The human adrenal cortex: growth control and disorders

This review summarizes key knowledge regarding the development, growth, and growth disorders of the adrenal cortex from a molecular perspective. The adrenal gland consists of two distinct regions: the cortex and the medulla. During embryological development and transition to the adult adrenal gland, the adrenal cortex acquires three different structural and functional zones. Significant progress has been made in understanding the signaling and molecules involved during adrenal cortex zonation. Equally significant is the knowledge obtained regarding the action of peptide factors involved in the maintenance of zonation of the adrenal cortex, such as peptides derived from proopiomelanocortin processing, adrenocorticotropin and N-terminal proopiomelanocortin. Findings regarding the development, maintenance and growth of the adrenal cortex and the molecular factors involved has improved the scientific understanding of disorders that affect adrenal cortex growth. Hypoplasia, hyperplasia and adrenocortical tumors, including adult and pediatric adrenocortical adenomas and carcinomas, are described together with findings regarding molecular and pathway alterations. Comprehensive genomic analyses of adrenocortical tumors have shown gene expression profiles associated with malignancy as well as methylation alterations and the involvement of miRNAs. These findings provide a new perspective on the diagnosis, therapeutic possibilities and prognosis of adrenocortical disorders.

Ação da melatonina sobre a apoptose e fator de crescimento endotelial vascular no córtex da adrenal de ratas pinealectomizadas / Melatonin action in apoptosis and vascular endothelial growth factor in adrenal cortex of pinealectomized female rats

OBJETIVO: avaliar os efeitos da melatonina na apoptose e atividade celular no córtex da adrenal de ratas pinealectomizadas. MÉTODOS: foram utilizadas 40 ratas adultas, divididas randomicamente em 4 grupos com 10 animais cada: GCont - sem intervenção cirúrgica e com ministração do veículo; GSham - sem retirar a pineal com ministração do veículo; GExpV - pinealectomizado e tratado com veículo; GExpM - pinealectomizado e tratado com melatonina (10 µg/animal, por dia) durante a noite. Após 60 dias de tratamento, todos os animais foram submetidos à eutanásia, as adrenais retiradas, fixadas em formol a 10 por cento e processadas para inclusão em parafina. Nos cortes histológicos com 5 µm de espessura, foram realizados métodos imunoistoquímicos para detecção da apoptose (Caspase-3-clivada) e da atividade celular (fator de crescimento endotelial vascular, VEGF-A). Para avaliar a percentagem de apoptose foram contadas as células reativas em 1.000 células de cada zona da região cortical da adrenal em cada animal; já o VEGF-A foi expresso em escores. Os dados quantitativos foram analisados pela análise de variância (ANOVA) e pelo teste de comparações múltiplas de Tukey-Kramer (p<0,05). RESULTADOS: na avaliação do índice apoptótico, não foram encontradas diferenças significantes na zona glomerulosa entre os vários grupos estudados. Na zona fasciculada (GExpV=15,51±3,12*, p<0,05) e na reticulada (GExpV=8,11±1,90*, p<0,05) houve redução no índice apoptótico no grupo GExpV em relação aos demais grupos de estudo. Na reatividade ao VEGF-A, houve maior positividade, indicando maior atividade celular na zona na fasciculada do GExpV em relação aos outros grupos. CONCLUSÕES: a melatonina atua na região cortical da adrenal, em especial nas zonas fasciculada e reticulada, que estão relacionadas com a produção de esteroides sexuais.

