Corticosteroid Production Research Articles

Developmental and geographic variation in stress hormones in wild Belding's ground squirrels ( Spermophilus beldingi)

Extensive research has been conducted on the role of glucocorticoids in regulating growth, mobilizing energy, responding to stressors and modulating learning and memory. However, little is known about the production of corticoids during early development in free-living animals, particularly during sensitive periods of acquisition of important behaviors. In a four-year study of Belding's ground squirrels, Spermophilus beldingi, a non-invasive assay of glucocorticoids was used to quantify age and population differences among juveniles from three California locations. Fecal–cortisol metabolites are elevated during a short period when juveniles first emerge aboveground from their natal burrows at about 4 weeks of age. This period of cortisol elevation coincides with when young are learning survival behaviors such as anti-predator responses and foraging strategies. Population differences in juvenile cortisol levels, which may reflect local variation in habitat quality and predator environments, were not evident until 2 weeks after emergence. Elevated cortisol at the age of emergence was also observed in juveniles born and reared in captivity without exposure to typical stressors that occur around the age of emergence. These results indicate that corticoids are regulated during early development, and the possible functions of age-related corticoid levels are discussed, including mobilization of glucose for natal emergence and later facilitation of growth and energy storage during the short summer before hibernation. In some species, elevated corticoids can also facilitate learning and memory, and current work is exploring whether the higher cortisol observed in all three S. beldingi populations just after emergence function to promote rapid acquisition of survival behaviors.

Why Does Acute Hyperglycemia Worsen the Outcome of Transient Focal Cerebral Ischemia?

Hyperglycemia adversely affects the outcome of stroke. Global ischemia data support that the harmful effect of hyperglycemia is mediated by glucose-induced elevated plasma glucocorticoids. Here we sought to evaluate the negative effects of hyperglycemia on transient focal ischemia in the rat, and to test whether these could be prevented by inhibition of either corticosteroid production or neutrophil infiltration. Sprague-Dawley rats (n=217) were used. Ischemia was induced by 1 hour middle cerebral artery occlusion (n=196). Acute hyperglycemia was induced by IP injection of dextrose 30 minutes before ischemia. Neutrophil infiltration was blocked by neutropenia with vinblastine. Corticosterone synthesis was inhibited by chemical adrenalectomy with metyrapone. We measured MRI lesion and tissue infarct volumes, evaluated the neurological function, brain myeloperoxidase and matrix metalloproteinase-9 activities, and protein O-glycosylation. Hyperglycemia significantly enhanced MRI diffusion-weighted imaging alterations, increased cortical, but not subcortical, infarct volume, worsened neurological score, and enhanced brain myeloperoxidase and matrix metalloproteinase-9 activities. Metyrapone did not prevent hyperglycemic brain damage despite successful reduction of plasma corticosterone. Yet, metyrapone tended to reduce cortical infarction and apparent diffusion coefficient lesion volume, indicating some negative contribution of corticosterone. Blocking neutrophil infiltration was also ineffective to prevent the harmful effect of hyperglycemia. A new finding was that O-linked glycosylation of cerebral proteins was increased under hyperglycemia. In transient middle cerebral artery occlusion, the hyperglycemia-exacerbated brain damage cannot be fully explained by the negative effects of plasma corticosteroids or neutrophil infiltration. The contribution of other intrinsic effects of high glucose, such as brain protein O-glycosylation, deserves further investigation.

Effect of desmopressin on the production of corticosteroids in patients with different forms of hypercorticism

То investigate the direct effect of desmopressin (DP), a vasopressin agonist, on the adrenal cortex, the authors studied a response of the pituitary and all three adrenal cortical areas in patients with different forms ofhypercorticism (active stage): ACTH-dependent Itsenko-Cushing syndrome, ectopic ACTH-dependent syndrome, corticosteroma. The levels of ACTH, cortisol, dehydroepiandros-terone sulfate, and aldosterone were used to assess a response to DP 15, 30, 60, 90, and 120 minutes after administration. There were several types of a response of corticosteroids to DP: 1) an increase in the level of ACTH and, subsequently, in the concentration of either all test steroids, one of the steroids, or two steroids in different combinations; 2) an elevation of the concentration of steroids in different combinations irrespective the response of ACTH to DP. Thus, there are patients with hypercorticism whose adrenals respond to DP by the higher synthesis and secretion of glucocorticoids (cortisol), mineralcorticoids (aldosterone), and adrenal androgens (dehydroepiandrosterone sulfate). The findings suggest that there are "ectopic" receptors to vasopressin in the adrenal cortex of patients.

