Objective-To test if transdermal progesterone (P) confers coronary vascular protection in surgically menopausal preatherosclerotic rhesus monkeys.Methods and Results-Ovariectomized rhesus monkeys fed an atherogenic diet (AD) for 19 months were treated with an investigational transdermal P cream (n=7) or identical placebo cream (n=5) for 4 weeks. Aorta and carotids showed fatty streaks and Oil Red O staining demonstrated lipid deposition. Serum P levels in P-treated rhesus monkeys (0.6 ng/mL) were significantly greater than placebo (0.2 ng/mL). Significant elevation of cholesterol, LDL cholesterol, and HDL cholesterol, was noted in all animals. Lp(a) was significantly attenuated in the AD-fed P-treated monkeys. Coronary angiographic experiments stimulating vasoconstriction by intracoronary injections of serotonin plus U46619 showed exaggerated prolonged actions amplified by AD, but significant protection against severe prolonged vasoconstriction in P-treated monkeys. Immunocytochemistry confirmed co-expression of P and thromboxane prostanoid (TP) receptors in coronaries and aorta. Western blotting demonstrated TP receptor attenuation in vascular muscle after P treatment.Conclusions-Coronary hyperreactivity, a putative component of coronary artery disease mediated via increased vascular muscle thromboxane prostanoid receptors, can be prevented by subphysiological levels of P, not only in nonatherosclerotic (previously shown) but also in preatherosclerotic primates. Keywords coronary occlusion; menopause; progesterone replacement; cardiac catheterizationThe production of ovarian steroid hormones (OSH) such as estrogen (E) and progesterone (P) is markedly reduced in postmenopausal women (PMW), with a concomitant increased risk for the development of coronary artery disease (CAD). 1 Based on several observational clinical studies, hormone therapy (HT) was suggested to be important in cardiovascular protection in PMW. However, recently reported results from the Women's Health Initiative (WHI) trial underscore those from the Heart and Estrogen/Progestin Replacement Study (HERS II) 2 and indicate that postmenopausal HT using a combination of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) should not be used for prevention of coronary heart Correspondence to Dr R. Kent Hermsmeyer, Dimera Incorporated, 2525 NW Lovejoy, Suite 311, Portland, OR 97210. Emailrkh@dimera.net. Dimera is pursuing development of prescription transdermal progesterone for treatment of angina pectoris. Both R.K.H. and R.G.M. are employees of Dimera. Most HT studies have tested E only or E combined with a synthetic progestin such as MPA, focusing primarily on favorable alteration in blood lipids and endothelial function as primary endpoints of cardiovascular protection. Animal data indicate that administration of MPA adversely affects coronary reactivity 7 and might counteract the improvement produced by CEE in atherosclerotic ovariectomized (ovx) primates. 5 Despite negative conclusions regarding HT, an important untes...

Coronary hyperreactivity (CH), characterized by persistent severe vasoconstrictions in response to vasoconstrictor challenge, is oppositely influenced by progesterone (P) and medroxyprogesterone acetate (MPA) treatment in surgically menopausal primates. In this study we tested whether multiweek MPA or dihydrotestosterone (DHT) exposure induced CH in intact male rhesus monkeys. Coronary angiographic experiments with intracoronary serotonin and the thromboxane A(2) analog U46619 stimulated brief vasoconstriction (for 1-3 min) in large epicardial coronaries in untreated male monkeys. In contrast, MPA- and DHT-treated monkeys displayed long-duration constrictions (>5 min), with significantly greater reductions in the minimal diameters of epicardial coronaries. Immunocytochemistry demonstrated androgen receptors (AR) and P receptors in aorta and coronary arteries, and immunocytochemistry and Western blotting showed AR and P receptors in rhesus coronary vascular muscle cells. In vivo, MPA or DHT increased thromboxane prostanoid (TP) receptor expression in the aorta. In vitro, MPA or DHT increased, whereas P did not change, TP receptor expression in primary coronary vascular muscle cell. This MPA- or DHT-mediated increase in TP receptor expression was attenuated by the AR antagonist flutamide. MPA or DHT induction of CH in intact adult male primates, hypothesized to occur via androgenic up-regulation of vascular muscle TP receptor expression, could predispose to CH-mediated myocardial ischemia.

