Anabolic and Inflammatory Responses to Short-Term Testosterone Administration in Older Men

Phase 4

Completed

Conditions: Sarcopenia

Interventions: Drug: Testosterone gel
Drug: Testosterone injection
Drug: Medrol

Registration Number: NCT00957801

Lead Sponsor: The University of Texas Medical Branch, Galveston

Brief Summary: Skeletal muscle loss is a common consequence of aging and in some individuals reaches a level that compromises health and quality of life. Age-associated increases in cytokine and inflammatory signaling may be important contributors to this process.

The investigators will assess the practical question of whether testosterone injection and gel application elicit similar responses. Resistance exercise will be used as a means of stimulating both inflammatory and anabolic responses in skeletal muscle. In order to assess the effects of testosterone on these responses, subjects will perform resistance exercise on two occasions separated by 7 days. The first session will be performed prior to the initiation of testosterone and/or medrol therapy and the second session will be performed after receiving therapy for 7 days.

Detailed Description: 4 groups of healthy men aged 60 - 85 years were studied over 15 days, in 2 distinct time periods, pre-treatment and treatment.

Pre treatment week from study day -7 to study day -1. Treatment week from study day 1 to study day 8.

Groups:

1. Testosterone by injection (100mg testosterone enanthate) administered on study day 1.

2. Testosterone by gel application (10g/day Androgel 1%) administered daily beginning on study day 1 through study day 7.

3. Methylpredisone (Medrol) dose pack beginning on study day 1 (24mg) and decreasing by 4mg each day, with an additional 4mg taken on study day 7. Study day 1 (24mg), study day 2 (20mg), study day 3 (16mg), study day 4 (12mg), study day 5 (8mg), study day 6 (4mg), study day 7 (4mg).

4. Testosterone by injection (100mg testosterone enanthate) administered on study day 1 and Methylpredisone (Medrol) dose pack beginning on study day 1 (24mg) and decreasing by 4mg each day, with an additional 4mg taken on study day 7. Study day 1 (24mg), study day 2 (20mg), study day 3 (16mg), study day 4 (12mg), study day 5 (8mg), study day 6 (4mg), study day 7 (4mg).

Subjects were asked to fill out the Brief Fatigue Inventory daily for all 15 days.

Subjects were studied at the clinical research center before treatment (study day 1) and after treatment (study day 8). Resistance exercise was performed on study days 1 and 8. Blood was drawn before and after exercise for measurement of serum cortisol. Subjects were asked to return to the clinical research center each day during the treatment week (study days 1-8) for blood draws for measurement of total testosterone, estradiol and C-reactive protein (CRP). Labs were drawn on study days 1 and 8 for complete blood count, comprehensive metabolic panel and lipid panel.

Part 1:

In this part of the project we will study the acute response to testosterone treatment between two groups of subjects, comparing two methods of administration (injection vs. topical gel) in order to obtain pilot information for a subsequent, randomized, blinded long-term investigation.

Part 2:

In this part of the project we will study the acute response to Medrol (methylprednisolone) taken over 7 days with or without testosterone (given as 100mg IM) in order to obtain pilot information for a subsequent, randomized, blinded long-term investigation.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 29

