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1.
Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome.
Carvajal, CA, Tapia-Castillo, A, Vecchiola, A, Baudrand, R, Fardella, CE
The Journal of clinical endocrinology and metabolism. 2020;(4)
Abstract
CONTEXT Arterial hypertension (AHT) is one of the most frequent pathologies in the general population. Subtypes of essential hypertension characterized by low renin levels allowed the identification of 2 different clinical entities: aldosterone-mediated mineralocorticoid receptor (MR) activation and cortisol-mediated MR activation. EVIDENCE ACQUISITION This review is based upon a search of Pubmed and Google Scholar databases, up to August 2019, for all publications relating to endocrine hypertension, apparent mineralocorticoid excess (AME) and cortisol (F) to cortisone (E) metabolism. EVIDENCE SYNTHESIS The spectrum of cortisol-mediated MR activation includes the classic AME syndrome to milder (nonclassic) forms of AME, the latter with a much higher prevalence (7.1%) than classic AME but different phenotype and genotype. Nonclassic AME (NC-AME) is mainly related to partial 11βHSD2 deficiency associated with genetic variations and epigenetic modifications (first hit) and potential additive actions of endogenous or exogenous inhibitors (ie, glycyrrhetinic acid-like factors [GALFS]) and other factors (ie, age, high sodium intake) (second hit). Subjects with NC-AME are characterized by a high F/E ratio, low E levels, normal to elevated blood pressure, low plasma renin and increased urinary potassium excretion. NC-AME condition should benefit from low-sodium and potassium diet recommendations and monotherapy with MR antagonists. CONCLUSION NC-AME has a higher prevalence and a milder phenotypical spectrum than AME. NC-AME etiology is associated to a first hit (gene and epigene level) and an additive second hit. NC-AME subjects are candidates to be treated with MR antagonists aimed to improve blood pressure, end-organ damage, and modulate the renin levels.
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2.
Medical Management of Cushing's Syndrome: Current and Emerging Treatments.
Hinojosa-Amaya, JM, Cuevas-Ramos, D, Fleseriu, M
Drugs. 2019;(9):935-956
Abstract
Endogenous Cushing's syndrome is a chronic disease associated with increased morbidity and mortality if not appropriately treated. Recurrence and/or persistence of hypercortisolemia after surgical treatment, especially for Cushing's disease, are high, and long-term medical treatment is used to decrease cortisol levels and risk of metabolic comorbidities. Medical treatment is also often required while waiting for radiation effects to take place. In some cases, severe or life-threatening hypercortisolism must be urgently and medically treated, via intravenous medications or with combination therapy, before patients can undergo surgery. In the last decade, medical treatment has progressed from a few steroidogenesis inhibitors to three novel drug groups: new inhibitors for steroidogenic enzymes with possibly fewer side effects, pituitary-directed drugs that aim to inhibit the pathophysiological pathways of Cushing's disease, and glucocorticoid receptor antagonists that block cortisol's action. Understanding the pathophysiology of Cushing's syndrome has also led to the identification of potential targets that may decrease adrenocorticotrophic hormone and/or cortisol excess, and/or decrease tumor cell proliferation, and induce senescence or apoptosis. We provide here a review of current and near-future medical options to treat Cushing's syndrome, and discuss updates on clinical trials and the efficacy and safety of novel or in-development drugs, as well as future potential targets.
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3.
Cortisol-related metabolic alterations assessed by mass spectrometry assay in patients with Cushing's syndrome.
Di Dalmazi, G, Quinkler, M, Deutschbein, T, Prehn, C, Rayes, N, Kroiss, M, Berr, CM, Stalla, G, Fassnacht, M, Adamski, J, et al
European journal of endocrinology. 2017;(2):227-237
Abstract
OBJECTIVE Endogenous hypercortisolism is a chronic condition associated with severe metabolic disturbances and cardiovascular sequela. The aim of this study was to characterize metabolic alterations in patients with different degrees of hypercortisolism by mass-spectrometry-based targeted plasma metabolomic profiling and correlate the metabolomic profile with clinical and hormonal data. DESIGN Cross-sectional study. METHODS Subjects (n = 149) were classified according to clinical and hormonal characteristics: Cushing's syndrome (n = 46), adrenocortical adenomas with autonomous cortisol secretion (n = 31) or without hypercortisolism (n = 27). Subjects with suspicion of hypercortisolism, but normal hormonal/imaging testing, served as controls (n = 42). Clinical and hormonal data were retrieved for all patients and targeted metabolomic profiling was performed. RESULTS Patients with hypercortisolism showed lower levels of short-/medium-chain acylcarnitines and branched-chain and aromatic amino acids, but higher polyamines levels, in comparison to controls. These alterations were confirmed after excluding diabetic patients. Regression models showed significant correlation between cortisol after dexamethasone suppression test (DST) and 31 metabolites, independently of confounding/contributing factors. Among those, histidine and spermidine were also significantly associated with catabolic signs and symptoms of hypercortisolism. According to an discriminant analysis, the panel of metabolites was able to correctly classify subjects into the main diagnostic categories and to distinguish between subjects with/without altered post-DST cortisol and with/without diabetes in >80% of the cases. CONCLUSIONS Metabolomic profiling revealed alterations of intermediate metabolism independently associated with the severity of hypercortisolism, consistent with disturbed protein synthesis/catabolism and incomplete β-oxidation, providing evidence for the occurrence of metabolic inflexibility in hypercortisolism.
