Development and Function of the Human Fetal Adrenal Cortex: A Key Component in the Feto-Placental Unit

Abstract

Continuous efforts have been devoted to unraveling the biophysiology and development of the human fetal adrenal cortex, which is structurally and functionally unique from other species. It plays a pivotal role, mainly through steroidogenesis, in the regulation of intrauterine homeostasis and in fetal development and maturation. The steroidogenic activity is characterized by early transient cortisol biosynthesis, followed by its suppressed synthesis until late gestation, and extensive production of dehydroepiandrosterone and its sulfate, precursors of placental estrogen, during most of gestation. The gland rapidly grows through processes including cell proliferation and angiogenesis at the gland periphery, cellular migration, hypertrophy, and apoptosis. Recent studies employing modern technologies such as gene expression profiling and laser capture microdissection have revealed that development and/or function of the fetal adrenal cortex may be regulated by a panoply of molecules, including transcription factors, extracellular matrix components, locally produced growth factors, and placenta-derived CRH, in addition to the primary regulator, fetal pituitary ACTH. The role of the fetal adrenal cortex in human pregnancy and parturition appears highly complex, probably due to redundant and compensatory mechanisms regulating these events. Mounting evidence indicates that actions of hormones operating in the human feto-placental unit are likely mediated by mechanisms including target tissue responsiveness, local metabolism, and bioavailability, rather than changes only in circulating levels. Comprehensive study of such molecular mechanisms and the newly identified factors implicated in adrenal development should help crystallize our understanding of the development and physiology of the human fetal adrenal cortex.

The influence of maternal cortisol and emotional state during pregnancy on fetal intrauterine growth

“…Due to the lack of expression of type 2 3β-hydroxysteroid dehydrogenase/Δ 4-5 isomerase, a crucial enzyme in the biosynthesis of cortisol, de novo cortisol biosynthesis appears to be suppressed until late gestation when cortisol production escalates. Mounting evidence indicates that cortisol may act as a "two-edged sword" for the fetus: it can promote maturation of fetal organs necessary for extra-uterine life, but it can also influence adversely fetal growth and postnatal development (26).…”

PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal

“…From the 10th week of gestation, the fetal adrenal cortex is divided into two distinct zones, the outer definitive zone, which remains minimally active until the end of the second trimester, and a large inner fetal zone. The fetal zone expresses CYP17, an enzyme that enables the synthesis of large amounts of dehydroepiandrosterone (DHEA)/DHEA sulfate (DHEAS), which serve as estrogen precursors for the placenta (1,2). Soon after birth, the outer definitive zone differentiates into zG and zF, while the inner fetal zone undergoes a marked involution with a corresponding decrease in adrenal androgen levels.…”

The Relationship between Umbilical Cord Estrogens and Perinatal Characteristics

“…The placenta is a highly steroidogenic organ responsible for the production of large amounts of free and conjugated estrogens from fetal adrenal precursors (15). 17b-estradiol (E2) is the most bioactive estrogen.…”