Therapeutic perspective: Issues in testosterone replacement in older men

Journal of Clinical Endocrinology and Metabolism

Volumn 83, Issue 10, 1998, Pages 3435-3448

  Bhasin, Shalender ^a   Bagatell, C J ^b   Bremner, William J ^b   Plymate, Steven R ^c   Tenover, J Lisa ^d   Korenman, Stanley G ^e   Nieschlag, Eberhard ^f  

^a CHARLES R DREW UNIVERSITY OF MEDICINE AND SCIENCE   (United States)

^b UNIVERSITY OF WASHINGTON   (United States)

^c UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^d EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e UNIVERSITY OF CALIFORNIA   (United States)

^f INST OF REPRO MED OF THE UNIV   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ESTROGEN; HIGH DENSITY LIPOPROTEIN; LOW DENSITY LIPOPROTEIN; PROSTATE SPECIFIC ANTIGEN; SEX HORMONE BINDING GLOBULIN; TESTOSTERONE; LIPID;

CARDIOVASCULAR DISEASE; CLIMACTERIUM; HORMONE SUBSTITUTION; HUMAN; HYPOGONADISM; LIPID METABOLISM; PRIORITY JOURNAL; REVIEW; RISK BENEFIT ANALYSIS; RISK MANAGEMENT; TESTOSTERONE METABOLISM; TREATMENT INDICATION; AGED; AGING; ANIMAL; ARTICLE; BLOOD; BODY COMPOSITION; DRUG EFFECT; EVALUATION; MALE; METHODOLOGY; PHYSIOLOGY; RISK FACTOR; SEXUAL DYSFUNCTION;

AGED; AGING; ANIMALS; BODY COMPOSITION; CARDIOVASCULAR DISEASES; EVALUATION STUDIES; HUMANS; LIPIDS; MALE; RESEARCH DESIGN; RISK FACTORS; SEXUAL DYSFUNCTION, PHYSIOLOGICAL; TESTOSTERONE;

EID: 0032187221     PISSN: 0021972X     EISSN: None     Source Type: Journal    
DOI: 10.1210/jc.83.10.3435     Document Type: Review

References (114)

