This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hayes, F. J. Articles by Crowley, W. F. Search for Related Content PubMed PubMed Citation Articles by Hayes, F. J. Articles by Crowley, W. F., Jr.

Differential Regulation of Gonadotropin Secretion by Testosterone in the Human Male: Absence of a Negative Feedback Effect of Testosterone on Follicle-Stimulating Hormone Secretion¹

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

Address all correspondence and requests for reprints to: Frances Hayes, M.B., M.R.C.P.I., Reproductive Endocrine Unit and National Center for Infertility Research, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114. E-mail: hayes.frances{at}mgh.harvard.edu

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 (E₂). The use of pharmacological doses of sex steroids in these studies has precluded conclusions about the relative roles of T and E₂ in gonadotropin feedback. Thus, the aims of the present study were to 1) determine the relative contributions of T vs. E₂ 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 E₂).

Two experimental interventions were used: 1) inhibition of aromatization by a selective aromatase inhibitor to examine the impact of selective E₂ withdrawal; and 2) acute medical castration to examine the effect of ablating both T and E₂. 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, five 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 E₂ (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 E₂ (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 E₂ withdrawal (275 ± 23% with ketoconazole vs. 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 E₂ 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 E₂. From these data we conclude that in terms of sex steroid feedback, E₂ is the predominant regulator of FSH secretion in the human male.

This article has been cited by other articles:

				J. Ahn, F. R. Schumacher, S. I. Berndt, R. Pfeiffer, D. Albanes, G. L. Andriole, E. Ardanaz, H. Boeing, B. Bueno-de-Mesquita, S. J. Chanock, et al. Quantitative trait loci predicting circulating sex steroid hormones in men from the NCI-Breast and Prostate Cancer Cohort Consortium (BPC3) Hum. Mol. Genet., October 1, 2009; 18(19): 3749 - 3757. [Abstract] [Full Text] [PDF]

				I. T. Huhtaniemi, S. R. Pye, K. L. Limer, W. Thomson, T. W. O'Neill, H. Platt, D. Payne, S. L. John, M. Jiang, S. Boonen, et al. Increased Estrogen Rather Than Decreased Androgen Action Is Associated with Longer Androgen Receptor CAG Repeats J. Clin. Endocrinol. Metab., January 1, 2009; 94(1): 277 - 284. [Abstract] [Full Text] [PDF]

				N. Pitteloud, A. A. Dwyer, S. DeCruz, H. Lee, P. A. Boepple, W. F. Crowley Jr., and F. J. Hayes The Relative Role of Gonadal Sex Steroids and Gonadotropin-Releasing Hormone Pulse Frequency in the Regulation of Follicle-Stimulating Hormone Secretion in Men J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2686 - 2692. [Abstract] [Full Text] [PDF]

				S. T. Page, J. K. Amory, and W. J. Bremner Advances in Male Contraception Endocr. Rev., June 1, 2008; 29(4): 465 - 493. [Abstract] [Full Text] [PDF]

				P. A. Boepple, F. J. Hayes, A. A. Dwyer, T. Raivio, H. Lee, W. F. Crowley Jr, and N. Pitteloud Relative Roles of Inhibin B and Sex Steroids in the Negative Feedback Regulation of Follicle-Stimulating Hormone in Men across the Full Spectrum of Seminiferous Epithelium Function J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1809 - 1814. [Abstract] [Full Text] [PDF]

				J. K. Amory, T. F. Kalhorn, and S. T. Page Pharmacokinetics and Pharmacodynamics of Oral Testosterone Enanthate Plus Dutasteride for 4 Weeks in Normal Men: Implications for Male Hormonal Contraception J Androl, May 1, 2008; 29(3): 260 - 271. [Abstract] [Full Text] [PDF]

				N. Pitteloud, A. A. Dwyer, S. DeCruz, H. Lee, P. A. Boepple, W. F. Crowley Jr., and F. J. Hayes Inhibition of Luteinizing Hormone Secretion by Testosterone in Men Requires Aromatization for Its Pituitary But Not Its Hypothalamic Effects: Evidence from the Tandem Study of Normal and Gonadotropin-Releasing Hormone-Deficient Men J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 784 - 791. [Abstract] [Full Text] [PDF]

				E.A.M. Kuijper, C.B. Lambalk, D.I. Boomsma, S. van der Sluis, M.A. Blankenstein, E.J.C. de Geus, and D. Posthuma Heritability of reproductive hormones in adult male twins Hum. Reprod., August 1, 2007; 22(8): 2153 - 2159. [Abstract] [Full Text] [PDF]

				V. Rochira, L. Zirilli, A. D Genazzani, A. Balestrieri, C. Aranda, B. Fabre, P. Antunez, C. Diazzi, C. Carani, and L. Maffei Hypothalamic-pituitary-gonadal axis in two men with aromatase deficiency: evidence that circulating estrogens are required at the hypothalamic level for the integrity of gonadotropin negative feedback. Eur. J. Endocrinol., October 1, 2006; 155(4): 513 - 522. [Abstract] [Full Text] [PDF]

