Brazilian adult individuals with untreated isolated GH deficiency do not have accelerated subclinical atherosclerosis

in Endocrine Connections
View More View Less
  • 1 Division of Cardiology, Division of Endocrinology, Division of Endocrinology, Federal University of Sergipe, Aracaju, SE 49060-100, Brazil

Abstract

GH and its principal mediator IGF1 have important effects on metabolic and cardiovascular (CV) status. While acquired GH deficiency (GHD) is often associated with increased CV risk, the consequences of congenital GHD are not known. We have described a large group of patients with isolated GHD (IGHD) due to a homozygous mutation (c.57+1G>A) in the GH releasing hormone receptor gene, and shown that adult GH-naïve individuals have no evidence of clinically evident premature atherosclerosis. To test whether subclinical atherosclerosis is anticipated in untreated IGHD, we performed a cross-sectional study of 25 IGHD and 27 adult controls matched for age and gender. A comprehensive clinical and biochemical panel and coronary artery calcium scores were evaluated by multi-detector tomography. Height, weight, IGF1, homeostasis model assessment of insulin resistance, creatinine and creatininekinase were lower in the IGHD group. Median and interquartile range of calcium scores distribution was similar in the two groups: IGHD 0(0) and control 0(4.9). The vast majority of the calcium scores (20 of 25 IGHD (80%) and 18 of 27 controls (66.6%)) were equal to zero (difference not significant). There was no difference in the calcium scores classification. None of IGHD subjects had minimal calcification, which were present in four controls. Three IGHD and four controls had mild calcification. There were two IGHD individuals with moderate calcification and one control with severe calcification. Our study provides evidence that subjects with congenital isolated lifetime and untreated severe IGHD do not have accelerated subclinical coronary atherosclerosis.

Abstract

GH and its principal mediator IGF1 have important effects on metabolic and cardiovascular (CV) status. While acquired GH deficiency (GHD) is often associated with increased CV risk, the consequences of congenital GHD are not known. We have described a large group of patients with isolated GHD (IGHD) due to a homozygous mutation (c.57+1G>A) in the GH releasing hormone receptor gene, and shown that adult GH-naïve individuals have no evidence of clinically evident premature atherosclerosis. To test whether subclinical atherosclerosis is anticipated in untreated IGHD, we performed a cross-sectional study of 25 IGHD and 27 adult controls matched for age and gender. A comprehensive clinical and biochemical panel and coronary artery calcium scores were evaluated by multi-detector tomography. Height, weight, IGF1, homeostasis model assessment of insulin resistance, creatinine and creatininekinase were lower in the IGHD group. Median and interquartile range of calcium scores distribution was similar in the two groups: IGHD 0(0) and control 0(4.9). The vast majority of the calcium scores (20 of 25 IGHD (80%) and 18 of 27 controls (66.6%)) were equal to zero (difference not significant). There was no difference in the calcium scores classification. None of IGHD subjects had minimal calcification, which were present in four controls. Three IGHD and four controls had mild calcification. There were two IGHD individuals with moderate calcification and one control with severe calcification. Our study provides evidence that subjects with congenital isolated lifetime and untreated severe IGHD do not have accelerated subclinical coronary atherosclerosis.

Introduction

Growth hormone (GH) and its principal mediator insulin-like growth factor 1 (IGF1) have important effects not only on the acquisition of normal body size, but also on metabolic and cardiovascular (CV) status (1). GH and IGF1 have synergistic anabolic effect on muscle mass, but antagonist effects on insulin action (GH-reducing and IGF1 increasing insulin sensitivity) and lipolysis (GH increasing and IGF1 reducing it) (2). Adult onset GH deficiency (GHD) has been described as model of metabolic syndrome, with visceral obesity, insulin resistance, endothelial dysfunction, increased sympathetic activity, and a pro-inflammatory profile (3, 4, 5). Although GH replacement therapy has been shown to reduce the risk profile (6), it is still unclear if this is due to GHD per se, or to confounding factors often found in acquired GHD (other pituitary hormone deficiencies, inadequate replacements and pituitary surgery or radiotherapy) (7, 8).

A model of isolated GHD (IGHD) would be preferable to study the relationship between the GH–IGF1 axis and CV risk. In Itabaianinha county, in the northeastern Brazilian state of Sergipe, we have described a large group of subjects with familial IGHD due to a homozygous (c.57+1G>A) mutation in the GHRH receptor gene (GHRHR) (9). The untreated IGHD adults have proportionate dwarfism, and otherwise normal pituitary function (10). They exhibit a balance between adverse and beneficial CV risk factors. The adverse factors are increased systolic blood pressure (BP), higher fat mass percentage, increased total and LDL-cholesterol and C-reactive protein (11), visceral obesity and elevated cortisol to cortisone ratio (12). The protective factors include normal serum leptin, increased adiponectin (13) and increased insulin sensitivity (14). The adult IGHD individuals do not present premature clinical carotid (15) or aortic atherosclerosis (16) nor coronary ischemia assessed by stress echocardiography (15, 17), and have similar longevity as non-affected siblings (18). Because coronary disease presents with a long latency period, it is important to know if subclinical atherosclerosis exists in these IGHD subjects. To answer this, it is necessary to assess asymptomatic individuals (19, 20, 21). Measurement of coronary artery calcium by multi-detector tomography has been shown to predict the risk of clinical coronary disease (22, 23, 24, 25). This study tested whether subclinical atherosclerosis is accelerated in these IGHD asymptomatic individuals by comparing calcium scores in IGHD and normal controls.

Subjects and methods

Subjects

In a cross-sectional study, asymptomatic IGHD and age- and sex-matched control subjects (controls) were recruited by advertising in the local Dwarfs Association building and by word of mouth among the inhabitants of Itabaianinha. Inclusion criterion for IGHD was genotype-proven homozygosity for the c.57+1G>A GHRHR mutation, whereas controls were normal statured individuals proven to be homozygous for the wt GHRHR allele. Exclusion criteria were: previous GH treatment, age under 18 years, CV symptoms or any evidence of active CV diseases. Twenty-five (13 females) IGHD and 27 (15 females) volunteered and were enrolled. None of these IGHD individual have participated in a previous 6-month GH depot trial (17). The Federal University of Sergipe Institutional Review Board approved these studies and all subjects gave written informed consent.

