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Review
. 2024 Nov 2;25(21):11779.
doi: 10.3390/ijms252111779.

Severe Hyperandrogenism in 46,XX Congenital Adrenal Hyperplasia: Molecular Physiopathology, Late Diagnoses, and Personalized Management

Gianluca Cera  1 , Andrea Corsello  2 , Roberto Novizio  1 , Vincenzo Di Donna  1 , Pietro Locantore  1 , Rosa Maria Paragliola  3
Affiliations
Review

Severe Hyperandrogenism in 46,XX Congenital Adrenal Hyperplasia: Molecular Physiopathology, Late Diagnoses, and Personalized Management

Gianluca Cera et al. Int J Mol Sci. .

Abstract

Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive endocrine disorders characterized by alteration in adrenal hormonal secretions. The most common form is caused by CYP21A2 mutations that result in 21-hydroxylase deficiency. Clinical features can vary, from salt-wasting forms, characterized by a lack of mineralocorticoid activity with a risk of perinatal-onset adrenal crises, to "simple-virilizing" forms with sufficient aldosterone secretion, up to milder "non-classical" forms, with a variable grade of hyperandrogenism but no severe hormonal deficiencies. During pregnancy, CAH 46,XX fetuses are exposed to elevated androgen levels, leading to a variable grade of virilization and potential central nervous system effects if untreated. These patients are usually (but not always) assigned female at birth, but some cases may be misdiagnosed and assigned male, potentially inducing fertility, gender identity, and sexual behavior issues in adulthood. In these patients, the benefits and risks of a late gender transition should be carefully evaluated. In this paper, we reviewed the literature concerning the most interesting peculiarities of these conditions.

Keywords: 21-OH deficiency; 46,XX disorders of sex development; congenital adrenal hyperplasia; gender dysphoria; sex assignment at birth; sex reassignment.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Steroid hormone synthesis pathway. P450scc: cholesterol side-chain cleavage enzyme; STAR: steroidogenic acute regulatory protein; POR: cytochrome P450 reductase; P450c17: steroid 17 alpha-hydroxylase/17,20 lyase; HSD: hydroxysteroid dehydrogenase; P450c21: 21-hydroxylase; P450c11: 11 β-hydroxylase; P450Aro: aromatase. Solid black arrows: conversion; solid blue circles: catalysis; dashed blue lines: stimulation; solid dashed red lines: associated disorders; red box and crosses: hormonal deficiencies in 21-OHD.
Figure 2
Figure 2
Differential diagnoses in suspected DSD: physiological steps in somatic sex development and potentially associated conditions.
See this image and copyright information in PMC

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