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Lifetime Growth Hormone (GH) Deficiency: Impact on Growth, Metabolism, Body Composition, and Survival Capacity

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Handbook of Growth and Growth Monitoring in Health and Disease

Abstract

A model of growth hormone (GH) deficiency (GHD) due to GH-releasing hormone (GHRH) resistance caused by a homozygous-inactivating mutation in the GHRH receptor gene was used to assess the impacts of lifetime GH deficiency on growth, metabolism, body composition, and survival capacity. Affected individuals go through life with very low activity of the GH–insulin-like growth factor-I (IGF-I) axis. As a result, they present severe short stature with adult height standard deviation score from – 9.6 to –5.1 and proportionate reduction of bone dimensions. The reduction of the cephalic perimeter is less accentuated than the reduction on the facial height, causing a disproportion between the calvarium and the face, resulting in a “doll” or cherubim angel facies, which together with the underdevelopment of larynx leads to high pitch voice. Even when corrected by body surface, they have reduced size of the pituitary, thyroid, heart, uterus, and spleen. They also exhibit an increase in total and LDL cholesterol that persists throughout adulthood together with high levels of C-reactive protein and higher blood pressure. Body composition is markedly changed since childhood with reduction in fat-free mass with a mirror increase in percent fat mass. Despite this, they have an increase in insulin sensitivity. Bone strength is somewhat reduced without apparent increase in fractures. Puberty is delayed, but reproductive life and quality of life are normal. Despite unfavorable metabolic, inflammatory, blood pressure, and body composition profile, they did not exhibit premature atherosclerosis, with longevity similar to their normal-stature relatives.

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Abbreviations

ALS:

Acid-labile subunit

AOGHD:

Adult-onset GH deficiency

BMI:

Body mass index

COGHD:

Childhood-onset GH deficiency

CRP:

C-reactive protein

FFM:

Fat-free mass

FM:

Fat mass

GH:

Growth hormone

GHD:

Growth hormone deficiency

GHRH:

Growth hormone-releasing hormone

GHRHR:

GHRH receptor

HtSDS:

Height standard deviation score

IGFBP:

IGF-binding protein

IGF-I:

Insulin-like growth factor type I

IGF-II:

Insulin-like growth factor type II

IGHD:

Isolated growth hormone deficiency

IMT:

Intima-media thickness

LDL cholesterol:

Low-density lipoprotein cholesterol

QoL:

Quality of life

References

  • Aguiar-Oliveira MH, Gill MS, Barretto ESA, Alcantara MRS, Miraki-Moud F, Menezes CA, Souza AHO, Martinelli CE, Pereira FA, Salvatori R, Levine M, Shalet SM, Camacho- Hubner C, Clayton PE. 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. J Clin Endocrinol Metab. 1999;84:4118–26.

    Article  PubMed  CAS  Google Scholar 

  • Alcantara MRS, Salvatori R, Alcantara PRS, Nobrega LMA,Campos VS, Oliveira ECO, Oliveira MHS, Souza AHO, Aguiar-Oliveira MH. Thyroid morphology and function in adults with untreated isolated growth hormone deficiency. J Clin Endocrinol Metab. 2006;91:860–64.

    Article  PubMed  CAS  Google Scholar 

  • Barbosa JA, Salvatori R, Oliveira CR, Pereira RM, Farias CT, Britto AV, Farias NT, Blackford A, Aguiar-Oliveira MH. Quality of life in congenital, untreated, lifetime isolated growth hormone deficiency. J Psyneuen. 2009;34:894–900.

    CAS  Google Scholar 

  • Barreto VM, D’Avila JS, Sales NJ, Gonçalves MI, Seabra JD, Salvatori R, Aguiar-Oliveira MH. Laryngeal and vocal evaluation in untreated growth hormone deficient adults. Otolaryngol Head Neck Surg. 2009;140:37–42.

    Article  PubMed  Google Scholar 

  • Barreto-Filho JAS, Alcantara MRS, Salvatori R, Barreto MA, Sousa ACS, Bastos V, Souza AHO, Pereira RMC, Clayton PE, Gill M, Aguiar-Oliveira MH. Familial isolated growth hormone deficiency is associated with increased systolic blood pressure, central obesity, and dyslipidemia. J Clin Endocrinol Metab. 2002;87:2018–23.

