• Extent to which the candidate specific estrogen receptor modulators (SERMs) tamoxifen and raloxifene increase myocardial fatty acid metabolism in ovariectomized mice and the comparison of the increase to that observed with estrogen [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: No ]
• Roles of the estrogen receptor isoforms alpha (α) and beta (ß) in modifying the roles of estrogen and the SERMs tamoxifen or raloxifene in heart metabolism of estrogen receptor knockout mice [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: No ]

• Extent to which the candidate SERMs Tamoxifen and Raloxifene increase myocardial fatty acid metabolism in ovariectomized mice and the comparison of the increase to that observed with estrogen [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: No ]
• Roles of the estrogen receptor isoforms alpha (α) and beta (ß) in modifying the roles of estrogen and the SERMs Tamoxifen or Raloxifene in heart metabolism of estrogen receptor knockout mice [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: No ]

Estrogen and progesterone are two main female sex hormones. When a woman goes through menopause, the body's production of estrogen and progesterone significantly decreases. Recent studies have shown that the breakdown of fatty acids in cardiac muscle is important in maintaining a healthy heart, and that estrogen may enhance this process. Also, cardiovascular disease (CVD) occurs more frequently in postmenopausal women than in premenopausal women. This study will determine in postmenopausal women whether estrogen increases the heart's ability to use fats as energy and whether progesterone decreases this effect.

Menopause is a natural event that generally occurs in women between the ages of 45 and 55. During menopause, the body starts producing less estrogen and progesterone until menstruation eventually stops. Estrogen and progesterone are involved in many important functions in a woman's body, and the drastic decline of these hormones in menopause leads to significant changes in the body. Along with such changes, postmenopausal women are at a higher risk than premenopausal women for certain health problems, such as CVD. Previous studies have revealed that alterations in the breakdown of fatty acids in cardiac muscle play a key role in a variety of cardiac disorders. In studies involving human skeletal muscle, estrogen has been shown to increase the breakdown of fatty acids, while progesterone lessens this effect. This study will determine in postmenopausal women whether estrogen increases the heart's ability to break down fats for energy use and whether progesterone decreases this effect. This study will also analyze ovariectomized mice to determine if the candidate specific estrogen receptor modulators (SERMs) raloxifene and tamoxifen increase the heart's ability to use fats as energy and whether the increase is similar to that seen with estrogen. Study investigators will also create estrogen receptor knock-out mice (mice with estrogen receptors removed) to further explore the roles of estrogen and SERMs in heart metabolism.

Participation in this double-blind study will last up to 1 month and will include three study visits. During Visit 1, participants will undergo three standard clinical evaluations. The first evaluation, a medical screening, will include a medical history exam and blood tests to measure estrogen and progesterone levels, liver and kidney function, cholesterol levels, and blood sugar and insulin levels. For the second evaluation, participants will undergo a body composition study to measure total body fat and muscle content using a dual-energy x-ray absorptiometry (DEXA) scan. During the third evaluation, participants will undergo an electrocardiogram (ECG) and an echocardiogram (ECHO), each performed immediately before and after walking on a treadmill. The ECG will measure electrical activity of the heart, and the ECHO will involve imaging the heart with an ultrasound.

Visits 2 and 3, occurring 3 days apart, will each include two imaging tests of the heart: a positron-emission tomographic (PET) scan and a resting ECHO. Throughout both tests an ECG and blood pressure cuff will be used to monitor heart rhythm and blood pressure, respectively. During the PET scan, participants will lie flat in an imaging machine for three 45- to 60- minute intervals. Blood will be drawn and radioactive tracers will be injected via intravenous lines placed in the arms. The ECHO test will also be done during the PET scan.

Between Visits 2 and 3, participants will be randomly assigned to one of two hormone replacement therapy (HRT) regimens: estrogen plus placebo or estrogen plus progesterone. All participants will wear a patch containing estrogen and take a pill of either placebo or progesterone for the 3 days leading up to Visit 3. All participants will be asked for permission to store a sample of their blood for up to 10 years to be used in future research studies.

• Drug: Estrogen
• Drug: Progesterone
• Drug: Placebo Progesterone

• Experimental: Hormone replacement therapy (HRT): estrogen plus progesterone
• Active Comparator: Hormone replacement therapy (HRT): estrogen plus placebo

• Castelli WP. Cardiovascular disease in women. Am J Obstet Gynecol. 1988 Jun;158(6 Pt 2):1553-60, 1566-7.
• Bokhari S, Bergmann SR. The effect of estrogen compared to estrogen plus progesterone on the exercise electrocardiogram. J Am Coll Cardiol. 2002 Sep 18;40(6):1092-6.
• Babiker FA, De Windt LJ, van Eickels M, Grohe C, Meyer R, Doevendans PA. Estrogenic hormone action in the heart: regulatory network and function. Cardiovasc Res. 2002 Feb 15;53(3):709-19. Review.
• Petrie MC, Dawson NF, Murdoch DR, Davie AP, McMurray JJ. Failure of women's hearts. Circulation. 1999 May 4;99(17):2334-41. Review. No abstract available.
• McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med. 1971 Dec 23;285(26):1441-6. No abstract available.

Inclusion Criteria:

• Healthy postmenopausal woman
• Body mass index less than 30
• Practices normal eating habits
• Stops hormone replacement therapy at least 6 months prior to study entry

Exclusion Criteria:

• Currently taking hormone replacement therapy
• History of cardiovascular disease
• Family history of coronary artery disease
• Recent history of smoking, high blood pressure, or hyperlipidemia