Estrogen, Diabetes, and Endothelial Function

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Cetrorelix acetate, 0.25 mg/day
* Drug: Estradiol Patch, 0.025 Mg/24 Hours Weekly Transdermal Film, Extended Release
* Drug: Placebo patch


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants were randomized to either receiving a gonadotropin-releasing antagonist (GnRHant) with estradiol add-back (+E2) or placebo (+PL). Investigators and participants were blinded to randomization status until the study was completed.
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 |