The Effects of Long Term Cyclic Testosterone Administration on Muscle Function and Bone in Older Men

The hypothesis is based on data from our current NIA-funded R01 protocol. The investigators
treated older men with weekly intramuscular injections of testosterone enanthate (100 mg)
for 4 weeks followed by 4 weeks of placebo injections. This 4-week-on, 4-week-off cycled
treatment regimen was repeated for 5 cycles (20 weeks). This group was compared with a group
of older men who received SOC weekly intramuscular injections of testosterone enanthate (100
mg) for 20 weeks, and another group who received placebo injections. Our preliminary data
showed equal gains over placebo in muscle strength and lean body mass in those who received
testosterone for 20 weeks, whether SOC continuous or cycled. Moreover, both groups showed
greater bone density and markers of bone formation over placebo. In terms of the anabolic
actions of testosterone on skeletal muscle in the older men, the investigators found that
continuous and cycled administration of testosterone primarily stimulated muscle protein
synthesis for the 20 weeks of the study. Cycled testosterone administration enhanced muscle
protein synthesis throughout the full 5 cycles of 20 weeks, with no significant loss in
muscle protein synthesis during the off-cycle weeks. Additionally, cycled and continuous
testosterone administration reduced serum markers of bone resorption compared with placebo.
These exciting findings of the benefits of a cycled testosterone regimen in older men
represent a novel therapeutic paradigm over the existing SOC approach of continuous
administration. The investigators believe the cycled regimen offers a more safe and
efficacious approach to combat sarcopenia and osteoporosis with equal anabolic benefit to
muscle and bone with only half the dose of testosterone. Critical to the application of this
significant paradigm shift in testosterone administration is to determine whether these
effects at 20 weeks can persist for the 52 weeks proposed in this study, which represents a
treatment duration applicable to the traditional SOC approach.

Thus, the central hypothesis is that cycled administration of testosterone for 52 weeks in
healthy, older men will increase muscle function as determined by muscle strength
measurements (Biodex dynamometer), lean body mass (DEXA) and muscle volume (MRI), and bone
density (DEXA) similar to SOC continuous testosterone administration. Moreover, the
investigators anticipate reduced side effects of testosterone administration in the cycled
group since they will receive one half the dose over the 52 weeks. The investigators will
test the following specific hypotheses in healthy older adults during 52 weeks of cycled,
continuous, or placebo testosterone:

1. Cycled and continuous testosterone will increase muscle strength of upper and lower
extremities compared with placebo as determined by Biodex dynamometer assessment.

2. Cycled and continuous testosterone will increase lean body mass and muscle volume
compared with placebo as determined by DEXA and MRI.

3. Cycled and continuous testosterone will increase bone density compared with placebo as
determined by DEXA. The following specific aims will be tested in a randomized
double-blind placebo-controlled trial in healthy, older men (60-75 years) undergoing 52
weeks of cycled, continuous, or placebo testosterone:

1. To determine if cycled and continuous testosterone administration increases muscle
strength compared to placebo. 2. To determine if cycled and continuous testosterone
administration increases lean body mass and muscle volume compared to placebo. 3. To
determine if cycled and continuous testosterone administration increases bone density
compared to placebo. Our overall goal is to complete a long-term study to determine whether
cycled testosterone achieves the same gains in muscle and bone function in older men as SOC,
continuous testosterone administration. If our hypothesis is correct, then the investigators
will validate an important paradigm shift in testosterone administration in older men that
will help combat the disability of sarcopenia and osteoporosis using half the dose of
testosterone of the current SOC approach. This reduction is testosterone dose should lessen
the side effects and improve the safety of testosterone administration in healthy older men
requiring androgen therapy.

Inclusion Criteria:

1. Age: 60-75 years

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

3. Mini Mental State Exam Score (MMSE) > 26

Exclusion Criteria:

1. Exclusionary medications will be an anticoagulant (Coumadin) because of the risk of
bleeding during the biopsy procedure and weekly injections and glucocorticoids
because of the risk of myopathy.

2. Subjects must be able to successfully complete an exercise stress test using the
Bruce protocol because the muscle biopsies in the protocol are stressful and muscle
strength measurements will be done. 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 ≥0.1 mV horizontal or
downsloping ST segment depression, a drop in systolic blood pressure of ≥10 mm Hg
millimeters mercury), and/or frequent or repetitive arrhythmias (defined as ≥10
premature ventricular contractions (PVC)/min, or couplets) during the stress test
will be excluded.

3. Subjects with a history of stroke will be excluded.

4. Subjects with LDL cholesterol above 200 mg/dL will be excluded because testosterone
administration may elevate LDL cholesterol levels further.

5. Diagnosed prostate cancer or prostatic intraepithelial neoplasia (PIN) or, by the
Prostate Cancer Risk Calculator, a >30% risk of having overall prostate cancer or >7%
risk of having high grade prostate cancer. This is the current exclusion criteria
employed by The National Institute on Aging sponsored Testosterone Trial.

6. Men with serum total testosterone concentrations greater than 500 ng/dL will be
excluded.

7. Subjects who engage in high intensity exercise training on a regular basis will be
excluded.

8. Any subject who has an established major medical illness such as chronic obstructive
pulmonary disease, or untreated sleep apnea will be excluded.

9. A hematocrit greater than 51%.

10. Any subject with a blood pressure on three consecutive measurements taken at one week
intervals that has a systolic pressure ≥ 160mm Hg or a diastolic blood pressure ≥
100mmHg will be excluded. Subjects will be included if they are on two or less blood
pressure medications and have a blood pressure below these criteria.

11. Any subject with a history of significant liver disorders or a 3-fold elevation of
liver function tests (Alk phos, alanine aminotransferase) (ALT), aspartate
aminotransferase (AST).

12. Subjects currently taking anti-bone-resorptive agents such as bisphosphonates,
parathyroid hormone, or calcitonin will be excluded from the study.

13. Subjects with uncontrolled endocrine or metabolic disease (e.g. liver disease, renal
disease, diabetes).

14. Subjects that are HIV-seropositive or have active hepatitis*.

15. Subjects with a history of recent anabolic or corticosteroids use (within 3 months).

16. Subjects with metal fragments or metal devices contained in their bodies.

17. Any other condition or event considered exclusionary by the PI and covering faculty
physician.