leptin and Cushing-Syndrome

Cushing's syndrome (CS) is associated with increased cardiovascular morbidity and mortality. Recent evidence also suggests that increased cardiovascular risk may persist even after long-term remission of CS. Increased central obesity, a typical feature of CS, is associated with altered production of adipokines, which contributes to the pathogenesis of several metabolic and cardiovascular complications observed in this condition. In vitro and in vivo studies have shown a relationship between cortisol and adipokines in several experimental settings. In patients with either active or 'cured' CS, an increase in leptin and resistin levels as well as the release of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, may be associated with increased cardiovascular risk. For other adipokines, including adiponectin, results are inconclusive. Studies are needed to further elucidate the interactions between clinical and subclinical increases in cortisol production and altered adipokine release in CS.

Topics: Adipokines; Cardiovascular Diseases; Cushing Syndrome; Humans; Hypothalamo-Hypophyseal System; Leptin; Pituitary-Adrenal System; Risk Factors

The prevalence of anorexia nervosa has increased in recent years and a large proportion of patients with this disorder have low bone density at diagnosis and, therefore, an increased risk of early and late fractures. The mechanism of bone loss in anorexia nervosa is not well understood, yet it likely includes hypogonadism, alterations of the GH-IGF-1 axis and hypercortisolism. DEXA is the most effective tool for assessing and monitoring bone density in these patients, and it is important to improve or at least stabilize bone metabolism in those with low bone mass. No agent has yet been proven to be effective in improving bone density. However, sustained weight recovery and menses besides an adequate intake of calcium and vitamin D are recommended to optimize the conditions in which bone mass accrual may occur.

Topics: Adipose Tissue; Adolescent; Adult; Anorexia Nervosa; Bone and Bones; Bone Density; Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcium; Cushing Syndrome; Fractures, Bone; Gonadal Steroid Hormones; Humans; Hypogonadism; Intercellular Signaling Peptides and Proteins; Leptin; Male; Minerals; Osteoporosis; Vitamin D; Young Adult

Obesity is associated with several endocrine diseases, including common ones such as hypothyroidism and polycystic ovarian syndrome to rare ones such as Cushing's syndrome, central hypothyroidism and hypothalamic disorders. The mechanisms for the development of obesity vary in according to the endocrine condition. Hypothyroidism is associated with accumulation of hyaluronic acid within various tissues, additional fluid retention due to reduced cardiac output and reduced thermogenesis. The pathophysiology of obesity associated with polycystic ovarian syndrome remains complex as obesity itself may simultaneously be the cause and the effect of the syndrome. Net excess of androgen appears to be pivotal in the development of central obesity. In Cushing's syndrome, an interaction with thyroid and growth hormones plays an important role in addition to an increased adipocyte differentiation and adipogenesis. This review also describes remaining rare cases: hypothalamic obesity due to central hypothyroidism and combined hormone deficiencies.

Topics: Catecholamines; Cushing Syndrome; Endocrine System Diseases; Female; Glucocorticoids; Humans; Hypothalamic Diseases; Hypothyroidism; Leptin; Male; Obesity; Polycystic Ovary Syndrome; Thyroid Function Tests; Triiodothyronine

Topics: Biomarkers; Cushing Syndrome; Diabetes Mellitus, Lipoatrophic; Diagnostic Techniques, Endocrine; Enzyme-Linked Immunosorbent Assay; Feeding and Eating Disorders; Gonadal Disorders; Humans; Leptin; Metabolic Syndrome; Obesity; Radioimmunoassay; Reagent Kits, Diagnostic; Receptors, Cell Surface; Receptors, Leptin; Reference Values; Specimen Handling

The article summarizes the endocrinology axis in relation to leptin in the obesity. There is a glucocorticoid hypothesis in the obesity origin. Human plasma leptin levels are elevated in Cushing's syndrome and there is a robust leptin secretory responses to dexamethasone. Obesity impacts on reproductive function in man and women. Leptin levels are higher in women than in men and a critical blood leptin level is necessary to trigger reproductive ability in women. The relationship between body mass index and circulating leptin varies during the course of spontaneous cycles in women, the best correlation occurring during the luteal phase when progesterone and leptin concentrations are highest. Obesity is associated with a decrease in growth hormone (GH) and reversible with weight loss. The influence of body composition on GH secretion in the obesity may be mediated through leptin, acting as a peripheral signal from adipose tissue. Thyroid dysfunction appear not associated with alterations in serum leptin levels. There is a significant relationship between insulin and leptin, but it is not immediate, since type 2 diabetics show similar leptin levels to those of nondiabetic humans of the same body mass index.

