Does Vitamin D Status Correlate with Cardiometabolic Risk Factors in Adults with Growth Hormone Deficiency?

Ivayla Uzunova; Georgi Kirilov; Sabina Zacharieva; Naydenka Zlatareva; Krasimir Kalinov

doi:10.1055/s-0043-100114

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2017; 49(07): 499-506
DOI: 10.1055/s-0043-100114

Endocrine Care

Does Vitamin D Status Correlate with Cardiometabolic Risk Factors in Adults with Growth Hormone Deficiency?

Authors

Ivayla Uzunova

¹Clinical Centre of Endocrinology, Medical University of Sofia, Sofia, Bulgaria
Georgi Kirilov

¹Clinical Centre of Endocrinology, Medical University of Sofia, Sofia, Bulgaria
Sabina Zacharieva

¹Clinical Centre of Endocrinology, Medical University of Sofia, Sofia, Bulgaria
Naydenka Zlatareva

²University Hospital “Tsaritsa Yoanna – ISUL”, Medical University of Sofia, Sofia, Bulgaria
Krasimir Kalinov

³New Bulgarian University, Sofia, Bulgaria

Abstract

Apart from being individually associated with cardiometabolic health, 25(OH)D and IGF-1 interplay with a positive correlation between them, which raises questions about the role of vitamin D for the adverse cardiovascular (CV) risk profile in hyposomatotropism. Thus, we aimed to investigate vitamin D status in GH deficiency (GHD) and the association between 25(OH)D and metabolic syndrome (MetS), its components, and other surrogate markers of CV risk. A total of 129 GHD adults (childhood-onset GHD, 41.9%) underwent blood testing (glucose, insulin, lipid profile, uric acid); blood pressure, anthropometric and bioelectrical-impedance measurements. Other CV risk markers were examined in a subsample of the initial population – hsCRP, adiponectin, and asymmetric dimethylarginine (n=88); carotid intima-media thickness (n=44). Total serum 25(OH)D, measured by electro-chemiluminescence binding assay, was used for vitamin D status assessment (adequate,≥30 ng/ml; insufficient, 20–29.9 ng/ml; deficient,<20 ng/ml). Data demonstrated high prevalence of hypovitaminosis D in GHD (deficiency 79.1%; insufficiency 14.7%), with lower 25(OH)D among adult-onset GHD subjects (14.0±7.2 vs. 16.8±8.0 ng/ml, p=0.039) and patients with MetS (11.8±4.5 vs. 16.3±8.1 ng/ml, p<0.0001). 25(OH)D correlated negatively and weakly with BMI, waist circumference, percent body fat, visceral fat area, and systolic BP. Regardless of whether vitamin D is a cause or a consequence of these metabolic abnormalities, 25(OH)D testing in hyposomatotropism is advisable. Normalization of vitamin D status is not proven to improve CV outcomes in general population, but it might have favorable effects in GHD, as its benefits might be restricted to patients with both low 25(OH)D and certain risk factors.

Key words

hyposomatotropism - hypovitaminosis D - cardiovascular risk - obesity - systolic blood pressure

