Skip to main content

Advertisement

SpringerLink
Log in

Infectious diseases and immunological responses in adult subjects with lifetime untreated, congenital GH deficiency

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Growth hormone is important for the development and function of the immune system, but there is controversy on whether growth hormone deficiency is associated to immune disorders. A model of isolated growth hormone deficiency may clarify if the lack of growth hormone is associated with increased susceptibility to infections, or with an altered responsiveness of the immune system. We have studied the frequency of infectious diseases and the immune function in adults with congenital, untreated isolated growth hormone deficiency. In a cross-sectional study, 35 adults with isolated growth hormone deficiency due to a homozygous mutation in the growth hormone releasing hormone receptor gene and 31 controls were submitted to a clinical questionnaire, physical examination serology for tripanosomiasis, leishmaniasis, HIV, tetanus, hepatitis B and C, and serum total immunoglobulin G, M, E and A measurement. The immune response was evaluated in a subset of these subjects by skin tests and response to vaccination for hepatitis B, tetanus, and bacillus Calmette-Guérin. There was no difference between the groups in history of infectious diseases and baseline serology. Isolated growth hormone deficiency subjects had lower total IgG, but within normal range. There was no difference in the response to any of the vaccinations or in the positivity to protein Purified Derived, streptokinase or candidin. Adult untreated isolated growth hormone deficiency does not cause an increased frequency of infectious diseases, and does not alter serologic tests, but is associated with lower total IgG levels, without detectable clinical impact.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. D. Le Roith, C. Bondy, S. Yakar, J.-L. Liu, A. Butler, The somatomedin hypothesis. Endocr. Rev. 22, 53–74 (2001)

    Article  PubMed  Google Scholar 

  2. E. Linehan, D.C. Fitzgerald, Ageing and the immune system: focus on macrophages. Eur. J. Microbiol. Immunol. 5, 14–24 (2015)

    Article  Google Scholar 

  3. P. Smith, The effect of hypophysectomy upon the involution of the thymus in the rat. Anat. Rec. 47, 119–129 (1930)

    Article  Google Scholar 

  4. C.J. Auernhammer, C.J. Strasburger, Effects of growth hormone and insulin-like growth factor I on the immune system. Eur. J. Endocrinol. 133, 635–645 (1995)

    Article  CAS  PubMed  Google Scholar 

  5. R. Clark, The somatogenic hormones and insulin-like growth factor I: stimulators of lymphopoiesis and immune function. Endocr. Rev. 18, 157–179 (1997)

    Article  PubMed  Google Scholar 

  6. Y. Yang, L. Guo, L. Ma, X. Liu, Expression of growth hormone and insulin-like growth factor in the immune system of children. Horm. Metab. Res. 31, 380–384 (1999)

    Article  CAS  PubMed  Google Scholar 

  7. D. Oberlin, C. Fellbaum, E. Eppler, Insulin-like growth factor I messenger RNA and protein are expressed in the human lymph node and distinctly confined to subtypes of macrophages, antigen-presenting cells, lymphocytes and endothelial cells. Immunology 128, 342–350 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. C.J. Auernhammer, C. Fottner, D. Engelhardt, M. Bidlingmaier, C.J. Strasburger, M.M. Weber, Differential regulation of insulin-like growth factor-(IGF)I and IGF-binding protein (IGFBP) secretion by human peripheral blood mononuclear cells. Horm. Res. 57, 15–21 (2002)

    Article  CAS  PubMed  Google Scholar 

  9. N. Hattori, T. Saito, T. Yagyu, B.H. Jiang, K. Kitagawa, C. Inagaki, GH, GH receptor, GH secretagogue receptor, and ghrelin expression in human T cells, B cells, and neutrophils. J. Clin. Endocr. Metab. 86, 4284–4291 (2001)

    Article  CAS  PubMed  Google Scholar 

  10. N. Hattori, Expression, regulation and biological actions of growth hormone (GH) and ghrelin in the immune system. Growth Horm. IGF Res. 19, 187–197 (2009)

    Article  CAS  PubMed  Google Scholar 

  11. K. Van Bilsen, G.J. Driessen, R.A. Paus, E.V. Van de Vosse, K. Van Lom, M.C. Van Zelm, K.H. Lam, N.G. Hartwig, G.S. Baarsma, M. Van de Burg, P.M. Van Hagen, Low level IGF-1 and common variable immune deficiency: an unusual combination. Neth. J. Med. 66, 368–372 (2008)

    PubMed  Google Scholar 

  12. E.M. Kofoed, V. Hwa, B. Little, K.A. Woods, C.K. Buckway, J. Tsubaki, K.L. Pratt, L. Bezrodnik, H. Jasper, A. Tepper, J. Heinrich, R.G. Rosenfeld, Growth-hormone insensitivity (GHI) associated with a STAT-5b mutation. N. Engl. J. Med. 349, 1139–1147 (2003)

