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Steroid Hormone Receptors Arch Dis Child: first published as 10.1136/adc.59.6.498 on 1 June 1984. Downloaded from Archives of Disease in Childhood, 1984, 59, 498-500 Annotations Steroid hormone receptors A hormone is classically defined as a physiological one, and dihydrotestosterone receptors. Even the regulator synthesised by ductless glands and trans- foreskin, usually redundant after circumcision, is a ported in plasma to act on target cells at a distant rich source of receptors useful for the study of site. How the specificity of action is conferred androgen receptor binding.2 The discovery of ster- remained unknown until target tissue was shown to oid receptors in peripheral blood lymphocytes (glu- contain receptors to which the hormone bound. It is cocorticoid) and in fibroblasts (glucocorticoid, now accepted that all classes of steroid hormones, androgen, vitamin D) has increased the availability including the vitamin D sterols, act by binding to of target cells for study, particularly in children. intracellular receptor proteins.1 Steroid receptor binding is a reversible reaction, saturable at low steroid concentrations. Binding is Mechanism of action measured by incubating a range of concentrations of radiolabelled steroid with either a cytosolic or whole The non-protein bound or 'free' fraction of steroid cell receptor preparation. Parallel incubations with in plasma enters target cells by passive diffusion an excess of unlabelled steroid allows measurement where a specific, high affinity, low capacity cytoplas- of non-specific binding to other cellular components mic protein binds the steroid. The binding affinity, a ('background noise'). Various mathematical trans- measure of how avidly a receptor binds minute formations such as the Scatchard plot are used to quantities of steroid, indicates the biological po- make the saturation curve linear, from which the tency of a hormone. For example, dexamethasone binding affinity and receptor concentration can be has a binding affinity 20 times greater than cortisol derived.1 More detailed analysis including binding for the glucocorticoid receptor. To discriminate to nuclei can be performed using techniques such as hormone signal from other 'noise' the receptor must sucrose density gradient analysis and two dimen- display specificity for a particular hormone-akin sional gel electrophoresis. http://adc.bmj.com/ to a high signal to noise ratio in 'hi-fi' equipment. Once formed the steroid receptor complex is Clinical applications activated by a presumed structural alteration to the receptor and translocated to the nucleus where it Steroid receptor analysis has been used in clinical binds to acceptor sites on chromatin. Subsequent practice for the management of endocrine related events are incompletely understood but there fol- cancers and to investigate the underlying cause in lows DNA directed, RNA mediated new protein syndromes associated with hormone resistance. synthesis and expression of biological function of the Solid tumours of the breast, uterus, and prostate on September 29, 2021 by guest. Protected copyright. steroid. This unified concept applies to all classes of gland have received most study. Quantitation of steroid hormones except androgens. Testosterone, oestrogen and progesterone receptors in breast the principal circulating androgen, is converted carcinoma plays a pivotal role in the choice of intracellularly by a Sa reductase enzyme to an active treatment in patients with metastatic disease. En- metabolite, dihydrotestosterone, before receptor docrine treatment for metastatic disease produces a binding. favourable response in 60% to 80% of patients with oestrogen and progesterone receptor positive Measurement of steroid receptors tumours as compared with a less than 10% response in receptor negative tumours.3 For uterine and Steroid receptors are distributed in many tissues of prostatic carcinoma the relation between tumour the body. The characteristics of steroid receptor receptor content and response to treatment is less binding have been studied largely in cytosol, pre- clear. pared by ultracentrifugation of homogenised tissue Glucocorticoids are invariably used for some part obtained mainly from experimental animals. Human of the treatment schedule in most leukaemias. In tissues such as breast, uterus, and prostate obtained childhood acute lymphoblastic leukaemia the inci- at surgery are used to measure oestradiol, progester- dence of remission after glucocorticoid inclusive 498 Arch Dis Child: first published as 10.1136/adc.59.6.498 on 1 June 1984. Downloaded from Steroid hormone receptors 499 chemotherapy is directly related to the concentra- puberty because of primary amenorrhoea. Plasma tion of glucocorticoid receptors in peripheral lym- testosterone