Full Text

References

References
1 Verstuyf A, Carmeliet G, Bouillon R, Mathieu C. Vitamin D: a pleiotropic hormone. Kidney Int 2010; 78: 140-145
2 Wacker M, Holick MF. Vitamin D – effects on skeletal and extraskeletal health and the need for supplementation. Nutrients 2013; 5: 111-148
3 Pludowski P, Holick MF, Pilz S, Wagner CL, Hollis BW, Grant WB, Shoenfeld Y, Lerchbaum E, Llewellyn DJ, Kienreich K, Soni M. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality - a review of recent evidence. Autoimmun Rev 2013; 12: 976-989
4 Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol 2014; 2: 76-89
5 Kendrick J, Targher G, Smits G, Chonchol M. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Atherosclerosis 2008; 205: 255-260
6 Pilz S, Tomaschitz A, März W, Drechsler C, Ritz E, Zittermann A, Cavalier E, Pieber TR, Lappe JM, Grant WB, Holick MF, Dekker JM. Vitamin D, cardiovascular disease and mortality. Clin Endocrinol 2011; 75: 575-584
7 Wang L, Song Y, Manson JE, Pilz S, Marz W, Michaelsson K, Lundqvist A, Jassal SK, Barrett-Connor E, Zhang C, Eaton CB, May HT, Anderson JL, Sesso HD. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes 2012; 5: 819-829
8 Earthman CP, Beckman LM, Masodkar K, Sibley SD. The link between obesity and low circulating 25-hydroxyvitamin D concentrations: considerations and implications. Int J Obes (Lond) 2012; 36: 387-396
9 Grimnes G, Emaus N, Joakimsen RM, Figenschau Y, Jenssen T, Njølstad I, Schirmer H, Jorde R. Baseline serum 25-hydroxyvitamin D concentrations in the Tromsø Study 1994–95 and risk of developing type 2 diabetes mellitus during 11 years of follow-up. Diabet Med 2010; 27: 1107-1115
10 Tamez H, Thadhani RI. Vitamin D and hypertension: an update and review. Curr Opin Nephrol Hypertens 2012; 21: 492-499
11 Guasch A, Bulló M, Rabassa A, Bonada A, Del Castillo D, Sabench F, Salas-Salvadó J. Plasma vitamin D and parathormone are associated with obesity and atherogenic dyslipidemia: a cross-sectional study. Cardiovasc Diabetol 2012; 11: 149
12 Gagnon C, Lu ZX, Magliano DJ, Dunstan DW, Shaw JE, Zimmet PZ, Sikaris K, Ebeling PR, Daly RM. Low serum 25-hydroxyvitamin D is associated with increased risk of the development of the metabolic syndrome at five years: results from a national, population-based prospective study (The Australian Diabetes, Obesity and Lifestyle Study: AusDiab). J Clin Endocrinol Metab 2012; 97: 1953-1961
13 Witham MD, Nadir MA, Struthers AD. Effect of vitamin D on blood pressure: a systematic review and meta-analysis. J Hypertens 2009; 27: 1948-1954
14 Ponda MP, Huang X, Odeh MA, Breslow JL, Kaufman HW. Vitamin D may not improve lipid levels: a serial clinical laboratory data study. Circulation 2012; 126: 270-277
15 Kupferschmidt K. Uncertain verdict as vitamin D goes on trial. Science 2012; 337: 1476-1478
16 Ryu OH, Chung W, Lee S, Hong KS, Choi MG, Yoo HJ. The effect of high-dose vitamin D supplementation on insulin resistance and arterial stiffness in patients with type 2 diabetes. Korean J Intern Med 2014; 29: 620-629
17 Pilz S, Verheyen N, Grübler MR, Tomaschitz A, März W. Vitamin D and cardiovascular disease prevention. Nat Rev Cardiol 2016; 13: 404-417
18 Johansson JO, Fowelin J, Landin K, Lager I, Bengtsson BA. Growth hormone-deficient adults are insulin-resistant. Metabolism 1995; 44: 1126-1129
19 Abs R, Feldt-Rasmussen U, Mattsson AF, Monson JP, Bengtsson BA, Góth MI, Wilton P, Koltowska-Häggström M. Determinants of cardiovascular risk in 2589 hypopituitary GH-deficient adults – a KIMS database analysis. Eur J Endocrinol 2006; 155: 79-90
