5-Alpha Reductase and Anabolic Effects of Testosterone

The purpose of this study is to determine whether a higher-than-replacement dose of testosterone and finasteride can be combined to safely increase muscle strength in older men who have a low blood concentration of testosterone.

Study Overview

• Status: Completed
• Conditions: Sarcopenia; Muscle Atrophy; Male Hypogonadism; Benign Prostate Hypertrophy
• Intervention / Treatment: Other: Placebo; Drug: Testosterone Enanthate; Drug: Finasteride

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32608
      • North Florida/South Georgia Veterans Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 58 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; testosterone enanthate	Drug: Testosterone Enanthate; 125 mg, i.m. injection, once/week, for 52 weeks; Other Names: Delatestryl
Experimental: Arm 2; finasteride	Drug: Finasteride; 5 mg, oral, once/day, for 52 weeks; Other Names: Proscar
Experimental: Arm 3; testosterone enanthate + finasteride	Drug: Testosterone Enanthate; 125 mg, i.m. injection, once/week, for 52 weeks; Other Names: Delatestryl; Drug: Finasteride; 5 mg, oral, once/day, for 52 weeks; Other Names: Proscar
Placebo Comparator: Arm 4; placebo	Other: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1 Repetition Maximum (1-RM) Strength Testing	1-RM strength testing for 5 exercises will be performed using dynamic resistance exercise machines. Testing will be performed before treatment (baseline), at 3, 6, 9 and 12 months after treatment.	baseline, 3 months, 6 months, 9 months, 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grip Strength kg	Grip strength in the dominant arm will be measured by using a dynamometer. Testing will be performed at baseline, after 3, 6, 9 and 12 months of treatment.	baseline, 3 months, 6 months, 9 months, 12 months
Lumbar Spine L2-L4 Bone Mineral Density	Dual x-ray absorptiometry (DXA): We will assess bone mineral density (BMD) and body composition using a fan-bean densitometer (Lunar Prodigy, General Electric Medical Systems).	baseline, 12 months
Geriatric Depression Scale	Geriatric Depression Scale (GDS): This 15-item, yes/no questionnaire will be administered at baseline, after 3, 6, 9 and 12 months of treatment. The minimum score is 0 = no depressive symptoms The maximum score is 15 = a very high level of depressive symptoms	baseline, 3 months, 6 months, 9 months, 12 months
30 Minute Recall Portion of Rey Osterrieth Complex Figure (ROCF) Test	Rey Osterrieth Complex Figure (ROCF) test is a widely used standardized neuropsychological test for assessing visuospatial constructional functions, visuographic memory, and some aspects of planning. The drawing is scored by a blinded neuropsychologist on a scale of 0 to 30 with 30 representing a perfect drawing.	baseline, 3 months, 6 months, 9 months, 12 months
Trail-Making Test, Part A	Trail-Making Test, Part A: is a standardized test of cognitive function which specifically assesses working memory, visual processing, visual spatial skills, selective and divided attention, and psychomotor coordination. the test is scored as seconds required to successful completion of the task with a lower score representing better performance. The mean score on test is 30.75 second with a standard deviation of 16.27.	baseline, 3 months, 6 months, 9 months, 12 months
Benton Judgment of Line Orientation Test	Benton Judgment of Line Orientation Test is a standardized test with 30 items that is specific for visual spatial cognition. Tests will be administered at baseline, after 3, 6, 9 and 12 months of treatment. The minimum score is 0, indicating low visual spatial cognition. The maximum score is 30, indicating high visual spatial cognition	baseline, 3 months, 6 months, 9 months, 12 months
Hematocrit	Hematocrit was assessed as a part of routine blood analysis at the indicated time points.	baseline, 3 months, 6 months, 9 months, 12 months
Dietary Protein Intake	Dietary protein intake will be assessed using a 3-day food log and subjects will be counseled to increase protein intake if needed using the guide "Healthy Ways to Eat More Protein".	baseline, 3 months, 6 months, 9 months, 12 months
Transrectal Ultrasound Sizing of Prostate	Transrectal ultrasound sizing of prostate will be performed using the B&K Diagnostic System 3535, with 7 mega hertz transrectal probe at baseline and after 6 and 12 months of treatment.	baseline, 6 month, 12 months
Life Satisfaction	Life Satisfaction: is a written test of psychological well-being that will be performed at baseline, after 3, 6, 9 and 12 months of treatment. This is a 20-point scale, with a possible range of scores from 0 to 20. A higher score represents greater life satisfaction.	baseline, 3 months, 6 months, 9 months, 12 months

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: Merck Sharp & Dohme LLC; Endo Pharmaceuticals
• Investigators: Principal Investigator: Stephen Borst, PhD, North Florida/South Georgia Veterans Health System

Publications and helpful links

General Publications

• Yarrow JF, Beck DT, Conover CF, Beggs LA, Goldberger BA, Borst SE. Invalidation of a commercially available human 5alpha-dihydrotestosterone immunoassay. Steroids. 2013 Dec 11;78(12-13):1220-5. doi: 10.1016/j.steroids.2013.08.013. Epub 2013 Sep 6.
• Borst SE, Yarrow JF, Conover CF, Nseyo U, Meuleman JR, Lipinska JA, Braith RW, Beck DT, Martin JS, Morrow M, Roessner S, Beggs LA, McCoy SC, Cannady DF 2nd, Shuster JJ. Musculoskeletal and prostate effects of combined testosterone and finasteride administration in older hypogonadal men: a randomized, controlled trial. Am J Physiol Endocrinol Metab. 2014 Feb 15;306(4):E433-42. doi: 10.1152/ajpendo.00592.2013. Epub 2013 Dec 10.

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: April 16, 2007
• First Submitted That Met QC Criteria: May 16, 2007
• First Posted (Estimate): May 21, 2007

Study Record Updates

• Last Update Posted (Actual): October 11, 2018
• Last Update Submitted That Met QC Criteria: September 10, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: sarcopenia; testosterone; male hypogonadism; finasteride; anabolic effects
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Endocrine System Diseases; Gonadal Disorders; Prostatic Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Atrophy; Prostatic Hyperplasia; Sarcopenia; Muscular Atrophy; Hypertrophy; Hypogonadism; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Urological Agents; Enzyme Inhibitors; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Steroid Synthesis Inhibitors; Androgens; 5-alpha Reductase Inhibitors; Anabolic Agents; Testosterone; Methyltestosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate; Finasteride
• Other Study ID Numbers: ENDA-014-05F; VA Merit Award (Other Grant/Funding Number: VHA AR6884R)