Insulin Resistance and Testosterone in Women

Phase 2

Completed

• Conditions: Insulin Resistance; Postmenopause
• Interventions: Drug: placebo pill; Drug: leuprolide injection; Drug: metformin; Drug: placebo injection

• Registration Number: NCT00123110
• Lead Sponsor: University of Pennsylvania

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.

Study Timeline

• Study Start: 2005-07
• Study First Submitted: 2005-07-19
• Study First Submitted QC: 2005-07-19
• Study First Posted: 2005-07-22
• Primary Completion: 2011-12
• Study Completion: 2011-12
• Results First Submitted: 2013-01-16
• Status Verified: 2019-05
• Results First Submitted QC: 2019-05-21
• Last Update Submitted: 2019-05-21
• Results First Posted: 2019-05-23
• Last Update Posted: 2019-05-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 35

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
3	placebo pill	placebo pill plus placebo injection
1	placebo injection	metformin pill plus placebo injection
2	leuprolide injection	leuprolide injection plus placebo pill
2	placebo pill	leuprolide injection plus placebo pill
3	placebo injection	placebo pill plus placebo injection
1	metformin	metformin pill plus placebo injection

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Percent Change in Homeostasis Model Assessment Index of Insulin Resistance (HOMA-IR)	baseline and 12 weeks	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.
Percent Change in Low Density Lipoprotein (LDL)	baseline and 12 weeks
Percent Change in Luteinizing Hormone (LH) From Baseline	baseline and 12 weeks
Percent Change in Systolic Blood Pressure	baseline and 12 weeks
Body Mass Index (BMI)	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

Trial Locations

Locations (1)

University of Pennsylvania Clinical and Translational Research Center; 🇺🇸 Philadelphia, Pennsylvania, United States