Importance of Inhibin B in the Regulation of FSH Secretion in the Human Male

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Abstract
Regulation of FSH secretion in the male involves a complex balance between stimulation by GnRH from the hypothala- mus, inhibitory feedback by sex steroids (T and E2) and in- hibin B (Inh B) from the gonads, and autocrine/paracrine mod- ulation by activin and follistatin within the pituitary. The aim of the present study was to delineate the feedback control of FSH in the human male with specific reference to the relative roles of sex steroids vs. Inh B. Two experimental human mod- els were used: 1) normal (NL) men subjected to acute sex ste- roid withdrawal (T, E2, Inh B), and 2) functional castrate males (T, E2, Inh B). Nine NL men (age range, 25- 45 yr) and three castrate males (age range, 23- 47 yr) were studied. The NL men underwent acute sex steroid suppression using high dose ketoconazole (1-g loading dose, followed by 400 mg, orally, four times daily for 150 h). Gonadotropin secretion was characterized by fre- quent blood sampling every 10 min for 12 h at baseline and on d 3 and 6 of sex steroid ablation. In the three castrate subjects, blood sampling was performed every 5 min for 2 4h8w kafter discontinuing androgen replacement therapy. In the NL men, treatment with ketoconazole resulted in a decline to castrate levels in T (451 20 to 38 7 ng/dl; P < 0.0005) and E2 (39 4t o 15 2 pg/ml; P < 0.005) and a modest, but significant, decline in Inh B levels, which remained within the normal range (183 19 to 136 13 pg/ml; P < 0.005). This suppression of sex steroids was associated with a more marked increase in mean LH (9.5 0.9 to 24.9 2.0 IU/liter; P < 0.0001) than FSH levels (5.1 0.7 to 10.0 1.5 IU/liter; P < 0.005), with the latter not exceeding the normal adult male range. The castrate subjects had a mean T level of 66 8 ng/dl, an E2 level of 20 1 pg/ml, and undetectable Inh B levels. Despite a similar sex steroid milieu, the mean FSH levels ob- served in NL men after acute sex steroid ablation were ap- proximately 6-fold lower than those seen in the castrate sub- jects (10.0 1.5 vs. 59.5 17.7 IU/liter; P < 0.0005). In contrast, mean LH levels in the NL men were less than 3-fold lower than those in castrate subjects (24.9 2.0 vs. 66.8 20.1 IU/liter; P < 0.005). From this human model of acute sex steroid withdrawal, we conclude that Inh B is likely to be the major feedback regu- lator of FSH secretion in the human male. (J Clin Endocrinol Metab 86: 5541-5546, 2001)

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