Advertisement

Pituitary

, Volume 18, Issue 4, pp 561–567 | Cite as

Frequent development of combined pituitary hormone deficiency in patients initially diagnosed as isolated growth hormone deficiency: a long term follow-up of patients from a single center

  • Aline P. Otto
  • Marcela M. França
  • Fernanda A. Correa
  • Everlayny F. Costalonga
  • Claudia C. Leite
  • Berenice B. Mendonca
  • Ivo J. P. Arnhold
  • Luciani R. S. Carvalho
  • Alexander A. L. Jorge
Article

Abstract

Background

Children initially diagnosed with isolated GH deficiency (IGHD) have a variable rate to progress to combined pituitary hormone deficiency (CPHD) during follow-up.

Objective

To evaluate the development of CPHD in a group of childhood-onset IGHD followed at a single tertiary center over a long period of time.

Patients and methods

We retrospectively analyzed data from 83 patients initially diagnosed as IGHD with a mean follow-up of 15.2 years. The Kaplan–Meier method and Cox regression analysis was used to estimate the temporal progression and to identify risk factors to development of CPHD over time.

Results

From 83 patients initially with IGHD, 37 (45 %) developed CPHD after a median time of follow up of 5.4 years (range from 1.2 to 21 years). LH and FSH deficiencies were the most common pituitary hormone (38 %) deficiencies developed followed by TSH (31 %), ACTH (12 %) and ADH deficiency (5 %). ADH deficiency (3.1 ± 1 years from GHD diagnosis) presented earlier and ACTH deficiency (9.3 ± 3.5 years) presented later during follow up compared to LH/FSH (8.3 ± 4 years) and TSH (7.5 ± 5.6 years) deficiencies. In a Cox regression model, pituitary stalk abnormalities was the strongest risk factor for the development of CPHD (hazard ratio of 3.28; p = 0.002).

Conclusion

Our study indicated a high frequency of development of CPHD in patients initially diagnosed as IGHD at childhood. Half of our patients with IGHD developed the second hormone deficiency after 5 years of diagnosis, reinforcing the need for lifelong monitoring of pituitary function in these patients.

Keywords

Isolated GH deficiency Follow-up studies Disease progression Combined pituitary hormone deficiency Kaplan–Meier estimate 

Notes

Acknowledgments

This work was supported by grants from Sao Paulo Research Foundation (FAPESP) (2013/03236-5) and from The National Council for Scientific and Technological Development (CNPq) (307922/2013-8 to I.J.P.A.; 305743/2011-2 to B.B.M.; 304678/2012-0 to A.A.L.J).

Conflict of interest

The authors declare there is no conflict of interest that could be perceived as influencing the impartiality of the research reported.