1. Fowles DG. 1997 A profile of older Americans: 1997. U.S. Department of Health and Human Services; Washington, DC: American Association of Retired Persons and the Administration on Aging.
2. Irvine W. 1928 John Hunter's experiments: evidence of an eyewitness. Letter to Professor Thomas Hamilton, University of Glasgow, June 17, 1771. Lancet. 359-360.
3. Berthold AA. 1849 Transplantation der Hoden. Arch Anat Physiol Wiss Med. 42-46.
4. Brown-Sequard CE. 1889 Des effects products chez Phomme par des injections souscutanées d'un liquide retire des testicules frais de cobaye et de chien. CR Seanc Soc Biol. 1:420-430.
5. Butenandt A. 1931 Uber die chemische Unterschung der sexual hormones. Z. Angew Chem. 44:905-908.
6. Gray A, Beline JA, McKinlay JB, Longcope C. 1991 An examination of research design effects on the association of testosterone and male aging: the results of a meta-analysis. J Clin Epidemiol. 44:671-684.
7. Tenover, JS. 1994 Androgen administration to aging men. Endo Metab Clin N Amer. 23:877-892.
8. Tsitoura P, Bulat T. 1995 The aging male reproductive system. Endo Metab Clin N Amer. 24:295-315.
9. Bremner WJ, Vitiello MV, Prinz PN. 1983 Loss of arcadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. 56:1278-1281.
10. Sih R, Morely JE, Kaiser FE, Perry HM, Patrick P, Ross C. 1997 Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 82:1661-1667.
11. Feldman HA, McKinlay JB, Longcope C. Hypogonadism: correlates in a large random sample of Massachusetts men. Proceedings of the 79th Annual Meeting of The Endocrine Society, Minneapolis, MN, 1997, p 1-317 (Abstract).
12. Gray A, Feldman HA, McKinley JB, Longcope C. 1991 Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 73:1016-11125.
13. Vermeulen A, Deslypere J. 1985 Testicular endocrine function in the ageing male. Maturitas. 7:273-279.
14. Tenover J, Dahl K, Hsueh A, Lim P, Matsumoto A, Bremner W. 1987 Serum bioactive and immunoreactive follicle-stimulating hormone levels and the response to clomiphene in healthy young and elderly men. J Clin Endocrinol Metabol. 64:1103-1108.
15. Tenover J, Matsumoto A, Clifton D, Bremner W. 1988 Age-related alterations in the circadian rhythms of pulsatile luteinizing hormone and testosterone secretion in healthy men. J Gerontol. 43:163-169.
16. Plymate SR, Tenover JS, Bremner WJ. 1989 Circadian variation in testosterone, sex hormone binding globulin, and calculated non-sex hormone binding globulin bound testosterone in healthy young and elderly men. J Androl. 10:366-371.
17. Pardridge W. 1988 Selective delivery of sex steroid hormones to tissues in vivo by albumin and by sex hormone-binding globulin. Ann NY Acad Sci. 538:173-192.
18. Hammond G, Nisker J, Jones L, Siiteri P. 1980 Estimation of the percentage of free steroid in undiluted serum by centrifugal ultrafiltration dialysis. J Biol Chem. 255:5023-5026.
19. Sodergard R, Backström T, Shanbhag V, Carstensen H. 1982 Calculation of free and bound fractions of testosterone and estradiol-170 to human plasma proteins at body temperature. J Steroid Biochem. 16:801-810.
20. Rosner W. 1997 Errors in measurement of plasma free testosterone. J Clin Endocrinol Metabol. 82:2014-2015.
21. Nankin H, Calkins J. 1986 Decreased bioavailable testosterone in aging normal and impotent men. J Clin Endocrinol Metab. 63:1418-1423.
22. Umstot E, Baxter J, Anderson R. 1985 A theoretically sound and practicable equilibrium dialysis method for measuring percentage of free testosterone. J Steroid Biochem. 22:639-648.
23. Giraudi G, Cenderelli G, Migliardi M. 1988 Effect of tracer binding to serum proteins on the reliability of a direct free testosterone assay. Steroids. 52:423-424.
24. Tenover J, Matsumoto A, Plymate S, Bremner W. 1987 The effects of aging in normal men on bioavailable testosterone and luteinizing hormone secretion: Response to clomiphene citrate. J Clin Endocrinol Metab. 65:1118-1126.
25. Morley J, Perry H, Kaiser F, et al. 1993 Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc. 41:149-152.
26. Peiris A, Stagner J, Plymate S, Vogel R, Heck M, Samols E. 1993 Sex hormone binding globulin levels in normal men: role of pulsatile insulin secretion. J Clin Endocrinol Metab. 76:279-282.
27. Plymate S, Matej L, Jones R, Friedl K. 1988 Inhibition of sex hormone binding globulin (SHBG) production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab. 67:460-464.
28. Bremner W, Vitiello M, Prinz P. 1983 Loss of arcadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. 56: 1278-1285.
29. Steen B. 1988 Body composition and aging. Nutr Rev. 46:45-51.
