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Transforming Growth Factor-β 1 Inhibits Ovarian Androgen Production: Gene Expression, Cellular Localization, Mechanisms(s), and Site(s) of Action^*

Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Maryland School of Medicine (E.R.H., A.H., D. W.P., E. Y.A.) Baltimore, Maryland 21201
The Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine (A.M.D.), Baltimore, Maryland 21205; and Oncogen (A.F.P.) Seattle, Washington 9812

Address all correspondence and requests for reprints to: Dr. Eleuterio R. Hernandez, Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Maryland School of Medicine, Room 11-007, Bressler Building, 655 West Baltimore Street, Baltimore, Maryland 21201.

Abstract

It is the aim of this study to establish ovarian transforming growth factor-βl (TGFβ1) gene expression, to reevaluate its cellular localization, and to explore potential interactions of this regulatory peptide on ovarian androgen biosynthesis. Northern analysis of whole ovarian polyadenylated RNA revealed a single 2.5-kilobase transcript corresponding to the TGFβ1 precursor. Immunohistochemical staining localized the protein to the thecal-interstitial (interfollicular) compartment. To explore potential autocrine effects of TGFβ1, use was made of whole ovarian dispersates from immature rats the differentiation of which was monitored by the acquisition of androgen biosynthetic capacity. The accumulation of androsterone, the major androgenic steroid detectable in this culture system, increased 5.4-fold over baseline in response to treatment with hCG (1 ng/ml). This effect was further optimized (2- to 4- fold) by supplementation with insulin (1 µg/ml) and insulin-like growth factor-I (50 ng/ml). In the absence of these optimizing supplements, TGFβ1 (10 ng/ml) was without effect on basal androsterone accumulation, producing distinct, albeit relatively limited (25%), inhibition of hCG hormonal action. In contrast, supplement-mediated optimization of ovarian androgen biosynthesis revealed TGFβ1 to be a highly potent inhibitor (>80%) of hCG hormonal action. This reversible TGFβ1 action proved time and dose dependent, with a minimal time requirement of 72 h and a median inhibitory dose of 2.6 ng/ml. TGFβ1 action was not due to diminution in the viable cell mass or altered cAMP generation and, therefore, most likely involved a site(s) of action distal to or independent of cAMP generation. Cellular radiolabeling studies of TGFβ1 -treated ovarian cells disclosed the accumulation of steroid intermediates proximal to the 17ahydroxylation step, suggesting TGFβ1-mediated blockade at the level of the steroidogenic enzyme 17a-hydroxylase/17-20-lyase. Taken together, these observations are in keeping with the view that TGFβ1, possibly of thecal-interstitial origin, may not only play a positive paracrine role at the level of the adjacent granulosa cell (as previously reported), but may also constitute one of several autocrine signals concerned with the regulation of ovarian androgen economy. As such, these findings reaffirm the polyfunctional nature of TGFβ1 action, as manifested by its diametrically opposed effects in different ovarian compartments. (Endocrinology 127: 2804–2811,1990)

Footnotes

^* This work was supported in part by a grant from the Frank C. Bressler Research Fund (to E.R.H.), the Lalor Foundation and the Rockefeller Foundation (to A.M.D.), NIH Research Grant HD-19998, and USPHS Research Career Development Award HD-00697 (to E.Y.A.).

Received September 24, 1990.

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