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Meta-analysis of metabolic changes in children with idiopathic growth hormone deficiency after recombinant human growth hormone replacement therapy

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Abstract

Purposes

We aimed to assess the effects of recombinant human growth hormone (rhGH) replacement therapy on metabolic changes by synthesizing data from clinical trials involving children with idiopathic growth hormone deficiency (IGHD).

Methods

Two investigators independently completed literature search, quality assessment, and data extraction. Effect-size estimates are expressed as weighted mean difference (WMD) with 95% confidence interval (CI).

Results

A total of 16 clinical trials involving 1319 children were eligible for analysis. Overall analyses showed that total cholesterol was significantly decreased after rhGH replacement therapy (WMD: −0.20 mmol/l; 95% CI: −0.30 to −0.10; p < 0.001), and high-density lipoprotein was significantly increased (WMD: 0.29 mmol/l; 95% CI: 0.24 to 0.33; p < 0.001). Marginal increase was noted for low-density lipoprotein (WMD: −0.22 mmol/l; 95% CI: −0.47 to 0.22; p = 0.092). Subsidiary and meta-regression analyses revealed that length of intervention and sample size were possible causes of heterogeneity. There was a low probability of publication bias.

Conclusions

Our findings indicate an obviously favorable role of rhGH replacement therapy in lipid metabolism in children with IGHD, and this role might be dependent on length of intervention.

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References

  1. X.L. Bao, Y.F. Shi, Y.C. Du, R. Liu, J.Y. Deng, S.M. Gao, Prevalence of growth hormone deficiency of children in Beijing. Chin. Med. J. 105(5), 401–405 (1992)

    CAS  PubMed  Google Scholar 

  2. A. Chinoy, P.G. Murray, Diagnosis of growth hormone deficiency in the paediatric and transitional age. Best Pract. Res. Clin. Endocrinol. Metab. 30(6), 737–747 (2016). https://doi.org/10.1016/j.beem.2016.11.002

    Article  CAS  PubMed  Google Scholar 

  3. R.C. Lindsey, S. Mohan, Skeletal effects of growth hormone and insulin-like growth factor-I therapy. Mol. Cell Endocrinol. 432, 44–55 (2016). https://doi.org/10.1016/j.mce.2015.09.017

    Article  CAS  PubMed  Google Scholar 

  4. D. Capalbo, A. Esposito, R. Di Mase, F. Barbieri, G. Parenti, P. Vajro, C. Pignata, M. Salerno, Update on early cardiovascular and metabolic risk factors in children and adolescents affected with growth hormone deficiency. Minerva Endocrinol. 37(4), 379–389 (2012)

    CAS  PubMed  Google Scholar 

  5. D. Capalbo, F. Barbieri, N. Improda, F. Giallauria, E. Di Pietro, A. Rapacciuolo, R. Di Mase, C. Vigorito, M. Salerno, Growth hormone improves cardiopulmonary capacity and body composition in children with growth hormone deficiency. J. Clin. Endocrinol. Metab. 102(11), 4080–4088 (2017). https://doi.org/10.1210/jc.2017-00871

    Article  PubMed  Google Scholar 

  6. J.H. Quitmann, A.C. Rohenkohl, U. Kammerer, C. Schofl, M. Bullinger, H.G. Dorr, [Quality of life of young adults after a growth hormone therapy with childhood onset]. Dtsch. Med. Wochenschr. 139(46), 2335–2338 (2014). https://doi.org/10.1055/s-0034-1387314

    Article  CAS  PubMed  Google Scholar 

  7. R. Lanes, Cardiovascular risk in growth hormone deficiency: beneficial effects of growth hormone replacement therapy. Endocrinol. Metab. Clin. North. Am. 45(2), 405–418 (2016). https://doi.org/10.1016/j.ecl.2016.01.005

    Article  PubMed  Google Scholar 

  8. G. Saggese, M.B. Ranke, P. Saenger, R.G. Rosenfeld, T. Tanaka, J.L. Chaussain, M.O. Savage, Diagnosis and treatment of growth hormone deficiency in children and adolescents: towards a consensus. Ten years after the Availability of Recombinant Human Growth Hormone Workshop held in Pisa, Italy, 27-28 March 1998. Horm. Res. 50(6), 320–340 (1998). https://doi.org/10.1159/000023298

    Article  CAS  PubMed  Google Scholar 

  9. C. De Leonibus, S. De Marco, A. Stevens, P. Clayton, F. Chiarelli, A. Mohn, Growth hormone deficiency in prepubertal children: predictive markers of cardiovascular disease. Horm. Res. Paediatr. 85(6), 363–371 (2016). https://doi.org/10.1159/000444143

