Brown Adipose Tissue Activity in Pre- and Postmenopausal Women

The Impact of Estrogen Status on the Biological Function of Brown Adipose Tissue in Women Measured Using Quantitative PET/CT

The physiological relevance of brown adipose tissue (BAT) in humans is largely unknown. The investigators have shown that suppressing ovarian function in premenopausal women reduces resting energy expenditure (REE), and this is prevented by adding back estradiol (E2). The investigators preliminary data suggest that this may be due, in part, to reduced brown adipose tissue (BAT) activity. The overarching hypothesis is that BAT activity in humans is modulated by E2. To determine if natural declines in endogenous E2 contribute to changes in BAT activity, we will compare BAT activity in pre-and post-menopausal women. The investigators will also explore whether suppression of ovarian hormones in pre-menopausal women impairs BAT activity. BAT activity will be quantified using dynamic positron emission topography/computed tomography (PET/CT) imaging combined with 11C-acetate tracers. We will assess the thermogenic response of BAT by measuring cold-induced changes in REE, shivering, and skin and core temperature.

Study Overview

• Status: Completed
• Conditions: Obesity; Menopause
• Intervention / Treatment: Drug: Leuprolide acetate

Detailed Description

Participants will be asked to perform studies to measure resting metabolic rate and activity of brown adipose tissue or brown fat. Brown fat is different from regular "white fat" in that it produces heat and burns calories. The investigators will measure how active brown fat is at normal room temperature and after participants have been exposed to cold.

The study will last 5-6 hours. It will consist of measurements made in warm temperatures and then after a period of cold exposure. For the cold exposure part of the study, participants will be asked to wear a cooling suit for 3 hrs. Skin temperature is normally about 90º Fahrenheit. The cooling suit will adjust the water temperature until your skin temperature is about 82º Fahrenheit. The suit will cover the entire body except for the face, hands, and feet. Participants may feel cold while wearing the suit and you may shiver some, but based on past studies, any shivering should be minor.

Before and after the cooling suit is turned on, body scans will be performed using a procedure called positron emission tomography (PET). These scans do not use radiation. Before the PET scans, the investigators will infuse radioactive tracer into an arm. These tracers have a low dose of radiation and will show us where the brown fat is and how active it is. One PET scan will be performed at room temperature, and the second scan will be performed after the cooling suit has been worn for 3 hours. Two additional scans using computed tomography (CT) will be performed at end of the study. CT scans are like an x-ray, and use radiation. The radiation dose in the CT scan is much higher than the tracers. When the CT scans are combined with the PET scans, we can separate brown fat from white fat.

15 pre-menopausal women will be asked to volunteer for a follow up study. For 5 months, pre-menopausal women in this study will receive monthly injections that contain a study drug (leuprolide) that reduces estrogen to postmenopausal levels. This drug is approved by the FDA to reduce estrogen for the treatment of uterine fibroids and endometriosis, but is not approved for use in healthy women. In this study, the drug is being used to decrease hormones to determine if this reduces brown fat activity. 6 months after the first injection, these women will be asked to repeat the PET/CT studies.

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Edward Melanson, PHD; Phone Number: 303-724-0935; Email: ed.melanson@cuanschutz.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Premenopausal volunteers will be healthy, eumenorrheic women, aged 18-45 yrs. Eumenorrheic status will be verified by regular menses (no missed cycles in previous year; cycle length 25-35 d).
• Postmenopausal volunteers will be healthy women who have no menses for at least 12 months

Exclusion Criteria:

- Body mass index (BMI) > 35 kg/m2

Additional exclusion criteria for premenopausal women

• Hormonal contraceptive use (past 6 mo.)
• Pregnant, lactating or intention to become pregnant during the period of study

Additional exclusion criteria for postmenopausal women

• History or current use of hormonal replacement therapy (HRT)
• Women who have undergone surgical menopause.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pre-menopausal women; To determine if natural declines in endogenous E2 contribute to changes in BAT activity, the investigators will compare BAT activity in pre-and post-menopausal women. We will also explore whether suppression of ovarian hormones in pre-menopausal women (using leuprolide acetate) impairs BAT activity.	Drug: Leuprolide acetate; A subset of premenopausal women will receive GnRHAG (leuprolide acetate) 3.75 mg/mo by intramuscular injection every 4 weeks for 24 weeks (6 doses).; Other Names: Lupron
No Intervention: Post-menopausal women; To determine if natural declines in endogenous E2 contribute to changes in BAT activity, the investigators will compare BAT activity in pre-and post-menopausal women.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brown Adipose Tissue Volume	Brown adipose tissue volume will be measured using the radioactive tracer 18Fluro-deoxyglucose.	5-6 hrs
Brown Adipose Tissue Activity -Warm Exposure	Brown adipose tissue activity in warm temperatures will be measured using the radioactive tracer 11C-acetate	5-6 hrs
Brown Adipose Tissue Activity - ColdExposure	Brown adipose tissue activity after cold exposure will be measured using the radioactive tracer 11C-acetate	5-6 hrs

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resting energy expenditure - before cold exposure	Resting energy expenditure is the calories burned when a person is at rest.	5-6 hrs.
Resting energy expenditure - after cold exposure	Resting energy expenditure is the calories burned when a person is at rest.	5-6 hrs

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Université de Sherbrooke; University of Ottawa
• Investigators: Principal Investigator: Edward Melanson, Ph.D., University of Colorado, Denver

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2017
• Primary Completion (Actual): May 2, 2023
• Study Completion (Actual): May 2, 2023

Study Registration Dates

• First Submitted: October 4, 2016
• First Submitted That Met QC Criteria: October 6, 2016
• First Posted (Estimated): October 7, 2016

Study Record Updates

• Last Update Posted (Estimated): December 4, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Leuprolide
• Other Study ID Numbers: 16-1479; 1R01DK112260-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

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