Insulin Resistance and Testosterone in Women

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT00123110
• Collaborator: National Institute on Aging (NIA) (NIH), The John A. Hartford Foundation (Other), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), University of Pennsylvania Diabetes and Endocrinology Research Center (DERC) (Other), TAP Pharmaceutical Products Inc. (Industry)
• Enrollment: 35
• Location: 1
• Arms: 3
• Duration (Months): 77
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Insulin Resistance; Postmenopause	Drug: metformin; Drug: leuprolide injection; Drug: placebo pill; Drug: placebo injection	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Insulin Resistance and Testosterone in Non-Diabetic Postmenopausal Women
• Study Start Date: Jul 1, 2005
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

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 pill; matching pill twice a day for 12 weeks; Drug: placebo injection; matching injection every 4 weeks (e.g. baseline, 4, and 8 weeks)

Outcome Measures

Primary Outcome Measures

1. Percent Change in Free Testosterone (T) [Baseline to 12 weeks]

   Percent change in free T by equilibrium dialysis between baseline and 12 weeks

2. Change in Insulin Sensitivity [baseline and 12 weeks]

   Change in insulin sensitivity (mg/kg/min) calculated from hyperinsulinemic euglycemic clamp

Secondary Outcome Measures

1. Percent Change in Luteinizing Hormone (LH) From Baseline [baseline and 12 weeks]

2. 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.

3. Percent Change in Low Density Lipoprotein (LDL) [baseline and 12 weeks]

4. Percent Change in Systolic Blood Pressure [baseline and 12 weeks]

5. Free T and IR in Women in Whom Metabolic Syndrome is Present vs. Absent [baseline and 12 weeks]

6. Dehydroepiandrosterone Sulfate (DHEA-S) [baseline and 12 weeks]

7. Body Mass Index (BMI) [baseline and 12 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 79 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pennsylvania Clinical and Translational Research Center	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania
• National Institute on Aging (NIA)
• The John A. Hartford Foundation
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• University of Pennsylvania Diabetes and Endocrinology Research Center (DERC)
• TAP Pharmaceutical Products Inc.

Investigators

• Principal Investigator: Anne R. Cappola, MD, ScM, University of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

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.
• 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.
• Larsson H, Ahrén B. Androgen activity as a risk factor for impaired glucose tolerance in postmenopausal women. Diabetes Care. 1996 Dec;19(12):1399-403.
• 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.

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT00123110
• Other Study ID Numbers: AG0031; K23AG019161; K23AG1916101A1; 5P30DK019525
• First Posted: Jul 22, 2005
• Last Update Posted: May 23, 2019
• Last Verified: May 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Insulin Resistance; Metformin; Leuprolide

Study Results

Participant Flow

Recruitment Details	The participants were recruited beginning 8/11/05 and continued until the last patient was consented on 4/8/08.

Arm/Group Title	Metformin	Leuprolide	Placebo
Arm/Group Description	metformin plus leuprolide placebo (LP) injection	leuprolide plus metformin placebo (MP) pill	MP placebo pill plus LP placebo injection
Period Title: Overall Study
STARTED	12	12	11
COMPLETED	12	12	11
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Metformin	Leuprolide	Placebo	Total
Arm/Group Description	metformin plus leuprolide placebo (LP) injection	leuprolide plus metformin placebo (MP) pill	MP placebo pill plus LP placebo injection	Total of all reporting groups
Overall Participants	12	12	11	35
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56 (4)	58 (7)	62 (7)	58 (7)
Sex/Gender, Customized (participants) [Number]
Female	12 100%	12 100%	11 100%	35 100%

Outcome Measures

1. Primary Outcome

Title	Percent Change in Free Testosterone (T)
Description	Percent change in free T by equilibrium dialysis between baseline and 12 weeks
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Leuprolide	Placebo
Arm/Group Description	Randomized to metformin plus leuprolide placebo, treating insulin resistance	Randomized to leuprolide plus metformin placebo, pharmacologic lowering of testosterone	Placebo metformin plus placebo leuprolide
Measure Participants	12	12	11
Mean (Standard Deviation) [percent change]	-6.9 (22.8)	-35.8 (31.8)	12.1 (17.8)

