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Differential Regulation of Inhibin B and Inhibin A by Follicle-Stimulating Hormone and Local Growth Factors in Human Granulosa Cells from Small Antral Follicles¹

Reproductive Endocrine Unit, Reproductive Endocrine Sciences Center and the National Center for Infertility Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Dr. C. K. Welt, Reproductive Endocrine Unit, Reproductive Endocrine Sciences Center and the National Center for Infertility Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: cwelt{at}partners.org

Serum inhibin B rises across the luteal-follicular transition, whereas inhibin A does not increase until the late follicular phase of the menstrual cycle. To test the hypothesis that inhibin B is secreted from preantral and small antral follicles and that FSH and local growth factors differentially regulate inhibin B and inhibin A from these developing follicles, human ovaries were obtained after oophorectomy. Basal secretion of inhibin B and inhibin A was examined in intact preantral follicles in culture (n = 6). Basal secretion and regulation of inhibin B and inhibin A secretion by gonadotropins, androstenedione, activin A, insulin, and IGF-I were examined in cultured granulosa cells from small antral follicles (n = 21). Inhibin B secretion from preantral follicle cultures was detectable at baseline (range, 17–96 pg/mL), whereas inhibin A was not detectable. In contrast, both inhibin B and inhibin A were detectable in granulosa cell cultures from small antral follicles. In granulosa cells from small antral follicles, FSH (30 ng/mL) stimulated inhibin A 3-fold (10.5 ± 2.2 to 32.5 ± 8.3 IU/mL; P < 0.001), but not inhibin B secretion (1730 ± 354 to 2314 ± 532 pg/mL; P = NS). Likewise, cAMP (1 mmol/L) stimulated inhibin A 4-fold (16.6 ± 4.3 to 62.5 ± 21.9 IU/mL; P < 0.002), but not inhibin B secretion (2327 ± 546 to 1877 ± 377 pg/mL; P = NS). hCG (30 ng/mL) did not stimulate inhibin A or inhibin B. Androstenedione (10^-7 mol/L), activin (30 ng/mL), insulin (30 ng/mL), and insulin-like growth factor I (IGF-I; 100 ng/mL) alone did not stimulate inhibin A or inhibin B secretion. Further, FSH-stimulated inhibin A secretion was not augmented by androstenedione, activin, insulin, or IGF-I. In contrast, the combination of IGF-I and FSH was the only treatment that stimulated inhibin B secretion (1742 ± 380 to 2881 ± 731 pg/mL; P < 0.03). However, FSH in combination with IGF-I resulted in greater stimulation of inhibin A (340%) than inhibin B (65%).

These findings demonstrate that inhibin B is secreted from developing preantral and small antral follicles, but is not directly stimulated by FSH. However, the combination of FSH and IGF-I enhanced inhibin B secretion. In contrast, inhibin A is not secreted from preantral follicles, but in small antral follicles FSH and cAMP stimulate inhibin A secretion. Further, FSH in combination with IGF-I results in a greater degree of stimulation of inhibin A than of inhibin B. These findings suggest that FSH and IGF-I differentially regulate inhibin A and inhibin B secretion. However, additional growth factors or increasing granulosa cell number may contribute to the preferential serum inhibin B increase across the luteal-follicular transition in the menstrual cycle.

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