Topics: Adult; Animals; Body Mass Index; Cushing Syndrome; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Human Growth Hormone; Humans; Hyperinsulinism; Hypertension; Hypothalamo-Hypophyseal System; Insulin; Leptin; Male; Menstrual Cycle; Mice; Mice, Obese; Middle Aged; Obesity; Pituitary-Adrenal System; Progesterone; Rats; Reproduction; Sex Factors

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 abso

Topics: Addison Disease; Adipose Tissue; Adolescent; Adult; Blood Glucose; Body Mass Index; Circadian Rhythm; Cushing Syndrome; Diabetes Mellitus; Down-Regulation; Female; Glucocorticoids; Hormones; Humans; Hydrocortisone; Insulin Resistance; Leptin; Middle Aged; Nutritional Status; Obesity; Tissue Distribution; Up-Regulation

The normal inverse relationship between leptin and cortisol is lost in chronic hypercortisolism. We studied this apparent dysregulation in patients with Cushing's syndrome to investigate 1) the effect of chronic hypercortisolemia on the circadian rhythm of leptin secretion, 2) the response of leptin after administration of CRH, and 3) the short term effect of curative surgery on leptin. The preoperative morning leptin concentration was 54.2 +/- 8.1 ng/mL, and the nighttime value was 68.6 +/- 9.8 ng/mL, reflecting a mean rise of 32.8 +/- 7.6%, similar to the nocturnal increase observed in normal subjects. By contrast, cortisol's diurnal variation (21.8 +/- 1.7 vs. 16.9 +/- 1.1 mg/dL) was blunted. In women, but not men, body mass index correlated with leptin (P = 0.001). Preoperative ACTH and cortisol (both P < 0.0001), but not leptin levels increased after CRH. Ten days after surgery, basal cortisol values were subnormal (1.1 +/- 0.6 mg/dL), but leptin levels remained unchanged and did not increase after CRH. Body mass index and insulin also remained unchanged. Insulin, but not age, urinary free cortisol, or plasma cortisol correlated with leptin (P < 0.05). In summary, patients with Cushing's syndrome have moderately elevated leptin levels that maintain an intact circadian rhythm but do not respond to acute or subacute alterations of cortisol.

Topics: Adenoma; Adolescent; Adrenocorticotropic Hormone; Adult; Body Mass Index; Child; Circadian Rhythm; Corticotropin-Releasing Hormone; Cushing Syndrome; Female; Follow-Up Studies; Humans; Hydrocortisone; Leptin; Male; Middle Aged; Pituitary Neoplasms; Proteins; Testosterone

To analyze changes in fat cell size, macrophage infiltration, and local adipose tissue adipokine profiles in different fat depots in patients with active Cushing's syndrome.. Subcutaneous (SC) and perirenal (PR) adipose tissue of 10 patients with Cushing's syndrome was compared to adipose tissue of 10 gender-, age-, and BMI-matched controls with regard to adipocyte size determined by digital image analysis on hematoxylin and eosin stainings, macrophage infiltration determined by digital image analysis on CD68 stainings, and adipose tissue leptin and adiponectin levels using fluorescent bead immunoassays and ELISA techniques.. Compared to the controls, mean adipocyte size was larger in PR adipose tissue in patients. The percentage of macrophage infiltration of the PR adipose tissue and PR adipose tissue lysate leptin levels were higher and adiponectin levels were lower in SC and PR adipose tissue lysates in patients. The adiponectin levels were also lower in the SC adipose tissue supernatants of patients. Associations were found between the severity of hypercortisolism and PR adipocyte size.. Cushing's syndrome is associated with hypertrophy of PR adipocytes and a higher percentage of macrophage infiltration in PR adipose tissue. These changes are associated with an adverse local adipokine profile.

Topics: Adipocytes; Adipokines; Adult; Aged; Body Mass Index; Cell Size; Cross-Sectional Studies; Cushing Syndrome; Female; Humans; Hypertrophy; Intra-Abdominal Fat; Leptin; Macrophages; Male; Middle Aged; Young Adult

Glucocorticoid receptor (GR) polymorphisms modulate glucocorticoid (GC) sensitivity and are associated with altered metabolic profiles.. To evaluate the presence of GR polymorphisms (BclI (rs41423247), N363S (rs56149945), ER22/23EK (rs6189/rs6190), and 9β (rs6198) and investigate their associations with metabolic alterations in patients in long-term remission of Cushing's syndrome (CS).. Cross-sectional case-control study.. Sixty patients in long-term remission of CS were genotyped. Associations between GR polymorphisms and multiple vascular, body composition and metabolic parameters were investigated.. Allelic frequencies of the polymorphisms and their associations with several cardiometabolic risk factors.. This study shows that carriers of the 9β polymorphism have a higher systolic blood pressure and lower resistin levels. The GC sensitizing BclI polymorphism is associated with an adverse cardiometabolic risk factor profile: higher fat percentages of extremities and legs, higher serum leptin and E-selectin levels, and higher intima media thickness in carriers versus non-carriers.. The 9β and BclI polymorphisms of the GR adversely affect the cardiometabolic profile in patients who are in remission after the treatment of CS. This suggests that genetically altered GC sensitivity modulates the long-term adverse cardiometabolic effects resulting from (endogenous) hypercortisolism.