Neuroendocrine and metabolic effects of adipocyte-derived hormones

Obesity is characterized by an increase in adipose tissue mass. Contrary to the previous view of adipose tissue as simply an inert tissue devoted to energy storage, studies over the past decade have shown that adipose tissue is actively involved in regulating physiological processes and participates in disease. Adipose tissue secretes factors that exert local and systemic effects. Leptin, pro-inflammatory cytokines, resistin and proteins involved in haemodynamic regulation and coagulation are increased in obesity while adiponectin is reduced. The production of active corticosteroids is also increased in obesity. There is now growing evidence that adipocyte secretory factors regulate energy homoeostasis, as well as cardiovascular and immune systems. Some adipocyte hormones, most notably leptin, act in the brain to influence the neuroendocrine axis and energy balance, whereas adiponectin and resistin exert opposing effects on glucose and lipids. Understanding the actions of adipocyte hormones will provide novel insights into the pathophysiology and treatment of obesity.

The Aldosterone Synthase (CYP11B2) and 11β-Hydroxylase (CYP11B1) Genes Are Not Expressed in the Rat Heart

Aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) catalyze the production of aldosterone and corticosterone, respectively, in the rat adrenal cortex. Recently, there has been some debate as to whether these corticosteroids are also produced in the hearts of rodents and humans, possibly contributing to the development of hypertrophy and myocardial fibrosis. To investigate this, we have used our established, highly sensitive real-time quantitative RT-PCR method to measure CYP11B1 and CYP11B2 mRNA levels in adrenal and cardiac tissue from several rat models of cardiovascular pathology. We have also studied isolated adult rat ventricular myocytes treated with angiotensin II and ACTH. Total RNA was isolated from the adrenal and cardiac tissue of 1) male Wistar rats with heart failure induced by coronary artery ligation and sham-operated controls; 2) stroke-prone spontaneously hypertensive rats and Wistar Kyoto rats as controls; 3) cyp1a1Ren-2 transgenic rats and Fischer controls; 4) isolated adult Sprague-Dawley ventricular myocytes incubated with 11-deoxycorticosterone (DOC), DOC plus angiotensin II, or DOC plus ACTH. Adrenal CYP11B2 expression was significantly increased in transgenic rats compared with Fischer controls (1.3 x 10(9)+/- 1.2 x 10(9) vs. 2.1 x 10(7) +/- 7.0 x 10(6) copies/microg RNA; P < 0.05). There were no other significant differences in adrenal CYP11B2 or CYP11B1 expression between the model animals and their respective controls. Cardiac CYP11B1 and CYP11B2 mRNA transcript levels from all in vivo and in vitro groups were never greater than 100 copies per microgram total RNA and therefore too low to be detected reproducibly. This suggests that cardiac corticosteroid production is unlikely to be of any physiological or pathological significance.

Expression Profiles for Steroidogenic Enzymes in Adrenocortical Disease

Excess production of aldosterone or cortisol has profound effects on cardiovascular function and impacts other major organ systems. The mechanisms leading to the autonomous hypersecretion of aldosterone or cortisol in aldosterone-producing adenoma (APA) or cortisol-producing adenoma (CPA) are unknown. The objective of this study was to compare the expression profiles of several steroid-metabolizing enzymes and transcription factors from normal adrenal (NA), APAs, and CPAs. RNA from NAs, APAs, and CPAs were analyzed by microarray and real-time RT-PCR. This study was performed at academic research laboratories. At least nine normal controls and 12 patients with APA or CPA were studied. There was no intervention procedure. The main outcome measure was the expression of steroidogenic enzymes in adrenocortical disease. A microarray indicated a greater than 3-fold increase in the expression of CYP11B2 (aldosterone synthase) in APA, whereas 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) and HSD17B1 had greater than 3-fold increases in expression in CPA compared with NA. Real-time RT-PCR showed that APAs produced higher levels of HSD3B2, CYP21 (21-hydroxylase), and CYP11B2 mRNA, whereas CPAs produced higher levels of CYP11A (cholesterol side-chain cleavage), CYP17 (17alpha-hydroxylase/17-20 lyase), HSD3B2, and CYP11B1 (11beta-hydroxylase) mRNA compared with normal adrenal. Steroidogenic factor-1, DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome gene 1), and GATA-6 were expressed at higher levels in APAs and CPAs, whereas NURR1 was expressed at higher levels in APAs than in CPAs or NAs. Elevated production of aldosterone in APAs and of cortisol in CPAs is associated with increased expression of enzymes needed for corticosteroid production along with alterations in transcription factors that enhance the expression of steroid-metabolizing enzymes.

