Adrenocortical Hormone Secretion Research Articles

Transcription factors β-catenin and Hex in postnatal development of the rat adrenal cortex: implication in proliferation control

Transcriptional regulation of growth, maturation, and cell turnover in adrenal cortex during postnatal development has been significantly less studied than in embryonic period, while elucidation of factors mediating its normal postnatal morphogenesis could clarify mechanisms of tumorigenesis in adrenal cortex. Expression of transcription factors Hex, β-catenin, and Wnt signaling in the adrenal cortex of male pubertal and postpubertal Wistar rats were examined. Adrenal cortex morphology and hormone production during postnatal development were also studied. Adrenocortical zones demonstrated similar reduction of Ki-67-expressing cells, but different patterns of morphological and functional changes. Age-dependent decrease in percentage of cells with membrane localization of β-catenin and stable rate of cells with nuclear β-catenin, indicative of Wnt signaling activation, were revealed in each cortical zone. Nuclear β-catenin was not observed in immature areas of zona fasciculata. No association between Wnt signaling activation and rates of proliferation as well as changes in secretion of adrenocortical hormones was observed in postnatal development of rat adrenal cortex. Hex, known as antiproliferative factor, showed up-regulation of expression after puberty. Strong inverse correlations between ratio of Hex-positive cells and proliferating cells were found in zona glomerulosa and zona fasciculata. Zona reticularis demonstrated moderate correlation. Thus, these findings suggest a role for Hex in proliferation control during postnatal development of the rat adrenal cortex and possible implication of Hex down-regulation in adrenocortical dysplasia and neoplasia, which requires further study. Evaluation of Hex expression may also be considered a potent tool in assessment of cell proliferation in rat adrenal cortex.

Kisspeptin deficiency leads to abnormal adrenal glands and excess steroid hormone secretion.

Knockout mice for the kisspeptin receptor, Kiss1r (Kiss1r-/-) and its ligand kisspeptin, Kiss1 (Kiss1-/-) replicate the phenotype of isolated hypogonadotropic hypogonadism (IHH) associated with variants of these genes in humans. A recent report suggests that kisspeptin may be involved in human fetal adrenocortical development and function. Herein, we characterized the adrenal function and morphology in Kiss1-/- mice that do not go through normal puberty. Two fetal markers were expressed in eosinophilic cells potentially derived from the X-zone that should disappear at puberty in male mice and during the first pregnancy in female animals. Although the hypercorticosteronism observed in Kiss1-/- females corrected overtime, hyperaldosteronism persisted at 14months and correlated with the overexpression of Star. To determine if KISS1 and KISS1R genes are involved in the development of primary aldosteronism (PA) and hypercortisolism [Cushing's syndrome (CS)] in humans, we sequenced these 2 genes in 65 patients with PA and/or CS. Interestingly, a patient with CS presented with a germline KISS1 variant (p.H90D, rs201073751). We also found three rare variants in the KISS1R gene in three patients with PA: p.C95W (rs141767649), p.A189T (rs73507527) and p.R229R (rs115335009). The two missense variants have been previously associated with IHH. Our findings suggest that KISS1 may play a role in adrenal function in mice and possibly adrenocortical steroid hormone secretion in humans, beyond its recently described role in human fetal adrenocortical development.

Adrenal venous sampling: cosyntropin stimulation or not?

Notwithstanding the high prevalence of primary aldosteronism (PA), probably the most common form of secondary hypertension, the diagnosis of PA is often neglected or delayed, thus precluding target treatment, which is curative in many cases. For selection of the most appropriate treatment, a fundamental step is the distinction between a lateralized form, mainly aldosterone-producing adenoma (APA), and bilateral adrenocortical hyperplasia (BAH), also known as idiopathic hyperaldosteronism (IHA). To this aim all current guidelines recommend adrenal vein sampling (AVS), a technically challenging procedure that often fails, particularly in non-experienced hands. Cosyntropin (synthetic ACTH) is administered in the attempt to maximize adrenal cortisol secretion and avoid pulsatile adrenocortical hormone secretion in about 40% of the referral centres around the world. However, the Endocrine Society guidelines do not advise about the use or not of cosyntropin as stimulus during AVS, as there are arguments in favour and against its use. These arguments are presented in this debate article reflecting the views of groups that currently use and do not use cosyntropin.

