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Cortisol reviews: 2003
(57 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.
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.
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.
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.
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.
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.
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.
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.
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.
Kendrick, M. (2003). "Does insulin resistance cause atherosclerosis in the post-prandial period?" Med Hypotheses 60(1): 6-11.
Insulin resistance would appear to be a causal factor for the development of early occlusive atherosclerosis. This paper proposes that post-prandial insulin resistance, in association with raised levels of cortisol and catecholamines, plays the major role, and may even be the primary causative factor. Therefore, factors that lead to insulin resistance in the post-prandial period, specifically stress, will accelerate the development of CHD. This may explain the low rate of CHD in France, as their eating habits (in common with many other Mediterranean countries) are more relaxed than those in Northern Europe.
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.
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.
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.
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.
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.
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.
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.
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.
Raff, H. and J. W. Findling (2003). "A physiologic approach to diagnosis of the Cushing syndrome." Ann Intern Med 138(12): 980-91.
Rammert, C. and G. A. Kullak-Ublick (2003). "[Management of ulcerative colitis]." Ther Umsch 60(3): 145-50.
Ulcerative colitis is a chronic inflammatory bowel disease. The disease is diagnosed on the basis of clinical parameters and endoscopic-histologic evaluation. 5-aminosalicylic acid (5-ASA, mesalamine) represents the first-line treatment of choice. For patients with distal and left-sided disease the use of rectal preparations is effective. Most patients respond to 5-ASA suppositories or to topic steroids such as budesonide suppositories or hydrocortisone foam. For patients with extended disease, oral medications are mandatory. In case of low- to moderate-grade inflammation, 5-ASA preparations should be implemented. In the case of severe disease treatment with steroids is required. Following induction of remission, prophylactic treatment with 5-ASA (1.5 g/d) should be maintained. For patients with frequent or severe relapses, immunosuppressive therapy with azathioprine or 6-mercaptopurine is indicated. In case of a fulminant course of disease, treatment with intravenous cyclosporine is required in patients who have not responded to high-dose intravenous steroids. When all conservative treatment options fail, proctocolectomy with construction of an ileoanal pouch should be performed. New therapeutic strategies such as infliximab and interferons are being evaluated in clinical trials. The long-term complications of ulcerative colitis include steroid-induced osteoporosis and anemia and should be treated adequately. Finally, the risk for development of colorectal cancer increases steadily with disease duration and dysplasia should be screened for by endoscopic surveillance programs.
Rosmond, R. (2003). "Stress induced disturbances of the HPA axis: a pathway to Type 2 diabetes?" Med Sci Monit 9(2): RA35-9.
Type 2 diabetes is the most common form of hyperglycemia. The disease exists in all populations, but in developed societies, the prevalence has risen as the population ages and above all becomes more obese. In the prediabetic state, type 2 diabetes involves two defects, peripheral insulin resistance and hyperinsulinemia, which is followed by the failure of insulin secretion to compensate for the insulin resistance. As with nearly any disease, it is likely that multiple environmental and genetic factors are involved in the development of insulin resistance. An acquired pathogenic factor is obesity, particularly visceral obesity. Compelling evidence suggests that progressive dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, with elevated levels of circulating cortisol, is implicated in the development of visceral obesity. The HPA axis perturbations associated with visceral obesity can be accounted for, in part, by increased environmental stress that destabilizes the hypothalamic-pituitary system in individuals with genetic susceptibility.
Rothschild, A. J. (2003). "Challenges in the treatment of depression with psychotic features." Biol Psychiatry 53(8): 680-90.
Major depression with psychotic features (MDpsy), a disorder with considerable morbidity and mortality, is more common than is generally realized and is a most difficult form of depression to treat. Patients with MDpsy exhibit more frequent relapses and recurrences and have increased use of services, greater disability, and a poorer clinical course when compared with nonpsychotically depressed patients. Patients with MDpsy demonstrate distinct biological abnormalities in studies of the hypothalamic-pituitary-adrenal (HPA) axis, dopaminergic activity, enzyme studies, brain imaging, electroencephalogram sleep profiles, and measures of serotonergic function when compared with nonpsychotic depression. The social and occupational impairment in MDpsy has been hypothesized to be secondary to subtle cognitive deficits caused by the higher cortisol levels frequently observed in MDpsy patients. Several studies support a relationship between bipolar disorder and MDpsy, particularly in young-onset MDpsy. The most efficacious treatments for MDpsy include the combination of an antidepressant and an antipsychotic, amoxapine, or electroconvulsive therapy. Atypical antipsychotic medications may have particular relevance for the treatment of MDpsy because of the potential for reduced risk of extrapyramidal side effects and tardive dyskinesia, as well as antipsychotic and possibly antidepressant qualities. Based on the observations that MDpsy patients exhibit marked dysregulation of the HPA axis and elevated cortisol levels, several antiglucocorticoid strategies have been employed to treat MDpsy patients. Many questions regarding the acute and long-term treatment of MDpsy remain for future studies to address.
