The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women

Abstract

To discern the pharmacological effects of dehydroepiandrosterone (DHEA) in older women with low endogenous DHEA and DHEA sulfate (DS), 1600 mg/day (in four divided doses) were administered orally to six postmenopausal women for 28 days in a double blind placebo-controlled crossover study. Serum concentrations of androgens after the first 400-mgdose of DHEA increased rapidly and reached a maximum at 180–240 min, resulting in increases over baseline of 6-fold for DHEA (5.8 ± 2.1 to 28.8 ± 5.5 nmol/L), 12-fold for DS (3.0 ± 1.6 to 28.2 ± 4.6 μmol/L) and androstenedione (1.4 ± 0.3 to 19.5 ± 9.8 nmol/L), 2.5-fold for testosterone (0.7 ± 0.1 to 2.2 ± 0.6 nmol/L), and 15-fold for dihydrotestosterone (0.2 ± 0.06 to 2.73 ± 1.0 nmol/L), but estrone, estradiol, and sex hormone-binding globulin (SHBG) were unchanged. Assessment at weekly intervals revealed a further increase in all androgens which was maximal at 2 weeks and remained markedly elevated, although it declined somewhat by 4 weeks. The increments observed after 2 weeks of DHEA administration reached 15-fold for DHEA (71.9 ± 14.2 nmol/L), 9-fold for testosterone (6.5 ± 1.7 nmol/L), and 20-fold for DS (65.1 ± 14.9 nmol/L), androstenedione (30.5 ± 11.5 nmol/L), and dihyrotestosterone (3.8 ± 1.5 nmol/L). Both estrone and estradiol showed a progressive increase to 2-fold the basal value at 4 weeks. Integrated SHBG and thyroid binding globulin levels decreased (P < 0.05) during DHEA treatment. However, LH, FSH, body weight, and percent body fat, as measured by underwater weighing, were unaltered during the 4-week experiment. A marked decline of 11.3% (P < 0.05) in serum cholesterol and 20.0% (P < 0.05) in high density lipoprotein noted within the first week of DHEA administration persisted for the 28-day period and was accompanied by a nonsignificant downward trend in low density lipoprotein, very low density lipoprotein, and triglycerides. Peak insulin levels during the 3-h oral glucose tolerance test were significantly higher (P < 0.05) after the 28 days of DHEA (1126 ± 165 vs. 746 ± 165 pmol/L) and were accompanied by a 50% increase in the integrated insulin response (P < 0.01) without a significant change in fasting glucose insulin or glucose-6-phosphate dehydrogenase values. These data show that oral DHEA is rapidly absorbed, and a prompt conversion to DS as well as all potent androgens and estrogens occurs with a sustained effect for the 28-day duration of treatment. Thus, in postmenopausal women there appears to be abundant and effective enzymatic systems for the biotransformation of DHEA to C-19 and C-18 sex steroids. Further, pharmacologically imposed DHEA in postmenopausal women induced insulin resistance, altered cholesterol and the high to low density lipoprotein ratio, and decreased circulating SHBG and thyroid binding globulin concentrations. Our findings, which contrast sharply with those of a previous experiment in young men, appear to result from the induction of a highly androgenic state and its impact on several endocrine-metabolic parameters in older postmenopausal women.