Expression profile of Galp, alarin and their receptors in rat adrenal gland.

Galanin-like peptide (Galp) and alarin (Ala) are 2 new members of the galanin peptide family. Galanin (Gal), the "parental" peptide of the entire family, is known to regulate numerous physiological processes, including energy and osmotic homeostasis, reproduction, food intake, and secretion of adrenocortical hormones. Galp and Ala are known to regulate food intake. In the rat, Galp mRNA has been found in the brain, exclusively in the hypothalamic arcuate nucleus (ARC) and median eminence, which are involved in the regulation of energy homeostasis. Alarin-like immunoreactivity is present in the locus coeruleus (LC) and the ARC of rats and mice. The aim of the study was to investigate the expression of Ala, Galp and their receptors in the organs of the hypothalamo-pituitary-adrenal (HPA) axis of the rat. The expression of the examined genes was measured in different models of adrenal growth of the rat in vivo (postnatal ontogenesis, compensatory adrenal growth, adrenocortical regeneration, adrenocorticotropic hormone (ACTH) administration). The expression was evaluated using the Affymetrix® microarray system or quantitative polymerase chain reaction (qPCR). The expression of Ala gene was observed in each organ of the HPA axis (the hypothalamus, hypophysis and adrenal gland). The elevated level of expression of this gene was observed in the pituitary of 2-day rats, while very low levels of Ala mRNA were observed in the adrenals. Galp mRNA expression was observed only in the hypothalamus and the hypophysis during postnatal ontogenesis. The expression of Gal receptors was demonstrated in the hypothalamus, the hypophysis and the adrenal gland. In different compartments of the adrenal glands of adult, intact male and female rats, the expression of Ala, Galp and galanin receptor 1 (Galr1) genes was negligible, but the expression of galanin receptor 2 (Galr2), galanin receptor 3 (Galr3) and neurotrophic receptor tyrosine kinase 2 (Ntrk2) genes was noticeable. The examined genes showed different expression levels within the studied HPA axis; some of them were neither expressed in the hypothalamus or the pituitary gland, nor in the adrenal gland.

The angiotensin type 2 receptor in the human adrenocortical zona glomerulosa and in aldosterone-producing adenoma: low expression and no functional role.

The angiotensin II (Ang II) type 2 receptor (AT2R) and the angiotensin-(1-7) (Ang-(1-7)) receptor (MasR) play a cardiovascular protective role by counter-regulating Ang II type 1 receptor (AT1R)-mediated effects, but whether this involves blunting of adrenocortical hormone secretion is unknown. We investigated the presence of AT1R, AT2R, and MasR in aldosterone-producing adenoma (APA), a condition featuring hyperaldosteronism, and in APA-adjacent tissue. The effect of Compound 21 (C21), an AT2R agonist, on CYP11B1 (cortisol synthase) and CYP11B2 (aldosterone synthase) gene expression in NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, was also assessed using the AT1R antagonist irbesartan to ascertain the specificity of C21 effect. We found that the AT1R, AT2R, and MasR were expressed in APA and APA-adjacent tissue, albeit heterogeneously. The gene expression of AT1R and AT2R was lower, and that of the MasR higher in APAs than in APA-adjacent tissue. In steroid-producing NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, C21 was ineffective at nanomolar concentrations, but increased CYP11B1 and CYP11B2 gene expression at micromolar concentrations through AT1R, as this effect was blunted by irbesartan. The scant expression of the AT2R, along with the lack of any effect of C21 at low concentrations on CYP11B2, do not support the contention that the protective arm of renin-angiotensin system (RAS) blunts aldosterone synthase in the normal adrenal cortex and primary aldosteronism.

The subtyping of primary aldosteronism by adrenal vein sampling: sequential blood sampling causes factitious lateralization.

