25 June 2012
An important and to date not clearly resolved question in clinical reproductive medicine has been whether premature loss of ovarian function (e.g. primary ovarian insufficiency (POI) below the age of 40 years) and iatrogenic premature loss of ovarian function (as a result of surgery, gonadotoxic chemotherapy or pelvic irradiation) result in a significant decrease in circulating testosterone concentrations and hence might merit testosterone treatment. Many published studies have included small sample sizes and/or non-uniform control groups. Janse and colleagues  have undertaken a systematic review and meta-analysis of the literature and conclude that testosterone levels are lower, though the magnitude of the difference is relatively small. They reviewed 206 articles on POI and 1358 on iatrogenic menopause, of which nine and 17, respectively, were selected for final analysis. In both groups, there was evidence of a lower testosterone concentration than in controls. Weighted mean differences were -0.38 nmol/l (95% confidence interval (CI) -0.55 to -0.22) and -0.29 nmol/l (95% CI -0.39 to -0.18), respectively. The mean differences represented a range of 1–49% lower (average 25%) in POI and a range of 11% higher to 77% lower (average 22% lower) for iatrogenic menopause. A sensitivity analysis of the three highest-quality studies in each group did not change the data substantially. The significance of such relatively small differences and their clinical importance are unclear.
The analysis by Janse and colleagues  supports the possibility that women with POI or iatrogenic menopause have somewhat lower circulating testosterone concentrations than control women who continue to cycle, though the magnitude of difference is relatively small, on average about 25%, with substantial overlap in concentrations between affected women and controls. The data may be contrasted with the lack of any significant change in total testosterone concentrations across the time of the menopausal transition and menopause . Because testosterone is widely regarded as having a significant role in female sexual function , it is necessary to place the results in that context. Several major studies [e.g. 4, 5] have documented the lack of correlation between testosterone levels and indices of female sexual function.
Hence, many challenges surround the interpretation of testosterone concentrations in women and the implications of differences between controls and women experiencing early or iatrogenic menopause. From a practical standpoint, the important decision that needs to be made by the clinician in conjunction with his/her patient is whether testosterone treatment should be used in addition to the estrogen therapy normally considered mandatory for women with POI. For women with iatrogenic menopause, standard indications and contraindications for estrogen therapy apply and, in both situations, clinical features of female androgen deficiency syndrome (FADS)  would constitute the major reason to actively consider testosterone therapy. Kalantaridou and colleagues  reported, in a group of 143 women with POI, compared with 70 regularly menstruating controls, that those with POI had significantly lower sexual function scores (using the Derogatis interview for sexual function self-report), compared with controls. Their serum total testosterone levels were significantly correlated with the composite score using that indicator, although this accounted for only 4% of the variance in the measure. They noted that patients with testosterone levels below normal tended to have lower composite scores. Of patients with POI, nine of 127 (7%) had scores below the 2nd percentile, compared with one of 49 controls (2%). Thus, although sexual function was in the normal range for most young women with 46XX spontaneous POI on physiological estrogen replacement, as a group they scored significantly lower on the sexual function scale than control women.
Testosterone treatment is available in only some countries, with the testosterone patch being approved for symptomatic surgically menopausal women in the UK and Europe, whereas testosterone is 'off label' in the USA and Australia, though relatively widely employed using products mainly available for the treatment of male hypogonadism, or a specifically formulated testosterone cream for women in Australia. Overall, the usual indication for testosterone treatment is the presence of features of the FADS, including dysphoria, unexplained fatigue and hypoactive sexual desire disorder. Many published studies [e.g. 8] now support the efficacy of testosterone therapy using transdermal patches, though in practice they are effective for only 50–60% of women with the relevant symptoms. To date, there are no indications that testosterone therapy is harmful in the long term, though more studies of this are required. Panay and Fenton  in a useful editorial have reviewed the role of testosterone in women and conclude that universally accepted and validated general quality- and sexual quality-of-life tools should be used in large enough populations to confirm the morbidity that androgen deficiency can create. Further randomized trials of androgen in women 'are required of sufficient magnitude and duration to satisfy the regulatory authorities'. A major concern is the possible effects of testosterone on the breast, which have been extensively reviewed by Somboonporn and Davis , who conclude that much of the data is controversial and that the inclusion of testosterone in postmenopausal estrogen–progestin regimens 'has the potential to ameliorate the stimulating effects of combined estrogen–progestin on the breast'.
Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia
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Content updated 25 June 2012