Modulation of Adrenocorticotropin-Stimulated Baboon Fetal Adrenal Dehydroepiandrosterone Formationin Vitroby Estrogen at Mid- and Late Gestation*

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Abstract
We have reported that ACTH stimulation of dehydroepiandrosterone (DHA) formation by the baboon fetal adrenal at midgestation was suppressed by estrogen. Because fetal adrenal regulation changes with advancing gestation, the action of estrogen on fetal adrenal steroidogenesis may also be dependent on the degree of fetal adrenal maturation. We examined this possiblity in the present study by determining the effects of ACTH and estrogen on DHA formation by adrenal cells of fetuses obtained from baboons at mid- and late gestation and from animals administered the andiestrogen MER-25 throughout late gestation. Because low density lipoprotein (LDL) provides substrate for the fetal adrenal, we also determined whether the effect of estrogen was mediated by LDL uptake. Adrenals were removed from baboon fetuses on day 100 (midgestation; n = 7) and day 170 (late gestation; n = 6; term day 184) of gestation from untreated animals and on day 170 from fetuses whose mothers were treated with MER-25 on days 140-170 (25 mg/kg BW .cntdot. day; n = 7). Cells were dispersed with 0.2% collagenase and incubated at 37 C for 3 h in 4 ml medium 199 with 10 nM ACTH, 10-6 M estradiol and/or 500 .mu.g LDL. The secretion of DHA into medium was determined by RIA. At midgestation, mean (.+-.SE) basal DHA formation (nanograms per 105 cells/3 h) was 5.8 .+-. 2.1, and DHA was increased (P < 0.01) by ACTH to 20.0 .+-. 5.9. Although estradiol alone had no effect, estradiol prevented the increase in DHA obtained with ACTH. Basal DHA production by adrenals of late gestation (0.7 .+-. 0.3 ng/105 cells) was lower (P < 0.01) than at midgestation. ACTH increased (P < 0.01). DHA in a comparable manner near term in the presence (2.0 .+-. 0.4) or absence (1.7 .+-. 0.4) of estradiol. Thus, in contrast to day 100, estrogen did not attenuate the action of ACTH on adrenal cells on day 170. In fetal adrenal cells obtained on day 170 from MER-25-treated baboons, DHA formation (1.4 .+-. 0.6 ng/105 cells) was comparably increased (P < 0.05) to 2.4 .+-. 0.2 and 3.0 .+-. 0.5 ng/105 cells by ACTH in the absence or presence of estradiol. Thus, ACTH remained effective in enhancing DHA by adrenal cells of fetuses exposed in utero to antiestrogen. DHA formation by adrenals of midgestation was increased (P < 0.05) to 15.4 .+-. 4.8 and 27.4 .+-. 7.5 ng/105 cells, respectively, by LDL and ACTH plus LDL. The increase in DHA elicited by LDL was not altered estradiol, suggesting that estrogen does not modify adrenal uptake and utilization of LDL for DHA formation. Thus, our study shows that estrogen modulated fetal adrenal DHA production at midgestation, and this effect was lost with advancing gestation. We propose that a negative feedback system for the regulation of fetoplacental steroidogenesis exists during early to mid primate pregnancy, which is modified during development, presumably as a result of adrenal differentiation.