The pulsatile secretion of adrenocortical hormones and a stress reaction occurring when starting adrenal vein sampling (AVS) can affect the selectivity and also the assessment of lateralization when sequential blood sampling is used. We therefore tested the hypothesis that a simulated sequential blood sampling could decrease the diagnostic accuracy of lateralization index for identification of aldosterone-producing adenoma (APA), as compared with bilaterally simultaneous AVS. In 138 consecutive patients who underwent subtyping of primary aldosteronism, we compared the results obtained simultaneously bilaterally when starting AVS (t-15) and 15 min after (t0), with those gained with a simulated sequential right-to-left AVS technique (R ⇒ L) created by combining hormonal values obtained at t-15 and at t0. The concordance between simultaneously obtained values at t-15 and t0, and between simultaneously obtained values and values gained with a sequential R ⇒ L technique, was also assessed. We found a marked interindividual variability of lateralization index values in the patients with bilaterally selective AVS at both time point. However, overall the lateralization index simultaneously determined at t0 provided a more accurate identification of APA than the simulated sequential lateralization indexR ⇒ L (P = 0.001). Moreover, regardless of which side was sampled first, the sequential AVS technique induced a sequence-dependent overestimation of lateralization index. While in APA patients the concordance between simultaneous AVS at t0 and t-15 and between simultaneous t0 and sequential technique was moderate-to-good (K = 0.55 and 0.66, respectively), in non-APA patients, it was poor (K = 0.12 and 0.13, respectively). Sequential AVS generates factitious between-sides gradients, which lower its diagnostic accuracy, likely because of the stress reaction arising upon starting AVS.

Arginine vasopressin (AVP): a review of its historical perspectives, current research and multifunctional role in the hypothalamo-hypophysial system.

This publication reviews the function of arginine vasopressin and focuses on the morphologic and functional correlation between the hormone and its effect on stress, the hypophysial-adrenocortical axis, neuroimmune responses, renal function and corticotroph pituitary tumors. A literature review was performed using various search engines for information regarding the morphology and the multifunctional role of arginine vasopressin. Although a large number of studies were published discussing these interactions, there are several important areas that are still obscure. The questions of how does arginine vasopressin affect the morphology and function of these various areas, and how does the secretion of ACTH and adrenocortical hormones influence the morphology of arginine vasopressin-producing cells and their hormone secretion requires further investigation.

Regulation of plasma testosterone, corticosterone, and metabolites in response to stress, reproductive stage, and social challenges in a desert male songbird

In many male vertebrates, the secretion of reproductive (gonadal androgens) and adrenocortical (glucocorticoids) hormones varies seasonally and in response to environmental stimuli, and these hormones exert numerous behavioral and metabolic effects. We performed two field studies on adult male Rufous-winged Sparrows, Peucaea carpalis, a Sonoran Desert rain-dependent sedentary species, to (a) determine seasonal changes in initial (baseline) and acute stress-induced plasma testosterone (T), corticosterone (CORT), and two metabolites (uric acid and glucose) and (b) compare the effects of two types of social challenge (song playback or simulated territorial intrusion consisting of song playback plus exposure to a live decoy bird) on plasma T, CORT, these metabolites, and territorial behavior. Initial plasma T was higher during the summer breeding period than during post-breeding molt. Acute stress resulting from capture and restraint for 30min decreased plasma T in breeding condition birds but not in the fall, revealing that this decrease is seasonally regulated. Initial plasma CORT did not change seasonally, but plasma CORT increased in response to acute stress. This increase was likewise seasonally regulated, being relatively smaller during autumnal molt than in the summer. We found no evidence that acute stress levels of CORT are functionally related to stress-depressed plasma T and, therefore, that plasma T decreases during stress as a result of elevated plasma CORT. Thirty minutes of exposure to simulated territorial intrusion resulted in different behavior than 30min of exposure to song playback, with increased time spent near the decoy and decreased number of overhead flights. Neither type of social challenge influenced plasma T, thus offering no support for the hypothesis that plasma T either responds to or mediates the behavioral effects of social challenge. Exposure to both social challenges elevated plasma CORT, but simulated territorial intrusion was more effective in this respect than song playback. Plasma uric acid and glucose decreased during acute stress, but only plasma uric acid decreased during social challenge. Thus, an elevation in plasma CORT was consistently associated with a decrease in plasma uric acid, but not with a change in glycemia. These results enhance our understanding of the short-term relationships between T, CORT, and avian territorial behavior. They provide novel information on the endocrine effects of acute stress, in particular on plasma T, in free-ranging birds, and are among the first in these birds to link these effects to metabolic changes.

Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation

Inflammation-related dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is central to the course of systemic inflammatory response syndrome or sepsis. The underlying mechanisms, however, are not well understood. Initial activation of adrenocortical hormone production during early sepsis depends on the stimulation of hypothalamus and pituitary mediated by cytokines; in late sepsis, there is a shift from neuroendocrine to local immune-adrenal regulation of glucocorticoid production. Therefore, the modulation of the local immune-adrenal cross talk, and not of the neuroendocrine circuits involved in adrenocorticotropic hormone production, may be more promising in the prevention of the adrenal insufficiency associated with prolonged sepsis. In the present work, we investigated the function of the crucial Toll-like receptor (TLR) adaptor protein myeloid differentiation factor 88 (MyD88) in systemic and local activation of adrenal gland inflammation and glucocorticoid production mediated by lipopolysachharides (LPSs). To this end, we used mice with a conditional MyD88 allele. These mice either were interbred with Mx1 Cre mice, resulting in systemic MyD88 deletion, predominantly in the liver and hematopoietic system, or were crossed with Akr1b7 Cre transgenic mice, resulting thereby in deletion of MyD88, which was adrenocortical-specific. Although reduced adrenal inflammation and HPA-axis activation mediated by LPS were found in Mx1(Cre+)-MyD88(fl/fl) mice, adrenocortical-specific MyD88 deletion did not alter the adrenal inflammation or HPA-axis activity under systemic inflammatory response syndrome conditions. Thus, our data suggest an important role of immune cell rather than adrenocortical MyD88 for adrenal inflammation and HPA-axis activation mediated by LPS.

Griseofulvin increases steroid hormone levels in the supernatant of adrenocortical cells in vitro

It has been shown that griseofulvin, which is an antifungal drug, inhibits growth of adrenocortical cancer cells in vitro. The inhibition of growth is caused by interactions with the microtubule apparatus. Interestingly, the microtubule apparatus is also involved in the regulation of steroidogenesis. Therefore we posed the question if griseofulvin also affects steroid hormone secretion. We have applied the NCI-H295R adrenocortical cancer cell line for the analysis of the effects of griseofulvin on adrenocortical steroid hormone secretion. Cells were incubated with or without griseofulvin at concentrations of 0.1µM, 1µM, 10µM, 40µM and 100µM for 24 hours. Concentrations of aldosterone, cortisol and dehydroepiandrostenedione (DHEA) were analyzed in the supernatants using Enzyme Linked Immunosorbent Assays (ELISAs). In addition, we measured concentrations of potassium levels to rule out that increased steroid hormone levels were a consequence of changed electrolyte concentrations. The incubation with griseofulvin leads to a dose dependent increase of Aldosterone-(approximately 2.3-fold), Cortisol-(approximately 1.3-fold) and DHEA-(approximately 4.3 fold) concentrations. The effects were, at least in part, independent from the concentration of potassium. Griseofulvin interfere with the microtubule apparatus and may disrupt regular trafficking of intracellular steroidal compounds. Apoptosis of adrenocortical cells may contribute to the release of steroid hormones. However, the exact mechanism how griseofulvin leads to increased concentrations of steroid hormones in the supernatant of adrenocortical cells is still unclear.

Adrenocortical and renin-angiotensin systems in dynamics of experimental diabetes

Components of the adrenocortical system (adrenal and blood corticosteroid hormones and hepatic and renal 11beta-hydroxysteroid dehydrogenase activity) and also activity of the most important enzyme of the renin-angiotensin system, tissue and blood angiotensin converting enzyme (ACE) have been investigated in dynamics of alloxan diabetes. The study has shown that the initial period of diabetes is characterized by activation of synthesis and secretion of adrenocortical hormones into blood. High blood glucose and glucocorticoid honnones increase activity of the renin-angiotensin system in lungs and decrease ACE secretion into blood. This is accompanied by a decrease of activity of the renin-angiotensin system in kidneys. Subsequent progression of diabetes resulted in impairments of physiologically determined correlations between the components of these systems. Development of experimental diabetes for 30 days was accompanied by sign of a decrease of the adrenal glucocorticoid function regardless of stable impairments of carbohydrate metabolism. Under these conditions increased adrenal and hepatic 11beta-hydroxysteroid dehydrogenase activity may be responsible for maintenance of elevated levels of the main glucocorticoid in blood and tissues. Factor analysis revealed impairments in intersystem relationships between the adrenocortical and renin-angiotensin systems in experimental diabetes thus suggesting disintegration of regulatory systems.

