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LE Magazine February 1997

Hormonal Effects Of Plant Extracts
Commonly occurring plant flavonoids have estrogenic activity

Miksicek RJ
Department of Pharmacological Sciences, State University of New York, StonyBrook 11794-8651
Mol Pharmacol (UNITED STATES) Jul 1993, 44 (1) p37-43,

A remarkable diversity of naturally occurring and synthetic compounds have been shown to mimic the biological effects of 17 beta-estradiol by virtue of their ability to bind to and activate the nuclear estrogen receptor. This report extends the family of nonsteroidal estrogens to include several multiply hydroxylated chalcones, flavanones, and flavones. The hormone-like activity of these natural plant products is indicated by their ability to stimulate an estrogen receptor-dependent transcriptional response and to promote growth of estrogen-dependent MCF7 cells in culture. The transcriptional response can be inhibited by the steroidal estrogen antagonist ICI-164,384 and is specific for the estrogen receptor. Evidence is presented to show that selected hydroxylated flavonoids interact directly with the estrogen receptor, based on their ability to compete for the binding of 17 beta-[3H]estradiol to the receptor in cell-free extracts. These compounds are less active, on a molar basis, than 17 beta-estradiol or the synthetic dihydroxystilbene estrogens, but they have potencies comparable to those of other known phytoestrogens. Together, these findings broaden our understanding of the structure-activity relationships for nonsteroidal estrogens and present a series of new chemical prototypes for the future development of potentially useful agonists and antagonists for this nuclear receptor. The wide distribution of weakly estrogenic flavonoid pigments in food crops and medicinal plants raises additional questions about the possible health risks and benefits of these compounds, meriting closer examination of their presence in the human diet.

Effect of paeoniflorin, glycyrrhizin and glycyrrhetic
acid on ovarian androgen production.

Takeuchi T; Nishii O; Okamura T; Yaginuma T
Dept. of Obstetrics and Gynecology, University of Tokyo, Japan
Am J Chin Med (UNITED STATES) 1991, 19 (1) p73-8,

We have shown that traditional herbal medicine, Shakuyaku-Kanzo-To consisted of Shakuyaku and Kanzo decreased serum testosterone levels in woman and rat. Therefore, paeoniflorin and glycyrrhizin, a main component of Shakuyaku and Kanzo, respectively, and glycyrrhetic acid, a metabolite of glycyrrhizin in vivo, were investigated for the steroid production in the rat ovary on the morning of proestrus. The homogenized tissues of one ovary were incubated in the Dulbecco's modified Eagle medium (pH 7.5) with 100 micrograms/ml of paeoniflorin, glycyrrhetic acid and glycyrrhizin and the medium only (the control) at 37 degrees C for 270 min. After the centrifugation, the concentrations of delta 4-androstenedione, testosterone and estradiol in the supernatants were determined by RIA. The production of the hormones expressed by [concentration x supernatant volume/weight of the ovary] was compared to the control. Paeoniflorin, glycyrrhetic acid and glycyrrhizin decreased significantly the testosterone production but did not change that of delta 4-androstenedione and estradiol. Testosterone/delta 4-androstenedione production ratio was lowered significantly by paeoniflorin, glycyrrhetic acid and glycyrrhizin. Estradiol/testosterone production ratio was increased significantly by glycyrrhetic acid and not changed by paeoniflorin and glycyrrhizin. These results suggest that paeoniflorin, glycyrrhetic acid and glycyrrhizin affect the conversion between delta 4-androstenedione and testosterone to inhibit testosterone synthesis and stimulate the aromatase activity to promote estradiol synthesis by the direct action on the rat proestrous ovary.

Glycyrrhetic acid as an active oestrogenic substance
separated from Glycyrrhiza glabra (liquorice)

Sharaf A.; Gomaa N.; El Gamal M.H.A.
Pharmacol. Dept., Nat. Res. Cent., Cairo EGYPT
EGYPT.J.PHARM.SCI. (EGYPT) , 1975, 16/2 (245-251)

Glycyrrhetic acid is a pentacyclic triterpenoid obtained by mineral acid hydrolysis of glycyrrhizin present in liquorice root. When glycyyrrhetic acid was tested for its oestrogenic activity, it was found that it posses an oestrogenic action when tested on uterine weight of immature mice. The estrogenic action of 5 mg. of glycyrrhetic acid corresponds approximately to that of 0.1 microgram of oestradiol. Moreover, glycrrhetic acid acts synergistically with the female hormone, estradiol, on uterine development when combined together.