Interview and physical examination

The subjects were submitted to a detailed interview including risk factors for CV disease, hypertension, smoking, dyslipidemia, familiar CV history, co-morbidities and treatments, and to a physical examination, with measurement of body weight and height. BP was obtained by the average of three measurements obtained in the left arm after 10 min of rest in the sitting position by one physicians (U M M C) using a mercury sphygmomanometer with a cuff appropriate for the size of the arm. The Framingham risk score was estimated (26).

Laboratory assessment

Blood was collected after an overnight fast. Total cholesterol, triglycerides, glucose, insulin, urea, creatinine and creatinine kinase were measured by standard techniques. The increase in total cholesterol in this IGHD cohort is due to an increase in LDL cholesterol (11, 13, 15). IGF1 was measured by a solid-phase, enzyme-labeled chemiluminescent immunometric assay (IMMULITE 2000, Siemens Healthcare Diagnostics Products Ltd, Malvern, PA, USA), with intra- and inter-assay variabilities of 3.1 and 6.1% respectively. Insulin was measured by a solid-phase, enzyme-labeled chemiluminescent immunometric assay (IMMULITE 2000 Siemens Healthcare Diagnostics Products Ltd), with intra- and inter-assay variabilities of 4.2 and 5.1% respectively. Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMAIR) with the formula: fasting serum insulin (μlU/ml) x fasting plasma glucose (mmol/l)/22.5. All the tests were carried out in the Laboratory of University Hospital of the Federal University of Sergipe, in Aracaju, Sergipe.

Coronary tomography for calcium score

Calcium score was calculated with the use of a 64-slice multi-detector tomography scanner (Siemens Somatom Definition AS) dedicated to ECG-synchronized cardiac studies, for a non-contrast ECG-triggered acquisition. Syngovia software (Siemens Healthcare Global) was employed to acquire the Agatston score. All computed tomographies were analyzed by a single reader. The classification of calcium score followed the American College of Cardiology/American Heart Association Task Force criteria. Calcium score >300=severe calcification, 101–300=moderate calcification, 11–100=mild calcification, 1–10=minimal calcification and 0=absence of calcification (25).

Statistical analysis

Data are expressed as mean (s.d.), except for IGF1, insulin, HOMAIR and calcium scores expressed as median (interquartile range). Student's t-test was used for variables with normal distribution, and Mann–Whitney U-test for variables without Gaussian distribution (IGF1, insulin, HOMAIR and calcium scores). Fisher's exact test was used to analyze classification of CAC sores and percentage of previous smoking, high BP and diabetes. Statistical analysis was performed using the statistical software SPSS 19.0 version. P values under 0.05 were considered significant.

Results

Table 1 shows the clinical and biochemical features of the two groups. Height, weight, IGF1, insulin, HOMAIR, creatinine, creatininekinase and were lower in IGHD group.

Table 1

Clinical and biochemical features of IGHD and control subjects.

IGHD (25)Control (27)P
Age (years)50.1 (15.9)51.1 (14.0)0.799
Sex (F/M)13/1215/120.764
Smoking121
Weight (kg)39.3 (8.7)71.8 (14.4)<0.0001
Diabetes history420.411
Dislipidemia history11111
Arterial hypertension 8160.058
Height (m)1.2 (0.18)1.6 (0.1)<0.0001
BMI (kg/m2)25.5 (5.7)26.7 (4.2)0.402
Systolic BP (mmHg)122.1 (18.9)124.4 (15.0)0.622
Diastolic BP (mmHg)78.8 (9.3)80.4 (6.5)0.486
IGF1 (ng/ml)1.9 (0)132 (55)<0.0001
Glucose (mg/dl)105.5 (22.7)105.9 (70.5)0.975
Insulin (mUI/ml)5.35 (3.8)17.3 (10.9)<0.0001
Homa IR1.4 (1.0)4.3 (3.1)0.012
Cholesterol (mg/dl)227.0 (65.1)210.7 (28.2)0.257
Tryglicerides (mg/dl)142.0 (95.5)135.3 (51.3)0.762
Urea (mg/dl)38.6 (9.8)34.7 (9.0)0.143
Creatinine (mg/dl)0.7 (0.1)0.9 (0.2)<0.0001
Creatininekinase (IU/l)82.0 (35.1)152.8 (141.0)0.017
Framingham score5.7 (6.4)4.9 (4.5)0.596

Table 2 shows the calcium scores. The distribution expressed as median and interquartile range was similar in the two groups: IGHD 0(0) and control 0(4.9). The vast majority of the CAC scores (20 out 25 IGHD (80%) and 18 out 27 controls (66.6%)) were equal to zero, p=0.354. The highest CAC scores were 128.1 in IGHD and 331.5 in controls. Two subjects were further evaluated. A 66-year-old IGHD female (with compliant of chest pain) underwent CT angiography and coronary angiogram, and a clinical three arterial lesion was found. The second, a 61-year-old control male exhibited normal exercise stress echocardiography. Both were recommended lifestyle modifications and statin use.

Table 2

Classification of calcium scores in IGHD and controls.

Calcium scoreIGHD (25)Controls (27)
0 (absent)2018
1–10 (minimal)04
11–100 (mild)34
101–300 (moderate)20
>300 (severe)01

Discussion

Acquired adult-onset GHD is a model of metabolic syndrome, with abdominal obesity, insulin resistance and dyslipidemia (3, 4, 5). Nevertheless, the relationship between GHD and obesity includes several mechanisms and including some degree of GH resistance in obesity (27). Although GH replacement therapy has been shown to reduce this risk profile (6), it is still unclear if the high risk is due to untreated GHD, or to confounding factors often found in acquired GHD. Some of these factors such as hypogonadism, excessive glucocorticoid replacement, craniopharyngioma, radiotherapy (implicated in cerebrovascular mortality or de novo brain tumors) and very recently adrenal crisis (7, 8, 28, 29, 30, 31, 32, 33) have been implicated in the increased mortality risk associated with hypopituitarism (28). Accordingly, very recent national or multicenter studies have suggested that GHD deficiency in the context of hypopituitarism does not cause an increase in CV mortality despite increased general mortality risk (8, 29, 30).

