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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 2163-2169
Copyright © 1999 by The Endocrine Society

From the Clinical Research Centers

Inhibin A and Inhibin B Responses to Gonadotropin Withdrawal Depends on Stage of Follicle Development1

Corrine K. Welt, Judith M. Adams, Patrick M. Sluss and Janet E. Hall

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

Address all correspondence and requests for reprints to: Dr. Corrine K. Welt, Reproductive Endocrine Unit, Reproductive Endocrine Sciences Center and National Center for Infertility Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114.

Previous studies demonstrate that inhibin A and B are differentially secreted across the menstrual cycle. To test the hypothesis that the responses of inhibin A and inhibin B to partial gonadotropin withdrawal are influenced by the stage of follicular development, a maximally suppressive dose of the Nal-Glu GnRH antagonist (150 µg/kg) was administered to normal cycling women during the midfollicular (MFP; n = 8), late follicular (LFP; n = 6), and midluteal phase (MLP; n = 5) to assess ovarian responsiveness over a broad range of developmental stages.

Administration of the GnRH antagonist resulted in a significant decrease in LH (75 ± 5%, 63 ± 3%, and 84 ± 7%; P < 0.05) and FSH (23 ± 9%, 32 ± 5%, and 39 ± 6%; P < 0.04) during the MFP, LFP, and MLP, respectively. During the MFP, partial withdrawal of gonadotropins resulted in disappearance of the dominant follicle on ultrasound accompanied by a decrease in estradiol (E2; 64.9 ± 11.4 to 23.9 ± 3.3 pg/mL; P < 0.02) and inhibin B levels (121.6 ± 14.8 to 28.4 ± 4.8 pg/mL; P < 0.002) from baseline to near the limit of detection. Inhibin A was near the limit of detection in this cycle stage (0.8 ± 0.1 IU/mL). When gonadotropins were withdrawn during the LFP, the size of the dominant follicle remained stationary in four of five subjects, and inhibin B (84.1 ± 14.1 to 22.2 ± 3.4 pg/mL; 71 ± 5%; P < 0.02), inhibin A (4.4 ± 1.1 to 1.3 ± 0.5 IU/mL; 71 ± 7%; P < 0.02), and E2 (236.8 ± 48.2 to 95.6 ± 39.0 pg/mL; 61 ± 12%; P < 0.02) decreased similarly. Time to ovulation was shorter in association with higher inhibin A (r = -0.67; P < 0.02) and E2 (r = -0.79; P < 0.003), but there was no relation to inhibin B. During the MLP, decreased gonadotropin levels resulted in the disappearance of corpus luteum function with a significant decrease in inhibin A (9.0 ± 0.4 to 0.7 ± 0.1 IU/mL; 92 ± 1%; P < 0.0001) in combination with decreased E2 (150.4 ± 22.9 to 23.8 ± 4.2 pg/mL; 83 ± 3%; P < 0.005) and progesterone (12.6 ± 2.6 to 0.9 ± 0.2 ng/mL; 92 ± 2%; P < 0.01).

Administration of a GnRH antagonist at precise stages of the menstrual cycle provides further evidence that differential regulation of inhibin A and inhibin B is critically dependent on the stage of follicular development. Inhibin B secretion is exquisitely sensitive to gonadotropin withdrawal during the MFP when inhibin A has not yet risen. Inhibin A and inhibin B decrease equally after GnRH antagonist administration during the LFP. However, before antagonist administration, the positive correlation between estradiol and inhibin A and time to ovulation and the lack of such a correlation with inhibin B suggest that the source of inhibin B secretion is different from that of inhibin A and E2. The decrease in inhibin A secretion after antagonist administration during the luteal phase confirms gonadotropin-dependent secretion of dimeric inhibin A by the corpus luteum.




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