concentrations are slightly above the phocytes. Furthermore, the receptor concentration normal adult male range but there are no signs of at diagnosis correlates with the duration of complete virilisation in adults with the classic syndrome. remission and is independent of other prognostic Variations of the syndrome where the external factors such as age, sex, white cell count, and cell genitalia are partially virilised may present as type.4 ambiguous genitalia of the newborn. Other causes of male pseudohermaphroditism such as a defect in Syndromes associated with hormone resistance testosterone biosynthesis must be excluded. Ter- minology used more recently refers to complete and Albright5 first used the term target organ unrespon- partial androgen insensitivity syndrome.10 The siveness in pseudohypoparathyroidism due to renal mechanism of androgen resistance has been exten- tubular resistance to the action of parathyroid sively investigated in this syndrome after the de- hormone. Several disorders such as nephrogenic velopment of reliable in vitro steroid receptor assays diabetes insipidus, insulin resistant diabetes melli- using fibroblasts cultured from genital skin.'1 Com- tus, pseudohypoaldosteronism, familial glucocorti- plete and partial androgen insensitivity syndrome coid resistance, vitamin D dependent rickets, and may be subdivided into receptor positive and testicular feminisation syndrome have now been negative variants based on quantitative receptor ascribed to some defect in hormone receptor in- analysis. Recent qualitative studies of steroid bind- teraction. The latter two disorders associated with ing in cells from receptor positive patients suggest steroid hormone resistance are described in more that possible structural abnormalities of the receptor detail. protein account for the phenotypic expression of androgen resistance. 12 No abnormality of the androgen receptor can be found in some patients, Vitamin D dependent rickets. Originally called available. Additional pseudovitamin D deficient rickets, this is an auto- using techniques currently somal recessive condition characterised by clinical post-receptor defects involving transcription of mes- and biochemical features of classic vitamin D senger RNA and new protein synthesis are likely to deficiency rickets but requiring large doses of be discovered once problems of methodology are vitamin D for treatment.6 Most patients have resolved. Not only is androgen receptor analysis decreased serum concentrations of 1,25- useful in diagnosis but it may influence a decision on the sex of rearing in male pseudohermaphroditism. http://adc.bmj.com/ dihydroxyvitamin D (type I), where the presumed Preliminary evidence indicates that androgens cause is deficiency of la-hydroxylase enzyme re- in this quired to convert 25-hydroxyvitamin D to its active augment androgen receptor binding vitro; metabolite. Some patients, however, have normal may serve as a bioassay to predict responsive- or increased serum concentrations of the active ness to exogenous androgens in vivo (personal vitamin D metabolite (type IL). The lack of response observation). D The mode of inheritance for both variants of to physiological doses of 1,25-dihydroxyvitamin is X linked reces- suggests resistance to the action of this steroid on androgen insensitivity syndrome sive. The heterozygote cannot be detected reliably on September 29, 2021 by guest. Protected copyright. target tissues. by current methods, although the discrimination is Since intestine, bone, and kidney are inaccessible improved when receptor analysis is performed on to measure vitamin D receptor binding, it is fortu- cloned cells. nate that specific, high affinity receptors for 1,25- dihydroxyvitamin D have been found in human skin Future developments fibroblasts. Recent studies have shown a variety of defects in steroid binding including absent nuclear The mechanism of steroid hormone action on target retention of radiolabelled 1,25-dihydroxyvitamin D cells has found ready application in the investigation and receptor positive resistance associated with and management of several endocrine related dis- impaired induction of 24-hydroxylase activity.78 orders. The processes of steroid receptor binding to nuclei, gene transcription, and specific protein Testicular feminisation syndrome. The name given synthesis, however, remain poorly understood. to this syndrome was first coined by Morris in 1953 More refined techniques to isolate and purify when he reported a series of patients with a normal receptors, the development of monoclonal anti- female phenotype but an XY karyotype and testes.9 bodies, and the use of specific DNA sequences will The diagnosis is established either in infancy be- result in an improved understanding of
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