As our previous studies indicated that this IGHD group has no premature clinical atherosclerosis (11, 15, 16, 17), we decided to assess subclinical atherosclerosis, by measuring the calcium content in the coronary arteries. Calcium score is an independent predictor of mortality in a multivariable model controlling for age, gender, ethnicity, and cardiac risk factors, and has been shown to provide additional risk prediction beyond the Framingham risk score in individuals with low and high CV risk (22, 23). Most of our IGHD and controls present with calcium score of zero. In subjects with positive values, the majority had mild calcification. There were two IGHD individuals with intermediate calcification (one of them underwent coronary angiography that showed non-critic lesions), and one control with severe calcification (had no symptoms, underwent to resting and exercise echocardiography that showed no ischemia). The lack of subclinical atherosclerosis corroborates our previous finding that congenital IGHD is not a cause of CV mortality (17).

The calcium scores of IGHD individuals expressed as percentage of the negative scores and the median and interquartile range (80% and 0(0)) are very similar to ones of a Portuguese cohort (Lisbon) of asymptomatic normal individuals (82% and 0(0)). Our control values (66.6% and 0(4.9)) were similar to the ones observed in area of southern Brazil (Sao Paulo) (54% and 1(0.68)), and lower than the ones observed in mainland USA (Columbus, Ohio and Nashville, Tennessee) (46% and 4(0.87)), in pooled genders (34). Because the state of Sergipe is one of the regions where the Portuguese colonization of Brazil had begun, 60% of the population is of Portuguese origin (35). It is possible that the Portuguese ancestry influenced the calcium scores in both IGHD and controls. However, as calcium scores parallel the CV mortality rates in the three nations (34), we can conclude that IGHD subjects have an atherosclerosis risk that is similar to non-GHD asymptomatic normal individuals form the same region.

Both IGHD and control groups have low Framingham risk scores, despite the fact that the IGHD group is exposed to higher burden of classical CV risks throughout life (in this particular sample the prevalence of hypertension was not different between the two groups). One explanation for this finding is the increased insulin sensitivity of IGHD subjects despite visceral adiposity (12). Another possible explanation lies on the degree of IGF1 reduction. It is possible that different degrees of IGF1 deficiency may result in different effects on the vascular wall (15). Mild IGF1 reduction in the general population has been linked to increased risk ischemic heart disease (36). Conversely, very severe IGF1 reduction, as found in our IGHD model, may be protective against atherosclerosis. This fits with the increase longevity of animal models of GHD or GH resistance (37). Accordingly, when we treated a subset of these patients with submaximal doses of GH for 6 months, converting a severe in a mild IGF1 deficiency we observed the appearance of atherosclerotic plaques (17).

Calcium scores of patients with IGHD due to large homozygous deletions in the GH-1 gene, or with GH resistance (Laron dwarfism) are not available to compare the frequency of subclinical atherosclerosis in these models with ours. Longevity, influenced not only by clinical atherosclerosis, but also from other conditions such as cancer, infectious diseases and accidents, seems to be reduced in the former model (38), but is not in the latter (39). Differently from subjects with large deletions in the GH-1 gene (complete lack of GH secretion) and Laron dwarfism (lack of GH action), our IGHD subjects have very low, but detectable serum GH levels (10). This residual GH secretion may exert some metabolic actions, resulting in differences between these disease models.

One limitation of our study is that the age of our sample is relatively young. However, near 80% of the IGHD subjects are ≧35 years, age sufficient in other studies to identify individuals who have subclinical atherosclerosis when CV risk factors are present (40, 41). It is also possible that subjects with worse health status would not have volunteered.

Other factors that may influence the development of atherosclerosis include environmental factors and dietary habits. Both GHD and controls reside in the same area, which is becoming progressively more urbanized. While we have recently reported that GHD subjects consume in percentage more proteins, less carbohydrates and equal amount of lipids in comparison with the controls (42), it is difficult to predict the role of such dietary differences on the development of subclinical coronary atherosclerosis.

In conclusion, subjects with congenital isolated lifetime and untreated severe IGHD do not have accelerated subclinical coronary atherosclerosis when compared with the normal controls from the same region.

Declaration of interest

R Salvatori serves in the advisory board of Novo Nordisk, Novartis and Pfizer.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Acknowledgements

The authors thank the ‘Associação do Crescimento Físico e Humano de Itabaianinha’ for their assistance and the Clinic CEMISE for Calcium scores measurements.

References

  • 1

    Aguiar-Oliveira MH & Salvatori R. Lifetime growth hormone (GH) deficiency: impact on growth, metabolism, body composition, and survival capacity Chapter ID 160. In Handbook of Growth and Growth Monitoring in Health and Disease. Ed VR Preedy. New York, NY, USA: Springer Science Business Media, LLC, 2011

  • 2

    Gharib H, Cook DM, Saenger PH, Bengtsson BA, Feld S, Nippoldt TB, Rodbard HW, Seibel JA & Vance ML 2003 American Associations of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in adults and children – UPDATE. Endocrine Practice 9 6476. doi:10.4158/EP.9.1.64.

    • Search Google Scholar
    • Export Citation
  • 3

    de Boer H, Blok GJ & Van der Veen EA 1995 Clinical aspects of growth hormone deficiency in adults. Endocrine Reviews 16 6386. doi:10.1210/er.16.1.63.

