This Article 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 FINKELSTEIN, J. S. Articles by CROWLEY, W. F. Search for Related Content PubMed PubMed Citation Articles by FINKELSTEIN, J. S. Articles by CROWLEY, W. F., JR.

Sex Steroid Control of Gonadotropin Secretion in the Human Male. I. Effects of Testosterone Administration in Normal and Gonadotropin-Releasing Hormone-Deficient Men^*

JOEL S. FINKELSTEIN, RANDALL W. WHITCOMB, LOUIS ST. L. O’DEA, CHRISTOPHER LONGCOPE, DAVID A. SCHOENFELD and WILLIAM F. CROWLEY, JR.

Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital Boston, Massachusetts 02114
The Departments of Obstetrics and Gynecology and Medicine, University of Massachusetts Medical Center Worcester, Massachusetts 01655

Address requests for reprints to: William F. Crouley, Jr., M.D., Reproductive Endocrine Unit, Bartlett Hall Extension 5, 40 Rear Blossom Street, Boston, Massachusetts 02114.

The precise sites of action of the negative feedback effects of gonadal steroids in men remain unclear. To determine whether testosterone (T) administration can suppress gonadotropin secretion directly at the level of the pituitary, the pituitary responses to physiological doses of GnRH were assessed in six men with complete GnRH deficiency, whose pituitary- gonadal function had been normalized with long term pulsatile GnRH delivery, before and during a 4-day continuous T infusion (15 mg/day). Their responses were compared with the effects of identical T infusions on spontaneous gonadotropin secretion and the response to a 100µg GnRH bolus in six normal men. Both groups were monitored with 15 h of frequent blood sampling before and during the last day of the T infusion. In the GnRH-deficient men, the first three GnRH doses were identical and were chosen to produce LH pulses with amplitudes in the midphysiological range of our normal men (i.e. a physiological dose), while the last four doses spanned 1.5 log orders (7.5, 25, 75, and 250 ng/kg). The 250 ng/kg dose was always administered last because it is known to be pharmacological.

In the GnRH-deficient men, mean LH (P < 0.02) and FSH (P < 0.01) levels as well as LH pulse amplitude (P < 0.05) decreased significantly during T infusion, demonstrating a direct pituitary-suppressive effect of T and/or its metabolites. Mean LH levels were suppressed to a greater extent in the normal than in the GnRH-deficient men (58 ± 15% vs. 28 ± 7%; P < 0.05). In addition, LH frequency decreased significantly (P < 0.01) during T administration in the normal men. These latter two findings suggest that T administration also suppresses hypothalamic GnRH release. T was unable to suppress gonadotropin secretion in one GnRH-deficient and one normal man. In both groups, the suppressive effect of T administration was present only in response to physiological doses of GnRH.

Because the pituitary- and hypothalamus-suppressive effects of T could be mediated by its aromatization to estrogens, five GnRH-deficient and five normal men underwent identical T infusions with concomitant administration of the aromatase inhibitor testolactone (TL; 500 mg, orally, every 6 h). As an additional control, four GnRH-deficient and four normal men received TL alone. TL administration completely prevented the effect of T administration to suppress gonadotropin secretion in both the normal and GnRH-deficient men, and mean LH levels increased significantly in both the GnRH-deficient (P < 0.01) and the normal (P < 0.001) men who received TL alone. The increase in mean LH levels was greater (P < 0.01) in the normal men who received TL alone than in the normal men who received T plus TL, thus revealing a direct effect of androgens in normal men. Measurements of T and estradiol production rates in three men demonstrated that TL effectively blocked aromatization.

These results demonstrate that 1) T or one of its metabolites inhibits gonadotropin secretion at both pituitary and hypothalamic levels in men; 2) aromatization of androgens to estrogens is required for part of this suppressive effect, while part is due to androgens themselves; 3) there is some heterogeneity in the susceptibility to the inhibitory effects of T administration; and 4) it is important to use physiological stimuli to assess the effects of neuromodulators on the pituitary.

