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

  • Manuel Herminio Aguiar-Oliveira
  • Roberto Salvatori


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.


Growth Hormone Growth Hormone Secretion Growth Hormone Therapy Height Standard Deviation Score Growth Hormone Peak 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Acid-labile subunit


Adult-onset GH deficiency


Body mass index


Childhood-onset GH deficiency


C-reactive protein


Fat-free mass


Fat mass


Growth hormone


Growth hormone deficiency


Growth hormone-releasing hormone


GHRH receptor


Height standard deviation score


IGF-binding protein


Insulin-like growth factor type I


Insulin-like growth factor type II


Isolated growth hormone deficiency


Intima-media thickness

LDL cholesterol

Low-density lipoprotein cholesterol


Quality of life



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.


  1. 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.PubMedCrossRefGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 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.Google Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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;147:75560.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. 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.Google Scholar
  15. Gola M, Bonadonna S, Doga M, Guistina A. Clinical review: growth hormone and cardiovascular risk factors. J Clin Endocrinol Metab. 2005;90:1864–70.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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
  18. 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;1:9–19Google Scholar
  19. 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;24:34956.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.PubMedGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. Rosen T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet. 1990;336:285–8.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.PubMedGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.CrossRefGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Manuel Herminio Aguiar-Oliveira
    • 1
    • 2
  • Roberto Salvatori
    • 3
  1. 1.Division of EndocrinologyFederal University of SergipeSergipeBrazil
  2. 2.Department of MedicineFederal University of SergipeSergipeBrazil
  3. 3.Division of EndocrinologyJohns Hopkins University School of MedicineBaltimoreUSA

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