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Abstract & Commentary
Synopsis: Monkeys fed a diet containing soy phytoestrogens showed a better lipid and lipoprotein profile than those fed an otherwise equivalent diet in which conjugated equine estrogens replaced the soy phytoestrogens. However, atherosclerosis was inhibited more in the monkeys whose diet contained CEE.
Source: Clarkson TB, et al. J Clin Endocrinol Metab. 2001;86:41-47.
In this study, 189 cynomolgus monkeys were randomized to 1 of 3 arms for 36 months. In 1 arm, monkeys were fed soy protein devoid of phytoestrogens; in another soy protein with phytoestrogens, and in the other soy protein with conjugated equine estrogens (CEE) given at a dose that approximates the standard 0.625 mg dose given to postmenopausal women. Outcome variables included measurement of plasma lipids and lipoproteins and extent of atherosclerosis. The groups that received phytoestrogen and CEE had comparable reductions in total cholesterol. The group that was given phytoestrogens had higher HDL levels, but the group that received CEE did not differ from the control group. Both the phytoestrogen and CEE groups had lower LDL levels than the control group. The group given CEE had higher triglyceride levels than the other 2 groups. Atherosclerosis progressed in the iliac arteries in 63% of the control group, 39% of the phytoestrogen group, and 35% of the CEE group. In the coronary arteries, CEE-treated monkeys had significantly less plaque than phytoestrogen-treated animals. In the carotid arteries, CEE was slightly more protective than phytoestrogens.
COMMENT BY SARAH L. BERGA, MD
Last month in OB/GYN Clinical Alert, I reviewed a study that reported the localization of estrogen receptor (ER) subtypes a and b in various human reproductive tissues.1 A key finding was that both estrogen receptor subtypes displayed similar distribution patterns in breast tissue, while vaginal tissues expressed only ERa. Granted, both ER subtypes may not initiate the same activities in breast tissue, but they are both there. Of course, the main rationale for wanting to know the distribution pattern of ERs is that we hope that this knowledge will help us to design a "smarter" selective estrogen receptor modulator (SERM). However, as the distribution of ER subtypes shows, the hope of finding a perfect SERM based on selective expression of ER subtypes in key tissues is unwarranted.
This month’s article concerns the cardiovascular actions in a cynomolgus monkey model of so-called "natural" SERMs, phytoestrogens. Phytoestrogens are isoflavones. They are primarily antioxidants, but they also bind to ERb with 80% of the affinity of 17b-estradiol while binding only weakly to ERa. It is hoped that phytoestrogens will behave as estrogen agonists in brain, heart, vagina, pelvic floor, and bone, but as estrogen antagonists in uterus and breast, thus making them the "perfect" SERM. The present study is intended to determine to what extent phytoestrogens mimic estrogen’s actions in the cardiovascular tree. However, we already know from last month’s study that phytoestrogens are unlikely to be the perfect SERM, because they bind mostly to ERb and the vagina does not express ERb. Therefore, phytoestrogens are not predicted to maintain the urogenital tract in postmenopausal women. In tissues that express both ERa and ERb, the consequences of only occupying ERb are not predictable. Perhaps some of the dissociation between the strongly beneficial change in lipoprotein profiles and the weakly beneficial change in atherosclerosis progression observed in the group given phytoestrogens relates to the downstream consequences of just occupying ERb. In some tissues such as breast, ERb is thought to inhibit ERa action, and in breast both subtypes are localized similarly. However, the localization study did not determine ERa and ERb distribution in the cardiovascular tree of humans. In the brain, the regions that express ERa differ markedly from those that express ERb. Thus, ERb occupancy alone may not be fully (or even partially) neuroprotective. In summary, one should be extremely cautious in advocating the use of phytoestrogens as a substitute for conventional estrogen preparations.
Let’s consider phytoestrogens in another light, that is, as food. Here, I think that the evidence in aggregate supports the notion that the best diet is one that is replete with vegetables and fruits. The current recommendation is for 5 servings of vegetables and 5 servings of fruit daily. While the average "western" vegetable may not contain the same amount of phytoestrogen as soy on a weight basis, most, if not all, vegetables do contain phytoestrogens. Still, the benefits of fruits and vegetables may not parallel phytoestrogen content. Fruits and vegetables contain many wondrous ingredients, many of which remain unnamed. What makes sense to me, given the state of our knowledge, is to recommend a diet rich in fruits and vegetable (such as the DASH diet) and HRT for most postmenopausal women.
1. Pelletier G, El-Alfy. J Clin Endocrinol Metab. 2000;85:4835-4840.