Science of Isoflavones

» Mechanism of action: SERM
Isoflavones are Selective Estrogen Receptor Modulators.

» Pharmacokinetics of Promensil
Absorption and Metabolism of Isoflavones.

» Epidemiology of isoflavone intake
Studies indicate a role for diet in reducing menopausal symptoms.

Mechanism of action: SERM

Figure 1. Schematic showing interaction of isoflavones and
the human estrogen receptor (adated from reference ⁶⁰)

The estrogenic activity of isoflavones is relatively weak, of the order of 1000 times less than that of 17ß-estradiol. However, when consumed in relatively large amounts, plasma levels of isoflavone active metabolites are significant ^23,24. Before menopause when endogenous estrogen levels are high, isoflavones may exert anti-estrogenic activity by competitive inhibition, preventing estrogen from binding to the estrogen receptor. During and after menopause when endogenous estrogens decline isoflavones produce a surrogate estrogen effect.

Isoflavones and their metabolites can preferentially activate the form of the estrogen receptor which predominates in brain, bone and heart (ER-ß) but show little activity against the form of estrogen receptor present in breast and uterine tissues (ER-α) ²⁵ (Table 2). Isoflavones do not bind or activate the androgen receptor. ²⁶

Figure 2. ER-α and ER-ß receptors predominate in various tissues

Compound	Relative Binding Affinity
	ER-α	ER-ß
17 ß-estradiol	100	100
2-OH-estrone	2	0.2
5-androstenediol	1	7
4-OH-tamoxifen	257	232
Raloxifene	69	16
Isoflavones Genistein Daidzein	4 0.1	87 0.5

Table 2. Relative binding affinity of compounds to ER-α and ER-ß

References

Collins BM, McLachlan JA, and Arnold SF.²³	Steroids 1997; 62 (4): 365-72.	The estrogenic and antiestrogenic activities of phytochemicals with the human estrogen receptor expressed in yeast.
Miksicek RJ. ²⁴	Proc Soc Exp Biol Med 1995; 208: 44-50.	Estrogenic flavonoids: Structural requirements for biological activity.
Couse JF, Lindzey J, Grandien K, Gustafsson JA, and Korach KS. ²⁵	Endocrinol 1997; 138 (11): 4613-21.	Tissue distribution and quantitative analysis of estrogen receptor-alpha and estrogen receptor-beta messenger ribonucleic acid in the wild-type and ER-alpha knockout mouse.
Cato AC, Miksicek R, Schütz G, Arnemann J, and Beato M. ²⁶	Embo J 1986; 5 (9): 2237-40.	The hormone regulatory element of mouse mammary tumour virus mediates progesterone induction.
Adlercreutz H. ⁶⁰	Bailliere's Clin. Endocrinol. Metab. 1998; 12:605-625.	Epidemiology of Phytoestrogens

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Pharmacokinetics of Promensil

The plasma and urinary profiles of isoflavones resulting from acute and chronic administration of Promensil were measured during a study involving 16 healthy men and women ⁴³. The participants were given one Promensil tablet in the morning after an overnight fast. Venous plasma and urine were collected at intervals for 24 h. After this time, two tablets were administered each day for 2 weeks, and samples collected over a 48 h period after the last dose.

The study demonstrated that:

Biochanin A, formononetin, genistein and daidzein all appeared rapidly in plasma, achieving maximum concentrations by 4-6 h post dose. Contrary to previous understanding, these data demonstrate that biochanin A and formononetin are not completely demethylated to form genistein and daidzein and therefore have additional biological effects to their demethylated counterparts.
The plasma half-lives of each of the isoflavones following chronic administration were 12-16 h, long enough to allow once-daily dosing.
Administration of one 40 mg tablet daily produced plasma levels similar to those found in populations consuming high-isoflavone diets ⁴⁴.

Biochanin A, formononetin, genistein and daidzein undergo extensive structural modification in the body ^45-47. There are two main sites of isoflavone metabolism, the gut and liver. The liver is responsible for demethylation of 60% of biochanin A and formononetin to form genistein and daidzein, respectively (Figure 4) ^48-50. Approximately 30-70% of the dietary isoflavones are converted into active metabolites by the gut flora. The active metabolites detected in urine following Promensil administration are equol, o-desmethylangolensin, dihydrodaidzein and dihydrogenistein (Figure 5).