Nocturnal Hormones and Clinical Rhythms in Rheumatoid Arthritis

It is well known that some clinical signs and symptoms of rheumatoid arthritis (RA) vary within a day and between days; the morning stiffness that is observed in patients who have RA has become one of the diagnostic criteria of the disease. The circadian changes in the metabolism or nocturnal secretion of endogenous corticosteroids is certainly responsible, in part, for the time-dependent changes that are observed in the inflammatory response and related clinical symptoms. More recently, melatonin (mLT), another circadian nocturnal hormone that is the secretory product of the pineal gland, has been implicated in time-dependent inflammatory reactions, with effects that are opposite of those of corticosteroids. Therefore, altered functioning of the hypothalamic-pituitary-adrenocortical axis (reduced corticosteroid production) and of the pineal gland (increased mLT production) found in RA patients seem to be important factors in the perpetuation and clinical circadian symptoms of the disease. Consistently, human proinflammatory Th1-type cytokine production (related to mLT stimulation) exhibits a diurnal rhythmicity, with peak levels during the night and early morning, at a time when plasma cortisol (inducing Th2-type cytokine production) is lowest and mLT is highest. Reduced daily light exposure as observed in northern Europe (Estonia), at least during the winter, might explain the higher and more prolonged mLT concentrations as well as some epidemiological features that are observed in northern European patients with RA versus southern European patients.

ACTH, α-MSH, and control of cortisol release: cloning, sequencing, and functional expression of the melanocortin-2 and melanocortin-5 receptor in Cyprinus carpio

Cortisol release from fish head kidney during the acute phase of the stress response is controlled by the adrenocorticotropic hormone (ACTH) from the pituitary pars distalis (PD). Alpha-melanocyte-stimulating hormone (alpha-MSH) and beta-endorphin, from the pars intermedia (PI), have been implicated in cortisol release during the chronic phase. The present study addresses the regulation of cortisol release by ACTH and alpha-MSH in common carp (Cyprinus carpio) and includes characterization of their receptors, namely, the melanocortin-2 and melanocortin-5 receptors (MC2R and MC5R). We could not demonstrate corticotropic activity of alpha-MSH, beta-endorphin, and combinations of these. We do show a corticotrope in the PI, but its identity is as yet uncertain. Carp restrained for 1 and 7 days showed elevated plasma cortisol and alpha-MSH levels; cortisol is still elevated but lower at day 7 than day 1 of restraint. Interrenal response capacity is unaffected, as estimated by stimulation with a maximum dose ACTH in a superfusion setup. MC2R and MC5R appear phylogenetically well conserved. MC2R is predominantly expressed in head kidney; a low abundance was found in spleen and kidney. MC5R is expressed in brain, pituitary PD, kidney, and skin. Quantitative PCR analysis of MC2R and MC5R expression in the head kidney of restrained fish reveals MC2R mRNA downregulation after 7 days restraint, in line with lower plasma cortisol levels seen. We discuss regulation of corticosteroid production from a phylogenetic perspective. We propose that increased levels of alpha-MSH exert a positive feedback on hypothalamic corticotropin-releasing hormone release to sustain a mild stress axis activity.

Should We Use Etomidate as an Induction Agent for Endotracheal Intubation in Patients With Septic Shock?: A Critical Appraisal

Etomidate is commonly used for the facilitation of endotracheal intubation. While etomidate possesses multiple qualities that are beneficial in hemodynamically unstable patients who require a sedative or amnestic, its potential to negatively impact corticosteroid production is well-documented. Given the frequency of relative adrenal insufficiency observed in the critically ill and the increasing use of corticosteroids in patients with septic shock, an appraisal of the status of etomidate as an induction agent in patients with evolving or established septic shock is indicated. A review of the relevant literature suggests that its use in this setting may be harmful. It is proposed that, pending the performance of a randomized, controlled clinical trial, considerable caution should accompany its administration in patients with evolving or established septic shock. The potential role for concomitant empiric steroid replacement and the comparability of alternative induction regimens are also discussed.