Sandborn, W. J. (2003). "Preventing antibodies to infliximab in patients with Crohn's disease: optimize not immunize." Gastroenterology 124(4): 1140-5.
Sessler, C. N. (2003). "Steroids for septic shock: back from the dead? (Con)." Chest 123(5 Suppl): 482S-9S.
The role of corticosteroid therapy in the management of septic shock has been debated for half a century. Results from large, well-designed, randomized clinical trials demonstrate no benefit, and perhaps harm, associated with short duration, high-dose methylprednisolone or dexamethasone administered at the onset of septic shock. Based on evidence of "relative adrenal insufficiency" and steroid-responsive adrenergic receptor desensitization in sepsis, administration of modest doses (200 to 300 mg/d) of hydrocortisone for 1 to 3 weeks has been investigated. A multicenter, placebo-controlled clinical trial demonstrated improved survival rates and faster cessation of vasopressors among patients with septic shock who have a poor response to corticotropin injection, consistent with relative adrenal insufficiency. However, concerns regarding a trend for higher mortality among corticotropin responders and the possibility that patients with true adrenal insufficiency may have been enrolled in this placebo-controlled trial, potentially skewing results, should be considered.
Speiser, P. W. and P. C. White (2003). "Congenital adrenal hyperplasia." N Engl J Med 349(8): 776-88.
Spiegel, D. and J. Giese-Davis (2003). "Depression and cancer: mechanisms and disease progression." Biol Psychiatry 54(3): 269-82.
Depression and cancer commonly co-occur. The prevalence of depression among cancer patients increases with disease severity and symptoms such as pain and fatigue. The literature on depression as a predictor of cancer incidence is mixed, although chronic and severe depression may be associated with elevated cancer risk. There is divided but stronger evidence that depression predicts cancer progression and mortality, although disentangling the deleterious effects of disease progression on mood complicates this research, as does the fact that some symptoms of cancer and its treatment mimic depression. There is evidence that providing psychosocial support reduces depression, anxiety, and pain, and may increase survival time with cancer, although studies in this latter area are also divided. Psychophysiological mechanisms linking depression and cancer progression include dysregulation of the hypothalamic-pituitary-adrenal axis, especially diurnal variation in cortisol and melatonin. Depression also affects components of immune function that may affect cancer surveillance. Thus, there is evidence of a bidirectional relationship between cancer and depression, offering new opportunities for therapeutic intervention.
Steiger, A. (2003). "Sleep and endocrinology." J Intern Med 254(1): 13-22.
A bidirectional interaction between sleep electroencephalogram and endocrine activity is well established in various species including humans. Various hormones (peptides and steroids) participate in sleep regulation. A key role was shown for the reciprocal interaction between sleep-promoting growth hormone-releasing hormone (GHRH) and sleep-impairing corticotropin-releasing hormone (CRH). Changes in the GHRH : CRH ratio result in changes of sleep-endocrine activity. It is thought that the change of this ratio in favour of CRH contributes to aberrations of sleep during ageing and depression (shallow sleep, blunted GH and elevated cortisol). Besides GHRH, ghrelin and galanin enhance slow wave sleep. Somatostatin is another sleep-impairing factor. Neuropeptide Y acts as a CRH antagonist and induces sleep onset. There are hints that CRH promotes rapid eye movement sleep (REMS). In animals prolactin enhances REMS. In humans vasoactive intestinal polypeptide (VIP) appears to play a role in the temporal organization of sleep as, after VIP, the non-REMS-REMS cycle decelerated. Cortisol appears to enhance REMS. Finally, gonadal hormones participate in sleep regulation. Oestrogen replacement therapy and CRH-1 receptor antagonism in depression are beneficial clinical applications of sleep-endocrine research.
Takenaka, H. (2003). "[Postpartum depression]." Ryoikibetsu Shokogun Shirizu(38): 318-21.
Thompson, B. T. (2003). "Glucocorticoids and acute lung injury." Crit Care Med 31(4 Suppl): S253-7.