Pituitary adenylate cyclase-activating polypeptide controls stimulus-transcription coupling in the hypothalamic-pituitary-adrenal axis to mediate sustained hormone secretion during stress.

External and internal stimuli that threaten homeostasis trigger coordinated stress responses through activation of specialised neuroendocrine circuits. In mammals, the hypothalamic-pituitary-adrenal (HPA) axis mediates responses to stressors such as restraint, ultimately enhancing adrenocortical hormone secretion. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in central control of the HPA axis, and we have recently shown PACAP-dependent expression of corticotropin-releasing hormone (CRH) and secretion of corticosterone in response to restraint. We now provide a more detailed analysis of PACAP-dependent HPA axis stimulation in the mouse, indicating that the hypothalamic paraventricular nucleus (PVN) is the primary site of action. We demonstrate by quantitative polymerase chain reaction and in situ hybridisation that up-regulation of mRNAs encoding CRH and inducible transcription factors, from the Nr4a family (Nur77, Nor1) in the PVN is PACAP-dependent. Furthermore, CRH hnRNA is rapidly up-regulated in cultured hypothalamic neurones after treatment with PACAP. Induction of Nr4a factors (Nur77, Nurr1) in response to restraint is attenuated in the pituitary gland of PACAP-deficient mice. In the adrenal glands, restraint elicits a marked PACAP-dependent increase in adrenocortical mRNA levels of all three Nr4a transcription factors, steroidogenic factor 1 (Nr5a1), steroidogenic acute regulatory protein and steroid 21-hydroxylase. Taken together, our results show that PACAP controls HPA responses to restraint primarily at the level of the hypothalamus by up-regulating CRH, possibly involving transcription factors such as Nur77 and Nor1. Subsequent adrenocortical steroidogenesis also appears to involve PACAP-dependent stimulus-transcription coupling, suggesting a mechanism by which PACAP exerts control over HPA axis function during stress.

Evaluation and Management of Hypothyroxinemia and Hypocortisolemia in Preterm Neonates: Current Concepts and Contentious Issues

Pediatricians, neonatologists and pediatric endocrinologists are often challenged with determining the significance of atypical thyroid and adrenocortical function studies in preterm, low birth-weight (gestational age <37 weeks; birth-weight <2500 g), very low birth-weight (gestational age <30 weeks; birth-weight <1500 g) or extremely low birth-weight (gestational age <27 weeks; birth-weight <1000 g) neonates. The neonatal period is defined as the first 30 days after birth. Often, these neonates are critically ill and being treated with several medications that further confound their evaluation and therapeutic management. Physicians who care for these patients are regularly faced with the questions: What are normal values of thyroid hormones and cortisol in preterm neonates? What is the significance of hypothyroxinemia or hypocortisolemia in these subjects? When is hormone-replacement therapy warranted? In this review, the physiology of thyroid and adrenocortical hormone secretion in the fetus and neonate is discussed and reference data for serum concentrations of thyroid and adrenocortical hormones in preterm and full-term neonates is presented. The evaluation and hormonal management of neonates with hypothyroxinemia and hypocortisolemia are outlined and critically analyzed.

Familial predisposition to adrenocortical tumors: Clinical and biological features and management strategies

The incidence of adrenocortical tumors (ACTs) is increased in several familial cancer syndromes resulting from abnormalities in genes that encode transcription factors implicated in cell proliferation, differentiation, senescence, apoptosis, and genomic instability. These include P53, MEN1, APC, and PRKAR1A. Adenomas are the most common ACTs, but adrenocortical carcinomas occur rarely as well. The clinical manifestations of ACTs, which result from increased secretion of adrenocortical hormones, are similar in the familial and sporadic forms of the disease. However, their management may differ because of unique aspects of the constitutional syndromes. The analysis of gene expression profiles of ACTs in these constitutional syndromes have contributed to our understanding of adrenal tumorigenesis and revealed new molecular diagnostic and prognostic markers and candidate genes for targeted therapies. This chapter summarizes the clinical and biological features, pathogenesis, and management strategies for ACTs that develop in patients with familial cancer syndrome.