PURPOSE: to evaluate the reactivity of VEGF-A and cleaved caspase-3 in the adrenal gland cortex of female pinealectomized rats treated with melatonin. METHODS: forty adult female rats were divided into 4 groups (G) of 10 animals: GI - no surgical intervention, with vehicle administration; GII - sham pinealectomized with vehicle administration; GIII - pinealectomized with vehicle administration; GIV - pinealectomized with melatonin administration (10 µg/animal) during the night. After 60 days of treatment, all animals were anesthetized, and the adrenal glands were removed and fixed in 10 percent formaldehyde (phosphate buffered) for histological processing and paraffin embedding. Sections (5 µm thick) were collected on silanized slides and submitted to imunnohistochemical methods for the detection of cleaved caspase-3 (apoptosis) and of vascular endothelial growth factor (VEGF-A) in the adrenal cortex. The data obtained were submitted to analysis of variance (ANOVA) complemented by the Tukey-Kramer test (p<0.05). RESULTS: reactivity to cleaved Caspase-3 was noted in the zona glomerulosa of the adrenal glands in all studied groups. There were no significant differences in the zona glomerulosa; however, the zona fasciculata (15.51±3.12*, p<0.05) and the zona reticularis (8.11±1.90*, p<0.05) presented the smallest percentage of apoptosis in the pinealectomized group (GIII). The reactivity to the VEGF-A was stronger in the zona glomerulosa and weaker in the zona reticularis in all groups. We found a stronger VEGF-A reactivity in the zona fasciculata in the pinealectomized group (GIII). CONCLUSIONS: the pineal gland affects the arrangement of the zona glomerulosa and reticularis of the adrenal glands, which are related to the production of sex hormones.

Effect of photoperiod on the adrenal activities of male rose ringed parakeet, Psittacala krameri.

Adult male rose ringed parakeets were exposed to very long photoperiod (22 hr L: 2 hr D) and very short photoperiod (2 hr L: 22 hr D) daily for 60 days during different phases of the annual testicular cycle. Adrenal activities of the experimental birds were compared with that of parallel held natural photoperiodic birds. Marked atrophy of adrenocortical cells was noted in the glands of long photoperiod (22 hr L:2 hr D) during different phases, i.e., post-breeding, quiescent and pre-breeding phases of annual gonadal cycle. The atrophied cells were not uniformly distributed in different groups of long photoperiod responsive birds. During pre-breeding, post-breeding and quiescent phases marked atrophy of the adrenocortical cells were restricted to the sub capsular zone of the gland. The cytometric and karyometric studies also revealed significant decrease in the cortical cord width and diameter of nuclei in the cortical cells in either subcapsular zone in the gland of long photoperiodic birds considered for treatment during pre-breeding, post-breeding and quiescent phase or in both the sub capsular zone and the inner zone. The cytometric and karyometric values did not show any change from control birds.

Age-related changes in the in vivo adrenocortical production of cAMP and corticosterone in response to exogenous ACTH in long-evans female rats

Ageing effects on the in vivo cyclic 3, 5'- adenosine monophosphate [cAMP] production by the adrenal cortex were studied in the rat. Materials and Methods: Eleven old [from 23 to 29 months] and 13 young [from 4 to 5 months], dexamethasone pre-treated Long-Evans female rats received 5.0 mu.i. [1-24] ACTH/100g b.w. by intravenous injection. The plasma concentration of corticosterone as well as the adrenal contents in cAMP and corticosterone were measured, by radioimmunoassay, just before and 45 min after the [1-24] ACTH injection. Results: The basal plasma corticosterone level and the adrenal contents in corticosterone and cAMP were low and no group difference was observed. The [1-24] ACTH injection causes significant increases in the plasma corticosterone level and the glandular contents in corticosterone and cAMP, which were lesser in the old animals than in the young ones; the differences aged/young were approximately -37%, -18% and -55% respectively. Conclusions: These results suggest that the reduced stero‹dogene response of the adrenal cortex in the old rat, to an acute ACTH administration is at least partly due to a decrease in the cellular production of the principal second messenger of this hormone, i.e. the cAMP

Changes in the fecal concentrations of cortisol and androgen metabolites in captive male jaguars (Panthera onca) in response to stress

In the present study we determined the efficacy of the measurement of fecal cortisol and androgen metabolite concentrations to monitor adrenal and testicular activity in the jaguar (Panthera onca). Three captive male jaguars were chemically restrained and electroejaculated once or twice within a period of two months. Fecal samples were collected daily for 5 days before and 5 days after the procedure and stored at -20ºC until extraction. Variations in the concentrations of cortisol and androgen metabolites before and after the procedure were determined by solid phase cortisol and testosterone radioimmunoassay and feces dry weight was determined by drying at 37ºC for 24 h under vacuum. On four occasions, fecal cortisol metabolite levels were elevated above baseline (307.8 ± 17.5 ng/g dry feces) in the first fecal sample collected after the procedure (100 to 350 percent above baseline). On one occasion, we did not detect any variation. Mean (± SEM) fecal androgen concentration did not change after chemical restraint and electroejaculation (before: 131.1 ± 26.7, after: 213.7 ± 43.6 ng/g dry feces). These data show that determination of fecal cortisol and androgen metabolites can be very useful for a noninvasive assessment of animal well-being and as a complement to behavioral, physiological, and pathological studies. It can also be useful for the study of the relationship between adrenal activity and reproductive performance in the jaguar.