    • Search Google Scholar
    • Export Citation
  • 4

    Gola M, Bonadonna S, Doga M & Giustina A 2005 Clinical review: Growth hormone and cardiovascular risk factors. Journal of Clinical Endocrinology and Metabolism 90 18641870. doi:10.1210/jc.2004-0545.

    • Search Google Scholar
    • Export Citation
  • 5

    Colao A 2008 The GH–IGF-I axis and the cardiovascular system: clinical implications. Clinical Endocrinology 69 347358. doi:10.1111/j.1365-2265.2008.03292.x.

    • Search Google Scholar
    • Export Citation
  • 6

    Gazzaruso C, Gola M, Karamouzis I, Giubbini R & Giustina A 2014 Cardiovascular risk in adult patients with growth hormone (GH) deficiency and following substitution with GH – an update. Journal of Clinical Endocrinology and Metabolism 99 1829. doi:10.1210/jc.2013-2394.

    • Search Google Scholar
    • Export Citation
  • 7

    Brada M, Ashley S, Ford D, Traish D, Burchell L & Rajan B 2002 Cerebrovascular mortality in patients with pituitary adenoma. Clinical Endocrinology 57 713717. doi:10.1046/j.1365-2265.2002.01570.x.

    • Search Google Scholar
    • Export Citation
  • 8

    Gaillard RC, Mattsson AF, Akerblad AC, Bengtsson BA, Cara J, Feldt-Rasmussen U, Kołtowska-Häggström M, Monson JP, Saller B & Wilton P 2012 Overall and cause-specific mortality in GH-deficient adults on GH replacement. European Journal of Endocrinology 166 10691077. doi:10.1530/EJE-11-1028.

    • Search Google Scholar
    • Export Citation
  • 9

    Salvatori R, Hayashida CY, Aguiar-Oliveira MH, Phillips JA III, Souza AH, Gondo RG, Toledo SP, Conceição MM, Prince M & Maheshwari HD 1999 Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene. Journal of Clinical Endocrinology and Metabolism 84 917923. doi:10.1210/jcem.84.3.5599.

    • Search Google Scholar
    • Export Citation
  • 10

    Aguiar-Oliveira MH, Gill MS, Barretto ES, Alcântara MR, Miraki-moud F, Souza AH, Martinelli CE, Pereira FA, Salvatori R & Levine MA 1999 Effect of Severe growth hormone (GH) deficiency due to a mutation in the GH-releasing hormone receptor on insulin-like growth factors (IGFs), IGF-binding proteins,and ternary complex formation throughout life. Journal of Clinical Endocrinology and Metabolism 84 41184126. doi:10.1210/jcem.84.11.6133.

    • Search Google Scholar
    • Export Citation
  • 11

    Barreto-Filho JAS, Alcântara MRS, Salvatori R, Barreto MA, Sousa ACS, Bastos V, Souza AH, Pereira RMC, Clayton PE & Gill MS 2002 Familial isolated growth hormone deficiency is associated with increased systolic blood pressure, central obesity, and dyslipidemia. Journal of Clinical Endocrinology and Metabolism 87 20182023. doi:10.1210/jcem.87.5.8474.

    • Search Google Scholar
    • Export Citation
  • 12

    Gomes-Santos E, Salvatori R, Ferrão TO, Oliveira CR, Diniz RD, Santana JA, Pereira FA, Barbosa RA, Souza AH & Melo EV 2014 Increased visceral adiposity and cortisol to cortisone ratio in adults with congenital lifetime isolated GH deficiency. Journal of Clinical Endocrinology and Metabolism 99 32853289. doi:10.1210/jc.2014-2132.

    • Search Google Scholar
    • Export Citation
  • 13

    Oliveira CR, Salvatori R, Meneguz-Moreno RA, Aguiar-Oliveira MH, Pereira RM, Valença EH, Araújo VP, Farias NT, Silveira DC & Vieira JG 2010 Adipokine profile and urinary albumin excretion in isolated growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 95 693698. doi:10.1210/jc.2009-1919.

    • Search Google Scholar
    • Export Citation
  • 14

    Oliveira CR, Salvatori R, Barreto-Filho JA, Rocha IE, Mari A, Pereira RM, Campos VC, Menezes M, Gomes-Santos E & Meneguz-Moreno RA 2012 Insulin sensitivity and -cell function in adults with lifetime, untreated isolated growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 97 10131019. doi:10.1210/jc.2011-2590.

    • Search Google Scholar
    • Export Citation
  • 15

    Oliveira JL, Marques-Santos C, Barreto-Filho JA, Ximenes-Filho R, Btitto AV, Souza AH, Prado CM, Oliveira CR, Pereira RM & Vicente TA 2006 Lack of evidence of premature atherosclerosis in untreated severe isolated growth hormone (GH) deficiency due to a GH-releasing hormone receptor mutation. Journal of Clinical Endocrinology and Metabolism 91 20932099. doi:10.1210/jc.2005-2571.

    • Search Google Scholar
    • Export Citation
  • 16

    Souza AH, Farias MI, Salvatori R, Silva GM, Santana JA, Pereira FA, de Paula FJ, Valença EH, Melo EV & Barbosa RA 2014 Lifetime, untreated isolated GH deficiency due to a GH-releasing hormone receptor mutation has beneficial consequences on bone status in older individuals, and does not influence their abdominal aorta calcification. Endocrine 47 191197. doi:10.1007/s12020-013-0118-5.

    • Search Google Scholar
    • Export Citation
  • 17

    Oliveira JL, Aguiar-Oliveira MH, D'Oliveira A, Pereira RM, Oliveira CR, Farias CT, Barreto-Filho JA, Anjos-Andrade FD, Marques-Santos C & Nascimento-Júnior AC 2007 Congenital growth hormone (GH) deficiency and atherosclerosis: effects of GH replacement in GH-naive adults. Journal of Clinical Endocrinology and Metabolism 92 46644670. doi:10.1210/jc.2007-1636.

