Primary glucocorticoid receptor resistance syndrome

Primary glucocorticoid receptor resistance syndrome is a disease characterized by hypercortisolemia, normal circadian rhythm of cortisol secretion, elevated ACTH levels in the blood, and increased excretion of free cortisol in the urine in the absence of clinical manifestations of Cushing's syndrome.

Causes of primary glucocorticoid receptor resistance syndrome

This syndrome, called “Spontaneous hypercortisolism without Cushing’s syndrome”, was first described by Vingerhoeds A. S. M., Tijssen J. H. H., Schwarz F. in 1976 in a father and son.

An increase in the serum cortisol level was found in a 52-year-old patient examined for arterial hypertension in combination with hypokalemic alkalosis of unknown genesis. In addition to an increase in the blood cortisol content, an increase in the excretion of 17 KS in the urine was noted. Clinical signs of Cushing's syndrome were absent. Plasma renin activity was normal, and the excretion of aldosterone in the urine was decreased. A 20-year-old son also had an increase in serum cortisol and an increase in the rate of its secretion. The excretion of 17 KS in the urine was increased. Blood pressure and electrolytes were within normal limits. Clinical signs of Cushing's syndrome were absent. According to ultrasound data, the size of the adrenal glands did not deviate from the norm. The genesis of the syndrome in the examined patients remained unclear.

In 1980, Kontula K. et al., studying peripheral receptors in patients with adrenal diseases, reported a patient with a high level of serum cortisol (in the absence of clinical Cushing's syndrome), in whom the number of glucocorticoid receptors on lymphocytes was significantly reduced with their normal affinity.

In 1982–1983, Chrousos et al. published the results of a detailed re-examination of the two patients with hypercortisolism described for the first time. Six years after the patients were found to have hypercortisolemia, clinical signs of Cushing's syndrome were absent. Serum cortisol, dehydroepiandrosterone, androstenedione levels, and daily free cortisol excretion were elevated in both patients and more significantly in the father.

17-hydroxyprogesterone and 11-deoxycortisol were elevated only in the father. ACTH levels were twice normal in both patients. The dexamethasone suppression test was positive (i.e., basal cortisol levels decreased to normal) after a single dose of 3 mg in the father and 1.2 mg in the son. The authors suggested that the degree of pituitary resistance to dexamethasone correlated with the severity of the syndrome. Glucocorticoid receptor testing on mononuclear leukocytes and fibroblasts showed normal levels but decreased affinity for cortisol in both patients, which led the authors to use the term "primary cortisol resistance" to characterize this syndrome.

Recently, the term “familial primary resistance to glucocorticoids” has been used more often in the literature, since partial resistance of glucocorticoid receptors (GR) to dexamethasone was also discovered during the research process.

Primary glucocorticoid receptor resistance syndrome is a rare disease. Up to 1999, about 50 cases were published in the literature, which include patients with both polymorphic clinical manifestations and asymptomatic forms manifested only by hormonal disorders. Most of the published cases are familial forms of the disease, characterized by autosomal dominant inheritance. However, sporadic cases of the syndrome have also been described. A study of possible causes of partial resistance of glucocorticoid receptors to cortisol, conducted in all published cases, both in probands and relatives, led to ambiguous results.

It turned out that the syndrome of primary resistance of receptors to glucocorticoids can be caused by quantitative and/or qualitative damage to glucocorticoid receptors in the form of a decrease in their number, affinity, thermolability and/or disruption of the interaction of nuclear GR with DNA. In addition, the cause may be mutations in the gene of glucocorticoid receptors, reducing the binding of GR to DNA, as well as deletions of the gene of glucocorticoid receptor. Point mutation and microdeletion of the gene of glucocorticoid receptors, accompanied by a decrease in the number of glucocorticoid receptors and their affinity for dexamethasone, was the cause of the syndrome of primary resistance to glucocorticoids. A mutation in the glucocorticoid receptor gene was found among relatives of four out of five families with glucocorticoid resistance syndrome, as well as the presence of decreased sensitivity to cortisol of the pituitary and hypothalamic receptors.