The Endocrine System during Sepsis

Endocrinopathy during sepsis can manifest as hyperglycemia and insulin resistance or as insufficient production of either adrenal corticosteroids or vasopressin. The results of a recent large clinical trial have demonstrated that tight glycemic control with insulin can confer survival benefit to selected intensive care unit patients. Relative impairment of adrenocortical reserve has been suggested to be an important contributor to the pathogenesis of shock in sepsis. Replacement doses of glucocorticoids and mineralocorticoids have been associated with improved survival in the subset of patients with blunted results on adrenocorticotropin hormone stimulation tests. Posterior pituitary production of vasopressin is diminished in septic shock while sensitivity to its vasopressor effects is enhanced. Clinical trials are underway to determine whether administration of vasopressin can improve outcomes in patients with septic shock. Whether the euthyroid sick syndrome represents an adaptive or a maladaptive response to severe illness remains unclear.

Corticosteroid resistance in rheumatoid arthritis: molecular and cellular perspectives.

Corticosteroids are often used to treat a range of chronic autoimmune inflammatory diseases such as asthma, inflammatory bowel disease and rheumatoid arthritis (RA). RA is the most prevalent autoimmune chronic inflammatory rheumatic disorder with a prevalence of 1% in developed nations. It is more common in women than men, suggesting that perturbations of the hormonal systems may be involved in disease pathophysiology. The aetiology of the disease is unknown, but the physiological mechanisms of inflammation involved in this disease share common pathways with other inflammatory situations [1, 2]. However, the reasons why inflammation persists in RA remain unknown but might relate in part to a dysregulation of the interactions between neuroendocrine and immune systems at the onset of acute inflammation [2–6]. Acute inflammation can be initiated by a number of inflammatory triggers. This results in a programmed sequence of physiological mechanisms which begin with the release of tumour necrosis factor alpha (TNF ), interleukin-1 (IL-1 ) and IL-6 [3]. These cytokines activate a cascade of reciprocal local and systemic responses which result in increased secretion of corticotrophin-releasing hormone (CRH) and arginine vasopressin by the hypothalamus and production of adrenocorticotrophic hormone (ACTH), prolactin and macrophage migration inhibitory factor (MIF) by the pituitary gland and cortisol by the adrenal glands. Cortisol dampens inflammation by down-regulating the release of TNF , IL-1 and IL-6 whilst MIF and prolactin counteract the effects of cortisol resulting in a balanced inflammatory/immune response [3–5]. If acute inflammation is not restrained, it enters a chronic phase, a central feature of many chronic autoimmune inflammatory diseases [6]. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. Corticosteroids are the main effector endpoint of the neuroendocrine immune response to inflammation. At the molecular level, IL-1 , IL-6 and TNF initiate a number of pro-inflammatory intracellular signalling events which include the activation of the transcriptional activities of activator protein-1 (AP-1) and nuclear factorB (NFB) by a phosphorylation-dependent dissociation and/or degradation of Iby specific kinases (Ikinase 1 and 2) in the case of NF-I[7, 8]. These in turn enhance the production of a whole range of pro-inflammatory cytokines. These transcription factors are targets of action by cortisol and other corticosteroid type drugs [9]. NFis involved in the pathogenesis of inflammation in RA [10]. In addition IL-l and TNF also activate the mitogenactivated protein kinase (MAPK) p38 pathway [11]. MAPK p38 activates the kinases MAPKAPK-2, which in turn targets adenosine/uridine-rich elements (AREs) of pro-inflammatory messenger ribonucleic acids (mRNAs) to bring about their stabilization [9, 12, 13]. IL-l and TNF activate the second wave of cytokine release mechanisms [IL-8, IL-12, IL-15, IL-17, IL-18, interferonand , granulocyte–macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor etc.] that augment the homeostatic signals necessary for the subsequent complex cellular/cytokine cascades of reactions, endothelial activation and enhanced cell adhesion. The body attempts to down-regulate inflammation by increasing corticosteroid production [3]. Synthetic corticosteroid analogues such as prednisolone have been made and are often used to treat chronic autoimmune inflammatory disease such as RA, asthma and inflammatory bowel disease. They can effectively reduce the parameters of inflammation such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and induce disease remission. However, in clinical practice, a proportion of patients fail to respond adequately to corticosteroid therapy [14–16]. On this basis, patients can be divided into corticosteroid sensitive (SS) and corticosteroid resistant (SR) subgroups. The underlying mechanisms involved in the SS and SR phenomenon in patients with RA remain unknown but are of considerable therapeutic interest.

