title: Hyperleptinemia in women with Cushing's disease is driven by high-amplitude pulsatile, but orderly and eurhythmic, leptin secretion.
abstract: 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.
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 AA Leiden, The Netherlands.
authors.forename: R G
authors.initials: RG
authors.lastname: Veldman
authors.forename: M
authors.initials: M
authors.lastname: Frölich
authors.forename: S M
authors.initials: SM
authors.lastname: Pincus
authors.forename: J D
authors.initials: JD
authors.lastname: Veldhuis
authors.forename: F
authors.initials: F
authors.lastname: Roelfsema
mesh_terms: D000328:Adult; D015992:Body Mass Index; D003480:Cushing Syndrome / Q000097:blood*; D005215:Fasting; D005260:Female; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis / Q000378:metabolism; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000032:analysis* / Q000378:metabolism*; D008875:Middle Aged; D010507:Periodicity
chemical_list: D007328:Insulin; D020738:Leptin; D019382:Human Growth Hormone; D006854:Hydrocortisone