Effects of herbal components of tokishakuyakusan
on progesterone secretion by corpus luteum in vitro

Usuki S Department of Obstetrics and Gynecology, University of Tsukuba, Ibaraki, Japan
Am J Chin Med (UNITED STATES) 1991, 19 (1) p57-60,

Twenty-seven-day old female rats received 20 IU PMS and 56 hours later, 40 IU hCG. Seven days after hCG treatment, the resected ovaries were incubated in vitro with herbal components of Tokishakuyakusan (TS). Mixture of hoelen + peony root + alisma rhizone + Japanese angelica root or hoelen + Japanese angelica root or Japanese angelica root + cnidium rhizome significantly increased progesterone secretion, and these levels tended to exceed the level by TS alone. These results suggest an exquisitely blended effect of herbal components of TS on progesterone secretion by corpora lutea.

Blended effects of herbal components of tokishakuyakusan
on rat corpus luteum function in vivo

Usuki S Department of Obstetrics and Gynecology, University of Tsukuba, Ibaraki, Japan
Am J Chin Med (UNITED STATES) 1988, 16 (3-4) p107-16,

The effect of herbal components of Tokishakuyakusan on progestin levels in serum and ovarian tissue from rats treated with PMS and hCG was examined in vivo. Hoelen + peony root + Japanese angelica root increased progesterone/20 alpha-OHP ratio in serum, and hoelen or peony root also increased the ratio in ovarian tissue, while atractylodes lanceae rhizome or hoelen + atractylodes lanceae rhizome decreased the ratio in serum and ovarian tissue. These data suggested that hoelen or peony root has a luteotropic effect but that atractylodes lanceae rhizome develops luteolysis. Furthermore, the data indicated a blended effect of herbal components of Tokishakuyakusan on the corpus luteum.

Effect of Japanese Angelica root and peony root
on uterine contraction in the rabbit in situ

Harada M; Suzuki M; Ozaki Y
J Pharmacobiodyn (JAPAN) May 1984, 7 (5) p304-11,

Intraduodenal administration of 70% MeOH extract of Japanese Angelica root (3 g/kg) and Peony root (3 g/kg) increased uterine contractile activities in anesthetized rabbits. The activities of both extracts shifted to the aqueous layer (positive at a dose of 1 g/kg) with successive fractionation of the extracts with hexane and BuOH, indicating contribution of a hydrophilic principle(s) to the effect. In some animal preparations, inhibiting effect of the extracts on uterine contraction was noted after the uterotonic effect terminated. The aqueous fraction (40 mg/kg) after being treated with hexane and BuOH also produced uterine contraction along with decrease of blood pressure through i.v. route, which was greatly inhibited by pretreatment of atropine, suggesting participation of cholinergic components in the effect of both extracts.

Antioxidant activity of dioscorea and dehydroepiandrosterone
(DHEA) in older humans

Araghiniknam M; Chung S; Nelson-White T; Eskelson C; Watson RR
Arizona Prevention Center, University of Arizona, School of Medicine, Tucson, 85724, USA
Life Sci (ENGLAND) 1996, 59 (11) pPL147-57,

Dioscorea is a yam steroid extract used in commercial steroid synthesis and consumed by people. DHEA is a steroid which declines with age, but without known activity. This study was designed to determine whether dioscorea supplementation could increase serum dehydroepiandrosterone sulfate (DHEAS) in humans and modulate lipid levels in older people. The subjects were selected volunteers aged 65-82 years. The serum DHEAS level, lipid peroxidation and lipid profile were assessed. Three weeks of dioscorea supplementation had no affect on serum DHEAS level. However DHEA intake of 85 mg/day increased serum DHEA levels 100.3%. DHEA and dioscorea significantly reduced serum lipid peroxidation, lowered serum triglycerides, phospholipid and increased HDL levels. Both DHEA and the steroid yam extract, dioscorea, have significant activities as antioxidant to modify serum lipid levels.

