Both low and high serum IGF-I levels associate with cancer mortality in older men.

BACKGROUND Although recent population-based studies suggest a U-shaped relationship between serum IGF-I concentration and all-cause mortality, the distribution of death causes underlying this association remains unclear. We hypothesized that high IGF-I levels associate with increased cancer mortality, whereas low IGF-I levels associate with increased cardiovascular disease (CVD) mortality. METHODS Serum IGF-I levels were measured in 2901 elderly men (mean age 75.4, range 69-81 yr) included in the prospective population-based Osteoporotic Fractures in Men Study (Sweden) study. Mortality data were obtained from central registers with no loss of follow-up. The statistical analyses included Cox proportional hazards regressions with or without a spline approach. RESULTS During the follow-up (mean 6.0 yr), 586 of the participants died (cancer deaths, n = 211; CVD deaths, n = 214). As expected, our data revealed a U-shaped association between serum IGF-I levels and all-cause mortality. Low as well as high serum IGF-I (quintile 1 or 5 vs. quintiles 2-4) associated with increased cancer mortality [hazard ratio (HR) = 1.86, 95% confidence interval (CI) = 1.34-2.58; and HR = 1.90, 95% CI = 1.37-2.65, respectively]. Only low serum IGF-I associated with increased CVD mortality (quintile 1 vs. quintiles 2-4, HR = 1.48, 95% CI = 1.08-2.04). These associations remained after adjustment for multiple covariates and exclusion of men who died during the first 2 yr of follow-up. CONCLUSIONS Our findings demonstrate that both low and high serum IGF-I levels are risk markers for increased cancer mortality in older men. Moreover, low IGF-I levels associate with increased CVD mortality.

[1]  G. Sesti,et al.  Reciprocal association of plasma IGF-1 and interleukin-6 levels with cardiometabolic risk factors in nondiabetic subjects. Diabetes Care 2008;31:1886–1888 , 2012, Diabetes Care.

[2]  H. Völzke,et al.  Improved prediction of all-cause mortality by a combination of serum total testosterone and insulin-like growth factor I in adult men , 2012, Steroids.

[3]  M. Zwahlen,et al.  Meta-analysis and dose-response metaregression: circulating insulin-like growth factor I (IGF-I) and mortality. , 2011, The Journal of clinical endocrinology and metabolism.

[4]  G. Hankey,et al.  Associations of IGF1 and IGFBPs 1 and 3 with all-cause and cardiovascular mortality in older men: the Health In Men Study. , 2011, European journal of endocrinology.

[5]  H. Völzke,et al.  All-cause mortality and serum insulin-like growth factor I in primary care patients. , 2011, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[6]  P. Lips,et al.  The association of serum insulin-like growth factor-I with mortality, cardiovascular disease, and cancer in the elderly: a population-based study. , 2010, The Journal of clinical endocrinology and metabolism.

[7]  P. Stewart,et al.  Mortality in patients with pituitary disease. , 2010, Endocrine reviews.

[8]  A. Tamakoshi,et al.  Relationship between serum levels of insulin-like growth factors and subsequent risk of cancer mortality: findings from a nested case-control study within the Japan Collaborative Cohort Study. , 2010, Cancer epidemiology.

[9]  E. Barrett-Connor,et al.  Insulin-like growth factor-I and cancer mortality in older men. , 2010, The Journal of clinical endocrinology and metabolism.

[10]  K. Sjögren,et al.  The role of liver-derived insulin-like growth factor-I. , 2009, Endocrine reviews.

[11]  G. Brabant,et al.  Mortality and serum insulin-like growth factor (IGF)-I and IGF binding protein 3 concentrations. , 2009, The Journal of clinical endocrinology and metabolism.

[12]  T. Takebayashi,et al.  Adipose endocrine function, insulin-like growth factor-1 axis, and exceptional survival beyond 100 years of age. , 2008, The journals of gerontology. Series A, Biological sciences and medical sciences.

[13]  G. Sesti,et al.  Reciprocal Association of Plasma IGF-1 and Interleukin-6 Levels With Cardiometabolic Risk Factors in Nondiabetic Subjects , 2008, Diabetes Care.