Inclusion Criteria

Age: 60-85
Gender: Male

Exclusion Criteria

Exclusionary medications will be an anticoagulant (Coumadin) because of the risk of bleeding during the biopsy procedure. Additional medications which will be disallowed for participation include: anabolic steroids, nitrates, antihistamines, and glucocorticoids.
The subjects must be able to successfully complete an exercise stress test using the Bruce protocol . Subjects will be excluded without exercise testing, with a history of angina that occurs with exertion or at rest, or a myocardial infarction within the last 12 months. Subjects that demonstrate ³0.1 milliVolts (mV) horizontal or downsloping ST segment depression, a drop in systolic blood pressure of ³10 mm Hg, and/or frequent or repetitive arrhythmias (defined as ³10 premature ventricular contractions (PVC)/min, or couplets) during the stress test will be excluded.
Subjects with LDL cholesterol above 200 mg/dL will be excluded .
Any man with a history of breast cancer or prostate cancer, or any indication of an occult carcinoma from an elevation of prostate specific antigen (PSA) above 4.0 mg/L (53), or severe benign prostatic hypertrophy (BPH) by history (frequent urination, reduced stream) will be excluded.
Subjects with liver dysfunction evidenced by a history of hepatitis B or hepatitis C, or by a three-fold elevation of liver enzymes (Alk phos, alanine aminotransferase (ALT), aspartate amino-transferase (AST) above normal on screening will be excluded from the study.
Any subject with a blood pressure on three consecutive measurements taken at one week intervals that has a systolic pressure ³ 140 or a diastolic blood pressure ³ 90 will be excluded.
Any subject who has a major medical illness such as diabetes, chronic obstructive pulmonary disease, or sleep apnea will be excluded. Moreover, subjects will not have a recent history of smoking tobacco. Morbidly obese older men (BMI > 35) will also be excluded.
Subjects will evidence of kidney disease (serum creatinine > 2.0mg/dl) will be excluded from participation.
Any subject with thyroid disease as determined by an abnormal thyroid stimulating hormone (TSH) level will be excluded from participation.
Any subject testing positive for HIV will be excluded .
Allergy to iodine, a component of Betadine which is used to prepare the subject's skin for invasive procedures, will be cause for exclusion from this study.
Men with serum total testosterone concentrations greater than 500 ng/dL will be excluded.
Subjects who engage in high intensity resistance training on a regular basis will be excluded.
Subjects with a known coagulation disorder or with clinical evidence indicative of a bleeding disorder (easy bruising, "free bleeders") will not be enrolled in this study due to potential problems that could arise from muscle biopsy procedures.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Testosterone gel	Testosterone gel	Testosterone topical gel (Androgel 1%) 10 mg administered daily for seven days
Testosterone injection and Medrol 6 day dose pack	Testosterone injection	Testosterone enanthate given as a single 100mg Intramuscular (IM) injection. Medrol 6 day dose pack was administered as directed with daily doses decreasing by 4mg per day with an additional 4mg given on day 7. Day one dose: 24mg, day two dose: 20mg, day three dose: 16mg, day four dose: 12mg, day five dose: 8mg, day six dose: 4 mg, day seven dose: 4mg.
Testosterone injection	Testosterone injection	Testosterone enanthate given as a single 100 mg Intramuscular (IM) injection
Testosterone injection and Medrol 6 day dose pack	Medrol	Testosterone enanthate given as a single 100mg Intramuscular (IM) injection. Medrol 6 day dose pack was administered as directed with daily doses decreasing by 4mg per day with an additional 4mg given on day 7. Day one dose: 24mg, day two dose: 20mg, day three dose: 16mg, day four dose: 12mg, day five dose: 8mg, day six dose: 4 mg, day seven dose: 4mg.
Medrol 6 day dose pack	Medrol	Medrol 6 day dose pack was administered as directed with daily doses decreasing by 4mg per day with an additional 4mg given on day 7. Day one dose: 24mg, day two dose: 20mg, day three dose: 16mg, day four dose: 12mg, day five dose: 8mg, day six dose: 4 mg, day seven dose: 4mg.

