Stratakis C A, Karl M, Schulte H M, Chrousos G P
Developmental Endocrinology Branch (DEB) National Institute of Child Health & Human Development, (NICHD) National Institutes of Health (NIH), Bethesda, Maryland 20892.
Ann N Y Acad Sci. 1994 Nov 30;746:362-74; discussion 374-6. doi: 10.1111/j.1749-6632.1994.tb39257.x.
Familial glucocorticoid resistance (FGR) is a rare hereditary disorder characterized by hypercortisolism and the absence of stigmata of Cushing's syndrome. The inability of glucocorticoids to exert their effects on target tissues is compensated for by increases in circulating corticotropin (ACTH) and cortisol, the former causing excess secretion of both adrenal androgens and adrenal steroid-biosynthesis intermediates with salt-retaining activity. There is considerable variability in the clinical presentations of FGR ranging from asymptomatic, to isolated chronic fatigue and to hypertension with or without hypokalemic alkalosis or to hyperandrogenism, or both. In women, hyperandrogenism can result in acne, hirsutism, menstrual irregularities, oligoanovulation, and infertility; in men it may lead to infertility and in children to precocious puberty. The reported molecular defects in FGR, such as point mutations and a microdeletion of the glucocorticoid receptor (GR) gene, cause partial resistance by, respectively, compromising the function of the GR or decreasing its intracellular concentration in glucocorticoid target tissues. Complete glucocorticoid resistance is believed to be incompatible with life in humans. Hence, the glucocorticoid resistance cases reported have been partial and of variable degree. The extreme variability in the clinical manifestations of the disorder can, additionally, be explained by differing sensitivity of target tissues to mineralocorticoids or androgens or both, and perhaps by different biochemical defects of the glucocorticoid receptor, causing selective resistance of certain glucocorticoid responses in specific tissues. Isolated tissue-resistance from a somatic mutation of the GR in a corticotropinoma from a patient with Nelson's syndrome was also found, suggesting that this may be a mechanism of tumorigenesis. There is additional evidence that defects of GR function can appear surreptitiously in a variety of clinical conditions, suggesting that glucocorticoid resistance in humans may be involved in the pathogenesis and/or clinical picture of a plethora of disease states, of which FGR is the archetype.
家族性糖皮质激素抵抗（FGR）是一种罕见的遗传性疾病，其特征为皮质醇增多症且无库欣综合征的体征。糖皮质激素无法对靶组织发挥作用，这通过循环促肾上腺皮质激素（ACTH）和皮质醇水平升高得到代偿，前者导致肾上腺雄激素和具有保盐活性的肾上腺类固醇生物合成中间体分泌过多。FGR的临床表现差异很大，从无症状，到孤立的慢性疲劳，再到伴有或不伴有低钾性碱中毒的高血压，或高雄激素血症，或两者皆有。在女性中，高雄激素血症可导致痤疮、多毛症、月经不规律、排卵稀少和不孕；在男性中，它可能导致不育，在儿童中则导致性早熟。FGR中报道的分子缺陷，如糖皮质激素受体（GR）基因的点突变和微缺失，分别通过损害GR的功能或降低其在糖皮质激素靶组织中的细胞内浓度而导致部分抵抗。完全的糖皮质激素抵抗被认为与人类生命不相容。因此，报道的糖皮质激素抵抗病例都是部分性的且程度各异。此外，该疾病临床表现的极端变异性可以通过靶组织对盐皮质激素或雄激素或两者的不同敏感性来解释，也许还可以通过糖皮质激素受体的不同生化缺陷来解释，这些缺陷导致特定组织中某些糖皮质激素反应的选择性抵抗。在尼尔森综合征患者的促肾上腺皮质激素瘤中，还发现了由GR体细胞突变引起的孤立组织抵抗，这表明这可能是肿瘤发生的一种机制。还有其他证据表明，GR功能缺陷可能在多种临床情况下隐匿出现，这表明人类的糖皮质激素抵抗可能参与了众多疾病状态的发病机制和/或临床表现，其中FGR是典型代表。