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Pathogenesis

The pathogenesis of the clinical manifestations of this syndrome is currently presented as follows. Partial resistance to cortisol of tissue receptors, including pituitary receptors, leads to a violation of feedback, due to which the secretion of cortisol increases compensatorily to overcome the resistance. Increased production of ACTH stimulates the secretion of mineralocorticoids and androgens, as a result of which an increase in the production of DOXA and corticosterone causes arterial hypertension with or without alkalosis. It is possible that the increase in the production of these adrenal steroids is present until the plasma volume increases, which leads to suppression of the secretion of aldosterone and renin without the development of arterial hypertension in some cases.

Increased secretion of 8-androstenedione, DHEA and DHEA sulfate causes signs of androgen excess. In women, this is manifested by a symptom complex with the development of acnehirsutism, baldness, dys- and opsomenorrhea, anovulation, and infertility. In men, spermatogenesis disorders and infertility may occur as a result of impaired feedback between androgens and FSH. A syndrome of primary cortisol resistance has been described in a 6-year-old boy, manifested by isosexual precocious puberty.

A large number of patients have only hormonal manifestations in the absence of clinical signs of primary glucocorticoid receptor resistance syndrome. These patients are detected only when examining the proband's relatives. Thus, M. Karl et al. described a 26-year-old woman with hirsutism, alopecia, and dysmenorrhea with a basal cortisol level of 1110-1290 nmol/l without arterial hypertension and hypokalemia. There was no clinical picture of Cushing's syndrome. The daily cortisol rhythm was normal, and the level of ACTH, 8-androstenedione, and testosterone was elevated. In response to insulin hypoglycemia, a normal ACTH and cortisol response was obtained. Hypercortisolemia was suppressed to 580 nmol/l by taking 1 mg dexamethasone. In the father and two brothers, the only sign of primary glucocorticoid receptor resistance syndrome was hypercortisolemia.

Thus, the nature of clinical manifestations of primary glucocorticoid receptor resistance syndrome is largely determined by the degree of glucocorticoid receptor resistance to cortisol and the ACTH response, which to a greater or lesser extent stimulates steroidogenesis of mineralocorticoids and androgens. In addition, individual sensitivity to hormones plays a role, which can vary significantly.

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Diagnostics of primary glucocorticoid receptor resistance syndrome

The diagnosis of primary glucocorticoid receptor resistance syndrome is quite difficult due to the high polymorphism of clinical manifestations and the absence of a cardinal clinical sign of the disease. Therefore, the diagnosis of the syndrome was largely accidental, when the nature of the disease implied the participation of adrenal hormones in its genesis. Most often, primary glucocorticoid receptor resistance syndrome can be suspected during examination of patients with arterial hypertension in combination with hypokalemia, as well as during examination of female patients with signs of androgenemia.

The diagnosis is confirmed by an increase in the content of cortisol and mineralocorticoid metabolites of steroidogenesis in the blood (with a normal or reduced level of aldosterone) or adrenal androgens (dehydroepiandrosterone or its sulfate, androstenedione in combination with testosterone). The main symptom is the presence of hypercortisolemia in relatives of the proband. Normal circadian rhythm and the suppressive effect of dexamethasone on the level of serum cortisol, and, if necessary, an insulin test, CT and MRI allow us to exclude other diseases and conditions that are not accompanied by clinical manifestations of Cushing's syndrome (ectopic ACTH syndrome, which in 60% of cases is not accompanied by clinical Cushing's syndrome, tumors of the adrenal cortex, resistance of glucocorticoid receptors to cortisol due to the therapeutic use of the drug Ru 486).

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Treatment of primary glucocorticoid receptor resistance syndrome

Treatment of primary glucocorticoid receptor resistance syndrome involves daily administration of a suppressive dose of dexamethasone, which can range from 1 to 3 mg depending on the severity of glucocorticoid resistance.

Treatment with dexamethasone helps to normalize ACTH, serum and daily excreted free cortisol, preventing possible hyperplasia of the adrenal glands and pituitary gland. Reducing the secretion of cortisol and ACTH to normal eliminates excess production of mineralocorticoid metabolites and androgens, which is expressed by the elimination of arterial hypertension and clinical manifestations of hyperandrogenism.