Maintenance of Cell Proliferation and Steroidogenesis in Cultured Human Fetal Adrenal Cells Chronically Exposed to Adrenocorticotropic Hormone: Rationalization of in Vitro and in Vivo Findings1

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Abstract
Previous studies indicated that acute exposure of adrenal cells to adrenocorticotropic hormone (ACTH) markedly stimulates steroidogenic capacity in vitro but also inhibits cell proliferation. However, in vivo, ACTH is known to stimulate adrenal cell growth. To address this discrepancy, we determined the effect of long-term (9 – 11 days) continuous or intermittent exposure to ACTH on human fetal adrenal cell proliferation and steroidogenesis. Adrenal glands from fetuses 18 – 22 wk gestation were studied. Fetal zone cells were plated either on plastic or on an extracellular matrix (ECM) in the presence and absence of basic fibroblast growth factor (bFGF) (0.5 ng/ml) and 1 or 10 nM ACTH. As determined by cell counting, bFGF stimulated cell proliferation during 9 days in culture. In the presence of bFGF, the average doubling time decreased from 44 to 30 h on plastic and from 37 to 26 h on ECM. Under these conditions, ACTH did not inhibit cell proliferation. Proliferation of fetal adrenal corticosteroid-producing cells in the ACTH-treated cultures also was assessed by histochemical staining for 3β-hydroxysteroid dehydrogenase (3β HSD). The number of positive cells increased more than 4-fold between Days 5 and 9 in culture. Continuous treatment with 1 nM ACTH increased dehydroepiandrosterone sulfate (DHAS) production 5- to 10-fold during the first 5 days in culture. Thereafter, the stimulated hormone production decreased over time, although there was still a difference of almost 100-fold between the control and ACTH-treated cultures at the end of 9 days. Fetal adrenal cells also responded to intermittent exposure to 1 nM ACTH; however, DHAS concentrations were not as high as those achieved with continuous exposure. Interestingly, basal steroidogenic activity was enhanced over control levels in the 24-h period when ACTH was not present in the culture medium. These results demonstrate that under appropriate in vitro conditions hwnan fetal adrenal cells can proliferate even in the continuous presence of ACTH. They also indicate that adrenal cells can maintain differentiated function while proliferating.

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