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4.
Stress hormone release is a key component of the metabolic response to lipopolysaccharide: studies in hypopituitary and healthy subjects.
Bach, E, Møller, AB, Jørgensen, JO, Vendelbo, MH, Jessen, N, Pedersen, SB, Nielsen, TS, Møller, N
European journal of endocrinology. 2016;(5):455-65
Abstract
OBJECTIVE Acute and chronic inflammatory and metabolic responses are generated by lipopolysaccharide (LPS) during acute illness and in the pathogenesis of the metabolic syndrome, type 2 diabetes and cardiovascular disease, but whether these responses depend on intact pituitary release of hormones are not clearly identified. We compared the metabolic effects of LPS in hypopituitary patients (HPs) (in the absence of growth hormone (GH) and ACTH responses) and healthy control subjects (CTR) (with normal pituitary hormone responses). DESIGN Single-blind randomized. METHODS We compared the effects of LPS on glucose, protein and lipid metabolism in eight HP and eight matched CTR twice during 4-h basal and 2-h hyperinsulinemic-euglycemic clamp conditions with muscle and fat biopsies in each period during infusion with saline or LPS. RESULTS LPS increased cortisol and GH levels in CTR but not in HP. Also, it increased whole-body palmitate fluxes (3-fold) and decreased palmitate-specific activity (SA) 40-50% in CTR, but not in HP. G(0)/G(1) Switch Gene 2 (G0S2 - an inhibitor of lipolysis) adipose tissue (AT) mRNA was decreased in CTR. Although LPS increased phenylalanine fluxes significantly more in CTR, there was no difference in glucose metabolism between groups and intramyocellular insulin signaling was unaltered in both groups. CONCLUSIONS LPS increased indices of lipolysis and amino acid/protein fluxes significantly more in CTR compared with HP and decreased adipocyte G0S2 mRNA only in CTR. Thus, in humans intact pituitary function and appropriate cortisol and GH release are crucial components of the metabolic response to LPS.
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5.
Nutritional, metabolic and cardiovascular correlations of morning cortisol in health care workers in a gastroenterology service.
Guerra, A, Soares, RM, Pezzi, F, Karkow, FJ, Faintuch, J
Arquivos de gastroenterologia. 2015;(2):88-93
Abstract
BACKGROUND Workplace stress has been associated with obesity. Diminished body weight has also been anticipated in some contexts. OBJECTIVE In a cohort of healthcare personnel, morning cortisol was compared to nutritional and metabolic variables, aiming to identify the correlates of such marker. METHODS Population n=185, 33.8 ± 9.8 years, 88.1% females, body mass index (BMI) 25.6 ± 4.4 kg/m2, included nurses and other nosocomial professionals, the majority with high social-economic status (75.2%). Participants were stratified according to BMI, fasting blood glucose (FBG) and metabolic syndrome (MS). Fasting plasma cortisol and the Framingham Coronary Risk Score was calculated. RESULTS Mean cortisol was acceptable (19.4 ± 7.9 µg/dL) although with elevation in 21.6%. No correlation with FBG or MS occurred, and nonobese persons (BMI <25) exhibited the highest values (P=0.049). Comparison of the lowest and highest cortisol quartiles confirmed reduced BMI and waist circumference in the former, with unchanged Framingham Coronary Risk Score. CONCLUSION Cortisol correlated with reduced BMI. Despite low BMI and waist circumference, Framingham Coronary Risk Score was not benefitted, suggesting that exposure to cardiovascular risk continues, besides psychological strain. Initiatives to enhance organizational and staff health are advisable in the hospital environment.
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6.
Clinical review: The pathogenetic role of cortisol in the metabolic syndrome: a hypothesis.
