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Dimeric Inhibin A and B Production Are Differentially Regulated by Hormones and Local Factors in Rat Granulosa Cells¹

Instituto de Biología Experimental (G.M.L., J.L.B.), CONICET and Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Argentina; School of Biological and Molecular Sciences (N.P.G.), Oxford Brookes University, Oxford OX3 OBP, United Kingdom; and Centro de Investigaciones Endocrinológicas (S.C.), Hospital de Niños "Ricardo Gutierrez", Buenos Aires, 1425 Argentina

Address all correspondence and requests for reprints to: J. Lino Barañao, Ph.D., Vuelta de Obligado 2490, 1428 Buenos Aires, Argentina. E-mail: lbaranao{at}dna.uba.ar

In the present study, we have examined the role of hormones and growth factors in regulating dimeric inhibin production in immature rat granulosa cells. Purified granulosa cells from estrogen-primed immature rats were cultured under defined conditions. Inhibins A and B in the culture media were measured using a two-site enzyme-linked immunosorbent assay specific for each dimer. Under basal conditions, granulosa cells produced 14-fold more inhibin A than inhibin B (inhibin A, 2.0; inhibin B, 0.14 ng/ml, measured against human standards; average A/B apparent ratio, 14). Addition of increasing doses of FSH elicited dose-dependent increases in both inhibins, the effects being more pronounced on inhibin A than on inhibin B (9.4- and 4.1-fold increases, respectively; average A/B ratio, 34). Estradiol, when added alone, stimulated inhibin A production 3- to 6-fold, whereas minor changes were observed in inhibin B production. Insulin-like growth factor-I produced a similar stimulation of both inhibins (3-fold stimulation over control). This growth factor, however, induced a marked dissociation in the sensitivity of inhibins A and B to FSH stimulation, with maximal stimulation of inhibin B observed at comparatively lower concentrations of the gonadotropin. Transforming growth factor-ß (TGF-ß, 5 ng/ml) had a more marked stimulatory effect on inhibin B than on inhibin A production (7- to 14-fold vs. 2- to 5-fold for inhibin B and A, respectively). A more pronounced differential stimulation of inhibin B was also exerted by another member of the TGF-ß superfamily, activin A (A/B ratio, 0.66). This preferential stimulation of inhibin B by TGF-ß and activin A was amplified in the presence of FSH. Coculture of rat granulosa cells with freshly isolated bovine oocytes was also associated with a marked stimulation of inhibin B production (100-fold increase) and a comparatively lower stimulation of inhibin A (10-fold increase; A/B ratio, 1). The discrepancy between the proportion of inhibin dimers in serum (A/B ratio, 0.13) and those produced by untreated granulosa cells may suggest that intraovarian factors, such as TGF-ß, activin A, or oocyte-derived factor(s), are responsible for the shift of the ratio toward the predominance of inhibin B.

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