Topics: Adiposity; Adult; Alleles; Blood Pressure; Carotid Intima-Media Thickness; Case-Control Studies; Cross-Sectional Studies; Cushing Syndrome; E-Selectin; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Glucocorticoid; Resistin; Risk Factors

We measured the serum adiponectin and leptin concentrations before and after successful removal of a left adrenal adenoma in a 46-year-old woman with Cushing's syndrome. The serum adiponectin level was 6.0 microg/ml before the operation and rose to 8.1 microg/ml after adrenalectomy. However, the serum leptin level was markedly high (24.8 ng/ml) before the operation and decreased to within the normal range (6.0 ng/ml) 6 months after adrenalectomy, concomitant with weight reduction and normalization of the serum cortisol level.

Topics: Adenoma; Adiponectin; Adrenal Gland Neoplasms; Adrenalectomy; Biomarkers; Blood Chemical Analysis; Cushing Syndrome; Female; Humans; Leptin; Middle Aged; Postoperative Period; Preoperative Care; Sensitivity and Specificity; Treatment Outcome

Despite major advances in understanding monogenic causes of morbid obesity, the complex genetic and environmental etiology of idiopathic metabolic syndrome remains poorly understood. One hypothesis suggests that similarities between the metabolic disease of plasma glucocorticoid excess (Cushing's syndrome) and idiopathic metabolic syndrome results from increased glucocorticoid reamplification within adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1). Indeed, 11beta-HSD-1 is now a major therapeutic target. Because much supporting evidence for a role of adipose 11beta-HSD-1 comes from transgenic or obese rodents with single-gene mutations, we investigated whether the predicted traits of metabolic syndrome and glucocorticoid metabolism were coassociated in a unique polygenic model of obesity developed by long-term selection for divergent fat mass (Fat and Lean mice with 23 vs. 4% fat as body weight, respectively). Fat mice exhibited an insulin-resistant metabolic syndrome including fatty liver and hypertension. Unexpectedly, Fat mice had a marked intra-adipose (11beta-HSD-1) and plasma glucocorticoid deficiency but higher liver glucocorticoid action. Furthermore, metabolic disease was exacerbated only in Fat mice when challenged with exogenous glucocorticoids or a high-fat diet. Our data suggest that idiopathic metabolic syndrome might associate with such a novel pattern of glucocorticoid action and sensitivity in humans, with implications for tissue-specific therapeutic targeting of 11beta-HSD-1.

Topics: Adipose Tissue; Animals; Blood Glucose; Corticosterone; Crosses, Genetic; Cushing Syndrome; Epididymis; Glucocorticoids; Insulin; Leptin; Liver; Male; Metabolic Syndrome; Mice; Mice, Obese; Models, Genetic; Obesity; RNA; Skin; Triglycerides

To determine if increased local production of glucocorticoids by the pancreatic islets might play a role in the spontaneous noninsulin-dependent diabetes mellitus of obesity, we compared islet 11beta-HSD-1 mRNA and activity in islets of obese prediabetic and diabetic Zucker Diabetic Fatty (ZDF) (fa/fa) rats and lean wild-type (+/+) controls. In diabetic rat islets, both mRNA and enzymatic activity of the enzyme were increased in proportion to the hyperglycemia. Troglitazone (TGZ) treatment, beginning at 6 weeks of age, prevented the hyperglycemia, the hyperlipidemia, and the increase in 11beta-HSD-1. To determine if the metabolic abnormalities had caused the 11beta-HSD-1 increase, prediabetic islets were cultured in high or low glucose or in 2:1 oleate:palmitate for 3 days. Neither nutrient enhanced the expression of 11beta-HSD-1. We conclude that 11beta-HSD-1 expression and activity are increased in islets of diabetic, but not prediabetic ZDF rats, and that TGZ prevents both the increase in 11beta-HSD-1 and the diabetes.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Animals, Genetically Modified; Blotting, Western; Chromans; Cushing Syndrome; Diabetes Mellitus, Experimental; Fatty Acids; Glucose; Hyperglycemia; Hypoglycemic Agents; Islets of Langerhans; Leptin; Microsomes, Liver; Obesity; Oleic Acid; Palmitates; Phenotype; Prednisone; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiazolidinediones; Troglitazone