Silenciamento de genes com RNA interferência: um novo instrumento para investigação da fisiologia e fisiopatologia do córtex adrenal / Gene silencing with RNA interference: a novel tool for the study of physiology and pathophysiology of adrenal cortex

A inativação de genes por knock-out ou por bloqueio da tradução de seus transcritos (silenciamento) constitui uma estratégia extremamente poderosa tanto para atribuir função aos genes como para mapear a inter-relação dos diferentes componentes das vias regulatórias intracelulares. Um dos meios para se obter o silenciamento pós-transcricional consiste na ativação de um mecanismo mediado por RNAs fita-dupla (dsRNA) conhecido como RNA interferência (RNAi). O RNAi se mostrou um instrumento extremamente versátil em pesquisa biomédica, podendo ser utilizado em experimentos de silenciamento pontual de genes ou ser adaptado para estudos em larga escala de genômica funcional, podendo, inclusive, ser utilizado como meio de terapia gênica. Neste trabalho, os autores discutem as vias intracelulares envolvidas no RNAi, bem como as principais estratégias e limitações técnicas para se obter o silenciamento em células de mamíferos. Fazem, também, uma revisão das principais aplicações do RNAi na terapêutica de doenças humanas e na investigação de fenômenos fisiológicos e fisiopatológicos do córtex adrenal.

Probable effect of photoperiod on seasonal variation in the nuclear volume of the adrenal cortex of viscacha (Lagostomus maximus maximus)

The neuroendocrine system regulates several organic functions such as reproduction, metabolism and adaptation to the environment. This system shows seasonal changes linked to the environment. The experimental model used in the present study was Lagostomus maximus maximus (viscacha). The reproduction of males of this species is photoperiod dependent. Twenty-four adult male viscachas were captured in their habitat at different times during one year. The adrenal glands were processed for light microscopy. Serial cuts were stained with hematoxylin-eosin for the morphometric study, and 100 nuclei of each zone of the adrenal cortex were counted per animal. Data were analyzed statistically by ANOVA and the Tukey test. The cells of the glomerulosa zone are arranged in a tube-shaped structure. The fasciculata zone has large cells with central nuclei and clearly visible nucleoli and with a vacuolar cytoplasm. In the reticularis zone there are two of types of cells, one with a nucleus of fine chromatin and a clearly visible nucleolus and the other with nuclear pycnosis. Morphometric analysis showed maximum nuclear volumes during the February-March period with values of 133 percet 7.3 µm3 for the glomerulosa, 286.4 percent 14.72 µm3 for the fasciculata, and 126.3 percent 9.49 µm3 for the reticularis. Minimum nuclear volumes were observed in August with values of 88.24 + or - 9.9 µm3 for the glomerulosa, 163.7 percent 7.78 µm3 for the fasciculata and 64.58 + or - 4.53 µm3 for the reticularis. The short winter photoperiod to which viscacha is subjected could inhibit the adrenal cortex through a melatonin increase which reduces the nuclear volume as well as the cellular activity

Effect of adrenalectomy and adrenalectomy+hydrocortisone treatment on histopathological, biochemical and zinc and copper profiles in rat testes.