20 Verhelst J, Abs R. Cardiovascular risk factors in hypopituitary GH-deficient adults. Eur J Endocrinol 2009; 161 (Suppl. 01) 41-49
21 Verhelst J, Mattsson AF, Luger A, Thunander M, Góth MI, Koltowska-Häggström M, Abs R. Prevalence and characteristics of the metabolic syndrome in 2479 hypopituitary patients with adult-onset GH deficiency before GH replacement: a KIMS analysis. Eur J Endocrinol 2011; 165: 881-889
22 Murray RD, Wieringa G, Lawrance JA, Adams JE, Shalet SM. Partial growth hormone deficiency is associated with an adverse cardiovascular risk profile and increased carotid intima-medial thickness. Clin Endocrinol (Oxf) 2010; 73: 508-515
23 Gazzaruso C, Gola M, Karamouzis I, Giubbini R, Giustina A. Cardiovascular risk in adult patients with growth hormone (GH) deficiency and following substitution with GH – an update. J Clin Endocrinol Metab 2014; 99: 18-29
24 Ameri P, Giusti A, Boschetti M, Murialdo G, Minuto F, Ferone D. Interactions between vitamin D and IGF-I: from physiology to clinical practice. Clin Endocrinol (Oxf) 2013; 79: 457-463
25 Bogazzi F, Rossi G, Lombardi M, Tomisti L, Sardella C, Manetti L, Curzio O, Marcocci C, Grasso L, Gasperi M, Martino E. Vitamin D status may contribute to serum insulin-like growth factor I concentrations in healthy subjects. J Endocrinol Invest 2011; 34: e200-e203
26 Gómez JM, Maravall FJ, Gómez N, Navarro MA, Casamitjana R, Soler J. Relationship between 25-(OH) D3, the IGF-1 system, leptin, anthropometric and body composition variables in a healthy, randomly selected population. Horm Metab Res 2004; 36: 48-53
27 Hyppönen E, Boucher BJ, Berry DJ, Power C. 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British Birth Cohort. Diabetes 2008; 57: 298-305
28 Ameri P, Giusti A, Boschetti M, Bovio M, Teti C, Leoncini G, Ferone D, Murialdo G, Minuto F. Vitamin D increases circulating IGF1 in adults: potential implication for the treatment of GH deficiency. Eur J Endocrinol 2013; 169: 767-772
29 Marcus R, Butterfield G, Holloway L, Gilliland L, Baylink DJ, Hintz RL, Sherman BM. Effects of short term administration of recombinant human growth hormone to elderly people. J Clin Endocrinol Metab 1990; 70: 519-527
30 Bianda T, Hussain MA, Glatz Y, Bouillon R, Froesch ER, Schmid C. Effects of short-term insulin-like growth factor-I or growth hormone treatment on bone turnover, renal phosphate reabsorption and 1,25 dihydroxyvitamin D3 production in healthy man. J Intern Med 1997; 241: 143-150
31 Fernández-Cancio M, Audi L, Carrascosa A, Toran N, Andaluz P, Esteban C, Granada ML. Vitamin D and growth hormone regulate growth hormone/insulin-like growth factor (GH-IGF) axis gene expression in human fetal epiphyseal chondrocytes. Growth Horm IGF Res 2009; 19: 232-227
32 Liao L, Chen X, Wang S, Parlow AF, Xu J. Steroid receptor coactivator 3 maintains circulating insulin-like growth factor I (IGF-I) by controlling IGF-binding protein 3 expression. Mol Cell Biol 2008; 28: 2460-2469
33 Peng L, Malloy PJ, Feldman D. Identification of a functional vitamin D response element in the human insulin-like growth factor binding protein-3 promoter. Mol Endocrinol 2004; 18: 1109-1119
34 Nesbitt T, Drezner MK. Insulin-like growth factor-I regulation of renal 25-hydroxyvitamin D-1-hydroxylase activity. Endocrinology 1993; 132: 133-138
35 Zoidis E, Gosteli-Peter M, Ghirlanda-Keller C, Meinel L, Zapf J, Schmid C. IGF-I and GH stimulate Phex mRNA expression in lungs and bones and 1,25-dihydroxyvitamin D(3) production in hypophysectomized rats. Eur J Endocrinol 2002; 146: 97-105