Cushing's syndrome (CS) is associated with central adiposity, insulin resistance and impaired glucose homeostasis. Adipose tissue is thought to regulates glucose homeostasis via circulating adipokines, such as resistin, leptin and adiponectin, although their role in the insulin resistance associated with CS has not been established.. We examined the relationship between insulin resistance and adipokine levels in CS patients. We compared plasma levels of resistin, leptin and adiponectin in 10 women and four men patients with CS, with 14 health subjects matched for age, gender and body mass index. A subgroup of three women and four men with pituitary-dependent CS were re-examined at least 9 months after curative surgery.. CS patients had significantly more truncal fat and less lean body mass as assessed by DEXA compared to control subjects. Total cholesterol, triglycerides and insulin resistance, as calculated using the homeostasis model assessment of insulin resistance (HOMA-R), was significantly increased in CS patients. Of the adipokines measured, only resistin was significantly different between female CS patients and female control subjects (5.05 +/- 0.56 vs. 2.91 +/- 0.39 micro g/l, P = 0.015). Curative surgery significantly reduced total body fat and truncal fat, leptin, total and low-density lipoprotein (LDL) cholesterol, glucose and HOMA-R. A reduction in both resistin and adiponectin was also observed but the differences between pre- and post-treatment levels did not achieve statistical significance.. Here we report for the first time that resistin levels are significantly elevated in CS patients and may be important in the insulin resistance associated with glucocorticoid excess.

Topics: Adiponectin; Adult; Body Mass Index; Case-Control Studies; Cholesterol; Cushing Syndrome; Female; Hormones, Ectopic; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Proteins; Regression Analysis; Resistin; Triglycerides

To investigate the circadian rhythmicity of adiponectin in patients with Cushing's syndrome and obesity, as well as in normal subjects. The effects of glucocorticoids, insulin and leptin on the secretion of adiponectin were also explored.. 15 patients with Cushing's syndrome and 10 with obesity as well as 9 normal subjects were recruited and their serum adiponectin, glucocorticoids, insulin and leptin levels were determined 6 times a day (8:00, 12:00, 16:00, 20:00, 24:00, 3:00).. Circadian rhythmicity of adiponectin was not observed, but the adiponectin levels in patients with obesity were lower than those in the normal subjects at all 6 time spots. The area under curve (AUC) of serum adiponectin concentrations were significantly negatively correlated with body mass index (BMI, r = 0.46, P < 0.01), waist circumference (r = -0.33, P < 0.05) and insulin AUC (r = -0.36, P < 0.05). A multiple linear regression analysis revealed that BMI and waist circumference were two significant independent parameters of the plasma adiponectin level. The adiponectin levels did not manifest any change after short term dexamethasone administration with both high and low doses, but were obviously decreased after surgery.. Neither long-term endogenous hyperglucocorticoidism nor short-term dexamethasone administration affects the serum adiponectin levels and the serum adiponectin concentrations remain unchanged even with elevated postprandial insulin levels.

Topics: Adiponectin; Adolescent; Adult; Area Under Curve; Body Mass Index; Circadian Rhythm; Cushing Syndrome; Female; Humans; Hydrocortisone; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Obesity

Simple obesity and Cushing's syndrome (CS) are two clinical models of leptin hypersecretion coupled with GH hyposecretion. Fasting inhibits leptin while stimulating GH secretion in normal human subjects.. To clarify the effect of fasting on leptin and GH secretion in obesity and CS. PATIENTS AND PROTOCOL: We studied six women with CS [age 17-66 years; body mass index (BMI) 28.6 kg/m2], seven women with visceral obesity (OB; 20-41 years; BMI 42.9 kg/m2) and seven normal women (NS; 25-31 years; BMI 19.3 kg/m2). The effects of 36-h fasting on 8-h diurnal mean leptin, GH, insulin and glucose concentrations (mLEPTc, mGHc, mINSc and mGLUc) as well as on the IGF/IGFBP system were studied.. Before fasting, mLEPTc in OB and in CS were similar and both were higher (P < 0.01) than in NS. OB and CS showed similar mGHc, which were lower (P < 0.05) than in NS. Fasting induced a reduction in mLEPTc that was significant in NS and CS (P < 0.04) but not in OB. The mLEPTc in OB and CS after fasting remained higher (P < 0.05) than in NS. After fasting, OB and CS showed no increase in mGHc, although this clearly increased (P < 0.02) in NS. IGF-I but not IGFBP-3 levels decreased in all groups (P < 0.05). Fasting reduced mINSc and mGLUc while increasing IGFBP-1 in all groups. After fasting, mINSc in OB and CS remained higher (P < 0.03) than in NS.. Short-term fasting has less inhibitory effect on leptin and no stimulatory effect on GH secretion in patients with Cushing's syndrome as well as simple obesity. After fasting, insulin levels in hypercortisolaemic and also in obese patients remained higher than in normal subjects suggesting that hyperinsulinism could play a role in the altered response of leptin and GH to starvation in these conditions.