^* This work was supported by NIH Grants HD-15788, HD-18169, and RR-1066; FDA Grant FD-U-000523-1; and an NIH Clinical Associate Physician Award (to J.S.F.).

Current address: Endocrine Unit, Bulfinch 3, Massachusetts General Hospital, Boston, Massachusetts 02114.

Current address: Division of Endocrinology and Metabolism, Montreal General Hospital, Montreal, Quebec, Canada H3G 1A4.

Current address: Departments of Obstetrics and Gynecology and Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.

Received October 29, 1990.

This article has been cited by other articles:

				M. G. Ropelato, M. C. Garcia Rudaz, M. E. Escobar, S. V. Bengolea, M. L. Calcagno, J. D. Veldhuis, and M. Barontini Acute Effects of Testosterone Infusion on the Serum Luteinizing Hormone Profile in Eumenorrheic and Polycystic Ovary Syndrome Adolescents J. Clin. Endocrinol. Metab., September 1, 2009; 94(9): 3602 - 3610. [Abstract] [Full Text] [PDF]

				B. Kornmann, E. Nieschlag, M. Zitzmann, J. Gromoll, M. Simoni, and S. Von Eckardstein Body Fat Content and Testosterone Pharmacokinetics Determine Gonadotropin Suppression After Intramuscular Injections of Testosterone Preparations in Normal Men J Androl, September 1, 2009; 30(5): 602 - 613. [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]

				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]

				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]

				K. L. Matthiesson and R. I. McLachlan Male hormonal contraception: concept proven, product in sight? Hum. Reprod. Update, July 1, 2006; 12(4): 463 - 482. [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]

				J. D. Jacobson and M. A. Ansari Immunomodulatory Actions of Gonadal Steroids May Be Mediated by Gonadotropin-Releasing Hormone Endocrinology, January 1, 2004; 145(1): 330 - 336. [Abstract] [Full Text] [PDF]

				M. A. Ansari, M. Dhar, S. Spieker, N. Bakht, A. M. Rahman, W. V. Moore, and J. D. Jacobson Modulation of Diabetes with Gonadotropin-Releasing Hormone Antagonists in the Nonobese Mouse Model of Autoimmune Diabetes Endocrinology, January 1, 2004; 145(1): 337 - 342. [Abstract] [Full Text] [PDF]

				Y. Okada, Y. Fujii, J. P. Moore Jr., and S. J. Winters Androgen Receptors in Gonadotrophs in Pituitary Cultures from Adult Male Monkeys and Rats Endocrinology, January 1, 2003; 144(1): 267 - 273. [Abstract] [Full Text] [PDF]

				B. L. Herrmann, B. Saller, O. E. Janssen, P. Gocke, A. Bockisch, H. Sperling, K. Mann, and M. Broecker Impact of Estrogen Replacement Therapy in a Male with Congenital Aromatase Deficiency Caused by a Novel Mutation in the CYP19 Gene J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5476 - 5484. [Abstract] [Full Text] [PDF]

				M. P. Gillam, S. Middler, D. J. Freed, and M. E. Molitch The Novel Use of Very High Doses of Cabergoline and a Combination of Testosterone and an Aromatase Inhibitor in the Treatment of a Giant Prolactinoma J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4447 - 4451. [Abstract] [Full Text] [PDF]

				V. Rochira, A. Balestrieri, M. Faustini-Fustini, S. Borgato, P. Beck-Peccoz, and C. Carani Pituitary Function in a Man with Congenital Aromatase Deficiency: Effect of Different Doses of Transdermal E2 on Basal and Stimulated Pituitary Hormones J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2857 - 2862. [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]

				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]

				S. Wickman and L. Dunkel Inhibition of P450 Aromatase Enhances Gonadotropin Secretion in Early and Midpubertal Boys: Evidence for a Pituitary Site of Action of Endogenous E J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4887 - 4894. [Abstract] [Full Text] [PDF]

