Syndromes of glucocorticoid and mineralocorticoid resistance.
Glucocorticoid resistance results from incomplete but apparently generalized inability of glucocorticoids to exert their effects on their target tissues. The condition is associated with compensatory elevation of circulating ACTH and cortisol, with the former causing excess secretion of both adrenal androgens and adrenal steroid biosynthesis intermediates with salt-retaining activity. The manifestations of glucocorticoid resistance vary from asymptomatic to different degrees of hypertension and/or hypokalemic alkalosis and/or hyperandrogenism, caused by elevation cortisol and other salt-retaining steroids, and of adrenal androgens, respectively. In women, hyperandrogenism can result in acne, hirsutism, male type baldness, menstrual irregularities, oligoanovulation, and infertility; in men, it may lead to infertility; and in children to precocious puberty. Different molecular defects, such as point mutations or microdeletions of the highly conserved glucocorticoid receptor gene, alter the functional characteristics or concentrations of the intracellular receptor and cause glucocorticoid resistance. The extreme variability in the clinical manifestations of glucocorticoid resistance and its mimicry of many common diseases can be explained by different degrees of glucocorticoid resistance, differing sensitivity of target tissues to mineralocorticoids and/or androgens or both, and perhaps different biochemical defects of the glucocorticoid receptor. Mineralocorticoid resistance results from the inability of aldosterone to exert its effect on target tissues. The syndrome is associated with salt loss, hypotension, and hyperkalemic acidosis. We have cloned and sequenced the cDNA of five unrelated patients with this syndrome and have not found any mutations of pathophysiological significance that would explain the resistance of these patients to aldosterone.(ABSTRACT TRUNCATED AT 250 WORDS)
Arai
K
K
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Chrousos
G P
GP
D003937:Diagnosis, Differential; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008901:Mineralocorticoids / Q000494:pharmacology*; D011546:Pseudohypoaldosteronism / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D013577:Syndrome
D005938:Glucocorticoids; D008901:Mineralocorticoids