36 Witkowska-Sędek E, Kucharska A, Rumińska M, Pyrżak B. Relationship Between 25(OH)D and IGF-I in Children and Adolescents with Growth Hormone Deficiency. Adv Exp Med Biol 2016; 912: 43-49
37 Ciresi A, Cicciò F, Giordano C. High prevalence of hypovitaminosis D in Sicilian children affected by growth hormone deficiency and its improvement after 12 months of replacement treatment. J Endocrinol Invest 2014; 37: 631-638
38 Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, Csiba L, Desvarieux M, Ebrahim S, Fatar M, Hernandez Hernandez R, Jaff M, Kownator S, Prati P, Rundek T, Sitzer M, Schminke U, Tardif JC, Taylor A, Vicaut E, Woo KS, Zannad F, Zureik M. Mannheim carotid intima-media thickness consensus (2004-2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis 2007; 23: 75-80
39 Wikstrand J. Methodological considerations of ultrasound measurement of carotid artery intima-media thickness and lumen diameter. Clin Physiol Funct Imaging 2007; 27: 341-345
40 Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML. Endocrine Society. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96: 1587-1609
41 Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM. Endocrine Society . Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96: 1911-1930
42 Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486-2497
43 Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy young adults. Am J Med 2002; 112: 659-662
44 Looker AC, Dawson-Hughes B, Calvo MS, Gunter EW, Sahyoun NR. Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone 2002; 30: 771-777
45 Harris SS, Soteriades E, Coolidge JA, Mudgal S, Dawson-Hughes B. Vitamin D insufficiency and hyperparathyroidism in a low income, multiracial, elderly population. J Clin Endocrinol Metab 2000; 85: 4125-4130
46 Savanelli MC, Scarano E, Muscogiuri G, Barrea L, Vuolo L, Rubino M, Savastano S, Colao A, Di Somma C. Cardiovascular risk in adult hypopituitaric patients with growth hormone deficiency: is there a role for vitamin D?. Endocrine 2016; 52: 111-119
47 Muscogiuri G, Nuzzo V, Gatti A, Zuccoli A, Savastano S, Di Somma C, Pivonello R, Orio F, Colao A. Hypovitaminosis D: a novel risk factor for coronary heart disease in type 2 diabetes?. Endocrine 2016; 51: 268-273
48 Daga RA, Laway BA, Shah ZA, Mir SA, Kotwal SK, Zargar AH. High prevalence of vitamin D deficiency among newly diagnosed youth-onset diabetes mellitus in north India. Arq Bras Endocrinol Metabol 2012; 56: 423-428
49 Ford ES, Ajani UA, McGuire LC, Liu S. Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults. Diabetes Care 2005; 28: 1228-1130
50 Kulshrestha S, Ojo AO, Luan FL. Metabolic syndrome, vitamin D deficiency and hypoadiponectinemia among nondiabetic patients early after kidney transplantation. Am J Nephrol 2013; 37: 399-404
51 Ghanei L, Ziaee A, Rostami P, Oveisi S, Esmailzadehha N, Kazemifar AM, Zargar A. Association of serum 25-hydroxyvitamin d levels and vitamin D dietary intake with metabolic syndrome: a case control study. J Res Health Sci 2015; 15: 32-36
52 Kramkowska M, Grzelak T, Walczak M, Bogdanski P, Pupek-Musialik D, Czyzewska K. Relationship between deficiency of vitamin D and exponents of metabolic syndrome. Eur Rev Med Pharmacol Sci 2015; 19: 2180-2187
53 Khan H, Kunutsor S, Franco OH, Chowdhury R. Vitamin D, type 2 diabetes and other metabolic outcomes: a systematic review and meta-analysis of prospective studies. Proc Nutr Soc 2013; 72: 89-97
54 Ju SY, Jeong HS, Kim DH. Blood vitamin D status and metabolic syndrome in the general adult population: a dose-response meta-analysis. J Clin Endocrinol Metab 2014; 99: 1053-1063