Pediatric emergency: adrenal insufficiency and adrenal crisis

Adrenal insufficiency is defined by impaired secretion of adrenocortical hormones. It is classified upon the etiology in primary and secondary. Rapid recognition and therapy of adrenocortical crisis are critical to survival. Patients often have nonspecific symptoms: anorexia, vomiting, weakness, fatigue and lethargy. They are followed by hypotension, shock, hypoglicemia, hyponatremia and hyperkalemia. All patients with adrenal insufficiency require urgent fluid reposition, correction of hypoglycemia and glucocorticoid replacement, in order to avoid serious consequences of adrenal crisis. After initial crisis treatment, maintenance dose of corticoids should be indicated. Mineralocorticoids replacement, if necessary, should also be initiated.

Effects of Acute Restraint Stress on Sperm Motility and Secretion of Pituitary, Adrenocortical and Gonadal Hormones in Adult Male Rats

The effects of acute restraint stress on sperm motility and reproductive endocrinology were investigated in adult rats. Sperm motility was determined by computer-assisted sperm analysis. Acute restraint stress reduced sperm motility starting after 30 min, and the sperm motility parameters, percentage of motile spermatozoa (%), straight-line velocity, curvilinear velocity, deviation of the sperm head from the mean trajectory and the maximum amplitude of lateral head displacement decreased. It also induced a significant elevation in plasma adrenocorticotropic hormone, prolactin, corticosterone and progesterone and decreased follicle-stimulating hormone, luteinizing hormone, testosterone and immunoreactive (ir-) inhibin. These results clearly demonstrated that the acute restraint stress rapidly suppressed sperm motility and increased the activity of the hypothalamus-pituitary-adrenal axis, whereas it disturbed hypothalamus- pituitary-gonadal axis activity.

Effect of hypercalcaemia on adrenocortical and growth hormone secretion.

The authors investigated in 19 healthy women changes in the plasma levels of cortisol and growth hormone during acute hypercalcaemia induced by a load of 8.9 mg Ca2+/kg body weight, administered as intravenous infusion and the effect of hypercalcaemia on the adrenocortical and somatotrophic secretory reserve assessed by the test with insulin hypoglycaemia. Hypercalcaemia causes a rise of the basal cortisol plasma level starting at the 90th minute from the onset of the infusion when the calcium level reaches values of 2.99 mmol/l. The adrenocortical secretory reserve is, however, significantly reduced by hypercalcaemia. Hypercalcaemia does not affect growth levels nor the somatotrophic secretory reserve.

Twenty-Four-Hour Rhythmic Gene Expression in the Rhesus Macaque Adrenal Gland

The suprachiasmatic nucleus plays a key role in the circadian secretion of adrenocortical hormones. However, there is evidence from mouse studies that components of the circadian clock are also expressed within the adrenal gland itself. In the present study we performed genome-wide expression profiling to determine whether the adrenal gland of rhesus monkeys shows temporal gene expression across a 24-h period. We identified 322 transcripts with rhythmic patterns of expression and found that the phase distribution of cycling transcripts varied across the day, with more genes showing activation during the night. We classified the transcripts by their function and clustered them according to their participation in common biochemical pathways: 1) catecholamine synthesis and reuptake; 2) cholesterol cleavage and dehydroepiandrosterone sulfate synthesis; 3) protein synthesis and turnover; and 4) the circadian clock mechanism. In an additional experiment, we assessed the expression of various clock genes at two time points, 12 h apart. We found that expression of Bmal1 and Cry1 was higher at 1300 h, or zeitgeber time 6, whereas expression of Per1 was higher at 0100 h (zeitgeber time 18). Expression levels of Rev-erbalpha were higher at 0100 h than at 1300 h (P<0.05), and immunohistochemistry revealed a strong expression of this transcription factor specifically in chromaffin cells of the adrenal medulla. Taken together, the data indicate that the primate adrenal gland shows rhythmic expression of genes associated with cell biology and synthesis of steroids and catecholamines. Moreover, they strongly imply the existence of an intrinsic circadian clock.

