Chemical Structure of Steroids in Relation to Promotion of Growth of the Vagina and Uterus of the Hypophysectomized Rat

Huggins, Charles; Jensen, Elwood V.; Cleveland, Anne Stack

doi:10.1084/jem.100.3.225

Cited by 115 publications

(21 citation statements)

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“…5 androstene-3 ,17 -diol (5-Adiol) has estrogenic activity in rats (Huggins et al, 1954) and binds to the ER in rat uterus (Garcia and Rochefort, 1979). Kuiper et al (1997) reported that 5Adiol has nM affinity for recombinant ER and ER .…”

Section: A Paradox the Er And Not The Pr Is Most Ancient: What Was Tmentioning

confidence: 99%

Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Baker

2004

Molecular and Cellular Endocrinology

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Abstract. Receptors for the adrenal and sex steroids arose by a series of gene duplications from an ancestral nuclear receptor in a primitive vertebrate, at least 540 million years ago. Sequence analysis indicates many steroidogenic and steroid-inactivating enzymes, including cytochrome P450s and hydroxysteroid dehydrogenases, arose at the same time. The estrogen receptor (ER) appears to be the ancestral steroid receptor. Initially, the redundant duplicated ER had a low specificity for its new ligand. This raises the question: "How was specificity for responses to different steroids regulated early in the evolution of steroid receptors?" Selective expression of these steroid-metabolizing enzymes provided specificity for different steroid responses in primitive vertebrates. 17 -hydroxysteroid dehydrogenase-type 1 (17 -HSD-type 1) and 17 -HSD-type 2, which preferentially catalyze the reduction and oxidation at C17 of androgens and estrogens, respectively, provide an example of this mechanism. Selective expression of either 17 -HSD-type 1 or 17 -HSD-type 2 can regulate synthesis or inactivation of androgens or estrogens in specific cells.Steroids also were important in the evolution of land animals, which began about 400 million years ago.Steroidogenic and steroid-inactivating enzymes were recruited to regulate steroid-mediated responses as organ function became more complex. For example, in the kidney 11 -HSD-type 2 prevents binding of glucocorticoids to the mineralocorticoid receptor, which is crucial for aldosterone-mediated regulation of electrolyte transport in the distal tubule. We propose that 5 steroids, such as dehydroepiandrosterone and its metabolites, were the ligands for the ancestral ER. Understanding the actions of 5 steroids in amphioxus and lamprey may shed light on adrenarche and neurosteroid actions in humans.

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Section: A Paradox the Er And Not The Pr Is Most Ancient: What Was Tmentioning

confidence: 99%

Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Baker

2004

Molecular and Cellular Endocrinology

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“…1) (Baker 2001a). For example, 5 -androstenediol has long been known to have estrogenic activity (Huggins et al 1954) and to bind to the ER (Garcia & Rochefort 1979). Kuiper et al (1997) showed that 5 -androstenediol and 3 -androstanediol bind to recombinant rat ER and ER with nanomolar affinity.…”

Section: Introductionmentioning

confidence: 99%

Recent insights into the origins of adrenal and sex steroid receptors

Baker¹

2002

Journal of Molecular Endocrinology

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The recent cloning by Thornton (2001) of estrogen, progesterone and corticoid receptors from lamprey provides important insights into the early evolution of adrenal and sex steroid receptors and an opportunity to elucidate the ancient steroids that regulated gene transcription. Inclusion of lamprey sequences in a steroid receptor phylogeny indicates that the estrogen receptor is the most ancient of these receptors, followed by the progesterone receptor and the corticoid receptor. Thornton proposed that estradiol was the earliest of the steroids to activate a steroid receptor. An alternative hypothesis is that a steroid in the ∆ 5 pathway activated the ancestral estrogen receptor.

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“…oestrogenic effects in the rat (Huggins et al, 1954), and more recently that, at concentrations found in the blood of Western women, it both increased uterine growth and DNA synthesis in this species (Seymour-Munn and Adams, 1983). Because of the androgenic origins of this oestrogen-like compound it has been dubbed 'hermaphrodiol' by Adams (1983).…”

Section: Discussionmentioning

confidence: 99%

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et al. 2000

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It would be very useful if it were possible to identify, within an apparently normal population, those who will develop breast cancer. Although this can be achieved by genetic testing for mutations of BRCA1 and BRCA2, such susceptibility genes are involved in the aetiology of only about 5% of breast cancer cases (Lynch and Lynch, 1986). By contrast, events related to a woman's menstrual and reproductive history, which have been widely recognized as determinants of breast cancer incidence, are not impressive predictors of individual risks. Such poor predictive performance could result from these epidemiological variables being only manifestations of other underlying factors. Indeed the size of the effects of the menstrual and reproductive variables and the observation that breast cancer rates change over a woman's life have stimulated investigation of endogenous sex hormones as potential causes underlying these observed effects (Key and Pike, 1988;Toniolo et al, 1995;Key et al, 1996). Methodological issues related to hormone measurements, however, complicate the study of their relationship with breast cancer. Furthermore, there is no general consensus regarding which biological forms of these hormones are actually associated with the observed changes in incidence rates.The role of steroids in the aetiology of breast cancer is uncertain. Extensive analysis of the scientific literature shows a highly significant increase in blood oestradiol levels in post-menopausal women with breast cancer (Thomas et al, 1997). The position of oestrogens and premenopausal women is uncertain (Key and Pike, 1988; Thomas et al, 1997). Androgens have been studied less extensively than oestrogens and no meta-analysis has yet been undertaken.The first prospective study in this field was performed by Bulbrook and Hayward who showed that levels of androsterone (A) and aetiocholanolone (E) were abnormally low in women who subsequently developed breast cancer (Bulbrook and Hayward, 1967;Bulbrook et al, 1971). Most of the cases were premenopausal and the abnormality was present up to 11 years before the clinical diagnosis of the disease, suggesting that high levels of androgen metabolites might have a protective effect, at least in younger women. However, other mainly retrospective casecontrol studies have claimed that high androgen excretion is positively associated with breast cancer risk (e.g. Secreto and Zumoff, 1994). Such contrasting results could be reconciled if the effects of androgens depended on menopausal status. This would occur if the androgens acted as oestrogen inhibitors in premenopausal women and as oestrogen enhancers (or even oestrogens) in the postmenopausal (Secreto and Zumoff, 1994;Adams, 1998 Summary Between 1961 and 1967 a cohort of over 5000 women volunteered for a prospective study to determine the relationship between the urinary androgen metabolites, androsterone (A) and aetiocholanolone (E), and risk of breast cancer. During the first 10 years of the study the concentration of urinary A and E was determined in 1...

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Chemical Structure of Steroids in Relation to Promotion of Growth of the Vagina and Uterus of the Hypophysectomized Rat

Cited by 115 publications

References 14 publications

Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Recent insights into the origins of adrenal and sex steroid receptors

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