Anagnostis, P, Athyros, VG, Tziomalos, K, Karagiannis, A, Mikhailidis, DP
The Journal of clinical endocrinology and metabolism. 2009;(8):2692-701
Abstract
CONTEXT The metabolic syndrome (MetS) is a cluster of metabolic abnormalities that increase the risk for type 2 diabetes mellitus and vascular disease. The common characteristics of MetS and hypercortisolemic conditions such as Cushing's syndrome (CS) suggest that the pathogenesis of MetS and central obesity might involve prolonged and excessive exposure to glucocorticoids. The present review summarizes the evidence on the potential role of cortisol in the pathogenesis of MetS and discusses new therapeutic approaches for these patients. EVIDENCE ACQUISITION Using PubMed, we searched for publications during the last 20 yr regarding the possible pathogenetic role of cortisol in the development of MetS. EVIDENCE SYNTHESIS Emerging data suggest that patients with MetS show hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, which leads to a state of "functional hypercortisolism." The cause for this activation of the HPA axis remains uncertain but may be partly associated with chronic stress and/or low birth weight, which are both associated with increased circulating cortisol levels and greater responsiveness of the HPA axis. Increased exposure to cortisol contributes to increased fat accumulation in visceral depots. However, cortisol metabolism is not only centrally regulated. The action of 11beta-hydroxysteroid dehydrogenase-1 at the tissue level also modulates cortisol metabolism. Increased 11beta-hydroxysteroid dehydrogenase-1 activity in adipose tissue and liver might contribute to the development of several features of the MetS. CONCLUSIONS MetS shares many characteristics of CS, and cortisol might play a role in the development of MetS at both a central and a peripheral level.
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7.
The metabolic syndrome X and peripheral cortisol synthesis.
Bähr, V, Pfeiffer, AF, Diederich, S
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2002;(7):313-8
Abstract
The metabolic syndrome X and Cushing's syndrome show similar symptoms but one major difference: Plasma cortisol is not elevated in the metabolic syndrome. Evidence is presented, that by the action of 11 beta-hydroxysteroid dehydrogenase 1 (11 beta HSD1) higher intracellular cortisol concentration may be created that may be relevant to induce insulin resistance and metabolic disturbances. Regulation of 11 beta HSD1 expression by hormones, growth factors, cytokines and transcription factors enables tissue specific adjustments of glucocorticoid receptor activation by cortisol. Specific inhibition of 11 beta HSD1 would help to understand aspects of the pathogenesis of syndrome X and to develop new therapeutic perspectives.
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8.
Effect of obesity and starvation on thyroid hormone, growth hormone, and cortisol secretion.
Douyon, L, Schteingart, DE
Endocrinology and metabolism clinics of North America. 2002;(1):173-89
Abstract
Obesity and starvation have opposing affects on normal physiology and are associated with adaptive changes in hormone secretion. The effects of obesity and starvation on thyroid hormone, GH, and cortisol secretion are summarized in Table 1. Although hypothyroidism is associated with some weight gain, surveys of obese individuals show that less than 10% are hypothyroid. Discrepancies have been reported in some studies, but in untreated obesity, total and free T4, total and free T3, TSH levels, and the TSH response to TRH are normal. Some reports suggest an increase in total T3 and decrease in rT3 induced by overfeeding. Treatment of obesity with hypocaloric diets causes changes in thyroid function that resemble sick euthyroid syndrome. Changes consist of a decrease in total T4 and total and free T3 with a corresponding increase in rT3. untreated obesity is also associated with low GH levels; however, levels of IGF-1 are normal. GH-binding protein levels are increased and the GH response to GHRH is decreased. These changes are reversed by drastic weight reduction. Cortisol levels are abnormal in people with abdominal obesity who exhibit an increase in urinary free cortisol but exhibit normal or decreased serum cortisol and normal ACTH levels. These changes are explained by an increase in cortisol clearance. There is also an increased response to CRH. Treatment of obesity with very low calorie diets causes a decrease in serum cortisol explained by a decrease in cortisol-binding proteins. The increase in cortisol secretion seen in patients with abdominal obesity may contribute to the metabolic syndrome (insulin resistance, glucose intolerance, dyslipidemia, and hypertension). States of chronic starvation such as seen in anorexia nervosa are also associated with changes in thyroid hormone, GH, and cortisol secretion. There is a decrease in total and free T4 and T3, and an increase in rT3 similar to findings in sick euthyroid syndrome. The TSH response to TRH is diminished and, in severe cases, thyroid-binding protein levels are decreased. In regards to GH, there is an increase in GH secretion with a decrease in IGF-1 levels. GH responses to GHRH are increased. The [table: see text] changes in cortisol secretion in patients with anorexia nervosa resemble depression. They present with increased urinary free cortisol and serum cortisol levels but without changes in ACTH levels. In contrast to the findings observed in obesity, the ACTH response to CRH is suppressed, suggesting an increased secretion of CRH. The endocrine changes observed in obesity and starvation may complicate the diagnosis of primary endocrine diseases. The increase in cortisol secretion in obesity needs to be distinguished from Cushing's syndrome, the decrease in thyroid hormone levels in anorexia nervosa needs to be distinguished from secondary hypothyroidism, and the increase in cortisol secretion observed in anorexia nervosa requires a differential diagnosis with primary depressive disorder.
