Bioenergetic Effects of Aging and Menopause (BEAM)

Study Overview
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Brief Summary
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The menopause transition is associated with increased risk for weight gain and a shift toward storing fat in the belly region, which may increase risk for cardiovascular disease and diabetes. The study will determine whether the stress hormone cortisol contributes to this shift.

Detailed Description
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The menopause transition is associated with increased risk for weight gain and a shift toward storing fat in the belly region, which may increase risk for cardiovascular disease and diabetes. The stress hormone cortisol is known to promote the accumulation of belly fat, and there is evidence that low estrogen is associated with higher cortisol levels. The first aim of the study is to determine whether low estrogen levels in premenopausal and early postmenopausal women increase cortisol levels in the blood and in fat tissue. When estrogen level decreases at the time of menopause, there is an increase in follicle-stimulating hormone, or FSH. Recent evidence in mice suggests that blocking FSH prevents the increase in belly fat. The second aim of the study is to determine whether decreasing the high FSH level in postmenopausal women causes a decrease in belly fat and changes other factors that are typically thought to be related to estrogen rather than FSH. Because estrogen and FSH levels fluctuate in premenopausal and early postmenopausal women, the investigators will use an approach that controls estrogen and FSH levels to address the aims. The investigators will use a drug that is typically used to treat endometriosis or uterine fibroids to reduce estrogen and FSH levels and an estrogen patch to increase estrogen in some women. The study will generate new knowledge on how menopause affects fat gain and disease risk.

Official Title
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Bioenergetic and Metabolic Consequences of the Loss of Ovarian Function in Women - 2018

Conditions
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Aging, Menopause, Obesity, Abdominal, Weight Gain

Intervention / Treatment
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* Drug: GnRH antagonist
* Drug: Estrogen Product
* Drug: Placebo estradiol
* Drug: Placebo GnRH antagonist


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Volunteers will be healthy peri/postmenopausal women who are willing and able to undergo the proposed hormone manipulation and study procedures. Women will be at least 6 months but not more than 7 years past the last menstrual period (i.e., late perimenopausal or early postmenopausal) with FSH >30 IU/L. We will make a major effort to ensure that the women enrolled in this study come from all races and ethnicities and a wide range of socioeconomic and educational levels. Women will be excluded for the reasons listed below. Exclusion Criteria: abnormal vaginal bleeding on hormonal contraceptive or menopausal therapy or intention to start during the period of study positive pregnancy test or intention to become pregnant during the period of study lactation known hypersensitivity to degarelix acetate, estradiol, or medroxyprogesterone acetate Center for Epidemiological Studies Depression Scale (CES-D) score <,16 (unless clinician follow-up and clinical judgement determine they are eligible (will be noted in study chart) current tobacco and/or vape use more than 2 times/week current marijuana or tetrahydrocannabinol (THC) use in any form more than 3 times/week regular self-reported alcohol consumption >14 drinks/week BMI >39 kg/m2 use of glucocorticoids or drugs that affect glucocorticoid metabolism (e.g., ketoconazole) severe osteopenia or osteoporosis, defined as femoral neck or lumbar spine t-score <-2.0 thyroid dysfunction, defined as an ultrasensitive TSH <0.5 or >5.0 mU/L; volunteers with abnormal thyroid stimulating hormone (TSH) values will be re-considered for participation in the study after follow-up evaluation by the PCP with initiation or adjustment of thyroid hormone replacement liver dysfunction, defined as liver function tests (AST, ALT) >1.5 times the upper limit of normal uncontrolled hypertension defined as resting systolic BP >150 mmHg or diastolic BP>90 mmHg; participants who do not meet these criteria at first screening will be re-evaluated, including after follow-up evaluation by the primary care provider (PCP) with initiation or adjustment of anti-hypertensive medications self-reported history of breast cancer or other estrogen-dependent neoplasms self-reported history of venous thromboembolism, pulmonary embolism, or other thromboembolic disorder self-reported history of cardiovascular disease

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Postmenopausal: GnRH antagonist + estradiol<br>GnRH antagonist is degarelix acetate, 80 mg, delivered twice as a subcutaneous injection (at baseline and after 12 weeks) Estradiol is a transdermal patch 0.075 mg, applied weekly for 24 weeks | Drug: GnRH antagonist<br>* GnRH antagonist will be given once for premenopausal women (12-week intervention) and twice for postmenopausal women (24-week intervention)<br>* Other names: Degarelix Acetate;Drug: Estrogen Product<br>* Estrogen patches will be worn by those randomized to the Estradiol arms in both premenopausal and postmenopausal groups. Patches will be applied weekly and will be worn for the for entirety of the intervention (12 or 24 weeks).<br>* Other names: Estrogen transdermal patch;|
| Experimental: Postmenopausal: GnRH antagonist + placebo<br>GnRH antagonist is degarelix acetate, 80 mg, delivered twice as a subcutaneous injection (at baseline and after 12 weeks) Placebo is a transdermal patch, applied weekly for 24 weeks | Drug: GnRH antagonist<br>* GnRH antagonist will be given once for premenopausal women (12-week intervention) and twice for postmenopausal women (24-week intervention)<br>* Other names: Degarelix Acetate;Drug: Placebo estradiol<br>* Placebo patches will be worn by those randomized to the placebo arms in both premenopausal and postmenopausal groups. Patches will be applied weekly and will be worn for the for entirety of the intervention (12 or 24 weeks).<br>* Other names: Placebo transdermal patch;|
| Placebo Comparator: Postmenopausal: placebo + placebo<br>Placebo (1) is normal saline, delivered twice as a subcutaneous injection (at baseline and after 12 weeks) Placebo (2) is a transdermal patch, applied weekly for 24 weeks | Drug: Placebo estradiol<br>* Placebo patches will be worn by those randomized to the placebo arms in both premenopausal and postmenopausal groups. Patches will be applied weekly and will be worn for the for entirety of the intervention (12 or 24 weeks).<br>* Other names: Placebo transdermal patch;Drug: Placebo GnRH antagonist<br>* Postmenopausal women randomized to the placebo injection arm will receive two placebo drug injections of normal saline (24-week intervention)<br>* Other names: Placebo injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Microdialysis Cortisone Challenge (MCC) Index | The MCC Index is an in vivo measurement of local cortisol production in abdominal adipose tissue. A higher MCC Index is an indicator of more local cortisol production. | Baseline, week 12 | 
| Change in the Oral Cortisone Challenge (OCC) Area Under the Curve (AUC) | The OCC AUC is a systemic measurement of peripheral glucocorticoid metabolism. A higher OCC AUC is an indicator of more production of cortisol. | Baseline, week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in lumbar spine Bone Mineral Density (BMD) | Lumbar spine BMD is measured by dual-energy x-ray absorptiometry. A higher BMD is a general indicator of less risk for osteoporosis. | Baseline, week 24 | 
| Change in resting energy expenditure (REE) | REE is an index of metabolic rate at rest, measured by indirect calorimetry. A higher REE is an indicator of greater energy expenditure at rest. | Baseline, week 12, week 24 | 
| Change in visceral fat area (VFA) | VFA of the abdominal visceral region is measured by computed tomography. VFA is an indicator of the amount of fat stored in this region. | Baseline, week 24 | 
| Change in flow-mediated dilation (FMD) | FMD of the brachial artery as an index of vascular function. A higher number is a general indicator of better vascular function. | Baseline, week 12, week 24 | 
| Change in proximal femur Bone Mineral Density (BMD) | Proximal femur BMD is measured by dual-energy x-ray absorptiometry. A higher BMD is a general indicator of less risk for osteoporosis. | Baseline, week 24 |