Studies on Testosterone Replacement in Women
Surgical menopause by bilateral oophorectomy is typically accompanied by an abrupt 50% drop in circulating testosterone levels. Investigators have noted that approximately half of the patients undergoing bilateral oophorectomy reported decreased sexual desire after surgery, frequently matching the proposed diagnostic criteria for HSDD. Several randomized studies have focused on the effect of testosterone replacement on the sexual parameters outcome in surgically menopausal patients with HSDD. Shifren et al. treated 75 oophorectomized women on estrogen replacement with transdermal testosterone patches (TTP), delivering 150 or 300 µg/day against placebo for 12 weeks. Normalization of serum-free testosterone was associated with an improvement in sexuality and well-being. This improvement was more substantial in patients receiving 300-µg testosterone daily; however, this dose resulted in slightly supraphysiological serum levels of testosterone. These observations were further confirmed in two bigger trials with a total of 1095 surgically menopausal women suffering with HSDD and receiving 300-µg testosterone patches for 24 weeks.[38,39]
As described above, physiological menopause is not associated with androgen deficiency per se and, therefore, does not routinely require androgen therapy. If problems with libido arise in women receiving oral postmenopausal estrogen treatment, known to increase SHBG levels and decrease free testosterone, one should consider reducing the dose of estrogen rather than initiating androgen therapy. Nevertheless, several clinical trials with testosterone treatment in naturally menopausal patients with sexual complaints have been performed. Davis et al. studied 814 naturally postmenopausal women with HSDD, without estrogen replacement, with daily 150 or 300 µg transdermal testosterone versus placebo. At 24 weeks, an increase of 2.1 satisfying sexual episodes per month was observed in the 300 µg/day TTP group. However, this so-called APHRODITE study recorded 30% androgenic skin effects, and 2.4% breast cancers were observed in the 300 µg study population. The recently published ADORE study evaluated the efficacy of a similar dosed testosterone patch in 272 naturally menopausal women with HSDD, predominantly not using hormone therapy and demonstrated significant improvements in satisfying sexual episodes at 6 months, without particular side effects after 24 weeks of treatment. Addition of 2 mg methyltestosterone daily for 12 months in addition to combined estrogen–progestin replacement in 60 postmenopausal women with onset of sexual dysfunction after menopause showed a significant increase in sexual energy.Table 1 summarizes the randomized controlled studies on testosterone replacement in postmenopausal women with regard to their outcomes, including sexual function, mood, bone density, body composition and lipids.[44–66] The main outcome in these studies is improvement in sexual function and well-being; comparing the different studies is challenging as study populations differ and a wide range of sexual questionnaires has been used. There are inherent difficulties with sexuality questionnaires, which may be compromised by insufficient validation and also the unavoidable need for self-reporting of domains such as sexual interest and desire, satisfaction, excitement/arousal, attitude/behavior and the quality of the relationship. A variety of physiologic, medical and psychological factors can contribute to sexual dysfunction, and a review on this topic did not yield a single questionnaire universally useful for researchers or clinicians who wish to measure sexual function.
Whether women with autoimmune-origin premature ovarian failure (POF) may also benefit from androgen replacement therapy is not yet clear. As one could expect based on their younger age and as observed by Benetti-Pinto et al., serum levels of DHEA and DHEAS levels were significantly higher in women with POF compared with postmenopausal women. However, a study of ovarian biopsies in POF patients nicely demonstrated that the autoimmune process does not affect granulosa and theca cells to the same extent and consequently circulating androgen levels can be either unchanged or decreased in POF. It is warranted to check the serum levels of androgen precursors and active androgens in women with nonsurgical POF as clinical experience demonstrates significant variability, with some suffering from pronounced androgen deficiency and others demonstrating normal circulating androgen levels.
Androgen levels can also be reduced in Turner syndrome due to failure of ovarian maturation. This can result in variable effects on body composition, neurocognition and quality of life, and these aspects have recently been shown to improve with administration of oral 1.5-mg methyltestosterone, in a small study on 12 months of treatment in 14 women.
The Endocrine Society Guidance from 2006 recommend against the general use of testosterone in postmenopausal women because the indications are ill defined, and evidence of safety in long-term studies is lacking. The presence of sexual dysfunction alone, in the context of normal circulating androgen levels, is certainly no justification for the initiation of androgen treatment, as supraphysiological androgen levels do not result in an additional improvement of sexual function over and above normal.
Expert Rev Endocrinol Metab. 2012;7(5):515-529. © 2012 Expert Reviews Ltd.