Home   About Us   eMedicine Search   Drug Development   Feedback   Google Scholar Search   Intranet 
Literature Database   News   Photo Gallery   Publications   Site Map   Site Search   Useful Links 
 

 Back to Literature Database

Enhanced by Neuroinformation

Cortisol reviews

(92 References)

Annane, D. (2003). "Sepsis clinical knowledge: a role of steroid treatment." Minerva Anestesiol 69(4): 254-7.

            After a period of initial enthusiasm, several trials cast serious doubts on the usefulness of corticosteroids for the treatment of patients with severe sepsis. Short course with high doses of steroides should not be given in patients with severe sepsis. The attention is now addressed to low-dose of corticosteroides. The rational for a replacement therapy with hydrocortisone in patients with cathecolamines-dependent septic shock is based on the concept that this may be complicated by an occult adrenal insufficiency and a glucocorticoid peripheral resistance syndrome. Low doses of hydrocortisone has been shown to reproduce the normal effects of cortisol: anti-inflammatory properties and an increased in the vasoconstrictor response to cathecolamines. There is no concordance in literature about the role of replacement therapy with hydrocortisone on survival in patients with septic shock. Waiting for the results of the European confirmatory phase III trial, and based on the results of the French phase III trial, one may recommended to treat septic shock patients who have a cortisol increment after ACTH of less than 9 micro g/dl with 50 mg of hydrocortisone every 6 hours for seven days combined with 50 micro g of fludrocortisone once a day for seven days.

Apter, A. J. (2003). "Clinical advances in adult asthma." J Allergy Clin Immunol 111(3 Suppl): S780-4.

            From October 2001 through September 2002, reports of clinical research on asthma in adults focused on the epidemiology of asthma, the investigation of pharmacologic and immunologic therapy in the context of new national guidelines, and discussions of medical economics. Epidemiologic findings include the observation that overall mortality has declined and hospitalizations have remained constant in the United States since 1995, although these rates are at least twice as high in Blacks. Socially and economically disadvantaged groups receive poorer health care for asthma. Young children who have fewer than 5 episodes of wheezing in conjunction with respiratory infections generally have a good prognosis and do not have compromised lung function as adults. Pharmacologic reports and the National Asthma Education and Prevention Program Update recommend low- to medium-dose inhaled steroids combined with a long-acting beta-agonist as the preferred therapy for moderate persistent asthma. The use of chlorofluorocarbon-free medications for asthma is increasing. Medications comprise the largest cost category for asthma.

Babisch, W. (2003). "Stress hormones in the research on cardiovascular effects of noise." Noise Health 5(18): 1-11.

            In recent years, the measurement of stress hormones including adrenaline, noradrenaline and cortisol has been widely used to study the possible increase in cardiovascular risk of noise exposed subjects. Since endocrine changes manifesting in physiological disorders come first in the chain of cause-effect for perceived noise stress, noise effects in stress hormones may therefore be detected in populations after relatively short periods of noise exposure. This makes stress hormones a useful stress indicator, but regarding a risk assessment, the interpretation of endocrine noise effects is often a qualitative one rather than a quantitative one. Stress hormones can be used in noise studies to study mechanisms of physiological reactions to noise and to identify vulnerable groups. A review is given about findings in stress hormones from laboratory, occupational and environmental studies.

Bailer, U. F. and W. H. Kaye (2003). "A review of neuropeptide and neuroendocrine dysregulation in anorexia and bulimia nervosa." Curr Drug Target CNS Neurol Disord 2(1): 53-9.

            Neuropeptides play an important role in the regulation of feeding behavior and obesity. The mechanisms for controlling food intake involve a complicated interplay between peripheral systems (including gustatory stimulation, gastrointestinal peptide secretion, and vagal afferent nerve responses) and central nervous system (CNS) neuropeptides and/or monoamines. These neuronal systems include neuropeptides (CRH, opioids, neuropeptide-Y (NPY) and peptide YY (PYY), vasopressin and oxytocin, CCK, and leptin) and monamines (serotonin, dopamine, norepinephrine). In addition to regulating eating behavior, a number of CNS neuropeptides participate in the regulation of neuroendocrine pathways. Thus, clinical studies have evaluated the possibility that CNS neuropeptide alterations may contribute to dysregulated secretion of the gonadal hormones, cortisol, thyroid hormones and growth hormone in the eating disorders. Most of the neuroendocrine and neuropeptide alterations apparent during symptomatic episodes of AN and BN tend to normalize after recovery. This observation suggests that most of the disturbances are consequences rather than causes of malnutrition, weight loss and/or altered meal patterns. Still, an understanding of these neuropeptide disturbances may shed light on why many people with AN or BN cannot easily "reverse" their illness and even after weight gain and normalized eating patterns, many individuals who have recovered from AN or BN have physiological, behavioral and psychological symptoms that persist for extended periods of time.

Balk, R. A. (2003). "Steroids for septic shock: back from the dead? (Pro)." Chest 123(5 Suppl): 490S-9S.

            The use of corticosteroids as adjunctive therapy for severe sepsis and septic shock has been a source of controversy for the past 35 years. Despite a wealth of preclinical data supporting both survival and physiologic benefit for early steroid use, the data in human sepsis have been much less convincing. There have even been reports suggesting the potential for harm associated with the administration of early high-dose corticosteroids in patients with severe sepsis and septic shock. Recent trials have reported hemodynamic and survival benefits associated with the use of more physiologic steroid replacement therapy in patients with vasopressor-dependent septic shock. These results coupled with the observation of "relative adrenal insufficiency" in some patients with severe sepsis and septic shock may once again establish a defined role for corticosteroid therapy in the management of severe sepsis and septic shock.

Bartels, M., M. Van den Berg, et al. (2003). "Heritability of cortisol levels: review and simultaneous analysis of twin studies." Psychoneuroendocrinology 28(2): 121-37.

            Cortisol has a pivotal role in physical and mental health, but relatively few studies have paid attention to individual differences in cortisol levels and the etiology of these differences, in particular their possible genetic basis. In this article we review the existing literature on the heritability of cortisol levels. Most of the studies, which have been carried out in genetically informative samples, lack methodological consistency with regard to frequency and timing of sample collection. The circadian rhythm in cortisol levels was often not taken into account. A power analysis shows that none of these studies used adequate sample sizes to distinguish genetic from shared environmental influences as a cause for familial aggregation. Results of a simultaneous analysis of 5 comparable twin studies suggest a heritability of 62%. Hence, we conclude that, to understand the contribution of genetic and (shared) environmental influences to variation in basal cortisol levels, future studies should be designed more rigorously with strict collection and sampling protocols, sufficient sample size and repeated measures across multiple days.

Barzon, L., N. Sonino, et al. (2003). "Prevalence and natural history of adrenal incidentalomas." Eur J Endocrinol 149(4): 273-85.

            Clinically silent adrenal masses discovered by imaging studies performed for unrelated reasons, i.e. adrenal incidentalomas, have become a rather common finding in clinical practice. However, only limited studies of incidence, prevalence, and natural history of adrenal incidentalomas are available. A comprehensive review of the literature shows the prevalence of adrenal incidentalomas to be 2.3% at autopsy and 0.5-2% at abdominal computed tomography scan. Most lesions are adrenocortical adenomas at histology, whereas the prevalence of adrenocortical carcinomas is relatively low. The risk of malignancy over time for masses defined as benign at diagnosis is estimated at about 1/1000, even though 5-25% of masses increase in size during follow-up. Hyperfunction develops in about 1.7% of cases and the risk is higher in patients with lesions larger than 3 cm. Cortisol hypersecretion is the most likely disorder that may ensue, and it remains subclinical in about two-thirds of cases. The lack of controlled studies precludes making specific management recommendations. Large perspective controlled studies to define the epidemiology, natural history, and possible associated morbidity of adrenal incidentalomas and their impact on the quality of life of patients are needed.

Beishuizen, A. and L. G. Thijs (2003). "Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis." J Endotoxin Res 9(1): 3-24.

            Endotoxin is considered to be a systemic (immunological) stressor eliciting a prolonged activation of the hypothalamo-pituitary-adrenal (HPA) axis. The HPA-axis response after an endotoxin challenge is mainly due to released cytokines (IL-1, IL-6 and TNF-alpha) from stimulated peripheral immune cells, which in turn stimulate different levels of the HPA axis. Controversy exists regarding the main locus of action of endotoxin on glucocorticoid secretion, since the effect of endotoxin on this neuro-endocrine axis has been observed in intact animals and after ablation of the hypothalamus; however, a lack of LPS effect has been described at both pituitary and adrenocortical levels. The resulting increase in adrenal glucocorticoids has well-documented inhibitory effects on the inflammatory process and on inflammatory cytokine release. Therefore, immune activation of the adrenal gland by endotoxin is thought to occur by cytokine stimulation of corticosteroid-releasing hormone (CRH) production in the median eminence of the hypothalamus, which, in turn stimulates the secretion of ACTH from the pituitary. Acute administration of endotoxin stimulates ACTH and cortisol secretion and the release of CRH and vasopressin (AVP) in the hypophysial portal blood. During repeated endotoxemia, tolerance of both immune and HPA function develops, with a crucial role for glucocorticoids in the modulation of the HPA axis. A single exposure to a high dose of LPS can induce a long-lasting state of tolerance to a second exposure of LPS, affecting the response of plasma TNF-alpha and HPA hormones. Although there are gender differences in the HPA response to endotoxin and IL-1, these responses are enhanced by castration and attenuated by androgen and estrogen replacement. Estrogens attenuate the endotoxin-induced stimulation of IL-6, TNF-alpha and IL-1ra release and subsequent activation in postmenopausal women. There appears to be a temporal and functional relation between the HPA-axis response to endotoxin and nitric oxide formation in the neuro-endocrine hypothalamus, suggesting a stimulatory role for nitric oxide in modulating the HPA response to immune challenges.

Bertagna, X., L. Groussin, et al. (2003). "Aberrant receptor-mediated Cushing's syndrome." Horm Res 59 Suppl 1: 99-103.