55 Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000; 72: 690-693
56 Pereira-Santos M, Costa PR, Assis AM, Santos CA, Santos DB. Obesity and vitamin D deficiency: a systematic review and meta-analysis. Obes Rev 2015; 16: 341-349
57 Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, Hiraki LT, Cooper JD, Dastani Z, Li R, Houston DK, Wood AR, Michaëlsson K, Vandenput L, Zgaga L, Yerges-Armstrong LM, McCarthy MI, Dupuis J, Kaakinen M, Kleber ME, Jameson K, Arden N, Raitakari O, Viikari J, Lohman KK, Ferrucci L, Melhus H, Ingelsson E, Byberg L, Lind L, Lorentzon M, Salomaa V, Campbell H, Dunlop M, Mitchell BD, Herzig KH, Pouta A, Hartikainen AL. Genetic Investigation of Anthropometric Traits-GIANT Consortium . Streeten EA, Theodoratou E, Jula A, Wareham NJ, Ohlsson C, Frayling TM, Kritchevsky SB, Spector TD, Richards JB, Lehtimäki T, Ouwehand WH, Kraft P, Cooper C, März W, Power C, Loos RJ, Wang TJ, Järvelin MR, Whittaker JC, Hingorani AD, Hyppönen E. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med 2013; 10: e1001383
58 Vimaleswaran KS, Cavadino A, Berry DJ. LifeLines Cohort Study investigators . Jorde R, Dieffenbach AK, Lu C, Alves AC, Heerspink HJ, Tikkanen E, Eriksson J, Wong A, Mangino M, Jablonski KA, Nolte IM, Houston DK, Ahluwalia TS, van der Most PJ, Pasko D, Zgaga L, Thiering E, Vitart V, Fraser RM, Huffman JE, de Boer RA, Schöttker B, Saum KU, McCarthy MI, Dupuis J, Herzig KH, Sebert S, Pouta A, Laitinen J, Kleber ME, Navis G, Lorentzon M, Jameson K, Arden N, Cooper JA, Acharya J, Hardy R, Raitakari O, Ripatti S, Billings LK, Lahti J, Osmond C, Penninx BW, Rejnmark L, Lohman KK, Paternoster L, Stolk RP, Hernandez DG, Byberg L, Hagström E, Melhus H, Ingelsson E, Mellström D, Ljunggren O, Tzoulaki I, McLachlan S, Theodoratou E, Tiesler CM, Jula A, Navarro P, Wright AF, Polasek O. International Consortium for Blood Pressure (ICBP); Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium; Global Blood Pressure Genetics (Global BPGen) consortium . Caroline H, Wilson JF, Rudan I, Salomaa V, Heinrich J, Campbell H, Price JF, Karlsson M, Lind L, Michaëlsson K, Bandinelli S, Frayling TM, Hartman CA, Sørensen TI, Kritchevsky SB, Langdahl BL, Eriksson JG, Florez JC, Spector TD, Lehtimäki T, Kuh D, Humphries SE, Cooper C, Ohlsson C, März W, de Borst MH, Kumari M, Kivimaki M, Wang TJ, Power C, Brenner H, Grimnes G, van der Harst P, Snieder H, Hingorani AD, Pilz S, Whittaker JC, Järvelin MR, Hyppönen E. Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study. Lancet Diabetes Endocrinol 2014; 2: 719-729
59 Forman JP, Williams JS, Fisher ND. Plasma 25-hydroxyvitamin D and regulation of the renin-angiotensin system in humans. Hypertension 2010; 55: 1283-1288
60 Carthy EP, Yamashita W, Hsu A, Ooi BS. 1,25-Dihydroxyvitamin D3 and rat vascular smooth muscle cell growth. Hypertension 1989; 13 6 Pt 2 954-959
61 Borges AC, Feres T, Vianna LM, Paiva TB. Effect of cholecalciferol treatment on the relaxant responses of spontaneously hypertensive rat arteries to acetylcholine. Hypertension 1999; 34 4 Pt 2 897-901
62 Mellenthin L, Wallaschofski H, Grotevendt A, Völzke H, Nauck M, Hannemann A. Association between serum vitamin D concentrations and inflammatory markers in the general adult population. Metabolism 2014; 63: 1056-1062
63 Barker T, Rogers VE, Levy M, Templeton J, Goldfine H, Schneider ED, Dixon BM, Henriksen VT, Weaver LK. Supplemental vitamin D increases serum cytokines in those with initially low 25-hydroxyvitamin D: a randomized, double blind, placebo-controlled study. Cytokine 2015; 71: 132-138