Insulin Resistance and Testosterone in Women

This study tests the central hypothesis that insulin resistance (IR) increases androgen (male
sex hormone) production in postmenopausal women. Participation will include five visits, each
lasting on average 2.5 hours, over a period of 13-20 weeks.

At the screening visit, the participant's medical history, current use of medications and
dietary supplements, and social habits will be recorded. This information will be reviewed on
each subsequent visit; participants are asked to maintain their current diet and physical
activity level throughout the study.

A brief physical exam will be performed, and blood will be drawn.

At the 2nd (baseline) visit, patients will undergo a euglycemic-hyperinsulinemic clamp (a
procedure to measure insulin sensitivity by continuous intravenous infusion of insulin, and
variable infusion of glucose). Blood samples will be drawn throughout the procedure. At
completion, the insulin infusion will be stopped, participants will be fed, and the glucose
infusion continued for at least 15 minutes to ensure stability of the blood glucose
concentration. After the procedure, participants will be randomized to receive either
metformin plus leuprolide placebo, leuprolide plus metformin placebo, or metformin placebo
plus leuprolide placebo. The leuprolide or leuprolide placebo will be administered as an
injection by a nurse. The metformin or metformin placebo will be dispensed to the participant
in the form of pills, with instructions for titrating the dose. Participants will be
contacted by telephone once weekly during the titration period to assess drug tolerability
and adverse events (AEs). Participants will be maintained at their maximum tolerated dose for
the duration of the study intervention period.

Participants will return every 4 weeks for follow-up. Blood will be drawn, the nurse will
administer the leuprolide or leuprolide placebo injection, and metformin or metformin placebo
will be dispensed. At the final visit (week 12), participants will undergo a brief physical
exam, and will then undergo a final euglycemic-hyperinsulinemic clamp.

Inclusion Criteria:

- Postmenopausal women aged 50-79 years with absence of menses for 12 months; for women
50-54 years, FSH>30 mIU/mL to confirm postmenopausal status

- At least one intact ovary

- Free testosterone and fasting insulin levels within required study parameters

- Willing to comply with all study-related procedures

- Capable of giving informed consent

Exclusion Criteria:

- History of cancer requiring treatment within the past 5 years (exceptions may be made
by investigator)

- Hospitalization for treatment of vascular disease in the past 6 months

- Uncontrolled hypertension

- Hospitalization for chronic obstructive pulmonary disease or asthma in the past 3
months

- Use of continuous oxygen at home

- Surgery in the last 30 days

- Positive for HIV

- Abnormal blood tests (hemoglobin, fasting triglycerides, fasting glucose, creatinine,
liver function)

- History of diabetes mellitus or use of any anti-hyperglycemic medication in the past 3
months

- Disease associated with disordered glucose metabolism (Cushing's disease, acromegaly,
pheochromocytoma not surgically cured, chronic pancreatitis)

- History of chronic renal insufficiency

- Intravenous (IV) contrast studies with iodinated materials planned for the 12 week
intervention period that cannot be postponed according to the participant's primary
care provider

- Acute or chronic metabolic acidosis

- History of liver disease

- Congestive heart failure

- History of androgen-secreting tumors

- Hormone replacement therapy or antiandrogen use in past 6 months

- Use of DHEA or other androgen-containing products in past 6 months

- Corticosteroid use, other than topical, ophthalmic, intraarticular, and inhaled
preparations, in past 3 months

- Undiagnosed current vaginal bleeding

- Excessive alcohol intake, either acute or chronic; current illicit substance abuse

- Participation in an investigational drug study within 6 weeks prior to screening visit

- Serious or unstable medical or psychological conditions that, in the opinion of the
investigator, would compromise the patient's safety or successful participation in the
study