Figure 4. Metabolism of isoflavones

Figure 5. HPLC analysis of urine 24 hours after a single tablet of Promensil

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Epidemiology of isoflavone intake

There are observed differences in incidence of cardiovascular disease, cancers and osteoporosis between population groups. Genetics, diet and lifestyle factors are all thought to be involved in the aetiology of these diseases, however epidemiological studies suggest that incidence of these "Western diseases" is inversely related to phytoestrogen consumption ²⁷. For instance, the total isoflavone intake is estimated to be highest in Japanese populations at 40 mg per day ²⁸ and in other Asian communities, this value has been calculated as 25-45 mg/day.

Epidemiological data indicate that Asian and particularly Japanese women have lower rates of osteoporosis, fractures, and cardiovascular disease than their Western counterparts who, on average, consume only 2-5 mg/day total isoflavones. Thus, attention has focused on the use of these plant-derived compounds as a method of alleviating menopausal symptoms and maintaining cardiovascular and bone health throughout post-menopausal life.

Reduced menopausal symptoms

While every woman experiences menopause, not every woman experiences adverse symptoms of menopause. This is highlighted by the reported experience of women with acute symptoms in Asia versus other countries:

85% of women in America ²⁹
70-80% of women in Europe ^30,31
57% of women in Malaysia ³²
25% of women in Japan ²⁹
18% of women in China ³³
14% of women in Singapore ³⁴

It is well known that a diet which is low in fat and high in complex carbohydrates derived from grains, fruits, and vegetables, is associated with a lower risk of chronic diseases. However, epidemiological studies now indicate a role for diet in reducing menopausal symptoms, particularly an Asian diet which is abundant in isoflavonoid phytoestrogens ^35,36.

Cardioprotective

The lower incidence of cardiovascular disease in Asian countries compared to Western countries, suggests that isoflavones may be cardioprotective (Figure 3). Similarly, there is a lower incidence in vegetarians, whose protein source is mainly from isoflavone rich foods, compared to omnivores ^27,37.

Figure 3. Coronary artery deaths and isoflavone intake in different countries^27,37.

Reduced incidence of hormonal cancers

Hormone dependent cancer rates also vary markedly between regionally diverse populations. Migrant studies indicate that this is largely due to environmental factors, rather than genetics ³⁷. Epidemiological evidence suggests that a major environmental contributor to this effect is the traditional diet of Asian populations which confers a lower risk of hormone dependent cancers such as breast, ovarian and uterine ^38,39. Table 3 demonstrates the low incidence of breast cancer rates in Asian compared to Western populations. Several studies have observed a link to dietary intake of isoflavones. In a case-control study, an increased breast cancer risk was strongly correlated with a low intake of isoflavones, as measured by urinary isoflavone excretion ⁴⁰. A similar association was reported in a case-control study in Singapore, and a study of Asian-Americans consuming isoflavone rich foods ⁴¹. Isoflavones are a dietary factor of particular interest when considering hormone-related cancers due to their ability to act as selective estrogen receptor agonists, antagonists as well as their anti-carcinogenic biological activities.

High Incidence Populations	Greater than 70 per 100,000	USA, Switzerland, Netherlands
Medium Incidence Populations	50-70 per 100,000	Canada, Australia, United Kingdom
Low Incidence Populations	Less than 50 per 100,000	Japan, China, India, Hong Kong, Singapore

Table 3. Breast cancer incidence in populations (adapted from Reference 38)

Osteoporosis

Incidence of osteoporosis and osteoporotic fractures varies among populations, with a lower incidence in Asian compared to Western countries ²⁷. However, the lower rate of osteoporotic fractures seen in, for example Japan, is paradoxical, since Japanese have a lower peak bone mass, a lower lifetime exposure to estrogen and a lower calcium intake compared to Western populations. Several factors have been proposed to explain the lower fracture rates observed in Asia. Lifestyle differences may offer some explanation. Physical activity such as sitting on the knees in the fully flexed position and frequent standing up in Japan is thought to develop hip musculature, as well as agility and balance. Also, it is proposed that due to cultural differences a greater proportion of the elderly population in Japan have adopted a lifestyle with restricted physical mobility which therefore reduces fracture rates ⁴². It has also been suggested that intake of isoflavones in the Asian diet prevents bone loss in post-menopausal women through their estrogenic action ³⁷.
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