DHEA Augmentation of Musculoskeletal Adaptations to Exercise in Older Women

This will be the first study to measure changes in areal bone mineral density (aBMD) and
fat-free mass (FFM) in response to dehydroepiandrosterone (DHEA) alone and combined with
exercise in postmenopausal women. The body of evidence from carefully executed Randomized
Controlled Studies (RCTs) provides support for DHEA therapy to increase aBMD and FFM in older
women. Less is known about whether DHEA therapy enhances the effects of exercise on the aging
musculoskeletal system when an appropriate mechanical stimulus is applied.

Inclusion Criteria:

- non-frail, as determined by short physical performance battery (SPPB) score > 9 (0-12
scale);

- 5 years or longer since menopause (defined as last menstrual period);

- willing to participate in a 36-week exercise program that will start at a moderate
intensity and gradually progress to a higher intensity;

- willing to be randomized to an exercise or a no-exercise arm of the study;

- willing to take DHEA (50mg/d) or a placebo pill daily and remain blinded for up to 36
weeks;

- not performing resistance exercise training or high impact weight-bearing exercise
(e.g., jogging) ≥ 2 days per week in the past 6 months;

- ambulatory without assistive devices;

- serum DHEAS < 140 μg/dL (3.8 μmol/L);

- low bone mass defined as lumbar spine or proximal hip aBMD t-scores < -1.0 and > -2.5;

- evidence of a negative (no findings suspicious for breast cancer) mammogram within the
past 12 months;

- planning to reside in the Denver area for the duration of the study.

Exclusion Criteria:

- uncontrolled hypertension defined as resting sBP >150 mmHg or dBP >90 mmHg;
participants who do not meet these criteria at first screening will be re-evaluated,
including follow-up evaluation by their Primary Care Physician (PCP) with initiation
or adjustment of anti-hypertensive medications;

- diagnosed ischemic heart disease or indicators of unstable ischemic heart disease
(e.g., angina, ST segment depression) or arrhythmias at rest or during the Gated
Exercise Test (GXT) without negative follow-up evaluation will be cause for exclusion;
follow-up evaluation must include diagnostic testing (e.g., thallium stress test) with
interpretation by a cardiologist;

- diagnosis of heart failure, clinically significant aortic stenosis, uncontrolled
angina, or uncontrolled arrhythmia.

- pulmonary disease requiring use of oral steroids within the previous 6 months or the
use of supplemental oxygen ≥ 4L with physical exertion

- orthopedic problems (e.g., severe osteoarthritis, rheumatoid arthritis) that greatly
limit the ability to perform moderate to high intensity resistance exercise (e.g.,
unable to be properly positioned in exercise equipment or to have severely restricted
range of motion even after modifications have been made)

- hip fracture, hip or knee replacement, or spinal surgery in the past 6 months;

- undergoing physical therapy involving the lower extremities;

- HCT > 54%;

- thyroid dysfunction, defined as an ultrasensitive thyroid stimulating hormone (TSH) <
0.5 or > 5.0 μU/mL; volunteers with abnormal TSH values will be re-considered for
participation in the study after follow-up evaluation by their PCP with initiation or
adjustment of thyroid hormone replacement;

- acute liver disease indicated by liver function tests (alanine aminotransferase (ALT),
aspartate aminotransferase (AST), alkaline phosphatase) ≥ 1.5X upper limits of normal;

- estimated glomerular filtration rate (eGFR) < 45, using MDRD equation (Levey et al,
Annals Inter Med, 1999; Munter et al, Clin J Am Soc Nephol, 2009);

- poorly controlled diabetes mellitus based on HbA1c > 8.5%, or use of insulin;

- fasted serum triglycerides > 400 mg/dL;

- serum 25-OH vitamin D <20 ng/mL; volunteers will be re-considered for participation in
the study after follow-up evaluation by their PCP with initiation or adjustment of
vitamin D supplementation;

- use of DHEA supplementation or sex hormones in the past 6 months;

- use in the past 6 months of any medications known to alter bone metabolism (e.g., oral
glucocorticoids, bone anti-resorptive agents);

- documented history of cognitive impairment or dementia, or Mini-Cog < 4;

- current smoker;

- personal history of breast, ovarian, metastatic endometrial, or cervical cancer;

- any cancer requiring treatment in the past 3 years except non-melanoma skin cancers;

- un-diagnosed vaginal bleeding;

- women who, in the judgment of the study physician, appear incapable of safely
participating in the exercise (e.g., neuromuscular/musculoskeletal impairment).