How to reduce the risk factors of osteoporosis in Asia

Kao PC; P'eng FK
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Chung Hua I Hsueh Tsa Chih (Taipei) (TAIWAN) Mar 1995,55 (3) p209-13,

Osteoporosis can be predicted to be a new burden to public health in Asia. Currently, the incidence of osteoporosis-related fractures is lower there than in most western communities. By the year 2050, however, 50% of the 6.3 million hip fractures which occur worldwide will be in Asians as a result of an aging population, a decrease in physical activity and westernization of lifestyles. The cost of treatment and cure of these patients will be enormous, a sufficient financial burden to consume current economic gain and cripple the future advancing development of Asian countries. Individual risk factors for osteoporosis have been identified by the extensive Mediterranean Osteoporosis Study (MEDOS). Fortunately, Asians, the rural population and farmers in particular, have the favorable lifestyle identified by the study, including high physical activity and exposure to sunlight. Strikingly, tea drinking, a daily habit in Asia, is also identified as a protective factor against osteoporosis. In addition, bioflavonoids and phytoestrogen-rich soybeans and vegetables are consumed in large quantities by Asians. A soy diet reduces mortality in breast and prostate cancer because it contains weak estrogens. The weakly estrogenic phytoestrogens require further study to demonstrate their pharmacological effect in reducing the rate of osteoporosis. Public health education, however, is needed to encourage the Asian population to maintain their traditionally good lifestyle and to reduce the risk factors for osteoporosis. In turn, these steps may reduce the public health burden by 2050.

Phytoestrogens: a short review

Knight DC; Eden JA
Royal Hospital for Women, New South Wales, Australia.
Maturitas (IRELAND) Nov 1995, 22 (3) p167-75,

The wide distribution of plant estrogens or 'phytoestrogens' in cereals, vegetables and medicinal plants raises questions concerning the possible health risks and benefits associated with their consumption. In this article, we provide a synopsis of the literature relating principally to the clinical effects of phytoestrogens on the diseases associated with ageing. The sources, metabolism and properties of the different phytoestrogens are also discussed. The studies included were primarily restricted to those with data pertinent to clinical practice. Our contention is that phytoestrogens are at least part of the reason why vegetarians and Asian populations have a low rate of cancer and heart disease. (89 Refs.)

A review of the clinical effects of phytoestrogens

Knight DC; Eden JA
Royal Hospital for Women, New South Wales, Australia.
Obstet Gynecol (U.S.) May 1996, 87 (5 Pt 2) p897-904,

OBJECTIVE:
To review the sources, metabolism, potencies, and clinical effects of phytoestrogens on humans. DATA SOURCES: The MEDLINE data base for the years 1980-1995 and reference lists of published articles were searched for relevant English-language articles concerning phytoestrogens, soy products, and diets with high-phytoestrogen content. METHODS OF STUDY SELECTION: We identified 861 articles as being relevant. Human cell line studies, human epidemiologic studies (case-control or cohort), randomized trials, and review articles were included. Animal studies regarding phytoestrogens were included when no human data were available concerning an important clinical area. TABULATION, INTEGRATION, AND RESULTS: Included were studies containing information considered pertinent to clinical practice in the areas of growth and development, menopause, cancer, and cardiovascular disease. When findings varied, those presented in this study reflect consensus. All studies concurred that phytoestrogens are biologically active in humans or animals. These compounds inhibit the growth of different cancer cell lines in cell culture and animal models. Human epidemiologic evidence supports the hypothesis that phytoestrogens inhibit cancer formation and growth in humans. Foods containing phytoestrogens reduce cholesterol levels in humans, and cell line, animal, and human data show benefit in treating osteoporosis.

CONCLUSION:
This review suggests that phytoestrogens are among the dietary factors affording protection against cancer and heart disease in vegetarians. With this epidemiologic and cell line evidence, intervention studies are now an appropriate consideration to assess the clinical effects of phytoestrogens because of the potentially important health benefits associated with the consumption of foods containing these compounds. (90 Refs.)

Phytoestrogens: epidemiology and a possible
role in cancer protection

Adlercreutz H
Department of Clinical Chemistry, University of Helsinki, Finland
Environ Health Perspect (U.S.) Oct 1995 103 Suppl 7 p103-12,

Because many diseases of the Western Hemisphere are hormone-dependent cancers, we have postulated that the Western diet, compared to a vegetarian or semivegetarian diet, may alter hormone production, metabolism, or action at the cellular level by some biochemical mechanisms. Recently, our interest has been mainly focused on the cancer-protective role of some hormonelike diphenolic phytoestrogens of dietary origin, the lignans and the isoflavonoids. The precursors of the biologically active compounds originate in soybean products (mainly isoflavonoids), whole grain cereal food, seeds, and probably berries and nuts (mainly lignans). The plant lignan and isoflavonoid glycosides are converted by intestinal bacteria to hormonelike compounds with weak estrogenic but also antioxidative activity; they have now been shown to influence not only sex hormone metabolism and biological activity but also intracellular enzymes, protein synthesis, growth factor action, malignant cell proliferation, differentiation, and angiogenesis in a way that makes them strong candidates for a role as natural cancer-protective compounds. Epidemiologic investigations strongly support this hypothesis because the highest levels of these compounds in the diet are found in countries or regions with low cancer incidence. This report is a review on recent results suggesting that the diphenolic isoflavonoids and lignans are natural cancer-protective compounds. (133 Refs.)

