Development of adrenal cortex zonation.

The human adult adrenal cortex is composed of the zona glomerulosa (zG), zona fasciculata (zF), and zona reticularis (zR), which are responsible for production of mineralocorticoids, glucocorticoids, and adrenal androgens, respectively. The final completion of cortical zonation in humans does not occur until puberty with the establishment of the zR and its production of adrenal androgens; a process called adrenarche. The maintenance of the adrenal cortex involves the centripetal displacement and differentiation of peripheral Sonic hedgehog-positive progenitors cells into zG cells that later transition to zF cells and subsequently zR cells.

Sonic hedgehog signaling during adrenal development.

It has been speculated for a number of years that Sonic hedgehog (Shh) signaling plays an important role in adrenal development. Over the past two years several reports have described the expression and function of Shh pathway genes in the adrenal cortex, using primarily mouse models. The key findings are that Shh signals produced by a population of partially differentiated cortical cells located in the outer cortex/zona glomerulosa are received by non-cortical mesenchymal cells located predominantly in the overlying capsule. This signal is required for growth of both the capsule and the cortex, but not for cortical zonation or steroidogenic cell differentiation. Using molecular genetic tools to define the adrenocortical cell lineages that are descended from both Shh signaling and receiving cells, both capsule and cortical cells were found to have properties of adrenocortical stem and/or progenitor cells. Here we place these observations within the context of prior studies on adrenal development, postnatal adrenal maintenance and adrenocortical stem/progenitor cell lineages.

Prenatal development of the adrenal gland in the one-humped camel (Camelus dromedarius).

UNLABELLED: With 14 figures and 3 tables SUMMARY: Each adrenal gland consisted of cortex and medulla that developed from different embryological origins and presented different cellular organization. One hundred male or female camel embryos or fetuses with crown vertebral rump lengths (CVRL) that ranged from 0.8 to 117 cm were examined. The adrenal cortex, which is derived from intermediate mesoderm, was first observed in the 0.8-cm CVRL camel embryo. The adrenal cortex initially was combined with the gonad as a thickened region of proliferating cells derived from splanchnic intermediate mesoderm. Adrenocortical tissue was first separated from the gonadal tissue in the 2-cm CVRL camel fetus and was observed as a separate dorso-medial mass of cells. At 2.5-cm CVRL, the adrenocortical tissue was surrounded by a capsule of undifferentiated mesenchymal cells, except at its proximal pole, where an invagination was located through which chromaffinoblast cells entered the cortex. The chromaffinoblast cells migrated from the neural crest to form the medulla of the developing adrenal gland. In the 3.5-cm CVRL camel fetus, the adrenocortical cells differentiated into two layers: the inner fetal cortex and the outer definitive cortex. As development proceeded, the fetal cortex degenerated and the definitive cortex formed the zona glomerulosa and zona fasciculata. The zona reticularis did not form until the end of gestation. During prenatal life, the adrenal medulla was much thicker than the cortex.

Development of functional zonation in the rat adrenal cortex.

In an attempt to elucidate the mechanism(s) through which the functional adrenal cortex is established, we analyzed immunohistochemically the expression of various markers for the adrenocortical zones, i.e. the zona glomerulosa (zG), the zona fasciculata (zF), and the zona reticularis (zR), as well as markers for the medulla, and further examined the distribution and behavior of DNA-synthesizing cells in rat adrenal glands during development. The results showed that 1) separation of the cortex and medulla, and the development of functional zonation in the cortex began at around the time of birth, 2) at fetal stages when cortical zonation was not established, DNA-synthesizing cells were found scattered throughout the gland, where they proliferated without significant migration, and 3) after birth in the adrenal cortex with established cortical zonation, DNA-synthesizing cells were localized near the undifferentiated zone between zG and zF, and then they migrated centripetally. Cell death appeared to occur in the innermost portion of the cortex, where many resident macrophages are present. These findings illustrate basic processes underlying adrenal development and suggest that the undifferentiated region is apparently the stem cell zone of the adrenal cortex that maintains the cortical zonation.

Comparative stereological study on zonation and cellular composition of adrenal glands of normal and anencephalic human fetuses. I. Zonation of the gland.

Comparative stereological studies were performed on zonation of adrenal glands in 10 anencephalic and 11 normal fetuses, aged between 24 and 39 postovulatory weeks. The development of adrenal fetal zone (FZ) is the main factor responsible for normal adrenal gland growth during the intra-uterine life. At the end of fetal period volume of this zone attains over 8200 mm3 and constitutes 69-70% of the total gland volume, while respective values for zona glomerulosa (ZG), zona fasciculata (ZF) and medulla (M) are 1665 mm3 (14%), 833 mm3 (7%) and 1071 mm3 (9%). These data were in striking contrast with those found in adrenals of anencephalic fetuses, in which volume of the gland attained only ca 35% of that in normal fetuses. In the oldest anencephalic fetus studied (39 weeks) the volume of the fetal zone was 962 mm3 (ca 8-folds lower than in normal fetus) comprising only 25% of the total gland volume. For the remaining zones the values were: ZG-1501 mm3 (ca 90% of the normal value and 39% of the total gland volume); ZF-770 mm3 (ca 92% and 20% respectively), and M-539 mm3 (ca 50% and 14%, respectively). This stereological study provides the first systemic description of the development of adrenal gland of anencephalic fetuses in comparison with the normally developing gland. Moreover, evidence is given that the growth of adrenal medulla is also retarded in anencephaly while the growth of the zona glomerulosa remains rather unaffected.

