Abstract
What biological processes underlie this “resistance” to cortisol? Because this resistance includes the hypothalamicpituitary-adrenal (HPA) axis negative feedback regulatory centers in the brain and pituitary gland, this axis is activated to “overcome” or compensate for the glucocorticoid action defect (Figure 1). The production of hypothalamic corticotropin-releasing hormone (CRH), arginine-vasopressin (AVP) and pituitary adrenocorticotropic hormone (ACTH) increase and the adrenal cortices hyperfunction, secreting large amounts of cortisol, adrenal steroid precursors and adrenal androgens. The adrenal steroid precursors include deoxy-corticosterone and corticosterone, both of which, as well as cortisol, have sodium-retaining activity through the mineralocorticoid receptor, which is normal in patients with cortisol resistance. Thus, the patient tissues are exposed to elevated levels of adrenal androgens and mineralocorticoids, which result in manifestations of hyperandrogenism and hypermineralocorticoidism.
Highlights
What is ‘Primary Generalized Glucocorticoid Resistance’ (PGGR)? PGGR means that all tissues in an organism have decreased sensitivity or “resistance” to the natural glucocorticoid, in us humans, cortisol
The patient tissues are exposed to elevated levels of adrenal androgens and mineralocorticoids, which result in manifestations of hyperandrogenism and hypermineralocorticoidism
Are there any non-hyperandrogenism and non-hypermineralocorticoidism-related manifestations linked to PGGR? Generally, there are no manifestations of glucocorticoid excess (Cushing syndrome) or deficiency (Addison disease), with the exception of chronic fatigue in some patients and profound hypoglycemia in a recently reported infant with complete glucocorticoid resistance
Summary
What is ‘Primary Generalized Glucocorticoid Resistance’ (PGGR)? PGGR means that all tissues in an organism have decreased sensitivity or “resistance” to the natural glucocorticoid, in us humans, cortisol. The patient tissues are exposed to elevated levels of adrenal androgens and mineralocorticoids, which result in manifestations of hyperandrogenism and hypermineralocorticoidism. The etiology of Familial or Sporadic Primary Generalized Glucocorticoid Resistance in most reported cases has been ascribed to molecular defects of the glucocorticoid receptor gene, one would expect manifestations of the syndrome in other faults of the glucocorticoid signaling system. Defects in shared transcriptional co-activators might result in manifestations of glucocorticoid and of other steroid hormone resistance states. We concluded that there must be a nodal molecule(s) shared by all steroid/sterol hormone action networks in the cells of these animals. The identity of this molecule(s) remains unknown to this day. Whether this pan-steroid/sterol resistance conferred some selective advantage or whether it was the result of tolerated genetic drift remains an enigma
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