Menopause Live - IMS Updates

Date of release: 15 December, 2008

The phytoestrogen genistein and cardiovascular risk factors in postmenopausal women

In the Journal of Clinical Endocrinology and Metabolism, Paola Villa and colleagues report the effect of genistein administration on cardiovascular risk factors, focusing on glucose metabolism and endothelial function, in postmenopausal women [1]. Fifty women (mean age 54 years, mean body mass index 27) were randomized to receive genistein (54 mg/day, n = 30) or placebo (n = 20) tablets for 6 months. Of the women receiving genistein, 14 were considered to be normoinsulinemic and 12 hyperinsulinemic. In addition to basal insulin and glucose levels, glycoinsulinemic metabolism was evaluated in detail by analyzing the response to glucose load, AUC-insulin as an index of hyperinsulinemia, as well as pancreatic insulin secretion (C-peptide levels) and hepatic insulin clearance (fractional hepatic insulin extraction (FHIE) values), by using both the homeostasis model and the euglycemic hyperinsulinemic clamp technique. Vascular function was evaluated by the flow-mediated dilatation (FMD) of the brachial artery in response to hyperemia of the arm and also by nitrate-mediated endothelium-independent dilatation (NMD).

Villa and colleagues found that, in women receiving genistein, basal insulin levels decreased and fasting glucose levels as well as the homeostasis model index of insulin sensitivity (HOMA-IR) improved, compared to the placebo-treated women. Furthermore, genistein administration in the hyperinsulinemic women reduced fasting insulin, fasting C-peptide and AUC-insulin levels while increasing FHIE values. Both FMD and NMD improved after genistein treatment, as compared to placebo; normoinsulinemic women showed both enhanced FMD and NMD, while no significant changes were found in the hyperinsulinemic women.


Phytoestrogens may be associated with reduced risk of cardiovascular disease, although the exact mechanisms of this protection are poorly understood. The study by Villa and colleagues adds further support to the possible beneficial role of the phytoestrogen genistein on glucose metabolism and endothelial function, as shown previously [2,3]. Although the study was carried out in a limited number of subjects (specifically when subgroups were analyzed), the methods used were strong, especially the euglycemic hyperisulinemic clamp technique that may be considered as the gold standard for the determination of body insulin action. The fact that genistein improved insulin metabolism particularly in the hyperinsulinemic women could be due to the effect on hepatic metabolism in these patients with higher basal pancreatic activation. Interestingly, only normoinsulinemic women showed enhanced FMD and NMD, while no changes were found in the hyperinsulinemic women. This could imply a beneficial genistein-mediated effect only in healthy vascular wall, once again emphasizing the role of possible pre-existing endothelial dysfunction when evaluating estrogen-like effects.
The overall clinical role of soy-derived phytoestrogens on the cardiovascular system remains to be determined. As Villa and colleagues point out, the pre-existing metabolic status of a single patient may determine different effects in response to isoflavone therapy, but also other individual differences may have an important role. One of the most interesting areas of research on soy phytoestrogens has been the finding that women’s gut flora that has the capacity to metabolize the phytoestrogen daidzein to equol also has the capacity to metabolize steroid hormones in ways different from women who lack this daidzein-metabolizing phenotype [4]. Even while not taking any soy phytoestrogens, tibolone hormone therapy-treated women with this daidzein-metabolizing capacity had lower blood pressure [5] and better endothelial function [6]. Thus, in further studies assessing phytoestrogen effects on cardiovascular end-points, these individual differences should be considered.


Tomi Mikkola
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland


  1. Villa P, Costantini B, Suriano R, et al. The differential effect of the phytoestrogen genistein on cardiovascular risk factors in postmenopausal women: relationship with the metabolic status. J Clin Endocrinol Metab 2008; November 18. [Epub ahead of print].

  2. Atteritano M, Marini H, Minutoli L, et al. Effects of the phytoestrogen genistein on some predictors of cardiovascular risk in osteopenic, postmenopausal women: a two-year randomized, double-blind, palcebo-controlled study. J Clin Endocrinol Metab 2007;92:3068-75. Published August, 2007.

  3. Squadrito F, Altavilla D, Crisafulli A, et al. Effect of genistein on endothelial function in postmenopausal women: a randomized, double-blind, controlled study. Am J Med 2003;114:470-6. Published April 15, 2003.

  4. Atkinson C, Frankenfeld CL, Lampe JW. Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health. Exp Biol Med 2005;230:155-170. Published March, 2005.

  5. Tormala RM, Appt S, Clarkson TB, et al. Individual differences in equol production capability modulate blood pressure in tibolone treated postmenopausal women; lack of effect of soy supplementation. Climacteric 2007;10:471-9. Published December, 2007.

  6. Tormala R, Appt S, Clarkson TB, et al. Equol production capability is associated with favorable vascular function in postmenopausal women using tibolone; no effect with soy supplementation. Atherosclerosis 2008;198:174-8. Published May, 2008.