Insulin Resistance and Testosterone in Women

Study Overview
=================
Brief Summary
-----------------
The purpose of this research study is to determine if a relationship between insulin resistance (IR) and testosterone (T) exists in women who have already gone through menopause.

Detailed Description
-----------------
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.

Official Title
-----------------
Insulin Resistance and Testosterone in Non-Diabetic Postmenopausal Women

Conditions
-----------------
Insulin Resistance, Postmenopause

Intervention / Treatment
-----------------
* Drug: metformin
* Drug: leuprolide injection
* Drug: placebo pill
* Drug: placebo injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Postmenopausal women aged 50-79 years with absence of menses for 12 months; for women 50-54 years, Follicle stimulating hormone>30 U/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 dehydroepiandosterone (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

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 79 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>metformin pill plus placebo injection | Drug: metformin<br>* Initiated on 500 mg daily and titrated up to 1000 mg twice a day during the first four weeks, remaining at that dose until 12 weeks<br>* Other names: Glucophage;Drug: placebo injection<br>* matching injection every 4 weeks (e.g. baseline, 4, and 8 weeks)<br>|
| Experimental: 2<br>leuprolide injection plus placebo pill | Drug: leuprolide injection<br>* 3.75 mg injection every 4 weeks (e.g. at baseline, 4, and 8 weeks)<br>* Other names: Lupron;Drug: placebo pill<br>* matching pill twice a day for 12 weeks<br>|
| Placebo Comparator: 3<br>placebo pill plus placebo injection | Drug: placebo pill<br>* matching pill twice a day for 12 weeks<br>Drug: placebo injection<br>* matching injection every 4 weeks (e.g. baseline, 4, and 8 weeks)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Free Testosterone (T) | Percent change in free T by equilibrium dialysis between baseline and 12 weeks | Baseline to 12 weeks | 
| Change in Insulin Sensitivity | Change in insulin sensitivity (mg/kg/min) calculated from hyperinsulinemic euglycemic clamp | baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Luteinizing Hormone (LH) From Baseline |  | baseline and 12 weeks | 
| Percent Change in Homeostasis Model Assessment Index of Insulin Resistance (HOMA-IR) | Insulin resistance calculated from homeostasis model assessment of insulin resistance (HOMA-IR) equation: fasting insulin x fasting glucose / 405. Higher values indicate more insulin resistance. | baseline and 12 weeks | 
| Percent Change in Low Density Lipoprotein (LDL) |  | baseline and 12 weeks | 
| Percent Change in Systolic Blood Pressure |  | baseline and 12 weeks | 
| Free T and IR in Women in Whom Metabolic Syndrome is Present vs. Absent |  | baseline and 12 weeks | 
| Dehydroepiandrosterone Sulfate (DHEA-S) |  | baseline and 12 weeks | 
| Body Mass Index (BMI) |  | baseline and 12 weeks |