ESPE Yearbook of Paediatric Endocrinology

Front Endocrinol (Lausanne). 2024; 15:1410122. PMID: 39175568 doi: 10.3389/fendo.2024.1410122. https://pubmed.ncbi.nlm.nih.gov/39175568/

Brief summary: This observational cohort study investigated 9 untreated Indonesian 46,XX individuals with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) (n=6) and 11-hydroxylase deficiency (11OHD) (n=3), who were reared as males. Despite markedly low cortisol concentrations, all patients survived without glucocorticoidtreatment and displayed androgen profiles within the normal male reference range.

Comment: This study presents a rare clinical and biochemical characterization of 9 untreated 46,XX individuals with CAH who were raised as males, highlighting the complex balance between androgen excess and cortisol deficiency. A particularly novel aspect is the quantification of 11-oxygenated androgens, which comprise a significant portion of the androgen pool and contribute to virilization. These patients displayed adrenal androgen concentrations within the male reference range and maintained a stable male phenotype during adolescence and adulthood. These findings indicate that these androgens have comparable receptor activity to testosterone and play an essential role in CAH pathophysiology (1).

Remarkably, despite all patients having extremely low cortisol concentrations and elevated ACTH baseline concentrations, with no meaningful cortisol response to ACTH stimulation, most did not experience clinical signs of adrenal insufficiency beyond early childhood. This clinical stability may be attributed to the compensatory activity of steroid precursors, such as 21-deoxycortisol and 11-deoxycortisol, which exhibit approximately 49% and 15% of cortisol’s biological activity on glucocorticoid receptors, respectively (2). However, this outcome must be interpreted with caution due to potential survival bias; only those who remained clinically stable without treatment are represented, potentially excluding more severe cases.

Current approaches emphasize delaying genital surgery and prioritizing shared decision-making in 46,XX patients with CAH, as male-reared individuals can establish a stable male gender identity and good quality of life (3). Clinically, the study underscores the dilemma in managing 46,XX CAH individuals reared as males, where conventional glucocorticoid therapy, while protective against adrenal crisis, may disrupt the established gender identity by reducing androgen concentrations and triggering feminization. This study highlights the importance of an individualized therapeutic approach, combined with culturally sensitive counseling, in such cases.

References: 1. Rege J, Turcu AF, Kasa-Vubu JZ, Lerario AM, Auchus GC, Auchus RJ, et al. 11-ketotestosterone is the dominant circulating bioactive androgen during normal andpremature adrenarche. J Clin Endocrinol Metab. 2018; 103(12):4589–98.2. Engels M, Pijnenburg-Kleizen KJ, Utari A, Faradz SMH, Oude-Alink S, van Herwaarden AE, et al. Glucocorticoid activity of adrenal steroid precursors in untreated patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2019; 104 (11):5065–72.3. Cools M, Cheng EY, Hall J, Alderson J, Amies Oelschlager AM, Balen AH, et al. Multi-stakeholder opinion statement on the care of individuals born with differences ofsex development: common ground and opportunities for improvement. Horm ResPaediatr. 2025;98(2):226-242.