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Reviews in Endocrine & Metabolic... Mar 2009The origin of circulating DHEA and adrenal-derived androgens in humans and nonhuman primates is largely distinct from other mammalian species. In humans and many Old... (Review)
Review
The origin of circulating DHEA and adrenal-derived androgens in humans and nonhuman primates is largely distinct from other mammalian species. In humans and many Old world primates, the fetal adrenal gland and adult zona reticularis (ZR) are known to be the source for production of DHEA (and DHEAS) in mg quantities. In spite of similarities there are also some differences. Herein, we take a comparative endocrine approach to the diversity of adrenal androgen biosynthesis and its developmental timing in three primate species to illustrate how understanding such differences may provide unique insight into mechanisms underlying adrenal androgen regulation and its pathophysiology in humans. We contrast the conventional developmental onset of adrenal DHEA biosynthesis at adrenarche in humans with (1) an earlier, peri-partutrition onset of adrenal DHEA synthesis in rhesus macaques (Old World primate) and (2) a more dynamic and reversible onset of adrenal DHEA biosynthesis in female marmosets (New World primate), and further consider these events in terms of the corresponding developmental changes in expression of CYP17, HSD3B2 and CYB5 in the ZR. We also integrate these observations with recently described biochemical characterization of CYP17 cDNA cloned from each of these nonhuman primate species and the corresponding effects of phosphorylation versus CYB5 coexpression on 17,20 lyase versus 17-hydroxylase activity in each case. In addition, female rhesus macaques exposed in utero to exogenous androgen excess, exhibit symptoms of adrenal hyperandrogenism in adult females in a manner reminiscent of that seen in the human condition of PCOS. The possible mechanisms underlying such adrenal hyperandrogenism are further considered in terms of the effects of altered relative expression of CYP17, HSD3B2 and CYB5 as well as the altered signaling responses of various kinases including protein kinase A, or the insulin sensitive PI3-kinase/AKT signaling pathway which may impact on 17,20 lyase activity. We conclude that while the triggers for the onset of ZR function in all three species show clear differences (age, stage of development, social status, gender), there are still common mechanisms driving an increase in DHEA biosynthesis in each case. A full understanding of the mechanisms that control 17,20 lyase function and dysfunction in humans may best be achieved by comparative studies of the endocrine mechanisms controlling adrenal ZR function and dysfunction in these nonhuman primate species.
Topics: Adrenal Cortex; Androgens; Animals; Callithrix; Dehydroepiandrosterone; Female; Fetus; Humans; Macaca mulatta; Male; Pregnancy; Primates
PubMed: 18683055
DOI: 10.1007/s11154-008-9099-8 -
Proceedings of the National Academy of... Dec 2018The adrenal gland is a master regulator of the human body during response to stress. This organ shows constant replacement of senescent cells by newly differentiated...
The adrenal gland is a master regulator of the human body during response to stress. This organ shows constant replacement of senescent cells by newly differentiated cells. A high degree of plasticity is critical to sustain homeostasis under different physiological demands. This is achieved in part through proliferation and differentiation of adult adrenal progenitors. Here, we report the isolation and characterization of a Nestin population of adrenocortical progenitors located under the adrenal capsule and scattered throughout the cortex. These cells are interconnected with progenitors in the medulla. In vivo lineage tracing revealed that, under basal conditions, this population is noncommitted and slowly migrates centripetally. Under stress, this migration is greatly enhanced, and the cells differentiate into steroidogenic cells. Nestin cells cultured in vitro also show multipotency, as they differentiate into mineralocorticoid and glucocorticoid-producing cells, which can be further influenced by the exposure to Angiotensin II, adrenocorticotropic hormone, and the agonist of luteinizing hormone-releasing hormone, triptorelin. Taken together, Nestin cells in the adult adrenal cortex exhibit the features of adrenocortical progenitor cells. Our study provides evidence for a role of Nestin cells in organ homeostasis and emphasizes their role under stress. This cell population might be a potential source of cell replacement for the treatment of adrenal insufficiency.
Topics: Adaptation, Physiological; Adrenal Cortex; Adrenocorticotropic Hormone; Animals; Cell Differentiation; Cells, Cultured; Homeostasis; Mice; Stem Cells; Stress, Physiological
PubMed: 30514817
DOI: 10.1073/pnas.1814072115 -
Journal of Anatomy Apr 1996Although many hypotheses concerning cell proliferation and renewal in the adrenal cortex of mammals have been proposed, this topic has so far not been elucidated....
