Development and Clinical Significance of the Human Fetal Adrenal Gland as a Key Component of the Feto-Placental System: A Systematic Review

Background: The human fetal adrenal gland is a unique endocrine organ with distinct morphology and functional dynamics, which is significantly different from the postnatal adrenal. Its rapid growth and vital steroidogenic role during gestation have positioned it as a key regulator of fetal development and pregnancy maintenance. Objectives: To provide a comprehensive overview of the morphogenesis, function, regulatory mechanisms, and clinical implications of the human fetal adrenal gland, highlighting recent advances in understanding its development and its role in prenatal and postnatal health outcomes. Methods: A systematic review was conducted, including original research articles focused on human fetuses or validated animal models, examining the genetic, molecular, and hormonal mechanisms underlying adrenal development and function. Studies were excluded if they were editorials, case reports, focused on adult adrenal physiology, had small sample sizes, or were non-English publications. Study quality was evaluated using PRISMA guidelines. Results: The fetal adrenal gland develops from both mesodermal and ectodermal origins, forming three primary zones: fetal, transitional, and definitive. Each zone has distinct functions and developmental pathways. The fetal zone, which predominates, is responsible for producing dehydroepiandrosterone sulfate, DHEA-S, which is crucial for placental estrogen synthesis. The adrenal gland undergoes rapid growth and functional maturation, regulated by ACTH, placental CRH, IGF, and the renin–angiotensin system. Disruption of adrenal function is associated with conditions such as preterm birth, adrenal hypoplasia, congenital adrenal hyperplasia, and intrauterine growth restriction. Emerging evidence suggests that fetal adrenal hormones may influence long-term health through fetal programming mechanisms. Conclusions: The fetal adrenal gland plays a critical and multifaceted role in fetal and placental development. This gland influences placental development via steroid precursors (DHEA-S → estrogen synthesis), while also being regulated by placental factors such as the corticotropin-releasing hormone. Understanding its complex structure–function relationships and regulatory networks is essential for predicting and managing prenatal and postnatal pathologies. Future research should focus on elucidating molecular mechanisms, improving diagnostic tools, and exploring long-term outcomes of altered fetal adrenal function.