Androgen Replacement Therapy in Women

Marie Lebbe; David Hughes; Nicole Reisch; Wiebke Arlt

Disclosures

Expert Rev Endocrinol Metab. 2012;7(5):515-529. 

In This Article

Studies on DHEA Replacement in Women

Women with adrenal insufficiency usually present with significant androgen deficiency due to the pathological loss in adrenal DHEA synthesis. Evidence exists that despite adequate replacement in glucocorticoids and mineralocorticoids, patients with adrenal insufficiency suffer from decreased well-being, increased fatigue, depression and loss of libido.[71–73] Arlt et al. were the first to report that daily oral administration of 50 mg of DHEA in women with adrenal insufficiency normalized serum androgen levels and improved overall well-being and sexual function.[74,75] It has been suggested that the beneficial effects of DHEA on mood and well-being may be centrally mediated as DHEA may have direct effects in the brain acting as a neurotransmitter rather than only through indirect action via downstream conversion to androgens. However, libido and sexual satisfaction are most likely a consequence of increased androgen activity derived from efficient conversion of exogenously administered DHEA to active androgens by peripheral bioconversion.[1]Table 2 shows the randomized controlled trials studying the role of DHEA replacement in primary and secondary hypoadrenal women, and the observed effects.[74–85] Several trials reported an improvement in subjective health status, anxiety, depression and sexuality,[74–79] but other studies concluded to no psychological beneficial effects of DHEA.[80,81,83–85] Again, the lack of comparable and appropriately validated sexual questionnaires challenges these results. Very few conclusive metabolic effects are reported, with the exception of a moderate HDL cholesterol-lowering effect[75,79,82] and no change in insulin sensitivity and body composition.[80,83] Reported androgenic skin effects are frequent and include acne and hirsutism and mainly occur in previously severely androgen-deprived women; however, they are usually mild and transient.

DHEA treatment has also been studied in women with normal adrenal function, in different settings, and randomized controlled trials are summarized in Table 3. It has been proposed that treatment of postmenopausal women with DHEA will result in androgenic effects and hence improve libido and well-being via its conversion to testosterone and estrogenic effects resulting in improvements in menopausal vasomotor symptoms. Two placebo-controlled double-blind trials were recently conducted with DHEA 50-mg daily for 12 months in 115 and 93 postmenopausal women, respectively, who all had intact adrenal function.[86,87] Both studies showed no improvement of sexual function and well-being, no change in menopause-related quality-of-life scores[86] and no benefit of DHEA in cognitive performance.[87] This has been confirmed by two recent reviews summarizing the available evidence on randomized controlled trials on DHEA replacement in postmenopausal women that has demonstrated no benefit with regard to sexual function, well-being and cognitive performance.[88,89] The age-related decline in circulating DHEA(S) has led to a number of randomized trials to assess the effect of oral DHEA in otherwise healthy elderly subjects.[90–93] The trial by Nair et al. investigated the effect of DHEA and testosterone on quality of life, body composition, physical performance and metabolism in elderly subjects during a period of 2 years.[93] The authors found no significant effects of DHEA in these healthy elderly individuals with low baseline DHEA levels on quality of life, body composition, physical performance or insulin sensitivity. One has to keep in mind that the decline in DHEA and active androgens observed over a woman's lifetime may represent a physiological, protective mechanism, for example, preventing increased sex steroid action in breast tissue.[94]

In patients with systemic lupus erythematosus, which in the overwhelming majority are female, supraphysiological doses has been shown to reduce disease activity and has a glucocorticoid-sparing effect.[95] DHEA has also been suggested as a steroid with immune-regulatory activity and this effect is more likely to be detected in patients with altered immune system at baseline.[96]

Over the last decade, a number of controlled studies have shown that adjuvant DHEA and testosterone treatment can enhance fertility in women with low ovarian reserve.[97–102] Low ovarian reserve is characterized by an impaired quantity and quality of the ovarian follicles, with advancing age as an important determinant. In a randomized open trial in 33 women with low ovarian reserve DHEA (75 mg/day) was associated with a higher oocyte yield and a significantly increased birth rate.[100] Despite the still weak overall evidence due to the current lack of rigorous randomized trials of sufficient size,[103] it is estimated that approximately one third of all IVF centers today use DHEA supplementation in women with low ovarian reserve.[104]

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