    Article  PubMed  CAS  Google Scholar 

  • Besson A, Salemi S, Gallati S, Jenal A, Horn R, Mullis PS, Mullis PE. Reduced longevity in untreated patients with isolated growth hormone deficiency. J Clin Endocrinol Metab. 2003;88:3664–7.

    Article  PubMed  CAS  Google Scholar 

  • Binder G, Nagel BH, Ranke MB, Mullis PE. Isolated GH deficiency (IGHD) type II: imaging of the pituitary gland by magnetic resonance reveals characteristic differences in comparison with severe IGHD of unknown origin. Eur J Endocrinol. 2002;147:755–60.

    Article  PubMed  CAS  Google Scholar 

  • Blum MF, Shavrikova EP, Edwards DJ, Rosilio M, Hartman ML, Marın F, Valle D, Lely AJ, Attanasio AF, Strasburger CJ, Henrich G, Herschbach P. Decreased quality of life in adult patients with growth hormone deficiency compared with general populations using the new, validated, self-weighted questionnaire, questions on life satisfaction hypopituitarism module. J Clin Endocrinol Metab. 2003;88:4158–67.

    Article  PubMed  CAS  Google Scholar 

  • Boot AM, Engels MA, Boerma GJ, Krenning EP, de-Muinck-Keizer SS. Changes in bone mineral density, body composition, and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency. J Clin Endocrinol Metab. 1997;82:2423–8.

    Article  PubMed  CAS  Google Scholar 

  • de A Barretto ES, Gill MS, Freitas MES, Magalhaes MMG, Souza AHO, Aguiar-Oliveira MH, Clayton PE. Serum leptin and body composition in children with familial GH deficiency (GHD) due to a mutation in the growth hormone-releasing hormone (GHRH) receptor. Clin Endocrinol (Oxf). 1999;51:559–64.

    Article  Google Scholar 

  • Delafontaine P, Song YH, Li Y. Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels. Arterioscler Thromb Vasc Biol. 2004;24:435–44.

    Article  PubMed  CAS  Google Scholar 

  • de Paula FJ, Gois-Junior MB, Aguiar-Oliveira MH, Pereira FA, Oliveira CRP, Pereira RMC, Farias CT, Vicente TAR, Salvatori R. Consequences of lifetime isolated growth hormone (GH) deficiency and effects of short-term GH treatment on bone in adults with a mutation in the GHRH-receptor gene 2009. Clin Endocrinol (Oxf). 2009;70:35–40.

    Article  Google Scholar 

  • Gleeson HK, Souza AHO, Gill MS, Wieringa GE, De A Barretto ES, Barretto-Filho JAS, Shalet SM, Aguiar-Oliveira MH, Clayton PE. Lipid profiles in untreated severe congenital isolated growth hormone deficiency through the lifespan. Clin Endocrinol (Oxf). 2002;57:89–95.

    Article  CAS  Google Scholar 

  • Gleeson HK, Barreto ESA, Salvatori R, Costa L, Oliveira CRP, Pereira RMC, Clayton PE, Aguiar-Oliveira MH. Metabolic effects of growth hormone (GH) replacement in children and adolescents with severe isolated GH deficiency due to a GHRH receptor mutation. Clin Endocrinol (Oxf). 2007;66:466–74.

    CAS  Google Scholar 

  • Gola M, Bonadonna S, Doga M, Guistina A. Clinical review: growth hormone and cardiovascular risk factors. J Clin Endocrinol Metab. 2005;90:1864–70.

    Article  PubMed  CAS  Google Scholar 

  • Gondo RG, Aguiar-Oliveira MH, Hayashida CY, Toledo SP, Abelin N, Levine MA, Bowers CY, Souza AH, Pereira RM, Santos NL, Salvatori R. Growth hormone-releasing peptide-2 stimulates GH secretion in GH-deficient patients with mutated GH-releasing hormone receptor. J Clin Endocrinol Metab. 2001;86:3279–83.

