• Preservation of growth hormone pulsatility despite pituitary pathology, surgery, and irradiation.

      Toogood, Andy; Nass, R M; Pezzoli, S S; O'Neill, Paul A; Thorner, M O; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Withington, Manchester, United Kingdom. (1997-07)
      Detailed assessment of physiological and pathophysiological GH secretion has, until recently, been limited by the poor sensitivity of the available assays. We have used an ultrasensitive chemiluminescence GH assay (sensitivity, 0.002 microgram/L) to study 24-h GH profiles (20-min sampling) from 24 patients who had been treated for hypothalamic-pituitary disease with surgery and irradiation and from 24 healthy control subjects matched for age, sex, and body mass index. Twenty-three of the 24 patients demonstrated pulsatile GH secretion, determined by Cluster. The median (range) area under the curve for GH, mean pulse area, mean pulse height, average valley mean level, and mean interpeak nadir were lower in the patients than in the controls [119.25 (7.273-843.600) vs. 968.539 (227.200-4625.000) min/microgram.L (P < 0.00001); 3.777 (0.288-30.850) vs. 61.390 (12.880-224.210) min/microgram.L (P < 0.00001), 0.107 (0.010-0.958) vs. 1.408 (0.368-5.050) micrograms/L (P < 0.00001), 0.074 (0.006-0.415) vs. 0.348 (0.048-2.350) microgram/L (P < 0.00001), and 0.066 (0.003-0.270) vs. 0.205 (0.021-1.838) microgram/L (P = 0.0004), respectively]. The median (range) number of pulses, mean pulse duration, and mean interval between pulses did not differ between the patients and controls [10 (4-15) vs. 10 (7-15; P = 0.36), 96.4 (68.0-220.0) vs. 104.0 (72.0-151.4) min (P = 0.65) and 128.0 (92.8-255.0) vs. 126.2 (90.0-180.0) min (P = 0.73), respectively]. The diurnal rhythm of GH secretion was present in the controls, but there was only limited evidence of residual diurnal rhythm in the patients. This study has demonstrated that GH secretion remains pulsatile in GH-deficient patients despite the mass effect of hypothalamic-pituitary pathology, pituitary surgery, and radiotherapy. With the development of potent GH secretagogues that are active orally, our findings may have important implications for the future management of GH-deficient subjects.
    • Relationship between growth hormone (GH) status, serum leptin and body composition in healthy and GH deficient elderly subjects.

      Gill, M S; Toogood, Andy; O'Neill, Paul A; Adams, J E; Thorner, M O; Shalet, Stephen M; Clayton, Peter E; Department of Medicine, University of Manchester, UK. (1997-08)
      OBJECTIVE: Growth hormone (GH) secretion declines with age and is affected by body composition. The signal that mediates the latter relationship remains III-defined. Leptin, the protein product of the adipocyte specific ob gene, is thought to accurately reflect fat mass and could therefore be a candidate to influence GH secretion. We have therefore investigated the relationship between GH status, leptin and body composition in normal and GH-deficient elderly subjects. DESIGN: GH Secretion was assessed by 20-minute sampling over 24 hours and serum leptin concentrations were measured in a single morning, fasted sample. PATIENTS: Twenty-one GH deficient elderly patients (61-83 years) and 22 gender- and BMI-matched controls (61-88 years). MEASUREMENTS: Body composition was assessed by dual-energy X-ray absorptiometry (DEXA). GH was measured in an ultrasensitive chemiluminescent assay and serum leptin was determined by radio-immunoassay. RESULTS: Leptin was correlated with percentage body fat in both sexes (male r = 0.75, female r = 0.89, both P < 0.001). Male patients had increased fat mass (FM) (P < 0.01) and leptin concentrations (P < 0.05) but similar lean mass (LM) compared with controls. However, leptin concentration per unit FM was identical in both groups (P = 0.3). In contrast, female patients had lower LM (P < 0.05) but similar FM to controls, yet their leptin concentration per unit FM was twice that of the controls (P < 0.05). In multiple linear regression (MLR) leptin was determined positively by FM and negatively by LM (controls r2 = 76%; patients r2 = 73%, both P < 0.0001). When controlled for gender, GH secretion in the controls was correlated negatively with leptin (r = -0.68, P < 0.01) and negatively with percentage body fat (r = -0.73, P < 0.01). In MLR, using leptin as a marker of body composition, 66% of the variability in GH secretion in the controls could be explained by gender (38%) and by leptin (28%). CONCLUSIONS: Both decreased lean mass and increased fat mass raise serum leptin concentrations in normal and growth hormone-deficient elderly subjects. Leptin is therefore a marker of body composition rather than fat mass alone. The influence of body composition on growth hormone secretion in the elderly may be mediated through leptin, acting as a peripheral signal from adipose tissue to decrease GH secretion.
    • Urinary growth hormone (GH), insulin-like growth factor I (IGF-I), and IGF-binding protein-3 measurements in the diagnosis of adult GH deficiency.

      Gill, M S; Toogood, Andy; O'Neill, Paul A; Thorner, M O; Shalet, Stephen M; Clayton, Peter E; Endocrine Sciences Research Group, University of Manchester, United Kingdom. (1998-07)
      The diagnosis of GH deficiency (GHD) in the elderly is based at present on the peak GH concentration during a stimulation test. We have now evaluated the performance of urinary GH (uGH), urinary insulin-like growth factor I (uIGF-I), and urinary IGF-binding protein-3 (uIGFBP-3) in the diagnosis of GHD in this group. Twenty GHD elderly patients with a history of pituitary disease and a peak GH response to arginine stimulation of less than 3 ng/mL (15 men and 5 women; age, 61.1-83.4 yr) and 19 controls (12 men and 7 women; age, 60.8-87.5 yr) were studied. GH secretion was assessed by 24-h profile and expressed as the area under the curve (AUCGH). Serum (s) IGF-I and sIGFBP-3 were measured in a single morning, fasted sample. Urinary GH, uIGF-I, and uIGFBP-3 were measured in a 24-h urine sample collected over the same interval as the GH profile, and results were expressed as total amount excreted in 24 h (tuGH24, nanograms; tuIGF-I24, nanograms; tuIGFBP-3(24), micrograms). Data are presented as the mean +/- SD, except for AUCGH, tuGH24, and tuIGFBP-3(24), which are presented as the geometric mean (-1, +1 tolerance factor). AUCGH, sIGF-I, and sIGFBP-3 were significantly lower in GHD subjects than in controls. Total uGH24 was lower in GHD subjects, but tuIGF-I24 and tuIGFBP-3(24) excretion were not different in the two groups. AUCGH provided the best separation between GHD and control subjects, whereas there was substantial overlap for sIGF-I, sIGFBP-3, and tuGH24. In both groups sIGF-I was correlated to sIGFBP-3 (GHD, r = 0.75; controls, r = 0.65; both P < 0.01), whereas tuIGF-I24 was not correlated to tuIGFBP-3(24) in either group. Moreover, tuIGF-I24 and tuIGFBP-3(24) were not related to their respective serum concentrations in either group. Total uGH24 was correlated with AUCGH only in controls (r = 0.54; P < 0.05). These data demonstrate that urinary GH and urinary and serum IGF-I and IGFBP-3 are not suitable diagnostic markers for GHD in elderly subjects.