DOI: 10.1530/eje.1.02069
European Journal of Endocrinology, Vol 154, Issue 1, 53-59
Copyright © 2006 by European Society of Endocrinology
Effects of gastric bypass on the GH/IGF-I axis in severe obesity – and a comparison with GH deficiency
Britt Edén Engström,
Pia Burman,
Camilla Holdstock,
Margareta Öhrvall1,
Magnus Sundbom2 and
F Anders Karlsson
Department of Medical Sciences, Internal Medicine, 1 Department of Public Health and Caring Sciences and 2 Department of Geriatrics and Surgery, Uppsala University Hospital, S-75185 Uppsala, Sweden
(Correspondence should be addressed to B Edén Engström; Email: britt.eden_engstrom{at}medsci.uu.se)
 |
Abstract
|
|---|
Objective: Overfeeding suppresses GH secretion and makes evaluation of a suspected GH deficiency (GHD) difficult. In normal weight subjects, gender is known to influence GH concentrations, which is most apparent in the ambulatory, morning-fasted state. In this study, we examined the GH/IGF-I axis in obese men and women and the effect of surgically induced weight loss.
Design: Sixty-three subjects (body mass index (BMI) 45 ± 6 kg/m2; 54 women, 9 men) were studied prior to, and 6 and 12 months following Roux-en-Y gastric bypass (RYGBP) surgery. Fifty-four patients with classic GHD (BMI 27 ± 6 kg/m2; 35 men, 19 women) were included for comparison. Methods: Hormones were analysed in fasting morning serum samples.
Results: RYGBP resulted in a decreased BMI to 35 ± kg/m2 at 6 months and 32 ± 6 kg/m2 at 12 months. GH and IGF-I increased at 6 months in the women and at 12 months in both sexes by 
300 and 11% respectively. Prior to RYGBP, GH concentrations were low in the obese men and similar to those of GHD men (mean 0.09 mU/l). Obese women had tenfold higher values than obese men and sevenfold higher than GHD women. IGF-I levels were in the low reference range in the obese and below –2 S.D. for age in 13%.
Conclusions: Surgically induced weight loss partially restores GH secretion. Despite a marked suppression of GH values, a gender influence is maintained in severe obesity. In obese women, single morning GH and IGF-I values seem sufficient to exclude a suspicion of classic GHD.
|
Introduction
|
|---|
Obesity is associated with reduced 24-h growth hormone (GH) secretion and lowered peak GH levels in response to provocative stimuli (1–3). Although GH secretion may be suppressed as a consequence of increased energy supply, it has nonetheless been speculated that hyposomatropism may further add to maintaining overweight since GH is a potent lipolytic hormone. Serum insulin-like growth factor-I (IGF-I) levels reflect the combined effects of the integrated GH secretion, the tissue responsiveness to GH and other, mainly nutrition-driven, components. Reports regarding IGF-I levels in obesity have shown conflicting results with normal (4, 5), decreased (6) or, in children, even increased levels (7). It has been suggested that insulin may augment intracellular GH signaling and thus promote IGF-I production (8). In patients with GH deficiency (GHD) due to an organic disorder, the IGF-I levels are usually reduced, in particular in younger patients and in adult women with GHD, while a proportion of elderly patients and adult men with GHD may have IGF-I levels in the low reference range (9–13). Since isolated GHD has recently been recognized as the most common endocrine manifestation following traumatic brain injury (14, 15) and cranial irradiation for some malignancies (16), conditions both associated with weight gain (17, 18), it will be a delicate task for endocrinologists to determine if GHD requiring treatment is present in these groups of patients.
In the present study, we took advantage of having a well-characterized group of severely obese patients investigated before and after weight reduction by Roux-en-Y gastric bypass (RYGBP) surgery, and examined their basal levels of GH and IGF-I in relation to body mass index (BMI) and markers of insulin sensitivity. Patients of comparable ages with GHD due to pituitary diseases, usually as a consequence of treatment for a pituitary tumor, were included for comparison. As gender is an important regulator of GH secretion in healthy subjects, in whom premenopausal women secrete two to three times more than men in spite of having similar IGF-I levels (19–21), an effect of gender was also examined.