OBJECTIVES: To describe hypothalamic-pituitary-adrenal (HPA) activation and the role of glucocorticoids in immune modulation during critical illness, and to review clinical trials of pharmacologic and "replacement"' doses of glucocorticoids in early and late acute respiratory distress syndrome (ARDS) and sepsis. DATA EXTRACTION AND SYNTHESIS: Selected review of published literature (1963 to present), clinical trials, and meta-analyses. DATA SUMMARY: HPA axis activation is an important component of the compensatory anti-inflammatory response to critical illness. Cortisol supports vascular tone and endothelial integrity, modulates a large number of proinflammatory cytokines, and suppresses phospholipase A(2), cyclo-oxygenase, and nitric oxide synthase. Cortisol has putative antifibrotic activities, including inhibition of fibroblast growth and collagen deposition and stimulation of T-cell and monocyte apoptosis. During critical illness, neurohumoral factors, cytokines, endothelin, and atrial natriuretic peptide all may participate in HPA axis activation, resulting in elevated plasma cortisol production and plasma concentrations. In general, cortisol concentrations correlate with severity of illness, and higher plasma concentrations are associated with a poorer outcome. Failure of adrenocorticotropic hormone to augment plasma cortisol appears to be a poor prognostic finding in vasopressor-dependent sepsis and may indicate "relative adrenal insufficiency." Replacement glucocorticoid/mineralocorticoid therapy over 7 days appears to be beneficial in such individuals. However, a meta-analysis of high-dose, short-course glucocorticoid treatment involving 1,297 patients with sepsis enrolled in nine trials showed a trend toward harm, and four trials in patients with, or at risk for, ARDS showed no benefit or a greater likelihood of progression to ARDS. In contrast, observational studies and one small randomized controlled trial suggest that lower pharmacologic doses of glucocorticoids given late (>1 wk) in the course of ARDS may be beneficial. The National Heart, Lung, and Blood Institute's ARDS Network currently is testing the use of methylprednisolone in late ARDS. This study was reviewed by an independent data safety monitoring board for safety and efficacy after enrolling 60 and 120 patients and is currently ongoing. CONCLUSION: Current evidence indicates that short-duration, high-dose glucocorticoid therapy is not effective for early ARDS or severe sepsis. One small randomized, controlled trial suggests that moderate doses of glucocorticoids may be beneficial for patients with late ARDS; a much larger randomized controlled trial is ongoing. Some patients with pressor-dependent severe sepsis appear to have relative adrenal insufficiency and benefit from replacement glucocorticoid/mineralocorticoid therapy. The accuracy of the diagnostic criteria for, and the prevalence of, relative adrenal insufficiency in patients with acute lung injury/ARDS is unknown. It is also unclear whether such a response, if present, predisposes patients to ongoing lung inflammation and the development of late fibroproliferative ARDS, or if it is predictive of a beneficial response to steroids. Studies of HPA axis activation and the role of relative adrenal insufficiency on the outcome of patients with acute lung injury are needed.
van Heeringen, K. (2003). "The neurobiology of suicide and suicidality." Can J Psychiatry 48(5): 292-300.
OBJECTIVE: To investigate the current state of knowledge regarding the neurobiology of suicide and suicidality. METHOD: The literature on the neurobiology of suicidality and suicide was reviewed. RESULTS: There is clear evidence that the activity of 3 neurobiological systems has a role in the pathophysiology of suicidal behaviour. This includes hyperactivity of the hypothalamo-pituitary-adrenal axis, dysfunction of the serotonergic (5-HTergic) system, and excessive activity of the noradrenergic system. While the first and the last system appear to be involved in the response to stressful events, dysfunction of the serotonergic system is thought to be trait-dependent and associated with disturbances in the regulation of anxiety, impulsivity, and aggression. It can be hypothesized that neurobiological dysfunctions mediate the occurrence of suicidal behaviour through the disturbed modulation of basic neuropsychological functions. CONCLUSION: Increasing insight into the neurobiological basis of suicidal behaviour suggests that serotonin (5-HT) agonists have an important role in the treatment and prevention of suicidal behaviour. Studies of the efficacy of such drugs have, however, been disappointing. Because suicidal behaviour continues to be a major public health problem, further study is clearly needed, including research on the effect of combined pharmacologic and psychotherapeutic approaches.
Vance, M. L. (2003). "Medical treatment of functional pituitary tumors." Neurosurg Clin N Am 14(1): 81-7.
