Insulin and Insulin-Like Growth Factor-I Stimulate the 3α-Hydroxysteroid Dehydrogenase Activity of Human Placental Cytotrophoblasts*

Abstract

The placenta is the primary source of progesterone during pregnancy. Because pregnant diabetic women are reported to have higher serum progesterone levels than nondiabetic pregnant women, we studied the roles of insulin and insulin-like growth factor-I (IGF-I) in the regulation of human cytotrophoblastic 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activity. Incubation of cytotrophoblasts with insulin or IGF-I for 24 h significantly increased the ability of these cells to convert pregnenolone to progesterone by 75.8 +/- 16.5% (+/- SE) and 65.4 +/- 12.7%, respectively. Treatment with either insulin or IGF-I did not alter cytotrophoblastic production of 20 alpha-hydroxypregn-4-en-3-one (the primary metabolite of progesterone), thus demonstrating that these peptides increased progesterone synthesis (i.e. 3 beta HSD activity) rather than decreased progesterone catabolism. Insulin and IGF-I stimulated 3 beta HSD activity at concentrations as low as 50 and 10 ng/ml, respectively. Insulin- and IGF-I-stimulated 3 beta HSD activities were completely inhibited by concurrent treatment with either actinomycin-D or cycloheximide, suggesting that new mRNA and protein synthesis are required for these peptides to exert their effects. Blockade of the IGF-I receptor of cytotrophoblasts with alpha IR-3, a monoclonal anti-IGF-I receptor antibody, prevented the stimulation of 3 beta HSD activity by IGF-I, but did not alter insulin's stimulatory effect. Thus, the two hormones can each stimulate 3 beta HSD activity via activation of their respective receptors. These studies indicate that insulin and IGF-I can regulate human cytotrophoblastic 3 beta HSD activity in vitro. Since pregnant diabetic women manifest peripheral hyperinsulinemia, and IGF-I levels in fetal cord sera from diabetic pregnancies may be elevated, these observations may help explain the elevated serum progesterone levels associated with pregnancy in the diabetic patient.