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It is not clear whether genistein and certain related isoflavones are 'pro-oestrogens' (i.e. whether they are metabolized to highly active oestrogenic compounds) as proposed by Biggers & Curnow (1954), or whether they are weak oestrogens which can interact with potent oestrogens as suggested by Folman & Pope (1966).
Jensen & Jacobson (1962) and Stone (1964) have shown that in rodents the uterus and vagina are able to incorporate and retain certain very active oestrogenic compounds. This fact was utilized in an attempt to demonstrate the presence of highly active oestrogenic metabolites of genistein in the reproductive tract of ovariectomized mice after the administration of genistein. Oestrogenic activity in extracts of the uterus and vagina from the mice were assayed by the intravaginal (i.vg.) tetrazolium method of Martin (1964).
Extracts were obtained from groups of ovariectomized mice (7–12 weeks old, 18–25 g.) of the Sydney White strain. Substances were administered as
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SUMMARY
The binding affinities and receptor specificity of sheep uterine cytosol for steroid oestrogens and also for weak plant oestrogens of the isoflavone and coumestan groups and some synthetic compounds were studied. The binding affinities of the weak oestrogens fall within a range which has usually been neglected. Relative molar binding (RMB) affinities for the steroid oestrogens confirmed the importance of the phenolic 3-hydroxyl group and the influence of substitutions at C-16 and C-17, as seen with uterine cytosols from other species. Relative molar binding affinities were very much lower when the oestrogens were present as sulphate esters, glucosiduronate and methyl ether derivatives; acetates showed similar RMB affinities to their parent compounds. Phyto-oestrogens were found to compete with oestradiol for binding sites. Coumestrol and miroestrol had the highest RMB affinities of about 5 (oestradiol-17β = 100) when incubated at 25 °C, and values for genistein, equol, daidzein and O-desmethylangolensin lay between 1 and 0·05. The mono-methoxy compounds, biochanin A, formononetin and 4′-methoxy-coumestrol had RMB affinities of less than 0·01. Incubation at 37, 25 and 4 °C showed that RMB affinities were greater at the lower temperatures.
Relative molar binding affinities of the phyto-oestrogens in vitro compared with their oestrogenic potencies in vivo showed that the ranking of most of the compounds by these two criteria was similar. Structure-activity correlations were deduced from the results. A similar relationship of RMB affinity to biological potency was also noted for the steroid oestrogens and a homologous series of stilbenediols. The results obtained are relevant to competitive protein-binding analyses and to the mechanism of action of oestrogens and phyto-oestrogens.
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SUMMARY
Marked rises in both unconjugated and sulphoconjugated oestrone, oestradiol-17β and oestriol were observed in human foetal plasma between mid-gestation and term. Significant arterio-venous differences for the individual oestrogens in the unconjugated form were found in the umbilical cord plasma. No consistent arterio-venous differences were found for the oestrogen sulphates. This indicates that all three oestrogens are secreted from the placenta into the foetal circulation in the unconjugated form. Mean unconjugated oestrogen (oestrone + oestradiol-17β + oestriol) levels rose from 22·7 ng/ml at 17–20 weeks of gestation to 108·9 ng/ml at term in umbilical venous plasma and from 4·3 ng/ml to 23·3 ng/ml in umbilical arterial plasma. This represents a secretion rate of approximately 30 mg oestrogen/day into the umbilical vein at term. Mean oestrogen sulphate levels rose from 128 ng/ml to 313 ng/ml in the cord plasma during the same period. Of the three oestrogens measured, oestriol was quantitatively the major oestrogen in foetal plasma. It consistently represented about 78% of the unconjugated fraction and 95% of the sulphate fraction at all stages of gestation.
The method of delivery did not have a significant effect on the oestrogen levels in uncomplicated pregnancies. Similar oestrogen levels were found in foetal heart blood after either hysterotomy or spontaneous abortion at 16–20 weeks of gestation, and no significant differences were found for oestrogen levels in cord plasma after elective Caesarean section at 38–39 weeks when compared with oestrogen levels after normal delivery at term.
A significant rise in foetal unconjugated oestrogens at a time when foetal corticosteroids are increasing may be of physiological importance for foetal maturation in women.
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Department of Obstetrics and Gynaecology, University of Sydney, NS. W. 2006, Australia
(Received 13 July 1976)
Prostaglandin F2α(PGF2α) secreted from the uterus exerts a luteolytic effect on the corpus luteum in a number of species of non-pregnant mammals (see review of Labhsetwar, 1974). This luteolytic mechanism has not been demonstrated in non-pregnant women (Lyneham, Korda, Shutt, Smith & Shearman, 1975). Nor were Leader, Bygdeman, Cekan, Diczfalusy, Guerrero, Martin & Wiqvist (1975) able to demonstrate an accelerative effect of intra-uterine 15 (S) 15-methyl PGF2α or an inhibitory effect of oral indomethacin on post-abortion luteolysis in women in early pregnancy. The presence of PGF2α receptors however, in human corpora lutea (Powell, Hammarström, Samuelsson & Sjöberg, 1974) suggested the possibility of a local production of PGF2α within the ovary being responsible for luteolysis in women, and Korda, Shutt, Smith, Shearman & Lyneham (1975) were able to obtain a transient luteolysis when 0·5–1·0 mg