    Article  CAS  PubMed  Google Scholar 

  10. F. Prodam, P. Marzullo, G. Aimaretti, Growth hormone deficiency in children. Best Pract. Res. Clin. Endocrinol. Metab. 30(6), 677–678 (2016). https://doi.org/10.1016/j.beem.2016.12.001

    Article  PubMed  Google Scholar 

  11. S.R. Daniels, F.R. Greer; Committee on Nutrition, Lipid screening and cardiovascular health in childhood. Pediatrics 122(1), 198–208 (2008). https://doi.org/10.1542/peds.2008-1349

    Article  PubMed  Google Scholar 

  12. A. Pires, C. Sena, R. Seica, Dyslipidemia and cardiovascular changes in children. Curr. Opin. Cardiol. 31(1), 95–100 (2016). https://doi.org/10.1097/HCO.0000000000000249

    Article  PubMed  Google Scholar 

  13. J. Rothermel, C. Knop, N. Lass, C. Toschke, R. Wunsch, T. Reinehr, Carotid intima-media thickness in children treated with growth hormone: a follow-up study over three years. Horm. Res. Paediatr. 87(2), 73–80 (2017). https://doi.org/10.1159/000450643

    Article  CAS  PubMed  Google Scholar 

  14. M. Chen, D. Gan, Y. Luo, S. Rampersad, L. Xu, S. Yang, N. Li, H. Li, Effect of recombinant human growth hormone therapy on blood lipid and carotid intima-media thickness in children with growth hormone deficiency. Pediatr. Res. 83(5), 954–960 (2018). https://doi.org/10.1038/pr.2017.271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. M. Crowther, W. Lim, M.A. Crowther, Systematic review and meta-analysis methodology. Blood 116(17), 3140–3146 (2010). https://doi.org/10.1182/blood-2010-05-280883

    Article  CAS  PubMed  Google Scholar 

  16. K. Slim, E. Nini, D. Forestier, F. Kwiatkowski, Y. Panis, J. Chipponi, Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J. Surg. 73(9), 712–716 (2003)

    Article  Google Scholar 

  17. S. Duval, R. Tweedie, Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56(2), 455–463 (2000). https://doi.org/10.1111/j.0006-341x.2000.00455.x

    Article  CAS  PubMed  Google Scholar 

  18. W. Lu, S. Shen, X. Luo, C. Gong, X. Gu, Y. Li, M. Du, R. Jin, Q. Zhou, W. Wang, Comparative evaluation of short-term biomarker response to treatment for growth hormone deficiency in Chinese children with growth hormone deficiency born small for or appropriate for gestational age: a randomized phase IV open-label study. Ther. Adv. Endocrinol. Metab. 4(2), 41–49 (2013). https://doi.org/10.1177/2042018813484051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. A. Ciresi, F. Ciccio, S. Radellini, V. Guarnotta, A.M. Calcaterra, C. Giordano, More favorable metabolic impact of three-times-weekly versus daily growth hormone treatment in naive GH-deficient children. Int. J. Endocrinol. 2017, 8469680 (2017). https://doi.org/10.1155/2017/8469680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. X. Luo, L. Hou, L. Liang, G. Dong, S. Shen, Z. Zhao, C.X. Gong, Y. Li, M.L. Du, Z. Su, H. Du, C. Yan, Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies. Eur. J. Endocrinol. 177(2), 195–205 (2017). https://doi.org/10.1530/EJE-16-0905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. C. Foster, A. Burton, J. Scholl, M.L. Scott, V. Gunter, K. McCormick, Lipid patterns in treated growth hormone deficient children vs. short stature controls. J. Pediatr. Endocrinol. Metab. 27(9–10), 909–914 (2014). https://doi.org/10.1515/jpem-2013-0488

    Article  CAS  PubMed  Google Scholar 

  22. E.O. Reiter, K.M. Attie, T. Moshang Jr., B.L. Silverman, S.F. Kemp, R.B. Neuwirth, K.M. Ford, P. Saenger, Genentech IAICSG, A multicenter study of the efficacy and safety of sustained release GH in the treatment of naive pediatric patients with GH deficiency. J. Clin. Endocrinol. Metab. 86(10), 4700–4706 (2001). https://doi.org/10.1210/jcem.86.10.7932

    Article  CAS  PubMed  Google Scholar 

  23. N. Mauras, K.M. Attie, E.O. Reiter, P. Saenger, J. Baptista, High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. Genentech, Inc., Cooperative Study Group. J. Clin. Endocrinol. Metab. 85(10), 3653–3660 (2000). https://doi.org/10.1210/jcem.85.10.6906

