The Influence of Gonadal Hormone Suppression on Adipocyte Lineage and the Microbiome

Not Applicable

Terminated

• Conditions: Microbiome; Adipose Tissue; Menopause
• Interventions: Other: GnRHag

• Registration Number: NCT03396978
• Lead Sponsor: University of Colorado, Denver

Brief Summary

This research study plans to learn more about the role of female sex hormones on adipose tissue (or fat) and the gut microbiome (or the organisms that are in your digestive tract). The rationale for this study is that the rate at which women gain fat (especially in the stomach region) increases after menopause. It is thought to be due to the loss of estrogen because post-menopausal women who take estrogen gain less weight than those who do not take estrogen. Gut bacteria process estrogen and help determine the types of estrogen that circulate in the body. These bacteria can be changed with lifestyle factors such as diet, and may therefore, also affect the risk of diseases that are more common in women after menopause i.e., cardiovascular disease and cancer. In this study the investigators will obtain fat biopsies before and after 6 months of ovarian hormone suppression to measure how the fat cells change with the loss of female sex hormones (e.g., medical menopause). The investigators will also obtain stool and urine samples before and every month during the study to measure changes in the microbiome.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-01-05
• Study First Submitted QC: 2018-01-05
• Study Start: 2018-01-11
• Study First Posted: 2018-01-11
• Primary Completion: 2019-12-18
• Study Completion: 2019-12-18
• Status Verified: 2021-08
• Last Update Submitted: 2021-08-18
• Last Update Posted: 2021-08-25

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Female
• Target Recruitment: 5

Inclusion Criteria

• Enrollment into the parent protocol (COMIRB 16-1479 - The impact of estrogen status on the biological function of brown adipose tissue in women measured using quantitative PET/CT; PI - Edward Melanson, PhD)
• Participation in GnRHag intervention

Exclusion Criteria

• Known allergy to lidocaine or other numbing medication
• Uncontrolled bleeding disorder or inability to withhold aspirin/NSAIDs or other blood thinning medications for 7 days prior to biopsy procedure.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
GnRHag	GnRHag	Participants will undergo 6 months of gonadotropin releasing hormone agonist (GnRHag) therapy (intramuscular injection of leuprolide acetate 3.75 mg for depot suspension; Lupron; TAP Pharmaceutical Products, Inc.; Lake Forest, IL) to chronically suppress ovarian hormones. A single injection of leuprolide acetate produces an initial stimulation (for up to 3 wk) followed by a prolonged suppression of pituitary gonadotropins and ovarian hormones. Repeated monthly dosing suppresses ovarian hormone secretion.

Primary Outcome Measures

Name	Time	Method
Accumulation of Myeloid Cells	8 months after enrollment of last participant	Quantification of accumulation of myeloid cells in abdominal subcutaneous adipose tissue of women before and after gonadal hormone suppression as assessed by CD45+/CD14+ staining via flow cytometry of isolated adipose stroma.
Progenitor proliferation and adipogenic potential	1 year after completion of last participant	Progenitor proliferation measured by BrdU and adipogenic potential as measured by Oil Red-O staining with quantification by absorbance. Adipocyte specific gene/protein expression will be measured to confirm adipocyte status.
Gut microbial diversity	1 year after completion of last participant	Comparison of gut microbial diversity before and after gonadal hormone suppression at monthly intervals as assessed by sequencing of the V4 region of 16s rRNA

Secondary Outcome Measures

Name	Time	Method
In Vitro Metabolic Phenotyping	2 years after completion of last participant	in vitro measurement of lipid and glucose uptake, insulin and adrenergic sensitivity, and mitochondrial content.
β-glucuronidase activity	2 years after completion of last participant	analysis of β-glucuronidase activity in fecal samples from premenopausal women under gonadal hormone suppression therapy via a 96-well assay. This will serve as a direct measure of fecal capacity for estrogen metabolism.
Estrogen parent: metabolite ratios	2 years after completion of last participant	comparison of estrogen parent: metabolite ratios in relation to changes in bacterial diversity and enzyme activity. We will use UPLC-MS/MS metabolomics.

Trial Locations

Locations (1)

University of Colorado Anschutz Medical Campus; 🇺🇸 Aurora, Colorado, United States