Adrenogenital Syndrome: Causes

Pathogenesis (disease development)

Adrenogenital syndrome (AGS) results from an enzyme defect. There are several enzymes that may be affected by the defect. The adrenal cortex requires these enzymes for the synthesis (production) of the steroid hormones cortisol and aldosterone. In over 90% of cases, a defect in the enzyme 21-hydoxylase is present in adrenogenital syndrome. Due to the enzyme defect-related cortisol deficiency, the negative feedback to the anterior pituitary lobe is absent, and the control and regulatory mechanism is disturbed. The pituitary gland tries to compensate the lack of cortisol by an increased secretion of the adrenocortical stimulating hormone ACTH (adrenocorticotropic hormone). This results in hyperplasia (increase in size) of the adrenal cortex. However, the metabolic pathways can only proceed to the point where the defective enzyme is located. Increased precursor molecules (hormone precursors) such as progesterone and 17α-OH-progesterone are produced, which are degraded to androgens by alternative metabolic pathways. Independently of this, androgens (male sex hormones) are formed in the adrenal cortex anyway and are increasingly synthesized by the increased ACTH secretion. The result is hyperandrogenemia, which leads to virilization (masculinization). Furthermore, the defect of 21-hydroxylase leads to an insufficient production of aldosterone or to a failure of it in the adrenal cortex. Aldosterone is a mineralocorticoid. It is an important link in the renin-angiotensin-aldosterone system (RAAS), which helps regulate blood pressure and salt balance. Hypoaldosteronism (deficiency of aldosterone) causes disturbances in salt balance with fluid loss, the so-called “salt wasting syndrome”.11ß- and 17α-hydroxylase deficiency is associated with increased production of mineralcorticoid-acting deoxycorticosterone (DOC) with mineralcorticoid excess.

Etiology (Causes)

Biographic causes

• Genetic burden
  • Genetic risk depending on gene polymorphisms:
    • Genes/SNPs (single nucleotide polymorphism):
      • Genes: CYP21A2, CYP11B1, HSD3B2, CYP17A1.
        • CYP21A2 SNPs (see table in Snpedia).
        • Mutation in the CYP21A2 gene in the context of classic adrenogenital syndrome. In multiple sufferers in a family, these are HLA genotypically identical.
  • The following enzymes may be affected by the defect, which is usually caused by point mutations:
    • 21-hydroxylase deficiency (>90% of cases).
    • 11ß-hydroxylase deficiency (about 5% of cases).
    • 17α-hydroxylase deficiency (very rare).
    • 3ß-hydroxysteroid dehydrogenase deficiency (very rare).

Causes due to disease

• Acquired androgenital syndrome:
  • Androgen-forming adrenocortical tumor.
  • Gonadal tumor (gonads: Gonads (ovaries/ovaries, testes))