Cycled Testosterone Therapy to Improve Physical Function in Frail Nursing Home Residents

Frailty with aging is a serious debilitating condition that can further contribute to a
downward spiraling of health and physical function. Many long term nursing home patients
enter into rehabilitative care programs with the intent to increase strength and physical
independence. However, many patients have lasting functional limitations despite
rehabilitation programs intended to improve their physical function and sarcopenia and
frailty is common among nursing home residents. Aging in general, and frailty in particular,
has been associated with decreases in sex hormones, and testosterone treatment has known
anabolic effects to muscle of hypogonadal as well has eugonadal males. Effective adjuvant
treatments that can be safely employed in conjunction with existing therapies such as
rehabilitative care intended to improve function can have profound benefits to the long-term
outcome of male and female patients.

The investigators have demonstrated that administration of testosterone (100 mg/wk) starts
showing improvements in lean body mass (LBM) as early as 4 weeks and muscle strength by 8
weeks in healthy older community dwelling males (Sheffield-Moore et al., 2011). In this
study, both continuous weekly treatment as well as intermittent treatment (4 weeks on
testosterone, 4 weeks off testosterone, etc) resulted in similar benefits after 20 weeks. In
addition, the investigators recently completed a 10-week study where the investigators showed
both the safety and efficacy of cycled testosterone treatment (100 mg/wk for 2 weeks,
alternated by 2 weeks of no treatment) in combination with regular exercise in healthy
eugonadal adult men confined to continuous bed rest (see preliminary data). In that study,
testosterone robustly increased LBM in as little as 2 weeks of bed rest and improvements in
LBM were associated with better protection of physical function upon reambulation.

It is proposed that a cycled testosterone paradigm may be a safe and effective adjuvant
therapy for frail older nursing home patients undergoing physical rehabilitation. The
investigators hypothesize that testosterone treatment in addition to standard-of-care (SOC)
physical therapy or rehabilitation will result in improved muscle mass and physical function
when compared to patients receiving SOC only. The long term goal is to develop effective
treatments against the functional declines in muscle mass and strength that contribute to the
development and progression of frailty. Therefore, the investigators will test the specific
aims outlined below in older male and female residents engaging in rehabilitation care at
health care centers in Texas City and Galveston. Men and women (age 60-up) will be recruited
as they enroll into rehabilitative care programs, screened upon informed consent, and if
eligible, block-randomized (double-blinded) to receive either testosterone enanthate (100
mg/wk for males and 25 mg/wk for females) or placebo (saline) treatment for 10 weeks. The
treatment will follow a 2-week cycle (2 weeks on-treatment, 2 weeks off, etc). Primary
outcomes will be assessed using non-invasive methods at baseline and at completion of the
study after 10 weeks. These outcomes will include body composition as determined with
bioelectric impedance analysis (BIA), muscle strength and fatigue by handgrip dynamometry,
physical function by a short physical performance battery (SPPB), and quality of life (QOL)
by a short battery of questionnaires. Blood samples will be collected at screening for safety
and will be repeated at completion of the study for secondary outcome measures (hormones,
lipid profiles and blood chemistries).

Specific Aim 1. Determine the effects of cycled testosterone treatment on body composition in
male and female nursing home residents undergoing rehabilitative care.

Specific Aim 2. Determine the effects of cycled testosterone treatment on physical function
in male and female nursing home residents undergoing rehabilitative care.

Data from this pilot/feasibility project will become the foundation for the development of a
larger long-term project solicitation to the NIH aimed at elucidating the efficacy of
testosterone treatment on physical function and independence in frail older adults.

Inclusion Criteria:

1. Male or Female

2. Ages: 60 years or older

3. Starting rehabilitative care

Exclusion Criteria:

1. Inability to perform the functional tests specific to the study protocol

2. Diagnosed with carcinomas of the breast or with known or suspected carcinomas of the
prostate.

3. Uncontrolled endocrine or metabolic disease (e.g. liver disease, renal disease,
diabetes).

4. Uncontrolled hypertension. Systolic blood pressure =/> 160mm Hg or a diastolic blood
pressure =/> 100mm Hg on three consecutive measurements taken at one-week intervals.
Testosterone, other anabolic steroids and glucocorticoids can cause fluid retention
that could worsen uncontrolled hypertension. Subjects will be included if they are on
two or less blood pressure medications and have a blood pressure below these criteria.

5. History of significant liver disorders or a 3-fold elevation of liver function tests
(Alk phos, ALT, AST). Testosterone can have hepatotoxic effects in some subjects and
should be used with careful monitoring of LFTs (liver function), though injections of
testosterone at a 100 mg dose is not typically sufficient to negatively affect LFTs.

6. History of angina that occurs with exertion or at rest or a myocardial infarction
within the last 12 months.

7. LDL cholesterol greater than 200 mg/dL as testosterone administration may elevate LDL
cholesterol levels further, though this is not anticipated with testosterone
injections of 100 mg/wk.

8. Hematocrit greater than 51%.

9. Established chronic obstructive pulmonary disease, or untreated sleep apnea.

10. Implanted artificial pacemaker/defibrillator. BIA uses small currents and is not
recommended for participants with a pacemaker.

11. Diagnosed systemic fungal infections.

12. Positive screening for HIV or active hepatitis*.

13. Use of or history of recent anabolic steroid use (within 3 months).

14. Alcohol or drug abuse.

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

16. Vulnerable populations including: individuals unable to consent on their own behalf,
prisoners and pregnant women.

- Subjects excluded due to positive screening results, including HIV, HBV or HCV,
will be immediately scheduled for counseling and follow-up testing as needed, and
will be advised to consult their primary physician.