            Multiple alterations of G-protein-coupled receptors and G-proteins regulating intracellular transduction signal have been described in endocrine tumours. In Cushing's syndrome, aberrant or 'illicit' expression of membrane receptors (mainly G-protein-coupled receptors) has been observed in adrenal adenomas and adrenocorticotropic hormone (ACTH)-independent macronodular bilateral adrenal hyperplasia. The best characterized example to date is the aberrant expression of the gastric inhibitory polypeptide receptor that causes 'food-dependent hypercortisolism'. Aberrant expression of the luteinizing hormone, 2-adrenergic, interleukin receptors have also been reported. The level of expression of the vasopressin V1a receptor correlates with the direct (ACTH-independent) cortisol response to vasopressin.

Bramnert, M., B. Ekman, et al. (2003). "[Guidelines for substitution therapy in pituitary insufficiency in adults]." Lakartidningen 100(39): 3043-9.

Buijs, R. M., C. G. van Eden, et al. (2003). "The biological clock tunes the organs of the body: timing by hormones and the autonomic nervous system." J Endocrinol 177(1): 17-26.

            The biological clock, the suprachiasmatic nucleus (SCN), is essential for our daily well-being. It prepares us for the upcoming period of activity by an anticipatory rise in heart rate, glucose and cortisol. At the same time the 'hormone of the darkness', melatonin, decreases. Thus, the time-of-day message penetrates into all tissues, interestingly not only by means of hormones but also by a direct neuronal influence of the SCN on the organs of the body. The axis between the SCN and the paraventricular nucleus of the hypothalamus (PVN) is crucial for the organization/synchronization of the neuroendocrine and autonomic nervous system with the time of day. This SCN-neuroendocrine PVN axis takes care of a timely hormonal secretion. At the same time, the SCN-autonomic PVN axis fine-tunes the organs by means of the autonomic nervous system for the reception of these hormones. Finally, the similar organization of the projections of the human SCN as compared with that in the rodent brain suggests that these basic principles of neuroendocrine autonomic interaction may also be true in the human. The physiological data collected in humans thus far seem to support this hypothesis, while pathological changes in the SCN of humans suffering from depression or hypertension indicate a role for the SCN in the etiology of these diseases.

Buitelaar, J. K., A. C. Huizink, et al. (2003). "Prenatal stress and cognitive development and temperament in infants." Neurobiol Aging 24 Suppl 1: S53-60; discussion S67-8.

            Studies in rodents and nonhuman primates indicate that maternal stress during pregnancy can influence the developing fetus, resulting in delay of motor and cognitive development and impaired adaptation to stressful situations. These effects may be mediated by the hypothalamic-pituitary-adrenal (HPA) axis. We examined whether stress during pregnancy predicted developmental outcome of human infants in a prospective design. Self-report data about daily hassles and pregnancy-specific anxiety and salivary cortisol levels were collected in nulliparous pregnant women. Dependent measures were scores on the Bayley Scales of Infant Development and on temperamental questionnaires at 3 and 8 months. Pregnancy-specific anxiety in mid pregnancy predicted lower mental and motor developmental scores at 8 months. Early morning values of cortisol in late pregnancy were negatively related to both mental and motor development at 3 months and motor development at 8 months. Pregnancy-specific anxiety explained 7% of the variance of test-affectivity and goal-directedness at 8 months. Increased maternal stress during pregnancy seems to be one of the determinants of temperamental variation and delay of development of infants and may be a risk factor for developing psychopathology later in life.

Cleare, A. J. (2003). "The neuroendocrinology of chronic fatigue syndrome." Endocr Rev 24(2): 236-52.

            Chronic fatigue syndrome (CFS) is a common and disabling problem; although most likely of biopsychosocial origin, the nature of the pathophysiological components remains unclear. There has been a wealth of interest in the endocrinology of this condition, which will be reviewed in this article. Most studied has been the hypothalamic-pituitary-adrenal (HPA) axis; although the quality of many studies is poor, the overall balance of evidence points to reduced cortisol output in at least some patients, with some evidence that this is linked to symptom production or persistence. There is evidence for heightened negative feedback and glucocorticoid receptor function and for impaired ACTH and cortisol responses to a variety of challenges. However, there is no evidence for a specific or uniform dysfunction of the HPA axis. Given the many factors that may impinge on the HPA axis in CFS, such as inactivity, sleep disturbance, psychiatric comorbidity, medication, and ongoing stress, it seems likely that HPA axis disturbance is heterogeneous and of multifactorial etiology in CFS. Studies assessing GH, dehydroepiandrostenedione and its sulfate, melatonin, leptin, and neuroendocrine-monoamine interactions are also reviewed. There is some evidence from these studies to suggest alterations of dehydroepiandrostenedione sulfate function and abnormal serotonin function in CFS, but whether these changes are of functional importance remains unclear. To obtain a clearer assessment of the etiological and pathophysiological relevance of endocrine changes in CFS, it is suggested that more prospective cohort studies be undertaken in groups at high risk for CFS, that patients with CFS are followed up into recovery, and that multidimensional assessments are undertaken to unravel the influence of the various confounding factors on the observed endocrine changes in CFS.

Connell, J. M., R. Fraser, et al. (2003). "Is altered adrenal steroid biosynthesis a key intermediate phenotype in hypertension?" Hypertension 41(5): 993-9.

            Approximately 10% of patients with hypertension have a high ratio of aldosterone to renin, but the reason for this and the relationships among low-renin essential hypertension, elevation of the ratio, and true primary aldosteronism are unclear. We have previously reported that a polymorphism of the gene (C-to-T conversion at position -344) encoding aldosterone synthase is associated with hypertension, particularly in patients with a high ratio. However, the most consistent association with this variant is a relative impairment of adrenal 11beta-hydroxylation. In this review, we propose that altered conversion of deoxycortisol to cortisol leads to a subtle, chronic increase in adrenocortrophin drive to the adrenal cortex, with eventual development of hyperplasia. In combination with other genetic or environmental factors (such as dietary sodium intake), we suggest that this might be responsible for the long-term development of a resetting of the aldosterone response to angiotensin II, giving rise to the phenotype of hypertension with a raised ratio. In some subjects, this may progress further to true primary aldosteronism with a dominant adrenal nodule. Thus, there may be a genetically influenced continuum from hypertension with a normal ratio, through hypertension with a raised ratio, and primary aldosteronism.

Cooper, M. S. and P. M. Stewart (2003). "Corticosteroid insufficiency in acutely ill patients." N Engl J Med 348(8): 727-34.

Crowley, S. (2003). "Inhaled glucocorticoids and adrenal function: an update." Paediatr Respir Rev 4(2): 153-61.

            For the vast majority of asthmatic children, treatment with inhaled glucocorticoids is safe and effective. Mild impairment of adrenal function of doubtful clinical significance is known to occur in some children inhaling > or = 400 micro g/day budesonide and beclomethasone or > or = 200 micro g fluticasone. Recent reports of life-threatening adrenal failure in asthmatic children inhaling glucocorticoids, some of whom were prescribed licensed doses, have prompted the recommendation that the use of high-dose inhaled glucocorticoids, particularly fluticasone, should be avoided. However, the importance of correctly diagnosing asthma, of using the minimum dose of inhaled glucocorticoid required for symptom control and of regular growth-velocity assessment cannot be over-emphasised. Appropriate asthma management including the early introduction of steroid-sparing agents such as a long-acting beta-agonist or leukotriene antagonist may reduce the morbidity associated with inhaled glucocorticoid use but some children, for reasons as yet unknown, may exhibit increased sensitivity to the systemic effects of inhaled glucocorticoid treatment. Possible explanations for this, with reference to the pharmacology and molecular mechanisms of glucocorticoid action, are accompanied in this review by a summary of the recent case reports and discussion of assessment of adrenal function.

Cutolo, M., A. Sulli, et al. (2003). "Hypothalamic-pituitary-adrenocortical and gonadal functions in rheumatoid arthritis." Ann N Y Acad Sci 992: 107-17.

            Rheumatoid arthritis (RA) as well as most autoimmune disorders results from a combination of several predisposing factors including the relations between epitopes of the trigger agent (i.e., virus, self-antigens) and histocompatibility epitopes (i.e., HLA), the status of the stress response system including the hypothalamic-pituitary-adrenocortical axis (HPA) and the sympathetic nervous system (SNS), as well as the gonadal hormones (hypothalamic-pituitary-gonadal axis, HPG), with estrogens implicated as enhancers of the immune response and androgens and progesterone as natural suppressors. The regular observation of reduced cortisol and adrenal androgen secretion during testing in RA patients not treated with glucocorticoids should clearly be regarded as "relative adrenal insufficiency" in the setting of a sustained inflammatory process, as shown by high interleukin (IL)-6 levels. In polymyalgia rheumatica, several pathogenetic and clinical aspects of the disease might well overlap RA, at least with elderly onset RA (EORA). Therefore, reduced production of adrenal hormones (i.e., cortisol, DHEAS) at baseline in active and untreated patients with polymyalgia rheumatica was detected. The defect was mainly related to altered adrenal responsiveness to ACTH stimulation (i.e., increased 17-OHP), at least in untreated patients with polymyalgia rheumatica. Finally, normal serum estrogen and low androgen levels, but high synovial fluid estrogen and much lower androgen levels, have been found in RA patients, supporting the fundamental role of the peripheral sex hormone metabolism in the manifestations of the disease.

Czarnecki, T. and E. Czarnecka (2003). "[Aspects of chronobiological effects of ethanol]." Psychiatr Pol 37(3): 503-10.

            Circadian rhythms regulate various life processes in plants, animals and in humans. These rhythms are generated by an endogenous mechanism called the biological clock. It has been known that there is circadian variability of receptors susceptibility to drugs and circadian changes of drugs kinetics. Biological effects of ethanol raise interest of many researchers due to consequences of its use. Effects of ethanol on various ion channels and receptors suggest that its action may also depend on circadian rhythms and may modulate action of the biological clock. Experimental studies on animals and humans have shown that circadian variability influences hypnotic and hypothermic effects of ethanol, cortisol levels, ethanol pharmacokinetics and ethanol intake. Chronic ethanol administration influence thyroid and sex hormones excretion, stimulate the HPA axis and changes various circadian rhythms (of sleep, motor activity and food intake). Changes in circadian ethanol effects may have significance for toxicity and interaction with drugs. Disturbances of circadian rhythms in alcohol-dependent patients may case therapeutic problems.