    Article  PubMed  CAS  Google Scholar 

  • Guevara-Aguirre J, Rosenbloom AL, Vaccarello MA, Fielder PJ, de la Vega A, Diamond FB Jr, Rosenfeld, RG. Growth hormone receptor deficiency (Laron syndrome): clinical and genetic characteristics. Acta Paediatr Scand. 1991;Suppl 377:96–103.

    Google Scholar 

  • Krzisnik C, Kolacio Z, Battelino T, Brown M, Parks JS, Laron Z. Little people of the Island of Krk – revisited. Etiology of hypopituitarism revealed. J Endocr Genet. 1999;1:9–19

    Google Scholar 

  • Lind S Rudling M, Ericsson S, Olivecrona H, Eriksson M, Borgström B, Eggertsen G, Berglund L, Angelin B. Growth hormone induces low-density lipoprotein clearance but not bile acid synthesis in humans. Arterioscler Thromb Vasc Biol. 2004;24:349–56.

    Article  PubMed  CAS  Google Scholar 

  • Maheshwari HG, Silverman BL, Dupuis J, Baumann G. Phenotype and genetic analysis of a syndrome caused by an inactivating mutation in the growth hormone-releasing hormone receptor: dwarfism of Sindh. J Clin Endocrinol Metab. 1998;83:4065–74.

    Article  PubMed  CAS  Google Scholar 

  • Maheshwari HG, Pezzoli SS, Rahim A, Shalet SM, Thorner MO, Baumann G. Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance. Am J Physiol Endocrinol Metab. 2002;282:E943–51.

    PubMed  CAS  Google Scholar 

  • Martari M, Salvatori R. Chapter 3 diseases associated with growth hormone-releasing hormone receptor (GHRHR) mutations. Prog Mol Biol Transl Sci. 2009;88:57. doi: 10.1016/S0079–6603(09) 88003–3.

    Article  PubMed  CAS  Google Scholar 

  • Menezes M, Salvatori R, Oliveira CR, Pereira RM, Souza AH, Nobrega LM, Cruz EA, Menezes M, Alves EO, Aguiar-Oliveira MH. Climacteric in untreated isolated growth hormone deficiency. Menopause. 2008;15:743–7.

    Article  PubMed  Google Scholar 

  • Murray RA, Maheshwari HG, Russel EJ, Baumann G. Pituitary hypoplasia in patients with a mutation in the growth hormone-releasing hormone receptor gene. AJNR Am J Neuroradiol. 2000;21:685–9.

    PubMed  CAS  Google Scholar 

  • Oliveira CRP, Salvatori R, Nobrega LMA, Carvalho EOM, Menezes M, Farias CT, Britto AVO, Pereira RMC, Sizes of abdominal organs in adults with severe short stature due to severe, untreated, congenital GH deficiency caused by a homozygous mutation in the GHRH receptor gene. Aguiar-Oliveira MH. Clin Endocrinol (Oxf). 2008;69:153–8.

    Article  CAS  Google Scholar 

  • Oliveira HA, Salvatori R, Kraus, Oliveira CRP, Silva PCR, Aguiar-Oliveira MH. Magnetic resonance imaging study of pituitary morphology in subjects homozygous and heterozygous for a null mutation of the GHRH receptor gene. Eur J Endocrinol. 2003;148:427–32.

    Article  PubMed  CAS  Google Scholar 

  • Oliveira JL, Marques-Santos C, Barreto-Filho JA, Filho RX, Britto AV, Souza AHO, Prado CM, Oliveira CRP, Pereira RMC, Vicente TBR, Farias CT, Aguiar-Oliveira MH, Salvatori R. Lack of evidence of premature atherosclerosis in untreated severe isolated growth hormone (GH) deficiency due to a GH-releasing hormone receptor mutation. J Clin Endocrinol Metab. 2006;91:2093–9.

    Article  CAS  Google Scholar 

  • Oliveira JLM, Aguiar-Oliveira MH, D’Oliveira Jr. A, Pereira RMC, Oliveira CRP, Farias CT, Barreto-Filho JA, Anjos-Andrade FD, Marques-Santos C, Nascimneto-Junior AC, Alves EO, Oliveira FT, Campos VC, Ximenes R, Blackford A, Parmigiani G, Salvatori R. Congenital growth hormone (GH) deficiency and atherosclerosis: effects of GH replacement in GH-naive adults. J Clin Endocrinol Metab. 2007;92:4464–70.