Topics: Adolescent; Adult; Aged; Blood Glucose; Case-Control Studies; Cushing Syndrome; Fasting; Fatty Acids, Nonesterified; Growth Hormone; Humans; Hydrocortisone; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Middle Aged; Obesity

The weight gain and visceral obesity associated with Cushing's syndrome (CS) has been linked to elevated plasma leptin levels, although the mechanism behind a central leptin resistance in these patients is unknown. Several studies describe interactions among the hypothalamic-pituitary-adrenal axis, leptin, and the IL-1 system. To investigate these interactions, we have evaluated changes in regional fat distribution, by DEXA, and the role of circulating cortisol, leptin, IL-1beta, and IL-1 receptor antagonist (IL-1Ra), in relation to these changes, in 27 (19 DEXA; 27 serum measurements) patients with CS, before and after surgical treatment (mean follow-up, 31 months; range, 5-80), and compared them with measurements of age-, sex-, and body mass index-matched healthy controls (also obtained longitudinally). We found that surgical treatment caused a decrease in all fat parameters, without changing lean body mass, and these changes were significantly larger than the so-called natural changes occurring in control subjects. These changes in CS patients were paralleled by decreases in cortisol, leptin, and IL-1Ra, whereas IL-1beta increased. Stepwise linear regression showed that serum IL-1Ra was strongly associated with regional fat distribution, and especially truncal fat mass, both at baseline and during treatment. In conclusion, the present study shows that treatment significantly changes body composition in CS patients by decreasing fat mass, especially in the truncal region, without major effects on lean body mass. We also show that circulating IL-1Ra is strongly associated with these changes, signifying a relationship among the hypothalamic-pituitary-adrenal axis, IL-1 system, and regional fat distribution in these patients.

Topics: Adipose Tissue; Adult; Body Composition; C-Peptide; Cushing Syndrome; Female; Humans; Hydrocortisone; Insulin; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Leptin; Longitudinal Studies; Male; Middle Aged; Sialoglycoproteins

It is known that body composition, especially body fat content, determines plasma leptin (LEP) levels. Clinical observation confirms that glucocorticoids (GS) have a considerable impact on body composition and body fat distribution which leads to visceral fat accumulation and a decrease in muscle mass in limbs. On the other hand, in experimental models GS stimulate ob mRNA expression in adipose tissue and LEP secretion into bloodstream. The aim of the study was to evaluate changes in body composition and fat and fat-free mass distribution in the conditions of endogenous hypercortisolism as well as to determine whether changes in body composition parameters may influence plasma LEP levels in patients with Cushing's syndrome (CUS). The study group was composed of 14 patients (12 F, 2 M) with ACTH-dependent and ACTH-independent CUS (BMI 29,5 +/- 1,0 kg/m2, aged 41,6 +/- 2,9 yrs.). The control group (KON) included 14 overweight/obese subjects (12 F, 2 M; WHR>0.8) matched for age, height, weight, and BMI with CUS group. Basal plasma LEP levels were measured by RIA kit. Total fat mass (BFM), fat-free mass (FFM), their regional depots (arms, legs, trunk) as well as bone mineral content (BMC) were determined by DEXA method (Lunar Co., USA). Values of BFM and %BF were comparable in both groups whereas the amount of FFM was lower in CUS group than in controls. Patients with CUS had less BF in limbs than controls whereas the difference in the amount of trunk BF in favour of CUS reached a borderline significance. Moreover, subjects with CUS exhibited decreased amount of FFM both in arms and legs when compared to controls, which may be explained by limb muscle and connective tissue wasting observed clinically. However, the amount of trunk FFM did not differ between both groups. Eventually, subjects with CUS had lower BMC values than controls. Absolute plasma LEP levels were 2-fold higher in CUS group than those in KON group (34,03 +/- 4,45 vs. 17,04 +/- 1,88, ng/ml; p=0.006), however, in both groups they were highly correlated with BFM and %BF. Multiple linear regression analysis revealed that in CUS group 64% of the variation of plasma LEP levels is explained by trunk BF and in KON group 92% of the variation of LEP levels is dependent of arms BF (+, 18%) and legs BF (+, 69%) and arms FFM (-, 5%). In conclusion, endogenous hypercortisolismus leads to the augmentation of truncal (visceral) fat accumulation as well as to a marked decrease in fat-free mass in limbs and i

Topics: Adipose Tissue; Adolescent; Adrenocorticotropic Hormone; Adult; Body Composition; Body Mass Index; Cushing Syndrome; Female; Humans; Leptin; Male; Middle Aged; Pituitary Neoplasms