    • Search Google Scholar
    • Export Citation
  • 18

    Aguiar-Oliveira MH, Oliveira FT, Pereira RM, Oliveira CR, Blackford A, Valença EH, Gomes-Santos E, Gois-Junior MB, Meneguz-Moreno RA & Araujo VP 2010 Longevity in untreated congenital growth hormone deficiency due to a homozygous mutation in the GHRH receptor gene. Journal of Clinical Endocrinology and Metabolism 95 714721. doi:10.1210/jc.2009-1879.

    • Search Google Scholar
    • Export Citation
  • 19

    Earls JP, Woodard PK, Abbara S, Akers SR, Araoz PA, Cummings K, Cury RC, Dorbala S, Hoffmann U & Hsu JY 2014 ACR appropriateness criteria asymptomatic patient at risk for coronary artery disease. Journal of the American College of Radiology 11 1219. doi:10.1016/j.jacr.2013.09.021.

    • Search Google Scholar
    • Export Citation
  • 20

    Park HE, Chun E-J, Choi S-I, Lee SP, Yoon C-H, Kim H-K, Youn T-J, Kim Y-J, Choi D-J & Sohn D-W 2013 Clinical and imaging parameters to predict cardiovascular outcome in asymptomatic subjects. International Journal of Cardiovascular Imaging 29 15951602. doi:10.1007/s10554-013-0235-5.

    • Search Google Scholar
    • Export Citation
  • 21

    Warraich HJ & Nasir K 2013 Subclinical cardiovascular disease assessment in persons with diabetes. Current Cardiology Reports 15 358 doi:10.1007/s11886-013-0358-2.

    • Search Google Scholar
    • Export Citation
  • 22

    Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, Liu K, Shea S, Szklo M & Bluemke DA 2008 Coronary calcium as a predictor of coronary events in four racial or ethnic groups. New England Journal of Medicine 358 13361345. doi:10.1056/NEJMoa072100.

    • Search Google Scholar
    • Export Citation
  • 23

    Budoff MJ, Nasir K, McClelland RL, Detrano R, Wong N, Blumenthal RS, Kondos G & Kronmal RA 2009 Coronary calcium predicts events better with absolute calcium scores than age-sex-race/ethnicity percentiles: MESA (Multi-Ethnic Study of Atherosclerosis). Journal of the American College of Cardiology 53 345352. doi:10.1016/j.jacc.2008.07.072.

    • Search Google Scholar
    • Export Citation
  • 24

    Sharma RK, Sharma RK, Voelker DJ, Singh VN, Pahuja D, Nash T & Reddy HK 2010 Cardiac risk stratification: role of the coronary calcium score. Vascular Health and Risk Management 6 603611. doi:10.2147/VHRM.S8753.

    • Search Google Scholar
    • Export Citation
  • 25

    Budoff MJ, Shaw LJ, Liu ST, Weinstein SR, Mosler TP, Tseng PH, Flores FR, Callister TQ, Raggi P & Berman DS 2007 Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients. Journal of the American College of Cardiology 49 18601870. doi:10.1016/j.jacc.2006.10.079.

    • Search Google Scholar
    • Export Citation
  • 26

    D'Agostino RB, Grundy S, Sullivan LM & Wilson P 2001 Validation of the framingham coronary heart disease prediction scores. Journal of the American Medical Association 286 180187. doi:10.1001/jama.286.2.180.

    • Search Google Scholar
    • Export Citation
  • 27

    Vijayakumar A, Yakar S & Leroith D 2011 The intricate role of growth hormone in metabolism. Frontiers in Endocrinology 2 32 doi:10.3389/fendo.2011.00032.

    • Search Google Scholar
    • Export Citation
  • 28

    Rosén T & Bengtsson BA 1990 Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 336 285283. doi:10.1016/0140-6736(90)91812-O.

    • Search Google Scholar
    • Export Citation
  • 29

    Van Bunderen CC, van Nieuwpoort IC, Arwert LI, Heymans MW, Franken AA, Koppeschaar HP, van der Lely AJ & Drent ML 2011 Does growth hormone replacement therapy reduce mortality in adults with growth hormone deficiency? Data from the Dutch National Registry of growth hormone treatment in adults.. Journal of Clinical Endocrinology and Metabolism 96 31513159. doi:10.1210/jc.2011-1215.

    • Search Google Scholar
    • Export Citation
  • 30

    Burmer P, Mattsson AF, Johannsson G, Höybye C, Holmer H, Dahlgvist P, Berinder K, Engström BE, Erkman B & Erfurth EM 2013 Deaths among adults patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality. Journal of Clinical Endocrinology and Metabolism 98 14661475. doi:10.1210/jc.2012-4059.

    • Search Google Scholar
    • Export Citation
  • 31

    Tomlinson JW, Holden N, Hills RK, Wheatley K, Clayton RN, Bates AS, Sheppard MC & Stewart PM 2001 Association between premature mortality and hypopituitarism. West Midlands Prospective Pituitary Study Group. Lancet 357 425431. doi:10.1016/S0140-6736(00)04006-X.

    • Search Google Scholar
    • Export Citation
  • 32

    Filipsson H, Monson JP, Koltowska-Häggström M, Mattsson A & Johannsson G 2006 The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. Journal of Clinical Endocrinology and Metabolism 91 39543961. doi:10.1210/jc.2006-0524.

    • Search Google Scholar
    • Export Citation
  • 33

    Bülow B, Hagmar L, Mikoczy Z, Nordström CH & Erfurth EM 1997 Increased cerbrovascular mortality in patients with hypopitutarism. Clinical Endocrinology 46 7581. doi:10.1046/j.1365-2265.1997.d01-1749.x.

    • Search Google Scholar
    • Export Citation
  • 34

    Santos RD, Nasir K, Rumberger JA, Budoff MJ, Braunstein JB, Meneghelo R, Barreiros M, Pereirinha A, Carvalho JA & Blumenthal RS 2006 Difference in atherosclerosis burden in different nations and continents assessed by coronary artery calcium. Atherosclerosis 187 378384. doi:10.1016/j.atherosclerosis.2005.09.017.