|
Materials and methods
|
|---|
Patients in the gastric bypass surgery study were recruited from the obesity program at Samariterhemmet Hospital in Uppsala, Sweden. Sixty-three patients were included, nine men with a mean age of 38.7 ± 6.54 years (range 30–51) and 54 women with a mean age of 39.0 ± 6.82 years (range 24–50 years). Mean BMI in the men was 46.1 ± 6.54 kg/m2 and in the women 44.7 ± 6.50 kg/m2. Two of the patients were on medical treatment for type 2 diabetes, one received metformin and the other glipizide and insulin. One woman was taking oral contraceptives. The patients underwent RYGBP at the Department of Surgery, University Hospital, Uppsala. RYGBP excludes the stomach and duodenum from the passage of food. A small pouch (15 ml) is created along the lesser curvature that is totally separated from the main stomach. The small bowel is divided 30 cm distal to the ligament of Treitz and a 50 cm long Roux limb is connected to the small gastric pouch directly below the esophagus. The small bowel continuity is maintained by an entero-enterostomy. This creates the Y-shaped junction at which the ingested food via the Roux limb and the gastric acid and bile is mixed. Serum samples were taken after an overnight fast preoperatively and 6 and 12 months postoperatively and analyzed for GH, IGF-I, glucose and insulin. Body height and weight were measured at each time-point to determine BMI.
Fifty-four patients with GHD were also included in the study, 35 men, mean age 40.6 ± 8.46 years (range 20–51) and 19 women, mean age 41.2 ± 6.96 years (range 26–51). All had GHD confirmed by stimulation tests (peak GH <3 µg/l – generally at an insulin tolerance test). BMI in the men was 27.9 ± 5.73 kg/m2 and in the women 25.4 ± 4.87 kg/m2. Most of the patients had panhypopituitarism (47 out of 54). Thirty-four of the 35 men had replacement therapy with testosterone, 31 with cortisone acetate and 33 with levothyroxine. Fourteen of the 19 omen had replacement therapy with estrogen (12 oral and two transdermal delivery), 15 with cortisone acetate and 17 with levothyroxine. Serum samples were taken fasting in the morning before the start of GH therapy and analysed for GH, IGF-I, glucose and insulin.
GH was measured with a non-competitive sandwich time-resolved fluoroimmunoassay (AutoDELFIA hGH kit; Wallac Oy, Turku, Finland) specific for the pituitary 22 kDa GH isoform. The results are expressed in mIU/l. The minimal detection limit was 0.009 mU/l. The within- and between-assay coefficients of variation (CV) were 1.1 and 2.3% respectively. IGF-I was measured by a non-extraction IGF-I immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA) using two region-restricted affinity-purified polyclonal antibodies. The within- and between-assay CV values were 5.6 and 14.6% respectively. Serum insulin was measured with an AutoDEL-FIA automatic immunoassay system (Wallac Oy). Fasting plasma glucose was measured with a routine clinical chemistry laboratory technique at the Department of Clinical Chemistry, University of Uppsala. Homeostatic model of assessment (HOMA) index was calculated according to Matthews et al. (22).
Serum values for GH were transformed into logarithms before analysis and are represented as geometric means (± S.D.). Values for BMI, IGF-I, IGF-I standard deviation score (SDS), glucose, insulin and HOMA indices are presented as means (± S.D.). Unpaired two-tailed Student’s t-test was used for differences amongst groups and paired two-tailed Student’s t-test for statistical comparisons within the same group.
