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a Department of Obstetrics and Gynecology, CSMC Burns and Allen Research Institute, UCLA School of Medicine,Los Angeles, California 90048-0750
Leptin blocks the insulin-like growth factor-I-induced increase in FSH-dependent estradiol-17ß (E2) production by rat ovarian granulosa cells (GC) in vitro. To determine whether the leptin effect extended to another positive modulator of FSH-dependent E2 production, the direct ovarian effects of leptin on transforming growth factor ß (TGF-ß) were investigated. Reverse transcription-polymerase chain reaction demonstrated that theca-interstitial cells (TIC) from hypophysectomized rats expressed only a nonsignal-transducing isoform (OB-Ra) of leptin receptor mRNA. Leptin had no effect on TIC androgen production. In contrast, mRNAs for OB-Ra and the signal-transducing (OB-Rb) leptin receptor isoforms were expressed in GC. When GC obtained from 26-day-old rats were cultured (48 h) with FSH and androstenedione, both estrone (E1) and E2 levels increased over those in untreated controls. In the presence of FSH (0.1 IU/ml), TGF-ß (10 ng/ml) potentiated E2 and E1 accumulation by 2.7- and 1.45-fold, respectively. Leptin did not alter basal or FSH-stimulated E2 and E1 levels. However, leptin suppressed the effect of TGF-ß on FSH-dependent E2 and E1 production by 39% and 29%, respectively. Aromatase cytochrome P450 (P450arom) mRNA expression and P450arom activity were increased by FSH and further augmented by the addition of TGF-ß. Leptin abolished the TGF-ß effect on P450arom mRNA expression, and it decreased P450arom activity by approximately 27%. These data support the hypothesis that leptin antagonizes the stimulatory effects of TGF-ß on FSH-dependent estrogen production by a mechanism involving the leptin-induced attenuation of P450arom activity and mRNA expression in GC.
2 Correspondence: Denis Magoffin, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Davis 2066, Los Angeles, CA 90048-0750. FAX: 310 652 8010; magoffin{at}cshs.org
3 Current address: Southern Illinois University, School of Dental Medicine, Department of Applied Dental Medicine, 2800 College Ave., Alton, IL 62002-4700.
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