Hyperleptinemia in women with Cushing's disease is driven by high-amplitude pulsatile, but orderly and eurhythmic, leptin secretion

Veldman, R. Groote; Frölich, Marijke; Pincus, Steve; Veldhuis, Johannes D.; Roelfsema, Ferdinand

doi:10.1530/eje.0.1440021

Cited by 20 publications

(14 citation statements)

References 61 publications

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“…These findings argue in favor of an unexpected synchrony between leptin and cortisol in CD, with a preservation of normal responsiveness of fat cells to cortisol, despite its excessive and dysregulated production in that disorder. This evidence supports a possible direct influence of hypercortisolemia on hyperleptinemia in CD, although the same group did not find any correlation between leptin and cortisol secretion rates [61] . Similarly, Weise et al [59] demonstrated maintenance of a normal diurnal leptin profile in 18 CS patients but did not observe any correlation between leptin and cortisol at any time point.…”

Section: Leptin and Cushing's Syndromesupporting

confidence: 55%

“…A study of leptin pulsatility in 7 women with CD revealed a more than 2-fold elevation in daily leptin production rates as compared with age-, gender-and BMImatched controls, which was driven by higher pulse am-plitude rather than frequency [61] . Of note, approximate entropy of leptin release and cross-approximate entropy of cortisol and leptin were superimposable to those measured in controls.…”

Section: Leptin and Cushing's Syndromementioning

confidence: 99%

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Adipokines and Cardiovascular Risk in Cushing’s Syndrome

et al. 2011

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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.

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Section: Leptin and Cushing's Syndromesupporting

confidence: 55%

Section: Leptin and Cushing's Syndromementioning

confidence: 99%

Adipokines and Cardiovascular Risk in Cushing’s Syndrome

et al. 2011

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“…growth hormone; cortisol; insulin resistance; estradiol; ghrelin; thyroid hormones LEPTIN IS A CYTOKINE expressed by adipose tissue that suppresses appetite by interactions with its receptor in the brain (5, 32, 46). There is evidence that leptin is secreted in a pulsatile manner (20,22,44), but secretory dynamics of leptin are unclear, especially in adolescents. Low levels of leptin have been reported in adolescent girls with anorexia nervosa (AN) by our group (15,28,38) and by other investigators (17, 40).…”

mentioning

confidence: 99%

Secretory dynamics of leptin in adolescent girls with anorexia nervosa and healthy adolescents

Misra

Miller

Kuo

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

146

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Leptin, an adipocytokine that suppresses appetite and may regulate neuroendocrine pathways, is low in undernourished states like anorexia nervosa (AN). Although leptin exhibits pulsatility, secretory characteristics have not been well described in adolescents and in AN, and the contribution of hypoleptinemia to increased growth hormone (GH) and cortisol in AN has not been explored. We hypothesized that hypoleptinemia in AN reflects decreased basal and pulsatile secretion and may predict increased GH and cortisol levels. Sampling for leptin, GH, cortisol, and ghrelin was performed every 30 min (from 2000 to 0800) in 23 AN and 21 controls 12-18 yr old, and data were analyzed using Cluster and deconvolution methods. Estradiol, thyroid hormones, and body composition were measured. AN girls had lower pulsatile and total leptin secretion than controls (P < 0.0001) subsequent to decreased burst mass (P < 0.0001) and basal secretion (P = 0.02). Nutritional markers predicted leptin characteristics. In a regression model including BMI, body fat, and ghrelin, leptin independently predicted GH burst interval and frequency. Valley leptin contributed to 56% of the variability in GH burst interval, and basal leptin and fasting ghrelin contributed to 42% of variability in burst frequency. Pulsatile leptin independently predicted urine free cortisol/creatinine (15% of variability). Valley leptin predicted cortisol half-life (22% of variability). Leptin predicted estradiol and thyroid hormone levels. In conclusion, hypoleptinemia in AN is subsequent to decreased basal and pulsatile secretion and nutritionally regulated. Leptin predicts GH and cortisol parameters and with ghrelin predicts GH burst frequency. Low leptin and high ghrelin may be dual stimuli for high GH concentrations in undernutrition.

