• DOI:10.7326/0003-4819-119-11-199312010-00009
• Corpus ID: 26040431

Syndromes of Glucocorticoid Resistance

@article{Chrousos1993SyndromesOG,
  title={Syndromes of Glucocorticoid Resistance},
  author={George P. Chrousos and S. D. Detera-Wadleigh and Michael Karl},
  journal={Annals of Internal Medicine},
  year={1993},
  volume={119},
  pages={1113-1124}
}

• G. Chrousos, S. Detera-Wadleigh, M. Karl
• Published 1 December 1993
• Medicine, Biology
• Annals of Internal Medicine

Dr. George P. Chrousos (Developmental Endocrinology Branch, National Institute of Child Health and Human Development [NICHD], National Institutes of Health [NIH], Bethesda, Maryland): Glucocorticoids have an important role in human physiology, and almost every tissue in the human body is affected by them [1]. Glucocorticoids are crucial for the integrity of central nervous system function and for the maintenance of cardiovascular and metabolic homeostasis [2]. Increased secretion of glucocorticoids during stress is also pivotal in altering central nervous system function [3], in preventing the inflammatory and immune response systems from over-reacting [4, 5], and in adjusting energy expenditures [6], all changes that improve chances for survival. Given this array of life-sustaining functions, the complete inability of glucocorticoids to exert their effects on target tissues would be incompatible with life; therefore, only syndromes of partial or incomplete glucocorticoid resistance exist. Several patients or members of kindreds with partial forms of this disease have been described [6-18]; they show a wide spectrum of clinical symptoms and an interesting set of pathophysiologic mechanisms (Table 1). Recent advances in our understanding of the mechanism of action of glucocorticoids at the molecular level have allowed a glimpse into the pathophysiology of resistance and have increased our awareness of the potential involvement of this condition in the pathogenesis of human disease. Table 1. Glucocorticoid Resistance in Humans: Reported Patients and Kindreds Familial Glucocorticoid Resistance: The Syndromes Pathophysiology An elaborate feedback system regulates glucocorticoid homeostasis. Of principal importance is the ability of glucocorticoids to exert negative feedback on secretion by the hypothalamic paraventricular nucleus of corticotropin-releasing hormone and arginine vasopressin, on secretion by the anterior pituitary of corticotropin, and on suprahypothalamic centers that control the activity of the hypothalamic-pituitary-adrenal axis [3, 19-21]. This complex system is activated in states of generalized glucocorticoid resistance and produces compensatory increases in corticotropin and cortisol secretion (Figure 1). Although the increased cortisol concentrations in most affected persons appear to compensate adequately for the inability of target tissues to respond to glucocorticoids, the excess corticotropin secretion results in the increased production of intermediate compounds in adrenal steroidogenesis that have salt-retaining (mineralocorticoid) activity (such as deoxycorticosterone and corticosterone [8]) and in the enhanced secretion of adrenal androgens (such as Delta 4-androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone-sulfate [12]). Figure 1. Pathophysiologic mechanism of glucocorticoid resistance. Clinical Presentation The clinical presentation of patients with glucocorticoid resistance is summarized in Table 1 and is related to the pathophysiology described in Figure 1. Generally, clinical manifestations of glucocorticoid deficiency were not present in most of the patients, and most of the patients evaluated in the context of family studies were asymptomatic despite biochemical indices of excessive cortisol production. The chief complaint of members of one particular family and an additional unrelated patient, however, was chronic fatigue, which might indicate inadequate compensation by the increased glucocorticoids in certain resistant target tissues, perhaps parts of the central nervous system or the muscles. In several patients, the increased concentrations of cortisol, deoxycorticosterone, and corticosterone (all steroids known to have inherent mineralocorticoid activity) caused signs of mineralocorticoid excess, such as hypertension and hypokalemic alkalosis. Finally, increased levels of adrenal androgens caused signs of androgen excess, including masculinization in women, with manifestations affecting the skin (acne and hirsutism) and the reproductive system (oligomenorrhea, oligoanovulation, and infertility). Also, early and excessive adrenarche was associated with precocious puberty, and interference of adrenal androgens on the feedback regulation of follicle-stimulating hormone caused abnormal spermatogenesis in men with the syndrome [17]. This abnormal spermatogenesis, however, could also be explained by corticotropin-induced intratesticular growth of adrenal rests, a phenomenon known to occur in classic and late-onset congenital adrenal hyperplasia [22]. Table 2. Syndromes of Glucocorticoid Resistance These clinical manifestations were not reported in all patients with symptomatic glucocorticoid resistance, and the clinical