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9.
[Evaluation of leptin levels in plasma and their reliance on other hormonal factors affecting tissue fat levels in people with various levels of endogenous cotisol].
Robaczyk, MG
Annales Academiae Medicae Stetinensis. 2002;:283-300
Abstract
The discovery of leptin (LEP) shed new light on mechanisms regulating body fat mass (BFM). In this aspect, interactions between LEP and glucocorticoids at hypothalamic level may be of great importance. Factors that influence plasma LEP levels have not been fully recognized and available data on LEP levels are often inconsistent. The aim of this study was to evaluate absolute and BFM-corrected plasma LEP levels and their diurnal variation, as well as to assess the relationship between LEP levels, body fat distribution, and hormones influencing body fat in subjects with various levels of endogenous cortisol and different nutritional status. Group I was composed of 14 women aged 14-58 yrs, BMI of 23.9-37.1 kg/m2, with hypercortisolism due to ACTH-dependent and ACTH-independent Cushing's syndrome (CUS). 17 women with visceral obesity (OTY) and normal or disturbed carbohydrate metabolism, i.e. impaired glucose tolerance (IGT) and diabetes mellitus (DM), aged 24 do 50 yrs, BMI 30.0-46.1 kg/m2, were included in group II. Group III consisted of 14 women with Addison's disease (AD), aged 18 do 63 yrs, BMI 15.4-31.6 kg/m2. The control group IV (KON) included 17 healthy women with normal BMI. BMI, WHR, body composition, and body fat distribution (DEXA method) were assessed in all subjects. Basal plasma levels of LEP, beta-endorphin (B-EP), cortisol (F), insulin-like growth factor-1 (IGF-1) were measured with RIA test kits. Plasma adrenocorticotrophin (ACTH) levels, serum levels of insulin (IRI) and growth hormone (GH) were measured with IRMA test kits. Blood glucose (G) concentration was determined with an enzymatic method. Adiposity-corrected LEP levels were expressed as LEP/BFM and LEP/%BF indices. Fasting insulin resistance index (FIRI) was also calculated. Higher BFM and %BF values were found in the OTY group as compared with CUS KON and AD groups. BFM distribution did not differ in KON and AD groups whereas CUS subjects exhibited a higher accumulation of fat in the trunk when compared to OTY subjects. Absolute LEP levels were correlated with trunk BF in CUS patients whereas in KON and AD groups these levels were correlated only with limb fat. Absolute LEP levels in CUS and OTY groups were comparable, whereas LEP/BFM and LEP/%BF indices were higher in the CUS group (Table 1) reflecting upregulation of LEP levels (Figs. 1, 2). BFM-corrected LEP levels were comparable in groups with normal cortisolemia, i.e. in OTY and KON groups, whereas in the AD group both absolute and BFM-corrected LEP levels were lower than in controls. No correlation was found between plasma levels of F and LEP in CUS and AD groups. This correlation was negative in KON (Fig. 3) and positive in OTY groups (Fig. 4). Moreover, KON and AD groups demonstrated a negative correlation between plasma ACTH and LEP levels. CUS patients showed positive, BFM-independent correlations between LEP levels, FIRI and G values, and a positive, BFM-dependent correlation between IRI and LEP levels. OTY patients exhibited a BFM-dependent positive correlation between FIRI and LEP levels. In these and in AD patients, a positive, BFM-independent correlation between IRI and LEP levels was found. Moreover, a negative, BFM-dependent correlation between GH and LEP levels was found in OTY patients. In this group, B-EP levels were positively correlated with LEP/BFM and LEP/%BF indices (Fig. 5). A negative correlation between LEP levels, LEP/BFM and LEP/%BF indices was ascertained in the AD group. In CUS, OTY, and KON groups, but not in the AD group, a midnight increase in leptin levels was observed. In conclusion, upregulation of leptin levels in relation to body fat in Cushing's syndrome is independent of the source of hypercortisolism. Apparently, it results from insulin resistance and hyperglycaemia and contributes to coexisting metabolic abnormalities. In Addison's disease, downregulation of leptin may reflect an adaptation mechanism to cortisol deficiency and result from low insulin and extremely high adrenocorticotrophin levels. In women with normal cortisol levels, irrespectively of nutritional status; leptin levels reflect body fat content. In obese subjects, leptin levels may be influenced by cortisol levels, high levels of insulin, IGF-1, and beta-endorphin as well as low levels of growth hormone. Disturbed function of hypothalamic-pituitary-adrenal axis (CUS, AD) does not directly influence diurnal variation in plasma leptin levels. In Cushing's syndrome, visceral fat may be a predominant source of leptin, whereas in women with normal or low cortisol levels peripherally accumulated fat may determine leptin secretion.