|
Results
|
|---|
Effects of gastric bypass on BMI, GH, IGF-I and glucose homeostasis
The gastric bypass surgery caused a marked reduction in body weight, with decreases in BMI from 45 ± 6 kg/m2 to 35 ± 6 kg/m2 and 32 ± 6 kg/m2 at 6 and 12 months respectively (Table 1
). After 6 months, the GH values had increased significantly in the women (Table 1), and at 12 months the GH values were higher than preoperatively in both men (P < 0.01) and women (P < 0.001) (Table 1 and Fig. 1). After 12 months, mean IGF-I values were increased compared with baseline (P < 0.05 in both men and women) (Table 1 and Fig. 2) and, in the women, also compared with 6 months after surgery (P < 0.05) (Table 1). Also age-adjusted mean IGF-I SDS increased after 12 months (Table 1). However, 10% of the patients (five out of 54 women and one out of nine men) still had IGF-I levels below –2 S.D. of the normal mean. Men and women with severe obesity had comparable levels of insulin, glucose and HOMA indices. All values were higher than in patients with GHD (Table 1). Twelve months after gastric bypass surgery, insulin decreased by 59 ± 26% (P < 0.001), glucose by 17 ± 14% (P < 0.001) and HOMA index by 65 ± 17% (P < 0.001). At this time-point, only glucose remained higher in the obese than in the GHD subjects (Table 1). Among the 63 morbidly obese subjects prior to gastric bypass, 41 had normal fasting plasma glucose levels (FPG; <5.6 mmol/l), 14 had impaired FPG (5.6–6.9 mmol/l) and eight had a diagnosis of diabetes (FPG 7.0 mmol/l) according to American Diabetes Association criteria (23). At 6 and 12 months postoperatively, corresponding figures were 57, 5 and 1, and 60, 2 and 1 subjects respectively.
View this table:
[in this window]
[in a new window]
|
Table 1 Measurements of metabolic markers in 54 women and nine men before and 6 and 12 months after gastric bypass surgery and in 35 men and 19 women with GHD.
|
|
View larger version (11K):
[in this window]
[in a new window]
|
Figure 1 (a) GH values (mU/l) in obese men before (Preop) and 12 months after gastric bypass compared with GHD men. The dashed lines indicate mean values. (b) GH values (mU/l) in obese women before (Preop) and 12 months after gastric bypass compared with GHD women. The dashed lines indicate mean values.
|
|
View larger version (15K):
[in this window]
[in a new window]
|
Figure 2 (a) IGF-I values (µg/l) in obese men and women before gastric bypass, (b) IGF-I values (µg/l) in obese men and women 12 months after gastric bypass and (c) IGF-I values (µg/l) in GHD men and women. Reference ranges (shaded area) for age (± 2 S.D.) were obtained from the manufacturer.
|
|
GH and IGF-I levels in obese individuals compared with patients with GHD
The GH levels in the severely obese women were sevenfold higher (P < 0.001) than in GHD women, whereas obese men and men with GHD had similar levels (Table 1
and Fig. 1). The IGF-I levels were in the low–normal reference range in most of the obese subjects (Table 1 and Fig. 2), and in 13% (six out of 54 women and two out of nine men) below –2 S.D. of the normal mean for their age. There were no differences in GH levels, HOMA index or BMI between those with the lowest IGF-I and those with IGF-I within the reference range. The IGF-I levels among the GHD subjects were below –2 S.D. of the normal mean for their age in 84% of the women and in 40% of the men. As can be seen in Fig. 2, IGF-I values within the reference range were most common among GHD men above 40 years of age.
|
Discussion
|
|---|
In the present study, gastric bypass surgery of the severely obese patients resulted in a similar reduction in BMI in men and women after 6 months and a further reduction after 12 months. In parallel, GH and IGF-I secretion increased in both men and women and resulted in a partial restoration of the GH/IGF-I axis. Metabolic markers such as lipids and glucose/insulin levels have been extensively studied, while there are only two reports (24, 25) examining the GH/IGF-I axis after massive weight loss (in nine and 15 subjects before and after massive weight loss respectively). The present findings based on 63 subjects seem to be in line with other studies regarding GH secretion in obese, fasting and anorectic states (26, 27). A positive effect of gastric bypass on glucose homeostasis was clearly demonstrated by a marked improvement in glucose metabolism postoperatively, with normalization of fasting glucose levels in all but one of the patients with diabetes and in 11 of 14 patients with impaired FPG. These findings confirm the large benefit of surgical weight loss on glucose metabolism.
Thirteen percent of the obese subjects had IGF-I levels below –2 S.D. of the age-related normal mean for age and gender. Since glucose homeostasis and IGF-I are inter-related and reciprocally dependent, in that insulin stimulates liver GH receptor expression (28) and acts to maintain systemic IGF-I levels and, conversely, deletion of IGF-I leads to muscle insulin insensitivity (29), we examined whether the ‘low IGF-I group’ of patients was characterized by a lower insulin sensitivity. No differences with respect to fasting glucose, insulin or HOMA index were found, and these patients also had BMI and GH levels similar to the ‘normal IGF-I group’. Given that the GH levels were analysed as fasting ambulatory levels we cannot, however, exclude differences in 24-h integrated levels. It may be hypothesized that obese patients with low IGF-I should be more intensely monitored for future cardiovascular diseases, as IGF-I levels within the normal reference range seem to protect against heart failure, ischemic heart disease (30–32) and diabetes (33), in particular if accompanied by low IGF-binding protein (IGFBP)-I (32, 33) or high IGFBP-3 levels (30).