The effects of lesions to the striatum on the function of the hypothalamo-hypophyseal-adrenal system in adrenalectomized rats.

Experiments on white rats were performed to study the effects of bilateral lesioning of the striatum on activation of the hypothalamo-hypophyseal-adrenal system (HHAS) after unilateral adrenalectomy. These studies showed that increases in the weight of the surviving adrenal gland were smaller in striatectomized rats than in controls. There was a significant decrease in corticosteroid production by the intact gland. These changes were most marked after destruction of the dorsal parts of the nucleus. These data provide evidence for involvement of the striatum in controlling HHAS activity via a feedback mechanism.

Corticosteroids for treating severe sepsis and septic shock.

Sepsis may be complicated by impaired corticosteroid production. Giving corticosteroids could potentially benefit patients. To examine the effects of corticosteroids on death at one month in patients with severe sepsis and septic shock. We searched the Cochrane Infectious Diseases Group's trial register (August 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2003), MEDLINE (August 2003), EMBASE (August 2003), LILACS (August 2003), reference lists of articles, and also contacted trial authors. Randomized and quasi-randomized controlled trials of corticosteroids versus placebo or supportive treatment in severe sepsis and septic shock. Two pairs of reviewers agreed the eligibility of trials. One reviewer extracted data, which was checked by the other reviewers and the primary author of the paper whenever possible. We obtained some missing data from the trial authors. We assessed trial methodological quality. We identified 15 trials (n =2023). Corticosteroids did not change 28-day all-cause mortality (15 trials, n = 2022, relative risk (RR) 0.92, 95% confidence interval (CI) 0.75 to 1.14; random effects model) and hospital mortality (13 trials, n = 1418, RR 0.89, 95% CI 0.71 to 1.11; random effects model); however, there was statistically significant heterogeneity, with some evidence that this was related to the dosing strategy. Corticosteroids reduced intensive care unit mortality (4 trials, n = 425, RR 0.83, 95% CI 0.70 to 0.97), increased the proportion of shock reversal by day 7 (6 trials, n = 728, RR 1.22, 95% CI 1.06 to 1.40) and by day 28 (4 trials, n = 425, RR 1.26, 95% CI 1.04 to 1.52), without increasing the rate of gastroduodenal bleeding (10 trials, n = 1321, RR 1.16, 95% CI 0.82 to 1.65), superinfection (12 trials, n = 1705, RR 0.93, 95% CI 0.73 to 1.18), and of hyperglycaemia (6 trials, n = 608, RR 1.22, 0.84 to 1.78). Overall, corticosteroids did not change 28-day mortality and hospital mortality in severe sepsis and septic shock. Long course of low dose corticosteroids reduced 28-day all-cause mortality, and intensive care unit and hospital mortality.

Is Reduced Cell Size the Mechanism for Shrinkage of the Adrenal Zona Reticularis in Aging?

In aging humans, corticosteroid production is preserved, or even increased, but there is an unexplained reduction in adrenal androgen secretion that likely has significant health implications. Preliminary analyses on adrenocortical morphology have revealed an age‐associated reduction in the thickness of the zona reticularis (ZR), the cortical zone responsible for the majority of DHEA/DHEA sulfate production in the adult human, but no change in the overall thickness of the adrenal cortex. The ZR width could decrease in aging due to loss of ZR cells and/or to shrinkage of ZR cells. In the current study, we investigated whether there was a relation between thickness of the zona reticularis in young and old humans and the cell density in this zone. Paraffin‐embedded sections of the adrenal cortex of 10 young (21–35 yr old) and 10 old (54–89 yr old) adults who had died suddenly as the result of trauma were stained with hematoxylin and eosin. These specimens were chosen from a larger cohort of samples for having a broad ZR in the young group and a narrower ZR in the older group. After determining the overall cortical thickness and the width of the ZR by use of computerized image analysis software, we counted the number of adrenocortical cells in two random high power fields of the ZR of each specimen. The ZR width of the older group (57 ± 7 arbitrary units, Mean ± SE) was significantly reduced compared to that of the young group (124 ± 21), P < 0.001. On the other hand, the overall cortical width in the old group (232 ± 17) was similar to that of the young adults (249 ± 38). In the old group, the ZR comprised 24.7 ± 3% of the total cortical width, whereas it was 50 ± 2% of the cortical width in the young adrenals, P < 0.001. The cell density (cell number/60 × high power field) of the ZR of old adults (83 ± 9) was similar to that of the young group (87 ± 5). In summary, although the width of the ZR regresses with aging, cell size in this zone is preserved. Therefore, loss of trophic support for ZR cells would not appear to be the explanation for zonal shrinkage in aging. Rather, it is likely that aging effects may be due to increased cell loss in the ZR or else reduced rates of differentiation/migration of cells into this cortical zone.