Effects of soya consumption for one month on steroid
hormones in premenopausal women:
implications for breast cancer risk reduction

Lu LJ; Anderson KE; Grady JJ; Nagamani M
Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TE 77555, USA.
Cancer Epidemiol Biomarkers Prev (U.S.) Jan 1996, 5 (1) p63-70,

Soybean consumption is associated with reduced rates of breast, prostate, and colon cancer, which is possibly related to the presence of isoflavones that are weakly estrogenic and anticarcinogenic. We examined the effects of soya consumption on circulating steroid hormones in six healthy females 22-29 years of age. Starting within 6 days after the onset of menses, the subjects ingested a 12-oz portion of soymilk with each of three meals daily for 1 month on a metabolic unit. Daily isoflavone intakes were approximately 100 mg of daidzein (mostly as daidzin) and approximately 100 mg of genistein (mostly as genistin). Serum 17 beta-estradiol levels on cycle days 5-7, 12-14, and 20-22 decreased by 31% (P = 0.09), 81% (P = 0.03), and 49% (P = 0.02), respectively, during soya feeding. Decreases persisted for two or three menstrual cycles after withdrawal from soya feeding. The luteal phase progesterone levels decreased by 35% during soya feeding (P = 0.002). Dehydroepiandrosterone sulfate levels decreased progressively during soya feeding by 14-30% (P = 0.03). Menstrual cycle length was 28.3 +/- 1.9 days before soymilk feeding, increased to 31.8 +/- 5.1 days during the month of soymilk feeding (P = 0.06), remained increased at 32.7 +/- 8.4 days (P = 0.11) at one cycle after termination of soymilk feeding, and returned to pre-soya diet levels five to six cycles later. These results suggest that consumption of soya diets containing phytoestrogens may reduce circulating ovarian steroids and adrenal androgens and increase menstrual cycle length. Such effects may account at least in part for the decreased risk of breast cancer that has been associated with legume consumption.

Vitamin E and Vitamin-C supplement use and risk
of all-cause and coronary heart disease
mortality in older persons:
the Established Populations for Epidemiologic
Studies of the Elderly

Losonczy KG; Harris TB; Havlik RJ
Epidemiology, Demography and Biometry Program, National Institute on Aging, Bethesda, MD 20892-9205, USA. klosoncz@gibbs.oit.unc.edu
Am J Clin Nutr (UNITED STATES) Aug 1996, 64 (2) p190-6,

We examined vitamin E and Vitamin-C supplement use in relation to mortality risk and whether vitamin C enhanced the effects of vitamin E in 11,178 persons aged 67-105 y who participated in the Established Populations for Epidemiologic Studies of the Elderly in 1984-1993. Participants were asked to report all nonprescription drugs currently used, including vitamin supplements. Persons were defined as users of these supplements if they reported individual vitamin E and/or Vitamin-C use, not part of a multivitamin. During the follow-up period there were 3490 deaths. Use of vitamin E reduced the risk of all-cause mortality [relative risk (RR) = 0.66; 95% CI: 0.53, 0.83] and risk of coronary disease mortality (RR = 0.53; 95% CI: 0.34, 0.84). Use of vitamin E at two points in time was also associated with reduced risk of total mortality compared with that in persons who did not use any vitamin supplements. Effects were strongest for coronary heart disease mortality (RR = 0.37; 95% CI: 0.15, 0.90). The RR for cancer mortality was 0.41 (95% CI: 0.15, 1.08). Simultaneous use of vitamins E and C was associated with a lower risk of total mortality (RR = 0.58; 95% CI: 0.42, 0.79) and coronary mortality (RR = 0.47; 95% CI: 0.25, 0.87). Adjustment for alcohol use, smoking history, aspirin use, and medical conditions did not substantially alter these findings. These findings are consistent with those for younger persons and suggest protective effects of vitamin E supplements in the elderly.