To investigate the effects of glucocorticoids and insulin on serum leptin level and its diurnal rhythmicity in patients with Cushing's syndrome and obesity as well as in normal subjects.. Fifteen patients with Cushing's syndrome and 10 with obesity as well as 9 normal subjects were investigated, with their serum leptin, cortisol and insulin levels measured 6 times a day (8:00, 12:00, 16:00, 20:00, 24:00, 3:00).. The diurnal rhythmicity of serum leptin was still preserved in all the three groups, with peak appearing at 24:00 approximately 3:00 and nadir at 8:00 approximately 12:00. However, the relative diurnal excursion was negatively correlated with body mass index (BMI). The peak positive effects of insulin on leptin secretion delayed by 4 to 8 hours.. Glucocorticoids can increase serum leptin levels, but the changes of the diurnal rhythmicity of cortisol do not affect the diurnal rhythmicity of leptin. The relative diurnal excursion of leptin is negatively correlated with body fat, i.e, the fatter subjects usually have the blunter leptin diurnal rhythmicity. Insulin exerts an effect on leptin secretion in a delayed manner, indicating its role in maintaining the diurnal rhythmicity of serum leptin.

Topics: Adult; Body Mass Index; Circadian Rhythm; Cushing Syndrome; Female; Humans; Hydrocortisone; Insulin; Leptin; Male; Middle Aged; Obesity; Sex Factors

The episodicity of 24 h leptin release was studied in seven women (mean age 39 years, range 22-56 years) with pituitary-dependent hypercortisolism and in seven age- and body mass index (BMI)-matched female controls. Pulsatile leptin release was quantified by model-free cluster analysis and deconvolution, the orderliness of leptin patterns by the approximate entropy statistic (ApEn), and nyctohemeral leptin rhythmicity by cosinor analysis. Blood samples were taken at 10 min intervals for 24 h. Both cluster and deconvolution analysis revealed 2.4-fold increased leptin secretion in patients, caused by combined and equal amplification of basal and pulsatile secretion. Cluster analysis identified 7.1+/-1.5 peaks per 24 h in patients and 6.0+/-0.5 in controls (not significant). The statistical distribution of the individual sample secretory rates was similarly skewed in patients and controls (0.55+/-0.12 vs 0.52+/-0.07). The acrophase (timing of the nyctohemeral leptin peak) in patients occurred at 2314 h (+/-76 min) and at 0058 h (+/-18 min) in controls (not significant). The approximate entropy of leptin release was equivalent in patients and controls (1.67+/-0.03 vs 1.61+/-0.05). The approximate entropy (ApEn) for cortisol in patients was 1.53+/-0.09 and in controls was 0.93+/-0.07 (P<0.0005). Cross-ApEn showed significant pattern synchrony between leptin and cortisol release, which (unexpectedly) was not disrupted by the cortisol excess (patients, 2.02+/-0.04; controls, 1.88+/-0.09; P=0.233). Insulin levels in fasting patients ('fasting insulin') were 27+/-5.7 mU/l vs 14+/-1.6 mU/l in controls (P=0.035). Leptin secretion correlated with fasting insulin levels (R(2)=0.34, P=0.028) and with the cortisol production rate (R(2)=0.33, P=0.033) when patients and controls were combined. In summary, Cushing's disease in women increases leptin production about twofold in an amplitude-specific way. The pulse-generating, nyctohemeral phase-determining, and entropy-control mechanisms that govern the 24 h leptin release are not altered. The increased secretion is not explained by BMI and is probably only partly explained by increased insulin production, suggesting a cortisol-dependent change in adipose leptin secretion.

Topics: Adult; Body Mass Index; Cushing Syndrome; Fasting; Female; Human Growth Hormone; Humans; Hydrocortisone; Insulin; Leptin; Middle Aged; Periodicity

Cushing's syndrome (CS) is associated with weight gain and visceral obesity. We examined the relationship between regional fat distribution and serum levels of leptin, cortisol and insulin. Twenty-three consecutive patients with recently diagnosed CS (18 with pituitary adenoma, 5 with adrenal tumor), where compared to obese controls, matched for age, sex and Body Mass Index (BMI). Serum insulin, leptin, cortisol, C-peptide and body composition determined by DEXA were measured. Serum leptin levels were significantly increased in patients with CS (36.9+/-3.8 vs 18.9+/-2.4 ng/ml, p<0.001; women: 40.1+/-4.6 vs 21.7+/-2.9 ng/ml, p<0.01; men: 27.9+/-5.7 vs 10.9+/-2.3 ng/ml; p<0.05), the same were fasting insulin levels (178+/-30 vs 81+/-10 pmol/l; p<0.01) and C-peptide (1.51+/-0.12 vs 0.77+/-0.07 nmol/l; p<0.001). In a subgroup of 12 patients, truncal fat mass was significantly elevated when compared to obese controls (19.2 kg vs 14.7 kg, p<0.01, and 42% vs 36% in percentage of truncal body tissue, p<0.05), whereas total fat mass was insignificantly increased. Serum leptin correlated positively to total body fat (%) as in patients with CS (r=0.94, p<0.001) as in controls (r=0.68, p<0.01). The correlation to truncal body fat (%) was also significant in both groups (CS: r=0.84, p<0.001; controls: r=0.63, p<0.01). Multiple regression showed that percent total body fat was the predictor of leptin concentrations among patients with CS (r2=0.88, p<0.001) whereas insulin did not contribute significantly to the variance in leptin concentrations. In controls, both leptin and insulin (r2=0.65, p<0.001) contributed significantly to the variations in leptin levels. Controlled for the differences in total body fat, patients with endogenous CS have significantly increased serum leptin levels, compared to BMI-matched obese controls. This suggests that hyperleptinemia in CS not primarily reflects changes in body composition, but is the result of different hormonal influences on adipose tissue.

