期刊
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
卷 86, 期 1, 页码 53-58出版社
OXFORD UNIV PRESS INC
DOI: 10.1210/jc.86.1.53
关键词
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资金
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [U54HD028138, R01HD015788] Funding Source: NIH RePORTER
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [U54HD029164] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR001066] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [T32DK007028] Funding Source: NIH RePORTER
- NCRR NIH HHS [MO1-RR-01066] Funding Source: Medline
- NICHD NIH HHS [U54 HD028138, R01 HD015788, R01-HD-15788-15, U54 HD029164] Funding Source: Medline
- NIDDK NIH HHS [DK-07028-24] Funding Source: Medline
Studies of sex steroid regulation of gonadotropin secretion in the human male have focused primarily on the respective site(s) of negative feedback of testosterone (T) and estradiol (E-2). The use of pharmacological doses of sex steroids in these studies has precluded conclusions about the relative roles of T and E-2 in gonadotropin feedback. Thus, the aims of the present study were to 1) determine the relative contributions of T vs. E-2 to the sex steroid component of gonadotropin regulation, and 2) distinguish the feedback effects of T that that are direct (i.e. mediated by the androgen receptor) vs. indirect (mediated by aromatization to E-2). Two experimental interventions were used: 1) inhibition of aromatization by a selective aromatase inhibitor to examine the impact of selective E-2 withdrawal; and 2) acute medical castration to examine the effect of ablating both T and E-2. Sixteen normal (NL) men (mean age, 30.5 +/- 2.2 yr) were studied. Nine NL subjects were treated with the aromatase inhibitor, anastrozole (10 mg, orally, daily, for 5 days). Twelve NL men underwent medical castration with ketoconazole (1-g loading dose followed by 400 mg, orally, four times a day for 5 days). Ketoconazole-treated subjects received concomitant treatment with dexamethasone (0.5 mg twice daily) to prevent the development of adrenal insufficiency. Single blood samples were drawn daily between 0800-1000 h. To ensure that dexamethasone was not altering the gonadotropin response to sex steroid ablation by a direct pituitary effect, live GnRH-deficient men (mean age, 37.6 +/- 3.9 yr) underwent GnRH dose-response studies at baseline and after treatment with dexamethasone (0.5 mg twice daily). Aromatase blockade caused significant lowering of E-2 (33 +/- 3 to 14 +/- 1 pg/mL; P < 0.0005) with a corresponding increase in T levels (563 +/- 42 to 817 +/- 81 ng/dL; P < 0.05). Treatment with ketoconazole resulted in equivalent suppression of E-2 (41 +/- 4 to 14 +/- 1 pg/mL; P < 0.0005), but also induced castrate levels of T (491 +/- 28 to 40 +/- 3 ng/dL; P < 0.0005). Both treatment regimens were associated with a significant increase in gonadotropin levels. For LH, the percent increase in serum levels after castration was almost 3-fold greater than that seen after selective E-2 withdrawal (275 +/- 23% with ketoconazole us. 95.6 +/- 21% with anastrozole; P < 0.005). Despite the divergent changes in T levels with these two maneuvers (a marked decrease after ketoconazole and a significant increase with anastrozole), the percent rise in FSH levels was similar in the two protocols (91 +/- 6% vs. 71 +/- 7%, respectively; P = NS). Inhibin B levels were unchanged after selective E-2 withdrawal (156 +/- 23 vs. 176 +/- 19 pg/mL), but decreased slightly with ketoconazole (156 +/- 15 to 131 +/- 11 pg/mL; P < 0.05). In contrast to the effects of glucocorticoid administration on gonadotropin secretion in women, no significant changes were observed in the GnRH-deficient men treated with dexamethasone in terms of mean LH levels (19.8 +/- 3.2 vs. 23.3 +/- 5.4 IU/L), mean LH pulse amplitude after GnRH (16.0 +/- 2.5 vs. 19.0 +/- 5.1 IU/L), or mean FSH levels (8.0 +/- 1.9 vs. 9.2 +/- 2.4 IU/L, pre vs. post). These studies provide evidence of differential regulation of gonadotropin secretion by T in the human male. T exerts both direct and indirect feedback on LH secretion, whereas its effects on FSH appear to be mediated largely by aromatization to E-2. From these data we conclude that in terms of sex steroid feedback, E-2 is the predominant regulator of FSH secretion in the human male.
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