The Role of 5-Alpha Reductase in Mediating Testosterone Actions

Condition(s) targeted: Healthy

Intervention: Lupron® (Drug); Testosterone Enanthate (Drug); Dutasteride (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Official(s) and/or principal investigator(s):
Shalender Bhasin, MD, Principal Investigator, Affiliation: Boston University

Overall contact:
John S garfi, MS, Phone: 617-414-2935, Email: john.garfi@bmc.org

In normal men, the male hormone testosterone affects a number of things in the body including muscle function and sexual function. An enzyme in the body called 5-alpha reductase converts testosterone into another form called dihydrotestosterone (DHT) which has slightly different effects. The purpose of this study is to find out how different amounts of the two different forms of testosterone affect muscle function and sexual function in healthy young men like you. This will be done by giving the men participating in the study different combinaitons of hormone-related medication for 20 weeks and making measurements before, during and after the medications to look for changes in lean body tissue, muscle size, muscle strength and leg power, as well as sexual function and sexual activity in all participants.

Official title: The Role of 5-Alpha Reductase in Mediating Testosterone Actions

Study design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: Change from baseline in fat-free mass, measured by DEXA scanning

Secondary outcome:

Body composition by Deuterium dilution method

Maximal voluntary strength in the leg press and chest press exercises.

Upper and lower extremity muscle power

Muscle volume by MRI scan

Prostate volume by MRI Scan

International Index of Erectile Function

Men's Sexual Health Questionnaire

Davidson Sexual Encounter Profile

Nocturnal penile tumescence and penile rigidity measures

Prostate specific antigen

Hematocrit

Fasting lipid profile / atherogenic markers

Detailed description: Testosterone, the predominant circulating androgen in men, also serves as a prohormone that is converted in the body to two active metabolites, estradiol 17 β and 5-α DHT (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-α 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-α 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-α 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-α reduction, we will compare testosterone dose response curves for each outcome measure in the absence and presence of a novel, potent 5-α reductase inhibitor (dutasteride)

that inhibits both type 1 and type 2 steroid 5-α - 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 dutasteride 2. 5-mg daily; group 6, TE 125-mg weekly, plus dutasteride daily; group 7, TE 300 mg weekly, plus dutasteride daily; group 8, 600-mg TE plus dutasteride 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.

Minimum age: 21 Years. Maximum age: 50 Years. Gender(s): Male.

Criteria:

Inclusion Criteria:

- Healthy males between 21 and 50 years of age.

- Ambulatory, physically active, but not in competitive sports.

- Eugonadal: Normal Serum Testosterone (300-1100 nmol/L).

- Normal LH

- Normal FSH

- Able and willing to comply with the trial protocol.

Exclusion Criteria:

- Known to have a primary or secondary hypogonadism? (e. g. pituitary disease, HIV

infection, Klineflter’s Syndrome)

- BMI > 35

- Disability that precludes participation in exercise testing

- Alcohol or illicit drug use in the preceding 6 months that would interfere with

participation and compliance with the protocol

- Known disorder that would be exacerbated by androgen treatment e. g. benign prostate

hyperplasia, prostate Ca, erthrocytosis, sleep apnea)

- Any abnormalities in the following laboratory tests PSA > 4 ng/ml AST, ALT or Alkaline

Phosphatase > 3x ULN? Creatinine level > 2 mg/dL Hematocrit > 51%

- Osteoporos by DEXA BMD T-Score < -2. 5

- Use of medications that affect muscle or bone metabolism within the revious 3 months

?(e. g. glucocorticoids, growth hormone, androgenic steroids, oral androgen precursors –i. e. androstenedione or DHEA)

- Use of medications that affect androgen metabolism, action or clearance within the

previous 3 months? (e. g. dilantin, phenobarbitol, aldactone, flutamide, finasterideand Ketoconazole)

- Use of ketoconazole or other potent CYP3A4 inhibitors that may affect learance of

dutasteride

- Use investigational medication as part of a research study in the last 3 months?

John S garfi, MS, Phone: 617-414-2935, Email: john.garfi@bmc.org

Boston University Medical Center, Boston, Massachusetts 02118, United States; Recruiting
Shalender Bhasin, MD, Principal Investigator
Philip Knapp, MD, Sub-Investigator
Norm Mazer, MD, PhD, Sub-Investigator

Last updated: June 28, 2007