Associate Provost for Research Boston University Medical Campus
NICHD - National Institute of Child Health & Human Development	Research Resources

Abstract

Abstract: DESCRIPTION (provided by applicant): 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.

Thesaurus Terms:
adipose tissue, body composition, libido, muscle strength, steroid metabolism, testosterone, testosterone 5 alpha reductase
dihydrotestosterone, enzyme inhibitor, estradiol, gonadotropin releasing factor, hormone inhibitor, outcomes research, penis erection
clinical research, high performance liquid chromatography, human middle age (35-64), human subject, magnetic resonance imaging, male, patient oriented research, radioimmunoassay, young adult human (21-34)

Institution:	BOSTON MEDICAL CENTER
	ONE BOSTON MEDICAL CENTER PLACE
	BOSTON, MA 02118
Fiscal Year:	2006
Department:
Project Start:	01-APR-2003
Project End:	31-MAR-2008
ICD:	NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG:	REN