Carotenoids, vitamins C and E, and mortality in an
elderly population

Sahyoun NR; Jacques PF; Russell RM
Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA. Am J Epidemiol (U.S.) Sep 1 1996, 144 (5) p501-11,

In 1981-1984, the nutritional status of 747 noninstitutionalized Massachusetts residents aged 60 years and over was assessed. Nine to 12 years later, the vital status of these subjects was determined. The data of a subset of 725 community-dwelling volunteers was used to examine associations between mortality and the nutrient antioxidants (carotenoids and vitamins C and E) in plasma, diet, and supplements. Results indicated that subjects with plasma Vitamin-C levels in the middle and high quintiles had a lower overall mortality (relative risk (RR) = 0.64, 95% confidence interval (CI) 0.44-0.94 and RR = 0.54, 95% CI 0.32-0.90, respectively) than those in the lowest quintile even after adjustment for potential confounders. These associations were largely due to reduced mortality from heart disease. Subjects in the highest quintile of total intake of vitamin C also had a significantly lower risk of overall mortality (RR = 0.55, 95% CI 0.32-0.93) and mortality from heart disease (RR = 0.38, 95% CI 0.19-0.75) than did those in the lowest quintile after potential confounders were controlled for. Intake of vegetables was inversely associated with overall mortality (p for trend = 0.003) and mortality from heart disease (p for trend = 0.04). No other significant associations were observed. In conclusion, the results indicate that high intakes and plasma levels of Vitamin-C and frequent consumption of vegetables may be protective against early mortality and mortality from heart disease.

Supplementation with vitamins C and E suppresses
leukocyte oxygen free radical production in
patients with myocardial infarction

Herbaczynska-Cedro K; K+osiewicz-Wasek B; Cedro K; Wasek W; Panczenko-Kresowska B; Wartanowicz M
Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
Eur Heart J (ENGLAND) Aug 1995, 16 (8) p1044-9,

Clinical studies suggest that neutrophil activation during acute myocardial infarction (MI) aggravates tissue injury. Activated neutrophils are an important source of oxygen free radicals (OFR), the injurious effects of which are counteracted by endogenous antioxidants. We have previously shown in healthy subjects that supplementation with antioxidant vitamins C and E suppresses OFR production by isolated neutrophils assayed by chemiluminescence (CL). The present study, performed in patients with acute MI aimed:

  1. to investigate the effect of Vitamin-C and E supplementation upon neutrophil OFR production and serum lipid peroxides,
  2. to evaluate serum levels of vitamins C and E in the course of MI. Forty-five patients with acute MI were randomized to receive either conventional treatment only (control, n=22).
All measurements were performed on the 1st and 14th day. Neutrophil OFR production assayed by CL decreased significantly in VIT patients (Wilcoxon test for paired data P<0.01, Chi square test P<0.01). In the control group, changes in OFR production were not significant. Serum lipid peroxides (measured as TBARS) increased in controls (P<0.05), but remained stable in VIT patients. Mean (+/-SE) serum ascorbic acid and tocopherol on the 1st day were 0.43 +/- 0.18% and 3.25 +/- 1.32 microM.M(-1) cholesterol, respectively, in all patients. On the 14th day in non-supplemented patients mean tocopherol was unchanged, whereas ascorbic acid increased significantly (0.63 +/- 0.24 mg%, P<0.01) suggesting that a low basal level was associated at least in part with the acute phase of the disease. An expected increase in serum vitamin levels occurred in VIT patients. In conclusion, supplementation with vitamins C and E suppresses neutrophil OFR production and lowers the marker of lipid peroxidation in patients with MI.

Effect of vitamin E, Vitamin-C and beta-carotene
on LDL oxidation and atherosclerosis

Jialal I; Fuller CJ
Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas 75235-9052, USA.
Can J Cardiol (CANADA) Oct 1995, 11 Suppl G p97G-103G,

OBJECTIVE:
The oxidative modification of low density lipoprotein (LDL) may be an early step in atherogenesis. Furthermore, evidence of oxidized LDL has been found in vivo. The most persuasive evidence shows that supplementation of some animal models with antioxidants slows atherosclerosis. The purpose of this review is to examine the roles that vitamin E, Vitamin-C and beta-carotene may play in reducing LDL oxidation.

DATA SOURCES: English language articles published since 1980, particularly from groups active in this field of research.

