Sex-Specific Effects of Dehydroepiandrosterone (DHEA) on Bone Mineral Density and Body Composition

A Pooled Analysis of Four Clinical Trials

Catherine M. Jankowski; Pamela Wolfe; Sarah J. Schmiege; K. Sreekumaran Nair; Sundeep Khosla; Michael Jensen; Denise von Muhlen; Gail A. Laughlin; Donna Kritz-Silverstein; Jaclyn Bergstrom; Richele Bettencourt; Edward P. Weiss; Dennis T. Villareal and Wendy M. Kohrt

Disclosures

Clin Endocrinol. 2019;90(2):293-300. 

In This Article

Discussion

The analysis of pooled data from four similar RCTs provided evidence that DHEA therapy has sex-specific effects on BMD and body composition in older adults. One year of DHEA therapy increased BMD in women, but not men, and decreased FM in men, but not women.

Effects of DHEA on T, E2, SHBG and IGF-1

The sex-specific effects of DHEA on BMD and body composition in older adults may be explained by differences in the hormonal milieu at baseline, the magnitude of change in circulating sex hormones and the specific actions of sex hormones in target tissues. In older women, the loss of gonadal function at an earlier age than in men increases the reliance on prohormones, such as DHEA, for the synthesis of biologically active androgens and oestrogens.[6] DHEAS is the precursor for 100% of circulating androgens and oestrogens in postmenopausal women.[3] However, at the menopause transition, adrenal production of DHEAS is reduced by ~40% of young adult levels and is not sufficient to prevent bone loss or menopause-related changes in body composition in women.

Across the 4 RCTs, the same dose of DHEA resulted in similar absolute increases in DHEAS in women and men. The concomitant decrease in SHBG indicated an increase in the unbound fraction of sex steroids (ie, biologically active). Even when serum DHEAS was restored to youthful levels in women, E2 and T remained below premenopausal levels. The increase in E2in DHEA-treated women was about one-third that of women treated with conjugated equine oestrogens for 1 year in the Women's Health Initiative clinical trial.[12]

Decreased ovarian hormone production during menopause disrupts the remodelling of mature bone resulting in increased bone resorption relative to bone formation.[13] Changes in total hip BMD in older DHEA-treated adults were mediated by increased serum oestrogens, as opposed to T or DHEA therapy, per se.[14] The increases in DHEAS, E2 and T combined with higher bone turnover may explain the more consistent increases in BMD in older DHEA-treated women compared to men. DHEA therapy suppresses bone resorption,[9,14] which is elevated in women after menopause as a result of the decrease in E2, but remains relatively stable in middle-aged and older men.[15]

Effects of DHEA on BMD

The observed benefit of DHEA therapy on lumbar spine BMD in older women and men combined was driven by the beneficial effects in women (Figure 1). The 1.0% increase from baseline in lumbar spine BMD in women on DHEA was less than that found with alendronate (3%-5%; 5 or 10 μg/d),[16] teriparatide (6%-12%; 10–40 μg/d)[17,18] or abaloparatide (10%; 80 μg/d).[19] Unlike these pharmaceutical trials, the DHEA trials did not target women with osteoporosis, which may have contributed to the modest increases in BMD.

There is limited knowledge regarding the effects of longer duration DHEA therapy on BMD and body composition in older women. In one trial,[10] the 12-month RCT was followed by 12 months of open-label treatment. Women taking DHEA had an increase in lumbar spine BMD of 1.7% after 12 months and a further increase of 1.8% after 24 months.[10] Another 2-year intervention8 suggested more modest incremental responses to DHEA therapy in lumbar spine BMD of older women (0.6% in 1 year; 1% over 2 years). No study of DHEA therapy in older adults has exceeded 2 years.

Effects of DHEA on Body Composition

Sex-specific effects of DHEA therapy on body composition included a 0.5 kg increase in FFM in women and a −0.4 kg loss of FM in men. For comparison, postmenopausal women treated with combined oestrogen and testosterone therapy for 6 months[20] or 2 years[21] had increases in FFM of 0.6 and 3.1 kg, while FM decreased by −0.3 and −1.5 kg.

None of the four RCTs controlled for exercise behaviour that might have explained some of the increase in FFM in women taking DHEA. Combining DHEA therapy with resistance exercise that imparts mechanical strain to bone may promote greater increases in muscle mass and BMD than either intervention alone. Two studies of exercise interventions suggest an additional increase in muscle mass in older adults treated with DHEA,[22] but the combined effects of bone-loading exercise and DHEA on BMD are not known.[23]

Dehydroepiandrosterone-treated men lost FM (~0.4 kg) but had no increase in FFM. The mechanisms underlying DHEA actions in human adipose tissue are not clear. DHEAS can enter mature human adipocytes and be converted to DHEA and androstenediol[24] and, in preadipocytes, exposure to DHEA attenuated differentiation, proliferation and lipid accumulation.[24]

Limitations

Despite many similarities among the four RCTs, there were differences. In two studies,[7,10] calcium and vitamin D supplements were provided to all participants but these studies did not have consistently larger increases in BMD. Low serum DHEAS concentration was required for study entry in two studies.[7,8] Different DXA instruments were used across the studies. Different assay methods likely contributed to the variability in the changes in sex hormones, particularly the immunoassays for T in women and E2 in men (Table 3, Table S1). Because of these limitations, the statistical approach included adjustment for performance site.

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