30. Reed RL, Pearlmutter L, Yochum K, et al. 1991 The relationship between muscle mass and muscle strength in the elderly J Am Geriatr Soc. 39:555-561.
31. Tenover JL. 1996 Effects of androgen supplementation in the aging male. In: Oddens BJ, Vermeulen A, eds. Androgens and the aging male. New York: Parthenon Publishing Group; 191-204.
32. Marin P, Holmang S, Gustafsson C, et al. 1993 Androgen treatment of abdominally obese men. Obes Res. 1:245-251.
33. Sih R, Morley JE, Kaiser FE, et al. 1997 Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 82:1661-1667.
34. Bagatell CJ, Bremner WJ. 1995 Androgen and progestagen effects on plasma lipids. Progress in Cardiovascular Disease. 38:255-271.
35. Lipid Research Clinics. 1980 Population Studies Data Book Vol 1: The Prevalence Study. Department of Health and Human Services.
36. Marcovina SM, Lippi G, Bagatell CJ, Bremner WJ. 1996 Testosterone induced suppression on lipoprotein (a) in normal men; relation to basal lipoprotein (a) level. Atherosclerosis. 132:89-95.
37. Bagatell CJ, Bremner WJ. 1996 Androgens in men: uses and abuses. N Eng J Med. 334:707-714.
38. Adams MR, Williams JK, Kaplan JR. 1995 Effects of androgens on coronary artery atherosclerosis and atherosclerosis-related impairment of vascular responsiveness. Aterioscler Thromb Vasc Biol. 15:562-570.
39. Polderman HK, Stehouwer CDA, van Kamp GJ, Dekker GA, Verheugt WA, Gooren LJG. 1993 Influence of sex hormones on plasma endothelin levels. Ann Intern Med. 118:429-432.
40. Marin P, Holman S, Fustafsson C, et al. 1993 Androgen treatment of abdominally obese men. Obes Res. 1:245-251.
41. Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A. 1996 Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab. 81:4358-4365.
42. Tsai EC, Boyko EJ, Newell-Lewis L, Leonetti DL, Fujimoto WY. 1997 Decreased testosterone is a predictor of increased intra-abdomenal fat in second-generation Japanese-American men. Diabetologia. 40:[Suppl 1]:A16.
43. Ellvin FM, Plunkett-Reid K, Rumilla AE. 1997 The long-term beneficial effect of low-dose testosterone in the aging male. Proceedings of the 79th Annual Meeting of the Endocrine Society, Minneapolis, MN, p. 236 (Abstract).
44. Tenover JS. 1992 Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab. 75:1092-1098.
45. Morley JE, Peny M, Kaiser FE, et al. 1993 Effects of testosterone replacement therapy in older hypogonadal males: a preliminary study. J Am Geriatr Soc. 41L:149-152.
46. Zgliczynski S, Ossowski M, Slowinska-Srzednicha J, et al. 1996 Effect of testosterone replacement on lipids and lipoproteins in hypogonadal and elderly men. Atherosclerosis. 121:35-43.
47. Korenman SG, Morley JE, Mooradian AD, et al. 1990 Secondary hypogonadism in older men: its relation to impotence. J Clin Endocrinol Metab. 71:763-769.
48. Gray A, Feldman HA, McKinlay JB, Longcope C. 1991 Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 73:1016-1025.
49. Gustafsson O, Norming U, Gustafsson S, Eneroth P, Astrom G, Nyman CR. 1996 Dihydrotestosterone, and testosterone levels in men screened for prostate cancer: a study of a randomized population. Br J Urol. 77:433-440.
50. Carter HB, Pearson JD, Metter EJ, et al. 1995 Longitudinal evaluation of serum androgen levels in men with and without prostate cancer. Prostate. 27:25-31.
51. Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ. 1996 Prospective study of sex hormone levels and risk of prostate carcinoma. J Natl Cancer Inst. 88:1118-1126.
52. Gann PH, Hennekens CH, Longcope C, Verhoek-Oftedahl W, Grodstein F, Stampfer MJ. 1995 A prospective study of plasma hormone levels, nonhormonal factors, and development of benign prostatic hyperplasia. Prostate. 26:40-49.
53. Meikle AW, Dobs AS, Adolfsson J, et al. 1997 Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system. Urology. 49:191-196.
54. Sih R, Morley JE, Kaiser FE, Perry III HM, Patrick P, Ross C. 1997 Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 82:1661-1667.
55. Meriggiola MC, Marcovina S, Paulsen CA, Bremner WJ. 1995 Testosterone enanthate at a dose of 200 mg/week decreases HDL-cholesterol levels in healthy men. Int J Androl. 18:237-242.
56. Zgliczynski S, Ossowski M, Slowinska-Srzednicka J, et al. 1996 Effect of testosterone replacement on lipids, and lipoproteins in hypogonadal and elderly men. Atherosclerosis. 121:35-43.
57. Winkler UH. 1996 Effects of androgens on haemostasis. Maturitas. 24:147-155.
58. Guay AT, Bansal S, Heatley GJ. 1995 Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism: double blind placebo-controlled trial with clomiphene citrate. J Clin Endocrinol Metab. 80:3546-3552.