Extra-adrenal production of corticosteroids.

1. The major corticosteroids aldosterone and cortisol (corticosterone in rodents) are secreted from the adrenal cortex under the regulation of the renin-angiotensin system and the hypothalamic-pituitary-adrenal axis. 2. In addition to their accepted roles in such processes as blood pressure regulation, glycogenesis, hepatic glyconeogenesis and immunosuppression, the corticosteroids have been implicated in the development of cardiac fibrosis, modulation of hippocampal neuron excitability, memory formation and neurodegeneration. 3. The advent of sensitive molecular biological techniques has produced a wealth of evidence to support the existence of extra-adrenal corticosteroidogenic systems. Most attention has been paid to the cardiovascular system and the central nervous system, where the full array of enzymes required for the de novo synthesis of corticosteroids from cholesterol has been identified. 4. Although the evidence for local corticosteroid production is strong, the quantities of steroid would be small compared with adrenal production. Therefore, it is still a matter of debate as to whether extra-adrenal corticosteroids are of any physiological significance. This will depend on factors such as local concentration, proximity to target cells and, possibly, to tissue-specific control mechanisms.

Dehydroepiandrosterone, a sex steroid metabolite in development for systemic lupus erythematosus

Deficiency of the weak androgen dehydroepiandrosterone (DHEA) and its sulfoconjugated metabolite DHEA-S has been associated with a number of serious illnesses, including lupus, diabetes, Alzheimer’s disease and some cancers. Accordingly, supplementation with DHEA has been proposed for a variety of illnesses. Observational clinical studies and in vitro experiments have suggested that DHEA treatment might have a significant impact on immunological function, bone density, cognition, atherosclerotic disease, some malignancies, insulin resistance and obesity. Endogenous circulating DHEA levels, however, may vary widely by gender, age and ethnicity and can be affected by acute changes in corticosteroid production, alcohol intake, smoking, body mass index, medications and thyroid function [1-3]. Clearly, these variables complicate the interpretation of clinical data. DHEA also gives rise to a number of as yet poorly characterised metabolites, further confusing the assessment of its net effects when considered as treatment in heterogenous populations. Given the complexity of potential effects of DHEA and its metabolites, coupled to the diversity of clinical conditions that they might, at least in theory, affect, it is not surprising that clinical confirmation of efficacy in several clinical contexts has been inconsistent and controversial, hampering drug development in what might potentially be an important and widespread market. The current review will consider recent work suggesting efficacy of DHEA (GL-701, prasterone, Prestara™ [US], Anastar™ [Europe]; Genelabs) in systemic lupus erythematosus.

Localization and role of serotonin in the adrenal gland of Podarcis sicula (Reptilia, Lacertidae)

The occurrence of serotonin (5-hydroxytryptamine; 5-HT) in the chromaffin cells of Podarcis sicula adrenal gland was demonstrated by immunocytochemical techniques: ABC and immunogold methods. At LM and EM levels, antiserum against 5-HT revealed serotonin immunoreactivity prevalently in noradrenalin (NA) cells, on and around secretory vesicles; adrenalin (A) cells appeared scarcely stained. The role of serotonin in the regulation of adrenal gland activity was studied in vivo using LM and EM techniques coupled to a specific radioimmunoassay for adrenocorticotropic hormone (ACTH) and corticosterone. 5-HT (0.7 mg/100 g body wt)/day for 4 days increased ACTH and corticosterone release; at LM and EM level clear signs of stimulation in the steroidogenic tissue were observed, as evidenced by the variations of lipid/cytoplasm ratio. In the chromaffin tissue, LM observations evidenced a variation of the numeric NA/A cell ratio; at EM level, chromaffin tissue showed intermediate cells with A, NA, and very clear granules with granular elements. The occurrence of these cells might be the result of a process of resynthesis following serotonin-stimulated catecholamine release. These data suggested that serotonin might be involved in the modulation of Podarcis pituitary–adrenal axis, and act as a paracrine factor to modulate corticosteroid production.