Although many hypotheses concerning cell proliferation and renewal in the adrenal cortex of mammals have been proposed, this topic has so far not been elucidated. Adrenocortical cells of adult mammals have low proliferative activity and take a considerable length of time to be renewed. This makes it difficult to investigate the dynamic features of their proliferation. To clarify the cell kinetics, we undertook a long term study in mice using an autoradiographic technique. We radiolabelled almost all the cells throughout the body in newborn mice with the exception of the neurons in central nervous system by the frequent subcutaneous injections of [3H]thymidine every 6 h for 30 d (pulse labelling). After this sequence of pulse labelling, we observed autoradiographically a decrease in the number of 3H-labelled cells in the adrenal cortex as a result of replacement with proliferated unlabelled cells (renewed cells). Single injections of [3H]thymidine (flash labelling) was also performed to examine DNA synthesis in the adrenal cortex. The investigations indicated that the adrenocortical cells proliferate at the border between the zona glomerulosa and the zona fasciculata, and that renewed cells which proliferated in that region move with time bidirectionally towards the cortical surface and the inner (medullary) surface. Half of the cortical cells in the zona glomerulosa, zona fasciculata and zona reticularis were replaced by renewed cells in 30, 60 and 120 d respectively. It took 200 d for almost all cortical cells to be replaced by renewed cells.
Topics: Adrenal Cortex; Animals; Autoradiography; Cell Division; DNA; Male; Mice; Mice, Inbred ICR; Thymidine; Time Factors
PubMed: 8621337
DOI: No ID Found -
Pathobiology : Journal of... 2007To review the existing literature for evidence that adrenocortical and adrenomedullary tumours develop through a multistep process of carcinogenesis. (Review)
Review
OBJECTIVE
To review the existing literature for evidence that adrenocortical and adrenomedullary tumours develop through a multistep process of carcinogenesis.
RESULTS
In the adrenal cortex hyperplasia and adenomas are frequently observed tumours or tumour-like conditions. In contrast, adrenocortical carcinomas are rare. Based on well-validated histopathological scoring systems, benign and malignant adrenocortical tumours can be separated, although a small subset of tumours remains hard to classify. Although extensive follow-up studies might argue against multistep carcinogenesis, analysis of chromosomal imbalances and gene expression profiling studies in these tumours are inconclusive and could give support for both multistep pathogenesis or de novo genesis of carcinomas. A major limit to most of these studies is the small sample size and the lack of extensive clinical (follow-up) data. In the adrenal medulla, pheochromocytomas (PCC) are the most frequent tumours in adults, with an incidence of 8 per million. They can be divided into benign and malignant PCC, but the distinction can only be made when metastases are present. Arbitrarily, lesions of less than 1 cm in diameter are called hyperplastic, but it should be expected that the majority of these are early lesions and if left in situ would grow to classify as PCC. In contrast to cortical tumours, the frequent 1p and 3q loss as an early event in tumourigenesis of benign PCC is verified in multiple studies. However, studies in malignant PCC yield divergent results, due to the small numbers analysed.
CONCLUSION
Taken together, there appears to be a relationship between cortical and medullary hyperplasia on the one hand and cortical adenomas and PCC on the other. However, whether there is a transition from benign to malignant tumours, both cortical and medullary, remains to be determined.
Topics: Adenoma; Adrenal Cortex; Adrenal Gland Neoplasms; Adrenal Medulla; Carcinoma; Disease Progression; Humans; Hyperplasia; Precancerous Conditions
PubMed: 17890895
DOI: 10.1159/000105811 -
Polski Przeglad Chirurgiczny Jun 2018Introduction Adrenal insufficiency is a typical complication after surgical treatment of adrenal tumors, especially after the removal of both adrenal glands. Human...
UNLABELLED
Introduction Adrenal insufficiency is a typical complication after surgical treatment of adrenal tumors, especially after the removal of both adrenal glands. Human beings are not able to survive without adrenal glands and without proper hormonal substitution. Autotransplantation of a fragment of the adrenal gland may prevent this complication. This can be done by transplanting the entire adrenal glands or its fragment, such as the adrenal cortex cells. In the case of adrenal tumors, the entire adrenal gland can not be transplanted. However, it is possible to transplant cells from the tumor-free part. Succesful adrenal autografts may result in a new treatment of adrenal insufficiency.
MATERIALS AND METHODS
Autograft transplantation was performed on 3 groups of Sprague Dawley rats. In the first group, physiological corticosterone concentrations were determined. These animals were not operated. In the second group, both adrenal glands were removed. Corticosterone concentrations were determined after bilateral adrenalectomy. The third group was divided into two parts. In the first subgroup, bilateral adrenalectomy was performed simultaneosly with adrenal transplant into the omentum. In the second subgroup, right adrenalectomy was performed simultaneosly with and adrenal transplant into the omentum followed a month later by left adrenalectomy. During the experiment, corticosterone concentrations were measured at 4 time points.