Primary Outcome Measures

Name	Time	Method
Serum Total Testosterone Measured on Treatment Day 2	treatment day 2	Testosterone was measured daily during the treatment week (treatment days 1 through 8). Serum testosterone was analyzed by UTMB clinical laboratory. Normal ranges are 72-623 ng/dL. Baseline testosterone was drawn before testosterone administration.
Dehydroepiandrosterone Sulfate (DHEA-S) Measured on Treatment Day 8 (Post Study)	treatment day 8	Dehydroepiandrosterone sulfate (DHEA-S) was measured before and after the treatment week on study treatment days 1 and 8. DHEA-S was analyzed by immunoassay on a Siemens Immulite 2000. Normal ranges are 28-290 ug/dL.
Insulin Like Growth Factor 1 (IGF-1) Measured on Treatment Day 1 (Baseline Study)	treatment day 1	Insulin like growth factor 1 (IGF-1) was measured before and after the treatment week on study treatment days 1 and 8. IGF-1 was analyzed by immunoassay on a Siemens Immulite 2000. Normal range is 33-220 ng/mL.
Insulin Like Growth Factor 1 (IGF-1) Measured on Treatment Day 8 (Post Study)	treatment day 8	Insulin like growth factor 1 (IGF-1) was measured before and after the treatment week on study treatment days 1 and 8. IGF-1 was analyzed by immunoassay on a Siemens Immulite 2000. Normal range is 33-220 ng/mL.
Insulin Measured on Treatment Day 1 (Baseline Study)	treatment day 1	Insulin was measured before and after the treatment week on study treatment days 1 and 8. Insulin was analyzed by immunoassay on a Siemens Immulite 2000. Normal range is less than 25 uIu/mL.
Serum Total Testosterone Measured on Treatment Day 4	treatment day 4	Testosterone was measured daily during the treatment week (treatment days 1 through 8). Serum testosterone was analyzed by UTMB clinical laboratory. Normal ranges are 72-623 ng/dL. Baseline testosterone was drawn before testosterone administration.
Serum Estradiol Measured on Treatment Day 8 (Post Study)	treatment day 8	Estradiol was measured during the treatment week (treatment days 1 and 8). Serum estradiol was analyzed by UTMB clinical laboratory. Normal ranges are 20-47 pg/mL.
Hematocrit Measured on Treatment Day 8 (Post Study)	treatment day 8	Hematocrit was measured before and after treatment week (study treatment days 1 and 8). Hematocrit was analyzed by UTMB clinical laboratory. Normal ranges are 38.4% - 49.3%.
Serum Total Testosterone Measured on Treatment Day 5	treatment day 5	TesTestosterone was measured daily during the treatment week (treatment days 1 through 8). Serum testosterone was analyzed by UTMB clinical laboratory. Normal ranges are 72-623 ng/dL. Baseline testosterone was drawn before testosterone administration.
Serum Total Testosterone Measured on Treatment Day 7	treatment day 7	Testosterone was measured daily during the treatment week (treatment days 1 through 8). Serum testosterone was analyzed by UTMB clinical laboratory. Normal ranges are 72-623 ng/dL. Baseline testosterone was drawn before testosterone administration.
Serum Total Testosterone Measured Before Treatment on Treatment Day 1 (Baseline Study)	treatment day 1	Testosterone was measured daily during the treatment week (treatment days 1 through 8). Serum testosterone was analyzed by UTMB clinical laboratory. Normal ranges are 72-623 ng/dL. Baseline testosterone was drawn before testosterone administration.
Prostate Specific Antigen (PSA) Measured on Treatment Day 8 (Post Study)	treatment day 8	Prostate Specific Antigen (PSA) was measured before and after treatment week (study treatment days 1 and 8). PSA was analyzed by UTMB clinical laboratory. Normal ranges are less than 4.0 ng/mL.
Hematocrit Measured on Treatment Day 1 (Baseline Study)	treatment day 1	Hematocrit was measured before and after treatment week (study treatment days 1 and 8). Hematocrit was analyzed by UTMB clinical laboratory. Normal ranges are 38.4% - 49.3%.
Triglycerides Measured on Treatment Day 8 (Post Study)	treatment day 8	Triglycerides were measured before and after treatment week (study treatment days 1 and 8). Total cholesterol was analyzed by UTMB clinical laboratory. Normal ranges are 30-170 mg/dL.