				G. Van den Berghe, F. Weekers, R. C. Baxter, P. Wouters, A. Iranmanesh, R. Bouillon, and J. D. Veldhuis Five-Day Pulsatile Gonadotropin-Releasing Hormone Administration Unveils Combined Hypothalamic-Pituitary-Gonadal Defects Underlying Profound Hypoandrogenism in Men with Prolonged Critical Illness J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3217 - 3226. [Abstract] [Full Text] [PDF]

				N. Pitteloud, P. A. Boepple, S. DeCruz, S. B. Valkenburgh, W. F. Crowley Jr., and F. J. Hayes The Fertile Eunuch Variant of Idiopathic Hypogonadotropic Hypogonadism: Spontaneous Reversal Associated with a Homozygous Mutation in the Gonadotropin-Releasing Hormone Receptor J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2470 - 2475. [Abstract] [Full Text] [PDF]

				J. A. Schnorr, M. J. Bray, and J. D. Veldhuis Aromatization Mediates Testosterone's Short-Term Feedback Restraint of 24-Hour Endogenously Driven and Acute Exogenous Gonadotropin-Releasing Hormone-Stimulated Luteinizing Hormone and Follicle-Stimulating Hormone Secretion in Young Men J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2600 - 2606. [Abstract] [Full Text] [PDF]

				A. S. Dobs, P. S. Bachorik, S. Arver, A. W. Meikle, S. W. Sanders, K. E. Caramelli, and N. A. Mazer Interrelationships among Lipoprotein Levels, Sex Hormones, Anthropometric Parameters, and Age in Hypogonadal Men Treated for 1 Year with a Permeation-Enhanced Testosterone Transdermal System J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1026 - 1033. [Abstract] [Full Text]

				F. J. Hayes, S. DeCruz, S. B. Seminara, P. A. Boepple, and W. F. Crowley Jr. Differential Regulation of Gonadotropin Secretion by Testosterone in the Human Male: Absence of a Negative Feedback Effect of Testosterone on Follicle-Stimulating Hormone Secretion J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 53 - 58. [Abstract] [Full Text]

				C. Castro-Fernández, A. Olivares, D. Söderlund, J. C. López-Alvarenga, E. Zambrano, J. D. Veldhuis, A. Ulloa-Aguirre, and J. P. Méndez A Preponderance of Circulating Basic Isoforms Is Associated with Decreased Plasma Half-Life and Biological to Immunological Ratio of Gonadotropin-Releasing Hormone-Releasable Luteinizing Hormone in Obese Men J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4603 - 4610. [Abstract] [Full Text]

				D. Vanderschueren and R. Bouillon Estrogen Deficiency in Men Is a Challenge for Both the Hypothalamus and Pituitary J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3024 - 3026. [Full Text]

				F. J. Hayes, S. B. Seminara, S. DeCruz, P. A. Boepple, and W. F. Crowley Jr. Aromatase Inhibition in the Human Male Reveals a Hypothalamic Site of Estrogen Feedback J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3027 - 3035. [Abstract] [Full Text]

				Is Obesity an Outcome of Gonadotropin-Releasing Hormone Agonist Administration? Analysis of Growth and Body Composition in 110 Patients with Central Precocious Puberty J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4480 - 4488. [Abstract] [Full Text]

				A. S. Dobs, A. W. Meikle, S. Arver, S. W. Sanders, K. E. Caramelli, and N. A. Mazer Pharmacokinetics, Efficacy, and Safety of a Permeation-Enhanced Testosterone Transdermal System in Comparison with Bi-Weekly Injections of Testosterone Enanthate for the Treatment of Hypogonadal Men J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3469 - 3478. [Abstract] [Full Text] [PDF]

				S. Kawakami and S. J. Winters Regulation of Lutenizing Hormone Secretion and Subunit Messenger Ribonucleic Acid Expression by Gonadal Steroids in Perifused Pituitary Cells from Male Monkeys and Rats Endocrinology, August 1, 1999; 140(8): 3587 - 3593. [Abstract] [Full Text]