Topics: Adipose Tissue; Adult; Body Composition; Body Mass Index; C-Peptide; Cushing Syndrome; Fasting; Female; Humans; Hydrocortisone; Insulin; Leptin; Male; Osmolar Concentration; Reference Values

Stimulation ofcortisol secretion by food intake has been implicated in the pathogenesis of some cases of ACTH-independent Cushing's syndrome, via an aberrant response of the adrenal glands to gastric inhibitory polypeptide (GIP). We report here a novel case of food-dependent Cushing's syndrome in a patient with bilateral macronodular adrenal hyperplasia. In this patient we were able to confirm a paradoxical stimulation of cortisol secretion by GIP in vivo as well as in vitro on dispersed tumor adrenal cells obtained at surgery. In addition to GIP, in vitro stimulation of these cultured tumor adrenal cells with leptin, the secreted product of the adipocyte, induced cortisol secretion. By comparison, no such stimulation was observed in vitro in adrenal cells obtained from another patient with bilateral macronodular adrenal hyperplasia and Cushing's syndrome that did not depend on food intake, in tumor cells obtained from a solitary cortisol-secreting adrenal adenoma, and in normal human adrenocortical cells. These results demonstrate that as in previously described cases of food-dependent Cushing's syndrome, GIP stimulated cortisol secretion from the adrenals of the patient reported here. Therefore, they indicate that such a paradoxical response probably represents the hallmark of this rare condition. In addition, they suggest that leptin, which normally inhibits stimulated cortisol secretion in humans, participated in cortisol hypersecretion in this case. Further studies in other cases of food-dependent Cushing's syndrome, however, will be necessary to better ascertain the pathophysiological significance of this finding.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Adult; Cushing Syndrome; Female; Food; Gastric Inhibitory Polypeptide; Humans; Hydrocortisone; Hyperplasia; Leptin; Middle Aged

Corticosteroids and insulin increase leptin expression in vivo and in vitro. To investigate whether increased serum cortisol influences serum leptin concentrations in humans, we analyzed fasting serum leptin and insulin levels in 50 patients with Cushing's syndrome [34 female patients: 27 with the pituitary form and 7 with the adrenal form; age, 41.6 +/- 2.7 yr; body mass index (BMI), 29.6 +/- 1.2 kg/m2; 16 male patients all with the pituitary form; age, 39.2 +/- 3.1 yr; BMI, 26.3 +/- 2.3 kg/m2] and in controls matched for BMI, age, and gender. Serum leptin levels were higher in female than in male patients in both the Cushing (P < 0.01) and control (P < 0.001) groups. Disease-specific differences in serum leptin levels were only detected in male (106 vs. 67 pmol/L; Cushing's syndrome vs. control, P < 0.05), not female, patients. Multiple stepwise regression analysis of both patient groups revealed insulin as the best predictor of serum leptin concentrations, accounting for 37% of the variance in serum leptin levels, in contrast to BMI or mean serum cortisol (as measured by sampling in 10-min intervals over 24 h). In the subgroup of patients (n = 9) with pituitary adenoma, serum leptin levels were reduced after tumor resection, with concurrent decreases in serum cortisol, insulin, and BMI. In conclusion, chronic hypercortisolemia in Cushing's syndrome appears not to directly affect serum leptin concentrations, but to have an indirect effect via the associated hyperinsulinemia and/or impaired insulin sensitivity.