    Article  Google Scholar 

  • Patel MB, Arden NK, Masterson LM, Phillips DI, Swaminathan R, Syddall HE, Byme CD, Wood PJ, Cooper C, Holt RI. Investigating the role of the growth hormone-insulin-like growth factor (GH-IGF) axis as a determinant of male bone mineral density (BMD). Bone. 2005;37:833–41.

    Article  PubMed  CAS  Google Scholar 

  • Rosen T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet. 1990;336:285–8.

    Article  PubMed  CAS  Google Scholar 

  • Salvatori R, Hayashida CY, Aguiar-Oliveira MH, Phillips JA 3rd, Souza AH, Gondo RG, Toledo SP, Conceicao MM, Prince M, Maheshwari HG, Baumann G, Levine MA. Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene. J Clin Endocrinol Metab. 1999;84:917–23.

    Article  PubMed  CAS  Google Scholar 

  • Salvatori R, Aguiar-Oliveira MH, Monte LV, Hedges L, Santos NL, Pereira RM, Phillips JA. Detection of a recurring mutation in the human growth hormone-releasing hormone receptor gene. Clin Endocrinol(Oxf). 2002;57:77–80.

    Article  CAS  Google Scholar 

  • Salvatori R, Serpa MG, Parmigiani G, Britto AV, Oliveira JL, Oliveira CR, Prado CM, Farias CT, Almeida JC, Vicente TA, Aguiar-Oliveira MH. GH response to hypoglycemia and clonidine in the GH-releasing hormone resistance syndrome. J Endocrinol Invest. 2006;29:805–8.

    PubMed  CAS  Google Scholar 

  • Segerlantz M, Bramnert M, Manhem P, Laurila E, Groop LC. Inhibition of lipolysis during acute GH exposure increases insulin sensitivity in previously untreated GH-deficient adults. Eur J Endocrinol. 2003;149:511–9.

    Article  PubMed  CAS  Google Scholar 

  • Tomlinson JW, Holden N, Hills RK, Wheatley K, Clayton RN, Bates AS, Sheppard MC, Stewart PM. Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet. 2001;357:425–31.

    Article  PubMed  CAS  Google Scholar 

  • Tsilchorozidou T, Conway GS. Uterus size and ovarian morphology in women with isolated growth hormone deficiency, hypogonadotrophic hypogonadism and hypopituitarism. Clin Endocrinol (Oxf). 2004;61:567–72.

    Article  Google Scholar 

  • Wajnrajch MP, Gertner JM, Harbinson MD, Chua SC Jr, Leibel RL. Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse. Nat Genet. 1996;12:88–90.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Manuel H. Aguiar-Oliveira was supported by a grant BEX 4309/08-1 from Capes, “Coordenação de Aperfeiçoamento de Pessoal de Nível Superior,” from the Brazilian government.

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Authors and Affiliations

  1. Division of Endocrinology, Federal University of Sergipe, 49060-100, Sergipe, Brazil

    Manuel Herminio Aguiar-Oliveira

  2. Department of Medicine, Federal University of Sergipe, 49060-100, Sergipe, Brazil

    Manuel Herminio Aguiar-Oliveira

  3. Division of Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD, 21212, USA

    Roberto Salvatori

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  1. Manuel Herminio Aguiar-Oliveira
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Correspondence to Manuel Herminio Aguiar-Oliveira .

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Editors and Affiliations

  1. Dept. Nutrition & Dietetics, King's College, Stamford St. 150, London, SE1 9NH, United Kingdom

    Victor R. Preedy

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Aguiar-Oliveira, M.H., Salvatori, R. (2012). Lifetime Growth Hormone (GH) Deficiency: Impact on Growth, Metabolism, Body Composition, and Survival Capacity. In: Preedy, V. (eds) Handbook of Growth and Growth Monitoring in Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1795-9_160

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  • DOI: https://doi.org/10.1007/978-1-4419-1795-9_160

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