    Article  CAS  PubMed  Google Scholar 

  13. J.L. Casanova, S.M. Holland, L.D. Notarangelo, Inborn errors of human JAKs and STATs. Immunity 36, 515–528 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. R.C. Scalco, P.N. Pugliese-Pires, A.A.L. Jorge, STAT5B deficiency: a new growth hormone insensitivity syndrome associated to immunological dysfunction. Arq. Bras. Endocrinol. Metab. 57, 333–338 (2013)

    Article  Google Scholar 

  15. V. Hwa, STAT5B deficiency: impacts on human growth and immunity. Growth Horm. IGF Res. 28, 16–20 (2016). doi:10.1016/j.ghir.2015.12.006

    Article  CAS  PubMed  Google Scholar 

  16. T.A. Fleisher, R.M. White, S. Broder, S.P. Nissley, R.M. Blaese, J.J. Mulvihill, G. Olive, T.A. Waldmann, X-linked hypogammaglobulinemia and isolated growth hormone deficiency. N. Engl. J. Med. 302, 1429–1434 (1980)

    Article  CAS  PubMed  Google Scholar 

  17. D.M. Stewart, L. Tian, L.D. Notarangelo, D.L. Nelson, X-linked hypogammaglobinemia and isolated growth hormone deficiency: an update. Immunol. Res. 40, 262–270 (2008)

    Article  CAS  PubMed  Google Scholar 

  18. R. Shohreh, C.A. Pardo, F. Guaraldi, A.V. Schally, R. Salvatori, GH, but not GHRH, plays a role in the development of experimental autoimmune encephalomyelitis. Endocrinology 152, 3803–3810 (2011)

    Article  CAS  PubMed  Google Scholar 

  19. R. Salvatori, C.Y. Hayashida, M.H. Aguiar-Oliveira, J.A. Phillips III, A.H. Souza, R.G. Gondo, S.P.A. Toledo, M.M. Conceição, M. Prince, H.D. Maheshwari, G. Baumann, M.A. Levine, Familial isolated growth hormone deficiency due to a novel mutation in the growth hormone releasing hormone receptor. J. Clin. Endocr. Metab. 84, 917–923 (1999)

    CAS  PubMed  Google Scholar 

  20. M.H. Aguiar-Oliveira, F.T. Oliveira, R.M.C. Pereira, C.R.P. Oliveira, A. Blackford, E.H.O. Valença, E.G. Santos, M.B. Gois-Junior, R.A. Meneguz-Moreno, V.P. Araujo, L.A. Oliveira-Neto, R.P. Almeida, M.A. Santos, N.T. Farias, D.C.R. Silveira, G.W. Cabral, F.R. Calazans, J.D. Seabra, T.F. Lopes, E.O. Rodrigues, L.A. Porto, I.P. Oliveira, E.V. Melo, M. Martari, R. Salvatori, Longevity in untreated congenital growth hormone deficiency due to a homozygous mutation in the ghrh receptor gene. J. Clin. Endocr. Metab. 95, 714–721 (2010)

    Article  CAS  PubMed  Google Scholar 

  21. A.R. Ahmed, D.A. Blose, Delayed-type hypersensitivity skin testing. Arch. Dermatol. 119, 934–945 (1983)

    Article  CAS  PubMed  Google Scholar 

  22. Ministério da Saúde, Secretaria de Vigilância em Saúde, Departamento de Vigilância das Doenças Transmissíveis (Brasil). técnicas de aplicação e leitura da prova tuberculínica. (Ministério da Saúde, Distrito Federal, Brasília), 2014)

    Google Scholar 

  23. A.Z. Bluming, J.L. Ziegler, L. Fass, R.B. Herberman, Delayed cutaneous sensitivity reactions to autologous Burkitt lymphoma protein extract. Results of a prospective two and a half year study. Clin. Exp. Immunol. 9, 713–719 (1971)

    CAS  PubMed  PubMed Central  Google Scholar 

  24. O. Kecha, F. Brilot, H. Martens, N. Franchimont, C. Renard, R. Greimers, M.P. Defresne, R. Winkler, V. Geenen, Involvement of insulin-like growth factors in early T cell development: a study using fetal thymic organ cultures. Endocrinology 141, 1209–1217 (2000)

    CAS  PubMed  Google Scholar 

  25. T. Taguchi, H. Takenouchi, J. Matsui, W.R. Tang, M. Itagaki, Y. Shiozawa, K. Suzuki, S. Sakaguchi, Y.U. Ktagiri, T. Takahashi, H. Okita, J. Fujimoto, N. Kiyokawa, Involvement of insulin-like growth factor-I and insulin-like growth factor binding proteins in pro-B-cell development. Exp. Hematol. 34, 508–518 (2006)