Influence of estradiol on cortisol secretion in ovariectomized cynomolgus macaques (Macaca fascicularis).

In an investigation of cortisol secretion in fully mature, ovariectomized cynomolgus monkeys (Macaca fascicularis), we compared monkeys that were given either placebo (OVX, n = 26) or 17beta estradiol (E(2 )) (EST, n = 26) in a daily oral dose. Serum cortisol concentrations were measured prior to the experimental manipulation and 3, 6, 9, and 12 months following initiation of treatment. Pretreatment cortisol values did not differ between groups. Assessment of the treatment period values revealed that cortisol concentrations were significantly higher ( approximately 10%) in the EST than in the OVX monkeys. Cortisol also varied significantly across periods of sampling. This time-dependent variation was attributable to elevations in months 6 and 9 (when daylight was generally long), relative to months 3 and 12 (when daylight was relatively short). The modest stimulatory effect of estrogen on corticosteroid production observed in this study is consistent with what has been seen in women, and contrasts with the more robust effects observed in New World monkeys. The possible relationship between season and cortisol secretion observed here has not been previously described in monkeys.

Seasonal alterations in adrenocortical cell function associated with stress-responsiveness and sex in the eastern fence lizard ( Sceloporus undulatus)

We characterized steroidogenic properties of dispersed adrenocortical cells from field-active male and female eastern fence lizards ( Sceloporus undulatus) to investigate whether alterations in cell function could, in part, explain seasonal variation in baseline and stress-induced plasma corticosterone (B). Lizards were collected during the breeding and postbreeding seasons and shortly prior to hibernation. Dispersed cells in vitro produced B, aldosterone (ALDO), and progesterone in response to 8-Br-cAMP, 25-(OH)cholesterol, adrenocorticotropin (ACTH; as little as 100 fM), and angiotensin II. Maximal progesterone, B, and ALDO responses to ACTH were roughly 1000%, 500%, and 100% greater than corresponding basal values. Angiotensin II was an effective steroidogenic stimulant but much less so than ACTH. Corticosteroid production exhibited considerable steroid-specific variation among seasons. Maximal ACTH-induced B production was lower in the postbreeding season than at either of the other two measurement points, essentially opposite to the pattern for ALDO. Males and females generally produced B at similar rates, but ALDO and progesterone showed numerous sex differences that usually covaried between the two steroids. Cellular sensitivity to 25-(OH)cholesterol and angiotensin II showed few sex differences or seasonal changes. In contrast, sensitivity to ACTH decreased markedly from the breeding to the postbreeding season in males, corresponding to the decrease in stress-responsiveness, and in both sexes was considerably lower prior to hibernation than during the breeding season. Under some conditions, plasma B may be limited by the production capacity of adrenocortical cells. In summary, seasonal variations in body condition, reproductive activity, and baseline and stress-induced plasma B may be attributed at least in part to alterations in adrenocortical cell steroidogenic function.

Dehydroepiandrosterone, a sex steroid metabolite in development for systemic lupus erythematosus

Deficiency of the weak androgen dehydroepiandrosterone (DHEA) and its sulfoconjugated metabolite DHEA-S has been associated with a number of serious illnesses, including lupus, diabetes, Alzheimer’s disease and some cancers. Accordingly, supplementation with DHEA has been proposed for a variety of illnesses. Observational clinical studies and in vitro experiments have suggested that DHEA treatment might have a significant impact on immunological function, bone density, cognition, atherosclerotic disease, some malignancies, insulin resistance and obesity. Endogenous circulating DHEA levels, however, may vary widely by gender, age and ethnicity and can be affected by acute changes in corticosteroid production, alcohol intake, smoking, body mass index, medications and thyroid function [1-3]. Clearly, these variables complicate the interpretation of clinical data. DHEA also gives rise to a number of as yet poorly characterised metabolites, further confusing the assessment of its net effects when considered as treatment in heterogenous populations. Given the complexity of potential effects of DHEA and its metabolites, coupled to the diversity of clinical conditions that they might, at least in theory, affect, it is not surprising that clinical confirmation of efficacy in several clinical contexts has been inconsistent and controversial, hampering drug development in what might potentially be an important and widespread market. The current review will consider recent work suggesting efficacy of DHEA (GL-701, prasterone, Prestara™ [US], Anastar™ [Europe]; Genelabs) in systemic lupus erythematosus.