Cardiometabolic Consequences of the Loss of Ovarian Function
Trial statusRecruiting
Trial phasePhase 4
Trial typeInterventional
Biological sexFemale
Age20-45
SponsorUniversity of Colorado, Denver
About this trial
The menopause transition is associated with a decrease in artery health and an increased risk for weight gain in storing fat in the stomach area which may increase the risk for heart disease. The purpose of this research is to study how the decrease in estrogen at menopause changes artery health and fat gain, and risk of disease in women as they age. The first aim in this study will determine whether short term and long term low estrogen levels in premenopausal women decreases artery function and whether this is related to an increase in fat in the stomach area. The second aim will determine whether the changes in artery health and body fat are related to changes in a pathway that breaks down an important amino acid called tryptophan. This pathway is thought to play a role in regulating the aging process. Therefore, the investigators will determine whether the decrease in artery health and the increase in body fat in the stomach region with low estrogen is related to changes in this pathway in the blood, in vascular cells and fat tissue. Because estrogen levels fluctuate in premenopausal women, the investigators will use an approach (intervention) that controls estrogen levels to address these aims. The investigators will use a medication that is typically used to treat endometriosis or uterine fibroids to lower estrogen levels and an estrogen patch to increase estrogen in some women. Some women will receive a patch that has no estrogen (called a placebo patch). The intervention period will be 20 weeks. The study will provide us with new knowledge on how low estrogen with menopause affects artery health and fat gain estrogen.
Eligibility criteria
This trial accepts healthy volunteersQualifiers
Age criteria of 20-45 years: the investigators are determining the effects of ovarian suppression on adiposity and vascular in premenopausal women;
Premenopausal defined as normal menstrual cycle function defined as no more than 1 missed cycle in the previous year: irregular menstrual or missed menstrual cycles could indicate that women are anovulatory and/or perimenopause;
Not pregnant or planning to become pregnant;
Not lactating in the last 3 months;
Disqualifiers
Diabetic or fasted glucose >126 mg/dL;
Body mass index (BMI) >35 kg/m2;
Weight change >5 kg in the last 3 months;
Use of glucocorticoids (inhaled, oral, topical) or drugs that affect glucocorticoid metabolism (e.g., ketoconazole) in the last 3 months;
Trial design
Design model
Parallel
Treatments tested in this trial
Degarelix
DrugAfter first undergoing a pregnancy test, a clinician will administer an 80-mg subcutaneous injection of degarelix acetate (20 mg/mL; Ferring Pharmaceuticals Inc, Parsippany, NJ) to the women. A second injection will occur at 10 weeks. Compliance to the intervention will be ensured by having participants receive injections in the Clinical and Translational Research Center (CTRC), where all study visits will take place.
Transdermal Estradiol Patch
DrugTreatment will be a weekly transdermal patch (0.075 mg) administered in a double-blinded manner. This estradiol dose increases serum estradiol to \~90 pg/mL. Compliance to the intervention will be monitored by having participants keep a log that tracks patch use.
Transdermal Placebo Patch
DrugTreatment will be a weekly transdermal patch (placebo inactive) administered in a double-blinded manner. Compliance to the intervention will be monitored by having participants keep a log that tracks patch use.
Treatment groups
100 Participants
are divided into 2 treatment groupsGroup A: Degarelix plus transdermal placeboExperimental treatment 2 interventions
Group B: Degarelix plus transdermal estradiolExperimental treatment 2 interventions
Trial outcomes
Primary outcomes
1
Brachial artery flow mediated dilation (FMD)
Ultrasound measurements of brachial artery FMD will be performed in the morning under fasted conditions, and analyzed (Vascular Analysis Tools 5.5.1) according to guidelines. Baseline FMD will be assessed during early follicular phase of menstrual cycle. Blood pressure will be measured prior to the FMD. To confirm endothelial-specific effects of the intervention, the investigators will also measure endothelium-independent dilation as brachial artery dilation to sublingual nitroglycerine (0.4 mg). All ultrasound images will be coded by number and blinded to group assignment.
Time frame
Baseline and at 2 and 20 weeksSecondary outcomes
1
Visceral fat area (VFA)
Participants will undergo a CT scan of the abdomen for the assessment of VFA and subcutaneous fat area (SFA). Axial CT images will be obtained through the center of the L2-L3 inter-vertebral disc space at 120 kVp (kilovoltage peak), 200-300 maS, and 10mm slice thickness. Digital images will be analyzed in a blinded manner by the University of Colorado Research Imaging Center (CU-RIC) using Interactive Data language software (ITT Visualization Solutions, Boulder, CO).
Time frame
Baseline and at 20 weeksOther outcomes
1
Subcutaneous fat area
Participants will undergo a CT scan of the abdomen for the assessment of VFA and subcutaneous fat area (SFA). Axial CT images will be obtained through the center of the L2-L3 inter-vertebral disc space at 120 kVp, 200-300 maS, and 10mm slice thickness. Digital images will be analyzed in a blinded manner by the University of Colorado Research Imaging Center (CU-RIC) using Interactive Data language software (ITT Visualization Solutions, Boulder, CO).
Time frame
Baseline and at 20 weeks2
Tryptophan-Kynurenine metabolites
Mechanistic outcome. Profiling of TRP-KYN metabolism in plasma, adipose tissue, adipocytes, and HAECs (human aortic endothelial cells) will be performed using a targeted mass spectrometry-based high throughput metabolomics platform at the CU-AMC Metabolomics Core (see Dr. D'Alessandro - LOS).114-116 Metabolites will be extracted using 5:3:2 methanol:acetonitrile:water according to established protocols.117 Extracts will be clarified by centrifugation, dried, resuspended in 0.1% formic acid, randomized, and data acquired on a Vanquish UHPLC coupled to a Q Exactive mass spectrometer (Thermo) as previously described.118 TRP-KYN pathway features will be annotated and peaks integrated using Maven (Princeton Univ) in conjunction with the KEGG database and an established in-house compound library. The Core assists with data analysis and interpretation.
Time frame
Baseline and at 2 and 20 weeks3
Body composition - mass
DXA (dual-energy X-ray absorptiometry) measurements of total and regional fat mass and fat-free mass in kilograms for screening
Time frame
Baseline and at 20 weeks4
Body composition - bone
DXA (dual-energy X-ray absorptiometry) measurements of bone density for screening
Time frame
Baseline and at 20 weeksSponsors and contacts
Click on the lead sponsor to view all of their trials.
University of Colorado, Denver
Lead sponsor
National Institute on Aging (NIA)
Collaborator
Source ClinicalTrials.gov