Insulin Resistance and Testosterone in Women

Insulin Resistance and Testosterone in Non-Diabetic Postmenopausal Women

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.

Study Overview

• Status: Completed
• Conditions: Insulin Resistance; Postmenopause
• Intervention / Treatment: Drug: metformin; Drug: placebo injection; Drug: leuprolide injection; Drug: placebo pill

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 Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Clinical and Translational Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 79 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1; metformin pill plus placebo injection	Drug: metformin; 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; Other Names: Glucophage; Drug: placebo injection; matching injection every 4 weeks (e.g. baseline, 4, and 8 weeks)
EXPERIMENTAL: 2; leuprolide injection plus placebo pill	Drug: leuprolide injection; 3.75 mg injection every 4 weeks (e.g. at baseline, 4, and 8 weeks); Other Names: Lupron; Drug: placebo pill; matching pill twice a day for 12 weeks
PLACEBO_COMPARATOR: 3; placebo pill plus placebo injection	Drug: placebo injection; matching injection every 4 weeks (e.g. baseline, 4, and 8 weeks); Drug: placebo pill; matching pill twice a day for 12 weeks

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

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute on Aging (NIA); TAP Pharmaceutical Products Inc.; The John A. Hartford Foundation; University of Pennsylvania Diabetes and Endocrinology Research Center (DERC)
• Investigators: Principal Investigator: Anne R. Cappola, MD, ScM, University of Pennsylvania

Publications and helpful links

General Publications

• Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002 Jan 16;287(3):356-9. doi: 10.1001/jama.287.3.356.
• Golden SH, Ding J, Szklo M, Schmidt MI, Duncan BB, Dobs A. Glucose and insulin components of the metabolic syndrome are associated with hyperandrogenism in postmenopausal women: the atherosclerosis risk in communities study. Am J Epidemiol. 2004 Sep 15;160(6):540-8. doi: 10.1093/aje/kwh250.
• Larsson H, Ahren B. Androgen activity as a risk factor for impaired glucose tolerance in postmenopausal women. Diabetes Care. 1996 Dec;19(12):1399-403. doi: 10.2337/diacare.19.12.1399.
• Oh JY, Barrett-Connor E, Wedick NM, Wingard DL; Rancho Bernardo Study. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care. 2002 Jan;25(1):55-60. doi: 10.2337/diacare.25.1.55.

Study record dates

Study Major Dates

• Study Start: July 1, 2005
• Primary Completion (ACTUAL): December 1, 2011
• Study Completion (ACTUAL): December 1, 2011

Study Registration Dates

• First Submitted: July 19, 2005
• First Submitted That Met QC Criteria: July 19, 2005
• First Posted (ESTIMATE): July 22, 2005

Study Record Updates

• Last Update Posted (ACTUAL): May 23, 2019
• Last Update Submitted That Met QC Criteria: May 21, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Leuprolide; Metformin
• Other Study ID Numbers: AG0031; K23AG019161 (NIH); K23AG1916101A1 (OTHER_GRANT: NIA); 5P30DK019525 (NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO