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


Clin Endocrinol. 2019;90(2):293-300. 

In This Article

Abstract and Introduction


Objective: Studies of dehydroepiandrosterone (DHEA) therapy in older adults suggest sex-specific effects on bone mineral density (BMD) and body composition, but the ability of a single study to reach this conclusion was limited. We evaluated the effects of DHEA on sex hormones, BMD, fat mass and fat-free mass in older women and men enrolled in four similar clinical trials.

Design: Pooled analyses of data from four double-blinded, randomized controlled trials.

Participants: Women (n = 295) and men (n = 290) aged 55 years or older who took DHEA or placebo tablet daily for 12 months.

Measurements: Twelve-month changes in BMD, fat mass, fat-free mass and serum DHEA sulphate (DHEAS), (17)estradiol, testosterone and insulin-like growth factor-1 (IGF-1).

Results: Women on DHEA had increases (mean ± SD; all P < 0.001 vs placebo) in DHEAS (231 ± 164 μg/dL), testosterone (18.6 ± 20.9 μg/dL), (17)estradiol (8.7 ± 11.0 pg/mL) and IGF-1 (25.1 ± 52.3 ng/mL), and men had increases in DHEAS (269.0 ± 177 μg/dL; P < 0.01), (17)estradiol (4.8 ± 12.2 pg/m; P < 0.01) and IGF-1 (6.3 ± 41.4 ng/mL; P < 0.05). Women on DHEA had increases in lumbar spine (1.0% ± 3.4%) and trochanter (0.5% ± 3.8%) BMD and maintained total hip BMD (0.0% ± 2.8%); men had no BMD benefit and a decrease in fat mass (−0.4 ± 2.6 kg; all P < 0.01 vs placebo).

Conclusions: Dehydroepiandrosterone therapy may be an effective approach for preserving bone and muscle mass in women. Key questions are (a) the extent to which longer duration DHEA can attenuate the loss of bone and muscle in women, and (b) whether DHEA has a more favourable benefit-to-risk profile for women than oestrogen therapy.


The adrenal steroid dehydroepiandrosterone (DHEA) is a prohormone for the synthesis of biologically active androgens and oestrogens.[1] Between the ages of 20 and 60 years, serum DHEA sulphate (DHEAS) levels decline approximately 70%,[2] reflecting the overall decrease in adrenal production of DHEA. The synthesis of androgens and oestrogens from DHEAS becomes increasingly important as gonadal sex hormone production declines with ageing. It has been estimated that DHEAS is the precursor for all oestrogens and androgens in postmenopausal women and 40% in older men.[3] Because age-related decreases in androgens and oestrogens contribute to the loss of bone mineral density (BMD) and muscle mass in older adults, maintaining youthful levels of DHEA may be an effective strategy for attenuating the rates of loss.[4,5] It has been postulated that DHEA therapy is safer than oestrogen or testosterone (T) therapy. The rationale for this is that DHEAS circulates as an inactive prohormone that is converted to biologically active sex steroids in a tissue-specific,[6] and presumably tissue-appropriate, manner.

Four single-site, double-blinded, randomized controlled trials (RCTs) sponsored by the National Institute on Aging determined the effects of DHEA therapy on BMD[7–10] and body composition[7–9] in older adults. Despite methodological consistencies across these studies (eg, age group, 12-month intervention), different conclusions regarding the effects of DHEA on changes in BMD, fat mass (FM) and fat-free mass (FFM; surrogate measure of muscle mass) were reached. Individually, the four RCTs suggested sex-specific effects of DHEA on BMD and body composition, but the ability of a single study to reach this conclusion was limited. Therefore, the data from these four RCTs were pooled to determine whether there are sex differences in the benefits of DHEA therapy on hip and lumbar spine BMD, FM and FFM and the associated changes in steroid hormones.