Endocrine Abstracts

Adrenal insufficiency (AI) is a life-threatening endocrine disorder arising from insufficient adrenal hormone production. Congenital adrenal hyperplasia (CAH), most commonly caused by 21-hydroxylase (CYP21A2) deficiency, which accounts for over 90–95% of CAH cases, represents the predominant etiology of primary adrenal insufficiency in pediatric populations. Standard of care relies on lifelong glucocorticoid and mineralocorticoid replacement, yet this approach fails to recapitulate the circadian rhythmicity and stress-responsive dynamics of endogenous adrenal hormone secretion. The consequent inadequacy of hormonal control predisposes patients to adrenal crises, impairs linear growth and metabolic homeostasis, and substantially diminishes quality of life, collectively underscoring the urgent need for innovative, physiologically faithful treatment modalities. Recent advances in regenerative medicine have enabled the directed differentiation of human induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) into fetal zone adrenocortical-like cells, a process guided by Sonic Hedgehog (SHH) signaling and the master steroidogenic transcription factor NR5A1/SF-1. In parallel, mouse ESCs have been successfully differentiated in vitro in three-dimensional (3D) cultures into adrenocortical-like cells that exhibit both angiotensin II- and ACTH-responsive steroidogenesis, recapitulating fundamental features of adrenal cortex physiology. Complementary advances in 3D human adrenocortical organoid systems have yielded expandable platforms that maintain zona fasciculata identity and sustain cortisol production. Encapsulation technologies, most notably alginate-based constructs housing bovine or porcine adrenocortical cells, afford immunoisolation and sustained hormone secretion, with successful reversal of adrenal insufficiency demonstrated in rodent models. For CAH, iPSC-derived human induced steroidogenic cells (hiSCs) from patients accurately model disease phenotypes, including hypocortisolism, which can be corrected ex vivo by lentiviral delivery of wild-type CYP21A2, restoring physiological steroid profiles. CRISPR/Cas9-mediated gene correction of CYP21A2 in patient-derived cells is advancing in preclinical studies, with lipid nanoparticle delivery strategies targeting adrenocortical progenitors. These novel cell and gene therapy strategies hold transformative promise for the treatment of adrenal insufficiency and CAH, aiming to restore autonomous, regulated adrenal hormone production and potentially obviate the need for lifelong hormone replacement. Key challenges remain, including durable engraftment, immune compatibility, physiological regulation, and scalability, but ongoing research is rapidly advancing the field toward functional cures that could fundamentally alter disease management and patient outcomes.