Primary Generalized Glucocorticoid Resistance and Hypersensitivity Syndromes: A 2021 Update

Abstract

Glucocorticoids are the final products of the neuroendocrine hypothalamic–pituitary—adrenal axis, and play an important role in the stress response to re-establish homeostasis when it is threatened, or perceived as threatened. These steroid hormones have pleiotropic actions through binding to their cognate receptor, the human glucocorticoid receptor, which functions as a ligand-bound transcription factor inducing or repressing the expression of a large number of target genes. To achieve homeostasis, glucocorticoid signaling should have an optimal effect on all tissues. Indeed, any inappropriate glucocorticoid effect in terms of quantity or quality has been associated with pathologic conditions, which are characterized by short-term or long-lasting detrimental effects. Two such conditions, the primary generalized glucocorticoid resistance and hypersensitivity syndromes, are discussed in this review article. Undoubtedly, the tremendous progress of structural, molecular, and cellular biology, in association with the continued progress of biotechnology, has led to a better and more in-depth understanding of these rare endocrinologic conditions, as well as more effective therapeutic management.

Hypercortisolaemia without clinical stigmata of Cushing syndrome

“…At least six patients with the disorder have been described in the absence of a detectable mutation 4. Testing for gene mutations should be performed by whole exome Sanger sequencing 5. The spectrum of manifestations is highly variable.…”

Molecular mechanisms of glucocorticoid resistance

“…Excessive adrenal androgens may lead to indeterminate karyotype of female genitalia, precocious puberty, acne, hirsutism, male pattern baldness and subfertility, amenorrhoea and menstrual irregularities in females, and oligospermia in males. 12 Secondary GCR is usually caused by homologous downregulation of GRα mRNA and protein due to increased circulating GC content under various chronic stimuli, autoimmune diseases, and inflammatory diseases. However, with further research, some other mechanisms are slowly being discovered, such as the impaired nuclear translocation of the GR complex and defects in GR binding to ligands and DNA, and so on.…”

“…Thus, patients with elevated concentrations of steroid precursors with mineralocorticoid activity may develop hypertension and/or hypokalemic alkalosis. Excessive adrenal androgens may lead to indeterminate karyotype of female genitalia, precocious puberty, acne, hirsutism, male pattern baldness and subfertility, amenorrhoea and menstrual irregularities in females, and oligospermia in males 12 . Secondary GCR is usually caused by homologous downregulation of GRα mRNA and protein due to increased circulating GC content under various chronic stimuli, autoimmune diseases, and inflammatory diseases.…”

The Role of Glucocorticoid Receptor in the Pathophysiology of Pituitary Corticotroph Adenomas

“…Ongoing research indicates that multiple factors may contribute to both the response and the development of GC resistance in CD. All these factors may impact GR functions by reducing its availability or altering structural and/or enzymatic properties, including agonists binding [ 26 ].…”