    Article  CAS  PubMed  Google Scholar 

  24. P. Cohen, J. Germak, A.D. Rogol, W. Weng, A.M. Kappelgaard, R.G. Rosenfeld; American Norditropin Study Group, Variable degree of growth hormone (GH) and insulin-like growth factor (IGF) sensitivity in children with idiopathic short stature compared with GH-deficient patients: evidence from an IGF-based dosing study of short children. J. Clin. Endocrinol. Metab. 95(5), 2089–2098 (2010). https://doi.org/10.1210/jc.2009-2139

    Article  CAS  PubMed  Google Scholar 

  25. Y. Xue, Y. Gao, S. Wang, P. Wang, An examination of the effects of different doses of recombinant human growth hormone on children with growth hormone deficiency. Exp. Ther. Med. 11(5), 1647–1652 (2016). https://doi.org/10.3892/etm.2016.3091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. A. Ciresi, S. Radellini, V. Guarnotta, M.G. Mineo, C. Giordano, The metabolic outcomes of growth hormone treatment in children are gender specific. Endocr. Connect. 7(7), 879–887 (2018). https://doi.org/10.1530/EC-18-0135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. F. Peter, M. Bidlingmaier, C. Savoy, H.J. Ji, P.H. Saenger, Three-year efficacy and safety of LB03002, a once-weekly sustained-release growth hormone (GH) preparation, in prepubertal children with GH deficiency (GHD). J. Clin. Endocrinol. Metab. 97(2), 400–407 (2012). https://doi.org/10.1210/jc.2011-2234

    Article  CAS  PubMed  Google Scholar 

  28. G. Radetti, F. Buzi, C. Paganini, C. Martelli, S. Adami, A four year dose-response study of recombinant human growth hormone treatment of growth hormone deficient children: effects on growth, bone growth and bone mineralization. Eur. J. Endocrinol. 142(1), 42–46 (2000). https://doi.org/10.1530/eje.0.1420042

    Article  CAS  PubMed  Google Scholar 

  29. W.V. Moore, H.J. Nguyen, G.B. Kletter, B.S. Miller, D. Rogers, D. Ng, J.A. Moore, E. Humphriss, J.L. Cleland, G.M. Bright, A. Randomized Safety and Efficacy Study of Somavaratan (VRS-317), a long-acting rhGH, in pediatric growth hormone deficiency. J. Clin. Endocrinol. Metab. 101(3), 1091–1097 (2016). https://doi.org/10.1210/jc.2015-3279

    Article  CAS  PubMed  Google Scholar 

  30. M. Rudling, G. Norstedt, H. Olivecrona, E. Reihner, J.A. Gustafsson, B. Angelin, Importance of growth hormone for the induction of hepatic low density lipoprotein receptors. Proc. Natl Acad. Sci. USA 89(15), 6983–6987 (1992). https://doi.org/10.1073/pnas.89.15.6983

    Article  CAS  PubMed  Google Scholar 

  31. H. Olivecrona, S. Ericsson, B. Angelin, Growth hormone treatment does not alter biliary lipid metabolism in healthy adult men. J. Clin. Endocrinol. Metab. 80(4), 1113–1117 (1995). https://doi.org/10.1210/jcem.80.4.7714078

    Article  CAS  PubMed  Google Scholar 

  32. S. Eden, O. Wiklund, J. Oscarsson, T. Rosen, B.A. Bengtsson, Growth hormone treatment of growth hormone-deficient adults results in a marked increase in Lp(a) and HDL cholesterol concentrations. Arterioscler. Thromb. 13(2), 296–301 (1993). https://doi.org/10.1161/01.atv.13.2.296

    Article  CAS  PubMed  Google Scholar 

  33. S. Lind, M. Rudling, S. Ericsson, H. Olivecrona, M. Eriksson, B. Borgstrom, G. Eggertsen, L. Berglund, B. Angelin, Growth hormone induces low-density lipoprotein clearance but not bile acid synthesis in humans. Arterioscler. Thromb. Vasc. Biol. 24(2), 349–356 (2004). https://doi.org/10.1161/01.ATV.0000110657.67317.90

    Article  CAS  PubMed  Google Scholar 

  34. A.M. Mahmoud, R.J. Hernandez Bautista, M.A. Sandhu, O.E. Hussein, Beneficial effects of citrus flavonoids on cardiovascular and metabolic health. Oxid. Med. Cell. Longev. 2019, 5484138 (2019). https://doi.org/10.1155/2019/5484138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. O. Guardamagna, F. Abello, G. Anfossi, M. Pirro, Lipoprotein(a) and family history of cardiovascular disease in children with familial dyslipidemias. J. Pediatr. 159(2), 314–319 (2011). https://doi.org/10.1016/j.jpeds.2011.01.038

