ACTIVATION OF THE BABOON FETAL PITUITARY-ADRENOCORTICAL AXIS AT MIDGESTATION BY ESTROGEN - RESPONSIVITY OF THE FETAL ADRENAL-GLAND TO ADRENOCORTICOTROPIC HORMONE IN-VITRO

We have previously demonstrated that increased expression of fetal pituitary proopiomelanocortin mRNA and the induction of enzymes catalyzing fetal adrenal cortisol formation at term are regulated by estrogen-induced changes in placental oxidation of maternal cortisol to cortisone. To test the hypothesis that induction of fetal pituitary adrenocorticotropic hormone (ACTH) production by estrogen-induced changes in placental cortisol oxidation results in increased responsivity of the fetal adrenal gland to ACTH, in the present study we compared fetal adrenal sensitivity to ACTH in vitro at midgestation in untreated controls and in animals treated at this time in gestation with estrogen, Fetal adrenals were obtained on Day 100 (n = 7) and Day 165 (n = 5; term = Day 184) from untreated baboons and on Day 100 following maternal treatment with estradiol (s.c.; Days 70-100; n = 10) or androgen precursor(n = 3). Adrenal slices (15-25 mg) were perifused (100 mu l/min; 37 degrees C) with Medium 199 (no phenol red); media were collected at 10-min intervals and assayed for cortisol and dehydroepiandrosterone. Secretion of cortisol and dehydroepiandrosterone reached equilibrium after 140 min of perifusion; therefore, basal release was calculated as the mean steroid concentrations during 190-240 min. Adrenal slices were then perifused for 20 min with saline or ACTH at 240 (0.001 nmol), 370 (0.01 nmol), and 490 (0.1 nmol) min, and an overall average cortisol/dehydroepiandrosterone secretion rate (pg/min/mg) between 240-600 min was calculated. Basal cortisol production at Day 165 (85 +/- 11) exceeded (p < 0.05) that at Day 100 in adrenals of control (9 +/- 3) and estrogen-treated (13 +/- 3) animals. In contrast, dehydroepiandrosterone production by control adrenals of Day 165 (13 +/- 4) was lower than that at Day 100 in control (30 +/- 6) and estrogen-treated (20 +/- 3) animals, Thus, the ratio of dehydroepiandrosterone:cortisol secretion was significantly (p < 0.05) higher at midgestation (4.93 +/- 2.15) than at term (0.16 +/- 0.05) and was reduced (p < 0.05) in adrenals of estrogen-treated baboons (1.87 +/- 0.38). In all groups, basal secretion of cortisol and dehydroepiandrosterone was not altered after infusion of saline, In contrast, ACTH increased (p < 0.05) cortisol secretion by greater than or equal to 50% in adrenals of Day 165 (116 +/- 20) and in those of estrogen-treated (18 +/- 3) but not untreated (10 +/- 4) baboons of Day 100. ACTH increased (p < 0.05) androgen production by estrogen-treated adrenals of Day 100 to a greater (p < 0.05) extent (515% +/- 161%) than that of controls at Day 100 (154% +/- 81%). These data indicate that estrogen treatment in vivo at midgestation induced a ratio of dehydroepiandrosterone:cortisol secretion in vitro in fetal adrenals that mimicked the ratio near term and was associated with increased steroid hormone production in response to ACTH. Therefore, we suggest that activation of the fetal hypothalamic-pituitary-adrenal axis at term and at midgestation following maternal estrogen administration is associated with increased responsivity of the fetal adrenal to ACTH.