Generalized glucocorticoid resistance or Chrousos syndrome is a rare genetic disorder that can run in families or be sporadic. It is characterized by partial or generalized target-tissue insensitivity to glucocorticoids. The clinical spectrum includes severe, potentially fatal conditions like hypoglycemia, alkalosis, or severe hypokalemia, as well as completely asymptomatic forms. The disease's most prevalent symptom is

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

. The elevated 24-hour urinary free cortisol (UFC) excretion in the absence of clinical signs of hypercortisolism and the elevated serum

cortisol Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...

concentrations point to the diagnosis of generalized glucocorticoid resistance. The goal of treatment for generalized glucocorticoid resistance is to reduce excessive ACTH secretion, which in turn reduces the production of more adrenal steroids that have androgenic and mineralocorticoid properties. High dosages of synthetic glucocorticoids that spare mineralocorticoids, like dexamethasone, are used as part of the treatment.

Signs and symptoms

Individuals who have generalized glucocorticoid resistance may exhibit biochemical hypercortisolism in the absence of Cushing's syndrome symptoms. The condition's clinical phenotype varies from cases with no symptoms to signs of excess mineralocorticoids in the body such as hypokalemic alkalosis and

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

and/or androgen excess, including oligospermia in males, menstrual irregularities, hypo fertility, and amenorrhea in females, precocious puberty,

male-pattern hair loss Pattern hair loss (also known as androgenetic alopecia (AGA)) is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss (MPHL), the hair loss typically presents itself as either a receding front ha ...

, acne, hirsutism, and ambiguous genitalia at birth with 46, XX. In rare instances,

glucocorticoid deficiency Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal gland normally secretes glucocorticoids (primarily cortisol), mineralocorticoids (primarily aldosterone), and androge ...

has been reported in the following cases: hypoglycemia, severe

, easy "fatigability" with feeding, growth hormone deficiency, and generalized seizures in a 2-year-old girl, adult patients with chronic

, and a newborn with hypoglycemia, hypokalemia, and increased

arterial pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...

Causes

De novo genetic defects ( point mutations, deletions, or insertions) in the NR3C1 gene can cause sporadic cases of Chrousos syndrome, or it can be inherited in an autosomal recessive or dominant manner. Defective human glucocorticoid receptors in the hypothalamus and pituitary cause impaired glucocorticoid

negative feedback Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused by ...

loops in patients with Chrousos syndrome, which leads to compensatory hypersecretion of adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH), and arginine vasopressin (AVP).

Mechanism

Steroid hormones known as " glucocorticoids" are produced in the zona fasciculata of the

adrenal cortex The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is ...

and numerous other extra-adrenal organs, such as the skin, thymus, and gut. These lipophilic molecules are essential for the maintenance of both resting as well as threatened homeostasis and are secreted in the circulatory system in reaction to stressors and also in an ultradian and

circadian A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...

manner.

Diagnosis

The elevated 24-hour urinary free cortisol (UFC) excretion with the absence of clinical signs of hypercortisolism and the elevated serum cortisol concentrations point to the diagnosis of generalized glucocorticoid resistance. ACTH plasma concentrations can range from low to high. To confirm the diagnosis, peripheral blood

mononuclear Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can cellular differentiation, differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune s ...

cells must be used in thymidine incorporation and dexamethasone-binding assays in conjunction with sequencing of the human glucocorticoid receptor gene. When diagnosing generalized glucocorticoid resistance, the differential diagnosis consists of additional factors that can lead to hyperandrogenism or virilization, including congenital adrenal hyperplasia, polycystic ovarian syndrome, and idiopathic hirsutism;

hyperaldosteronism Hyperaldosteronism is a medical condition wherein too much aldosterone is produced by the adrenal glands, which can lead to lowered levels of potassium in the blood (hypokalemia) and increased hydrogen ion excretion (alkalosis). This cause of min ...

, essential hypertension, and additional mineralocorticoid-induced hypertensive disorders; circumstances like a typical pregnancy and

estrogen therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal ...

that are linked to increased serum concentrations of corticosteroid-binding globulin; pseudo-Cushing's conditions, like melancholic depression and

generalized anxiety Generalized anxiety disorder (GAD) is a mental and behavioral disorder, specifically an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functioni ...

; and mild variations of Cushing's disease, in which normal or slightly elevated ACTH concentrations coexist with hypercortisolism.

Treatment

The goal of treatment for generalized glucocorticoid resistance is to reduce excessive ACTH secretion, which in turn reduces the production of more adrenal steroids that have androgenic and mineralocorticoid properties. High dosages of mineralocorticoid-sparing synthetic glucocorticoids, like dexamethasone, are used as a form of treatment to activate the mutant and/or wild-type hGRα and suppress the affected subjects' natural secretion of ACTH.

References

External links

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{{Adrenal gland disorder, state=collapsed Adrenal gland disorders Rare syndromes Syndromes affecting the endocrine system Transcription factor deficiencies