Most of the obese subjects rather had high IGF-I levels for their GH status. This could indicate that clearance of circulating GH is reduced or tissue sensitivity to GH is enhanced in the obese state. Abdominal fat mass determines circulating levels of GH-binding protein (GHBP) (34), a protein which protects GH from degradation and elimination. The levels were elevated in severely obese subjects (5, 35) and this has been suggested to compensate for the low GH secretion (34). Others have found levels of GHBP to be similar in obese and lean subjects (36). IGFBP-1 levels are known to be inversely related to insulin levels and thus lower in obese subjects (37). Frystyk et al. (38) found free IGF-I to be increased in obese subjects, and suggested that the observed hyposecretion of GH would represent a stage of pseudohyposomatropism. However, since some effects of GH are independent of IGF-I it seems likely that, for instance, fat mobilization is truly attenuated in obesity due to low GH levels. Few studies have addressed tissue responsiveness to GH in morbid obesity. By using IGF-I generation tests, Maccario et al. (36) found a more prominent response in obese women compared with lean women. Among the obese subjects, a subgroup with Cushing’s disease had the most marked response, leading the authors to conclude that both hyperinsulinemia and hypercortisolism enhance sensitivity to GH. Gianotti et al. (39) observed a tendency for a more marked IGF-I response to GH in obese men compared with lean men. Buijs et al. (40) found no differences between obese and normal weight women with respect to adipose tissue responsiveness to GH, determined as glycerol rate of appearance per kg fat mass. This is in keeping with another study (41) where no differences in plasma free fatty acid, glycerol, glucose and insulin were found in obese and lean subjects after a single intramuscular dose of GH. Taken together, these observations may indicate a tissue-specific adaptation to GH in severe obesity with an enhanced sensitivity to the anabolic effects, but not to the energy-mobilizing actions of GH. The existence of normal longitudinal growth in some obese children with clearly low GH levels, for instance after surgery for craniopharyngioma (42), may support the notion of an enhanced GH effect with respect to anabolism in states of severe obesity.
In the present study, 44% of the patients with GHD had IGF levels above –2 S.D. of the reference age despite having clearly low GH peaks (below 3 µg/l) at an insulin tolerance test. Most of the patients had complete pituitary insufficiency supporting the likelihood of having a true GHD (43). Normal IGF-I levels within the reference range were, in particular, seen in men above the age of 40. Our data corroborate previous observations in GHD patients (12, 13) where 51 and 34% respectively had normal IGF-I values. The reason for normal IGF-I levels in patients with GHD is poorly understood. Nutritional factors, hyperinsulinemia due to visceral obesity and differences in GH sensitivity have all been implicated. Since GH secretion declines approximately 14% every decade above the age of 20 years (44), is influenced by gender (19–21, 45–47) and by obesity (48, 49), and the definition of GHD is based on results of an insulin tolerance test in middle-aged healthy subjects (50, 51), any defined single GH cut-off level must be regarded as arbitrary. The recent findings of a close relationship between BMI and GH response to both an arginine–GH-releasing hormone (GHRH) stimulation test (49, 52) and a GHRH/GHRP-6 test (53) underline the necessity for fine tuning the diagnostic measures. It may well be that the criteria used today are too strict for younger women but too broad for elderly men.
A finding in this study that warrants further investigation is that a single serum sample of GH and IGF-I in the fasting, ambulatory state appears helpful in differentiating hyposomatropism of obesity from ‘true’ GHD in women. This is explained by the maintained gender difference in GH secretion in hyposomatropism of obesity, but not in classic GHD, in combination with the lower responsiveness to GH in women compared with men (54, 55).
