Timing Estrogen After MenoPaUSe (TEMPUS)

February 26, 2021 updated by: University of Colorado, Denver

Time Past Menopause, Duration of Estrogen Deficiency, and Insulin Action

The aim of the current study is to test whether the effect of estrogen on insulin metabolism depends on the timing of treatment relative to when a woman went through menopause. The investigators hypothesize that estrogen will improve insulin sensitivity in early postmenopausal women, but decrease insulin sensitivity in late postmenopausal women.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Large clinical trials have shown a reduced incidence of type 2 diabetes in postmenopausal women randomized to estrogen-based hormone therapy compared to placebo. Moreover, studies suggest development of diabetes is reduced in postmenopausal women who used hormone therapy for a part of the postmenopausal period compared to women who never used hormone therapy. Consistent with this, our preliminary data suggest that the timing of estrogen treatment relative to the menopause may be an important determinant of whether there are favorable effects on insulin action. Our observations suggest that estrogen improves insulin sensitivity in early postmenopausal women, but may decrease insulin sensitivity in those more than 10 years past menopause. More and more studies suggest estrogens have divergent effects on cardiovascular risk when initiated close to the onset of menopause rather than distant from the menopause; we hypothesize this is also true for diabetes risk. The goal of this study is to determine whether the effects of estrogen on insulin metabolism are different in women who are early postmenopausal compared to late postmenopausal. To meet our goal, we propose to measure insulin sensitivity in women who are within 6 years of the onset of menopause or more than 10 years beyond the menopause and who have not used hormone therapy previously. All women will be studied on two separate occasions, one day with and one day without short-term (1 week) treatment with transdermal estradiol. We expect that estradiol will increase insulin sensitivity in early postmenopausal women and decrease insulin sensitivity in late postmenopausal women. We also expect that estrogen receptors in fat and muscle may change with increasing time after menopause. Thus, we will collect fat and muscle biopsies to compare changes in estrogen receptors between early and late postmenopausal women and in response to 1 week of estradiol treatment. We believe these studies will provide evidence for a benefit of estradiol on insulin sensitivity when administered early, but not late, after menopause; likely contributing to delayed onset of type 2 diabetes in postmenopausal women.

Study Type

Interventional

Enrollment (Actual)

53

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Colorado
      • Aurora, Colorado, United States, 80045
        • University of Colorado Denver

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • aged 45-70 yr
  • postmenopausal (no menses ≥12 mo or bilateral oophorectomy and FSH >30 IU/L)
  • ≤6yrs or ≥10yrs of menopause (last menses or oophorectomy)
  • BMI <30 kg/m2 and weight stable (±2kg in past 2mo)
  • non-smokers
  • sedentary to moderately active (<3 days/wk of structured exercise)
  • naïve to estrogen-based hormone therapies (previous use ≤6 months)
  • CBC, CMP and TSH values within normal ranges specified by lab

Exclusion Criteria:

  • underwent a partial hysterectomy (i.e., one or both ovaries left intact)
  • underwent menopause (natural, chemical, or surgical) prior to age 45yr
  • are between >6yr and <10yr of menopause (last menses or oophorectomy)
  • previously used (>6 mo) or are currently using any formulation of estrogen-based HT (e.g., oral Premarin, transdermal 17beta-estradiol, selective estrogen receptor modulators)
  • have T2DM or are being treated with glucose-lowering/ insulin sensitizing medications
  • have uncontrolled hypertension (SBP>140 and/or DBP>90 mmHg)
  • have hypertriglyceridemia (>400 mg/dL)
  • have contraindications to estrogen therapy (history of venous thromboembolism, heart disease, myocardial infarction, hormone sensitive cancer)
  • have contraindications to biopsies (severe anemia, blood clotting disorders)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Early Postmenopausal
Postmenopausal women within 6 years of last menses who never used estrogen-based hormone therapy
Drug: Estradiol

1 week of transdermal estradiol (0.15mg)

1 week of transdermal placebo

Other Names:
  • Climara
Active Comparator: Late Postmenopausal
Postmenopausal women more than 10 years since last menses who never used estrogen-based hormone therapy
Drug: Estradiol

1 week of transdermal estradiol (0.15mg)

1 week of transdermal placebo

Other Names:
  • Climara

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Insulin-mediated Glucose Disposal Rate (Hyperinsulinemic-euglycemic Clamp)
Time Frame: after 1wk estradiol or placebo

Estrogen mediated change in glucose disposal rate and time since menopause

  • Baseline GDR (no difference between groups)
  • E2 mediated change (significant difference between groups)

randomized order of testing, cross-over design
after 1wk estradiol or placebo

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Skeletal Muscle Estrogen Receptor Expression
Time Frame: after 1wk estradiol or placebo

Estrogen receptors (ERα and ERβ) differences in time since menopause and estrogen treatment

randomized order of testing, cross-over design
after 1wk estradiol or placebo
Skeletal Muscle Estrogen Receptor Expression (Protein/Cyto Protein)
Time Frame: after 1wk estradiol or placebo

Estrogen receptors (ERα and ERβ) differences in time since menopause and estrogen treatment

randomized order of testing, cross-over design
after 1wk estradiol or placebo
Adipose Tissue Estrogen Receptor Expression
Time Frame: Baseline

Adipose tissue estrogen receptor expression associated with age and menopause

Abdominal and femoral subcutaneous adipose tissue ERα and ERβ expression
Baseline
Adipose Tissue Estrogen Receptor Expression (ERα:ERβ)
Time Frame: Baseline

Adipose tissue estrogen receptor expression associated with age and menopause

Abdominal and femoral subcutaneous adipose tissue ratio of ERα:ERβ expression
Baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Colorado, Denver

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2011

Primary Completion (Actual)

November 1, 2015

Study Completion (Actual)

January 1, 2017

Study Registration Dates

First Submitted

May 22, 2012

First Submitted That Met QC Criteria

May 23, 2012

First Posted (Estimate)

May 24, 2012

Study Record Updates

Last Update Posted (Actual)

March 1, 2021

Last Update Submitted That Met QC Criteria

February 26, 2021

Last Verified

February 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 11-0788
  • R01DK088105 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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