De Bellis, M. D. and L. A. Thomas (2003). "Biologic findings of post-traumatic stress disorder and child maltreatment." Curr Psychiatry Rep 5(2): 108-17.

            Child maltreatment is a serious problem in US society, affecting approximately three million children. Children and adolescents exposed to child abuse and neglect experience high rates of post-traumatic stress disorder (PTSD). In addition, they are at risk for comorbid mental illness. Biologic stress systems affected in trauma and in PTSD are complex. Findings in cognitive testing, neuroimaging, and affected pathways shed light on the consequences of child maltreatment. What is known about treatment and outcomes for children with history of maltreatment and maltreatment-related PTSD indicates the need for prevention, intervention, and treatment of children exposed to abuse and neglect. The following is a brief review of the most recent neurobiologic findings in child maltreatment and related PTSD.

de Kloet, E. R. (2003). "Hormones, brain and stress." Endocr Regul 37(2): 51-68.

            The stress system orchestrates body and brain responses to the environment. This action exerted by the mediators of the stress system has two modes of operation. The immediate response mode driven by corticotropin-releasing hormone (CRH) organises via CRH-1 receptors the behavioural, sympathetic and hypothalamic-pituitary-adrenal (HPA) responses to a stressor. In the other - slower - mode, which facilitates behavioural adaptation, the urocortins acting through CRH-2 receptors seem prominent. Corticosteroid hormones secreted by the adrenal cortex are implicated in both modes through their high affinity type 1 (mineralocorticoid receptors - MR) and lower affinity type 2 (glucocorticoid receptors - GR) receptors that are co-localised in limbic neural circuitry. Current data suggest that MR controls in specific afferents the threshold or sensitivity of the fast CRH-1 driven stress system mode and thus prevents disturbance of homeostasis, while GR facilitates its recovery by restraining in these very same circuits stress responses and by mobilising energy resources. In preparation for future events GR facilitates behavioural adaptation and promotes storage of energy. The balance in the two stress system modes is thought to be essential for cell homeostasis, mental performance and health. Imbalance induced by genetic modification or chronic stressors changes specific neural signalling pathways underlying psychic domains of cognition and emotion, anxiety and aggression. This Yin-Yang stress concept is fundamental for genomic strategies to understand the mechanistic underpinning of cortisol-induced stress-related disorders such as i.e. severe forms of depression and co-morbid diseases.

Dorin, R. I., C. R. Qualls, et al. (2003). "Diagnosis of adrenal insufficiency." Ann Intern Med 139(3): 194-204.

            BACKGROUND: The cosyntropin stimulation test is the initial endocrine evaluation of suspected primary or secondary adrenal insufficiency. PURPOSE: To critically review the utility of the cosyntropin stimulation test for evaluating adrenal insufficiency. DATA SOURCES: The MEDLINE database was searched from 1966 to 2002 for all English-language papers related to the diagnosis of adrenal insufficiency. STUDY SELECTION: Studies with fewer than 5 persons with primary or secondary adrenal insufficiency or with fewer than 10 persons as normal controls were excluded. For secondary adrenal insufficiency, only studies that stratified participants by integrated tests of adrenal function were included. DATA EXTRACTION: Summary receiver-operating characteristic (ROC) curves were generated from all studies that provided sensitivity and specificity data for 250-microg and 1-microg cosyntropin tests; these curves were then compared by using area under the curve (AUC) methods. All estimated values are given with 95% CIs. DATA SYNTHESIS: At a specificity of 95%, sensitivities were 97%, 57%, and 61% for summary ROC curves in tests for primary adrenal insufficiency (250-microg cosyntropin test), secondary adrenal insufficiency (250-microg cosyntropin test), and secondary adrenal insufficiency (1-microg cosyntropin test), respectively. The area under the curve for primary adrenal insufficiency was significantly greater than the AUC for secondary adrenal insufficiency for the high-dose cosyntropin test (P < 0.001), but AUCs for the 250-microg and 1-microg cosyntropin tests did not differ significantly (P > 0.5) for secondary adrenal insufficiency. At a specificity of 95%, summary ROC analysis for the 250-microg cosyntropin test yielded a positive likelihood ratio of 11.5 (95% CI, 8.7 to 14.2) and a negative likelihood ratio of 0.45 (CI, 0.30 to 0.60) for the diagnosis of secondary adrenal insufficiency. CONCLUSIONS: Cortisol response to cosyntropin varies considerably among healthy persons. The cosyntropin test performs well in patients with primary adrenal insufficiency, but the lower sensitivity in patients with secondary adrenal insufficiency necessitates use of tests involving stimulation of the hypothalamus if the pretest probability is sufficiently high. The operating characteristics of the 250-microg and 1-microg cosyntropin tests are similar.

Enberg, U., C. Volpe, et al. (2003). "New aspects on primary aldosteronism." Neurochem Res 28(2): 327-32.

            The adrenal cortex synthesizes and releases steroid hormones, mainly mineralocorticoids and glucocorticoids. There is a functional zonation of the adrenal cortex and steroid synthesis is thoroughly regulated. Overproduction of aldosterone, primary aldosteronism, may be much more common than previously known and may be responsible for 10% of essential hypertension. Primary aldosteronism is characterized by autonomous production of aldosterone, suppressed renin activity, hypokalemia, and hypertension. The two most common forms are unilateral adenoma and bilateral hyperplasia. In spite of thorough clinical workup and careful histopathology it is often difficult to differentiate between adenoma and hyperplasia. The gene CYP11B2 encodes the steroid synthesizing enzymes for aldosterone production, while the genes CYP17 and CYP11B1 are needed for cortisol production. Most normal controls show expression of CYP11B2 in zona glomerulosa. Expression of CYP11B1 and CYP17 is seen in zona fasciculata and reticularis, whereas the expression of CYP21 is present in all three cortical layers. Adenomas from patients with primary aldosteronism show considerable variation in the expression of CYP11B2. Adenomas from patients with Cushing's syndrome have a strong expression of CYP11B1 and CYP17. In a patient material of 29 cases of primary aldosteronism, 4 patients had small nodules detected with expression of CYP11B2 gene. These nodules were not visualized on CT, whereas adrenal masses seen on CT in these patients showed CYP11B1 and CYP17 gene expression. This suggests that these small nodules are responsible for the aldosterone production and this is characteristic of nodular hyperplasia in patients with primary aldosteronism. In conclusion, this method to visualize mRNA gene expression of steroidogenic enzymes, and especially expression of CYP11B2, has increased the knowledge of adrenal pathophysiology. The results emphasize the value to include functional studies (venous sampling and/or scintigraphy) in the preoperative work up of patients with primary aldosteronism.

Erickson, K., W. Drevets, et al. (2003). "Glucocorticoid regulation of diverse cognitive functions in normal and pathological emotional states." Neurosci Biobehav Rev 27(3): 233-46.

            The glucocorticoid hormone cortisol is essential for many forms of regulatory physiology and for cognitive appraisal. Cortisol, while associated with fear and stress response, is also the hormone of energy metabolism and it coordinates behavioral adaptation to the environmental and internal conditions through the regulation of many neurotransmitters and neural circuits. Cortisol has diverse effects on many neuropeptide and neurotransmitter systems thus affecting functional brain systems. As a result, cortisol affects numerous cognitive domains including attention, perception, memory, and emotional processing. When certain pathological emotional states are present, cortisol may have a role in differential activation of brain regions, particularly suppression of hippocampal activation, enhancement of amygdala activity, and dendritic reshaping in these regions as well as in the ventral prefrontal cortex. The coordinated actions of glucocorticoid regulation on various brain systems such as those implicated in emotional processing can lead to perceptual and cognitive adaptations and distortions of events that may be relevant for understanding mood disorders.

Espinosa, G., E. Santos, et al. (2003). "Adrenal involvement in the antiphospholipid syndrome: clinical and immunologic characteristics of 86 patients." Medicine (Baltimore) 82(2): 106-18.

            To describe the clinical and immunologic characteristics of patients with adrenal involvement and antiphospholipid syndrome (APS), we conducted a computer-assisted (PubMed) search of the literature to identify all cases of primary adrenal insufficiency associated with antiphospholipid antibodies published in English, French, and Spanish from 1983 (when APS was first defined) through March 2002. We reviewed 86 patients (80 from the literature plus 6 from our cohort); 55% were male, and the mean age at presentation was 43 +/- 16 years. Sixty-one (71%) patients had primary APS, and 14 (16%) had systemic lupus erythematosus. In 31 (36%) patients, adrenal insufficiency was the first clinical manifestation of APS. Abdominal pain was present in 55% of patients, followed by hypotension (54%), fever (40%), nausea or vomiting (31%), weakness or fatigue (31%), and lethargy or altered mental status (19%). The main finding in imaging techniques was compatible with adrenal hemorrhage (59%) and in histopathologic study was a hemorrhagic infarction with vessel thrombosis (55%). Lupus anticoagulant was detected in 97% of patients and the anticardiolipin antibodies titer was positive in 93% of patients. Most patients (95%) were positive for the IgG isotype of anticardiolipin antibodies, whereas 40% were positive for the IgM isotype. Baseline cortisol levels were decreased in 98% of patients, ACTH hormone levels were increased in 96% of patients, and the cosyntropin stimulation test was positive in 100% of patients tested. Steroid replacement therapy was the most frequent treatment (84%), followed by anticoagulation (52%) and aspirin (6%). Thirty-two of 35 (91%) patients with prolonged anticoagulant therapy were in good health with a mean follow-up of 25 months, whereas 25 of the 69 (36%) patients with outcome data available had died. The results of the present review stress the clinical importance of systematic screening for lupus anticoagulant and anticardiolipin antibodies in all cases of adrenal hemorrhage or infarction. An initial screening for hypoadrenalism is mandatory in any antiphospholipid antibody-positive patient who complains of abdominal pain and undue weakness or asthenia.

Fazio, E. and A. Ferlazzo (2003). "Evaluation of stress during transport." Vet Res Commun 27 Suppl 1: 519-24.