In conclusion, the results in the present study have shown a marked impact of morbid obesity on the GH/IGF-I axis and have demonstrated the ability of surgical weight loss to restore GH secretion. Since the influence of gender on GH secretion is preserved in hyposomatropism of obesity, but not in classic GHD, it appears that, in women, single fasting, morning GH and IGF-I values could be helpful in selecting those subjects who will need further work-up of their GH secretory status.
|
Acknowledgements
|
|---|
We thank Margareta Ericson for expert laboratory assistance.
|
References
|
|---|
1. Procopio M, Maccario M, Savio P, Valetto MR, Aimaretti G, Grottoli S, Oleandri SE, Baffoni C, Tassone F, Arvat E, Camanni F & Ghigo E. GH response to GHRH combined with pyridostigmine or arginine in different conditions of low somatotrope secretion in adulthood: obesity and Cushing’s syndrome in comparison with hypopituitarism. Minerva Endocrinologica 1999 24 107–111.[Medline]2. Alvarez P, Isidro L, Leal-Cerro A, Casanueva FF, Dieguez C & Cordido F. Effect of withdrawal of somatostatin plus GH-releasing hormone stimulus of GH secretion in obesity. Clinical Endocrinology 2002 56 487–492.[CrossRef][Medline]3. Cordido F, Alvarez-Castro P, Isidro MI, Casanueva FF & Dieguez C. Comparison between insulin tolerance test, growth hormone releasing hormone (GHRH), GHRH plus acipimox and GHRH plus GH-releasing peptide-6 for the diagnosis of adult GH deficiency in normal subjects, obese and hypopituitary patients. European Journal of Endocrinology 2003 149 117–122.[Abstract]4. Park MJ, Kim HS, Kang JH, Kim DH & Chung CY. Serum levels of insulin-like growth factor (IGF)-I, free IGF-I, IGF binding (IGFBP)-1, IGFBP-3 and insulin in obese children. Journal of Pediatric Endocrinology and Metabolism 1999 12 139–144.5. Ballerini MG, Ropelato MG, Domene HM, Pennisi P, Heinrich JJ & Jasper HG. Differential impact of simple childhood obesity on the components of the hormone-insulin-like growth factor (IGF)-IGF binding proteins axis. Journal of Pediatric Endocrinology and Metabolism 2004 17 749–757.6. Attia N, Tamborlane WV, Heptulla R, Maggs D, Grozman A, Sherwin RS & Caprio S. The metabolic syndrome and insulin-like growth factor I regulation in adult obesity. Journal of Clinical Endocrinology and Metabolism 1998 83 1467–1471.[Abstract/Free Full Text]7. Állemand D, Schmidt S, Rousson V, Brabant G, Gasser T & Gruters A. Associations between body mass, leptin, IGF-I and circulating adrenal androgens in children with obesity and premature adrenarche. European Journal of Endocrinology 2002 146 537–543.[Abstract]8. Kaytor EN, Zhu JL, Pao CI & Phillips LS. Physiologic concentrations of insulin promote binding of nuclear proteins to the insulin-like growth factor I gene. Endocrinology 2001 142 1041–1049.[Abstract/Free Full Text]9. Hoffman DM, O’Sullivan AJ, Baxter RC & Ho KK. Diagnosis of growth hormone deficiency in adults. Lancet 1994 343 1064–1068.[CrossRef][ISI][Medline]10. Bates AS, Evans AJ, Jones P & Clayton RN. Assessment of GH status in adults with GH deficiency using serum growth hormone, serum insulin-like growth factor-I and urinary growth hormone excretion. Clinical Endocrinology 1995 42 425–430.[Medline]11. Thissen JP, Ketelslegers JM & Maiter D. Use of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in the diagnosis of acromegaly and growth hormone deficiency in adults. Growth Regulation 1996 6 222–229.[Medline]12. Svensson J, Johannsson G & Bengtsson BA. Insulin-like growth factor-I in growth hormone-deficient adults: relationship to population-based normal values, body composition and insulin tolerance test. Clinical Endocrinology 1997 46 579–586.