The Enigma of the Adrenarche: Identifying the Early Life Mechanisms and Possible Role in Postnatal Brain Development.

Angela L Cumberland,Margaret Zacharin,Emilio Badoer,David W Walker,Jonathan J Hirst,Ronda F Greaves,Stefan A Wudy

doi:10.3390/ijms22094296

Abstract

Dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEAS) are dynamically regulated before birth and the onset of puberty. Yet, the origins and purpose of increasing DHEA[S] in postnatal development remain elusive. Here, we draw attention to this pre-pubertal surge from the adrenal gland—the adrenarche—and discuss whether this is the result of intra-adrenal gene expression specifically affecting the zona reticularis (ZR), if the ZR is influenced by the hypothalamic-pituitary axis, and the possible role of spino-sympathetic innervation in prompting increased ZR activity. We also discuss whether neural DHEA[S] synthesis is coordinately regulated with the developing adrenal gland. We propose that DHEA[S] is crucial in the brain maturation of humans prior to and during puberty, and suggest that the function of the adrenarche is to modulate, adapt and rewire the pre-adolescent brain for new and ever-changing social challenges. The etiology of DHEA[S] synthesis, neurodevelopment and recently described 11-keto and 11-oxygenated androgens are difficult to investigate in humans owing to: (i) ethical restrictions on mechanistic studies, (ii) the inability to predict which individuals will develop specific mental characteristics, and (iii) the difficulty of conducting retrospective studies based on perinatal complications. We discuss new opportunities for animal studies to overcome these important issues.

Highlights

The intention of this article is to discuss the possible physiological mechanisms that initiate and support the hormonal changes that characterize adrenarche in humans and some non-human primates
There is a possibility that adrenarche results primarily from an intra-adrenal maturational event—i.e., changes intrinsic to the genetic maturation of the adrenal gland—as recently suggested [12]. What exactly are these processes, and how do they involve the zona reticularis (ZR)? Do they involve changes in gene expression upstream of the genes that directly produce the proteins for steroid synthesis, or by interactions with paracrine growth factors synthesized within the adrenal cortex (e.g., IGFs, FGFs, TGFβ) that promote or inhibit enzyme activity in the ZR preferentially to the other cortical zones [18]?
It remains unclear whether the guinea pig undergoes adrenarche-like changes in these androgens during postnatal maturation, and if the spiny mouse—which does have a pre-pubertal surge of peripheral DHEA [24]— synthesizes and releases the 11-oxygenated androgens known to be associated with adrenarche in children

Summary

Introduction

The intention of this article is to discuss the possible physiological mechanisms that initiate and support the hormonal changes that characterize adrenarche in humans and some non-human primates. Our objective is to suggest how the fundamental mechanisms that lead to the remarkable increase of steroidogenesis in the adrenal cortex in early life can be identified, and to determine what the coordinate changes in the adrenal gland and brain might be. The increased secretion of adrenal androgens that essentially defines adrenarche is thought to modulate brain development, both before and after puberty [10], suggesting a role for adrenarche in determining sex-dependent, post-pubertal behavior and phenotype. These early-life endocrinal changes are widely considered to essentially be a human phenomenon, with only some higher-order primates undergoing a similar developmental change [11,12]—see further discussion below. The following discussion is designed to review our current knowledge in relation to these questions and highlight areas that require increased knowledge to enable translation into clinical care

Production of DHEA

Steroids

Why Is This Important?

A New Approach to an Old Problem

Conclusions