            Domestic animals are transported for a variety of reasons including breeding, biomedical purposes, slaughter and, in the case of sporting horses, for competitions, pleasure activities or ceremonial proceedings. Studies to determine the amount of stress on farm animals during transport often have highly variable results and are difficult to interpret. The reaction of animals to stressors depends on the duration and intensity of the stressors, the animal's previous experience, its physiological status and the immediate environmental restraints. Behavioural, haematological, haematochemical, physiological and neuro-hormonal (beta-endorphin, ACTH, cortisol, iodothyronines) variables are discussed on the basis of handling, loading and transport procedures of animals.

Ferrari, P. and O. Bonny (2003). "Forms of mineralocorticoid hypertension." Vitam Horm 66: 113-56.

            Hypertension with hypokalemia, metabolic alkalosis, and suppressed plasma renin activity defines mineralocorticoid hypertension. Mineralocorticoid hypertension is the consequence of an overactivity of the epithelial sodium channel expressed at the apical membrane of renal cells in the distal nephron. This is usually the case when the mineralocorticoid receptor is activated by its physiologic substrate aldosterone. The best known form of mineralocorticoid hypertension is an aldosterone-producing adrenal tumor leading to primary aldosteronism. Primary aldosteronism can also be caused by unilateral or bilateral adrenal hyperplasia and rarely adrenal carcinoma. Interestingly, most of the inherited monogenic disorders associated with hypertension involve an excessive activation of the mineralocorticoid axis. In some of these disorders, mineralocorticoid hypertension results from activation of the mineralocorticoid receptor by other steroids (cortisol, deoxycorticosterone), by primary activation of the receptor itself, or by constitutive overactivity of the renal epithelial sodium channel. The present review addresses the physiology and significance of the key players of the mineralocorticoid axis, placing emphasis on the conditions leading to mineralocorticoid hypertension.

Frishman, W. H., V. Azer, et al. (2003). "Drug treatment of orthostatic hypotension and vasovagal syncope." Heart Dis 5(1): 49-64.

            Orthostatic hypotension is a common problem, estimated to occur in 5 out of every 1000 individuals and in as many as 7% to 17% of patients in an acute care setting. Moreover, orthostatic hypotension may be more prominent in elderly patients due to the increased intake of vasoactive medications and concomitant decrease in physiologic function, such as baroreceptor sensitivity, often seen with aging. Orthostatic hypotension is a fall in blood pressure on assuming an upright position. Absolute cutoffs for the drop in blood pressure are often difficult to determine because different patients exhibit varying degrees of tolerance to falls in blood pressure. Therefore, strict numerical criteria may lead to underdiagnosis and improper intervention. A thorough review of patient symptomatology combined with appropriate clinical tests should be employed to narrow the vast differential diagnosis and pinpoint the etiology. The fall in blood pressure seen in orthostatic hypotension results from the inability of the autonomic nervous system to adequately compensate for the 500 mL blood that is estimated to pool in the lower extremities on assuming an upright posture. The decrease in venous return results in a concomitant decrease in cardiac output and thus hypoperfusion of the cerebral circulation, possibly resulting in syncope or various other symptoms. A complete investigation should consider hypovolemia, removal of offending medications, primary autonomic disorders, secondary autonomic disorders and, of course, vasovagal syncope, the most common cause of syncope. Although further research is still necessary to rectify the disease process responsible for orthostatic hypotension, patients suffering from this disorder can effectively be treated through a combination of nonpharmacologic treatment, pharmacologic treatment and patient education. Agents such as fludrocortisone, midodrine and erythropoietin show promising results as therapeutic adjuncts. Treatment for recurrent vasovagal syncope includes increased salt intake, and various drug treatments, most of which are still under investigation.

Fukuda, M., T. Uehara, et al. (2003). "[Establishing biological markers for diagnosis and treatment of depression: possible availability of PET, NIRS, and DST]." Nippon Rinsho 61(9): 1667-82.

            Current diagnosis of depression depends on its clinical symptoms and signs, not on the results of any laboratory examinations. Establishing biological markers for diagnosis and treatment of depression is one of the most important problems to be solved in psychiatry practice. Near infrared spectroscopy(NIRS) is one of the recently developed methodologies, and can measure cerebral blood volumes simultaneously in multiple points with high time resolution. Multi-channel NIRS machines for clinical use have recently been developed by two medical companies in Japan. Authors presented the preliminary NIRS data showing that depression is characterized by decrease in cerebral blood volume activation during a word fluency task, and discussed their possible availability for diagnosis of depression.

Goustas, P., M. J. Cork, et al. (2003). "Eumovate (clobetasone butyrate 0.05%) cream: a review of clinical efficacy and safety." J Dermatolog Treat 14(2): 71-85.

            Topical steroid creams and ointments have been available as over-the-counter (OTC) medications for the self treatment of acute dermatitis and other steroid responsive skin disorders for more than ten years. Despite earlier fears, widespread availability and use of these creams is not associated with clinically significant adverse effects. In dermatological practice, hydrocortisone 1% remains the mainstay of treatment for facial eczema, but it is often not effective in eczema affecting other body areas. Eumovate(TM) (clobetasone butyrate 0.05%) cream has recently been made available as a pharmacy medication for the short-term management of acute eczema and allergic dermatitis by adults and children aged 10 or older, based on evidence derived from clinical trials involving over 3500 patients. This review summarises the key efficacy and safety data derived from 29 clinical trials and the post-licensing pharmacovigilance safety information, which supported the reclassification of this product for OTC use. These data show clobetasone butyrate 0.05% is more effective than 1.0% hydrocortisone in the treatment of eczema and more effective than flurandrenolone 0.0125% (p=0.01%) and a potent topical steroid hydrocortisone butyrate (p<0.05), in the treatment of psoriasis. A review of the effect of topical steroids on skin thickness concluded that, following short term application, there was no clinically significant difference between hydrocortisone 1.0% and clobetasone butyrate 0.05% in terms of potential for skin thinning. Similarly, even under extreme conditions, clobetasone butyrate 0.05% has negligible systemic absorption and has almost no effect on HPA axis function.

Greenwood, P. L. and A. W. Bell (2003). "Consequences of intra-uterine growth retardation for postnatal growth, metabolism and pathophysiology." Reprod Suppl 61: 195-206.

            Intra-uterine growth retardation (IUGR), caused by maternal undernutrition or placental insufficiency, is usually associated with disproportionately large reductions in the growth of some fetal organs and tissues (thymus, liver, spleen, thyroid) and impaired cellular development of other tissues (small intestine, secondary wool follicles, skeletal muscle). Growth of other tissues, most notably brain, is relatively unimpaired. In our restudy of postnatal consequences of IUGR in the offspring of prolific ewes, growth-retarded newborn lambs tended to be hypoglycaemic and showed sluggish postnatal engagement of the growth hormone (GH)-insulin-like growth factor (IGF) system. When artificially reared in an optimum environment, low birth weight lambs grew at rates similar to those of normal lambs. However, low birth weight lambs were fatter at any given weight, apparently related to their high energy intakes, especially soon after birth, had low maintenance energy requirements, and limited capacity for bone and muscle growth. These growth characteristics were accompanied by higher plasma concentrations of GH and leptin, and lower concentrations of insulin-like growth factor I (IGF-I) during the first 2 weeks of postnatal life, and higher concentrations of insulin during subsequent growth up to 20 kg body weight. Emerging evidence indicates that in sheep, as in rodents, fetal programming of postnatal cardiovascular and metabolic dysfunctions is associated with IUGR and may be mediated partly by overexposure of the fetus to cortisol. Similar postnatal responses can be elicited by maternal undernutrition or cortisol treatment in early to mid-pregnancy without changing the growth of the fetus or placenta.

Haff, G. G., M. J. Lehmkuhl, et al. (2003). "Carbohydrate supplementation and resistance training." J Strength Cond Res 17(1): 187-96.

            There is a growing body of evidence suggesting that the performance of resistance-training exercises can elicit a significant glycogenolytic effect that potentially could result in performance decrements. These decrements may result in less than optimal physiological adaptations to training. Currently some scientific evidence suggests that carbohydrate supplementation prior to and during high-volume resistance training results in the maintenance of muscle glycogen concentration, which potentially could result in the maintenance or increase of performance during a training bout. Some researchers suggest that ingesting carbohydrate supplements prior to and during resistance training may improve resistance-training performance. Additionally, the ingestion of carbohydrates following resistance exercise enhances the resynthesis of muscle glycogen, which may result in a faster time of recovery from resistance training, thus possibly allowing for a greater training volume. On the basis of the current scientific literature, it may be advisable for athletes who are performing high-volume resistance training to ingest carbohydrate supplements before, during, and immediately after resistance training.

Hagemann, D., J. J. Meier, et al. (2003). "[Appetite regulation by ghrelin - a novel neuro-endocrine gastric peptide hormone in the gut-brain-axis]." Z Gastroenterol 41(9): 929-36.

            Ghrelin a novel peptide consisting of 28 amino acids was first identified in the stomach in 1999. It is mainly produced in endocrine cells of the human gastric mucosa, but it was also found in several other tissues e. g. in the pituitary, the hypothalamus and the pancreas. The functional receptor belongs to the family of the 7-transmembrane G-protein receptors and is predominantly detected in the pituitary and at lower levels in hypothalamic nuclei, the stomach, heart, lungs, kidneys, gut, the adipose and many other tissues. According to the widespread distribution of the peptide and its receptor, ghrelin has multiple biological effects: it stimulates the release of growth hormone in the pituitary and induces a rise in the serum concentration of ACTH, cortisol, catecholamines and prolactin. Ghrelin causes an increase of food intake and body weight by stimulating the production of neuropeptide Y (NPY) and agouti-related protein (AGP) in the nucleus arcuatus. It further leads to elevated concentrations of plasma glucose. A physiological antagonism between ghrelin and GLP-1 in the hypothalamic regulation of appetite is being discussed. The basic serum level of ghrelin depends on the state of nutrition and is negatively correlated with the body-mass-index. It shows a certain pattern of variation before and after food intake with a preprandial increase and a postprandial decrease. Ghrelin modulates gastric acid secretion and the gastrointestinal motility via vagal cholinergic pathways. The discovery of ghrelin definitely contributes to the understanding of the growth-hormone secretion and of the regulation of appetite and food intake.

