Leptin inhibits steroid biosynthesis by human granulosa-lutein cells

Absence of leptin secretion compromises reproductive function and fertility in the ob/ob mouse which, when given leptin, shows a rise in serum LH leve ls and becomes fertile. Recently, the long and active isoform of the leptin receptor was detected in the ovary. indicating that leptin may also show d irect gonad-related activity. To examine this, we studied the effect of gra ded doses of human leptin on estradiol (E-2) and progesterone (P-4) concent rations in the culture media of human granulosa-lutein cells obtained from follicular fluid of women undergoing in vitro fertilization. We also evalua ted the mRNA expression of steroidogenic acute regulatory protein (StAR), a romatase, and cytochrome P450 17 alpha (CYP17) in these cells at baseline a nd after exposure to leptin, Estradiol levels were significantly decreased in the media 24 hours after incubation of the cells with increasing hLeptin concentrations (10(-11) -10(-7) mol/l). The maximal 30 % decrease in E-2 p roduction was caused by the 10(-9) mol/l hLeptin concentration; however, P- 4 levels in the media were not influenced by leptin, Exposure of granulosa- lutein cells to 10-9 mol/l hLeptin did not produce any measurable changes o n StAR, aromatase, or CYP17 mRNA expression, When hLeptin (10(-9) mol/l) wa s co-incubated with increasing concentrations of hCC (1.25-10 mIU/ml), IGF- II (15-50 ng/ml) or 1-6 desaminated ICF-II (desIGF-II; 15-60 ng/ml), it did not modify the elevation of E, concentrations caused by each of the differ ent stimuli, We conclude that leptin suppresses E-2 secretion by human gran ulosa-lutein cells but does not impair the stimulatory effects of hCG and I GFs on these cells. Leptin may play a minor, but direct regulatory role on unstimulated human ovarian steroidogenesis by interfering with either the t ranslational or post-translational steps of the baseline C/P17 and/or aroma tase synthesis and/or the activation of the enzymes.