J. KOUDY WILLIAMS & MICHAEL R. ADAMS

Department of Comparative Medicine Bowman Gray School of Medicine Wake Forest University Winston-Salem, North Carolina 27157-1040, USA.

Introduction

Coronary heart dis-ease (CHD) is the Leading cause of death and a major cause of dis Ability among postmenopausal women in most Western societies [1]. Although a direct causal relationship has not been shown, it has been established that risk of CHD is reduced by as much as 50 percent in postmenopausal women who take 0.625 mg of conjugated equine estrogens (the estrogens most commonly given to American women; CEE) or the equivalent daily [2]. Although estrogen use is associated with a reduced risk of CHD, when taken long-term it has been reported to increase the risk of endometrial and breast cancer. To offset this effect postmenopausal women on hormone replacement therapy are recommended to take estrogen in combination with either progesterone (the natural hormone) or synthetic progestin derivatives. However, the impact of the coadministration of a progestin on the cardioprotective effects of estrogen is unclear. On page 324 of this issue Miyagawa et al.[3] show that coadministration of estradiol-17β with the synthetic progestin medroxyprogesterone acetate (MPA) diminishes estrogen-induced protection against coronary vasoconstriction in ovariectomized rhesus monkeys. By contrast, estradiol-17β combined with progesterone protected against coronary vasoconstriction. These results suggest that certain progestins may oppose favorable effects of estrogens on the cardiovascular system.

Although some types and doses of progestins have been shown to have deleterious effects on plasma lipid and lipoprotein concentrations, it should be pointed out that sex hormone effects on lipid concentrations explain only about 30 percent to 50 percent of their CHD risk effects [4]. It has been hypothesized that the remaining effects of sex hormones may be mediated in the artery wall. Our studies indicate that MPA diminishes the vasodilator effects of CEE in response to acetylcholine independently of plasma lipid and lipoprotein concentrations [5,6]. The Miyagawa study is significant because the investigators compare the effects of estradiol-17β and progesterone versus estradiol-17β and MPA on coronary artery responses to constrictors (serotonin/thromboxane) released during platelet activation, a situation that may very well occur in vivo at the site of a coronary artery plaque rupture.

Why do progesterone and MPA have seemingly contrasting effects on vascular reactivity and atherogenesis? There are no definitive studies that identify a mechanism(s) by which progesterone and MPA affect vascular reactivity differently. However, the example of well- characterized anti-estrogenic effects of progestins on the reproductive system may be instructive. The extent of the anti-estrogenic effects of a progestin on pathophysiologic processes of the endometrium, for example, depend on several factors, including dose, potency (or type), and route or pattern of administration. Although the effects of progestins on arterial walls remain unclear, there is evidence suggesting that estrogens may modulate vascular reactivity through mediating nitric oxide production, low density lipoprotein oxidation, ion channel activity, and expression of vasoactive biomolecules such as endothelin. Some, or all, of these processes may be targets antagonized by progestins.

Do other progestins have vascular effects similar to MPA? Progestins are known to differ in their potency. Because MPA is more potent than progesterone, it may more effectively antagonize the vascular benefits of estrogen. Furthermore, progestins also differ in their androgenicity. MPA has more potent androgenic properties than progesterone. We have found that a nonandrogenic progestin, nomegestrol acetate, does not diminish the beneficial effects of estrogen on coronary dilator responses in monkeys, thus supporting the notion that relative androgenicity may play a role in determining a progestin's effects on vascular reactivity. Progestins also differ in their capacity to stimulate glucocorticoid release, which may also explain differential effects on vascular reactivity.

The dose of hormone and hormone kinetics are very important factors in the interpretation of data from animal models. Care must be taken to approximate the dose of hormone in the animal to that given to women. However, it cannot be ruled out in the Miyagawa study, and other studies using animal models, that the kinetics of metabolism may be different in monkeys and people. If this is so, blood and tissue concentrations of the hormones may differ between species. Thus, the results of the current study are important because they suggest that a particular progestin or estrogen may act differently at the same tissue site.

New approaches to hormone replacement therapy may involve developing estrogens that prevent cardiovascular disease and osteoporosis but do not increase the risk of breast and uterine cancer. For example, 17 alpha-dihydroxy- equilenin (one of the estrogens in CEE) has little effect on the uterus of monkeys, but does benefit the cardiovascular system [7]. Furthermore, certain plants, such as soybeans, contain a significant amount of isoflavones, compounds with structures similar to estradiol that bind weakly to the estrogen receptor. These plant "estrogens" have beneficial effects on vascular reactivity of coronary arteries [8] but have few effects on breast and uterine tissue [9].

The public health importance of these issues cannot be underestimated. Despite epidemiologic evidence that hormone replacement therapy reduces the risk of CHD, osteoporosis, and possibly dementia in postmenopausal women, in the United States less than eight percent of this group take hormone replacement therapy. Poor compliance is accounted for, in large part, by fear of cancer (associated with unopposed estrogen) and side effects (such as menstrual bleeding). The perfect hormone replacement therapy might be one that affords cardiovascular and bone protection without causing unwanted side effects or increasing the risk of breast or uterine cancer. To date, no such therapy exists. The Miyagawa study is an important contribution to our understanding of the interactive effects of estrogens and progestins on the cardiovascular system. Future research may focus on the development of estrogens (such as 17 alpha-dihydroequi- lenin and soy "estrogens") that do not have harmful effects on the breast and uterus, and progestins (such as nomegestrol acetate) that may not reduce the beneficial effects of estrogen on cardiovascular tissue.

References

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Washburn, S.A. et al. Effects of 17 alpha-dihydroxy equilenin sulfate on atherosclerotic male and female rhesus monkeys. Am. ]. Obstet. Gynecol. 175, 341-351 (1996). 

Honoré, E.K., Williams, J.K., Anthony, M.S. St Clarkson, T.B. Soy isoflavones enhance coronary vascular reactivity in atherosclerotic female macaques. Fertil. Steril. 67,148-154 (1997). 

Foth, D. St Cline, J.M. Effects of mammalian and plant estrogens on mammary glands and uteri of macaques. Am. /. Clin. Nutr. (in the press).