Degenerative changes such as decreased seminiferous tubule diameter, Leydig cell nuclear diameter, spermatogenic arrest, oedematous fluid in the interstitium and lumen of seminiferous tubules and increased levels of zinc, copper and enzymes (lactate dehydrogenase, LDH; leucine aminopeptidase, LAP; and aryl sulphatase) in adrenalectomised rats suggest a possible role of adrenal cortex and its hormones in spermatogonial cell proliferation and subsequent differentiation, homeostasis of biological trace elements and behaviour of enzymes. Atrophy of Leydig cells and the degenerative changes in testes of adrenalectomised rats can be attributed to reduced supply of testosterone. Hydrocortisone, administered through a single dose acted as hyperstate of hydrocortisone for a short duration, thereby inhibiting steroidogenesis either directly by affecting Leydig cell testosterone production or indirectly by affecting the release of LH from pituitary gland and thus caused degeneration of germinal epithelium. Once hydrocortisone (half life < 12 hr) was metabolized, the animals returned to adrenalectomised state, the degeneration persisted. Thus, hydrocortisone administered through a single dose was insufficient to sustain spermatogenesis. Chronic administration at physiological dose may renew spermatogenesis. Increased levels of LDH, LAP and arylsulphatase are, probably, necessary for cellular degeneration. Zinc and copper exhibited an increase and the rise can be corroborated to (1) failure of regulatory mechanism(s) that control the flow of the elements across the blood-testes barrier; and (2) increased oedematous fluid formed by cellular deaths of the germinal epithelium.

Enzimología de la biosíntesis de aldosterona: una revisión / Enzymology of the biosynthesis of aldosterone: a review

La última etapa de la biosíntesis de aldosterona (ALDO) involucra la oxidación mitocondrial de 11-desoxicorticosterona (DOC), a través de varios caminos, que comienzan en sus metabolicos corticosterona (B) y 18-hidroxi-11-desoxicorticosterona (18OHDOC). Todas las reacciones de estos caminos son catalizadas por enzimas de la familia de los citocromos P450. El número y la identidad de cada una de ellas han sido objeto de investigaciones en los últimos treinta años. El modelo, actualmente en vigencia, postula que en la adrenal de la vaca todas las reacciones que llevan desde DOC a ALDO son catalizadas por un único citocromo P450-11ß/18 hidroxilasa/aldosintetasa, presente en toda la corteza adrenal. En cambio, en la adrenal de rata, ratón y humano, la catálisis total es llevada a cabo por el citocromo P450 CYP11B2 sólo presente en la zona glomerulosa, mientras que en la zona fasciculata existe el citocromo P450 CYP11B1, que sólo cataliza la transformación de DOC en B o en 18 OH-DOC. Este modelo, avalado por experimentos de bioquímica celular y molecular, no explica, sin embargo, algunos hechos experimentales

Activity of the adrenal cortex in Trichinella pseudospiralis infection before and after administration of levamisole

During its adaptation to parasitism T. pseudospiralis appears to have acquired the ability to modulate mammalian host response to infection by directly or indirectly altering the neuroendocrine function of the host. The aim of the present work was to study the histopathological and histochemical changes that may take place in the adrenal cortex during T. pseudospiralis infection and after modulating the course of the infection by administration of an immunostimulant drug, levamisole. Two experimental groups were studied: Group I, early muscle stage [26 days p.i.], group II, late muscle stage [50 days p.i.]. Each group was further subdivided into three equal subgroups: T. pseudospiralis infected mice, infected mice receiving Levamisole on the 6th day p.i., and infected mice receiving the drug on the 14th day p.i. The adrenal cortices of T. pseudospiralis infected mice in both early and late muscle stages of infection showed hyperplasia of the zona fasiculata, increased cytoplasmic fat vacuoles associated with increased activity of alpha esterase and succinic dehydrogenase enzymes. These changes were more pronounced in infected mice which received levamisole early on the 6th day p.i

Respuesta glucocorticoides y lipoperoxidación adrenal en ratas sometidas a hipoxia hipobárica crónica / Glucococorticoid and adrenal lipoperoxidation response in rats subjected to chronic hypobaric hipoxia

En el presente estudio experimental fue realizado en condiciones fisiológicas de hipoxia:adaptación crónica de ratas 4400 m de altura simulada (HHC).En este trabajo se resumen nuestros resultados de función,histología y lipoperoxidabilidad adrenal en ratas de ambos sexos enteras y castradas.Se reiteran observaciones previa de diferencias asociadas al sexo en las respuestas a la HHC del hematocrito,el peso adrenal y el peso seco cardíaco.Los niveles circulantes de corticosterona (B) y de ácido úrico (AU) no se afectaron por HHC en ambos sexos pero si en los machos castrados en los que B disminuyó respecto de su control normóxico (p<0,001) y del animal entero(p<0,001) y el ácido úrico aumentó por HHC (p<0,05).Los machos normóxicosintactos mostraron correlación directa entre la lipoperoxidabilidad adrenal y el AU que desapareció por HHC y por castración.A pesar de estos cambios se observó que las adrenales de todos los grupos adaptados eran histológica e histoquímicamente normales,o sea en disidencia a lo propuesto por Selye de que estas glándulas se agotan ante cronicidad del estímulo.Se concluye que las hormonas esteroideas en genral participan directa e indirectamente en la respuesta fisiológica a la HHC y modulan la lipoperoxibilidad adrenal en estas condiciones experimentales