				F. J. Hayes, D. J. McNicholl, D. Schoenfeld, E. E. Marsh, and J. E. Hall Free {alpha}-Subunit Is Superior to Luteinizing Hormone as a Marker of Gonadotropin-Releasing Hormone Despite Desensitization at Fast Pulse Frequencies J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 1028 - 1036. [Abstract] [Full Text]

				M. R. Palmert, H. V. Malin, and P. A. Boepple Unsustained or Slowly Progressive Puberty in Young Girls: Initial Presentation and Long-Term Follow-Up of 20 Untreated Patients J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 415 - 423. [Abstract] [Full Text]

				M. R. Palmert, S. Radovick, and P. A. Boepple Leptin Levels in Children with Central Precocious Puberty J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2260 - 2265. [Abstract] [Full Text]

				D. M. Keenan and J. D. Veldhuis A biomathematical model of time-delayed feedback in the human male hypothalamic-pituitary-Leydig cell axis Am J Physiol Endocrinol Metab, July 1, 1998; 275(1): E157 - E176. [Abstract] [Full Text] [PDF]

				B. M. Kudielka, J. Hellhammer, D. H. Hellhammer, O. T. Wolf, K.-M. Pirke, E. Varadi, J. Pilz, and C. Kirschbaum Sex Differences in Endocrine and Psychological Responses to Psychosocial Stress in Healthy Elderly Subjects and the Impact of a 2-Week Dehydroepiandrosterone Treatment J. Clin. Endocrinol. Metab., May 1, 1998; 83(5): 1756 - 1761. [Abstract] [Full Text]

				M. R. Palmert, S. Radovick, and P. A. Boepple The Impact of Reversible Gonadal Sex Steroid Suppression on Serum Leptin Concentrations in Children with Central Precocious Puberty J. Clin. Endocrinol. Metab., April 1, 1998; 83(4): 1091 - 1096. [Abstract] [Full Text]

				C. Wang, N. G. Berman, J. D. Veldhuis, T. Der, V. McDonald, B. Steiner, and R. S. Swerdloff Graded Testosterone Infusions Distinguish Gonadotropin Negative-Feedback Responsiveness in Asian and White Men--A Clinical Research Center Study J. Clin. Endocrinol. Metab., March 1, 1998; 83(3): 870 - 876. [Abstract] [Full Text]

				G.B. Kletter, V. Padmanabhan, I.Z. Beitins, J.C. Marshall, R.P. Kelch, and C.M. Foster Acute Effects of Estradiol Infusion and Naloxone on Luteinizing Hormone Secretion in Pubertal Boys J. Clin. Endocrinol. Metab., December 1, 1997; 82(12): 4010 - 4014. [Abstract] [Full Text] [PDF]

				C. Foresta, P. Bordon, M. Rossato, R. Mioni, and J. D. Veldhuis Specific Linkages Among Luteinizing Hormone, Follicle-Stimulating Hormone, and Testosterone Release in the Peripheral Blood and Human Spermatic Vein: Evidence for Both Positive (Feed-Forward) and Negative (Feedback) Within-Axis Regulation J. Clin. Endocrinol. Metab., September 1, 1997; 82(9): 3040 - 3046. [Abstract] [Full Text] [PDF]

				C. Carani, K. Qin, M. Simoni, M. Faustini-Fustini, S. Serpente, J. Boyd, K. S. Korach, and E. R. Simpson Effect of Testosterone and Estradiol in a Man with Aromatase Deficiency N. Engl. J. Med., July 10, 1997; 337(2): 91 - 95. [Full Text] [PDF]

				A. D. Zwart, A. Iranmanesh, and J. D. Veldhuis Disparate Serum Free Testosterone Concentrations and Degrees of Hypothalamo-Pituitary-Luteinizing Hormone Suppression Are Achieved by Continuous Versus Pulsatile Intravenous Androgen Replacement in Men: A Clinical Experimental Model of Ketoconazole-Induced Reversible Hypoandrogenemia with Controlled Testosterone Add-Back J. Clin. Endocrinol. Metab., July 1, 1997; 82(7): 2062 - 2069. [Abstract] [Full Text] [PDF]