Primary Generalized Glucocorticoid Reaction - An Overview

Introduction

All tissues expressing the human growth hormone (hGR) are affected by primary generalized glucocorticoid resistance, also known as Chrousos syndrome. It is characterized by a generalized, partly diminished sensitivity to glucocorticoids. Due to de novo genetic abnormalities (point mutations, deletions, or insertions) in the NR3C1 gene, Chrousos syndrome can be inherited in an autosomal recessive or dominant manner or occur sporadically. Defective hGRs in the hypothalamus and pituitary cause impaired glucocorticoid negative feedback loops in patients with Chrousos syndrome, which leads to compensatory hypersecretion of adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH), and arginine vasopressin (AVP).

Primary generalized glucocorticoid resistance is a genetic disease in which tissue resistance toward glucocorticoids develops. It is a rare endocrinological condition. Tissues naturally develop resistance to cortisol. Glucocorticoids are steroid hormones that generally regulate inflammation and autoimmunity. Glucocorticoid regulates a broad spectrum of physiologic functions. It plays a very important role in various biological processes, such as growth, reproduction, intermediary metabolism, and the immune system. In this disease, patient tissue is exposed to elevated levels of adrenal androgens and mineralocorticoids, resulting in hyperandrogenism (occurs when a person's body contains an excessive amount of androgens, a class of sex hormones) and hypermineralocorticoidism (a mineralocorticoid excess condition most likely brought on by elevated corticosteroid production).

What Is Glucocorticoid?

The adrenal gland cortex produces steroid hormones known as glucocorticoids. A crucial part of the body's metabolism of fat, protein, and glucose is played by glucocorticoids. They mostly arise from steroid precursors and are produced in the adrenal cortex's zona fasciculata. Their ability to suppress the immune system, reduce inflammation, and reduce allergies in the body makes them significant from a medical standpoint. This specific ability is utilized in medical treatments. Recall that glucocorticoids are not the same as the notorious anabolic steroids that bodybuilders use to gain bulk. Rather, the breakdown of peripheral muscle is brought on by these catabolic steroids. Cortisol is the primary glucocorticoid in the body. It is secreted according to a diurnal circadian rhythm, peaking at roughly 8 AM and troughing its lowest points between midnight and 4 AM.

What Is a Human Glucocorticoid Receptor?

Membrane glucocorticoid receptors are proteins that are either a part of the plasma membrane or connected to it; they bind glucocorticoids specifically and cause the body to react quickly to these hormones.

The mechanism of action of glucocorticoid hormone is mediated by a protein 94-kDa protein, the glucocorticoid receptor. It is a nuclear receptor and functions as “a ligand-dependent” transcription factor. It regulates the expression of glucocorticoid-responsive genes.

What Are the Causes of Primary Generalized Glucocorticoid Reactions?

Primary generalized glucocorticoid reactions are genetic diseases caused by a gene mutation that encodes glucocorticoid receptors. Alteration of signal transduction leads to impaired sensitivity of glucocorticoid towards the tissue. Chrousos syndrome can be inherited in an autosomal recessive or dominant fashion or may be sporadic due to de novo genetic defects (point mutations, deletions, or insertions) in the NR3C1 gene. Due to this mutation, there is an alteration defect in glucocorticoid signal transduction.

What Are the Clinical Manifestations of Primary Generalized Glucocorticoid Reactions?

It is a genetic disease characterized by generalized partial insensitivity toward glucocorticoids. It is mainly associated with:

• Hypertension (increased blood pressure).

• Hirsutism (usually evident around the mouth and chin - extra hair).

• Hypokalemic alkalosis (resulting from high-grade gastric outlet blockage and major loss of gastric H+ and Cl− ions).

• In a young child, there is the presence of hypoglycemia.

• Generalized tonic-clonic seizures (a kind of seizure in which there are strong muscle contractions and a loss of consciousness) are reported in many cases.

• In a newborn baby, there is the presence of a febrile illness along with severe hypoglycemia.

• There is the presence of excessive fatigability during feeding. The child is more prone to infections, and retardation of growth is seen.

• There is the presence of precocious puberty in children of both genders.

• Decreased fertility is seen in males.

• Hair loss as seen in men, acne, menstrual irregularities, and oligo-anovulation are noticed in females.

• Patients are predisposed to the development of adrenocorticotropic hormone-secreting pituitary adenoma.

• There is an increased level of anxiety and depression, and central nervous system dysfunction such as headaches, visual impairment, and seizures are also noted.

What Are the Complications of Primary Generalized Glucocorticoid Reactions?

Effects can range from mild to severe according to the severity of the disease.

It includes:

• Increased appetite leads to weight gain.

• Increased risk of infections.

• Diabetes.

• High blood pressure.

• Osteoporosis.

• Withdrawal symptoms.

• Thinning of the skin due to which skin becomes more prone to bruises.

How Can Primary Generalized Glucocorticoid Reaction Be Diagnosed?

Accurate and sensitive laboratory methods and proper clinical examination help in the diagnosis of primary glucocorticoid reactions.

• Pituitary magnetic resonance imaging.

• Adrenal computed tomography.

• Complete personal and family history of a patient should be taken.

• Physical examination should include an assessment of signs of hyperandrogenism, acne, axillary hair development, and cilantro legally.

• An endocrinologic evaluation of the patient is advised. The concentrations of plasma corticotropin, plasma renin, aldosterone, serum cortisol, testosterone, androstenedione, total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting glucose insulin are evaluated.

What Is the Differential Diagnosis of Primary Generalized Glucocorticoid Reactions?

Following are the differential diagnosis of primary generalized glucocorticoid reactions.

• Adrenocortical Imaging.

• Congenital adrenal hyperplasia.

• Polycystic ovarian syndrome.

• Precocious Puberty.

What Is the Treatment for Primary Generalized Glucocorticoid Reactions?

As there is excessive secretion of adrenocorticotropic hormone and increased production of ‘’adrenal steroids,’’ there is an increase in androgenic activity. The major aim of treatment is to suppress the increased production of adrenal steroids. A high dose of synthetic glucocorticoid is administered to activate the mutant gene and suppress the endogenous secretion of adrenocorticotropic hormone. A high dose of a synthetic glucocorticoid such as dexamethasone (1 to 3 mg given once daily at night) is given in a biochemically titrated dose. This helps suppress adrenocorticotropic hormones without stimulating mineralocorticoid receptors. Hyperandrogenism and hyper-mineralocorticoids can be corrected while compensating for the glucocorticoid action on target tissues.

Conclusion

The glucocorticoid receptor is an intracellular transcription factor that mediates the action of glucocorticoids. It influences all the physiological functions which are essential for life. It has an important role in the regulation of crucial biological processes. There it is very important to diagnose this disease along the proper line of management.