Cardiometabolic Consequences of the Loss of Ovarian Function

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.

Menopause accelerates cardiovascular disease (CVD) risk due to adverse changes in risk factors (e.g., increased body fat) and vascular health, related to changes in the hormone environment. The investigators showed that measures of vascular health progressively worsen across the menopause transition, related to increased oxidative stress. The oxidative stress-mediated vascular dysfunction was related to the loss of estrogen. The loss of estrogen with menopause also causes an increase in percent body fat levels, particularly in the abdominal region. However, it is unknown if the increase in abdominal body fat worsens vascular dysfunction with the loss of estrogen. Thus Aim 1 of Project 1 will investigate the impact of increased abdominal adiposity superimposed on the direct effects of estrogen deficiency on vascular function in women. In collaboration with SCORE Projects 2 and 3, Aim 2 and an Exploratory aim will investigate the underlying causes for the increase in abdominal body fat and vascular dysfunction. There is emerging evidence that links the tryptophan-kynurenine (TRP-KYN) pathway as a regulator of vascular function, body fat and the aging process. TRP is an essential amino acid that is metabolized to KYN and various metabolites. KYN and some of its breakdown products have been associated with an increase in body fat and an impairment in vascular function. It is unknown if estrogen regulates this pathway. Thus, Aim 2 and the Exploratory aim will investigate if the TRP-KYN pathway is dysregulated with the loss of estrogen, and if this is associated with an increase in abdominal body fat and an impairment in endothelial function.

The Aims of Project 1 will be accomplished by conducting an intervention trial in premenopausal women randomized to a low estrogen condition (gonadotropin releasing hormone antagonist, GnRHant, plus a placebo patch) or a high estrogen condition (GnRHant plus an estrogen patch) to isolate the actions of estrogen. Women will wear a patch daily that will be switched out weekly. At weeks 9 and 17, women will receive 5 mg of medroxyprogesterone acetate (MPA) for 12 days to prevent endometrial hyperplasia. Outcomes will be assessed before the intervention and after 2 and 20 weeks of the intervention, except where indicated. All women will continue their intervention until testing has been completed. Initially, women interested in the study will undergo a phone or e-mail screening to assess likelihood for eligibility.

Eligibility Criteria:
Inclusion Criteria:

* 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;
* Serum FSH \<10 IU/L measured during days 1-10 of the menstrual cycle: to ensure the woman is premenopausal and not perimenopausal;
* Not on hormonal contraception in the last 3 months;
* Sedentary or recreationally active (\<2 days/wk vigorous exercise);
* No use of medications that might influence vascular function (i.e., antihypertensives, lipid lowering medications, blood thinners);
* No use of antioxidant supplements or chronic NSAIDs or be willing to go off them for 4 weeks prior to enrollment in the study;

Exclusion Criteria:

* 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;
* Excess alcohol consumption, defined as \>14 drinks per week by self-report;
* Known hypersensitivity to study medications;
* Depressive symptoms, defined as a CES-D score \>16;
* Resting blood pressure \>150/90 mmHg;
* Preexisting or active cardiac, renal, or hepatic disease: past or current history of these diseases or conditions;
* Active or chronic infection: inflammation associated with active or chronic infections impair vascular function;
* Thyroid dysfunction, defined as an ultrasensitive TSH \<0.5 or \>5.0 mU/L; volunteers with abnormal TSH values will be reconsidered for participation in the study after follow-up evaluation by the PCP with initiation or adjustment of thyroid hormone replacement;
* Smoking or Tobacco use within the previous 12 months;
* Severe low bone mass or osteoporosis, defined as a hip or lumbar spine T-score \<-2.0: safety reasons, women who are randomized to the ovarian suppression plus placebo group could see a decrease in bone mineral density due to the suppression of estrogen;
* History of venous thromboembolic event (VTE): safety reasons, estradiol therapy can increase the risk of VTE;
* History of breast cancer or other estrogen-dependent neoplasm: estradiol therapy is contraindicated;