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Why do some people become resistant to steroids? A deep dive into the surprising mechanisms of systemic steroid resistance!
Systemic steroid resistance, also known as Chrousos syndrome, is a rare genetic disorder that may run in families or occur independently. This condition is characterized by partial or systemic reduced target tissue sensitivity to steroids and has a wide range of clinical manifestations, including severe and potentially fatal conditions such as hypoglycemia, alkalosis, or severe hypokalemia, and may even be completely asymptomatic. . The most common symptom of the disease is fatigue. In the absence of clinical symptoms of hypercortisolism, the patient had elevated 24-hour urinary free cortisol (UFC) excretion and elevated serum cortisol concentrations, features that underscore the diagnosis of systemic steroid resistance.
The goal of treatment for systemic steroid resistance is to reduce excess ACTH secretion, thereby reducing the production of additional adrenal steroids.
Symptoms and signs
People with systemic steroid resistance may exhibit biochemical hypercortisolemia in the absence of Cushing symptoms. The clinical manifestations of this condition range from asymptomatic to symptoms of excess mineralocorticoids in the body, such as hypokalemic alkalosis and hypertension, with ovarian atrophy in men, irregular menstruation, subfertility, and amenorrhea in women and sexual disorders. Premature puberty, male pattern baldness, acne, hirsutism and many other symptoms. In rare cases, steroid deficiency has also been reported, including hypoglycemia, severe hypertension, feeding-induced fatigue, growth hormone deficiency, and generalized epilepsy in a two-year-old girl.
Reason
Spontaneous cases of systemic steroid resistance may be due to de novo genetic defects (point mutations, deletions, or insertions) in the NR3C1 gene, or may be inherited in an autosomal recessive or dominant manner. In patients with Chrousos syndrome, a deficiency in pseudo-anti-stress hormones leads to dysfunction of steroid receptors in the hypothalamus and pituitary gland, resulting in the production of adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH), and arginine. Excessive secretion of acid vasopressin (AVP).
"Steroid hormones, so-called "glucocorticoids," are produced in the zona fasciculata of the adrenal cortex as well as in many other extra-adrenal organs."
Mechanism
Glucocorticoids are secreted hormones originating from the adrenal glands and are also produced by additional glands such as the skin, thymus, and intestines. These lipophilic molecules are essential for maintaining body homeostasis and are released into the bloodstream in the face of stressors and are secreted in a supra-diurnal and diurnal manner.
Diagnosis
Together with elevated 24-hour urinary free cortisol (UFC) excretion and elevated serum cortisol concentrations in the absence of clinical symptoms of hypercortisolism, this points to the diagnosis of systemic steroid resistance. ACTH plasma concentrations may range from low to high. To confirm the diagnosis, thymidine uptake and dexamethasone binding tests on peripheral blood mononuclear cells are required, combined with sequencing of the human glucocorticoid receptor gene. Differential diagnoses to consider when diagnosing systemic steroid resistance include other factors that lead to hyperandrogenism or virilization, such as congenital adrenal hyperplasia, polycystic ovary syndrome, and idiopathic hirsutism.
Treatment
The goal of treatment for systemic steroid resistance is to reduce excess ACTH secretion, thereby reducing the production of more adrenal steroids. High doses of mineralocorticoid-sparing synthetic glucocorticoids, such as dexamethasone, are used as part of treatment to activate mutant and/or wild-type hGRα and suppress natural ACTH secretion in affected individuals.
The success of treatment ultimately depends on our ability to gain a deeper understanding of the complex mechanisms underlying systemic steroid resistance.
As Chrousos syndrome and the mechanisms behind it become more understood, will this change our basic understanding of steroid therapy?
