Bioenergetic Effects of Aging and Menopause (BEAM)

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.

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.

Eligibility Criteria:
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