[14]  S. Lamberts,et al.  Low circulating insulin-like growth factor I bioactivity in elderly men is associated with increased mortality. , 2008, The Journal of clinical endocrinology and metabolism.

[15]  L. Kuller,et al.  Total Insulinlike Growth Factor 1 and Insulinlike Growth Factor Binding Protein Levels, Functional Status, and Mortality in Older Adults , 2008, Journal of the American Geriatrics Society.

[16]  S. Bandinelli,et al.  Relationship between low levels of anabolic hormones and 6-year mortality in older men: the aging in the Chianti Area (InCHIANTI) study. , 2007, Archives of internal medicine.

[17]  B. Graubard,et al.  Insulin-like growth factors and subsequent risk of mortality in the United States. , 2007, American journal of epidemiology.

[18]  M. Frydenberg,et al.  Morbidity and GH deficiency: a nationwide study. , 2007, European journal of endocrinology.

[19]  D. Leroith,et al.  The role of the IGF system in cancer growth and metastasis: overview and recent insights. , 2007, Endocrine reviews.

[20]  O. Johnell,et al.  Free Testosterone is an Independent Predictor of BMD and Prevalent Fractures in Elderly Men: MrOS Sweden , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[21]  S. Cummings,et al.  Design and baseline characteristics of the osteoporotic fractures in men (MrOS) study--a large observational study of the determinants of fracture in older men. , 2005, Contemporary clinical trials.

[22]  J. Svensson,et al.  Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. , 2004, Journal of Clinical Endocrinology and Metabolism.

[23]  Ralph D'Agostino,et al.  Serum Insulin-like Growth Factor I and Risk for Heart Failure in Elderly Individuals without a Previous Myocardial Infarction: The Framingham Heart Study , 2003, Annals of Internal Medicine.

[24]  L. Ferrucci,et al.  Insulin-like growth factor I and interleukin-6 contribute synergistically to disability and mortality in older women. , 2003, The Journal of clinical endocrinology and metabolism.

[25]  T. Jørgensen,et al.  Heart Disease : A Population-Based Case-Control Study Low Serum Insulin-Like Growth Factor I Is Associated With Increased Risk of Ischemic , 2002 .

[26]  W. Drake,et al.  Optimizing gh therapy in adults and children. , 2001, Endocrine reviews.

[27]  K. Wheatley,et al.  Association between premature mortality and hypopituitarism , 2001, The Lancet.

[28]  B. Bengtsson,et al.  Pituitary adenomas in Sweden between 1958 and 1991: incidence, survival, and mortality. , 2000, The Journal of clinical endocrinology and metabolism.

[29]  A. Renehan,et al.  Response: More About: Prospective Study of Colorectal Cancer Risk in Men and Plasma Levels of Insulin-Like Growth Factor (IGF)-I and IGF- Binding Protein-3 , 1999 .

[30]  S. Obradovic,et al.  Increased incidence of neoplasia in patients with pituitary adenomas , 1998, Clinical endocrinology.

[31]  R. McNally,et al.  Mortality and Cancer Incidence in Acromegaly: A Retrospective Cohort Study , 1998 .

[32]  David J Hunter,et al.  Circulating concentrations of insulin-like growth factor I and risk of breast cancer , 1998, The Lancet.

[33]  Meir J. Stampfer,et al.  Plasma Insulin-Like Growth Factor-I and Prostate Cancer Risk: A Prospective Study , 1998 .

[34]  B. Bengtsson,et al.  Premature mortality due to cardiovascular disease in hypopituitarism , 1990, The Lancet.

[35]  R. Simon,et al.  Flexible regression models with cubic splines. , 1989, Statistics in medicine.

[36]  P. Hildebrandt,et al.  IGF1 as predictor of all cause mortality and cardiovascular disease in an elderly population. , 2009, European journal of endocrinology.

[37]  E. Barrett-Connor,et al.  The prospective association of serum insulin-like growth factor I (IGF-I) and IGF-binding protein-1 levels with all cause and cardiovascular disease mortality in older adults: the Rancho Bernardo Study. , 2004, The Journal of clinical endocrinology and metabolism.

[38]  Nils Lid Hjort,et al.  Model Selection and Model Averaging , 2001 .