The Role of 5-alpha Reductase in Mediating Testosterone Actions
Condition: Healthy
Study type: Interventional
Phase: Phase 4

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.
    

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.
    

Intervention name(s): Testosterone Enanthate; Dutasteride
Intervention type(s): Drug; Drug
Intervention description(s): testosterone ester; 5 alpha-reductase inhibitor
Intervention MeSH terms: Methyltestosterone; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate; Dutasteride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Testosterone; Androgens; Dihydrotestosterone; 5-alpha reductase; Body Composition; Muscle; Sexual function; Men; Healthy Men