    Article  CAS  PubMed  Google Scholar 

  26. A. Mukherjee, M. Helbert, W.D.J. Ryder, R. Borrow, J.R.E. Davis, S.M. Shalet, Failure of antibody response to polysaccharide antigen in treated panhypopituitary adults. Clin. Exp. Immunol. 156, 271–277 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. G.L. Spadoni, P. Rossi, W. Ragno, E. Galli, S. Cianfarani, C. Galasso, B. Boscherini, Immune function in growth hormone-deficient children treated with biosynthetic growth hormone. Acta Paediatr. Scand. 80, 75–79 (1991)

    Article  CAS  PubMed  Google Scholar 

  28. K. Dorshkind, N.D. Horseman, The roles of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormones in lymphocyte development and function: insights from genetic models of hormone and hormone receptor deficiency. Endocr. Rev. 21, 292–312 (2000)

    CAS  PubMed  Google Scholar 

  29. L. Matera, Endocrine, paracrine and autocrine actions of prolactin on immune cells. Life Sci. 59, 599–614 (1996)

    Article  CAS  PubMed  Google Scholar 

  30. A. De Bellis, A. Bizzarro, R. Pivonello, G. Lombardi, A. Bellastella, Prolactin and autoimmunity. Pituitary 8, 25–30 (2005)

    Article  CAS  PubMed  Google Scholar 

  31. V. Abassi, J.A. Bellanti, Humoral and cell-mediated immunity in growth hormone-deficient children: effect of therapy with human growth hormone. Pediatr. Res. 19, 299–301 (1985)

    Article  Google Scholar 

  32. M.H. Aguiar-Oliveira, M.S. Gill, E.S.A. Barretto, M.R.S. Alcântara, F. Miraki-Moud, C.A. Menezes, A.H.O. Souza, C.E. Martinelli, F.A. Pereira, R. Salvatori, M.A. Levine, S.M. Shalet, C. Camacho-Hubner, P.E. Clayton, 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. Endocr. Metab. 84, 4118–4126 (1999)

    CAS  PubMed  Google Scholar 

  33. R. Salvatori, M.G. Serpa, G. Parmigiani, A.V.O. Britto, J.L.M. Oliveira, C.R.P. Oliveira, C.M. Prado, C.T. Farias, J.C. Almeida, T.A.R. Vicente, M.H. Aguiar-Oliveira, GH response to hypoglycemia and clonidine in the GH-releasing hormone resistance syndrome. J. Endocrinol. Invest. 29, 805–808 (2006)

    Article  PubMed  Google Scholar 

  34. M. Menezes, R. Salvatori, L.D. Melo, I.E.S. Rocha, C.R.P. Oliveira, R.M.C. Pereira, A.H.O. Souza, E.H.O. Valença, E.V. Melo, V.C. Campos, F.O. Costa, M.H. Aguiar-Oliveira, Prolactin and sex steroids levels in congenital lifetime isolated GH deficiency. Endocrine 44, 207–211 (2013)

    Article  CAS  PubMed  Google Scholar 

  35. K.W. Kelley, D.A. Weigent, R. Kooijman, Protein hormones and immunity. Brain Behav. Immun. 21, 384–392 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Y.K. Fu, S. Arkins, G. Fuh, B.C. Cunningham, J.A. Wells, S. Fong, M.J. Cronin, R. Dantzer, K.W. Kelley, Growth hormone augments superoxide anion secretion of human neutrophils by binding to the prolactin receptor. J. Clin. Invest. 89, 451–457 (1992)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. P.R. Ogershok, M.B. Hogan, J.E. Welch, W.T. Corder, N.W. Wilson, Spectrum of illness in pediatric common variable immunodeficiency. Ann. Allergy Asthma Immunol. 97, 653–656 (2006)

    Article  PubMed  Google Scholar 

  38. Z. Laron, Lifespan and Mortality of patients with Laron Syndrome. In: Z. Laron, J.J. Kopchick, (eds) Laron Syndrome from Man to Mouse: Lessons from Clinical Experimental Experience, pp. 341–342. Springer-Verlag, Berlin Heidelberg (2011)

  39. C. Prakash, R. Bhatia, S. Kumari, T. Verghese, K. Datta, Response to hepatitis B vaccination in high-risk population. J. Commun. Dis. 32, 17–21 (2000)

    CAS  PubMed  Google Scholar 

  40. D. Lithgow, C. Cole, A reinvestigation of seroconversion rates in hepatits b–vaccinated individuals. Biol. Res. Nurs. 17(1), 49–54 (2014). doi:10.1177/1099800414524619

    Google Scholar 

  41. J.N. Zuckerman, Protective efficacy, immunotherapeutic potential, and safety of hepatitis b vaccines. J. Med. Virol. 78, 169–177 (2006)