    • Search Google Scholar
    • Export Citation
  • 35

    Pena SD, Pietro GD, Fuchshuber-Moraes M, Genro JP, Hutz MH & Kehdy FS 2011 The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS ONE 6 e17063 doi:10.1371/journal.pone.0017063.

    • Search Google Scholar
    • Export Citation
  • 36

    Juul A, Scheike T, Davidsen M, Gyllenborg J & Jorgensen T 2002 Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case–control study. Circulation 106 939944. doi:10.1161/01.CIR.0000027563.44593.CC.

    • Search Google Scholar
    • Export Citation
  • 37

    Bartke A, Sun LY & Longo V 2013 Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiological Reviews 93 571598. doi:10.1152/physrev.00006.2012.

    • Search Google Scholar
    • Export Citation
  • 38

    Besson A, Salemi S, Gallati S, Jenal A, Horn R, Mullis PS & Mullis RE 2003 Reduced longevity in untreated patients with isolated growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 88 36643667. doi:10.1210/jc.2002-021938.

    • Search Google Scholar
    • Export Citation
  • 39

    Laron Z. Lifespan and mortality of patients with Laron Syndrome in Chapter ID 41. In Laron Syndrome – from man to mouse. Lessons from Clinical and Experimental experience. Eds Z Laron & J Kopchick. Berlin, Heidelberg, Germany: Springer-Verlag, 2011

  • 40

    Tzou WS, Douglas PS, Srinivasan SR, Bond MG, Tang R, Chen W, Bereson GS & Stein JH 2005 Increased subclinical atherosclerosis in young adults with metabolic syndrome. Journal of the American College of Cardiology 46 457463. doi:10.1016/j.jacc.2005.04.046.

    • Search Google Scholar
    • Export Citation
  • 41

    Dawson JD, Sonka M, Blecha MB, Lin W & Davis PH 2009 Risk factors associated with aortic and carotid intimal medial thickness in adolescents and young adults: the muscatine offspring study. Journal of the American College of Cardiology 53 22732279. doi:10.1016/j.jacc.2009.03.026.

    • Search Google Scholar
    • Export Citation
  • 42

    Oliveira-Santos AA, Salvatori R, Gomes-Santos E, Santana JA, Leal AC & Barbosa AA Subjects with isolated GH deficiency due to a null GHRHR mutation eat proportionally more, but healthier than controls Endocrine 2015 [in press] doi:10.1007/s12020-015-0670-2.

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

     European Society of Endocrinology

     Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 455 49 3
PDF Downloads 186 39 3
  • 1

    Aguiar-Oliveira MH & Salvatori R. Lifetime growth hormone (GH) deficiency: impact on growth, metabolism, body composition, and survival capacity Chapter ID 160. In Handbook of Growth and Growth Monitoring in Health and Disease. Ed VR Preedy. New York, NY, USA: Springer Science Business Media, LLC, 2011

  • 2

    Gharib H, Cook DM, Saenger PH, Bengtsson BA, Feld S, Nippoldt TB, Rodbard HW, Seibel JA & Vance ML 2003 American Associations of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in adults and children – UPDATE. Endocrine Practice 9 6476. doi:10.4158/EP.9.1.64.

    • Search Google Scholar
    • Export Citation
  • 3

    de Boer H, Blok GJ & Van der Veen EA 1995 Clinical aspects of growth hormone deficiency in adults. Endocrine Reviews 16 6386. doi:10.1210/er.16.1.63.

    • Search Google Scholar
    • Export Citation
  • 4

    Gola M, Bonadonna S, Doga M & Giustina A 2005 Clinical review: Growth hormone and cardiovascular risk factors. Journal of Clinical Endocrinology and Metabolism 90 18641870. doi:10.1210/jc.2004-0545.

    • Search Google Scholar
    • Export Citation
  • 5

    Colao A 2008 The GH–IGF-I axis and the cardiovascular system: clinical implications. Clinical Endocrinology 69 347358. doi:10.1111/j.1365-2265.2008.03292.x.

    • Search Google Scholar
    • Export Citation
  • 6

    Gazzaruso C, Gola M, Karamouzis I, Giubbini R & Giustina A 2014 Cardiovascular risk in adult patients with growth hormone (GH) deficiency and following substitution with GH – an update. Journal of Clinical Endocrinology and Metabolism 99 1829. doi:10.1210/jc.2013-2394.

    • Search Google Scholar
    • Export Citation
  • 7

    Brada M, Ashley S, Ford D, Traish D, Burchell L & Rajan B 2002 Cerebrovascular mortality in patients with pituitary adenoma. Clinical Endocrinology 57 713717. doi:10.1046/j.1365-2265.2002.01570.x.

    • Search Google Scholar
    • Export Citation
  • 8

    Gaillard RC, Mattsson AF, Akerblad AC, Bengtsson BA, Cara J, Feldt-Rasmussen U, Kołtowska-Häggström M, Monson JP, Saller B & Wilton P 2012 Overall and cause-specific mortality in GH-deficient adults on GH replacement. European Journal of Endocrinology 166 10691077. doi:10.1530/EJE-11-1028.

    • Search Google Scholar
    • Export Citation
  • 9

    Salvatori R, Hayashida CY, Aguiar-Oliveira MH, Phillips JA III, Souza AH, Gondo RG, Toledo SP, Conceição MM, Prince M & Maheshwari HD 1999 Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene. Journal of Clinical Endocrinology and Metabolism 84 917923. doi:10.1210/jcem.84.3.5599.

    • Search Google Scholar
    • Export Citation
  • 10

    Aguiar-Oliveira MH, Gill MS, Barretto ES, Alcântara MR, Miraki-moud F, Souza AH, Martinelli CE, Pereira FA, Salvatori R & Levine MA 1999 Effect of Severe growth hormone (GH) deficiency due to a mutation in the GH-releasing hormone receptor on insulin-like growth factors (IGFs), IGF-binding proteins,and ternary complex formation throughout life. Journal of Clinical Endocrinology and Metabolism 84 41184126. doi:10.1210/jcem.84.11.6133.