STUDY SELECTION: In vitro, animal, and human studies on antioxidants, LDL oxidation, and atherosclerosis were selected.

DATA SYNTHESIS: Vitamin E has shown the most consistent effects with regard to LDL oxidation. Beta-carotene appears to have only a mild or no effect on oxidizability. Ascorbate, although it is not lipophilic, can also reduce LDL oxidative susceptibility.

CONCLUSIONS: LDL oxidizability can be reduced by antioxidant nutrients. However, more research is needed to establish their utility in the prevention of coronary artery disease. (97 Refs.)

Effect of intake of exogenous vitamins C, E and
beta-carotene on the antioxidative status in kidneys
of rats with streptozotocin-induced diabetes

Mekinova D; Chorvathova V; Volkovova K; Staruchova M; Grancicova E; Klvanova J; Ondreicka R Research Institute of Nutrition, Bratislava, Slovak Republic Nahrung (GERMANY) 1995, 39 (4) p257-61,

We studied the effect of supplementation with vitamins C, E and beta-carotene (PARABION, produced by Syndipharma) on antioxidative status in kidneys of male Wistar rats with diabetes induced by intravenous application of streptozotocin (45 mg.kg-1 of body weight). The animals received subtherapeutic doses of Insulin Interdep (6 U.kg-1 of body weight). A significant decrease of malondialdehyde (MDA), reduced (GSH) and oxidized (GSSG) glutathione and reduction of the activities of Se-glutathione peroxidase (Se-GSH-PX, EC. 1.11.1.9.) and glutathione S-transferase (GST, EC. 2.5.1.18.) were observed in kidneys of diabetic rats treated with these vitamins. On the contrary, the activity of CuZn-superoxide dismutase (CuZn-SOD, EC. 1.15.1.1) and the level of Vitamin-C (vit. C) increased significantly. No changes were observed for vitamin E (vit. E), beta-carotene and catalase (CAT, EC. 1.11.1.6). Supplementation with vitamins C, E and beta-carotene resulted in an improvement of antioxidative status of kidneys of rats with streptozotocin-induced diabetes.

Serial coronary angiographic evidence that
antioxidant vitamin intake reduces progression
of coronary artery atherosclerosis

Hodis HN; Mack WJ; LaBree L; Cashin-Hemphill L; Sevanian A; Johnson R; Azen SP
Atherosclerosis Research Unit, University of Southern California School of Medicine, Los Angeles 90033, USA.
JAMA (UNITED STATES) Jun 21 1995, 273 (23) p1849-54,

OBJECTIVE
To explore the association of supplementary and dietary vitamin E and C intake with the progression of coronary artery disease. DESIGN-A subgroup analysis of the on-trial antioxidant vitamin intake database acquired in the Cholesterol Lowering Atherosclerosis Study, a randomized, placebo-controlled, serial angiographic clinical trial evaluating the risk and benefit of colestipol-niacin on coronary artery disease progression. SETTING-Community- and university-based cardiac catheterization laboratories.

SUBJECTS-A total of 156 men aged 40 to 59 years with previous coronary artery bypass graft surgery. INTERVENTION-Supplementary and dietary vitamin E and C intake (nonrandomized) in association with cholesterol-lowering diet and either colestipol-niacin or placebo (randomized).

OUTCOME-Change per subject in the percentage of vessel diameter obstructed because of stenosis (%S) determined by quantitative coronary angiography after 2 years of randomized therapy on all lesions, mild/moderate lesions (< 50%S), and severe lesions (> or = 50%S).

RESULTS-Overall, subjects with supplementary vitamin E intake of 100 IU per day or greater demonstrated less coronary artery lesion progression than did subjects with supplementary vitamin E intake less than 100 IU per day for all lesions (P = .04) and for mild/moderate lesions (P = .01). Within the drug group, benefit of supplementary vitamin E intake was found for all lesions (P = .02) and mild/moderate lesions (P = .01). Within the placebo group, benefit of supplementary vitamin E intake was not found. No benefit was found for use of supplementary Vitamin-C exclusively or in conjunction with supplementary vitamin E, use of multivitamins, or increased dietary intake of vitamin E or Vitamin-C.

CONCLUSIONS-These results indicate an association between supplementary vitamin E intake and angiographically demonstrated reduction in coronary artery lesion progression. Verification from carefully designed, randomized, serial arterial imaging end point trials is needed.