References

  1. 1.
    Growth Hormone Research Society (2000) Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society. J Clin Endocrinol Metab 85(11):3990–3993. doi: 10.1210/jcem.85.11.6984 Google Scholar
  2. 2.
    Schneider HJ, Aimaretti G, Kreitschmann-Andermahr I, Stalla GK, Ghigo E (2007) Hypopituitarism. Lancet 369(9571):1461–1470. doi: 10.1016/S0140-6736(07)60673-4 PubMedCrossRefGoogle Scholar
  3. 3.
    Shulman DI, Palmert MR, Kemp SF (2007) Adrenal insufficiency: still a cause of morbidity and death in childhood. Pediatrics 119(2):e484–e494. doi: 10.1542/peds.2006-1612 PubMedCrossRefGoogle Scholar
  4. 4.
    Bozzola M, Mengarda F, Sartirana P, Tato L, Chaussain JL (2000) Long-term follow-up evaluation of magnetic resonance imaging in the prognosis of permanent GH deficiency. Eur J Endocrinol 143(4):493–496. doi: 10.1530/eje.0.1430493 PubMedCrossRefGoogle Scholar
  5. 5.
    di Iorgi N, Secco A, Napoli F, Tinelli C, Calcagno A, Fratangeli N, Ambrosini L, Rossi A, Lorini R, Maghnie M (2007) Deterioration of growth hormone (GH) response and anterior pituitary function in young adults with childhood-onset GH deficiency and ectopic posterior pituitary: a two-year prospective follow-up study. J Clin Endocrinol Metab 92(10):3875–3884. doi: 10.1210/jc.2007-1081 PubMedCrossRefGoogle Scholar
  6. 6.
    Jagtap VS, Acharya SV, Sarathi V, Lila AR, Budyal SR, Kasaliwal R, Sankhe SS, Bandgar TR, Menon PS, Shah NS (2012) Ectopic posterior pituitary and stalk abnormality predicts severity and coexisting hormone deficiencies in patients with congenital growth hormone deficiency. Pituitary 15(2):243–250. doi: 10.1007/s11102-011-0321-4 PubMedCrossRefGoogle Scholar
  7. 7.
    Deal C, Hasselmann C, Pfaffle RW, Zimmermann AG, Quigley CA, Child CJ, Shavrikova EP, Cutler GB Jr, Blum WF (2013) Associations between pituitary imaging abnormalities and clinical and biochemical phenotypes in children with congenital growth hormone deficiency: data from an international observational study. Horm Res Paediatr 79(5):283–292. doi: 10.1159/000350829 PubMedCrossRefGoogle Scholar
  8. 8.
    Blum WF, Deal C, Zimmermann AG, Shavrikova EP, Child CJ, Quigley CA, Drop SL, Cutler GB Jr, Rosenfeld RG (2014) Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated GH deficiency. Eur J Endocrinol 170(1):13–21. doi: 10.1530/EJE-13-0643 PubMedCrossRefGoogle Scholar
  9. 9.
    Lange M, Feldt-Rasmussen U, Svendsen OL, Kastrup KW, Juul A, Muller J (2003) High risk of adrenal insufficiency in adults previously treated for idiopathic childhood onset growth hormone deficiency. J Clin Endocrinol Metab 88(12):5784–5789. doi: 10.1210/jc.2003-030529 PubMedCrossRefGoogle Scholar
  10. 10.
    Leger J, Danner S, Simon D, Garel C, Czernichow P (2005) Do all patients with childhood-onset growth hormone deficiency (GHD) and ectopic neurohypophysis have persistent GHD in adulthood? J Clin Endocrinol Metab 90(2):650–656. doi: 10.1210/jc.2004-1274 PubMedCrossRefGoogle Scholar
  11. 11.
    Tauber M, Chevrel J, Diene G, Moulin P, Jouret B, Oliver I, Pienkowski C, Sevely A (2005) Long-term evolution of endocrine disorders and effect of GH therapy in 35 patients with pituitary stalk interruption syndrome. Horm Res 64(6):266–273. doi: 10.1159/000089425 PubMedCrossRefGoogle Scholar
  12. 12.
    Fernandez-Rodriguez E, Quinteiro C, Barreiro J, Marazuela M, Pereiro I, Peino R, Cabezas-Agricola JM, Dominguez F, Casanueva FF, Bernabeu I (2011) Pituitary stalk dysgenesis-induced hypopituitarism in adult patients: prevalence, evolution of hormone dysfunction and genetic analysis. Neuroendocrinology 93(3):181–188. doi: 10.1159/000324087 PubMedCrossRefGoogle Scholar
  13. 13.
    Mullis PE, Robinson IC, Salemi S, Eble A, Besson A, Vuissoz JM, Deladoey J, Simon D, Czernichow P, Binder G (2005) Isolated autosomal dominant growth hormone deficiency: an evolving pituitary deficit? A multicenter follow-up study. J Clin Endocrinol Metab 90(4):2089–2096. doi: 10.1210/jc.2004-1280 PubMedCrossRefGoogle Scholar
  14. 14.
    Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, Mei Z, Curtin LR, Roche AF, Johnson CL (2000) CDC growth charts: United States. Adv Data (314):1–27. http://www.ncbi.nlm.nih.gov/pubmed/11183293
  15. 15.
    Silva EG, Slhessarenko N, Arnhold IJ, Batista MC, Estefan V, Osorio MG, Marui S, Mendonca BB (2003) GH values after clonidine stimulation measured by immunofluorometric assay in normal prepubertal children and GH-deficient patients. Horm Res 59(5):229–233. doi: 10.1159/000070222 PubMedCrossRefGoogle Scholar
  16. 16.
    Osorio MG, Marui S, Jorge AA, Latronico AC, Lo LS, Leite CC, Estefan V, Mendonca BB, Arnhold IJ (2002) Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRH-R, GH-1, or PROP-1 genes. J Clin Endocrinol Metab 87(11):5076–5084PubMedCrossRefGoogle Scholar
  17. 17.
    Carvalho LR, Woods KS, Mendonca BB, Marcal N, Zamparini AL, Stifani S, Brickman JM, Arnhold IJ, Dattani MT (2003) A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction. J Clin Invest 112(8):1192–1201. doi: 10.1172/JCI18589 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Rocha MG, Marchisotti FG, Osorio MG, Marui S, Carvalho LR, Jorge AA, Mendonca BB, Arnhold IJ (2008) High prevalence of pituitary magnetic resonance abnormalities and gene mutations in a cohort of Brazilian children with growth hormone deficiency and response to treatment. J Pediatr Endocrinol Metab 21(7):673–680PubMedCrossRefGoogle Scholar
  19. 19.
    Franca MM, Jorge AA, Carvalho LR, Costalonga EF, Vasques GA, Leite CC, Mendonca BB, Arnhold IJ (2010) Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly. J Clin Endocrinol Metab 95(11):E384–E391. doi: 10.1210/jc.2010-1050 PubMedCrossRefGoogle Scholar
  20. 20.
    Marui S, Trarbach EB, Boguszewski MC, Franca MM, Jorge AA, Inoue H, Nishi MY, de Lacerda Filho L, Aguiar-Oliveira MH, Mendonca BB, Arnhold IJ (2012) GH-releasing hormone receptor gene: a novel splice-disrupting mutation and study of founder effects. Horm Res Paediatr 78(3):165–172. doi: 10.1159/000342760
  21. 21.
    Makino S, Kawasaki D, Irimoto H, Tanimoto M (2002) Late onset of adrenocortical failure in GH deficiency with invisible pituitary stalk: a case report of a 48-year-old Japanese man and review of the literature. Endocr J 49(2):231–240PubMedCrossRefGoogle Scholar
  22. 22.
    Garel C, Leger J (2007) Contribution of magnetic resonance imaging in non-tumoral hypopituitarism in children. Horm Res 67(4):194–202. doi: 10.1159/000097755 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Aline P. Otto
    • 1
  • Marcela M. França
    • 1
  • Fernanda A. Correa
    • 1
  • Everlayny F. Costalonga
    • 1
  • Claudia C. Leite
    • 2
  • Berenice B. Mendonca
    • 1
  • Ivo J. P. Arnhold
    • 1
  • Luciani R. S. Carvalho
    • 1
  • Alexander A. L. Jorge
    • 3
  1. 1.Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42 do Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HC da FMUSP), Disciplina de EndocrinologiaUniversidade de Sao PauloSão PauloBrazil
  2. 2.Departamento de Radiologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HC da FMUSP)Universidade de Sao PauloSão PauloBrazil
  3. 3.Unidade de Endocrinologia Genetica, Laboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de MedicinaUniversidade de Sao PauloSão PauloBrazil

Personalised recommendations