C-Reactive Protein (CRP) Measured on Treatment Day 8 (Post Study)	treatment day 8	C-Reactive Protein (CRP) was measured during the treatment week (study treatment days 1 and 8). CRP was analyzed by UTMB clinical laboratory. Normal ranges are 0.0 - 0.8 mg/dL.
Dehydroepiandrosterone Sulfate (DHEA-S) Measured on Treatment Day 1 (Baseline Study)	treatment day 1	Dehydroepiandrosterone sulfate (DHEA-S) was measured before and after the treatment week on study treatment days 1 and 8. DHEA-S was analyzed by immunoassay on a Siemens Immulite 2000. Normal ranges are 28-290 ug/dL.
Serum Total Testosterone Measured on Treatment Day 6	treatment day 6	Testosterone was measured daily during the treatment week (treatment days 1 through 8). Serum testosterone was analyzed by UTMB clinical laboratory. Normal ranges are 72-623 ng/dL. Baseline testosterone was drawn before testosterone administration.
Serum Total Testosterone Measured on Treatment Day 8 (Post Study)	treatment day 8	Testosterone was measured daily during the treatment week (treatment days 1 through 8). Serum testosterone was analyzed by UTMB clinical laboratory. Normal ranges are 72-623 ng/dL. Baseline testosterone was drawn before testosterone administration.
Serum Estradiol Measured on Treatment Day 1 (Baseline Study)	treatment day 1	Estradiol was measured during the treatment week (treatment days 1 and 8). Serum estradiol was analyzed by UTMB clinical laboratory. Normal ranges are 20-47 pg/mL.
Prostate Specific Antigen (PSA) Measured on Treatment Day 1 (Baseline Study)	treatment day 1	Prostate Specific Antigen (PSA) was measured before and after treatment week (study treatment days 1 and 8). PSA was analyzed by UTMB clinical laboratory. Normal ranges are less than 4.0 ng/mL.
Total Cholesterol Measured on Treatment Day 8 (Post Study)	treatment day 8	Total Cholesterol was measured before and after treatment week (study treatment days 1 and 8). Total cholesterol was analyzed by UTMB clinical laboratory. Normal ranges are 120-200 mg/dL.
High-Density Lipoproteins (HDL) Measured on Treatment Day 8 (Post Study)	treatment day 8	High Density Lipoproteins (HDL) was measured before and after treatment week (study treatment days 1 and 8). HDL was analyzed by UTMB clinical laboratory. Normal ranges are higher than 35 mg/dL.
Low-Density Lipoproteins (LDL) Measured on Treatment Day 1 (Baseline Study)	treatment day 1	Low Density Lipoproteins (LDL) was measured before and after treatment week (study treatment days 1 and 8). LDL was analyzed by UTMB clinical laboratory. Normal ranges are less than 160 mg/dL.
Very Low-Density Lipoproteins (VLDL) Measured on Treatment Day 8 (Post Study)	treatment day 8	Very Low Density Lipoproteins (VLDL) was measured before and after treatment week (study treatment days 1 and 8). VLDL was analyzed by UTMB clinical laboratory. Normal ranges are 5-60 mg/dL.
Very Low-Density Lipoproteins (VLDL) Measured on Treatment Day 1 (Baseline Study)	treatment day 1	Very Low Density Lipoproteins (VLDL) was measured before and after treatment week (study treatment days 1 and 8). VLDL was analyzed by UTMB clinical laboratory. Normal ranges are 5-60 mg/dL.
C-Reactive Protein (CRP) Measured on Treatment Day 1 (Baseline Study)	treatment day 1	C-Reactive Protein (CRP) was measured during the treatment week (study treatment days 1 and 8). CRP was analyzed by UTMB clinical laboratory. Normal ranges are 0.0 - 0.8 mg/dL.
Insulin Measured on Treatment Day 8 (Post Study)	treatment day 8	Insulin was measured before and after the treatment week on study treatment days 1 and 8. Insulin was analyzed by immunoassay on a Siemens Immulite 2000. Normal range is less than 25 uIu/mL.
Serum Total Testosterone Measured on Treatment Day 3	treatment day 3	TTestosterone was measured daily during the treatment week (treatment days 1 through 8). Serum testosterone was analyzed by UTMB clinical laboratory. Normal ranges are 72-623 ng/dL. Baseline testosterone was drawn before testosterone administration.