    • Search Google Scholar
    • Export Citation
  • 11

    Barreto-Filho JAS, Alcântara MRS, Salvatori R, Barreto MA, Sousa ACS, Bastos V, Souza AH, Pereira RMC, Clayton PE & Gill MS 2002 Familial isolated growth hormone deficiency is associated with increased systolic blood pressure, central obesity, and dyslipidemia. Journal of Clinical Endocrinology and Metabolism 87 20182023. doi:10.1210/jcem.87.5.8474.

    • Search Google Scholar
    • Export Citation
  • 12

    Gomes-Santos E, Salvatori R, Ferrão TO, Oliveira CR, Diniz RD, Santana JA, Pereira FA, Barbosa RA, Souza AH & Melo EV 2014 Increased visceral adiposity and cortisol to cortisone ratio in adults with congenital lifetime isolated GH deficiency. Journal of Clinical Endocrinology and Metabolism 99 32853289. doi:10.1210/jc.2014-2132.

    • Search Google Scholar
    • Export Citation
  • 13

    Oliveira CR, Salvatori R, Meneguz-Moreno RA, Aguiar-Oliveira MH, Pereira RM, Valença EH, Araújo VP, Farias NT, Silveira DC & Vieira JG 2010 Adipokine profile and urinary albumin excretion in isolated growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 95 693698. doi:10.1210/jc.2009-1919.

    • Search Google Scholar
    • Export Citation
  • 14

    Oliveira CR, Salvatori R, Barreto-Filho JA, Rocha IE, Mari A, Pereira RM, Campos VC, Menezes M, Gomes-Santos E & Meneguz-Moreno RA 2012 Insulin sensitivity and -cell function in adults with lifetime, untreated isolated growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 97 10131019. doi:10.1210/jc.2011-2590.

    • Search Google Scholar
    • Export Citation
  • 15

    Oliveira JL, Marques-Santos C, Barreto-Filho JA, Ximenes-Filho R, Btitto AV, Souza AH, Prado CM, Oliveira CR, Pereira RM & Vicente TA 2006 Lack of evidence of premature atherosclerosis in untreated severe isolated growth hormone (GH) deficiency due to a GH-releasing hormone receptor mutation. Journal of Clinical Endocrinology and Metabolism 91 20932099. doi:10.1210/jc.2005-2571.

    • Search Google Scholar
    • Export Citation
  • 16

    Souza AH, Farias MI, Salvatori R, Silva GM, Santana JA, Pereira FA, de Paula FJ, Valença EH, Melo EV & Barbosa RA 2014 Lifetime, untreated isolated GH deficiency due to a GH-releasing hormone receptor mutation has beneficial consequences on bone status in older individuals, and does not influence their abdominal aorta calcification. Endocrine 47 191197. doi:10.1007/s12020-013-0118-5.

    • Search Google Scholar
    • Export Citation
  • 17

    Oliveira JL, Aguiar-Oliveira MH, D'Oliveira A, Pereira RM, Oliveira CR, Farias CT, Barreto-Filho JA, Anjos-Andrade FD, Marques-Santos C & Nascimento-Júnior AC 2007 Congenital growth hormone (GH) deficiency and atherosclerosis: effects of GH replacement in GH-naive adults. Journal of Clinical Endocrinology and Metabolism 92 46644670. doi:10.1210/jc.2007-1636.

    • Search Google Scholar
    • Export Citation
  • 18

    Aguiar-Oliveira MH, Oliveira FT, Pereira RM, Oliveira CR, Blackford A, Valença EH, Gomes-Santos E, Gois-Junior MB, Meneguz-Moreno RA & Araujo VP 2010 Longevity in untreated congenital growth hormone deficiency due to a homozygous mutation in the GHRH receptor gene. Journal of Clinical Endocrinology and Metabolism 95 714721. doi:10.1210/jc.2009-1879.

    • Search Google Scholar
    • Export Citation
  • 19

    Earls JP, Woodard PK, Abbara S, Akers SR, Araoz PA, Cummings K, Cury RC, Dorbala S, Hoffmann U & Hsu JY 2014 ACR appropriateness criteria asymptomatic patient at risk for coronary artery disease. Journal of the American College of Radiology 11 1219. doi:10.1016/j.jacr.2013.09.021.

    • Search Google Scholar
    • Export Citation
  • 20

    Park HE, Chun E-J, Choi S-I, Lee SP, Yoon C-H, Kim H-K, Youn T-J, Kim Y-J, Choi D-J & Sohn D-W 2013 Clinical and imaging parameters to predict cardiovascular outcome in asymptomatic subjects. International Journal of Cardiovascular Imaging 29 15951602. doi:10.1007/s10554-013-0235-5.

    • Search Google Scholar
    • Export Citation
  • 21

    Warraich HJ & Nasir K 2013 Subclinical cardiovascular disease assessment in persons with diabetes. Current Cardiology Reports 15 358 doi:10.1007/s11886-013-0358-2.

    • Search Google Scholar
    • Export Citation
  • 22

    Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, Liu K, Shea S, Szklo M & Bluemke DA 2008 Coronary calcium as a predictor of coronary events in four racial or ethnic groups. New England Journal of Medicine 358 13361345. doi:10.1056/NEJMoa072100.

    • Search Google Scholar
    • Export Citation
  • 23

    Budoff MJ, Nasir K, McClelland RL, Detrano R, Wong N, Blumenthal RS, Kondos G & Kronmal RA 2009 Coronary calcium predicts events better with absolute calcium scores than age-sex-race/ethnicity percentiles: MESA (Multi-Ethnic Study of Atherosclerosis). Journal of the American College of Cardiology 53 345352. doi:10.1016/j.jacc.2008.07.072.

    • Search Google Scholar
    • Export Citation
  • 24

    Sharma RK, Sharma RK, Voelker DJ, Singh VN, Pahuja D, Nash T & Reddy HK 2010 Cardiac risk stratification: role of the coronary calcium score. Vascular Health and Risk Management 6 603611. doi:10.2147/VHRM.S8753.

