Insulin-Like Growth Factor I Regulates Gonadotropin Responsiveness in the Murine Ovary

Abstract

The present study shows that insulin-like growth factor I (IGF-I) and FSH receptor (FSHR) mRNAs are selectively coexpressed in a subset of healthy-appearing follicles in murine ovaries, irrespective of cycle stage. Aromatase gene expression, a prime marker for FSH effect, is found only in IGF-I/FSHR-positive follicles, showing that these are healthy, gonadotropin-responsive follicles. Given the striking coexpression of FSHR and IGF-I, we hypothesized that FSH was responsible for follicular IGF-I expression. We found, however, that granulosa cell IGF-I mRNA levels are not reduced in hypophysectomized (+/-PMSG) or FSH knockout mice, indicating that FSH does not have a major role in regulation of granulosa cell IGF-I gene expression. To test the alternative hypothesis that IGF-I regulates FSHR gene expression, we studied ovaries from IGF-I knockout mice. FSHR mRNA was significantly reduced in ovaries from homozygous IGF-I knockout compared with wild type mice and was restored to control values by exogenous IGF-I treatment. The functional significance of the reduced FSHR gene expression in IGF-I knockout ovaries is suggested by reduced aromatase expression and by the failure of their follicles to develop normally beyond the early antral stage. In fact, IGF-I knockout and FSH knockout ovaries appear very similar in terms of arrested follicular development. In summary, we have shown that IGF-I and FSHR are selectively coexpressed in healthy, growing murine follicles and that FSH does not affect IGF-I expression but that IGF-I augments granulosa cell FSHR expression. These data suggest that ovarian IGF-I expression serves to enhance granulosa cell FSH responsiveness by augmenting FSHR expression.

cAMP-dependent regulation of ovulatory response genes is amplified by IGF1 due to synergistic effects on Akt phosphorylation and NF-κB transcription factors

“…Studies in the mouse and rat showed that IGF1 increases the responsiveness of granulosa cells to FSH due to increased expression of the FSH receptor (Zhou et al 1997, Minegishi et al 2000. However, in our study, the cooperative increases in Areg, Ereg, Btc, and Il6 mRNAs by cAMP and IGF1 were rapid (i.e.…”

Life and death of female gametes during oogenesis and folliculogenesis

“…Indeed, knockout of IGF-I in mice results in arrested follicular development at the preantral and early antral stages, leading to ovulation failure [139,140]. In addition, IGF-I seems to play a crucial role in the responsiveness of the ovary to FSH action, because FSH receptor expression was severely reduced in preantral IGF-I null follicles, and restored to wild type levels after two weeks of exogenous IGF-I supplementation [140]. Treatment of the rat pre-ovulatory follicles with IGF-I prevents spontaneous onset of apoptosis [141].…”

FSHβ knockout mouse model: a decade ago and into the future

“…Many other collaborations turned out to be fruitful and provided interesting new results on FSH role in conjunction with activin signaling [28], in testicular Sertoli and germ cells [22, 29], anti-Mullerian hormone (AMH) secretion coupled to nonclassical FSH-R mediated signaling in Sertoli cells [30], spermatogonial differentiation [31], IGF-I, and AMH regulation of ovarian folliculogenesis [32, 33] and oocytesomatic cell communication [34]. Many of these studies have been discussed elsewhere [1–3].…”