Testosterone, the predominant circulating androgen in men, also serves as a prohormone that is converted in the body to two active metabolites, estradiol 17beta and 5-alpha dihydrotestosterone (DHT). Testosterone serves as the active hormone in some target tissues; however, androgen effects in other target organs require its conversion to estradiol or DHT. The role of 5-alpha reduction of testosterone in mediating its effects on the muscle and sexual function remains unclear. Therefore, the primary objective of this project is to determine whether 5-alpha reduction of testosterone to DHT is obligatory for mediating its effects on fat-free mass, muscle size, muscle strength, and leg power in men. The secondary objective is to determine whether 5-alpha reduction of testosterone is necessary for maintenance of androgen effects on sexual function (sexual desire, overall sexual activity, nocturnal penile tumescence (NPT), response to visual erotic stimulus, and penile rigidity) in men. In order to test these hypotheses about the role of 5-alpha reduction, we will compare testosterone dose response curves for each outcome measure in the absence and presence of a novel, potent 5-alpha reductase inhibitor (duasteride) that inhibits both type 1 and type 2 steroid 5-alpha -reductase isoenzymes. Healthy young men, 21-40 years of age, will be treated with a long acting GnRH agonist to suppress endogenous testosterone production, and concomitantly, randomly assigned to one of 8 groups: group 1, testosterone enanthate (TE) 50-mg weekly, plus placebo tablets daily; group 2, TE 125-mg weekly plus placebo daily; group 3, TE 300-mg weekly plus placebo daily; group 4, TE 600 mg TE weekly plus placebo; group 5, 50-mg weekly, plus duasteride 2.5-mg daily; group 6, TE 125-mg weekly, plus duasteride daily; group 7, TE 300 mg weekly, plus duasteride daily; group 8, 600-mg TE plus duasteride daily. Energy and protein intake, and exercise stimulus will be standardized. The following outcomes will be measured at baseline and after 20 weeks: body composition by DEXA scan, deuterium oxide and sodium bromide dilution; thigh muscle volume by MRI scan; muscle performance by measurements of 1-repetition maximum strength and leg power; sexual function by International Index of Erectile Function, Sexual Desire Inventory, and daily logs of sexual activity; and penile erections and rigidity during EEG-coupled, NPT recoding and in response to a visual erotic stimulus; total and free testosterone, DHT, estradiol, SHBG, and LH levels. For safety, we will follow hemoglobin/hematocrit, sleep apnea scores, AST and ALT, PSA, plasma lipids, apolipoproteins, and lipoprotein particles, and prostate examinations. A multi-disciplinary team of investigators, the use of a previously validated """"""""Leydig Cell Clamp"""""""" model, the use of a potent inhibitor of both subtypes of 5-alpha reductase enzyme, attention to potential confounding variables such as energy intake and exercise stimulus, and power and effect size should help elucidate the role of 5-alpha reduction in mediating androgen action. This study will enhance our understanding of the biologic role of the steroid 5-alpha-reductase system, and has immediate clinical relevance in establishing whether selective androgen receptor modulators that do not undergo 5-alpha reduction would be useful as anabolic agents.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD043348-05
Application #
7065596
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Rankin, Tracy L
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
5
Fiscal Year
2006
Total Cost
$343,254
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
Tapper, J; Arver, S; Pencina, K M et al. (2018) Muscles of the trunk and pelvis are responsive to testosterone administration: data from testosterone dose-response study in young healthy men. Andrology 6:64-73
Gagliano-Jucá, T; Tang, E R; Bhasin, S et al. (2017) Effects of testosterone administration (and its 5-alpha-reduction) on parenchymal organ volumes in healthy young men: findings from a dose-response trial. Andrology 5:889-897
Bhasin, Shalender; Travison, Thomas G; Storer, Thomas W et al. (2012) Effect of testosterone supplementation with and without a dual 5?-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial. JAMA 307:931-9
Bhasin, Shalender; Jasuja, Ravi (2009) Selective androgen receptor modulators as function promoting therapies. Curr Opin Clin Nutr Metab Care 12:232-40
Storer, Thomas W; Woodhouse, Linda; Magliano, Lynne et al. (2008) Changes in muscle mass, muscle strength, and power but not physical function are related to testosterone dose in healthy older men. J Am Geriatr Soc 56:1991-9
Araujo, Andre B; Travison, Thomas G; Bhasin, Shalender et al. (2008) Association between testosterone and estradiol and age-related decline in physical function in a diverse sample of men. J Am Geriatr Soc 56:2000-8
Singh, Rajan; Artaza, Jorge N; Taylor, Wayne E et al. (2006) Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with beta-catenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors. Endocrinology 147:141-54
Jasuja, R; Catlin, D H; Miller, A et al. (2005) Tetrahydrogestrinone is an androgenic steroid that stimulates androgen receptor-mediated, myogenic differentiation in C3H10T1/2 multipotent mesenchymal cells and promotes muscle accretion in orchidectomized male rats. Endocrinology 146:4472-8
Bhasin, Shalender; Woodhouse, Linda; Casaburi, Richard et al. (2005) Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 90:678-88
Artaza, Jorge N; Bhasin, Shalender; Magee, Thomas R et al. (2005) Myostatin inhibits myogenesis and promotes adipogenesis in C3H 10T(1/2) mesenchymal multipotent cells. Endocrinology 146:3547-57

Showing the most recent 10 out of 14 publications