Total Cholesterol Measured on Treatment Day 1 (Baseline Study)	treatment day 1	Total Cholesterol was measured before and after treatment week (study treatment days 1 and 8). Total cholesterol was analyzed by UTMB clinical laboratory. Normal ranges are 120-200 mg/dL.
Triglycerides Measured on Treatment Day 1 (Baseline Study)	treatment day 1	Triglycerides were measured before and after treatment week (study treatment days 1 and 8). Total cholesterol was analyzed by UTMB clinical laboratory. Normal ranges are 30-170 mg/dL.
High-Density Lipoproteins (HDL) Measured on Treatment Day 1 (Baseline Study)	treatment day 1	High Density Lipoproteins (HDL) was measured before and after treatment week (study treatment days 1 and 8). HDL was analyzed by UTMB clinical laboratory. Normal ranges are higher than 35 mg/dL.
Cortisol Measured on Treatment Day 1 (Baseline Study) BEFORE Exercise Protocol	treatment day 1 - before exercise	Cortisol was measured before and immediately after the exercise protocol, before and after the treatment week on study treatment days 1 and 8. Serum Cortisol was analyzed by immunoassay on a Siemens Immulite 2000. Normal range is 5-25 ug/dL.
Cortisol Measured on Treatment Day 8 (Post Study) AFTER Exercise Protocol	treatment day 8 - after exercise	Cortisol was measured before and immediately after the exercise protocol, before and after the treatment week on study treatment days 1 and 8. Serum Cortisol was analyzed by immunoassay on a Siemens Immulite 2000. Normal range is 5-25 ug/dL.
Global Fatigue Score as Measured by Brief Fatigue Inventory (BFI) in the Pre-treatment Week	Study days -7 to -1 (Pre - treatment)	The Brief Fatigue Inventory is a 9 item questionnaire that assesses perceptual fatigue as well as fatigue interferences (e.g. interference with enjoyment of life), with "0" being no fatigue and "10" being as bad as you can imagine. The Global Fatigue score is calculated by averaging the answers of all the questions. This data is presented as the pre-treatment week average of study days -7 to -1.
Low-Density Lipoproteins (LDL) Measured on Treatment Day 8 (Post Study)	treatment day 8	Low Density Lipoproteins (LDL) was measured before and after treatment week (study treatment days 1 and 8). LDL was analyzed by UTMB clinical laboratory. Normal ranges are less than 160 mg/dL.
Sex Hormone Binding Globulin (SHBG) Measured on Treatment Day 1 (Baseline Study)	treatment day 1	Sex Hormone Binding Globulin (SHBG) was measured before and after the treatment week on study treatment days 1 and 8. SHBG was analyzed by immunoassay on a Siemens Immulite 2000. Normal ranges are 10-57 nmol/L.
Sex Hormone Binding Globulin (SHBG) Measured on Treatment Day 8 (Post Study)	treatment day 8	Sex Hormone Binding Globulin (SHBG) was measured before and after the treatment week on study treatment days 1 and 8. SHBG was analyzed by immunoassay on a Siemens Immulite 2000. Normal ranges are 10-57 nmol/L.
Cortisol Measured on Treatment Day 1 (Baseline Study) AFTER Exercise Protocol	treatment day 1 - after exercise	Cortisol was measured before and immediately after the exercise protocol, before and after the treatment week on study treatment days 1 and 8. Serum Cortisol was analyzed by immunoassay on a Siemens Immulite 2000. Normal range is 5-25 ug/dL.
Cortisol Measured on Treatment Day 8 (Post Study) BEFORE Exercise Protocol	treatment day 8 - before exercise	Cortisol was measured before and immediately after the exercise protocol, before and after the treatment week on study treatment days 1 and 8. Serum Cortisol was analyzed by immunoassay on a Siemens Immulite 2000. Normal range is 5-25 ug/dL.
Global Fatigue Score as Measured by Brief Fatigue Inventory (BFI) During the Treatment Week	Study days 1-7 (treatment week)	The Brief Fatigue Inventory is a 9 item questionnaire that assesses perceptual fatigue as well as fatigue interferences (e.g. interference with enjoyment of life), with "0" being no fatigue and "10" being as bad as you can imagine. The Global Fatigue score is calculated by averaging the answers of all the questions. This data is presented as the treatment week average of study days 1-8.