				G. Raven, F. H. de Jong, J.-M. Kaufman, and W. de Ronde In Men, Peripheral Estradiol Levels Directly Reflect the Action of Estrogens at the Hypothalamo-Pituitary Level to Inhibit Gonadotropin Secretion J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3324 - 3328. [Abstract] [Full Text] [PDF]

				L. Soriano-Guillen, N. Lahlou, G. Chauvet, M. Roger, J. L. Chaussain, and J. C. Carel Adult Height after Ketoconazole Treatment in Patients with Familial Male-Limited Precocious Puberty J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 147 - 151. [Abstract] [Full Text] [PDF]

				J. S. Jorgensen, C. C. Quirk, and J. H. Nilson Multiple and Overlapping Combinatorial Codes Orchestrate Hormonal Responsiveness and Dictate Cell-Specific Expression of the Genes Encoding Luteinizing Hormone Endocr. Rev., August 1, 2004; 25(4): 521 - 542. [Abstract] [Full Text] [PDF]

				A. Hestiantoro and D. F. Swaab Changes in Estrogen Receptor-{alpha} and -{beta} in the Infundibular Nucleus of the Human Hypothalamus Are Related to the Occurrence of Alzheimer's Disease Neuropathology J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1912 - 1925. [Abstract] [Full Text] [PDF]

				L. Maffei, Y. Murata, V. Rochira, G. Tubert, C. Aranda, M. Vazquez, C. D. Clyne, S. Davis, E. R. Simpson, and C. Carani Dysmetabolic Syndrome in a Man with a Novel Mutation of the Aromatase Gene: Effects of Testosterone, Alendronate, and Estradiol Treatment J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 61 - 70. [Abstract] [Full Text] [PDF]

				R. M. Martin, C. J. Lin, M. Y. Nishi, A. E. C. Billerbeck, A. C. Latronico, D. W. Russell, and B. B. Mendonca Familial Hyperestrogenism in Both Sexes: Clinical, Hormonal, and Molecular Studies of Two Siblings J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3027 - 3034. [Abstract] [Full Text] [PDF]

				R. A. Anderson, A. M. Wallace, N. Sattar, N. Kumar, and K. Sundaram Evidence for Tissue Selectivity of the Synthetic Androgen 7{alpha}-Methyl-19-Nortestosterone in Hypogonadal Men J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2784 - 2793. [Abstract] [Full Text] [PDF]

				R. A. Anderson and D. T. Baird Male Contraception Endocr. Rev., December 1, 2002; 23(6): 735 - 762. [Abstract] [Full Text] [PDF]

				T Hanaoka, N Kawamura, K Hara, and S Tsugane Urinary bisphenol A and plasma hormone concentrations in male workers exposed to bisphenol A diglycidyl ether and mixed organic solvents Occup. Environ. Med., September 1, 2002; 59(9): 625 - 628. [Abstract] [Full Text] [PDF]

				A. Tiitinen and M. Valimaki Primary Infertility in 45-Year-Old Man with Untreated 21-Hydroxylase Deficiency: Successful Outcome with Glucocorticoid Therapy J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2442 - 2445. [Abstract] [Full Text] [PDF]

				C. A. Oliveira, Q. Zhou, K. Carnes, R. Nie, D. E. Kuehl, G. L. Jackson, L. R. Franca, M. Nakai, and R. A. Hess ER Function in the Adult Male Rat: Short- and Long-Term Effects of the Antiestrogen ICI 182,780 on the Testis and Efferent Ductules, without Changes in Testosterone Endocrinology, June 1, 2002; 143(6): 2399 - 2409. [Abstract] [Full Text] [PDF]

				R.I. McLachlan, L. O'Donnell, S.J. Meachem, P.G. Stanton, D.M. de Kretser, K. Pratis, and D.M. Robertson Identification of Specific Sites of Hormonal Regulation in Spermatogenesis in Rats, Monkeys, and Man Recent Prog. Horm. Res., January 1, 2002; 57(1): 149 - 179. [Abstract] [Full Text] [PDF]

				T. M. Plant and G. R. Marshall The Functional Significance of FSH in Spermatogenesis and the Control of Its Secretion in Male Primates Endocr. Rev., December 1, 2001; 22(6): 764 - 786. [Abstract] [Full Text] [PDF]

				H.M. Behre, S. Kliesch, B. Lemcke, S. von Eckardstein, and E. Nieschlag Suppression of spermatogenesis to azoospermia by combined administration of GnRH antagonist and 19-nortestosterone cannot be maintained by this non-aromatizable androgen alone Hum. Reprod., December 1, 2001; 16(12): 2570 - 2577. [Abstract] [Full Text] [PDF]

				F. J. Hayes, N. Pitteloud, S. DeCruz, W. F. Crowley Jr., and P. A. Boepple Importance of Inhibin B in the Regulation of FSH Secretion in the Human Male J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5541 - 5546. [Abstract] [Full Text] [PDF]

				L. O'Donnell, K. M. Robertson, M. E. Jones, and E. R. Simpson Estrogen and Spermatogenesis Endocr. Rev., June 1, 2001; 22(3): 289 - 318. [Abstract] [Full Text] [PDF]