Fetal programming of adrenal androgen excess: lessons from a nonhuman primate model of polycystic ovary syndrome

Abstract

Adrenal androgen excess is found in adult female rhesus monkeys previously exposed to androgen treatment during early gestation. In adulthood, such prenatally androgenized female monkeys exhibit elevated basal circulating levels of dehydroepiandrosterone sulfate (DHEAS), typical of polycystic ovary syndrome (PCOS) women with adrenal androgen excess. Further androgen and glucocorticoid abnormalities in PA female monkeys are revealed by acute ACTH stimulation: DHEA, androstenedione and corticosterone responses are all elevated compared to responses in controls. Pioglitazone treatment, however, diminishes circulating DHEAS responses to ACTH in both prenatally androgenized and control female monkeys, while increasing the 17-hydroxyprogesterone response and reducing the DHEA to 17-hydroxyprogesterone ratio. Since 60-min post-ACTH serum values for 17-hydroxyprogesterone correlate negatively with basal serum insulin levels (all female monkeys on pioglitazone and placebo treatment combined), while similar DHEAS values correlate positively with basal serum insulin levels, circulating insulin levels may preferentially support adrenal androgen biosynthesis in both prenatally androgenized and control female rhesus monkeys. Overall, our findings suggest that differentiation of the monkey adrenal cortex in a hyperandrogenic fetal environment may permanently upregulate adult adrenal androgen biosynthesis through specific elevation of 17,20-lyase activity in the zona fasciculata-reticularis. As adult prenatally androgenized female rhesus monkeys closely emulate PCOS-like symptoms, excess fetal androgen programming may contribute to adult adrenal androgen excess in women with PCOS.

Figure 1

Steroid biosynthesis in the mid- to inner adrenal cortical zones, zona fasciculata and zona reticularis, of Old World primates and humans. Steroids in bold represent the predominant pathway for androgen biosynthesis, steroids within boxes represent the predominant pathway for cortisol biosynthesis, and underlined steroids represent the predominant pathway for corticosterone biosynthesis. The larger arrows reflect the proposed enhanced 3β-HSD II and 17,20 lyase enzymatic function in PA female monkeys, while the lighter arrows reflect relative low enzymatic activity in both control and PA females. Double underlining reflects the extent of zona fasciculata enzymatic activity, while triple underlining reflects the extent of zona reticularis enzymatic activity. 17OHP5: 17α-hydroxypregnenelone; 17OHP4: 17α-hydroxyprogesterone; CYP11A: P450scc, CYP 17: P450c17, ST: SULT2A1 sulfotransferase; 3β-HSD II: 3β-hydroxysteroid dehydrogenase II, CYP21: P450c21, CY11B1: P450c11. Modified from (31).

Figure 2

The differential in circulating adrenal steroid values between 0 and 60 min following an intravenous injection of 50μg ACTH in adult control (open bars) and prenatally androgenized (hatched bars) female rhesus monkeys for adrenal androgen-related steroids (a) DHEA, (b) androstenedione, and (c) DHEAS, as well as adrenal glucocortoicoid-related steroids (d) 17-hydroxyprogesterone, (e) cortisol, and (f) corticosterone. Modified from (31).

Figure 3

Associations between serum values of (a) 17-hydroxyprogesterone at 60 minutes following an intravenous injection of 50μg ACTH and basal insulin, (b) DHEAS at 60 minutes following an intravenous injection of 50μg ACTH and basal insulin, and (c) DHEAS and 17-hydroxyprogesterone at 0 minutes following an intravenous injection of 50μg ACTH in control (open triangle: receiving placebo treatment (27), solid triangle: receiving pioglitazone treatment; 27) and PA (open square: placebo, solid square: pioglitazone) female monkeys. Data are expressed as log₁₀ transformed serum values only in (a) and (c). Units used: (a) 17-hydroxyprogesterone, log₁₀ ng/ml; insulin, log₁₀ μU/ml; (b) DHEAS, μg/dl; insulin, μU/ml; and (c) DHEAS, log₁₀ μg/dl; 17-hydroxyprogesterone, log₁₀ ng/ml.