Cycled Testosterone Replacement Study

Phase 1

Completed

Conditions: Hypogonadism

Interventions: Drug: Testosterone
Drug: Placebo

Registration Number: NCT00957528

Lead Sponsor: The University of Texas Medical Branch, Galveston

Brief Summary: The purpose of this study is to determine whether testosterone (male hormone) therapy is effective if administered in a cyclic fashion (periodic dosing) compared to continuous dosing in men aged 60 to 85 years. Effectiveness will be determined based on improvements in body composition, muscle metabolism, muscle strength, and bone metabolism.

Detailed Description: Men and women undergo a progressive reduction in lean muscle mass (sarcopenia) with advancing age regardless of their level of physical activity. A 12-yr longitudinal study in healthy sedentary older men showed a correlation between loss of muscle cross-sectional area and muscle strength of the thigh, quadriceps, and flexor muscles. Once weakened, older individuals are prone to falls that prevent independent living and diminish the quality of life. There is a need to develop therapies to counteract losses in skeletal muscle strength with aging. Studies show that exercise and testosterone administration increase skeletal muscle mass and strength in older men. However, the increase in muscle strength by testosterone in older men has not been consistent in all studies. Androgens increase muscle mass by either increasing muscle protein synthesis or inhibiting muscle protein breakdown. This proposal will investigate the hypothesis that cyclic testosterone administration (monthly on/off cycles) will preferentially increase muscle protein synthesis and result in a consistent and greater improvement in muscle strength than continuous testosterone administration.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 26

Inclusion Criteria

Availability of transportation (i.e., subjects must be able to provide their own transportation to UTMB).

Exclusion Criteria

Medications such as anticoagulants (Coumadin) and glucocorticoids.
History of angina that occurs with exertion or at rest.
History of myocardial infarction within the last 12 months.
Failure to successfully complete an exercise stress test using the Bruce protocol. Subjects that demonstrate ≥ 0.1 mV horizontal or downsloping ST segment depression, a drop in systolic blood pressure of ≥ 10 mm Hg, and/or frequent or repetitive arrhythmias (defined as ≥ 10 PVC/min, or couplets) during the stress test will be excluded.
LDL cholesterol above 200 mg/dL.
History of prostatic cancer.
Elevated prostate specific antigen (PSA) above 4.0 µg/L, or severe benign prostatic hypertrophy (BPH) by history (frequent urination, reduced stream).
Serum total testosterone concentrations of greater than 500 ng/dL.
Subjects who engage in high intensity, elite training on a regular basis.
Major medical illness such as diabetes, chronic obstructive pulmonary disease, or sleep apnea.
Recent history of smoking tobacco.
Hematocrit greater than 51%.
Morbidly obese older men (BMI > 35).
Hypertension: Blood pressure on three consecutive measurements taken at one week intervals that has a systolic pressure ≥ 140 or a diastolic blood pressure ≥ 90. Subjects will be included if they are on two or less blood pressure medications and have a blood pressure below these criteria.
History of hepatitis or a 3-fold elevation of liver function tests (Alk phos, ALT, AST).
Bone related disorders such as osteoporosis or parathyroid disease.
DEXA scans revealing lumbar spine T-scores of less than -2.5.
Subjects currently taking anti-bone-resorptive agents such as bisphosphonates, parathyroid hormone, or calcitonin.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Monthly Cycled Testosterone	Placebo	A month of weekly testosterone treatment alternated by a month of weekly placebo treatment for a duration of 5 months.
Placebo	Placebo	Weekly placebo treatment for a duration of 5 months.
Continuous Testosterone	Testosterone	Weekly testosterone treatment for a duration of 5 months
Monthly Cycled Testosterone	Testosterone	A month of weekly testosterone treatment alternated by a month of weekly placebo treatment for a duration of 5 months.

Primary Outcome Measures

Name	Time	Method
Changes in Basal Muscle Protein Synthesis and Breakdown as Measured by Stable Isotope Metabolic Studies at Baseline and at Five Months	5 Months	The fractional synthetic rate (FSR) of mixed muscle is calculated by directly measuring the incorporation of L-\[ring-13C6\]-phenylalanine into protein (%/hr),, using the precursor-product model: FSR = \[(EP2 - EP1)/(EM•t)\]•60•100, where EP1 and EP2 are the enrichments of bound L-\[ring-13C6\]-phenylalanine in the first and second muscle biopsies, t is the time interval (min) between biopsies, and EM is the mean L-\[ring-13C6\]-phenylalanine enrichment in the muscle intracellular pool.
Changes in Muscle Strength as Measured by Maximal Voluntary Contraction Tests (Arm Curl) at Baseline, One Month, Two Months, Three Months, Four Months, and at Five Months	5 months	Maximum weight (pounds) lifted using Cybex weight machine in a single effort(1-RM) for upper extremities (biceps and triceps) and lower extremities quadriceps and hamstrings).
Changes in Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry (DEXA)	5 months	Lean body mass is expressed in grams as calculated by Hologic DEXA.

Secondary Outcome Measures

Name	Time	Method
Changes in Bone Mineral Density as Measured by Dual Energy X-ray Absorptiometry (DEXA)	5 months	Bone mineral density measure by measured by dual energy x-ray absorptiometry (DEXA)measured at baseline and a five months
Changes in Serum Markers of Bone Turnover.	5 months	Measures of bone turnover markers in serum samples at baseline and at five months.The bone turnover markers analyzed include: Markers associated with bone breakdown NTX (N-telopeptide) TRAP5b (tartrate-resistant acid phosphatase isoform 5b) Markers associated with bone formation Osteocalcin BAP (bone specific alkaline phosphatase) Regulators of bone formation iPTH (intact parathyroid hormone) increases in response to bone loss Calcitonin inhibits bone formation in response to elevated levels of serum calcium
9473Changes in Serum Inflammatory Biomarkers and Muscle Inflammatory Cytokines	5 months	Serum inflammatory biomarkers (Interleukin B-1, 2,5,6,7,8,10,12 13, Interferon gamma, GM-CSF, and Tumor Necrosis Factor alpha)as measured by immunoassay at baseline and at five months