Syndrome of primary resistance of receptors to glucocorticoids

Syndrome of primary resistance of receptors to glucocorticoids is a disease manifested by hypercortisolemia, normal daily rhythm of cortisol secretion, increased level of ACTH in the blood, increased excretion of free cortisol in the urine in the absence of clinical manifestations of Cushing's syndrome.

Causes of the syndrome of primary resistance of receptors to glucocorticoids

For the first time this syndrome called "Spontaneous hypercortisolism without Cushing's syndrome" was described by Vingerhoeds ASM, Tijssen JHH, Schwarz F. In 1976 from 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 an unknown genesis. In addition to an increase in cortisol in the blood, an increase in the excretion of 17 CS with urine was noted. Clinical signs of Cushing's syndrome were absent. The plasma renin activity was normal, and the aldosterone release in the urine was decreased. The son at the age of 20 also found an increase in serum cortisol and an increase in the rate of its secretion. Isolation of 17 CS with urine was increased. Arterial pressure and electrolytes were within normal limits. Clinical signs of Cushing's syndrome were absent. According to the US, the size of the adrenal glands did not represent deviations from the norm. The genesis of the syndrome in the examined patients remained unclear.

In 1980, Kontula K. Et al., Examining peripheral receptors in patients with adrenal disease, reported a patient with a high serum cortisol level (in the absence of clinical Cushing's syndrome), whose glucocorticoid receptor counts on lymphocytes were significantly reduced with normal affinity .

In 1982-1983 years. Chrousos et al. Have published the results of a repeated detailed examination of two first-described patients with hypercortisolism. Six years after the hypercortisolemia found in patients, there were no clinical signs of Cushing's syndrome. Levels of serum cortisol, dehydroepiandrosterone, androstenedione and daily excretion of free cortisol were increased in both patients and more significantly in the father.

17-hydroxyprogesterone and 11-deoxycortisol were increased only in the father. The content of ACTH was twice as high as normal in both. The suppressive dexamethasone test was positive (that is, the basal level of cortisol decreased to normal) after a single dose of 3 mg of the drug in the father and 1.2 mg in the son. The authors suggested that the detected degree of pituitary resistance to dexamethasone correlates with the degree of severity of the syndrome. The study of glucocorticoid receptors on mononuclear leukocytes and fibroblasts indicated normal number but reduced affinity for cortisol in both patients, which allowed the authors to apply the term "primary cortisol resistance" to characterize this syndrome.

Recently, the term "family primary resistance to glucocorticoids" is more often used in the literature, since a partial resistance of glucocorticoid receptors (GR) to dexamethasone was also discovered during the research.

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

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

[1], [2], [3], [4]

Pathogenesis

The pathogenesis of the clinical manifestations of this syndrome is currently presented as follows. Partial resistance to cortisol of tissue receptors, including the pituitary receptors, leads to a disruption of the feedback, and thus the secretion of cortisol is compensated for overcoming resistance. The increase in the production of ACTH stimulates the secretion of mineralocorticoids and androgens, as a result of which the increase in the production of DOXA and corticosterone causes arterial hypertension with or without the presence of alkalosis. Perhaps the increase in production of these adrenal steroids is available until the volume of plasma 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 indications of an excess of androgens. In women, this manifests itself as a symptom-complex with the development of anknehirsutism, baldness, dis- and oposomenorei, anovulation, infertility. In men, spermatogenesis disorders and infertility can occur as a result of a disturbance in the feedback between androgens and FSH. The syndrome of primary resistance to cortisol in a 6-year-old boy is shown, which is manifested by isosexual premature puberty.

A large number of patients have only hormonal manifestations in the absence of clinical signs of a syndrome of primary resistance of receptors to glucocorticoids. These patients are identified only when the relatives of the proband are examined. Thus, M. Karl et al. Described a woman of 26 years with hirsutism, baldness and dysmenorrhea with a basal level of cortisol 1110-1290 nmol / L without hypertension and hypokalemia. The clinic of Cushing's syndrome was absent. The circadian rhythm of cortisol was normal, and the level of ACTH, 8-androstenedione and testosterone increased. In response to insulin hypoglycemia, a normal response of ACTH and cortisol was obtained. Hypercortisollemia was suppressed up to 580 nmol / l by taking 1 mg of dexamethasone. At the father and two brothers the only sign of the syndrome of primary resistance of the receptors to glucocorticoids was hypercortisoloma.

Thus, the nature of the clinical manifestations of the primary resistance syndrome of receptors to  glucocorticoids  is largely due to the degree of resistance of glucocorticoid receptors to cortisol and the response of ACTH, to a greater or lesser degree stimulating the steroidogenesis of mineralocorticoids and androgens. In addition, the individual sensitivity to hormones plays a role, which can vary considerably.

[5], [6], [7], [8], [9], [10]

Diagnostics of the syndrome of primary resistance of receptors to glucocorticoids

Diagnosis of the syndrome of primary resistance of receptors to glucocorticoids presents significant difficulties due to the large polymorphism of clinical manifestations and the absence of a cardinal clinical sign of the disease. Therefore, the diagnosis of the syndrome was largely random, when the nature of the disease involved participation in its genesis of adrenal hormones. Most often the syndrome of primary resistance of receptors to glucocorticoids can be suspected when examining patients with arterial hypertension in combination with hypokalemia, as well as when examining patients - women with androgenemia symptoms.

Confirmation of the diagnosis is an increase in the content of  cortisol  and mineralocorticoid metabolites of steroidogenesis in the blood (with normal or decreased aldosterone levels) or adrenal androgens (dehydroepiandrosterone or its sulfate, androstenedione in combination with testosterone). The main feature is the presence of hypercortisoloma in the relatives of the proband. The normal diurnal rhythm and suppressive effect of dexamethasone on the serum cortisol level, and if necessary, the test with insulin, CT and MNR, exclude other diseases and conditions 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, caused by the therapeutic use of the drug Ru 486).

[11], [12]

Treatment of the syndrome of primary resistance of receptors to glucocorticoids

Treatment of the syndrome of primary resistance of receptors to glucocorticoids is the daily administration of a suppressive dose of dexamethasone, which can range from 1 to 3 mg, depending on the degree of resistance to glucocorticoids.

Treatment with dexamethasone helps normalize ACTH, serum and excreted per day free cortisol, preventing possible hyperplasia of the adrenal and pituitary gland. Reduction to the norm of secretion of cortisol and ACTH eliminates the excess production of metabolites of mineralocorticoids and androgens, which is expressed by the elimination of arterial hypertension and clinical manifestations of hyperandrogenism.