Estrogen, medroxyprogesterone acetate, endothelial function, and biomarkers of cardiovascular risk in young women

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Medroxyprogesterone acetate (MPA) is widely known for its use in combination hormone therapy for postmenopausal women. However, MPA is also commonly used in young women for contraception and treatment of a number of gynecological conditions. Despite its widespread use, the cardiovascular effects of MPA in young women are unclear. Therefore, the purpose of this study was to determine the acute effects of MPA when used in combination with estradiol on markers of cardiovascular risk in young women. We suppressed endogenous estrogens and progesterone in 10 premenopausal women using a gonadotropin-releasing hormone antagonist (GnRHa) for 10 days. On day 4 of GnRHa subjects received 0.1 mg of estradiol (GnRHa+E2), and on day 7 5 mg of MPA was added (GnRHa+E2+MPA). Endothelium-dependent vasodilation and endothelium-independent vasodilation of the brachial artery, lipids, homocysteine, high-sensitivity C-reactive protein, and endothelin-1 were assessed during treatment with GnRHa, GnRHa+E2, and GnRHa+E2+MPA. Four additional subjects were tested to validate the efficacy of the GnRHa model and confirm the findings. Endothelium-dependent vasodilation was greater during GnRHa+E2 than during GnRHa or GnRHa+E2+MPA (P = 0.006). Endothelin-1 was lower during GnRHa+E2 than GnRHa alone (P = 0.039). Endothelin-1 increased with the addition of MPA and was not significantly different from GnRHa alone. There were no differences in the other markers of cardiovascular risk between hormone treatment days. These data suggest that acute MPA administration negates the beneficial effects of estradiol on endothelium-dependent vasodilation in young women. In addition, these data suggest that estradiol decreases endothelin-1 concentrations and the addition of MPA may counteract the effect of estradiol on endothelin-1.

there is substantial evidence to suggest that estrogens have a cardioprotective influence in women by improving endothelial function (11, 14, 19, 24) and low-density lipoprotein (LDL) concentrations (45) while decreasing concentrations of endothelin-1 (ET-1) (4, 26, 31, 32, 56) and homocysteine (9). In contrast, medroxyprogesterone acetate (MPA) has been shown to counteract the beneficial effects of estrogens in animals (1, 52) and in some studies in postmenopausal women (18, 44, 49). Recently, the estrogen plus MPA arm of the Women's Health Initiative clinical trial was terminated because of a trend toward negative cardiovascular outcomes (37). These findings raise questions about the use of progestins, and specifically MPA, in hormone treatments.

In addition to postmenopausal women, premenopausal women are also commonly prescribed MPA. MPA is used in the injectable progestin-only contraceptive Depo-Provera, which is a popular contraceptive choice, particularly for younger premenopausal women because of the ease of use and high compliance. Oral MPA hormone treatments are also used to treat a number of gynecological conditions in young women, such as endometriosis, polycystic ovarian syndrome, and irregular uterine bleeding (7). Despite numerous reports that MPA may impair the benefits of estradiol in postmenopausal women (18, 49), MPA continues to be used regularly in conjunction with estrogens to treat young women for many of the common disorders listed above. However, the effect of clinically relevant doses of MPA on cardiovascular indexes in young women has not been evaluated. Thus it remains unknown whether MPA antagonizes the beneficial cardiovascular effects of estrogen in reproductive-age women.

Therefore, the aim of our study was to investigate whether MPA antagonizes the favorable effects of exogenous estradiol on vascular function and biomarkers of cardiovascular risk by measuring endothelium-dependent vasodilation of the brachial artery, serum lipid concentrations, homocysteine, high-sensitivity C-reactive protein (hs-CRP), and ET-1 in young women after acute estradiol and combination estradiol and MPA treatment. We hypothesized that short-term estradiol treatment would increase endothelium-dependent vasodilation, improve lipid panel variables, and decrease homocysteine, hs-CRP, and ET-1 concentrations. We further hypothesized that the addition of MPA to estradiol treatment would negate the improvements in these markers of cardiovascular risk in young women.

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American Journal of Physiology Heart and Circulatory Physiology



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American Physiological Society