Han, Y. Y., J. A. Carcillo, et al. (2003). "Early reversal of pediatric-neonatal septic shock by community physicians is associated with improved outcome." Pediatrics 112(4): 793-9.

            OBJECTIVE: Experimental and clinical studies of septic shock support the concept that early resuscitation with fluid and inotropic therapies improves survival in a time-dependent manner. The new American College of Critical Care Medicine-Pediatric Advanced Life Support (ACCM-PALS) Guidelines for hemodynamic support of newborns and children in septic shock recommend this therapeutic approach. The objective of this study was to determine whether early septic shock reversal and use of resuscitation practice consistent with the new ACCM-PALS Guidelines by community physicians is associated with improved outcome. METHODS: A 9-year (January 1993-December 2001) retrospective cohort study was conducted of 91 infants and children who presented to local community hospitals with septic shock and required transport to Children's Hospital of Pittsburgh. Shock reversal (defined by return of normal systolic blood pressure and capillary refill time), resuscitation practice concurrence with ACCM-PALS Guidelines, and hospital mortality were measured. RESULTS: Overall, 26 (29%) patients died. Community physicians successfully achieved shock reversal in 24 (26%) patients at a median time of 75 minutes (when the transport team arrived at the patient's bedside), which was associated with 96% survival and >9-fold increased odds of survival (9.49 [1.07-83.89]). Each additional hour of persistent shock was associated with >2-fold increased odds of mortality (2.29 [1.19-4.44]). Nonsurvivors, compared with survivors, were treated with more inotropic therapies (dopamine/dobutamine [42% vs 20%] and epinephrine/norepinephrine [42% vs 6%]) but not increased fluid therapy (median volume; 32.9 mL/kg vs 20.0 mL/kg). Resuscitation practice was consistent with ACCM-PALS Guidelines in only 27 (30%) patients; however, when practice was in agreement with guideline recommendations, a lower mortality was observed (8% vs 38%). CONCLUSIONS: Early recognition and aggressive resuscitation of pediatric-neonatal septic shock by community physicians can save lives. Educational programs that promote ACCM-PALS recommended rapid, stepwise escalations in fluid as well as inotropic therapies may have value in improving outcomes in these children.

Harvey, P. W. and D. J. Everett (2003). "The adrenal cortex and steroidogenesis as cellular and molecular targets for toxicity: critical omissions from regulatory endocrine disrupter screening strategies for human health?" J Appl Toxicol 23(2): 81-7.

            Current testing strategies to assess the endocrine disrupting properties of chemicals have omitted examination of the adrenal gland and do not adequately cover the process of steroidogenesis. Steroidogenesis is critical for adrenocortical function as well as that of the testes and ovaries, and presents multiple molecular targets for toxicity, ranging from general effects on all steroidogenic tissues (e.g. via StAR protein or CYP11A1 cholesterol side-chain cleavage) through to specific targets affecting only adrenocortical function (e.g. CYP11beta/18 and glucocorticoid synthesis). Numerous chemicals of environmental relevance are now being shown to affect adrenocortical function both in vivo in aquatic species and in vitro in human cell lines, and given the vital role of the adrenal gland to human health and development, there is a strong case for including dedicated assessment techniques in screening batteries for endocrine-disrupting chemicals, not least to assist in general data interpretation (e.g. whether adrenal hypertrophy is due to stress or to a more sinister adrenocortical insufficiency). Cell lines such as H295R (derived from a human adrenocortical adenocarcinoma) currently exist that will allow assessment of cortisol production and most of the major enzymes and functional proteins in the steroidogenic pathway (e.g. StAR; CYP11A1/scc; CYP11beta/18; CYP17; CYP19; CYP21; 3beta-hydroxysteroid dehydrogenase). Adequate assessment of adrenocortical function, as with any component of the integrated endocrine system, probably also will require the development of specific in vivo methodology to include effects on hypothalamo-pituitary function. Finally, although there is currently no direct evidence that environmental exposure to endocrine-disrupting (oestrogenic) chemicals has actually caused adverse human health effects, lessons have been learned on their potential from the diethylstilboestrol case. Similar evidence exists from aminoglutethimide and etomidate on the lethal impact of unpredicted chemically induced adrenal insufficiency in sensitive human subgroups, and it would seem prudent to incorporate relevant tests for adrenal function and steroidogenesis into current regulatory validation programmes.

Holsboer, F. (2003). "Corticotropin-releasing hormone modulators and depression." Curr Opin Investig Drugs 4(1): 46-50.

            Basic and clinical studies demonstrate that the central corticotropin-releasing hormone (CRH) circuits are overactive among depressives, a phenomenon frequently reflected by enhanced cortisol and corticotropin levels in the peripheral blood of these patients. Behavioral pharmacology provided evidence that CRH overexpression accounts for many signs and symptoms characteristic of depression. CRH-type 1 receptors (CRHR), were identified as responsible for conveying the CRH signal into cellular circuitries, thereby inducing depression-related symptoms. In order to decrease CRH signaling, many pharmaceutical companies have developed small molecules that after oral ingestion, penetrate the blood-brain barrier and selectively bind at CRHR1 with high affinity. These compounds have been tested in animal models and patients with major depression. One of these compounds, R-121919 (Neurocrine Biosciences Inc), ameliorated depressive symptomatology without unwanted endocrine side effects or other adverse effects. While clinical trials of R-121919 have been discontinued after phase IIa studies, a number of other CRHR1 antagonists are being developed, and hopefully this advance will ultimately lead to a favorable alternative to currently available antidepressant drugs.

Hornsby, P. J., M. Chen, et al. (2003). "Using cell transplantation to investigate genes involved in aging." Mech Ageing Dev 124(1): 79-84.

            Cell transplantation provides a way to study genes that may be important in human tissue aging. Studies on gene action in human cells are usually restricted to cell culture investigations and clinical observations. Differences in human and rodent cellular biology, particularly with respect to telomere dynamics, show the need for new systems for investigating aging that use human cells or cells of other large, long-lived mammals, such as bovine cells. The system we describe uses human and bovine adrenocortical cells transplanted into scid (severe combined immunodeficiency) mice. They form a vascularized tissue structure that can replace the essential functions of the animals' own adrenal glands. The cells may be genetically modified before introduction into the animal. Using hTERT (telomerase reverse transcriptase) and oncoproteins, we show the potential for investigating gene action in genetically modified tissues created by cell transplantation.

Huitinga, I., Z. A. Erkut, et al. (2003). "The hypothalamo-pituitary-adrenal axis in multiple sclerosis." Ann N Y Acad Sci 992: 118-28.

            During multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), activation of the hypothalamo-pituitary-adrenal (HPA) axis is considered to modulate the immune system in such a way that the probability of recovery from a relapse is increased. In a series of postmortem studies we observed a significant activation of corticotropin releasing hormone (CRH) neurons and increased cortisol in the cerebrospinal fluid (CSF) of MS patients, indicating activation of the HPA axis in this disease. On the other hand, sepsis, while elevating cortisol in control subjects, did not associate with a further increase of cortisol in MS patients. Thus, the activated HPA-system in MS does not respond to an acute inflammatory stimulus. In order to investigate the role of chronic inflammation in the CNS in the activation of the HPA axis in MS, MS lesions in the hypothalamus were quantified and interleukin (IL)-6 levels in the CSF were determined. There was no difference in IL-6 levels between MS and control patients. A positive correlation was found between cortisol and IL-6 in control subjects with sepsis, but not in MS patients with sepsis or MS and control groups without sepsis. Thus, IL-6 in the CSF of MS patients is not the cause of the activation of the HPA system in MS. We found a remarkably high incidence (95% of the patients) of MS lesions in the hypothalamus, of which the majority (60%) were active. The more active lesions were present in the hypothalamus, the shorter the disease duration to the moment of death, indicative of a worse disease course. Preliminary data show suppression of the activation of CRH neurons by active hypothalamic MS lesions. We propose that this suppression of CRH neurons by active hypothalamic MS lesions causes the concomitant unfavorable disease course via an inadequate cortisol response during relapses of MS.

Imbriano, L. J., J. H. Durham, et al. (2003). "Treating interdialytic hyperkalemia with fludrocortisone." Semin Dial 16(1): 5-7.

            Hyperkalemia is a frequent and dangerous problem in dialysis patients. Many factors contribute to potentially life-threatening potassium elevation and most remedies used to treat hyperkalemia are handicapped by the consequences of the separate pools of intra- and extracellular potassium. Besides the kidney, the colon has the ability to excrete potassium, which can help lower total body potassium. Several prior authors have addressed the colon's ability to up-regulate potassium secretion, including the effect of aldosterone on fecal potassium content. Potentially dangerous intradialytic maneuvers to lower potassium levels may be avoidable with the use of the mineralocorticoid agonist fludrocortisone.

Kirk-Bayley, J. and R. Venn (2003). "Recently published papers: inflammation, elucidation, manipulation?" Crit Care 7(4): 282-4.

Lakier Smith, L. (2003). "Overtraining, excessive exercise, and altered immunity: is this a T helper-1 versus T helper-2 lymphocyte response?" Sports Med 33(5): 347-64.

            Overtraining syndrome (OTS) occurs where an athlete is training vigorously, yet performance deteriorates. One sign of OTS is suppressed immune function, with an increased incidence of upper respiratory tract infection (URTI). An increased incidence of URTIs is also associated with high volume/intensity training, as well as with excessive exercise (EE), such as a marathon, manifesting between 3-72 hours post-race. Presently, there is no encompassing theory to explain EE and altered immune competence. Recently, it has been conclusively established that T helper lymphocytes (T(H)), a crucial aspect of immune function, represent two distinct functional subsets: T(H)1 and T(H)2 lymphocytes. T(H)1 lymphocytes are associated with cell-mediated immunity (CMI) and the killing of intracellular pathogens, while T(H)2 lymphocytes are associated with humoral immunity and antibody production. When T(H)-precursor cells are activated, the balance is tipped in favour of one or the other. Furthermore, the most appropriate means of determining the T(H)-subset, is by the prevailing cytokine 'pattern'. This paper hypothesises that exercise-related immunosuppression is due to tissue trauma sustained during intense exercise, producing cytokines, which drive the development of a T(H)2 lymphocyte profile. A T(H)2 cell response results in simultaneous suppression of CMI, rendering the athlete susceptible to infection. Additionally, increased levels of circulating stress hormones (cortisol and catecholamines), as well as prostaglandin E(2), support up-regulation of T(H)2 lymphocytes. Marathon-related data are presented to support this hypothesis. It is concluded that an increased incidence of illness associated with OTS and in response to EE is not due to immunosuppression per se, but rather to an altered focus of immune function, with an up-regulation of humoral immunity and suppression of CMI.

