Novel Insight into Etiology, Diagnosis and Management of Primary Adrenal Insufficiency

Abstract

Primary adrenal insufficiency (PAI) is a rare condition in childhood which is either inherited (mostly) or acquired. It is characterized by glucocorticoid and maybe mineralocorticoid deficiency. The most common form in children is 21-hydroxylase deficiency, which belongs to the steroid biosynthetic defects causing PAI. Newer forms of complex defects of steroid biosynthesis are P450 oxidoreductase deficiency and (apparent) cortisone reductase deficiency. Other forms of PAI include metabolic disorders, autoimmune disorders and adrenal dysgenesis, e.g. the IMAGe syndrome, for which the underlying genetic defect has been recently identified. Newer work has also expanded the genetic causes underlying isolated, familial glucocorticoid deficiency (FGD). Mild mutations of CYP11A1 or StAR have been identified in patients with FGD. MCM4 mutations were found in a variant of FGD in an Irish travelling community manifesting with PAI, short stature, microcephaly and recurrent infections. Finally, mutations in genes involved in the detoxification of reactive oxygen species were identified in patients with unsolved FGD. Most mutations were found in the enzyme nicotinamide nucleotide transhydrogenase, which uses the mitochondrial proton pump gradient to produce NADPH. NADPH is essential in maintaining high levels of reduced forms of antioxidant enzymes for the reduction of hydrogen peroxide. Similarly, mutations in the gene for TXNRD2 involved in this system were found in FGD patients, suggesting that the adrenal cortex is particularly susceptible to oxidative stress.

Resveratrol alleviates endotoxemia-associated adrenal insufficiency by suppressing oxidative/nitrative stress

“…In recent years, accumulating evidence indicates that oxidative stress resulting from an imbalance between pro-oxidants and anti-oxidants plays an important role in the pathogenesis of adrenal insufficiency [6,7]. As a result, overproduction of reactive oxygen species (ROS) can oxidize thiols, lipids, proteins and nucleic acids, consequently leading to oxidative injury in adrenal glands.…”

The diagnosis and treatment of adrenal insufficiency during childhood and adolescence

“…Other causes of primary adrenal insufficiency are listed in box 1 4. Patients with midline abnormalities of the brain affecting the hypothalamic–pituitary axis may experience adrenal insufficiency as a consequence of CRH (tertiary adrenal insufficiency) or ACTH deficiency (secondary adrenal insufficiency).…”

The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature

“…Once again, while produced as an intermediate in the adrenal ZF itself, circulating levels of 17-hydroxyprogesterone are not normally a reflection of adrenal production, but of both ovarian pre-ovulatory theca and post-ovulatory luteinized theca cell function, particularly from the latter during the post-ovulatory luteal phase of the ovarian or menstrual cycle 35; 36 . Only in conditions of CYP21A1 deficiency will circulating levels of 17-hydroxyprogesterone reflect adrenal activity 6; 37; 38 and so are used as diagnostic criteria for congenital adrenal hyperplasia 39; 40; 41; 42 .…”