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In Vivo Comparison of the Follicle-Stimulating Hormone-Suppressing Activity of Follistatin and Inhibin in Ovariectomized Rats^*

Department of Molecular Endocrinology (L.V.D., M.S., N.L.), The Whittier Institute for Diabetes and Endocrinology La Jolla, California 92037
Department of Developmental Biology (R.H.S.), Genentech, Inc. South San Francisco, California 9408

Abstract

The present study was performed to compare and contrast the effects of two gonadal polypeptides, inhibin and follistatin, on ovariectomy-induced hypersecretion of FSH and LH. Ovariectomies were performed 1 week before study. Follistatin was purified from porcine follicular fluid, and human inhibin A was produced by recombinant DNA technology. On the day of study, a blood sample was taken from intraatrial cannulae inserted on the previous day, the materials were injected, and additional blood samples were taken at various times thereafter. Serum FSH and LH levels were determined by RIA. Both follistatin and inhibin exhibited dose-dependent suppression of circulating FSH but not LH levels, with initial decreases in FSH levels by both materials observed between 2–4 h post injection. Maximal suppression of FSH by each polypeptide occurred between 4–6 h depending on dose. Based on the doseresponse relationships, it was determined that inhibin was approximately five times as potent as follistatin in suppressing FSH release. However, despite the greater biopotency of inhibin than follistatin, the duration of action of even the highest dose of inhibin (50 µg) was between 4–9 h, whereas the duration of FSH-suppressing activity by the two highest doses of follistatin (40 and 80 µg) was between 10–21 h. Data obtained from a second experiment conducted to examine the effects of inhibin and follistatin on anterior pituitary gonadotropin responses to LHRH were consistent with in vitro data showing direct pituitary effects of the gonadal polypeptides. Collectively, these results demonstrate that both purified porcine follistatin and recombinant human inhibin A profoundly suppress serum FSH levels in a dose- and time-dependent manner, with inhibin being more potent in this regard. Whereas the onset of action is similar for the two polypeptides, the duration of action of follistatin is longer than that for inhibin, suggesting, among other factors, different metabolic clearance rates or different pretranscriptional mechanisms of action of follistatin and inhibin. (Endocrinology 128: 668–674, 1991)

Footnotes

^* This work was supported by PHS Grants P01-HD-09690 and K04-AG00309 (to L.V.D.) and NICHD Contract N01-HD-0-2902 (to N.L.). Portions of this work were presented at the 23rd Annual Meeting of the Society for the Study of Reproduction, Knoxville, TN, 1990.

Received August 13, 1990.

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