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Genistein administration & climacteric symptoms: from plasma levels to biological activity.

Southeast Asians, who subsist on a soybean-based diet, are known to experience a lower incidence of menopausal symptoms and hormone related cancers. Soy components have been claimed for these beneficial effects and the phytoestrogen genistein seems to be the most involved in this processes. Genistein has numerous biological activities including inhibition of tyrosine kinase and DNA topoisomerases I and II, antioxidant activity and estrogenic activity. The estrogenic activity of genistein has been the reason for its use as a dietary supplement for postmenopausal women. These actions of genistein are strictly related to its plasma levels and to the reach of a "steady state" which allows a complete interaction with the subtype beta of estrogen receptor (ER-[beta]), which is known to be the preferential target of genistein (1).

Indeed several studies dealt with the pharmacokinetic profile of genistein in healthy women at different ages showing that it is possible to attain the same concentration of the phytoestrogen found in Asian population and consequently to obtain the same beneficial effects (2). In this issue Joshi and co-workers (3) studied in a well-designed study the pharmacokinetic profile of genistein in peri- and post-menopausal Indian vegetarian women, after a single dose of soy extract capsule and found a certain inter-individual variability due to intestinal absorption of the isoflavone, in agreement with a large body of literature (2).

Typical isoflavones intake has been estimated around 15-50 mg/day in women living in Asian countries, especially China and Japan, this intake provides an optimal serum concentration of phytoestrogens. In the several studies that have been performed it is not always clear how the isoflavone intake is calculated because the absolute level of isoflavone is considerably higher if expressed as total isoflavones (including the glycoside portion) as compared with aglycons only. In fact 90 mg of total isoflavones correspond to only 50-55 mg of isoflavones after the removal of the glycoside moiety by gut microflora. This consideration is extremely important when analyzing clinical trials in which soy beverages or isoflavones mixtures have been used.

Through a series of investigations, driven by epidemiological evidence, we have shown that genistein supplementation, especially in its aglycone form, has great potentiality in reducing bone loss and cardiovascular risk in postmenopausal women with a high degree of compliance and a very good safety profile (4-7). In our randomized clinical trials we studied the effect of pure genistein, administered orally in its aglycone form at a dose of 54 mg/day in postmenopausal women. This specific dose of pure aglycone genistein allowed us to reach the optimal serum concentrations comparable to those reported for Asian women. Our results overall demonstrated a strong positive effect on bone loss as well as on some markers of cardiovascular risk and a significant decrease in hot flushes with a high safety profile on the reproductive system. More specifically, genistein administration (54 mg/day), caused a significant increase in lumbar spine and femoral neck bone mineral density (BMD) without any significant adverse effect on the breast and uterus. This effect was substantially equivalent to that observed for HRT in postmenopausal women. Furthermore, we suggested that these positive effects could be related to action of genistein on the soluble receptor activator of nuclear factor kB ligand (sRANKL)/osteoprotegerin (OPG) balance in a manner to improve bone turnover. In both trials isolated genistein administration warranted a highly standardized bioavailability and pharmacokinetic behaviour.

These evidences although are extremely interesting and important but are still too few to draw definitive conclusions. Further studies, possibly long-term and with large cohort are needed to provide definitive answers to the efficacy of phytoestrogens and especially genistein as a possible alternative to pharmacological treatments of menopause and related diseases.


(1.) Rowland IR, Wiseman H, Sanders TA, Adlercreutz H, Bowey EA. Interindividual variation in metabolism of soy isoflavones and lignans: influence of habitual diet on equol production by the gut microflora. Nutr Cancer 2000; 36 : 27-32.

(2.) McCarty ME Isoflavones made simple--genistein's agonist activity for the beta-type estrogen receptor mediates their health benefits. Med Hypotheses 2006; 66 : 1093-114.

(3.) Joshi JV, Vaidya RA, Pandey SN, Agashe S, Chandrasekharan S, Menon SK, et al. Plasma levels of genistein following a single dose of soy extract capsule in Indian women. Indian J Med Res 2007; 125 : 534-41.

(4.) Morabito N, Crisafulli A, Vergara C, Gaudio A, Lasco A, Frisina N, et al. Effects of genistein and hormone-replacement therapy on bone loss in early postmenopansal women" a randomized double-blind placebo-controlled study. J Bone Miner Res 2002; 17 : 1904-12.

(5.) Crisafulli A, Altavilla D, Squadrito G, Romeo A, Adamo EB, Marini R, et al. Effects of the phytoestrogen genistein on the circulating soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin system in early postmenopausal women. J Clin Endocrinol Metab 2004; 89 : 188-92.

(6.) Crisafulli A, Marini H, Bitto A, Altavilla D, Squadrito G, Romeo A, et al. Effects of genistein on hot flushes in early potmenopausal women: a randomized, double-blind EPT- and placebo-controlled study. Menopause 2004; 11 : 400-4.

(7.) Crisafulli A, Altavilla D, Marini H, Bitto A, Cucinotta D, Frisina N, et al. Effects of the phytoestrogen genistein on cardiovascular risk factors in postmenopausal women. Menopause 2005; 12 : 186-92.

Alessandra Bitto, Letteria Minntoli, Francesco Squadrito, Rosario D'Anna * Francesca Polito & Domenica Altaviila

Department of Clinical & Experimental Medicine & Pharmacology, Section of Pharmacology, School of Medicine

University of Messina, Messina, Italy & * Department of Obstetrics and Gynaecology

School of Medicine

University of Messina

Messina, Italy

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Title Annotation:Commentary
Author:Bitto, Alessandra; Minutoli, Letteria; Squadrito, Francesco; D'Anna, Rosario; Polito, Francesca; Alt
Publication:Indian Journal of Medical Research
Geographic Code:9INDI
Date:Apr 1, 2007
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