59. Feldman HA, Goldstein I, Hatzchristou DG, Krane RJ, McKinlay JB. 1994 Impotence and its medical and psychological correlates: results of the Massachusetts Male Aging Study. J Urol. 151:54-61.
60. Anderson FH, Francis RM, Faulkner K. 1996 Androgen supplementation in eugonadal men with osteoporosis: effects of 6 months of treatment on bone mineral density and cardiovascular risk factors. Bone. 18:171-177.
61. Nieschlag E, Behre HM, eds. 1997 Andrology: male reproductive health and dysfunction. Heidelberg/New York: Springer; 297-309.
62. Nieschlag E, Behre HM, eds. 1998 Testosterone: action, deficiency, substitution, 2nd ed. Heidelberg/New York: Springer.
63. Kaufman M, Vermeulen A. 1998 Androgens in male senescence. In: Nieschlag E, Behre HM, eds. Testosterone: action, deficiency, substitution, 2nd ed. Heidelberg/New York: Springer; 437-471.
64. Nieschlag E, Wang C, et al, eds. 1992 Guidelines for the use of androgens. Geneva:World Health Organization.
65. Hajjer RR, Kaiser FE, Morley JE. 1997 Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab. 82:3793-3796.
66. Sih R, Morley JE, Kaiser FE, Perry HM, Patrick P, Ross C. 1996 Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 82:1661-1667.
67. Behre HM, Kliesch S, Leifke E, Link TM, Peters PE, Nieschlag E. 1997 Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 82:2386-2390.
68. Schröder FH. 1996 The prostate and androgens: the risk of supplementation. In: Oddens B, Vermeulen A, eds. Androgens and the aging male. London, New York: Parthenon Publishing Group; 223-226.
69. Behre HM, Bohmeyer J, Nieschlag E. 1994 Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf). 40:341-349.
70. Meikle AW, Arver S, Dobs AS, et al. 1996 Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system. Urology. 49:191-196.
71. Behre HM, Nieschlag E. 1992 Testosterone buciclate (20 Aet-1) in hypogonadal men: pharmacokinetics and pharmacodynamics of the new long-acting androgen ester. J Clin Endocrinol Metab. 75:1204-1210.
72. Bhasin S, Swerdloff RS. 1996 Sustained delivery of testosterone by a long acting, biodegradable testosterone microsphere formulation in hypogonadal men. In: Bhasin S, Gabelnick HL, Spieler JM, Swerdloff RS, Wang C, Kelly C, eds. Pharmacology, biology and clinical applications of androgens. Current status and future prospects. New York: Wiley-Liss; 481-486.
73. Salehian B, Wang C, Alexander G, et al. 1996 Pharmacokinetics, bioefficacy, and safety of sublingual testosterone cyclodextrin in hypogonadal men: comparison to testosterone enanthate - a clinical research center study. J Clin Endocrinol Metab. 80:3567-3575.
74. Suvisaari J, Sundararn K, Noé G, et al. 1997 Pharmacokinetics and pharmacodynamics of 7α-methyl-19-nortestosterone after intramuscular administration in healthy men. Hum Reprod. 12:967-973.
75. Young J, Couzinet B, Nahoul K, et al. 1997 Panhypopituitarism as a model to study the metabolism of dehydroepiandrosterone (DHEA) in humans. J Clin Endocrinol Metab. 82:2578-2585.
76. Wilson JD. 1988 Androgen abuse by athletes. Endocr Rev. 9:181-200.
77. Mooradian AD, Morley JE, Korenman SG. 1987 Biological actions of androgens. Endocr Rev. 8:1-28.
78. Bardin CW. 1996 The anabolic action of testosterone. N Engl J Med. 335:52-53.
79. Elashoff JD, Jacknow AD, Shain SG, Braunstein GD. 1991 Effects of anabolic/androgenic steroids on muscle strength. Ann Intern Med. 115:387-393.
80. Bhasin S, Bremner WJ. 1997 Emerging issues in androgen replacement therapy. J Clin Endocrinol Metab. 82:3-8.
81. Bhasin S, Tenover JS. 1997 Sarcopenia: Issues in testosterone replacement of older men. J Clin Endocrinol Metab. 82:1659-1660.
82. Kenyon AT, Knowlton K, Sandiford I, Kock FC, Lotwin G. 1940 A comparative study of the metabolic effects of testosterone propionate in normal men and women and in eunuchoidism. Endocrinology. 26:26-45.
83. Kochakian CD. 1950 Comparison of protein anabolic properties of various androgens in the castrated rat. Am J Physiol. 60:553-558.
84. Mauras N, Haymond MW, Darmaun D, Vieira NE, Abrams SA, Yergey AL. 1994 Calcium and protein kinetics in pre-pubertal boys. J Clin Invest. 93:1014-1019.
85. Arslanian S, Suprasongsin C. 1997 Testosterone treatment in adolescents with delayed puberty: changes in body composition, protein, fat and glucose metabolism. J Clin Endocrinol Metab. 82:2313-3220.
86. Soliman AT, Khadir MM, Asfour M. 1995 Testosterone treatment in adolescent boys with constitutional delay of growth and development. Metabolism. 44:1013-1016.
87. Gregory JW, Greene SA, Thompson J, Scrimgeour CM, Rennie MJ. 1992 Effects of oral testosterone undecanoate on growth, body composition, strength, and energy expenditure of adolescent boys. Clin Endocrinol (Oxford) 37:207-213.