Larina, I. M. (2003). "[Hormonal regulation of metabolism in the human body in microgravity and during simulation of its physiological effects]." Aviakosm Ekolog Med 37(2): 32-41.

            The paper presents results of investigations into the effects of space flight and simulation experiments of various length on the hormonal regulation of metabolism in the human body. Microgravity was shown to instigate shifts on different levels of the hormonal regulation and consequent adjustment of metabolism to this new environment. For instance, adaptation occurs on the level of basal secretory activity resulting in altered metabolism and formation of a pool of hormones. Metabolism readaptation to the Earth's gravity is dependent on polymorphic processes in the system of hormonal regulation developing in the course of time. Trends in the hormonal regulation of water-electrolyte metabolism during early adaptation point to inequality of contributions of the antidiuretic hormone, natriuretic peptide, and the renin-angiotensin-aldosterone system. In the ground-based simulations responses of the hormonal regulation of water-electrolyte metabolism differ in intensity and types of hormones involved. Temperature variation can modify reactions of the comosis and volume regulating hormones at the beginning of adaptation. Physical-chemical regulation of calcium homeostasis in microgravity reveals itself by a rapid decline of the calcium-binding ability of blood buffers and, later on, degradation of the relative ability of extraplasmic structures to bind calcium. Qualitative and quantitative changes in the diurnal rhythm of the suprarenal steroidogenesis are indicative of modification of intensity of reactions of the main biosynthetic sequences. Countermeasures used by test-subjects in these investigations loosened significantly the aldosterone-secreting biosynthetic sequences but were favorable to the synthesis of testosterone and hydrocortisone. Some of the highly variable processes of hormonal regulation were mute to the diurnal rhythms in the pre-flight and preexperimental periods.

Leserman, J. (2003). "The effects of stressful life events, coping, and cortisol on HIV infection." CNS Spectr 8(1): 25-30.

            What is the role of stress and coping in changes in immunologic and clinical indicators of human immunodeficiency virus disease progression? There is substantial evidence that stressful life events and passive coping strategies, such as denial, may have a detrimental effect on HIV disease progression. Given the harmful effects of stress and passive coping, the author reviews the limited research testing the efficacy of interventions, such as cognitive-behavioral therapies for HIV-infected persons. Finally, in trying to understand psychoimmune relationships in HIV, the evidence is examined for the mediating and direct effects of cortisol, a hormone associated with stress, on HIV disease progression. Delineating the role of psychosocial factors and cortisol on HIV disease progression may aid in the development of new interventions for this devastating disease.

Liu, A. H. and S. J. Szefler (2003). "Advances in childhood asthma: hygiene hypothesis, natural history, and management." J Allergy Clin Immunol 111(3 Suppl): S785-92.

            There is significant interest in early identification and intervention in childhood asthma. Current asthma guidelines identify inhaled corticosteroids (ICS) as the preferred initial long-term control therapy even in young children. ICS clearly improve asthma control in children with mild to moderate persistent asthma, but it is not clear that they can alter the natu-ral history and progression of asthma. New insights regarding the origins of asthma and allergy and their natural history will continue to stimulate questions regarding the appropriate time for intervention and will stimulate the design of new treatment strategies and the discovery of new medications.

Llanos, A. J., R. A. Riquelme, et al. (2003). "The fetal llama versus the fetal sheep: different strategies to withstand hypoxia." High Alt Med Biol 4(2): 193-202.

            The pregnant llama (Lama glama) has walked for millions of years through the thin oxygen trail of the Andean altiplano. We hypothesize that a pool of genes has been selected in the llama that express efficient mechanisms to withstand this low-oxygen milieu. The llama fetus responds to acute hypoxia with an intense peripheral vasoconstriction that is not affected by bilateral section of the carotid sinus nerves. Moreover, the increase in fetal plasma concentrations of vasoconstrictor hormones, such as catecholamines, neuropeptide Y, and vasopressin, is much greater in the llama than in the sheep fetus. Furthermore, treatment of fetal llamas with an alpha-adrenergic antagonist abolished the peripheral vasoconstriction and resulted in fetal cardiovascular collapse and death during acute hypoxia, suggesting an indispensable upregulation of alpha-adrenergic mechanisms in this high altitude species. Local endothelial factors such as nitric oxide (NO) also play a key role in the regulation of fetal adrenal blood flow and in the adrenal secretion of catecholamines and cortisol. Interestingly, in contrast to the human or sheep fetus, the llama fetus showed a small increase in brain blood flow during acute hypoxia, with no increase in oxygen extraction across the brain, and thereby a decrease in brain oxygen consumption. These results suggest that the llama fetus responds to acute hypoxia with hypometabolism. How this reduction in metabolism is produced and how the cells are preserved during this condition remain to be elucidated.

Maheu, F. S. and S. J. Lupien (2003). "[Memory in the grip of emotions and stress: a necessarily harmful impact?]." Med Sci (Paris) 19(1): 118-24.

            While intense negative events are vividly recalled, information learned during stressful situations is poorly remembered. These differential effects of emotions and stress on memory have been attributed to the physiological manifestations generated during those affective states. Intense emotional and stressful events trigger the secretion of catecholamines and of glucocorticoids, in particular. These hormones would be modulatory agents of memory functions. In the first part of this paper, we review the specific effects emotions and stress have on memory. We then summarize the psychological and biological determinants responsible for these effects. Finally, we discuss different methodological issues that could explain the discrepancy found between the impact of emotions and stress on memory. Defining more precisely the effects emotion and stress have on memory will lead to a better comprehension of the cognitive problems that characterize patients dealing with emotional turmoil, such as patients suffering from depression or post-traumatic stress disorder.

Marai, I. F. and L. B. Bahgat (2003). "Fat-tailed sheep traits as affected by docking." Trop Anim Health Prod 35(4): 351-63.

            The literature mostly indicates that docking fat-tailed lambs initially reduces growth but that post-weaning growth and feed conversion efficiency then increase. The amount of fat deposited, the total separable lean meat to fat ratio and the meat quality all increase, while the percentage of bone in the carcase either decreases or does not change in the carcases of the docked lambs. Wool growth and characteristics are, in general, not affected and reproductive traits in ewes and lambs are improved by docking. The rectal temperature, respiration rate and pulse rate are decreased following docking. The concentrations of immunoreactive beta-endorphin and cortisol in the plasma and the incidence of foot stamping and restlessness, as indicators of stress, increase after docking. Other constituents of the blood are not significantly altered following docking or by the methods of docking. Docking of fat-tailed sheep using rubber rings at one day of age can be recommended.

Martinez-Riquelme, A. E. and S. P. Allison (2003). "Insulin revisited." Clin Nutr 22(1): 7-15.

            Injury and critical illness are characterised by hyperglycaemia, high free fatty acids and high net protein catabolism, due partly to suppression of insulin secretion in the shock phase and insulin resistance in the flow phase of injury, accompanied by high levels of cytokines and the catabolic hormones cortisol, glucagon and catecholamines. Pre-operative carbohydrate loading reduces post-operative insulin resistance and its consequences. Insulin has been shown to reduce the catabolic response as well as controlling hyperglycaemia. In contrast to its sodium retaining properties in normal, obese and diabetic subjects, insulin-glucose-potassium therapy may induce a sodium diuresis in catabolic patients with salt and water overload and in patients with congestive heart failure in whom haemodynamic improvement has also been observed. Diabetic patients with myocardial infarction and cardiac surgery also benefit from insulin treatment. Recent studies have described positive effects on clinical outcome in critical illness. Whether this is due simply to maintenance of euglycaemia or to the other effects of insulin remains to be determined.

Massin, M. (2003). "Neurocardiogenic syncope in children : current concepts in diagnosis and management." Paediatr Drugs 5(5): 327-34.

            A wide variety of pharmacologic agents are currently used for the prevention of recurrent neurocardiogenic syncope in children and adolescents. Significant advances in the understanding of this syncopal disorder have occurred in the past decade, and the list of medications recommended has changed, reflecting the evolving understanding of the pathophysiology and development of agents with enhanced efficacy and fewer adverse effects. Clinicians have few randomized controlled trials available to guide their decisions about treating neurocardiogenic syncope, and even fewer when it comes to medications targeting the pediatric population. At the present time, beta-adrenergic receptor blockers, fludrocortisone, and also specific serotonin reuptake inhibitors and midodrine, appear to be favored treatment options. Ideally, specific therapy would be tailored to specific pathophysiologic mechanisms. Unfortunately, at present, specific treatments based on those abnormalities have not been identified.

McCoy, S. J., J. M. Beal, et al. (2003). "Endocrine factors and postpartum depression. A selected review." J Reprod Med 48(6): 402-8.

            This review examines proposed endocrine-based etiologies of postpartum depression (PPD) and how knowledge of these etiologies may affect future treatments. It is based on a review of papers shedding light on the etiology of PPD with special emphasis on research into endocrine-related depression. A picture of PPD is starting to emerge that suggests a variety of endocrine root causes as well as psychosocial risk factors. Hormones reviewed include progesterone, estradiol and estriol, cortisol, corticotropin-releasing hormone, prolactin, thyroid-stimulating hormone and triiodothyronine/thyroxine. Other substances examined include 3 antithyroid autoantibodies. Better understanding of the physiologic bases for depressive symptoms may lead to correction of the underlying pathology of PPD rather than treatment of symptoms.

Meduri, G. U., P. Carratu, et al. (2003). "Evidence of biological efficacy for prolonged glucocorticoid treatment in patients with unresolving ARDS." Eur Respir J Suppl 42: 57s-64s.