2. Primary Outcome

Title	Change in Insulin Sensitivity
Description	Change in insulin sensitivity (mg/kg/min) calculated from hyperinsulinemic euglycemic clamp
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Leuprolide	Placebo
Arm/Group Description	Randomized to metformin plus leuprolide placebo, treating insulin resistance	Randomized to leuprolide plus metformin placebo, pharmacologic lowering of testosterone	Placebo metformin plus placebo leuprolide
Measure Participants	12	12	11
Mean (Standard Deviation) [mg/kg/min]	0.44 (0.80)	0.04 (0.81)	-0.08 (0.73)

3. Secondary Outcome

Title	Percent Change in Luteinizing Hormone (LH) From Baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Leuprolide	Placebo
Arm/Group Description	Randomized to metformin plus leuprolide placebo, treating insulin resistance	Randomized to leuprolide plus metformin placebo, pharmacologic lowering of testosterone	Placebo metformin plus placebo leuprolide
Measure Participants	12	12	11
Median (Full Range) [percent change]	4.6	-96.5	-1.2

4. Secondary Outcome

Title	Percent Change in Homeostasis Model Assessment Index of Insulin Resistance (HOMA-IR)
Description	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.
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Leuprolide	Placebo
Arm/Group Description	Randomized to metformin plus leuprolide placebo, treating insulin resistance	Randomized to leuprolide plus metformin placebo, pharmacologic lowering of testosterone	Placebo metformin plus placebo leuprolide
Measure Participants	12	12	11
Mean (Standard Deviation) [percent change]	-31.0 (24.39)	-8.18 (35.3)	4.67 (38.16)

5. Secondary Outcome

Title	Percent Change in Low Density Lipoprotein (LDL)
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Leuprolide	Placebo
Arm/Group Description	Randomized to metformin plus leuprolide placebo, treating insulin resistance	Randomized to leuprolide plus metformin placebo, pharmacologic lowering of testosterone	Placebo metformin plus placebo leuprolide
Measure Participants	12	12	11
Mean (Standard Deviation) [percent change]	-10.8 (22.2)	5.3 (19.3)	25.3 (50.8)

6. Secondary Outcome

Title	Percent Change in Systolic Blood Pressure
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Leuprolide	Placebo
Arm/Group Description	Randomized to metformin plus leuprolide placebo, treating insulin resistance	Randomized to leuprolide plus metformin placebo, pharmacologic lowering of testosterone	Placebo metformin plus placebo leuprolide
Measure Participants	12	12	11
Mean (Standard Deviation) [percent change]	-4.2 (8.6)	4.0 (13.6)	-0.3 (8.6)

7. Secondary Outcome

Title	Free T and IR in Women in Whom Metabolic Syndrome is Present vs. Absent
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

Data were not collected and the outcome will never be analyzed.

Arm/Group Title	Metformin	Leuprolide	Placebo
Arm/Group Description	Randomized to metformin plus leuprolide placebo, treating insulin resistance	Randomized to leuprolide plus metformin placebo, pharmacologic lowering of testosterone	Placebo metformin plus placebo leuprolide
Measure Participants	0	0	0

8. Secondary Outcome

Title	Dehydroepiandrosterone Sulfate (DHEA-S)
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Leuprolide	Placebo
Arm/Group Description	Randomized to metformin plus leuprolide placebo, treating insulin resistance	Randomized to leuprolide plus metformin placebo, pharmacologic lowering of testosterone	Placebo metformin plus placebo leuprolide
Measure Participants	12	12	11
Median (Full Range) [percent change]	2.6	0.9	-2.9

9. Secondary Outcome

Title	Body Mass Index (BMI)
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Leuprolide	Placebo
Arm/Group Description	Randomized to metformin plus leuprolide placebo, treating insulin resistance	Randomized to leuprolide plus metformin placebo, pharmacologic lowering of testosterone	Placebo metformin plus placebo leuprolide
Measure Participants	12	12	11
Mean (Standard Deviation) [percent change]	-1.3 (3.2)	0.1 (1.5)	0.3 (1.1)

Adverse Events

Arm/Group Title	Metformin		Leuprolide		Placebo
Arm/Group Description	metformin plus leuprolide placebo (LP) injection		leuprolide plus metformin placebo (MP) pill		MP placebo pill plus LP placebo injection
All Cause Mortality
	Metformin		Leuprolide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/11 (0%)
Serious Adverse Events
	Metformin		Leuprolide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	Metformin		Leuprolide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/11 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.