Experimentally-induced hyperthyroidism is associated with activation of the rat hypothalamic–pituitary–adrenal axis

Previous studies on the effects of altered thyroid function on the secretion and metabolism of adrenocortical hormones suggest a degree of adrenocortical hyperactivity in hyperthyroidism. We have previously shown that experimentally-induced hyperthyroidism is associated with significant alterations in pituitary-adrenal responsiveness to synthetic ovine corticotropin-releasing hormone (oCRH) that are contingent upon the duration of the altered thyroid function. The purpose of this study was to assess the time-dependent effects of hyperthyroidism on the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis by in vivo stimulation of the hypothalamic CRH neuron and adrenal cortex. The functional integrity of the HPA axis was examined in vivo in sham-thyroidectomized male Sprague-Dawley rats given placebo or in thyroidectomized rats given 50 mug of thyroxine every day for 7 or 60 days. Responses to insulin-induced hypoglycemia and IL-1alpha stimulation were used to assess the hypothalamic CRH neuron. Adrenocortical reserve was assessed in response to low-dose adrenocorticotropic hormone (ACTH), following suppression of the HPA axis with dexamethasone. Adrenal and thymus tissue weight, in addition to basal plasma ACTH, corticosterone and thyroid indices were also determined. Basal plasma corticosterone and corticosterone binding globulin (CBG) concentrations were significantly increased in short- and long-term hyperthyroid rats, and by 60 days, cerebrospinal fluid (CSF) corticosterone levels were significantly increased. Basal plasma ACTH levels were similar to controls. Although plasma ACTH responses to hypoglycemic stress and IL-1alpha administration in both short- and long-term hyperthyroidism were normal, corticosterone responses to the ACTH release during the administration of these stimuli were significantly increased. The adrenal reserve was significantly elevated in short-term hyperthyroidsim. Long-term hyperthyroidism, however, was associated with a significant reduction in adrenocortical reserve. A significant increase in adrenal weights and a decrease in thymus weights were observed in both short- and long-term hyperthyroidism. The available data confirms that hyperthyroidism is associated with hypercorticosteronemia, although the locus that is principally affected still remains unclear. Despite the sustained hyperactivity of the HPA axis, long-term experimentally-induced hyperthyroidism is associated with diminished adrenal functional reserve. The alterations in HPA function in states of disturbed thyroid function were found to be somewhat more pronounced as the duration of thyroid dysfunction increased.

Role of the Inhibin/Activin System and Luteinizing Hormone in Adrenocortical Tumorigenesis

Adrenal masses are one of the most common endocrine tumors diagnosed. Although most adrenal tumors are inactive adenomas, a considerable proportion is associated with hormonal hyperfunction and/or malignancy. The adrenocortical carcinoma (ACC) is a rare but highly malignant tumor. Most ACCs in adults are diagnosed in an advanced tumor stage limiting therapeutic options. Accordingly, despite some progress in diagnostic and therapeutic approaches, the overall survival rate of patients with ACC remains poor. However, the prerequisite for the development of new diagnostic tools and therapeutic options in the management of patients with ACC is the elucidation of the molecular pathogenesis of adrenal tumorigenesis. Although our understanding of adrenal tumor biology has increased substantially over the last decades, the regulation of many molecular pathways involved in adrenocortical growth and differentiation awaits further elucidation. Luteinizing hormone (LH) and activin have only recently emerged as hormones likely to play opposite roles in adrenocortical hormone secretion and cellular proliferation. Recent evidence from studies on human surgical tumor sample expression and detailed characterization of murine adrenal tumor models suggests stimulatory effects of LH on adrenocortical growth and function. On the contrary, activin, which plays a critical role as a paracrine and autocrine factor regulating cellular growth and differentiation, has been demonstrated to induce apoptosis and suppress proliferation in the human and murine adrenal cortex. In this review, we will summarize molecular and functional aspects of adrenal tumorigenesis and highlight some prospects for future clinical applications.