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

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 deconvolut ion, the orderliness of leptin patterns by the approximate entropy statisti c (ApEn), and nyctohemeral leptin rhythmicity by cosinor analysis, Blood sa mples were taken at 10 min intervals for 24 h, Both CLUSTER and deconvoluti on analysis revealed 2.4-fold increased leptin secretion in patients. cause d by combined and equal amplification of basal and pulsatile secretion. Clu ster 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 ind ividual sample secretory rates was similarly skewed in patients and control s (0.55 +/- 0.12 vs 0.52 +/- 0.07). The acrophase (timing of the nyctohemer al 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 r elease 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 sig nificant pattern synchrony between leptin and cortisol release, which (unex pectedly) 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') cz ere 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 = 0.03 3) when patients and controls were combined. In summary Cushing's disease i n women increases leptin production about twofold in an amplitude-specific way The pulse-generating, nyctohemeral phase-determining, and entropy-contr ol mechanisms that govern the 24 h leptin release are not altered. The incr eased secretion is not explained by BMI and is probably only partly explain ed by increased insulin production, suggesting a cortisol-dependent change in adipose leptin secretion.