    • Search Google Scholar
    • Export Citation
  • 25

    Budoff MJ, Shaw LJ, Liu ST, Weinstein SR, Mosler TP, Tseng PH, Flores FR, Callister TQ, Raggi P & Berman DS 2007 Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients. Journal of the American College of Cardiology 49 18601870. doi:10.1016/j.jacc.2006.10.079.

    • Search Google Scholar
    • Export Citation
  • 26

    D'Agostino RB, Grundy S, Sullivan LM & Wilson P 2001 Validation of the framingham coronary heart disease prediction scores. Journal of the American Medical Association 286 180187. doi:10.1001/jama.286.2.180.

    • Search Google Scholar
    • Export Citation
  • 27

    Vijayakumar A, Yakar S & Leroith D 2011 The intricate role of growth hormone in metabolism. Frontiers in Endocrinology 2 32 doi:10.3389/fendo.2011.00032.

    • Search Google Scholar
    • Export Citation
  • 28

    Rosén T & Bengtsson BA 1990 Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 336 285283. doi:10.1016/0140-6736(90)91812-O.

    • Search Google Scholar
    • Export Citation
  • 29

    Van Bunderen CC, van Nieuwpoort IC, Arwert LI, Heymans MW, Franken AA, Koppeschaar HP, van der Lely AJ & Drent ML 2011 Does growth hormone replacement therapy reduce mortality in adults with growth hormone deficiency? Data from the Dutch National Registry of growth hormone treatment in adults.. Journal of Clinical Endocrinology and Metabolism 96 31513159. doi:10.1210/jc.2011-1215.

    • Search Google Scholar
    • Export Citation
  • 30

    Burmer P, Mattsson AF, Johannsson G, Höybye C, Holmer H, Dahlgvist P, Berinder K, Engström BE, Erkman B & Erfurth EM 2013 Deaths among adults patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality. Journal of Clinical Endocrinology and Metabolism 98 14661475. doi:10.1210/jc.2012-4059.

    • Search Google Scholar
    • Export Citation
  • 31

    Tomlinson JW, Holden N, Hills RK, Wheatley K, Clayton RN, Bates AS, Sheppard MC & Stewart PM 2001 Association between premature mortality and hypopituitarism. West Midlands Prospective Pituitary Study Group. Lancet 357 425431. doi:10.1016/S0140-6736(00)04006-X.

    • Search Google Scholar
    • Export Citation
  • 32

    Filipsson H, Monson JP, Koltowska-Häggström M, Mattsson A & Johannsson G 2006 The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. Journal of Clinical Endocrinology and Metabolism 91 39543961. doi:10.1210/jc.2006-0524.

    • Search Google Scholar
    • Export Citation
  • 33

    Bülow B, Hagmar L, Mikoczy Z, Nordström CH & Erfurth EM 1997 Increased cerbrovascular mortality in patients with hypopitutarism. Clinical Endocrinology 46 7581. doi:10.1046/j.1365-2265.1997.d01-1749.x.

    • Search Google Scholar
    • Export Citation
  • 34

    Santos RD, Nasir K, Rumberger JA, Budoff MJ, Braunstein JB, Meneghelo R, Barreiros M, Pereirinha A, Carvalho JA & Blumenthal RS 2006 Difference in atherosclerosis burden in different nations and continents assessed by coronary artery calcium. Atherosclerosis 187 378384. doi:10.1016/j.atherosclerosis.2005.09.017.

    • Search Google Scholar
    • Export Citation
  • 35

    Pena SD, Pietro GD, Fuchshuber-Moraes M, Genro JP, Hutz MH & Kehdy FS 2011 The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS ONE 6 e17063 doi:10.1371/journal.pone.0017063.

    • Search Google Scholar
    • Export Citation
  • 36

    Juul A, Scheike T, Davidsen M, Gyllenborg J & Jorgensen T 2002 Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case–control study. Circulation 106 939944. doi:10.1161/01.CIR.0000027563.44593.CC.

    • Search Google Scholar
    • Export Citation
  • 37

    Bartke A, Sun LY & Longo V 2013 Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiological Reviews 93 571598. doi:10.1152/physrev.00006.2012.

    • Search Google Scholar
    • Export Citation
  • 38

    Besson A, Salemi S, Gallati S, Jenal A, Horn R, Mullis PS & Mullis RE 2003 Reduced longevity in untreated patients with isolated growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 88 36643667. doi:10.1210/jc.2002-021938.

    • Search Google Scholar
    • Export Citation
  • 39

    Laron Z. Lifespan and mortality of patients with Laron Syndrome in Chapter ID 41. In Laron Syndrome – from man to mouse. Lessons from Clinical and Experimental experience. Eds Z Laron & J Kopchick. Berlin, Heidelberg, Germany: Springer-Verlag, 2011

  • 40

    Tzou WS, Douglas PS, Srinivasan SR, Bond MG, Tang R, Chen W, Bereson GS & Stein JH 2005 Increased subclinical atherosclerosis in young adults with metabolic syndrome. Journal of the American College of Cardiology 46 457463. doi:10.1016/j.jacc.2005.04.046.

    • Search Google Scholar
    • Export Citation
  • 41

    Dawson JD, Sonka M, Blecha MB, Lin W & Davis PH 2009 Risk factors associated with aortic and carotid intimal medial thickness in adolescents and young adults: the muscatine offspring study. Journal of the American College of Cardiology 53 22732279. doi:10.1016/j.jacc.2009.03.026.

    • Search Google Scholar
    • Export Citation
  • 42

    Oliveira-Santos AA, Salvatori R, Gomes-Santos E, Santana JA, Leal AC & Barbosa AA Subjects with isolated GH deficiency due to a null GHRHR mutation eat proportionally more, but healthier than controls Endocrine 2015 [in press] doi:10.1007/s12020-015-0670-2.

    • Search Google Scholar
    • Export Citation