Previous reports showed that 17␤-estradiol implants attenuate in vivo coronary hyperreactivity (CH), characterized by long-duration vasoconstrictions (in coronary angiographic experiments), in menopausal rhesus monkeys. Prolonged Ca 2ϩ contraction signals that correspond with CH in coronary vascular muscle cells (VMC) to the same dual-constrictor stimulus, serotonin ϩ the thromboxane analog U-46619, in estrogen-deprived VMC were suppressed by Ͼ72 h in 17␤-estradiol. The purpose of this study was to test whether an endogenous estrogen metabolite with estrogen receptor-␤ (ER-␤) binding activity, estriol (E 3), suppresses in vivo and in vitro CH. E 3 treatment in vivo for 4 wk significantly attenuated the angiographically evaluated vasoconstrictor response to intracoronary serotonin ϩ U-46619 challenge. In vitro treatment of rhesus coronary VMC for Ͼ72 h with nanomolar E 3 attenuated late Ca 2ϩ signals. This reduction of late Ca 2ϩ signals also appeared after Ͼ72 h of treatment with subnanomolar 5␣-androstane-3␤,17␤-diol (3␤-Adiol), an endogenous dihydrotestosterone metabolite with ER-␤ binding activity. R,R-tetrahydrochrysene, a selective ER-␤ antagonist, significantly blocked the E 3-and 3␤-Adiol-mediated attenuation of late Ca 2ϩ signal increases. ER-␤ and thromboxane-prostanoid receptor (TPR) were coexpressed in coronary arteries and aorta. In vivo E3 treatment attenuated aortic TPR expression. Furthermore, in vitro treatment with E3 or 3␤-Adiol downregulated TPR expression in VMC, which was blocked for both agonists by pretreatment with R,R-tetrahydrochrysene. E 3-and 3␤-Adiol-mediated reduction in persistent Ca 2ϩ signals is associated with ER-␤-mediated attenuation of TPR expression and may partly explain estrogen benefits in coronary vascular muscle. menopause; calcium; thromboxane-prostanoid receptor; angiography CARDIOVASCULAR PHYSIOLOGY is profoundly regulated by multiple endocrine signals via nuclear and cell surface receptors, and age-related hormonal decline may increase the risk of cardiovascular disease (1). Current controversy regarding cardiovascular effects of hormone therapy (35, 38) emphasizes the need for research to enhance our understanding of steroid hormone actions on structural and functional changes in the blood vessel wall (7). Growing evidence suggests a role for estrogen receptors (ER) in regulation of vascular healing and proliferation following injury as well as ER-mediated regulation of endothelial-dependent vasodilator reactivity responses (23). However, published data on ER-mediated effects on coronary vasoconstrictor reactivity responses are sparse.Despite a large body of evidence on the biological actions of 17␤-estradiol (E 2 ) (33), there is a paucity of information on the biological actions of metabolites of E 2 , such as the endogenous ER ligand estriol (E 3 ), which can be present at significant concentrations at the tissue level (5,11,19). E 3 is abundantly produced during late-stage pregnancy and, thus, is present in conjugated equine estrogen preparations, which are kno...

Heart disease presentation can differ between the sexes because nonobstructive coronary disease and angina unrelated to exercise are considerably more prevalent in women than in men. When the outcomes of large, randomized, controlled trials failed to demonstrate cardiac risk protection, many women and their physicians abandoned hormone replacement therapy as primary or secondary prevention for cardiovascular disease. We are concerned that the apparent blanket condemnation of steroids has not sufficiently distinguished between the cardiovascular actions of estrogen, progesterone and the synthetic progestin medroxyprogesterone acetate. The actions of active metabolites of progestins are not well understood and in some cases have not been explored. We intend to present what is known and what is not known about progesterone per se versus medroxyprogesterone acetate, particularly with regard to cardiovascular effects. This Review considers the mounting evidence that progesterone improves cardiovascular function and proposes its mechanism of action-restoration of a threshold level of progesterone as preventive of microvascular cardiac ischemia-and compares oral and transdermal routes of administration. We hope to stimulate research to determine whether progesterone, with or without estrogen, has a role in reducing cardiovascular risk and treating cardiovascular disease including myocardial ischemia in postmenopausal women.

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