ESPE Yearbook of Paediatric Endocrinology

Brief summary: This review covers the recent advances in the understanding of fetal adrenal development and the interplay with the feto-placental unit. A short overview of related adrenal disorders is presented. The effect of other hormone systems is also discussed and the reliability of using rodent models to study adrenal pathophysiology.

Structural development of the fetal adrenal and its transition to the adult organ: There are differences in the development of the human and mouse fetal adrenal. The human fetal adrenal anlage/primordium (AP) is formed in parallel with the genital primordium (GP), the former in the anterior coelomic epithelium at 30 dpc, and the latter in the posterior coelomic epithelium at 33 dpc. In mouse, there is first a common AGP at E9.0 that expresses WT1, GATA4 and CITED2. At E10.5 there is a split to the mouse AP and GP, where WT1 is suppressed in the AP. In human, the adrenal precursors are devoid of GATA4 and have low expression of CITED2, but as in mouse have a strong expression of SF1 (stimulated by WT1). Contrary to WT1, CITED2 and GATA4, whose expressions in steroidogenic cells are confined to embryonic stages, SF1 is expressed in both embryonic and postnatal adrenals in mouse and human. It acts as a master regulator of the transcription of cytochrome P450 steroid hydroxylases involved in steroidogenesis. In mouse, high SF1 expression is needed for proper adrenal development, while sex determination and the gonadal development are not affected by SF1 haploinsufficiency. This suggests that gonadal specification in mouse relies on a threshold of SF1 expression, whereas high SF1 levels are associated with the development of adrenocortical cells. In humans, gonadal development and function is more commonly affected than adrenal function even in SF1 haploinsufficiency.

At around 48-52 dpc in human (E12.5 in the mouse) a subset of neural crest cells invades the AP to form the chromaffin cells and form the adrenal medulla. At this stage the adrenal capsule forms from mesenchymal cells surrounding the AP and the adrenal anlage stratifies into an outer definitive zone and an inner fetal zone. The middle transitional zone develops during mid-gestation. The fetal zone disappears by apoptosis after birth and there is a rapid fall in DHEA and DHEAS. The definitive zone and the transitional zone give rise to the adult adrenal cortex. In mouse, inherent proliferation of adrenocortical cells and recruitment of progenitor cells from the capsule that migrate towards the center of the cortex maintain the adrenocortical cellularity and the progenitors differentiate into cells of the steroidogenic lineage. To conclude, the structural features of the fetal adrenal are outlined by gestational week 8, while the steroidogenic production during fetal stage changes throughout gestation to support the development of the fetus.

Fetal adrenal function and its role in the feto-placental unit: The fetal steroidogenesis is a combined contribution of the fetal adrenal, the 46, XY gonad, the placenta and the shuttling of steroids from the mother. The fetal zone produces DHEAS from cholesterol and is converted in the placenta to androstenedione (A4), estrone (E1) and estradiol (E2). E1 and E2 enter the maternal circulation. Maternal DHEA(S) also contributes to placental estrogen biosynthesis. Estrogens, GC and PROG are metabolized by the feto-placental unit and regulate fetal development. Fetal cortisol is produced from placental PROG by GW8-10 (post conception) together with de novo cortisol production from the fetal adrenal by GW8-14. The Leydig cells synthesize testosterone (T) from cholesterol and T and DHT bind to the AR (expressed 8-20 wpc) in the testis and initiate the differentiation of male external genitalia. The C11-oxy androgens (11OHA4, 11KA4, 11KT) are produced in the so called back-door pathway via fetal origin of 11OHA4 and its conversion in the placenta to 11KA4 and 11KT. PROG, allopregnanolone and androsterone are produced in the placenta. PROG is the precursor to the back-door pathway. DHT is produced from PROG and 17OHP via catalytic pathways in the fetal liver, fetal adrenal, fetal genital skin and the placenta. The feed-back between placental CRH and fetal adrenal cortisol is essential for parturition and fetal organ maturation. Prior to parturition there is an increase in cortisol in amniotic fluid due to an increase of 11bHSD1 activity in placenta, amnion and chorion.