Oestrogens discovery

For the last forty years, many reports have emerged on the hormone-like effects of chemical compounds such as pesticides and industrial chemicals upon wildlife and humans. The effects of these materials are believed to be either direct or indirect. Direct effects involve positive or negative interactions with the hormone receptors. Indirect effects may result when the synthesis of hormones or their receptors is altered, or the transport, metabolism, or elimination of hormones is modified in some way. The discovery of hormone-like properties of some compounds was made long after their release into the environment. It was shown soon after their introduction that aviation crop dusters handling DDT had low sperm counts and workers at a plant producing the insecticide kepone were reported to have low libido, sperm counts and to be impotent. Subsequently, experiments conducted in laboratory animals demonstrated unambiguously the oestrogenic activity of these pesticides. 9 refs. 

The cDNAs for the glucocorticoid and the oestrogen receptors were isolated more than 15 years ago. They were among the first genes, coding for transcriptional gene activators, to be identified. The family of nuclear receptors is the largest family of transcription factors. Until now, more than 150 different members of the superfamily of nuclear receptors, from worms to insects to humans, have been described. The discovery of an insect receptor for a steroid hormone, ecdysone, indicated that this kind of receptor must have evolved prior to the separation of vertebrates and invertebrates. 

Welch et al., 1969 Cecil et al., 1971). After the discovery of the oestrogen action of o,p -DDT, Bitman and Cecil (1970) established in their comparative investigations that those diphenylmethane and diphenylethane derivatives have an oestrogen action in which at least one of the two p-positions is unsubstituted or carries a hydroxy or a methoxy substituent. A further factor connected with bioactivity is that o,p -DDT has two enantiomeric forms (McBlain et al., 1976 1977). 

Initial attempts to develop aromatase inhibitors for use in the treatment of oestrogen-dependent breast cancer involved the use of synthetic steroid analogues of the natural substrates androstenedione and testosterone [53]. Such steroidal inhibitors are reviewed in on p. 272. An alternative approach to the design of aromatase inhibitors was suggested by the discovery [54-56]... 

This discovery shows that the steroid ring is not necessary for oestrogenic function. The derivative diethyl stilboestrol is about two and a half times more potent than oestrone, but not as active as oestradiol. 

Further investigations resulted in the discovery that etherification of the 3-hydroxy group of ethinyl estradiol resulted in formation of potent orally active oestrogens such as mestranol (the 3-methyl ether) and quinestrol (the 3-cyclopentyl ether), although this is not now used in oral contraceptives (Fig. 20.27). 

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