative in breast tissue, but promote growth in a subset of breast tumors that have androgen receptors.⁶ In both the Nurses’ Health Study II and the New York University Women’s Health Study, higher endogenous serum testosterone in premenopausal women is associated with increased risk of invasive breast cancer.^7,8

If giving testosterone to premenopausal women does not improve their sexual desire, why prescribe a treatment that could increase their risk of breast cancer?

References

1. Brotto LA, Petkau AJ, Labrie F, Basson R. Predictors of sexual desire disorders in women. J Sex Med. 2011;8(3):742–753.

2. Rosen RC, Maserejian NN, Connor MK, Krychman ML, Brown CS, Goldstein I. Characteristics of premenopausal and postmenopausal women with acquired, generalized hypoactive sexual desire disorder: the Hypoactive Sexual Desire Disorder Registry for women. Menopause. 2012;19(4):396–405.

3. Davis S, Papalia MA, Norman RJ, et al. Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women: a randomized trial. Ann Intern Med. 2008;148(8):569–577.

4. Schover LR. Androgen therapy for loss of desire in women: is the benefit worth the breast cancer risk? Fertil Steril. 2008;90(1):129-140.

5. Katz M, DeRogatis LR, Ackerman A. Hedges P, Lesko L, Garcia M, Sand M; BEGONIA trial investigators. Efficacy of flibanserin in women with hypoactive sexual desire disorder: results from the BEGONIA trial. J Sex Med. 2013;10(7);1807–1815.

6. Hickey TE, Robinson JLL, Carroll JS, Tilley WD. Minireview: The androgen receptor in breast tissues: growth inhibitor, tumor suppressor, oncogene? Mol Endocrinol. 2012;26(8):1252–1267.

7. Fortner RT, Eliassen AH, Spiegelman D, Willett WC, Barbieri RL, Hankinson SE. Premenopausal endogenous steroid hormones and breast cancer risk: results from the Nurses’ Health Study II. Breast Cancer Res. 2013;15(2):R19.

8. Zeleniuch-Jacquotte A, Afanasyeva Y, Kaaks R, et al. Premenopausal serum androgens and breast cancer risk: a nested case-control study. Breast Cancer Res. 2012;14(1):R32.