Estrogen, Diabetes, and Endothelial Function (EDEN)

Vascular Disease, Inflammation and Hormones in Women With Type 1 Diabetes

This study planned to learn more about women and how the drop in estradiol levels during menopause may affect their cardiovascular risk. With aging, the arteries that are located around the heart get stiffer, and this increase in arterial stiffness can lead to a number of health problems such as high blood pressure and heart disease. In this study, the investigators examined whether a short-term drop in estrogen levels caused arteries to become stiffer, and explored potential reasons for stiffening arteries.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: Cetrorelix acetate, 0.25 mg/day; Drug: Estradiol Patch, 0.025 Mg/24 Hours Weekly Transdermal Film, Extended Release; Drug: Placebo patch

Detailed Description

Participants completed two study visits. The baseline study visit occurred during the early follicular phase of the menstrual cycle, confirmed via take-home ovulation testing. On the day of the baseline study visit, all participants underwent ovarian sex hormone suppression with GnRHant therapy (cetrorelix acetate, 0.25 mg/day) delivered daily as subcutaneous injections for a 1-week period. Participants were randomized to one of two concurrent intervention groups: transdermal estradiol patch (0.075 mg/day) (+E2) or placebo patch (+PL) and returned for a follow-up visit after 1 week of the intervention. Both study visits included collection of anthropometric measures, a fasting blood sample, measures of arterial stiffness, flow-mediated dilation, and endothelial cells via an intravenous catheter.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Premenopausal
• Euthyroid
• Not currently planning to become pregnant
• Not currently breastfeeding
• No recent history of amenorrhea in the previous 6 months
• Consent to data and specimen banking
• No use of hormonal contraceptives

Inclusion Criteria, type 1 diabetes only:

• Diagnosis of type 1 diabetes for at least 5 years
• On insulin within a year of diagnosis
• Current insulin therapy
• Hemoglobin A1c < 9.5%
• No macroalbuminuria (AER < 200 ug/min)

Inclusion Criteria, non-diabetic controls only:

• Hemoglobin A1c < 5.7%

Exclusion Criteria:

• Pregnant and/or breastfeeding
• Have not had a menstrual cycle in the last 6 months

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: GnRHant + E2; Participants in this arm received GnRHant and a transdermal estradiol patch (0.075 mg/day) for a period of 1 week.	Drug: Cetrorelix acetate, 0.25 mg/day; All participants self-administered GnRHant daily between the baseline and follow-up visits (cetrorelix acetate, 0.25 mg/day).; Other Names: Cetrotide; GnRHant; Drug: Estradiol Patch, 0.025 Mg/24 Hours Weekly Transdermal Film, Extended Release; Active estradiol transdermal patch.; Other Names: Climara
Placebo Comparator: GnRHant + PL; Participants in this arm received GnRHant and a placebo patch for a period of 1 week.	Drug: Cetrorelix acetate, 0.25 mg/day; All participants self-administered GnRHant daily between the baseline and follow-up visits (cetrorelix acetate, 0.25 mg/day).; Other Names: Cetrotide; GnRHant; Drug: Placebo patch; Placebo patch designed to match active Climara patches.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Flow-mediated dilation (FMD) at baseline	FMD will be measured following an intravenous saline infusion and ascorbic acid infusion.	1 week
Flow-mediated dilation (FMD) at follow-up	FMD will be measured following an intravenous saline infusion and ascorbic acid infusion.	1 week
Change in flow-mediated dilation (FMD)	FMD will be measured following an intravenous saline infusion and ascorbic acid infusion at baseline and follow-up.	Baseline and 1 week
Quantitative immunuofluorescence of endothelial cell proteins at baseline	Expression of estrogen receptor alpha, estrogen receptor beta, endothelial nitric oxide synthase, and phosphorylated endothelial nitric oxide synthase in endothelial cells	Baseline
Quantitative immunuofluorescence of endothelial cell proteins at follow-up	Expression of estrogen receptor alpha, estrogen receptor beta, endothelial nitric oxide synthase, and phosphorylated endothelial nitric oxide synthase in endothelial cells	1 week
Change in quantitative immunuofluorescence of endothelial cell proteins	Expression of estrogen receptor alpha, estrogen receptor beta, endothelial nitric oxide synthase, and phosphorylated endothelial nitric oxide synthase in endothelial cells	Baseline and 1 week

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Investigators: Principal Investigator: JANET K SNELL-BERGEON, PhD, MPH, University of Colorado, Denver

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2010
• Primary Completion (Actual): October 22, 2018
• Study Completion (Actual): October 22, 2018

Study Registration Dates

• First Submitted: May 26, 2020
• First Submitted That Met QC Criteria: June 2, 2020
• First Posted (Actual): June 5, 2020

Study Record Updates

• Last Update Posted (Actual): June 5, 2020
• Last Update Submitted That Met QC Criteria: June 2, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Hormone Antagonists; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Estradiol; Cetrorelix
• Other Study ID Numbers: 10-0591

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.: Yes