Impact of Estradiol on Endothelial Function in Peri-Menopausal Women

The purpose of this study is to identify the impact of estradiol (E2) on the mechanisms that regulate vascular endothelial function in peri-menopausal (PERI) women. This study is the first step in understanding factors contributing to endothelial dysfunction in women with advancing reproductive age and in response to E2 administration.

Study Overview

• Status: Recruiting
• Conditions: Vasodilation; Perimenopause; Estrogen
• Intervention / Treatment: Drug: Estradiol (mylan or vivelle dot patch); Other: Placebo

Detailed Description

Cardiovascular disease (CVD) is the leading cause of death in women. Although overall CVD-related mortality has declined, there has been an increase in CVD mortality in women aged 35-54 years, prior to menopause. It is unclear what contributes to this increased mortality rate, and is a significant problem for women's health. Endothelial function is considered a biomarker of cardiovascular health; declines in endothelial function are considered a precursor to the development of atherosclerosis and CVD. Thus, changes in endothelial function in women as they advance through reproductive stages towards menopause may play a role in the greater prevalence of CVD mortality. However, very few studies have focused on cardiovascular health in women leading up to menopause, during the PERI transition. The PERI period is a critical time point where reproductive hormones and ovarian function change rapidly. Recent data demonstrate that endothelial function begins to decline during PERI. Furthermore, despite women being of similar biological age, significant differences in endothelial function were noted when classified based on reproductive age - specifically between early PERI and late PERI. These data show that the decline initially occurs in the early PERI phase, making this a key time point for intervention to offset the future development of CVD. Our central hypothesis is that increased Endothelin-1 (ET-1) and a loss of Endothelin-1 B (ETB) mediated vasodilation play a primary role in contributing to impaired endothelial function with advancing reproductive age. We will assess macro- and micro- vascular endothelial function, assess intracellular ET-1 protein and ETB receptor expression in harvested endothelial cells from peripheral veins, and use the cutaneous circulation as an in vivo model to explore the receptor mechanisms (ETBR and ETAR) in early and late PERI in response to E2 or placebo.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Megan M Wenner, PhD; Phone Number: (302) 831-7343; Email: mwenner@udel.edu
• Study Contact Backup: Name: Kathy Masso, BS; Phone Number: (302) 831-3493; Email: kcmasso@udel.edu

Study Locations

• United States
  • Delaware
    • Newark, Delaware, United States, 19716
      • Recruiting
      • University of Delaware
      • Contact: Megan M Wenner, PhD; Phone Number: 302-831-7343; Email: mwenner@udel.edu
      • Contact: Kathy Masso, BS; Phone Number: 302-831-3493; Email: kcmasso@udel.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 38 years to 56 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Peri-menopausal women between 40-58 years of age with variable cycles as defined by increase in cycle length of greater than 7 days within ten consecutive cycles, or amenorrhea for more than 2 months, but less than 12 months.

Exclusion Criteria:

• Women who are pregnant, planning on becoming pregnant, or are breast feeding;
• Women who have a history of cardiovascular disease, blood clots (e.g, pulmonary embolism or deep vein thrombosis), stroke, cancer, or liver disease;
• Women who have a body mass index less than 18 or greater than 35kg/m2;
• Women who use tobacco products;
• Women who's blood pressure is greater than 140/90 mmHg, have been diagnosed by a physician with hypertension or are taking medication for high blood pressure;
• Women who have a neurological disease, or diabetes;
• Women who have had a hysterectomy or have used hormones (birth control or hormone replacement) within the past 3 months;
• Women who have a latex allergy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; A placebo patch that is visually similar to the estradiol patch will be used for the group not receiving estradiol.
Experimental: Estradiol; Transdermal estradiol (0.1mg/day patch)	Drug: Estradiol (mylan or vivelle dot patch); Transdermal estradiol (0.1mg/day patch) will be used by women for 7 days. Administration of the patch will follow the package guidelines to change the patch after 3-4 days of use.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vascular Endothelial Function (Flow mediated dilation or FMD)	The capacity of the large and small blood vessels to dilate.	Change in FMD from Baseline to Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endothelial Cell Protein Expression	Venous endothelial cells will be harvested from peripheral veins of women during the hormone intervention and stained for expression of ET-1 and ETB receptors.	Change in fluorescent intensity from Baseline to Day 7
Endothelin Receptor Responses	The contribution of Endothelin A (ETA) and Endothelin B (ETB) receptors on changes in endothelial function will be assessed in the cutaneous circulation via microdialysis. Blood flow responses to local heating will be assessed under control and blockade sites in women during estradiol or placebo administration.	Change from Baseline to Day 7

Collaborators and Investigators

• Sponsor: University of Delaware
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2020
• Primary Completion (Anticipated): June 30, 2024
• Study Completion (Anticipated): June 30, 2025

Study Registration Dates

• First Submitted: January 27, 2020
• First Submitted That Met QC Criteria: February 1, 2020
• First Posted (Actual): February 5, 2020

Study Record Updates

• Last Update Posted (Estimate): May 11, 2023
• Last Update Submitted That Met QC Criteria: May 10, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Vasodilation; Estrogen; Perimenopause
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Estradiol
• Other Study ID Numbers: 1508142; R01HL146558 (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: Yes
• Studies a U.S. FDA-regulated device product: No