[CrossRef][Medline]13. Hilding A, Hall K, Wivall-Helleryd IL, Saaf M, Melin AL & Thoren M. Serum levels of insulin-like growth factor I in 152 patients with growth hormone deficiency, aged 19–82 years, in relation to those in healthy subjects. Journal of Clinical Endocrinology and Metabolism 1999 84 2013–2019.[Abstract/Free Full Text]14. Lieberman SA, Oberoi AL, Gilkison CR, Masel BE & Urban RJ. Prevalence of neuroendocrine dysfunction in patients recovering from traumatic brain injury. Journal of Clinical Endocrinology and Metabolism 2001 86 2752–2756.[Abstract/Free Full Text]15. Aimaretti G, Ambrosio MR, Di Somma C, Fusco A, Cannavo S, Gasperi M, Scaroni C, De Marinis L, Benvenga S, degli Uberti EC, Lombardi G, Mantero F, Martino E, Giardano G & Ghigo E. Traumatic brain injury and subarachnoidal haemorrhage are conditions at high risk for hypopituitarism: screening study at 3 months after the brain injury. Clinical Endocrinology 2004 61 320–326.[CrossRef][Medline]16. Lissett CA, Saleem S, Rahim A, Brennan BM & Shalet SM. The impact of irradiation on growth hormone responsiveness to provocative agents is stimulus dependent: results in 161 individuals with radiation damage to the somatotropic axis. Journal of Clinical Endocrinology and Metabolism 2001 86 663–668.[Abstract/Free Full Text]17. Didi M, Didcock E, Davies HA, Ogilvy Stuart AL, Wales JK & Shalet SM. High incidence of obesity in young adults after treatment of acute lymphoblastic leukaemia in childhood. Journal of Pediatrics 1995 127 63–67.[CrossRef][ISI][Medline]18. Sklar CA, Mertens AC, Walter A, Mitchell D, Nesbit ME, O’Leary M, Hutchinson R, Meadows AT & Robison LL. Changes in body mass index and prevalence of overweight in survivors of childhood acute lymphoblastic leukaemia: role of cranial irradiation. Medical and Pediatric Oncology 2000 35 91–95.[CrossRef][ISI][Medline]19. Winer LM, Shaw MA & Baumann G. Basal plasma growth hormone levels in man: new evidence for rhytmicity of growth hormone secretion. Journal of Clinical Endocrinology and Metabolism 1990 70 1678–1686.[Abstract]20. van den Berg G, Veldhuis JD, Frölich M & Roelfsema F. An amplitude-specific divergence in the pulsatile mode of growth hormone (GH) secretion underlies the gender difference in mean GH concentrations in men and premenopausal women. Journal of Clinical Endocrinology and Metabolism 1996 81 2460–2467.[Abstract]21. Pincus SM, Gevers EF, Robinson ICA, van den Berg G, Roelfsema F, Hartman ML & Veldhuis JD. Females secrete growth hormone with more process irregularity than males in both humans and rats. American Journal of Physiology 1996 270 E107–E115.22. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF & Turner RC. Homeostasis model assessments insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985 28 412–419.[CrossRef][ISI][Medline]23. American Diabetes Association, Diagnosis and classification of diabetes mellitus. Diabetes Care 2005 28 S4–S36.[Free Full Text]24. Rasmussen MH, Hvidberg A, Juul A, Main KM, Gotfredsen A, Hilsted J & Skakkebaek NE. Massive weight loss restores 24-hour growth hormone release and serum insulin-like growth factor-I levels in obese subjects. Journal of Clinical Endocrinology and Metabolism 1995 80 1407–1415.[Abstract]25. De Marinis L, Bianchi A, Mancini A, Gentilella R, Perelli M, Giampietro A, Porcelli T, Tilaro L, Fusco A, Valle D & Tacchino RM. Growth hormone secretion and leptin in morbid obesity before and after biliopancreatic diversion: relationship with insulin and body composition. Journal of Clinical Endocrinology and Metabolism 2004 89 174–180.