Understanding Zona Reticularis Function and Its Transformation by Adrenarche
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109 EDITORIAL In the zone: understanding zona reticularis function and its transformation by adrenarche Ian M Bird Perinatal Research Laboratories, Department of Obstetrics and Gynecology, University of Wisconsin–Madison, 7E Meriter Hospital/Park, 202 South Park Street, Madison, Wisconsin 53715, USA (Correspondence should be addressed to I M Bird; Email: [email protected]) Abstract The human adrenal cortex comprises three distinct zones we are in our current understanding of what adrenarche is, with unique steroid products, namely the zona glomerulosa, and indeed if it is unique to humans at all. Furthermore, these which secretes the mineralocorticoids, the zona fasciculate, reviews describe what is also known of how the functional which secretes the glucocorticoids and the zona reticularis ZR emerges during adrenarche and what steroids of (ZR), which at adrenarche, begins to produce the so-called physiologic relevance result beyond the widely known adrenal androgens. Of all the adrenal zones, we still DHEA and DHEAS elevated at this time. Such advances in understand control of ZR emergence the least, and yet the human, primate and indeed stem-cell biology are clearly consequences of such dysregulation can be devastating. laying the foundation for new directions in the hunt for the Premature adrenarche is a growing problem and the factors involved in the regulation and functional emergence of correspondingly inappropriate emergence of ZR function a ZR at the appropriate time, as well as insight into how they can negatively influence puberty and lead to adult infertility. may fail. Given support for these new directions, considerable Our understanding is limited and more needs to be done. The progress can clearly be made. purpose of these three reviews is to provide a survey of where Journal of Endocrinology (2012) 214, 109–111 A classic feature of the mammalian adrenal cortex is its distinct reticularis (ZR) are also age dependent in vivo and the exact histologic zonation. Studies over many decades have further mechanisms are far from clear. A fully functional ZR requires shown that, beyond each zone having a unique function, the conditions of high CYP17 combined with low HSD3B2 and centrepetal migration theory says the three zones are in fact also CytB5 expression. It is also important to note that while formed by a single cell that initiates somewhere in the region ACTH is the primary driving force for cortisol production of the capsule and migrates to the medullary junction, from the ZF and this cortisol in turn delivers clear feedback to changing its phenotype as it goes. This of course has echoes of the hypothalamus–pituitary to prevent over secretion of stem-cell biology, and even before pluripotent stem cells were ACTH, the ZR can also respond to ACTH (as well as other isolated, it was known that transformation of an adreno- factors such as CRH) without providing a comparable cortical cell from one zonal phenotype to another is at least feedback response given the major ZR products are DHEA in part under endocrine control. Zona glomerulosa (ZG) cells and DHEAS. At first glance, the system seems poorly are devoid of any detectable CYP17 (CYP17A1; Fig. 1) and designed, with the clear possibility that over activity or C are most responsive to the Ca2 -mobilizing hormones such premature activity has no checks and balances in the form of a C as angiotensin II (AII) and indeed K , while the zona feedback mechanism. It is thus no surprise that dysfunction fasciculate (ZF) cells are more driven by ACTH and, through can indeed occur and, while not lethal, mistimed early associated increases in cAMP, become CYP17 positive. Who development of ZR capacity to make abundant DHEA can in wins the battle between ACTH and AII in particular for turn lead to inappropriate and unopposed hyperandrogenism. influence over the cells defines the resulting phenotype, and As the normal compartmentalization of adrenal and gonadal this can be recapitulated in the H295R cell model (reviewed C19 steroidogenesis (Conley & Bird 1997) breaks down, in Bird et al. (1998)). Nonetheless, the endocrine events that reproductive disruption can result. Of all the adrenal zones, regulate further transformation of the ZF to a functional zona we still understand control of ZR emergence the least, and Journal of Endocrinology (2012) 214, 109–111 DOI: 10.1530/JOE-12-0246 0022–0795/12/0214–109 q 2012 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 10/03/2021 01:10:20AM via free access 110 I M BIRD . In the zone: adrenarche CYP17 Other ZR Pathway Components phenotypes but also the ZR phenotype in humans. This question remains stubborn to dissection; while transplantation C of human cells to mice hosts yields steroidogenically ZG functional structures, the transplantation has not yet yielded HSD3B2 positive, CytB5 low, a completely zonal