Disorders of the Aldosterone Synthase and Steroid 11β-Hydroxylase Deficiencies

Abstract

The most potent corticosteroids are 11β-hydroxylated compounds. In humans, two cytochrome P450 isoenzymes with 11β-hydroxylase activity, catalysing the biosynthesis of cortisol and aldosterone, are present in the adrenal cortex. CYP11B1, the gene encoding 11β-hydroxylase (P450c11), is expressed on high levels in the zona fasciculata and is regulated by ACTH. CYP11B2, the gene encoding aldosterone synthase (P450c11Aldo), is expressed in the zona glomerulosa under primary control of the renin-angiotensin system. Aldosterone synthase has 11β-hydroxylase activity as well as 18-hydroxylase activity and 18-oxidase activity. The substrate for CYP11B2 is 11-deoxycorticosterone, that of CYP11B1 is 11-deoxycortisol. Mutations in CYP11B1 cause congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency. This disorder is characterized by androgen excess and hypertension. Mutations in CYP11B2 cause congenital hypoaldosteronism (aldosterone synthase deficiency) which is characterized by life-threatening salt loss, failure to thrive, hyponatraemia and hyperkalaemia in early infancy. Both disorders have an autosomal recessive inheritance. Classical and nonclassical forms of 11β-hydroxylase deficiency can be distinguished. Studies in heterozygotes for classical 11β-hydroxylase deficiency show inconsistent results with no or only mild hormonal abnormalities (elevated plasma levels of 11-deoxycortisol after ACTH stimulation). In infants with congenital hypoaldosteronism, a comparable frequency of 18-hydroxylase deficiency (aldosterone synthase deficiency type I) and of 18-oxidase deficiency (aldosterone synthase deficiency type II) can be found. Molecular genetic studies of the CYP11B1 and CYP11B2 genes in 11β-hydroxylase deficiency or aldosterone synthase deficiency have led to the identification of several mutations. Transfection experiments showed loss of enzyme activity in vitro. In some of the patients with 18-oxidase deficiency (aldosterone synthase deficiency type II) no mutations in the CYP11B2 gene were identified. Refined methods for steroid determination are the basis for the diagnosis of inborn errors of steroidogenesis. Molecular genetic studies are complementary; on the one hand, they have practical importance for the prenatal diagnosis of virilizing CAH forms and on the other hand, they are of theoretical importance in terms of our understanding of the functioning of cytochrome P450 enzymes.

Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency: functional consequences of four CYP11B1 mutations

“…Therefore, the classical form of 11b-OHD, with an estimated frequency of 1:200 000 live births, is characterized by genital ambiguity in affected girls and postnatal hyperandrogenism in both sexes resulting in precocious pseudopuberty with rapid somatic growth, bone age acceleration and hypertension in about two-thirds of patients. 3,4 The milder nonclassical forms are very similar to the 21-OHD non-classical forms characterized by mild virilization and precocious pseudopuberty. 5,6 In these mild forms, whose frequency is unknown, hypertension does not occur often.…”

Effects of fluorotelomer alcohol 8:2 FTOH on steroidogenesis in H295R cells: Targeting the cAMP signalling cascade

“…These hormones are associated with a variety of physiological processes including metabolism, stress responses, immune responses, vasoconstriction, growth, development, salt and water homeostasis and vascular tone (Mommsen et al, 1999;Osborn, 1991). Studies have shown that decreased production of these hormones may impair normal physiological processes and cause pathologic effects in vivo (Peter et al, 1999;Ueshiba et al, 2002).…”

The Prevalence of Late Onset Congenital Adrenal Hyperplasia in Hirsute Women from Central Anatolia

“…The mean ages and age ranges of women in PCOS, IH and CS groups were as follows: 24.71 ± 3.92 years (17-34), 22.19 ± 3.71 years (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and 23.18 ± 4.50 years (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), respectively. None of the subjects in any group had received any hormonal medication at least eight weeks before the study.…”

“…There is no doubt that the main diagnostic evaluation should be based on molecular studies [16,17], but this may limit the uncovering of some cases since molecular studies are neither prevalent nor easy to do. On the other hand, while there is still an enigma about the diagnosis of LO CAH by using hormonal analysis, ACTH stimulation test still consists of the gold standard test for the evaluation of adrenal response and enzyme deficiencies causing LO CAH [18,19].…”