[Abstract/Free Full Text]26. Maccario M, Aimaretti G, Grottoli S, Gauna C, Tassone F, Corneli C, Rossetto R, Wu Z, Strasburger CJ & Ghigo E. Effects of 36 hour fasting on GH/IGF-I axis and metabolic parameters in patients with simple obesity. Comparison with normal subjects and hypopituitary patients with severe GH deficiency. International Journal of Obesity and Related Metabolic Disorders 2001 25 1233–1239.27. Misra M, Miller KK, Bjornson J, Hackman A, Aggarwal A, Chung J, Herzog DB, Johnson MI & Klibanski A. Alterations in growth hormone secretory dynamics in adolescence with anorexia nervosa and effects on bone metabolism. Journal of Clinical Endocrinology and Metabolism 2003 88 5615–5623.[Abstract/Free Full Text]28. Jones JL & Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocrine Reviews 1995 16 3–34.[CrossRef][ISI][Medline]29. Yakar S, Liu JL, Fernandez AM, Wu Y, Schally AV, Frystyk J, Chernausek SD, Mejia W & Le Roith D. Liver-specific IGF-I gene deletion leads to muscle insulin insensitivity. Diabetes 2001 50 1110–1118.[Abstract/Free Full Text]30. Juul A, Scheike T, Davidsen M, Gyllenbrog J & Jorgensen T. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation 2002 106 939–944.[Abstract/Free Full Text]31. Vasan RS, Sullivan LM, D’Agostino RB, Roubenoff R, Harris T, Sawyer DB, Levy D & Wilson PW. Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study. Annals of Internal Medicine 2003 139 642–648.[Abstract/Free Full Text]32. Laughlin GA, Barrett-Connor E, Criqui MH & Kritz-Silverstein D. The prospective association of serum insulin-like growth factor I (IGF-I) binding protein-1 levels with all cause and cardiovascular disease mortality in older adults: the Rancho Bernardo Study. Journal of Clinical Endocrinology and Metabolism 2004 89 114–120.[Abstract/Free Full Text]33. Sandhu MS, Dunger DB & Giovannucci EL. Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet 2002 359 1740–1745.[CrossRef][ISI][Medline]34. Fisker S, Vahl N, Jorgensen JO, Christiansen JS & Orskov H. Abdominal fat determines growth hormone-binding protein levels in healthy non-obese adults. Journal of Clinical Endocrinology and Metabolism 1997 82 123–128.[Abstract/Free Full Text]35. Hochberg Z, Hertz P, Colin V, Ish-Shalom S, Yeshurun D & Youdim MB. The distal axis of growth hormone (GH) in nutritional disorders: GH-binding protein, insulin-like growth factor-I (IGF-I), and IGF-I receptors in obesity and anorexia nervosa. Metabolism 1992 41 106–112.[CrossRef][ISI][Medline]36. Maccario M, Tassone F, Gauna C, Oleandri SE, Aimaretti G, Procopio M, Grottoli S, Pflaum CD, Strasburger CJ & Ghigo E. Effects of short-term administration of low-dose rhGH on IGF-I levels in obesity and Cushing’s syndrome: indirect evaluation of the sensitivity to GH. European Journal of Endocrinology 2001 144 251–256.[Abstract]37. Frystyk J, Skjaerbaek C, Vestbo E, Fisker S & Orskov H. Circulating levels of free insulin-like growth factors in obese subjects: the impact of type 2 diabetes. Diabetes Metabolism Research and Reviews 1999 15 314–322.38. Frystyk J, Vestbo E, Skjaerbaek C, Mogensen CE & Orskov H. Free insulin-like growth factor in human obesity. Metabolism 1995 44 37–44.[CrossRef][ISI][Medline]39. Gianotti L, Pivetti S, Lanfranco F, Tassone F, Vittori E, Rossetto R, Gauna C, Destefanis S, Grottoli S, De Giorgi R, Gai V, Ghigo E & Maccario M. Concomitant impairment of growth hormone secretion and peripheral sensitivity in obese patients with obstructive sleep apnoea syndrome. Journal of Clinical Endocrinology and Metabolism 2002 87 5052–5057.[Abstract/Free Full Text]40. Buijs MM, Romijn JA, Burggraaf J, De Kam MI, Cohen AF, Frolich M, Stellaard F, Meinders AE & Pijl H. Growth hormone blunts protein oxidation and promotes protein turnover to a similar extent in abdominally obese and normal-weight women. Journal of Clinical Endocrinology and Metabolism 2002 87 5668–5674.[Abstract/Free Full Text]41. Seng G, Galgoti C, Louisy P, Drouin P & Debry G. Metabolic effects of a single administration of growth hormone on lipid and carbohydrate metabolism in normal-weight and obese subjects. American Journal of Clinical Nutrition 1989 50 1348–1354.