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Orientador: Patricia Simone Leite Vilamaior / Resumo: É conhecido que o processo de envelhecimento ocasiona em machos um desequilíbrio hormonal devido à redução gradual da síntese de testosterona pelos testículos, que afeta a maioria dos órgãos sensíveis a hormônios e dentre eles a adrenal, que é responsável pela síntese e secreção de hormônios esteroides como mineralocorticoides, glicocorticoides e andrógenos. Estudos anteriores reconhecem o importante papel da adrenal na regulação do sistema reprodutor e também é conhecido, por meio de estudos com castração, que esta é sensível à redução de andrógenos, no entanto, há pouco entendimento do papel dessa glândula no processo de andropausa e há uma dificuldade em encontrar modelos experimentais representativos, uma vez que há muitas diferenças morfofuncionais entre as adrenais dos roedores e primatas. As adrenais dos gerbilos da Mongólia têm características ultraestruturais peculiares que sugerem uma maior similaridade à dos primatas. Apesar de serem modelos experimentais utilizados em estudos de desregulação endócrina e do sistema reprodutor, há poucos estudos sobre a fisiologia do córtex adrenal dessa espécie. Considerando essa afirmação, esse estudo descreveu pela primeira vez a morfofisiologia da adrenal de gerbilos adultos e durante o envelhecimento, trazendo resultados que demonstram similaridades do córtex adrenal dessa espécie com o humano e de outros primatas, desde a morfologia à expressão de enzimas da biossíntese de cortisol e andrógenos e de receptores de andrógeno e e... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The aging process in males is known by occasioning a hormonal imbalance due to the gradual reduction in the testicular testosterone synthesis, which affects most of the organs sensitive to this hormone and, among them the, adrenal glands which its cortex is responsible to synthesize and secrete steroidogenic hormones as mineralocorticoids, glucocorticoids, and androgens. Existing research recognizes the significant role played by this gland in the regulation of the reproductive system; it is also known that it is sensitive to the reduction of testosterone caused by castration, although there is still very little scientific understanding of its role in the andropause process. Moreover, Mongolian gerbils are experimental models for studies in reproductive biology and endocrine deregulation, their adrenal glands present a peculiar structure and suggest having more similar morphophysiology to the primates than others rodents, although there have been few investigations about the gerbils' adrenocortical physiology. Considering this, this study has described the morphophysiology of this gland in gerbil for the first time and showed particular similarities between the adrenal cortex of M. unguiculatus and primates, since the morphology, to the expression of enzymes of cortisol and androgens biosynthesis and androgen and estrogen receptors. During aging was an hypertrophy in the adrenal cortex, based on the gradual increase in adrenal absolute weight of the adrenals in the older grou... (Complete abstract click electronic access below) / Mestre

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Sciences in Medicine Johannesburg 2005 / Objectives: To document baseline pituitary-adrenal hormonal and related metabolic variables in 16 female patients with burnout. Then, following stress management intervention, to compare the changes with an equal number of untreated control subjects. / IT2017

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The adrenal cortex is classically divided into three morphologically and biochemically distinct zones, covered by a thin, cellular capsule. The adult adrenal cortex is a dynamic tissue in which distinct regions of cell proliferation, movement and death have been identified. Several models for stem cell maintenance of the adult adrenal cortex have been proposed, but adrenocortical stem cells have not yet been identified. Adrenal cortices of 21OH/LacZ transgenic mice show similar mosaic patterns of β-galactosidase staining to X- inactivation mosaics and LacZ ↔ wildtype chimeras. 21OH/LacZ mice provide a tool for lineage analysis, which may help to i) identify clones of cells produced by stem cells in the adult, ii) determine when stem cells begin to function and iii) evaluate different models of how stem cells maintain the adrenal cortex. Analysis of 21OH/LacZ transgenic adrenal cortices showed that the randomly orientated clusters of fetal patches change progressively during the perinatal period to adult radial stripes. Correlation of changes in mosaic patterns and the locations of cell proliferation suggests that the stripes arise by edge-biased growth during the perinatal growth period. Although stem cells may not be involved in the initial formation of stripes, it seems likely that stem cells later maintain the stripes by producing clones of cells that move centripetally to displace the earlier fetal patterns and later replace aging cells. Various combinations of BrdU labelling and chase periods demonstrated that most cell division occurred in the outer 40% of the adrenal cortex, confirmed that cells moved towards the medulla and identified a population of label-retaining cells near the capsule, which could include stem cells. (Stem cells have been recognised as BrdU label-retaining cells in other tissues because they divide less frequently than their daughter cells so dilute the incorporated BrdU more slowly.) Stripe patterns in adult 21OH/LacZ transgenic adrenal cortices were examined to try to distinguish between various models proposed for stem cell maintenance of the adrenal cortex. The observed continuous radial stripe pattern favours the general hypothesis that a single population of stem cells in the periphery maintains the entire adrenal cortex, although other explanations are possible. Quantitative analysis of adult stripe patterns did not show the reduction in stripe number that might be predicted if an age-related decline in adrenocortical stem cell function occurs, as may happen in some other tissues.