            Acute respiratory distress syndrome (ARDS) is a disease of multifactorial etiology characterised by rapid development of severe diffuse and nonhomogenous inflammation of the pulmonary lobules causing life-threatening hypoxaemic respiratory failure. The current authors tested a therapeutic intervention on a previously defined pathophysiological model of ARDS. The model was defined by investigating, during the natural history of ARDS, the relationship among the three fundamental elements of a disease process pathogenesis, structural alterations, and functional consequences. In these studies, the present authors provided biological and morphological evidence indicating that ARDS patients failing to improve after 1 week of mechanical ventilation (unresolving ARDS) have intense and protracted (dysregulated) pulmonary and systemic inflammatory and neo-fibrogenetic activity. Nuclear factor-kappaB and the glucocorticoid receptor have diametrically opposed functions in regulating inflammation. This chapter will review recent data indicating that poor outcome in acute respiratory distress syndrome might be related in part to failure of the activated glucocorticoid receptors to downregulate the transcription of inflammatory cytokines despite elevated levels of circulating cortisol. In a small randomised study of patients with unresolving acute respiratory distress syndrome, the current authors have shown that prolonged glucocorticoid supplementation improved all aspects of glucocorticoid receptors function and enhanced glucocorticoid-mediated anti-inflammatory action by interfering with nuclear factor-kappaB activation.

Meyer, G. and K. Badenhoop (2003). "[Glucocorticoid-induced insulin resistance and diabetes mellitus. Receptor-, postreceptor mechanisms, local cortisol action, and new aspects of antidiabetic therapy]." Med Klin (Munich) 98(5): 266-70.

            BACKGROUND: Glucocorticoids are frequently prescribed drugs. Nearly half of the patients treated with glucocorticoids over a longer period develop a deranged glucose metabolism. In about 50%, these disturbances persist despite reduction or even withdrawal of the drug. PATHOPHYSIOLOGY: Glucocorticoids antagonize the insulin-mediated inhibition of hepatic glucose release, decrease glucose utilisation in muscle, and reduce the binding affinity of insulin receptors. Therefore, glucocorticoid-induced diabetes mellitus is equivalent to unmasked type 2 diabetes. New studies presume that an increased endogenous production of glucocorticoids particularly in adipocytes could play a role in type 2 diabetes as well. THERAPY: Patients with glucocorticoid-induced diabetes bear, comparable to patients with other types of diabetes, a considerable risk of arteriosclerotic and cardiovascular diseases and should therefore receive an intensified treatment. Therapy of glucocorticoid-induced diabetes basically corresponds to that of type 2 diabetes. Applicable are oral antidiabetic drugs, particularly metformin and the glitazones as insulin sensitizers both requiring consideration of contraindications, or treatment with insulin.

Middleton, C. (2003). "Understanding the physiological effects of unrelieved pain." Nurs Times 99(37): 28-31.

            Pain produces a physiological stress response that includes increased heart and breathing rates to facilitate the increasing demands of oxygen and other nutrients to vital organs. Failure to relieve pain produces a prolonged stress state, which can result in harmful multisystem effects. Good acute pain management is an essential part of holistic nursing care.

Moreira-Andres, M. N., F. J. del Canizo Gomez, et al. (2003). "[Update in the diagnosis and differential diagnosis of Cushing's syndrome]." Rev Clin Esp 203(3): 142-54.

Murphy, K. D., J. O. Lee, et al. (2003). "Current pharmacotherapy for the treatment of severe burns." Expert Opin Pharmacother 4(3): 369-84.

            The pharmacotherapy of burn care has evolved from the first topical antibiotics instituted > 30 years ago. These have helped greatly to reduce the incidence of burn wound sepsis, but a better understanding of the principles of burn care has resulted in earlier burn wound excision and complete coverage with autograft, cadaver skin, synthetic dressings, and amnion. This has markedly reduced septic complications and ameliorated the hypermetabolic response to burn injury. The hypermetabolic response, which is mediated by hugely increased levels of circulating catecholamines, prostaglandins, glucagon and cortisol, causes profound skeletal muscle catabolism, immune deficiency, peripheral lipolysis, reduced bone mineralisation, reduced linear growth, and increased energy expenditure. Supportive therapy and pharmacological manipulation, acutely and during rehabilitation, with growth hormone, insulin and related proteins, oxandrolone and propranolol can ameliorate the hypermetabolic response, improving survival and long-term outcome. Despite judicious use of topical and systemic antibiotics, opportunistic nosocomial bacterial resistance threatens to annul the improved survival of patients with severe burns. Patterns of emerging resistance encountered in burn units need to be considered, in light of a decreasing antibiotic armamentarium. A holistic approach to pharmacotherapy of severely burned patients including current practice in antimicrobial control, analgesia, sedation, and anxiety management is required. Current therapy of frequently encountered problems, such as post-burn pruritus, prophylaxis of deep venous thrombosis and peptic ulceration, and pharmacological manipulation of inhalation injury in the burned patient is described. Current pharmacotherapy to ameliorate psychosocial problems associated with burns such as acute stress disorder, depression and post traumatic stress disorder are discussed. Better analgesics, newer antibiotics and immune stimulating drugs are required to reduce mortality and morbidity in large burns.

Nelson, H. S. (2003). "Advances in upper airway diseases and allergen immunotherapy." J Allergy Clin Immunol 111(3 Suppl): S793-8.

            Epidemiologic studies continue to find an increased prevalence of rhinitis, asthma, and atopy in more westernized countries. Both allergic and nonallergic rhinitis are risk factors for development of asthma, particularly in adulthood. In patients who have both asthma and rhinitis, treatment of the latter decreases the likelihood of emergency department visits or hospitalization for asthma. The protective effect of intranasal cortico-steroids is much greater than that of antihistamines. This mirrors the effect on rhinitis symptoms, in which nasal corticosteroids are much more effective than antihistamines, leukotriene receptor antagonists, or the combination of both. In patients with severe asthma, sinus mucosal thickening on computed tomography (CT) correlates with the severity of lower airway disease indicated by sputum eosinophilia, exhaled nitrous oxide (NO), functional residual capacity, and diffusing capacity. Preseasonal specific immunotherapy (SIT) is less effective, but additive to treatment with omalizumab. It is also somewhat less effective in reducing nasal symptoms than nasal corticosteroids; however, it is superior to them for reducing lower airway inflammation. SIT in children with only allergic rhinitis reduces both the incidence of asthma and bronchial hyperresponsiveness to methacholine. High-dose sublingual immunotherapy appears to be safe and effective, but less effective than injection immunotherapy. It is not clear that there are cost savings with sublingual immunotherapy, as home administration savings may be offset by the much larger amount of allergen extracts required. New approaches to allergen immunotherapy, designed to increase efficacy and safety, include conjugation of allergens to immunostimulatory sequences and encapsulation in liposomes. Cross-reactivity between inhalants and foods demonstrated by skin prick tests is more predictive of clinically important sensitivity than is that demonstrated by RAST testing. The latter, because of cross-reacting profilins, is often clinically irrelevant.

Nishikawa, T. (2003). "Flexion contractures possibly reflect the existence of hypocortisolism." Intern Med 42(8): 629-31.

Nussberger, J. (2003). "Investigating mineralocorticoid hypertension." J Hypertens Suppl 21 Suppl 2: S25-30.

            About 3% of our hypertensive patients have high blood pressure induced by corticosteroids. Muscle weakness, tiredness, polyuria and polydipsia may indicate hypokalaemia. Hypokalaemic hypertension in the presence of a low plasma renin activity is the typical finding of corticosteroid hypertension. The most frequent cause of corticosteroid hypertension is primary aldosteronism (Conn's syndrome) due to an adrenal adenoma or bilateral hyperplasia of the adrenal glands. The plasma concentration of aldosterone and the ratio between plasma aldosterone and renin concentrations are high, and the kaliuresis exceeds 30 mmol/24 h in the presence of hypokalaemia. Adrenal carcinomas are rare and very malignant. The localization of an adrenal tumour is made by computer tomography (CT-scan) or nuclear magnetic resonance imaging and by measurement of the aldosterone/cortisol concentrations in the adrenal venous blood. Adenomas are removed under laparoscopy, and adrenal hyperplasias are treated with spironolactone (50-400 mg daily) or amiloride (5-30 mg daily). In rare cases (<1%), excessive stimulation of the mineralocorticoid receptor is due to cortisol (apparent mineralocorticoid excess, Cushing's disease, liquorice, or hereditary deficiency of 11beta-hydroxysteroid dehydrogenase) or to a chimeric gene coding for 11beta-hydroxylase (CYP11B1/CYP11B2). In these rare cases, the synthesis of aldosterone is under the control of the adrenocorticotrophic hormone, so treatment with glucocorticoids (dexamethasone 0.25-1.0 mg daily) is therefore possible (glucocorticoid-remediable aldosteronism). Excessive deoxycorticosterone (DOC) causes the same symptoms and signs as hyperaldosteronism. Excessive DOC is found in patients with adrenal tumours that secrete DOC, in those with hereditary or acquired disorders with dysfunctioning glucocorticoid receptors, or in those with congenital hyperplasia of the adrenal glands (deficiency of 17alpha-hydroxylase or 11beta-hydroxylase). Liddle's syndrome is a constitutive hyperactivity of the transepithelial transport of sodium, which under normal conditions is controlled by the mineralocorticoid receptor. Plasma renin and aldosterone concentrations are suppressed and the plasma potassium concentration may be normal. In contrast, plasma aldosterone and renin concentrations are increased in patients with hypokalaemic hypertension which represents secondary aldosteronism. The increased aldosterone is the consequence of stimulated renin activity due to renal or renovascular or other disorders, antihypertensive drugs or other medications. In conclusion, a work-up for corticosteroid-induced hypertension is indicated in patients with hypokalaemic hypertension and in those with severe hypertension even in the absence of hypokalaemia, and in hypertensive patients with a family history of cardiovascular diseases.

Oettel, M., D. Hubler, et al. (2003). "Selected aspects of endocrine pharmacology of the aging male." Exp Gerontol 38(1-2): 189-98.

            This minireview explores the endocrinology and the clinical consequences of age-related hypogonadism (hypotestosteronemia). In addition, pharmacological and clinical applicability of new androgen formulations is described briefly. Other topics include selective androgen receptor modulators, non-feminizing estrogens, and the possible use of selective aromatase modulators. Finally, a theoretical concept of hormone displacement (i.e. excessive hormone production) is introduced using cortisol as an example.