RESULTS
The statistical difference between corticosterone concentrations in rats after two timed adrenalectomies and rats after bilateral adrenalectomy was statistically different, but these results were far from physiological concentrations.
Topics: Adrenal Cortex; Adrenal Gland Neoplasms; Adrenal Glands; Adrenalectomy; Animals; Autografts; Corticosterone; Disease Models, Animal; Male; Rats; Rats, Sprague-Dawley
PubMed: 30220673
DOI: 10.5604/01.3001.0011.8178 -
Molecular and Cellular Endocrinology Jun 2021Adequate access to fresh or frozen normal adrenal tissue has been a primary limitation to the enhanced characterization of the adrenal zones via RNA sequencing (RNAseq)....
Adequate access to fresh or frozen normal adrenal tissue has been a primary limitation to the enhanced characterization of the adrenal zones via RNA sequencing (RNAseq). Herein, we describe the application of targeted RNAseq to formalin-fixed paraffin-embedded (FFPE) normal adrenal gland specimens. Immunohistochemistry (IHC) was used to visualize and guide the capture of the adrenocortical zones and medulla. Following IHC-based tissue capture and isolation of RNA, high-throughput targeted RNAseq highlighted clear transcriptomic differences and identified differentially expressed genes among the adrenal zones. Our data demonstrate the ability to capture FFPE adrenal zone tissue for targeted transcriptomic analyses. Future comparison of normal adrenal zones will improve our understanding of transcriptomic patterns and help identify potential novel pathways controlling zone-specific steroid production.
Topics: Adrenal Cortex; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Paraffin Embedding; Sequence Analysis, RNA; Tissue Fixation
PubMed: 33915228
DOI: 10.1016/j.mce.2021.111296 -
Endocrine Reviews May 2009Scientists have long hypothesized the existence of tissue-specific (somatic) stem cells and have searched for their location in different organs. The theory that... (Review)
Review
Scientists have long hypothesized the existence of tissue-specific (somatic) stem cells and have searched for their location in different organs. The theory that adrenocortical organ homeostasis is maintained by undifferentiated stem or progenitor cells can be traced back nearly a century. Similar to other organ systems, it is widely believed that these rare cells of the adrenal cortex remain relatively undifferentiated and quiescent until needed to replenish the organ, at which time they undergo proliferation and terminal differentiation. Historical studies examining cell cycle activation by label retention assays and regenerative potential by organ transplantation experiments suggested that the adrenocortical progenitors reside in the outer periphery of the adrenal gland. Over the past decade, the Hammer laboratory, building on this hypothesis and these observations, has endeavored to understand the mechanisms of adrenocortical development and organ maintenance. In this review, we summarize the current knowledge of adrenal organogenesis. We present evidence for the existence and location of adrenocortical stem/progenitor cells and their potential contribution to adrenocortical carcinomas. Data described herein come primarily from studies conducted in the Hammer laboratory with incorporation of important related studies from other investigators. Together, the work provides a framework for the emerging somatic stem cell field as it relates to the adrenal gland.
Topics: Adrenal Cortex; Animals; Cell Differentiation; Clone Cells; Humans; Organogenesis; Stem Cells
PubMed: 19403887
DOI: 10.1210/er.2008-0039 -
European Journal of Endocrinology Dec 2020Endocrine Society guidelines recommend adrenal venous sampling (AVS) in primary aldosteronism (PA) if adrenalectomy is considered. We tested whether functional imaging...
OBJECTIVE
Endocrine Society guidelines recommend adrenal venous sampling (AVS) in primary aldosteronism (PA) if adrenalectomy is considered. We tested whether functional imaging of adrenal cortex with 11C-metomidate (11C-MTO) could offer a noninvasive alternative to AVS in the subtype classification of PA.
DESIGN
We prospectively recruited 58 patients with confirmed PA who were eligible for adrenal surgery.
METHODS
Subjects underwent AVS and 11C-MTO-PET without dexamethasone pretreatment in random order. The lateralization of 11C-MTO-PET and adrenal CT were compared with AVS in all subjects and in a prespecified adrenalectomy subgroup in which the diagnosis was confirmed with immunohistochemical staining for CYP11B2.