    Article  CAS  PubMed  Google Scholar 

  36. Z. Quijada, M. Paoli, Y. Zerpa, N. Camacho, R. Cichetti, V. Villarroel, G. Arata-Bellabarba, R. Lanes, The triglyceride/HDL-cholesterol ratio as a marker of cardiovascular risk in obese children; association with traditional and emergent risk factors. Pediatr. Diabetes 9(5), 464–471 (2008). https://doi.org/10.1111/j.1399-5448.2008.00406.x

    Article  CAS  PubMed  Google Scholar 

  37. D. Capalbo, A. Lo Vecchio, V. Farina, L. Spinelli, A. Palladino, C. Tiano, T. Lettiero, G. Lombardi, A. Colao, M. Salerno, Subtle alterations of cardiac performance in children with growth hormone deficiency: results of a two-year prospective, case-control study. J. Clin. Endocrinol. Metab. 94(9), 3347–3355 (2009). https://doi.org/10.1210/jc.2008-2639

    Article  CAS  PubMed  Google Scholar 

  38. E. Gomez-Guzman, M.D. Canete, R. Valle-Martos, R. Canete, M. Valle, L. Jimenez-Reina, J. Caballero-Villarraso, Short-term evaluation of left ventricular mass and function in children with growth hormone deficiency after replacement treatment. Front. Pediatr. 6, 174 (2018). https://doi.org/10.3389/fped.2018.00174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. C. Azzarito, L. Boiardi, M. Zini, A. Agosti, M. Biacchessi, R. Biagi, I. Portioli, Short and long-term effects of growth hormone treatment on lipid, lipoprotein, and apolipoprotein levels in short normal children. Horm. Metab. Res. 26(9), 432–435 (1994). https://doi.org/10.1055/s-2007-1001724

    Article  CAS  PubMed  Google Scholar 

  40. K.A. Metwalley, H.S. Farghaly, H.A. Abd El-Hafeez, Evaluation of left ventricular mass and function, lipid profile, and insulin resistance in Egyptian children with growth hormone deficiency: a single-center prospective case-control study. Indian J. Endocrinol. Metab. 17(5), 876–882 (2013). https://doi.org/10.4103/2230-8210.117234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. C.J. Child, A.G. Zimmermann, R.S. Scott, G.B. Cutler Jr., T. Battelino, W.F. Blum; GeNe SISIAB, Prevalence and incidence of diabetes mellitus in GH-treated children and adolescents: analysis from the GeNeSIS observational research program. J. Clin. Endocrinol. Metab. 96(6), E1025–E1034 (2011). https://doi.org/10.1210/jc.2010-3023

    Article  PubMed  Google Scholar 

  42. F. Baronio, L. Mazzanti, Y. Girtler, F. Tamburrino, A. Fazzi, F. Lupi, S. Longhi, G. Radetti, The influence of growth hormone treatment on glucose homeostasis in growthhormone-deficient children: a six-year follow-up study. Horm. Res. Paediatr. 86(3), 196–200 (2016). https://doi.org/10.1159/000448841

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Graduate School, Beijing University of Chinese Medicine, Beijing, China

    Yuan Yuan & Bo Zhou

  2. International Medical Services, China–Japan Friendship Hospital, Beijing, China

    Yuan Yuan, Bo Zhou & Zhixin Zhang

  3. Department of Pediatrics, China–Japan Friendship Hospital, Beijing, China

    Yuan Yuan, Shufang Liu, Yunfeng Wang & Kundi Wang

  4. Institute of Clinical Medical Sciences, China–Japan Friendship Hospital, Beijing, China

    Wenquan Niu

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Contributions

Conceived and designed the experiments: Y.Y., Z.Z., and W.N. Performed the experiments: Y.Y., B.Z., and W.N. Analyzed the data: Y.Y. and W.N. Contributed materials/analysis tools: Y.Y., B.Z., S.L., and Z.Z. Wrote the paper: Y.Y. and W.N. All authors read and approved the final manuscript prior to submission.

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Correspondence to Zhixin Zhang or Wenquan Niu.

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The authors declare that they have no conflict of interest.

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Ethical approval is waived for the present study because this is a meta-analysis based on the results of individual studies that had been reviewed and approved by localized ethics committees.

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Yuan, Y., Zhou, B., Liu, S. et al. Meta-analysis of metabolic changes in children with idiopathic growth hormone deficiency after recombinant human growth hormone replacement therapy. Endocrine 71, 35–46 (2021). https://doi.org/10.1007/s12020-020-02435-w

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