Article title and citation: Effects of the phytoestrogen genistein on some predictors of cardiovascular risk in osteopenic, postmenopausal women: a 2-years randomized, double blind, placebo-controlled study. J Clin Endocrin Metab doi:10.1210/jc.2006-2295
Study coordinating site: Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Messina, Italy
Population: Population of 389 women, 49?67 yr of age, into at least one year of menopause (NOT surgically induced), in good general health, with reduced hip bone density, not using any hormone replacement, cardiovascular/lipid-modifying, or anti-osteoporotic drugs, and not smoking more than two cigarettes daily
Intervention: All women were provided a calorie-matched, fat-reduced diet (25-30% energy from fat, <10% of energy from saturated fatty acids, 55-60% energy from carbohydrates, 15% energy intake from proteins, cholesterol intake of <300 mg/day and fiber intake of ≥35 g /day; soy products, legumes or other nutrient supplements were completely prohibited) for four weeks BEFORE baseline blood measures were taken. Subjects were asked to maintain this diet through the remainder of the study and then they were randomized to receive 54 mg/day of pure genistein (G; purified from soy; Laboratori Plants, Messina, Italy) (n = 198) or placebo (PL; n =191), administered in two tablets daily. [Note: the baseline dietary intake of genistein was estimated to be 1-2 mg/day, via food frequency questionnaires] ALL of the tablets (genistein and placebo) also provided calcium carbonate (NOTE : the article described the amount as 500 mg, although it was likely 500 mg of calcium from calcium carbonate) and vitamin D (400 IU) (per tablet).
Disclosures of interest: None of the authors had any disclosures
Funding source: Italian Ministry of Education, University and Research, and the University of Messina, Italy
Rationale: A notable suite of clinical trials have examined the impact of genistein, delivered in various forms and doses, upon blood lipids, insulin sensitivity, and circulating markers of oxidative stress. However, a number of these studies have used less than pure sources of genistein1, which obscures the contributory effect of genistein alone. Additionally, the implementation of short duration studies, or the use of smaller populations, further renders the available evidence base. These shortcomings, coupled with two recent reviews2,3 asserting that soy products or soy isoflavones have a clinically insignificant upon heart disease risk—predicated primarily upon their modest impact on blood lipids—demand a more rigorous investigation of the influence of genistein on other surrogate markers associated with cardioprotective and vasoprotective efficacy. This 2-year study among Italian women was designed to assess the protective effects of genistein upon both cardiovascular and skeletal markers and ascertain mechanistic insights related to atherosclerosis risk and involutional osteoporosis.
Assessment: Subjects entered the laboratory in a fasting state after being on the standardized diet for 4 weeks, and had blood withdrawn, to assess the following constituents: glucose, insulin (these two, when expressed in a mathematically derived formula, yields the Homeostatic Model Assessment of Insulin Resistance [HOMA-IR], a surrogate measure of whole body insulin sensitivity), fibrinogen, osteoprotegerin (OPG; a circulating receptor produced by several tissues that serves as a decoy to a specific activator of bone metabolism and calcification, the latter explaining its asserted role with calcification of blood vessels), soluble intercellular adhesion molecule (sICAM-1) and soluble vascular cellular adhesion molecule (sVCAM-1) (both expression products of the inner wall (endothelium) of blood vessels, which mediate the attachment of white blood cells to the endothelium and their invasion/migration into the vessel wall interior, and thereby influence inflammation and atherosclerosis), blood lipids and lipoprotein [a], and genistein. Morning first void urine was collected to measure F2-isoprostanes, a marker of oxidative stress. The above parameters, and body mass index (BMI; also measured at baseline), were also measured at 12 and 24 months.
The subjects in both groups (average age of 54 years) had been menopausal for approximately 5 years, on average. All other baseline parameters, including bone density, did not differ significantly between groups. Notably, the average BMI of each group was at or just under 25—this population appeared to be relatively lean, although soft tissue body composition was not assessed. Body weight/BMI did not change within, or differ between, groups over the course of the study. In the G group 198 women were included in the final analysis (intent-to-treat), with 191 in the PL group. Serum genistein concentrations did not change in PL, but were increased fivefold in G, at both 1 and 2 years, suggestive of good compliance among G. Remarkably, ALL of the non-lipid parameters improved in G, and were sustained at 2 years, achieving statistical significance over PL. As a group, PL displayed worsening trends for all non-lipid values of the metabolic surrogates. For example, the HOMA-IR value increased by 11% in P, while in G it decreased by the same magnitude, these combined alterations likely rendering the between groups significantly different. The within group changes were not provided by the authors. In contrast, none of the blood lipid parameters differed between groups over the 2-year interval, reinforcing the inability of genistein to exert any impact upon blood lipids.
Adverse events were significantly greater in G: during the first year there were 16 reported in G, with 8 in placebo (PL). During the second year 21 adverse events were recorded among the G group, with only 7 in PL. Nineteen percent of the women in G, and 8% of PL, withdrew from the study due to adverse events. All of the adverse events were limited to gastrointestinal effects, especially upper GI pain/ discomfort, and constipation, being 2-3 times more prevalent with G. Endometrial thickness, assessed by ultrasound at baseline, and years 1 and 2, did not change in either group.
Dietary intake values after baseline, although described as being captured in the follow up period, were not provided in this report.
Comment: These results, which offer mechanistic insights into the effects of genistein + calcium and vitamin D (no genistein alone group was employed, for obvious ethical reasons), illuminate promising new areas of cardiovascular protective effects in non-overweight postmenopausal women with reduced bone mass. This study is the first report from this group, which also had several other primary and secondary outcome measures:
- Bone turnover/metabolism surrogates
- Bone mineral density (spine and hip)
- Hot flushes reduction
- Cytokines (IL-6, and OPG's companion family, RANK and RANKL)
- Vaginal cell maturation index (PAP smear)
This first report from a study that concluded at least 1 year ago, surprisingly did not report on any of the cytokine data, vaginal cytology, or mammographic results, which would appear to align with the data presented here. One parameter that was not captured was actual progression of atherosclerosis (e.g. coronary artery calcium content; total plaque volume) in this population, using non-invasive techniques. Perhaps the greatest anticipation resides with the bone density and hot flushes data, the most germane outcome data for postmenopausal women. These data are, hopefully, imminent.
1. Kreijkamp-Kaspers S, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA. 2004; 292:65-74.
2. Sacks FM, et al; American Heart Association Nutrition Committee. Soy protein, isoflavones, and cardiovascular health: an American Heart Association Science Advisory for professionals from the Nutrition Committee. Circulation 2006; 113:1034-44.
3. Dewell A, et al. A critical evaluation of the role of soy protein and isoflavone supplementation in the control of plasma cholesterol concentrations. J Clin Endocrin Metab 2006; 91:772?80.