RESULTS
In the whole study population, the concordance of AVS and 11C-MTO-PET was 51% and did not differ from that of AVS and adrenal CT (53%). The concordance of AVS and 11C-MTO-PET was 55% in unilateral and 44% in bilateral PA. In receiver operating characteristics analysis, the maximum standardized uptake value ratio of 1.16 in 11C-MTO-PET had an AUC of 0.507 (P = n.s.) to predict allocation to adrenalectomy or medical therapy with sensitivity of 55% and specificity of 44%. In the prespecified adrenalectomy subgroup, AVS and 11C-MTO-PET were concordant in 10 of 19 subjects with CYP11B2-positive adenoma and in 6 of 10 with CYP11B2-positivity without an adenoma.
CONCLUSIONS
The concordance of 11C-MTO-PET with AVS was clinically suboptimal, and did not outperform adrenal CT. In a subgroup with CYP11B2-positive adenoma, 11C-MTO-PET identified 53% of cases. 11C-MTO-PET appeared to be inferior to AVS for subtype classification of PA.
Topics: Adrenal Cortex; Adult; Aged; Carbon Radioisotopes; Female; Humans; Hyperaldosteronism; Male; Middle Aged; Positron-Emission Tomography; Prospective Studies; Young Adult
PubMed: 33055298
DOI: 10.1530/EJE-20-0532 -
Quarterly Journal of Experimental... Jan 1983The effects of hypophysectomy on the cell population of the adrenal cortex has been examined with light and electron microscopy. The sensitivity of the adrenal cortical...
The effects of hypophysectomy on the cell population of the adrenal cortex has been examined with light and electron microscopy. The sensitivity of the adrenal cortical cells to exogenous ACTH in both normal and hypophysectomized fetuses has been investigated by comparing plasma cortisol concentrations with structural changes in the adrenal cortex. Hypophysectomy was carried out at about 100 d and the subsequent analysis was made at about 135 d on fetuses catheterized at least 6 d earlier. The zona fasciculata of intact fetuses contained about 25% mature and 75% immature cells at 130-136 d. After hypophysectomy this zone contained a uniform population of immature cells and no mature cells; there was a significant reduction in both adrenal weight and cortical thickness. The zona glomerulosa was unaffected by hypophysectomy. The infusion of Synacthen 0 . 25 mg/d I.V. for 48 h did not affect the zona glomerulosa but resulted in a 2-fold increase in the thickness of the zona fasciculata in hypophysectomized and intact fetuses. This cortical growth was due to both hypertrophy and hyperplasia. All the cells in the zona fasciculata were mature following Synacthen treatment in both groups. The most striking difference between the secretory response of the adrenal cortex to Synacthen in the two groups was found within 3-6 h of the onset of infusion. Within this period there was a significant increment in the plasma cortisol concentration in the intact fetuses while no response was observed in the hypophysectomized animals. After 12 h infusion by contrast, a steadily rising response was observed in both groups. There was a significant correlation between the final plasma cortisol concentration and both the adrenal weight and cortical thickness after 48 h treatment. The increased sensitivity of the adrenal cortex to exogenous ACTH as term approaches in the sheep is considered to be dependent upon the increasing proportion of mature zona fasciculata cells within the adrenal cortex.
Topics: Adrenal Cortex; Adrenocorticotropic Hormone; Animals; Cosyntropin; Fetus; Hydrocortisone; Hypophysectomy; Organ Size; Sheep
PubMed: 6298852
DOI: 10.1113/expphysiol.1983.sp002697 -
Molecular and Cellular Endocrinology Apr 2011Sonic hedgehog signaling was recently demonstrated to play an important role in murine adrenal cortex development. The organization of the rat adrenal differs from that...
Sonic hedgehog signaling was recently demonstrated to play an important role in murine adrenal cortex development. The organization of the rat adrenal differs from that of the mouse, with the zona glomerulosa and zona fasciculata separated by an undifferentiated zone in the rat, but not in the mouse. In the present study we aimed to determine the mRNA expression patterns of Sonic hedgehog and the hedgehog signaling pathway components Patched-1 and Gli1 in the developing and adult rat adrenal. Sonic hedgehog expression was detected at the periphery of the cortex in cells lacking CYP11B1 and CYP11B2 expression, while signal-receiving cells were localized in the overlying capsule mesenchyme. Using combined in situ hybridization and immunohistochemistry we found that the cells expressing Sonic hedgehog lie between the CYP11B2 and CYP11B1 layers, and thus Sonic hedgehog expression defines one cell population of the undifferentiated zone.
Topics: Adrenal Cortex; Aging; Animals; Gene Expression Regulation, Developmental; Hedgehog Proteins; Kruppel-Like Transcription Factors; Mice; Patched Receptors; Patched-1 Receptor; Protein Transport; Rats; Receptors, Cell Surface; Zinc Finger Protein GLI1
PubMed: 21094676
DOI: 10.1016/j.mce.2010.11.010