structure comprising ZG, ZF, and ZR. SULT2A1 none Likewise, expressions of adrenal-related transcriptional factors ZF in pluripotent stem-cell lines have succeeded in directing HSD3B2 positive, CytB5 low, steroidogenic pathway expression to some degree but have SULT2A1 none not yet recapitulated zonal adrenocortical function in vivo. Nonetheless, progress is being made and Hornsby (2012) discusses in detail how further transcription factors such as ZR Pre-adrenarche: HSD3B2 positive, GATA6 (known to be associated with ZR function) could be CytB5 low, SULT2A1 low prime candidates for targeted expression in these new cell Post Adrenarche: HSD3B2 low systems. CytB5 high, SULT2A1 high Beyond humans, there is also longstanding debate on M whether adrenarche is also a widespread event that occurs Figure 1 Rhesus adrenal zonation and distribution of ZR-specific across all primates. In 2012, Hornsby introduces his review steroidogenic enzymes and cofactors known to change in with the classic view that, beyond humans, only a limited adrenarche. The image shows a cross section of a mature rhesus number of primates also undergo adrenarche. By contrast, adrenal stained for CYP17 (Peterson et al. 2001). Staining for CYP17 is indicated by brown color and zones ZG, ZF, and ZR are marked. Conley et al. (2012) put forward the emerging evidence that Width of each zone is also indicated by brackets. C indicates the the occurrence of adrenarche is far more widespread among capsular layer and M indicates the medulla. Alongside each zone is nonhuman primates. Indeed, Conley et al. (2012) argue what a further description of the presence or absence of HSD3B2, CytB5, is variable is not if it occurs, but when it occurs, and the and SULT2A1 in each zone of the adrenal and the pre- and post-adrenarche levels respectively. Alterations in these combined reason this has often been missed is that the period of proteins at the time of adrenarche give rise to dramatic increases in DHEA/DHEAS ‘quiescence’ between the regression of the the clinical markers DHEA and DHEAS. fetal zone and emergence of the functional ZR is highly variable. In certain cases, the events of fetal zone (FZ) still the consequences of such dysregulation are devastating. regression and ZR emergence may even be so close as to Clearly more needs to be done. The purpose of these three appear to overlap and so circulating DHEA does not disappear reviews (Hornsby 2012, Conley et al. 2012, Rege & Rainey during the functional transition. This is not just a trivial 2012) is to provide an up to date survey of where we are in our debate of purely academic relevance, it has direct relevance to understanding of how the functional ZR emerges and what progression of the field as a whole. Many other research steroids of physiologic relevance result from the progression of studies in general are undertaken each year in rats and mice normal and indeed abnormal adrenarche. The good news is that one could argue have little or no relevance to humans, progress in several areas provides a basis for advances on and yet the overwhelming argument to do so often revolves multiple fronts in the near future. around the time to maturity and so option for rapid While the overall concept of adrenal centripetal migration developmental and indeed trans-generational studies. Rats and the corresponding need to alter phenotypic function in and mice lack CYP17 expression completely while many each zone is readily understandable, the molecular endocrine other mammals lack ZR function, and only humans and details remain elusive. There have been many debates that a nonhuman primates express a FZ during development single ‘stem-cell layer’ exists and this began with observations (Conley & Bird 1997). This gives us few choices for of a zona intermedia layer of cells located between the ZG and experimental models to study ZR function. If adrenarche is ZF that does not stain for either zone (neither AT1R positive indeed more widespread than initially reported, then not only (ZG) or CYP17 positive (ZF)). Examples of such obser- would comparative studies between primate species be of vations in mammalian species as diverse as the marmoset (Bird relevance, but primate models that reach a functional ZR in & Pattison 2004) and the sheep (Peterson et al. 2001) are !1 year and maturity by 18 months offer further options for intriguing, but in themselves they do not provide proof of controlled trans-generational study of endocrine disruptor adrenal stem cells. Early studies by Morley et al. (1996) using effects in utero and during early life that would not be possible B-Gal reporter under the control of the CYP21 (CYP21A2) in humans. The argument by Conley et al. (2012) that promoter in heterozygous mice demonstrated clearly the adrenarche occurs in a wider list of nonhuman and human directional migration of cells of a single lineage from the primates than has previously been acknowledged is thus not outside to the inside of the adrenal cortex.