Medical therapy with a dopamine agonist is the most effective for treatment of a prolactin-producing adenoma and is considered as primary treatment. Surgery and pituitary radiation are reserved for patients who either do not tolerate or do not respond to a dopamine agonist drug. A somatostatin analogue is effective medical therapy for patients with acromegaly, and this is usually administered if there is persistent GH hypersecretion after surgical resection. Medical treatment for patients with Cushing's disease is directed at the adrenal glands to reduce cortisol hypersecretion. Unfortunately, there is no effective medical therapy to reduce pituitary corticotropin production. Medical therapy for a gonadotrope adenoma with a dopamine agonist or somatostatin analogue has limited utility but is employed in patients who are unable to undergo surgery and may delay or prevent additional tumor growth. Many patients with a pituitary adenoma can be successfully treated with one treatment, either a dopamine agonist for a prolactinoma or surgery for other types of tumors. A substantial number of patients require multimodality therapy, however, including medical therapy, surgery, and pituitary radiation. Because the biologic behavior of pituitary adenomas varies considerably, a patient with a pituitary adenoma requires lifelong regular monitoring for hormone hypersecretion, tumor recurrence, and development of new pituitary hormone deficiency. A coordinated plan of care among endocrinologists, neurosurgeons, neuroophthalmologists, and radiation therapists is necessary to provide optimal care for these patients.
Weibel, L. (2003). "[Methodological guidelines for the use of salivary cortisol as biological marker of stress]." Presse Med 32(18): 845-51.
AN EASY TO DETERMINE, RELIABLE, MARKER: The measurement of cortisol in saliva provides to the basic scientist as well as to the clinician a reliable tool for investigations of the hypothalamic-pituitary-adrenal axis activity. As with plasma cortisol, the level of cortisol in the saliva is a reliable marker of stress. The major advantage of salivary cortisol is that its sampling technique is non-invasive and can be performed in non-stressful conditions and without laboratory surroundings. INDICATIONS: The use of salivary cortisol hence widens the perspectives of interesting research in "out of laboratory" scientific research and clinical research since the samples can be taken at home by the patients themselves. IN PRACTICE: However, the reliable use of salivary cortisol requires certain methodological prerequisites concerning the sampling technique (collection and storing) and the control of endogenous (individual factors, circadian variations, age, gender, hormonal status, weight) or behavioural (smoking, meals, posture) factors implied in the regulation of saliva. The respect of these prerequisites is essential in order to avoid the potential influence of artefacts during the development of a protocol for clinical research or diagnosis.
Wheeler, M. H. and D. A. Harris (2003). "Diagnosis and management of primary aldosteronism." World J Surg 27(6): 627-31.
Identifying primary aldosteronism within the hypertensive population is an important clinical challenge, as most patients with a unilateral source of excess aldosterone secretion are amenable to surgical cure. At least 20% of patients with primary aldosteronism have normal serum potassium levels. Therefore, screening tests should not be based on recognition of hypokalemia alone. Rather, the diagnosis should depend on identifying renin suppression and measuring the ratio of plasma aldosterone concentration to plasma renin activity. The diagnosis may be confirmed by performing an aldosterone suppression test after oral salt loading. Once primary aldosteronism has been established, it is necessary to exclude glucocorticoid-remediable aldosteronism and then proceed to localization studies. Detecting a unilateral source of aldosterone, usually due to an adenoma (Conn syndrome), is achieved by postural hormonal testing and confirmed by selective venous sampling (SVS) with measurement of aldosterone concentrations (expressed as the aldosterone/cortisol ratio) in each adrenal vein. SVS is enjoying a revival in many institutions as it is more sensitive and specific than either cross-sectional imaging or scintigraphy and has the potential to influence significantly both the diagnosis and clinical decision-making. Patients with unilateral disease are ideally treated by laparoscopic adrenalectomy. Patients in whom localization is not achieved usually have bilateral adrenal hyperplasia and are treated medically.
Yehuda, R. (2003). "Hypothalamic-pituitary-adrenal alterations in PTSD: are they relevant to understanding cortisol alterations in cancer?" Brain Behav Immun 17 Suppl 1: S73-83.
Recent studies of hypothalamic-pituitary-adrenal axis alterations in PTSD have demonstrated a specific type of hyperresponsivity of this stress hormonal system characterized by a greater negative feedback inhibition of cortisol, which may paradoxically serve to lower cortisol levels. The occurrence of cancer has been recently described by many investigators as an event that fulfills the DSM-IV criteria for a "traumatic event" that has been demonstrated in some cases to be linked with the subsequent development of PTSD. This review considers the extent to which neuroendocrine alterations observed in PTSD may be useful in understanding cortisol alterations involved in cancer.