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“…Finally, leptin might also be involved in the GH regulation. Circulating leptin concentrations in Cushing's syndrome are disproportionately increased compared with BMI-matched healthy controls (7,15,36). Short-term fasting in Cushing's syndrome did not restore normal leptin levels, and GH secretion remained blunted (19).…”

Section: Discussionmentioning

confidence: 86%

Growth hormone secretion in primary adrenal Cushing's syndrome is disorderly and inversely correlated with body mass index

Aken

Pereira

Frölich

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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. Growth hormone secretion in primary adrenal Cushing's syndrome is disorderly and inversely correlated with body mass index. Am J Physiol Endocrinol Metab 288: E63-E70, 2005. First published August 24, 2004; doi:10.1152/ajpendo.00317.2004.-To evaluate the impact on the somatotropic axis of endogenous cortisol excess in the absence of primary pituitary disease, we investigated spontaneous 24-h growth hormone (GH) secretion in 12 adult patients with ACTH-independent hypercortisolism. Plasma GH concentration profiles (10-min samples) were analyzed by deconvolution to reconstruct secretion and approximate entropy to quantitate orderliness of the release process. Comparisons were made with a body mass index (BMI)-, age-, and gender-matched control group and an age-and gender-matched lean control group. GH secretion rates did not differ from BMI-matched controls but were twofold lower compared with lean subjects, mainly due to a 2.5-fold attenuation of the mean secretory burst mass (P ϭ 0.001). In hypercortisolemic patients, GH secretion was negatively correlated with BMI (R ϭ Ϫ0.55, P ϭ 0.005) but not cortisol secretion. Total serum IGF-I concentrations were similar in the three groups. Approximate entropy (ApEn) was increased in patients with Cushing's syndrome compared with both control groups (vs. BMI-matched, P ϭ 0.04; vs. lean, P ϭ 0.001), denoting more irregular GH secretion patterns. ApEn in patients correlated directly with cortisol secretion (R ϭ 0.77, P ϭ 0.003). Synchrony between cortisol and GH concentration series was analyzed by cross-correlation, cross-ApEn, and copulsatility analyses. Patients showed loss of pattern synchrony compared with BMImatched controls, but copulsatility was unchanged. We conclude that hyposomatotropism in primary adrenal hypercortisolism is only partly explained (ϳ30%) by increased body weight and that increased GH secretory irregularity and loss of synchrony suggest altered coordinate regulation of GH release. cortisol; entropy; adrenal adenoma CUSHING'S SYNDROME is characterized by increased cortisol secretion and is caused by ACTH-dependent cortisol excess (Cushing's disease or the rare ectopic tumoral ACTH production syndrome) or by ACTH-independent cortisol excess. The latter syndrome is caused by a unilateral adenoma (seldom a carcinoma) and less frequently by ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH). The latter syndrome is characterized by bilateral nodular enlargement of the adrenal glands and clinical and biochemical signs of cortisol excess with low or undetectable ACTH concentrations (25). The detrimental metabolic consequences of chronic cortisol excess are manifold and include loss of lean body mass, increased adiposity, bone loss, and repression of the thyrotropic, gonadotropic, and somatotropic axes. Indeed, the diminished growth hormone (GH) response to various stimuli, including insulin-induced hypoglycemia, GH-releasing hormone (GHRH), growth hormone secretagogues (GHS), and ghrelin, is well described in pituitary-dependent hyperco...

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Hyperleptinemia in women with Cushing's disease is driven by high-amplitude pulsatile, but orderly and eurhythmic, leptin secretion

Cited by 20 publications

References 61 publications

Adipokines and Cardiovascular Risk in Cushing’s Syndrome

Adipokines and Cardiovascular Risk in Cushing’s Syndrome

Secretory dynamics of leptin in adolescent girls with anorexia nervosa and healthy adolescents

Growth hormone secretion in primary adrenal Cushing's syndrome is disorderly and inversely correlated with body mass index

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