Oldfeld, E. H. (2003). "Cushing disease." J Neurosurg 98(5): 948-51; discussion 951.

Olson, D. M. (2003). "The role of prostaglandins in the initiation of parturition." Best Pract Res Clin Obstet Gynaecol 17(5): 717-30.

            Parturition is composed of five separate but integrated physiological events: fetal membrane rupture, cervical dilatation, myometrial contractility, placental separation and uterine involution. Prostaglandins (PGs) have central roles in each of these, but the most studied is myometrial contraction. Elevated uterine PGs or the enhanced sensitivity of the myometrium to PGs leads to contractions and labour. The regulator of PG synthesis is the mRNA expression of PGHS-2. Cytokines are important stimulators of this gene expression, and cortisol and other factors may be as well. This enzyme is an important therapeutic target in the prevention of preterm labour. Some preterm births occur without an elevation of uterine PGs, even though they are delayed by non-steroidal anti-inflammatory drugs (NSAIDs), suggesting enhanced myometrial sensitivity to PGs. The PGF(2alpha) receptor, FP, is emerging as a central component of uterine sensitivity and may prove to be involved with preterm birth and a reasonable target for tocolysis.

Parker, K. J., A. F. Schatzberg, et al. (2003). "Neuroendocrine aspects of hypercortisolism in major depression." Horm Behav 43(1): 60-6.

            A consistent finding in biological psychiatry is that hypothalamic-pituitary-adrenal (HPA) axis physiology is altered in humans with major depression. These findings include hypersecretion of cortisol at baseline and on the dexamethasone suppression test. In this review, we present a process-oriented model for HPA axis regulation in major depression. Specifically, we suggest that acute depressions are characterized by hypersecretion of hypothalamic corticotropin-releasing factor, pituitary adrenocorticotropic hormone (ACTH), and adrenal cortisol. In chronic depressions, however, enhanced adrenal responsiveness to ACTH and glucocorticoid negative feedback work in complementary fashion so that cortisol levels remain elevated while ACTH levels are reduced. In considering the evidence for hypercortisolism in humans, studies of nonhuman primates are presented and their utility and limitations as comparative models of human depression are discussed.

Paulmyer-Lacroix, O., S. Boullu-Ciocca, et al. (2003). "[Glucocorticoids, 11 beta-hydroxysteroid dehydrogenase type 1, and visceral obesity]." Med Sci (Paris) 19(4): 473-6.

            Glucocorticoids are implicated as a pathophysiological mediator of obesity and its accompanying metabolic and cardiovascular complications. Obese patients exhibit normal circulating cortisol levels, related to increased glucocorticoid production and degradation. However, it has been demonstrated that local production of active cortisol from inactive cortisone driven by 11 beta-hydroxysteroid dehydrogenase type 1 is exaggerated in adipose tissue of obese subjects. Such local hypercortisolism may be responsible for increased adipocyte differentiation and enhanced secretion of free fatty acids and other substances involved in the metabolic and cardiovascular complications observed in obesity.

Peake, J. M. (2003). "Vitamin C: effects of exercise and requirements with training." Int J Sport Nutr Exerc Metab 13(2): 125-51.

            Ascorbic acid or vitamin C is involved in a number of biochemical pathways that are important to exercise metabolism and the health of exercising individuals. This review reports the results of studies investigating the requirement for vitamin C with exercise on the basis of dietary vitamin C intakes, the response to supplementation and alterations in plasma, serum, and leukocyte ascorbic acid concentration following both acute exercise and regular training. The possible physiological significance of changes in ascorbic acid with exercise is also addressed. Exercise generally causes a transient increase in circulating ascorbic acid in the hours following exercise, but a decline below pre-exercise levels occurs in the days after prolonged exercise. These changes could be associated with increased exercise-induced oxidative stress. On the basis of alterations in the concentration of ascorbic acid within the blood, it remains unclear if regular exercise increases the metabolism of vitamin C. However, the similar dietary intakes and responses to supplementation between athletes and nonathletes suggest that regular exercise does not increase the requirement for vitamin C in athletes. Two novel hypotheses are put forward to explain recent findings of attenuated levels of cortisol postexercise following supplementation with high doses of vitamin C.

Pitt, B., C. T. Jr, et al. (2003). "Mineralocorticoid receptor blockade: new insights into the mechanism of action in patients with cardiovascular disease." J Renin Angiotensin Aldosterone Syst 4(3): 164-8.

            Mineralocorticoid receptor (MR) blockade is effective in reducing total mortality and the incidence of heart failure in patients with systolic left ventricular dysfunction (SLVD) associated with chronic heart failure or post myocardial infarction. Pre-clinical and clinical studies in SLVD have shown that MR blockade reduces sudden cardiac death, left ventricular remodelling, left ventricular hypertrophy, endothelial dysfunction, autonomic imbalance, renal dysfunction and improves fibrinolysis. While MR blockade promotes sodium excretion and the combination of an angiotensin-converting enzyme inhibitor and a MR blocker have been shown to be more effective than either alone in causing natriuresis, it is unlikely that their beneficial effects can be explained solely on this basis. Aldosterone has been shown to have a number of adverse effects, including activation of other neurohumeral mediators, stimulation of active reactive oxygen species (ROS), activation of the NF-Greek small letter kappa kappabeta and AP-1 signalling pathways, vascular inflammation and fibrosis, myocardial hypertrophy, autonomic imbalance, and a decrease in fibrinolysis. MR blockade is, however, effective both in situations with and without an increase in serum aldosterone level, since the MR can be occupied and activated by cortisol as well as by aldosterone. In view of these mechanisms, MR blockade may play an important role not only on SLVD, but also in essential hypertension with normal systolic function, diastolic heart failure, valvular heart disease, vascular stiffening with ageing, progression of renal disease, and diabetes mellitus. This hypothesis will, however, require further prospective evaluation.

Quinkler, M., J. Lepenies, et al. (2003). "[Therapy of adrenal cortex insufficiency]." Dtsch Med Wochenschr 128(12): 617-8.

Quinkler, M., J. Lepenies, et al. (2003). "[Diagnosis of adrenal cortex insufficiency]." Dtsch Med Wochenschr 128(11): 556-61.

Quinkler, M. and P. M. Stewart (2003). "Hypertension and the cortisol-cortisone shuttle." J Clin Endocrinol Metab 88(6): 2384-92.

            11 beta-Hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) plays a crucial role in converting hormonally active cortisol to inactive cortisone, thereby conferring specificity on the mineralocorticoid receptor. Mutations in the gene encoding 11 beta-HSD2 (HSD11B2) account for an inherited form of hypertension, the syndrome of apparent mineralocorticoid excess, in which cortisol induces hypertension and hypokalemia. A similar clinical picture to apparent mineralocorticoid excess occurs after the ingestion of licorice and carbenoxolone, which are competitive inhibitors of 11 beta-HSD2. Reduced 11 beta-HSD2 activity may explain the increased sodium retention in preeclampsia, renal disease, and liver cirrhosis. Substrate saturation of 11 beta-HSD2 occurs in Cushing's syndrome and explains the mineralocorticoid excess state that characterizes ectopic ACTH syndrome. Polymorphic variability in the HSD11B2 gene in part determines salt sensitivity, a forerunner for adult onset hypertension. Furthermore, reduced placental 11 beta-HSD2 expression might underpin the Barker hypothesis, the epidemiological link between reduced birth weight and adult hypertension. At a prereceptor level, 11 beta-HSD2 plays a key role in normal physiology in the corticosteroid regulation of sodium homeostasis and pathophysiology of hypertension.

Rabbitt, E. H., N. J. Gittoes, et al. (2003). "11beta-hydroxysteroid dehydrogenases, cell proliferation and malignancy." J Steroid Biochem Mol Biol 85(2-5): 415-21.

            The enzymes 11beta-hydroxysteroid dehydrogenase type 1 and 2 (11beta-HSD1 and 2) have well-defined roles in the tissue-specific metabolism of glucocorticoids which underpin key endocrine mechanisms such as adipocyte differentiation (11beta-HSD1) and mineralocorticoid action (11beta-HSD2). However, in recent studies we have shown that the effects of 11beta-HSD1 and 2 are not restricted to distinct tissue-specific hormonal functions. Studies of normal fetal and adult tissues, as well as their tumor equivalents, have shown a further dichotomy in 11beta-HSD expression and activity. Specifically, most normal glucocorticoid receptor (GR)-rich tissues such as adipose tissue, bone, and pituitary cells express 11beta-HSD1, whereas their fetal equivalents and tumors express 11beta-HSD2. We have therefore postulated that the ability of 11beta-HSD1 to generate cortisol acts as an autocrine anti-proliferative, pro-differentiation stimulus in normal adult tissues. In contrast, the cortisol-inactivating properties of 11beta-HSD2 lead to pro-proliferative effects, particularly in tumors. This proposal is supported by experiments in vitro which have demonstrated divergent effects of 11beta-HSD1 and 2 on cell proliferation. Current studies are aimed at (1) characterizing the underlying mechanisms for a "switch" in 11beta-HSD isozyme expression in tumors; (2) defining the molecular targets for glucocorticoids as regulators of cell proliferation; (3) evaluating the potential for targeting glucocorticoid metabolism as therapy for some cancers. These and other issues are discussed in the present review.

Raff, H. and J. W. Findling (2003). "A physiologic approach to diagnosis of the Cushing syndrome." Ann Intern Med 138(12): 980-91.

Raison, C. L. and A. H. Miller (2003). "When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders." Am J Psychiatry 160(9): 1554-65.

            OBJECTIVE: Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH). METHOD: The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed. RESULTS: Although not occurring together, both hypocortisolism and reduced responsiveness to glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychiatric disorders were also associated with immune system activation/inflammation, high SNS tone, and CRH hypersecretion, which are all consistent with insufficient glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced glucocorticoid signaling. CONCLUSIONS: Neuroendocrine data provide evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and acquired immune responses. From an evolutionary perspective, reduced glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increase arousal. Emphasis on insufficient glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance glucocorticoid signaling pathways.