5-Alpha Reductase and Anabolic Effects of Testosterone

Approximately 40% of older male veterans have a low serum testosterone concentration. The
latter is associated with diminished muscle strength and bone mineral density, depressed
mood, low pain tolerance, frailty, and increased mortality. Replacement doses of testosterone
have been administered to hypogonadal men for the purpose of reversing deficits in muscle and
bone. Although testosterone is clearly important for maintaining muscle and bone in men,
there are problems associated with T replacement. First, testosterone causes a number of
undesired effects, including fluid retention, gynecomastia, worsening of sleep apnea,
polycythemia, prostate enlargement and acceleration of early-stage prostate cancer. The
anabolic effects obtained to date from testosterone replacement have been relatively modest,
especially in older men. Our hypothesis is that combined treatment with a
higher-than-replacement dose of testosterone and a 5- reductase inhibitor will produce
substantial anabolic effects, while preventing testosterone-induced prostate enlargement and
possibly other adverse effects.

We plan to investigate the efficacy and safety of combined treatment with testosterone and
finasteride in older hypogonadal male veterans by conducting a 12-month randomized,
placebo-controlled trial. We will administer a higher-than-replacement dose of testosterone
plus the 5- reductase inhibitor finasteride to a group of hypogonadal, but otherwise healthy
older men. We will determine whether this treatment is a safe and effective means to increase
muscle mass and strength. Men aged 60 to 80, with circulating total testosterone 300 ng/dL or
bioavailable testosterone 70 ng/dL, will be treated with 125 mg testosterone enanthate/week 5
mg finasteride/day for 1 year. We will assess the effects on body composition, 1- repetition
maximum (1-RM) strength, grip strength, functional reach, bone mineral density, mood,
cognition, hematopoiesis and prostate volume. We have chosen a moderately high dose of
testosterone that may cause some adverse effects. We predict that finasteride will not block
the anabolic effects of testosterone, but will block any prostate enlargement or symptoms and
possibly other adverse effects as well.

Inclusion Criteria:

- Age > 60 years males

- Primary care at the Malcolm Randall VA Medical Center in Gainesville, Florida.

- Consenting subjects who have a morning (between 6:00 AM and 10:00 AM) serum total
testosterone 300 ng/dL or bioavailable testosterone concentration 70 ng/dL and no
exclusion criteria will be randomized to receive either testosterone or placebo.

Exclusion Criteria:

- Subjects with cognitive impairment will be identified by the Mini-Cog test and
excluded. The Mini-Cog has high sensitivity and specificity for cognitive impairment,
and is not affected by level of education.

- We will also exclude subjects with receptive aphasia, or a contraindication to
testosterone replacement (i.e., history of or active prostate or breast cancer, severe
benign prostatic hyperplasia as assessed by elevated American Urologic Association
Symptom Index (AUASI) score > 25), congestive heart failure (Class 3 or 4), sleep
apnea syndrome, polycythemia (Hct > 55%), or prostate specific antigen (PSA) > 2.6
ng/mL) will be excluded.

- Obese subjects (BMI > 35) will also be excluded.

- Subjects currently receiving testosterone supplementation or subjects who have an
allergy to testosterone will also be excluded.

- Subjects previously receiving testosterone replacement therapy must be off such
medication for at least four weeks.