The Role of 5-alpha Reductase in Mediating Testosterone Actions (5aR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00493987
Recruitment Status : Completed
First Posted : June 29, 2007
Last Update Posted : May 13, 2010
Information provided by:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Brief Summary:
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 combinations 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.

Condition or disease Intervention/treatment Phase
Healthy Drug: Testosterone Enanthate Drug: Dutasteride Phase 4

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 184 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Role of 5-alpha Reductase in Mediating Testosterone Actions
Study Start Date : November 2002
Actual Primary Completion Date : December 2009
Actual Study Completion Date : March 2010

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Active Comparator: Testosterone enanthate Drug: Testosterone Enanthate
testosterone ester
Placebo Comparator: Duatesteride
Drug: Dutasteride
5 alpha-reductase inhibitor

Primary Outcome Measures :
  1. Change from baseline in fat-free mass, measured by DEXA scanning [ Time Frame: 20 weeks ]

Secondary Outcome Measures :
  1. Body composition by Deuterium dilution method [ Time Frame: 20 weeks ]
  2. Maximal voluntary strength in the leg press and chest press exercises. [ Time Frame: 20 weeks ]
  3. Upper and lower extremity muscle power [ Time Frame: 20 weeks ]
  4. Muscle volume by MRI scan [ Time Frame: 20 weeks ]
  5. Prostate volume by MRI Scan [ Time Frame: 20 weeks ]
  6. International Index of Erectile Function [ Time Frame: 20 weeks ]
  7. Men's Sexual Health Questionnaire [ Time Frame: 20 weeks ]
  8. Davidson Sexual Encounter Profile [ Time Frame: 20 weeks ]
  9. Nocturnal penile tumescence and penile rigidity measures [ Time Frame: 20 weeks ]
  10. Prostate specific antigen [ Time Frame: 20 weeks ]
  11. Hematocrit [ Time Frame: 20 weeks ]
  12. Fasting lipid profile / atherogenic markers [ Time Frame: 20 weeks ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Healthy males between 18 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, Klinefelter'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, erythrocytosis, 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%
  • Osteoporosis by DEXA BMD T-Score < -2.5
  • Use of medications that affect muscle or bone metabolism within the previous 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, phenobarbital, aldactone, flutamide, finasteride and Ketoconazole)
  • Use of ketoconazole or other potent CYP3A4 inhibitors that may affect clearance of dutasteride
  • Use investigational medication as part of a research study in the last 3 months?

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00493987

United States, Massachusetts
Boston University Medical Center
Boston, Massachusetts, United States, 02118
Sponsors and Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: Shalender Bhasin, MD Boston University

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Dr. Shalender Bhasin, Boston University Medical Center Identifier: NCT00493987     History of Changes
Other Study ID Numbers: R01HD043348 ( U.S. NIH Grant/Contract )
R01HD043348 ( U.S. NIH Grant/Contract )
First Posted: June 29, 2007    Key Record Dates
Last Update Posted: May 13, 2010
Last Verified: January 2009

Keywords provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):
5-alpha reductase
Body Composition
Sexual function
Healthy Men

Additional relevant MeSH terms:
Testosterone enanthate
Testosterone undecanoate
Testosterone 17 beta-cypionate
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anabolic Agents
5-alpha Reductase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hormone Antagonists