Activation of the Baboon Fetal Pituitary-Adrenocortical Axis at Midgestation by Estrogen: Adrenal Δ⁵-3β-Hydroxysteroid Dehydrogenase and 17α-Hydroxylase-17,20-Lyase Activity*

We have recently demonstrated that treatment of pregnant baboons with androstenedione (Δ4 A) at midgestation to increase estrogen production induced a pattern of placental cortisol (F) metabolism which was similar to that at term and resulted in de novo F production by the fetus, presumably by activation of the fetal hypothalamic-pituitary-adrenocortical axis. The present study was designed to examine the subcellular events in the fetal adrenal that were apparently stimulated by estrogen-induced alterations in transplacental corticosteroid metabolism. Therefore, we determined the effects of estrogen treatment at midgestation and removal of estrogen action near term on the specific activity of the rate-limiting enzymes D5-3β- hydroxysteroid dehydrogenase (3βHSD) and 17-hydroxylase- 17,20-lyase (17α-0Hase). Fetal adrenals were obtained on day 100 (n = 11) or day 165 (n = 11) of gestation (term = day 184) from untreated animals, on day 100 from animals receiving Δ4A daily between days 70–100 (n = 9) to increase placental estrogen production, and on day 165 from baboons treated daily between days 130–164 with antiestrogen ethamoxytriphetol (MER-25; n = 7). The activity of 177alpha;-OHase was determined by incubating adrenal microsomes (105,000 × g) with [3H]progesterone, NAD+, and NADH in phosphate buffer. The radiolabeled products 17- hydroxyprogesterone, Δ4A, and testosterone were purified, and enzyme activity expressed as picograms of product per min/mg tissue. The activity of 3βHSD was determined by incubating adrenal microsomes with [3H]pregnenolone and NAD+ in phosphate buffer. The radiolabeled progesterone product was purified, and enzyme activity was expressed as nanograms per min/ mg tissue. Treatment with Δ4 A increased estrogen concentrations at midgestation 3-fold to levels comparable to those measured near term. Although fetal adrenal weight was greater at term than at midgestation (P < 0.05), weight was not increased by Δ4A treatment. The specific activity (mean ± SE) of fetal adrenal 17α-OHase at midgestation (181 ± 29) was increased (P < 0.05) 3-fold by treatment with Δ4A to levels (591 ± 105) comparable to those in adrenal microsomes prepared from untreated animals near term (816 ± 130). Enzyme activity in adrenals of MER-25- treated baboons was 40%, but not significantly lower than that in term controls. The specific activity of 3βHSD at term (41 ± 11) was 100-fold greater (P < 0.05) than that at midgestation and was reduced (P < 0.05) by more than 60% by treatment in vivo with MER-25. Enzyme activity at midgestation (0.4 ± 0.1) was increased 4-fold, but not significantly, by treatment with Δ4A. These findings indicate that the specific activities of 3βHSD and 17α-OHase in fetal adrenals were significantly increased with advancing gestation, enhanced prematurely at midgestation by treatment with Δ4A, and reduced at term after treatment with MER-25. We propose that the ontogenesis of de novo F synthesis at term and in Δ4A-treated animals at midgestation is the result of an increase in specific activities of adrenal 3βHSD and 17α-0Hase. (Endocrinology128: 2395–2401, 1991)