Relationship Between the Menstrual Cycle and Heart Disease in Women

Identification of the Menstrual Cycle-Associated Factors That Modulate Circulating Lipid Levels in Premenopausal Women

Women who have regular menstrual cycles have a lower risk of heart disease than men of the same age or women who no longer have menstrual cycles. The purpose of this study is to help determine why the menstrual cycle causes a lower risk of heart disease. The investigators believe that the hormones (estradiol and progesterone) produced during the menstrual cycle, as well as the normal processes occurring in the follicle and corpus luteum (transformed follicle), change levels of "good" and "bad" cholesterol in the blood-stream. These levels of good and bad cholesterol are an important risk factor for heart disease. Therefore, our goal is to determine what effects each of these factors (estradiol, progesterone, follicle, corpus luteum) have on the levels of good and bad cholesterol in the woman's bloodstream. As many women take birth control pills, which contain synthetic forms of estradiol and progesterone that block ovulation and development of a corpus luteum, the investigators also want to determine what effect one common type of birth control pill has on levels of good and bad cholesterol.

Premenopausal women are at a lower age-adjusted risk of coronary heart disease (CHD) than men or postmenopausal women. This decreased risk of CHD is likely due, in part, to the more favorable lipid profile observed in premenopausal women. The menstrual cycle is associated with the ovarian processes of follicular growth and ovulation, and corpus luteum (CL) development, function, and regression. The steroids estrogen (E2) and progesterone (P4) are secreted from the follicle and CL, which travel via the bloodstream to elicit their effects on target tissues. The production of E2 has been implicated as the menstrual cycle-associated factor underlying the favorable lipid profile as it is known to increase atheroprotective high density lipoprotein and decrease atherogenic low density lipoprotein. However, other factors may play a role such as direct ovarian metabolism of circulating lipids. Furthermore, the role of P4 is unclear and there is some evidence that it may inhibit the beneficial effects of E2. Therefore, we aim to determine the contributions of ovarian metabolism of lipids, independent of the effects of ovarian-derived E2 and P4, to the circulating lipid profile in premenopausal women. Also, we will determine the relationship between E2 and P4, both natural and synthetic forms found in hormonal oral contraceptives, on circulating lipids. With the recent controversial findings of the Women's Health Initiative, further evaluation of the factors underlying menstrual cycle protection from CHD is warranted. This study may have implications for the management of CHD and the use of hormonal therapies in women.

Natural menstrual cycle versus Estrogen/Progesterone replacement cycle. Interventions include leuprolide acetate to induce hypogonadism and estradiol and progesterone to replace hormone levels.

Oral contraceptive cycle versus Eligard treatment. Interventions include ethinyl estradiol-levonorgestrel combination and leuprolide acetate.

Estrogen/Progesterone replacement cycle versus Eligard treatment. Interventions include leuprolide acetate, estradiol, and progesterone.

Inclusion Criteria: Normal menstrual cycles of 25-35 days in length for at least previous 3 cycles 21-40 years of age BMI > 18, < 30 Serum P4 > 9 ng/ml on single sample collected between days 18-25 of self-reported menstrual cycle Flexible schedule allowing morning blood draws on less than 48 hour notice In good general health Commit to remain on stable diet during study period (no changes to normal dietary habits) Commit to using non-hormonal contraceptive methods during study period except those prescribed in the experimental protocol No objections to taking study drugs Exclusion Criteria: Oral contraceptive use or other hormone supplement within the preceding 2 months Long-acting hormonal contraceptive use in the past 12 months (e.g., Depo-Provera®) Contraindications to study drugs Current or past pregnancy within the previous 6 months or currently trying to conceive Desiring to conceive in the next 8 months Breastfeeding in the past 2 months Diagnosed Diabetes or Metabolic Syndrome Current or previous use of cholesterol lowering drugs within the preceding 12 months Diagnosed Polycystic Ovary Syndrome History of, or self-reported, substance abuse Smoker Previous infertility treatment excluding male factor issues Use of an investigational drug within the past 2 months

Oregon Health & Sciences University, Department of Obstetrics and Gynecology, Women's Health Research Unit