Clinical trial NCT00123110: Insulin Resistance and Testosterone in Women
Official title: Insulin Resistance and Testosterone in Non-Diabetic Postmenopausal Women
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Insulin Resistance
Postmenopause
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
name: The John A. Hartford Foundation
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: University of Pennsylvania Diabetes and Endocrinology Research Center (DERC)
name: TAP Pharmaceutical Products Inc.
First posted: 2005-07-22
Enrollment: 35
Sex: FEMALE
Minimum age (years): 50
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Percent Change in Free Testosterone (T)
timeFrame: Baseline to 12 weeks
measure: Change in Insulin Sensitivity
timeFrame: baseline and 12 weeks
Secondary outcomes:
measure: Percent Change in Luteinizing Hormone (LH) From Baseline
timeFrame: baseline and 12 weeks
measure: Percent Change in Homeostasis Model Assessment Index of Insulin Resistance (HOMA-IR)
timeFrame: baseline and 12 weeks
measure: Percent Change in Low Density Lipoprotein (LDL)
timeFrame: baseline and 12 weeks
measure: Percent Change in Systolic Blood Pressure
timeFrame: baseline and 12 weeks
measure: Free T and IR in Women in Whom Metabolic Syndrome is Present vs. Absent
timeFrame: baseline and 12 weeks
measure: Dehydroepiandrosterone Sulfate (DHEA-S)
timeFrame: baseline and 12 weeks
measure: Body Mass Index (BMI)
timeFrame: baseline and 12 weeks
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: University of Pennsylvania Clinical and Translational Research Center
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Anne R. Cappola, MD, ScM
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.