Direct intraovarian effects of leptin: impairment of the synergistic action of insulin-like growth factor-I on follicle-stimulating hormone-dependent estradiol-17 beta production by rat ovarian granulosa cells

Endocrinology. 1997 Feb;138(2):847-50. doi: 10.1210/endo.138.2.5035.


The Ob gene product, leptin, is secreted by adipocytes and is required for fertility in the mouse. Leptin-deficient mice are obese and infertile, symptoms reminiscent of polycystic ovary syndrome (PCOS). Prior studies have shown that serum leptin levels are elevated in a significant sub-population of anovulatory women with PCOS, suggesting that elevated leptin levels may adversely affect ovarian function. Since leptin receptor mRNA has been detected in the ovary, this study was designed to test the hypothesis that leptin may impair granulosa cell (GC) estradiol-17 beta (E2) production by a direct mechanism. GC were isolated from the ovaries of 26-day-old Sprague-Dawley rats, and were cultured (60,000 GC/well) in 96-well plates in the presence and absence of ovine FSH (0.001-100 ng/ml) and androstenedione (0.1 microM), with and without recombinant murine leptin (0.1-100 ng/ml) for 48 h. Leptin alone had no effect on E2 production. FSH caused a dose-related increase in E2 production by GC (ED50 = 1.9 +/- 0.4 ng/ml). Addition of leptin did not alter FSH-stimulated B2 levels. Concomitant treatment with FSH and IGF-I (30 ng/ml) augmented maximal FSH-dependent E2 production five-fold. Leptin caused a dose-dependent (IC50 = 2.7 +/- 0.6 ng/ml) inhibition (30-50%) of the IGF-I increase in FSH-stimulated E2 production. The inhibitory effect of leptin was specific for E2 production since there was no effect on basal, FSH-, or FSH+ IGF-I-dependent progesterone levels. The results of this study demonstrate that leptin can directly impair the IGF-I-mediated augmentation of FSH-stimulated E2 synthesis by GC. These data raise the possibility that high leptin levels may contribute to infertility in some women with PCOS by counteracting the sensitizing effects of IGF-I in dominant follicles.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Drug Synergism
  • Estradiol / biosynthesis*
  • Female
  • Follicle Stimulating Hormone / pharmacology*
  • Granulosa Cells / drug effects
  • Granulosa Cells / metabolism*
  • Humans
  • Insulin-Like Growth Factor I / pharmacology*
  • Leptin
  • Mice
  • Ovary / drug effects*
  • Progesterone / biosynthesis
  • Proteins / pharmacology*
  • Rats
  • Rats, Sprague-Dawley


  • Leptin
  • Proteins
  • Progesterone
  • Estradiol
  • Insulin-Like Growth Factor I
  • Follicle Stimulating Hormone