Eje hipotalamo-hipofisiario-suprarrenal en pacientes con terapia corticoesteroidea / Hypothalamus-hypophysial-suprarenal axis in patients with corticosteroid therapy

Se hizo un estudio prospectivo de pacientes sometidos a terapia corticoesteroidea por diversas causas, con el objeto de evaluar la integridad del eje hipotálamo-hipofisiario-suprarrenal. Cuatro pacientes habían recibido terapia corticoesteroidea a corto plazo (menor o igual a una semana). 6 pacientes, terapia intermedia (entre 1 y 2 semanas) y 20 pacientes recibieron terapia corticoesteroidea a tiempo prolongado (mayor a 6 semanas). Se describe el tipo de inhibición del eje hipotálamo-hipofisiario-suprarrenal, y se hizo un seguimiento en aquellos pacientes inhibidos a quienes se pudo descontinuar la terapia corticoesteroidea. Con respecto a la inhibición del eje hipotálamo-hipofisiario-suprarrenal nos encontramos lo siguiente: 12 casos (un 40%) tenían niveles normales de cortisol basal; mientras que los 18 pacientes restantes, (un 60%) mostraron niveles plasmáticos de cortisol basal bajo, luego de suspendido el tratamiento. Se observó que el mayor número de pacientes inhibidos corresponden al grupo que recibió tratamiento corticoesteroideo prolongado, (mayor a 6 semanas)

Funçäo do córtex adrenal em recém-nascidos prematuros de mäes pré-eclâmpticas / Adrenal cortex function in premature infants of mothers with pre-eclampsia

Com a finalidade de avaliar a influência da pré-eclâmpsia sobre a funçäo adrenal fetal, estudaram-se 51 recém-nascidos prematuros, nascidos de parto cesariano, sem uso antenatal de corticosteróides, dosando-se os níveis de cortisol e sulfato de deidroepiandrosterona no sangue do cordäo umbilical. Os recém-nascidos de mäes com pré-eclâmpsia apresentaram diminuiçäo dos níveis de sulfato de deidroepiandrosterona sem alteraçäo significante nos níveis de cortisol. Com base neste achado, sugere-se que a excreçäo urinária subnormal de estriol apresentada pelas gestantes pré-eclâmpticas se deve, em parte, à depressäo da funçäo adrenal fetal

Septum and adrenocortical function.

Dorsal septum is an intermediary centre in between the hippocampus and hypothalamus and it has got inhibitory influence over the hypothalamo-pituitary-adrenal axis. Stimulation of the dorsal septum manifested with fall in adrenocortical output whereas its lesion has opposite response. Ventral septum is a facilitatory area regarding activation of the hypothalamo-pituitary-adrenal axis. It is a balancing centre lying in between the higher central nervous system structures and the hypothalamus. Stimulation and lesion of the ventral septum led to rise and fall in adrenal venous 17-OHCS output respectively. Adrenocortical response to stress of burn was not blocked or inhibited following lesion of the dorsal as well as ventall septum.

Effect of centrally administered glucagon on urine output in dogs.

The effect of minimal doses of glucagon, administered by intracerebroventricular (ICV) and intracisternal(IC) routes, on urine output in mongrel dogs have been studied. The dose of 2.0 mug of glucagon was found to be the minimal dose for diuresis on peripheral administration. This dose when centrally administered, produced an oliguric effect in animals. This effect was not observed in vagosympathectomised-spinal cord transectomised or adrenalectomised animals. It is suggested that the probable efferents might be the sympathetic fibres as they are present in vagi nerves as well in the spinal cord (26). The observations made in an attempt to find out the organ responsible for the oliguric effect, showed that some substance released from the adrenal cortex has an influence on the kidney's excretory function.