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Circadian and Ultradian Rhythm and Leptin Pulsatility in Adult GH Deficiency: Effects of GH Replacement

Department of Diabetes and Endocrinology, Royal Liverpool University Hospital (A.M.A., R.G., J.T., J.P.V.), Liverpool, United Kingdom L7 8XP; University Department of Pathological Biochemistry, Glasgow Royal Infirmary (A.M.W.), Glasgow, United Kingdom G4 0SF; and Department of Clinical Chemistry, Royal Liverpool University Hospital (W.D.F.), Liverpool, United Kingdom L69 3GA

Address all correspondence and requests for reprints to: Dr. A. M. Ahmad, Research Fellow, Link 7-C, Department of Diabetes and Endocrinology, Royal Liverpool University Hospital, Prescot Street, Liverpool, United Kingdom L7 8XP. E-mail: draahmad{at}yahoo.com

Abstract

Leptin contributes to the regulation of body weight in healthy individuals and is secreted by adipocytes in a diurnal pattern, with superimposed pulsatility. The circulating leptin concentration is increased in both normally obese and untreated adult GH deficiency, a syndrome characterized by increased adiposity. Leptin circadian rhythm is preserved in adult GH deficiency patients; however, an ultradian rhythm and pulsatility has previously not been reported. Alterations in plasma leptin concentration in obese individuals and adult GH deficiency patients after GH replacement have been attributed to changes in body fat mass. In our present study leptin circadian and ultradian rhythm, leptin pulsatility and its relationship with body fat mass were examined in 12 adult GH deficiency patients (6 men) before and 1 month after GH replacement. All subjects with adult GH deficiency had hypopituitarism subsequent to pituitary surgery and were stabilized on conventional pituitary hormone replacement. Plasma leptin was measured over 24 h at 30-min intervals, and changes in body composition were recorded using bioelectrical impedance.

The 24-h mean leptin concentration decreased from 2.04 ± 0.04 nmol/liter in untreated adult GH deficiency patients to 1.64 ± 0.03 nmol/liter after 1 month of GH replacement (P < 0.0001). Before GH replacement, patients demonstrated a significant mean leptin circadian rhythm (P < 0.001), with a mesor of 2.05 ± 0.03 nmol/liter and a superimposed ultradian frequency of 2.0 ± 0.1 cycles/d. After GH replacement, the circadian rhythm was preserved (P < 0.001), but mesor decreased to 1.65 ± 0.01 nmol/liter (P < 0.0001), and leptin ultradian frequency increased to 16.0 ±0.2 cycles/d (P < 0.0001). Pulse analysis (ULTRA) revealed 3.1 ± 0.9 pulses/24 h in untreated adult GH deficiency patients, which significantly increased to 9.9 ± 2.2 pulses/24 h after 1 month of GH replacement (P < 0.001). There was no significant change in body mass index or body fat mass after 1 month of GH replacement. The body fat percentage significantly reduced from 36.5 ± 2.8% to 35.5 ± 2.7% after 1 month of GH replacement (P < 0.05). This change in body fat percentage was explained by a significant increase in lean body mass, from 56.2 ± 2.8 kg at baseline to 57.4 ± 2.7 kg after 1 month (P < 0.05). A significant correlation was observed between plasma leptin and body fat percentage at baseline and 1 month after GH replacement (both, r = 0.7; P < 0.01) in the absence of a significant correlation between leptin and body fat mass before and after GH replacement (P = 0.13 and P = 0.11, respectively).

Thus, untreated adult GH deficiency is associated with elevated 24-h leptin concentration, preserved circadian rhythm, and decreased pulsatility. The secretory pattern is restored after GH replacement, with a significant reduction in the 24-h mean leptin concentration, maintenance of circadian rhythm, and increased pulsatility. This GH-induced change in the leptin secretory pattern precedes significant changes in body fat mass and may therefore be independent of changes in adipose tissue. Restoration of leptin pulsatility may be of clinical benefit, and our data could lead to novel approaches for leptin manipulation in the future.

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