Lack of effect of short-term DHEA supplementation on the perimenopausal ovary†

Abstract

Dehydroepiandrosterone (DHEA) hormonal supplementation can improve oocyte quality in women with diminished ovarian function. However, it is unclear whether DHEA supplementation can also enhance ovarian function during the perimenopause (i.e., when the number of follicles in the ovary has undergone a marked reduction). To address this question, we examined the impact of 2.5-months of daily 5-mg oral DHEA supplementation on the number of ovarian follicles and the concentration of anti-Müllerian hormone (AMH) in perimenopausal rhesus macaques. Like women, these long-lived nonhuman primates have ~ 28-day menstrual cycles and eventually undergo menopause. They also show similar age-related neuroendocrine changes, including a marked decrease in circulating concentrations of DHEA and DHEA sulfate (DHEAS). Our experimental design involved the following three groups of animals (N = 6 per group): Young adult (mean age = 11.6 years), Old control (mean age = 23.1 years), and Old DHEA-treated (mean age = 23.5 years). Histological examination of the ovaries revealed a significant age-related decrease in the mean number of primordial follicles despite DHEA supplementation. Moreover, AMH concentrations within the ovaries and circulation, assessed by Western analysis and ELISA, respectively, showed significant age-related decreases that were not attenuated by DHEA supplementation. Taken together, these results fail to show a clear effect of short-term physiological DHEA supplementation on the perimenopausal ovary. However, they do not exclude the possibility that alternative DHEA supplementation paradigms (e.g., involving an earlier start date, longer duration and using pharmacological doses) may extend reproductive potential during aging.

Keywords: AMH; DHEA supplementation; FSH; menopause.

Figure 1

Effect of age and DHEA supplementation on body weight and paired ovarian weight of female rhesus macaques. Bar graphs display means ± SEMs (^**P < 0.01, NS = nonsignificant, by Mann–Whitney U test relative to Old control group).

Figure 2

Representative images of ovarian sections from young (A), old (B), and old-DHEA-treated (C) rhesus macaques. Immunohistochemical staining of AMH is depicted in brown and histological staining of cells with Harris hematoxylin is depicted in blue. Arrowhead = primordial follicle; single arrow = primary follicle; double arrow = secondary follicle; triple arrow = tertiary antral follicle; asterisk = oocyte. Scale bar for all panels = 100 μm.

Figure 3

Effect of age and DHEA supplementation on the number of primordial (A) and preantral (B) follicles. Bar graphs display means ± SEMs (^**P < 0.01, NS = nonsignificant, by Mann–Whitney U test relative to Old control group).

Figure 4

Effect of age and DHEA supplementation on the concentration of hormones in female rhesus macaques. (A) Serum follicle-stimulating hormone (FSH); (B) serum anti-Müllerian hormone (AMH); and (D) ovarian AMH, determined by Western blot analysis. Bar graphs display means ± SEMs (^*P < 0.05, ^**P < 0.01, NS = nonsignificant, by Mann–Whitney U test relative to Old control group).

Figure 5

Representative immunoblots from young, old, and old-DHEA-treated rhesus macaques, depicting an age-associated decrease in ovarian AMH concentrations, relative to β-actin.

Figure 6

Effect of age and DHEA supplementation on the concentration of hormones in female rhesus macaques. (A) Serum dehydroepiandrosterone sulfate (DHEAS); (B) serum estradiol; (C) serum testosterone; (D) serum 5α-dihydrotestosterone (DHT). Bar graphs display means ± SEMs (^**P < 0.01, NS = nonsignificant, by Mann–Whitney U test relative to Old control group).