Comparative stereological studies on zonation and cellular composition of adrenal glands of normal and anencephalic human fetuses. II. Cellular composition of the gland.

In our previous paper (Bocian-Sobkowska et al., 1997) we demonstrated a striking difference in development of zonation in adrenals of normal and anencephalic human fetuses. The purpose of the present study was to characterize, by means of stereology, the cellular composition of developing adrenals in the same case. Studies were performed on 11 pairs of adrenal glands from normal fetuses and 10 from anencephalic fetuses. In the studied period of development (24 to 39 weeks of intra-uterine life) the average volume of cells in normal glands increased as follows: zona glomerulosa (ZG) from 355 to 870 microns3; zona fasciculata (ZF) from 779 to 1200 microns3; fetal zone (FZ) from 2004 to 2380 microns3: and medulla (M) from 600 to 970 microns3. In anencephalic fetuses, the appropriate values were: ZG-380-680 microns3; ZF-460-680 microns3; FZ-1820-1680 microns3; and M-870-1400 microns3. At the end of the studied period the number of ZG cells in normal fetuses was two fold higher than in anencephalics, ZF cells-6-fold and in FZ-5-fold higher, while in the M the number of cells was nearly equal in both groups. During the whole investigated period of intra-uterine development the total number of adrenocortical cells in normal glands increased ca 2.5-fold, while in anencephalic glands only ca 0.5-fold, reaching at the end ca 40% of normal value. In both normal and anencephalic adrenals the number of ZG and M cells was highly correlated with ZG/M cell ratio, being slightly higher in normal glands. No such relation was demonstrated for cells of the remaining adrenocortical zones.

Cytological aspects of the human adrenal cortex development in the course of intra-uterine life.

Stereological studies were performed on 20 pairs of adrenal glands of human foetuses. The volume of particular adrenocortical zones, average cell volume and number of parenchymal cells were calculated. In 50 to 320 mm crown-rump length (C.-R.L.) foetuses (9-38 weeks of the intra-uterine life) an exponential increase in adrenal gland weight was found. If compared with the earlier period, the rate of increase was evidently higher beginning from the 20th week and depended mainly upon enlargement of the foetal zone, with less marked changes in the glomerulosa-fasciculata zone. The zona glomerulosa (ZG) and the outer zona fasciculata (ZF) began to delineate by the 20th week of gestation. Zona reticularis was not observed in our material. From the beginning of development, fasciculata cell volume was markedly higher than that of ZG cells and lower than foetal zona (ZX) cells. Until the 20th week of intra-uterine life the volume of glomerulosa-fasciculata zone (G-FZ) increased at a slow rate, while the rate of increase in volume of ZX was higher. After 20 weeks the rate of increase in volume of all adrenocortical zones was markedly higher (the same as that of the stroma). The volume of stroma in ZX markedly exceeded that in the remaining parts of the cortex. The average cell volume of ZG and ZF remained constant during the foetal period, while the average cell volume of ZX cells increased gradually from the 9th to the 20th foetal week and afterwards remained unchanged. (ABSTRACT TRUNCATED AT 250 WORDS)

Human fetal adrenal definitive and fetal zone metabolism of pregnenolone and corticosterone: alternate biosynthetic pathways and absence of detectable aldosterone synthesis.

In the rhesus monkey and ovine fetus in utero, aldosterone concentrations do not rise in response to surgical stress, ACTH, or angiotensin-II, all of which are secretagogues for this mineralocorticoid in the adult. To assess the mechanism of this phenomenon in the human fetus, metabolism of pregnenolone and corticosterone by second trimester human fetal adrenal definitive zone and fetal zone tissue was studied. After incubation of fresh tissue with trace amounts of [3H]pregnenolone or [3H]corticosterone, the products of metabolism were separated using high performance liquid chromatography and quantified. The delta 5-3 beta-hydroxysteroids 17-hydroxypregnenolone and dehydroepiandrosterone and their sulfates comprised 85-90% of metabolized pregnenolone. In the fetal zone, cortisol was the predominant secreted delta 4-3-ketosteroid, accounting for 6-8% of the metabolized pregnenolone. In the definitive zone, progesterone and corticosterone were the predominant secreted delta 4-3-ketosteroids, each accounting for about 2% of the metabolized pregnenolone. 11-Dehydrocorticosterone and sulfates were the only metabolites detected after incubation of fetal adrenal tissue with corticosterone. 11-Dehydrocorticosterone accounted for more than 80% of the metabolized corticosterone in the definitive zone and 50% in the fetal zone. Incubations with secretagogues or antioxidants (10 nmol/L ACTH, 10 nmol/L angiotensin-II, 21 mmol/L potassium, 100 mmol/L dimethylsulfoxide, 5 mumol/L metyrapone, or 100 mumol/L butylated hydroxyanisole) did not change the pattern or extent of precursor metabolism. No aldosterone, 18-hydroxycorticosterone, or 18-hydroxydeoxycorticosterone was detected in baseline or stimulated incubations of human fetal tissue. In contrast, adult human zona glomerulosa metabolized corticosterone to aldosterone, 18-hydroxycorticosterone, and 11-dehydrocorticosterone under similar conditions.(ABSTRACT TRUNCATED AT 250 WORDS)