88. Brodsky IG, Balagopal P, Nair KS. 1996 Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men-a Clinical Research Center Study. J Clin Endocrinol Metab. 81:3469-3475.
89. Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A. 1996 Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab. 81:4358-4365.
90. Bhasin S, Storer TW, Berman N, Yarasheski K, Phillips J, Clevenger B, Lee WP, Casaburi R. 1997 A replacement dose of testosterone increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab. 82:407-413.
91. Wang C, Eyre DR, Clark R, et al. 1996 Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone resorption markers in hypogonadal men-a Clinical Research Center Study. J Clin Endocrinol Metab. 81:3654-3662.
92. Bhasin S, Storer TW, Berman N, et al. 1996 The effects of supraphysiologic doses of testosterone on muscle size and strength in men. N Engl J Med. 335:1-7.
93. Forbes GB, Porta CR, Herr B, Griggs RC. 1992 Sequence of changes in body composition induced by testosterone and reversal of changes after the drug is stopped. JAMA. 267:397-399.
94. Griggs RC, Kingston W, Josefowicz RF, Herr BE, Forbes G, Halliday D. 1989 Effect of testosterone on muscle mass and muscle protein synthesis. J Appl Physiol. 66:498-503.
95. Urban RJ, Bodenburg YH, Gilkison C, et al. 1995 Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol 269:E820-E826.
96. Young NR, Baker HWG, Liu G, Seeman E. 1993 Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception. J Clin Endocrinol Metab. 77:1028-1032.
97. Morley JE, Perry III HM, Kaiser FE, et al. 1993 Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc. 41:149-152.
98. Sih R, Morley JE, Kaiser FE, Perry HM, Patrick P, Ross C. 1997 Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 82:1661-1667.
99. Tenover JS. 1992 Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab. 75:1092-1098.
100. Janowsky JS, Oviatt SK, Orwoll ES. 1994 Testosterone influences spatial cognition in older men. Behav Neurosci. 108:625-632.
101. Heymsfield SB, Gallagher D, Visser M, Nunez C, Wang Z-M. 1995 Measurement of skeletal muscle: laboratory and epidemiological methods. J Gerontol. 50A:23-29.
102. Dutta C, Hadley EC. 1995 The significance of sarcopenia in old age. J Gerontol. 50A:1-4.
103. O'Shea JP, Winkler W. 1970 Biochemical and physical effects of an anabolic steroid in competitive swimmers and weightlifters. Nutr Rep Int. 2:351-355.
104. Loughton SJ, Ruhling RO. 1977 Human strength and endurance responses to anabolic steroid and training. J Sports Med Phys Fitness. 17:285-296.
105. Fahey TD, Brown CH. 1973 The effects of an anabolic steroid on the strength, body composition, and endurance of college males when accompanied by a weight training program. Med Sci Sports Exer. 5:272-277.
106. Casaburi R, Storer T, Bhasin S. 1996 Androgen effects on body composition and muscle performance. In: Bhasin S, Gabelnick H, Spieler JM, Swerdloff RS, Wang C, eds. Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Llss; pp 283-288.
107. Forbes GB. 1985 The effect of anabolic steroids on lean body mass: the dose response curve. Metabolism. 34:571-573.
108. Byerley LO, Lee WNP, Swerdloff RS, et al. 1993 Effect of modulating serum testosterone levels in normal male range on protein, glucose, and lipid metabolism in men: implications for testosterone replacement therapy. Endocr J. 1:253-262.
109. Michel G, Bauheu EE. 1980 Androgen receptor in skeletal muscle: characterization and physiologic variations. Endocrinology. 107:2088.
110. Mayer M, Rosen F. 1975 Interaction of anabolic steroids with glucocorticoid receptor sites in rat muscle cytosol. Am J Physiol. 229:1381-1386.
111. Dahlberg E, Snochowski M, Gustaffsson JA. 1981 Regulation of the androgen and glucocorticoid receptors in the rat and mouse muscle cytosol. Endocrinology. 108:1431-1436.
112. Blanco CE, Popper P, Micevych P. 1997 Anabolic-androgenic steroid induced alterations in choline aceryltransferase messenger RNA levels of spinal cord motoneurons in the male rat. Neuroscience. 78:973-982.
113. Leslie M, Forger NG, Breedlove SM. 1991 Sexual dimorphism and androgen effects on spinal motoneurons innervating the rat felxor digitorum brevis. Brain Res. 561:269-273.
114. Fryburg DA, Weltmen A, Jahn LA, et al. 1997 Short-term modulation of the androgen milieu alters pulsatile, but not exercise- or growth hormone (GH-releasing hormone stimulated GH secretion in healthy men: impact of gonadal steroid and GH secretory changes on metabolic outcomes. J Clin Endocrinol Metab. 82:3710-3719.