Topics: Adolescent; Adult; Aged; Body Mass Index; Cushing Syndrome; Fasting; Female; Humans; Hydrocortisone; Insulin; Leptin; Male; Middle Aged; Proteins; Regression Analysis; Sex Characteristics

Leptin communicates nutritional status to regulatory centers in the brain. Because peripheral leptin influences the activity of the highly pulsatile adrenal and gonadal axes, we sought to determine whether leptin levels in the blood are pulsatile. We measured circulating leptin levels every 7 minutes for 24 hours, in six healthy men, and found that total circulating leptin levels exhibited a pattern indicative of pulsatile release, with 32.0 +/- 1.5 pulses every 24 hours and a pulse duration of 32.8 +/- 1.6 minutes. We also show an inverse relation between rapid fluctuations in plasma levels of leptin and those of adrenocorticotropic hormone (ACTH) and cortisol that could not be accounted for on the basis of glucocorticoid suppression of leptin. As leptin levels are pulsatile, we propose that a key function of the CNS is regulated by a peripheral pulsatile signal. In a separate pilot study we compared leptin pulsatility in 414 plasma samples collected every 7 minutes for 24 hours from one obese woman and one normal-weight woman. We found that high leptin levels in the obese subject were due solely to increased leptin pulse height; all concentration-independent pulsatility parameters were almost identical in the two women. Leptin pulsatility therefore can be preserved in the obese.

Topics: Adrenocorticotropic Hormone; Adult; Algorithms; Corticotropin-Releasing Hormone; Cushing Syndrome; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Leptin; Male; Menstruation; Obesity; Pilot Projects; Pituitary-Adrenal System; Proteins

Leptin, the obese (ob) gene product, is an adipocyte-derived satiety factor that is involved in the regulation of food ingestion and body weight. To investigate glucocorticoid regulation of leptin synthesis and secretion in humans, we measured plasma leptin levels in patients with Cushing's syndrome with adrenal or pituitary adenoma and in patients with iatrogenic Cushing's syndrome. Plasma leptin levels in patients with Cushing's syndrome were significantly elevated compared to those in nonobese healthy subjects and obese subjects without any metabolic or endocrine diseases at a given percentage of body fat by analysis of covariance. In patients with adrenal or pituitary adenoma, after the tumor resection, plasma leptin levels were reduced, with a concurrent decrease in plasma cortisol levels. With no significant changes in body weight, plasma leptin levels were also elevated significantly in lean healthy volunteers 24 h after the administration of 1 mg dexamethasone. Dexamethasone potently induced ob gene expression and leptin secretion in the organ culture of human adipose tissue. The data demonstrate that glucocorticoids act, at least in part, directly on the adipose tissue and increase leptin synthesis and secretion in humans.

Topics: Adenoma; Adipose Tissue; Adolescent; Adrenal Gland Neoplasms; Adult; Cushing Syndrome; Dexamethasone; Female; Gene Expression; Glucocorticoids; Humans; Hydrocortisone; Leptin; Male; Middle Aged; Organ Culture Techniques; Pituitary Neoplasms; Protein Biosynthesis; Proteins

In the present study, we characterized the changes in plasma leptin levels in patients with pituitary Cushing's disease and in age- and sex-matched controls. Plasma levels of ACTH, cortisol, and leptin were measured before and after iv administration of ovine CRH in controls once and in patients twice (while they had active hypercortisolism and 10 days after successful surgery). Cushing's patients had elevated body mass indexes (34 +/- 1.9 vs. 22.9 +/- 0.8) and plasma leptin levels (35.6 +/- 3.4 vs. 9.2 +/- 1.9 ng/mL) compared to controls, which remained unchanged 10 days after successful transsphenoidal surgery and directly proportional to the body mass index. Plasma leptin levels were not affected by CRH infusion in either the controls or the patients despite clear-cut elevations in plasma ACTH and cortisol. These findings suggest that although acute changes in plasma cortisol do not affect plasma leptin, chronic hypercortisolism results in elevated leptin levels, probably by causing visceral obesity.

Topics: Adenoma; Adrenocorticotropic Hormone; Adult; Body Mass Index; Corticotropin-Releasing Hormone; Cushing Syndrome; Female; Humans; Hydrocortisone; Leptin; Male; Middle Aged; Obesity; Pituitary Neoplasms; Proteins

Leptin, the product of the ob gene, is a recently discovered hormone secreted by adipocytes. Cushing's syndrome is a disease state usually associated with weight gain due to the accumulation of adipose tissue. In order to study the effect of chronic glucocorticoid excess upon serum leptin levels; in the present work, four patients with recently diagnosed Cushing's syndrome and a group of control subjects matched for age, sex and body mass index (BMI) were studied. Serum leptin concentrations, measured by radioimmunoassay, were assessed in samples taken every 60 minutes over a 24 hour period. Assessment of leptin concentrations over 24 hours, by means of the area under curve showed a twofold increase in serum leptin levels in patients with Cushing's syndrome (mean+/-SEM 54.3+/-14) in comparison to control subjects (29.3+/-4.4; p<0.05). In conclusion, our data show that leptin levels are markedly increased in Cushing's syndrome patients. The relevance of this finding to the increased body fat present in patients with Cushing's syndrome merits further studies.

Topics: Adult; Circadian Rhythm; Cushing Syndrome; Female; Humans; Leptin; Obesity; Proteins; Reference Values