[Abstract/Free Full Text]42. Phillip M, Moran O & Lazar L. Growth without growth hormone. Journal of Paediatric Endocrinology and Metabolism 2002 15 1267–1272.43. Toogood AA. Growth hormone (GH) status and body composition in normal ageing and in elderly adults with GH deficiency. Hormone Research 2003 60 105–111.[ISI][Medline]44. Iranmesh A, Lizaralde G & Veldhuis JD. Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. Journal of Clinical Endocrinology and Metabolism 1991 75 530–535.45. Ho KY, Evans WS, Blizzard RM, Veldhuis JD, Merriam GR, Samojlik E, Furlanetto R, Rogol AD, Kaiser DL & Thorner MO. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. Journal of Clinical Endocrinology and Metabolism 1987 64 51–58.[Abstract]46. Edén Engström B, Karlsson FA & Wide L. Gender differences in diurnal growth hormone and epinephrine values in young adults during ambulation. Clinical Chemistry 1999 45 1235–1239.[Abstract/Free Full Text]47. Edén Engström B, Karlsson FA & Wide L. Marked gender differences in ambulatory morning growth hormone values in young adults. Clinical Chemistry 1998 44 1289–1295.[Abstract/Free Full Text]48. Maccario M, Gauna C, Procopio M, Di Vito L, Rossetto R, Oleandri SE, Grottoli S, Ganzaroli C, Aimaretti G & Ghigo E. Assessment of GH/IGF-I axis in obesity by evaluation of IGF-I and the GH response to GHRH + arginine test. Journal of Endocrinological Investigation 1999 22 424–429.[Medline]49. Bonert VS, Elashoff JD, Barnett P & Melmed S. Body mass index determines evoked growth hormone (GH) responsiveness in normal healthy male subjects: diagnostic caveat for adult GH deficiency. Journal of Clinical Endocrinology and Metabolism 2004 89 3397–3401.[Abstract/Free Full Text]50. Ho KK & Hoffman DM. Defining growth hormone deficiency in adults. Metabolism 1995; 44: (Suppl. 4) 91–96.[Medline]51. Ho KK. Diagnosis of adult GH deficiency. Lancet 2000 356 1125–1126.[Medline]52. Corneli G, Di Somma C, Baldelli R, Rovere S, Gasco V, Croce CG, Grottoli S, Maccario M, Colao A, Lombardi G, Ghigo E, Camanni F & Aimaretti G. The cut-off limits of the GH response to GH-releasing hormone-arginine test related to body mass index. European Journal of Endocrinology 2005 153 257–264.[Abstract/Free Full Text]53. Hajina SV, van Dam PS, de Vries WR, Maitimu-Smeele I, Dieguez C, Casanueva FF & Koppeschaar HPF. The GHRH/GHRP-6 test for the diagnosis of GH deficiency in elderly or severely obese men. European Journal of Endocrinology 2005 152 575–580.[Abstract/Free Full Text]54. Burman P, Johansson AG, Siegbahn A, Vessby B & Karlsson FA. Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women. Journal of Clinical Endocrinology and Metabolism 1997 82 550–555.[Abstract/Free Full Text]55. Edén Engström B, Burman P, Johansson AG & Wide L. Effects of short-term administration of growth hormone in healthy young men, women, and women taking oral contraceptives. Journal of Internal Medicine 2000 247 570–578.[CrossRef][Medline]
Received 25 April 2005
Accepted 14 October 2005
This article has been cited by other articles:
|
|
|
|
 
J. Terrien, P. Zizzari, M.-T. Bluet-Pajot, P.-Y. Henry, M. Perret, J. Epelbaum, and F. Aujard
Effects of age on thermoregulatory responses during cold exposure in a nonhuman primate, Microcebus murinus
Am J Physiol Regulatory Integrative Comp Physiol,
August 1, 2008;
295(2):
R696 - R703.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. H. Rasmussen, A. Juul, L. L. Kjems, and J. Hilsted
Effects of short-term caloric restriction on circulating free IGF-I, acid-labile subunit, IGF-binding proteins (IGFBPs)-1-4, and IGFBPs-1-3 protease activity in obese subjects.
Eur. J. Endocrinol.,
October 1, 2006;
155(4):
575 - 581.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