presentation varied even within families. Two main explanations can be given for this: First, the degree of resistance, as indicated by the compensatory increases of cortisol production, has generally differed among patients, with associated variability in the production of mineralocorticoid and androgen compounds and, therefore, differing effects resulting from excess production. Second, the sensitivity of target tissues to mineralocorticoids and androgens can also vary among persons, resulting in unequal responsiveness to similar increases of circulating steroids. The factors responsible for the different sensitivity of target tissues to these hormones could be individual differences in 1) the activity of key hormone-inactivating or -activating enzymes, such as 11--ketosteroid reductase in the kidney, which inactivates cortisol, deoxycorticosterone, or corticosterone [23], or 5 -reductase and 17-ketosteroid dehydrogenase in the skin, which convert adrenal androgens to more potent metabolites [24]; or 2) the cascades of the mineralocorticoid and androgen-receptor transduction systems, which can vary at different steps [25, 26]. In addition, other genetic or epigenetic factors, such as insulin resistance or upper body (abdominal) obesity or both, may influence the clinical manifestations of the syndrome by altering pituitary and gonadal function and peripheral steroid metabolism. Diagnostic Evaluation Of major importance is the definition of appropriate criteria for the correct diagnosis of glucocorticoid resistance and its differentiation from the many diseases it mimics clinically or biochemically. These criteria are summarized in Table 2. First, the patient should not have clinical evidence of the Cushing syndrome, including the phenotypic changes and biochemical consequences of hypercortisolism. Second, indices of increased cortisol production should be present, such as increased 24-hour urinary free cortisol levels or increased 17-hydroxysteroid per gram creatinine excretion, increased plasma total and free cortisol concentrations, or an increased rate of cortisol production. Third, glucocorticoid resistance should be present as determined by dexamethasone testing using either a complete dose-response test, as previously described [8], or by using one or two doses of the compound. The results of this test should be validated against the plasma levels of dexamethasone, because absorption or metabolism of this synthetic glucocorticoid may vary from person to person. Finally, the hypothalamic-pituitary-adrenal axis should retain its normal circadian rhythmicity and its responsiveness to stressors such as hypoglycemia; however, its basal and stimulated activities should be higher than those of normal persons. Although the single-dose overnight dexamethasone suppression test may be appropriate for screening patients with potential generalized glucocorticoid resistance, its high false-positive rate of 15% to 20% makes measurement of 24-hour urinary free cortisol excretion preferable, if this syndrome is suspected. Levels above 100% (twofold) of the upper normal range are suggestive of glucocorticoid resistance or the Cushing syndrome [27]. Levels between the upper normal range and the 100% limit, however, are compatible with these diagnoses, along with a host of other states characterized by mild hypercortisolism [27, 28]. Assuming proper procedures and techniques, the syndrome of generalized glucocorticoid resistance should be easily distinguished on biochemical grounds from the chronic fatigue syndrome, essential hypertension, hyperaldosteronism, idiopathic hirsutism, polycystic ovarian disease, female infertility, precocious puberty, or male infertility, because none of these conditions is associated with hypercortisolism. It may be difficult to distinguish this syndrome in its mild biochemical form (increases in urinary free cortisol up to 100% of the upper normal range) from other mild forms of hypercortisolism, such as mild or early Cushing syndrome with a lack of or borderline manifestations of hypercortisolism, hypercortisolemic melancholic depression, anorexia nervosa, chronic active alcoholism, and hypercortisolism in persons who exercise heavily [27, 28]. In the case of mild or early Cushing syndrome, the absence of circadian rhythmicity and lack of responsiveness of plasma cortisol during an insulin tolerance test should aid the physician in diagnosing this condition. The patient's clinical course, which is frequently characterized by progressive deterioration and development of the classic Cushing phenotype, should allow eventual differentiation. The history or concurrent symptomatology and the dependence of the hypercortisolism on the actual state of the condition should differentiate glucocorticoid resistance from the other states. Therapy Synthetic glucocorticoids with minimal intrinsic mineralocorticoid activity, such as dexamethasone, provide a rational treatment for familial glucocorticoid resistance. These patients should receive oral doses of dexamethasone, usually ranging between 1 and 3 mg/d, that are clearly pharmacologic for normal persons but are equivalent to glucocorticoid replacement for the glucocorticoid-resistance