    Article  CAS  PubMed  Google Scholar 

  42. C.-F. Jan, K.-C. Huang, Y.-C. Chien, D.E. Greydanus, H.D. Davies, T.-Y. Chiu, L.-M. Huang, C.-J. Chen, D.-S. Chen, Determination of immune memory to hepatitis b vaccination through early booster response in college students. Hepatology 51, 1547–1554 (2010)

    Article  PubMed  Google Scholar 

  43. R.J. Thomas, G.J. Fletcher, H. Kirupakaran, M.P. Chacko, S. Thenmozhi, C.E. Eapen, G. Chandy, P. Abraham, Prevalence of non-responsiveness to an indigenous recombinant hepatitis B vaccine: a study among South Indian health care workers in a tertiary hospital. Indian J. Med. Microbiol. 33, 32–36 (2015)

    Article  PubMed  Google Scholar 

  44. J. Guevara-Aguirre, M. Guevara-Aguirre, J. Saavedra, G. Bernstein, Low serum levels of IGF-1, BP3 and ALS are associated to severe short stature, obesity premature aging, increased cardiovascular mortality and absence of cancer in the Ecuadorian cohort of Laron syndrome subjects. Hormone Res. 68(Suppl. 1), 175 (2007)

    Google Scholar 

  45. R.G. Rosenfeld, L. Arlan, J. Guevara-Aguirre, Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr. Rev. 15, 369–390 (1994)

    Article  CAS  PubMed  Google Scholar 

  46. M. Kanariou, E. Petridou, M. Liatsis, K. Revinthi, K. Mandalenaki-Lambrou, D. Trichopoulos, Age patterns of immunoglobulins G, A & M in healthy children and the influence of breast feeding and vaccination status. Pediatr. Allergy Immunol. 6, 24–29 (1995)

    Article  CAS  PubMed  Google Scholar 

  47. M. Menezes, R. Salvatori, C.R.P. Oliveira, R.M.C. Pereira, A.H.O. Souza, L.M.A. Nobrega, E. Cruz, A.C. do, M. Menezes, E.O. Alves, M.H. Aguiar-Oliveira, Climacteric in untreated isolated growth hormone deficiency. Menopause 15, 743–747 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  48. C.R.P. Oliveira, R. Salvatori, L.M.A. Nóbrega, E.O.M. Carvalho, M. Menezes, C.T. Farias, A.V.O. Britto, R.M.C. Pereira, M.H. Aguiar-Oliveira, 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. Clin. Endocrinol. (Oxf.) 69, 153–158 (2008)

    Article  CAS  Google Scholar 

  49. M. Alba, D. Fintini, R. Salvatori, Effects of recombinant mouse growth hormone treatment on growth and body composition in GHRH knock out mice. Growth Horm. IGF Res. 15, 275–282 (2005)

    Article  CAS  PubMed  Google Scholar 

  50. L. Zhao, L. Liu, B. Guo, B. Zhu, Regulation of adaptive immune responses by guiding cell movements in the spleen. Front Microbiol. 6, 645–650 (2015)

    PubMed  PubMed Central  Google Scholar 

  51. R. Lindsay, M. Feldkamp, D. Harris, J. Robertson, M. Rallison, Utah growth study: growth standards and the prevalence of growth hormone deficiency. J. Pediatr. 125, 29–35 (1994)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the Associação do Crescimento Físico e Humano de Itabaianinha, for assistance.

Funding

This work was supported by Foundation Research and Technological Innovation of Sergipe-FAPITEC/SE/FUNTEC/CNPq No. 12/2009 (to A.R.J.).

Author information

Authors and Affiliations

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

    Viviane C. Campos, Enaldo V. de Melo, Ana C. S. Nascimento & Manuel H. Aguiar-Oliveira

  2. Federal University of Sergipe, Division of Immunology and Molecular Biology Laboratory, Aracaju, Sergipe, 49060–100, Brazil

    Mônica R. Barrios, Roque Pacheco de Almeida & Amélia Ribeiro de Jesus

  3. Division of Endocrinology, Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Roberto Salvatori

Authors
  1. Viviane C. Campos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mônica R. Barrios
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roberto Salvatori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roque Pacheco de Almeida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Enaldo V. de Melo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ana C. S. Nascimento
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Amélia Ribeiro de Jesus
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manuel H. Aguiar-Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roberto Salvatori.

Ethics declarations

Conflict of interest

R.S. serves in the advisory board of Novo Nordisk and Pfizer.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Campos, V.C., Barrios, M.R., Salvatori, R. et al. Infectious diseases and immunological responses in adult subjects with lifetime untreated, congenital GH deficiency. Endocrine 54, 182–190 (2016). https://doi.org/10.1007/s12020-016-1061-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-016-1061-z

Keywords

Search

Navigation