The adrenal gland is an important endocrine organ, protecting the body against acute and chronic stress. The adrenal cortex consists of three morphologically and functionally distinct zones: the outer zona glomerulosa (zG), the zona fasciculata (zF), and the innermost zona reticularis (zR). In rodents, zG cells produce mineralocorticoids (mainly aldosterone), while zF cells secrete glucocorticoids (mainly corticosterone). The functions of zG and zF are defined by the mutually exclusive expression of Cyp11b2 and Cyp11b1 that encode the enzymes aldosterone synthase and 11β-hydroxylase, which catalyze the terminal reactions in the production of aldosterone and corticosterone, respectively. This thesis aims to investigate the maintenance of the definitive mouse adrenal cortex. This involves studies to identify the location of adrenal stem/progenitor cells, and the mechanisms by which differentiated adrenocortical cells are replenished in the adult mice. BrdU pulse-chase studies provided valuable information about cell division and cell fate under physiological or pathophysiological stimulations. The distribution of adrenocortical cells with nuclei stained positively for BrdU and/or Ki67 was identified. Ki67 labelling marked actively dividing cells and showed that adrenocortical cells originate at or around the zG/zF interface. BrdU labelling indicated that, following cell division, cells are displaced inwards and outwards. Acute angiotensin II treatment was shown to have no significant effects on the cell proliferation or turnover in any of the adrenocortical zones. The pathophysiological effects of long-term ACTH treatment were analyzed in a mouse model of congenital adrenal hyperplasia caused by a null mutation of Cyp11b1. Cell hypertrophy was evident in all regions of the adrenal cortex due to the impaired negative-feedback of the HPA axis. Adrenocortical cell proliferation was also increased particularly in the outer zona fasciculata at the border between zG and zF where adrenocortical stem/progenitor cells might be located. The intervening steps between cell proliferation and the final differentiation into steroidogenic zG and zF cells have yet to be discovered. A visual method of monitoring levels of Cyp11b2 and Cyp11b1would offer a convenient approach to track the stages of adult stem cell differentiation that lead to normal adrenal maintenance in vivo and in vitro. In the present study an AS-mCherry-11B-EGFP BAC construct was successfully engineered, in which Cyp11b2 and Cyp11b1 were substituted by mCherry and EGFP, respectively. This BAC construct was characterized in mouse adrenocortical Y1 cells. It was determined that EGFP faithfully recapitulated the expression of Cyp11b1. Forskolin or cAMP treatment induced a rapid cell rounding effect and caused the increased expression of EGFP transgene and endogenous Cyp11b1. An attempt was made to establish a transgenic mouse model, in which zG and zF cells would be marked with mCherry and EGFP respectively, allowing the differentiation of an adrenocortical stem cell to be traced. Following microinjection of the BAC into mouse zygotes, twoAS-mCherry-11B-EGFP transgenic founder mice were identified. Unfortunately, neither of them was able to transmit the transgene through germline, suggesting the mosaicism of transgene integration. Indeed, mosaicism of the transgenic adrenals was demonstrated by RT-PCR and immunostaining, which also revealed that the exogenous EGFP expression faithfully recapitulated the endogenous Cyp11b1 in adrenals. Although it is assumed that expression of Cyp11b2 and Cyp11b1 are mutually exclusive, zG and zF cells may have the plasticity to allow the transition from one cell type into another. The AS-mCherry-11B-EGFP BAC construct is a useful tool for studying in vitro ES cell differentiation towards the adrenocortical lineage. Transgenic AS-mCherry-11B-EGFP ES cells were successfully differentiated into mesenchymal stem cells, as identified by the expression of molecular markers for the mesenchymal lineage. It has been reported that steroidogenic factor (Sf1) can promote the differentiation of MSCs into steroidogenic cells, and Shh plays an important role in Sf1 expression and the consequent adrenal development. However, Shh treatment failed to achieve transformation of mesenchymal cells into adrenocortical cells. It is thought there might be a requirement for additional factors to combine with Shh in promoting the transdifferentiation of ESC-derived mesenchymal cells. Future studies will focus on the genetic control of Cyp11b1 and Cyp11b2 in transgenic AS-mCherry-11B-EGFP ES cells. In conclusion, the location and fate of the adrenocortical progenitor cells were demonstrated by the BrdU pulse-chase studies in different mouse models. An AS-mCherry-11B-EGFP BAC construct was generated, and used to study the mutual and differential controls of Cyp11b1 and Cyp11b2 expression in adrenocortical cells in vitro and in transgenic mice in vivo.

The Siberian hamster (Phodopus sungorus) undergoes a suite of physiological changes in response to short day (SD) photoperiod which includes a marked reduction in body mass (up to 40%). This altered physiology can be reversed by a return to long day (LD) photoperiod and is driven by changes hypothalamic gene expression. Additionally, stimulation of weight regain occurs through spontaneous exercise when hamsters are provided with a running wheel (RW), despite intact photoperiod appropriate hypothalamic gene expression. The foundation hypothesis for this investigation was that the change in body weight in both paradigms is underpinned by an alteration of the growth hormone (GH) axis. Pasireotide, a somatostatin agonist, was utilised to inhibit GH secretion from the pituitary in both paradigms. Measurement of body mass, mass of internal organs, body composition by magnetic resonance imaging, hormonal analysis and in situ hybridization were used to determine the effect of a blockade of GH secretion by pasireotide. Pasireotide suppressed the GH axis in Siberian hamsters; with reduced circulating insulin-like growth factor-1 and altered hypothalamic gene expression of somatostatin (srif) and growth hormone – releasing hormone (ghrh) consistent with an inhibition of pituitary GH secretion. Pasireotide treatment inhibited RW and LD stimulated growth, and when administered to LD hamsters caused weight loss in a similar manner to that which occurs in SD and accompanied by testicular atrophy. In addition, pasireotide increased the incidence of torpor and increased bout length of this hypometabolic state in sedentary SD hamsters. In conclusion, evidence is provided for the hypothalamic – pituitary – growth hormone axis in the determination of photoperiod and RW induced body weight changes. Furthermore, the data show evidence for a novel muscle – brain pathway and evidence for a neuroendocrine pathway involved in torpor induction.

published_or_final_version / Zoology / Master / Master of Science