Russian national consensus. Diagnostics and treatment of hypopituitarism in children and adolescences

The materials of the National Consensus reflect the modern domestic and international experience on this issue.

Before conducting a specialized endocrinological examination of a short child, all other causes of short stature should be excluded: severe somatic diseases in a state of decompensation that can affect growth velocity, congenital systemic skeletal diseases, syndromic short stature (all girls with growth retardation require a mandatory study of karyotype, depending on the presence or absence of phenotypic signs of Turner syndrome), endocrine diseases in decompensation.

A specialized examination of the state of GH-IGF-I axis is carried out when the proportionally folded child has pronounced short stature: if the child’s height is < –2.0 SDS, if the difference between the child’s height SDS and child’s midparental height SDS exceeds 1.5 SDS and/or a low growth velocity.

The consensus reflects clear criteria for the diagnosis of GH-deficiency, central hypothyroidism, central hypocorticosolism, central hypogonadism, diabetes insipidus, hypoprolactinemia, and also the criteria for their compensation.

The dose of somatropin with GH-deficiency in children and adolescents is 0.025–0.033 mg/kg/day. With total somatotropic insufficiency, especially in young children, it is advisable to start therapy with somatropin from lower doses: 25–50% of the substitution, gradually increasing it within 3–6 months to optimal. In children with a growth deficit when entering puberty, the dose may be increased to 0.045–0.05 mg/kg/day.

With the development of side effects, the dose of somatropin can be reduced (by 30–50%), or temporarily canceled (depending on the severity of the clinical picture) until the complete disappearance of undesirable symptoms. With swelling of the optic nerve, treatment is temporarily stopped until the picture of the fundus of the eye fully normalizes. If therapy has been temporarily discontinued, treatment is resumed in smaller doses (50% of the initial) with a gradual (within 1–3 months) return to the optimum.

GH treatment at pediatric doses not continue beyond attainment of a growth velocity below 2–2.5 cm/year, closure of the epiphyseal growth zones, or earlier, when: the achievement of genetically predicted height, but not more than 170 cm in girls, 180 cm in boys, the patient’s desire and his parents / legal representatives satisfied with the achieved result of the final height.

Re-evaluation of the somatotropic axis is carried out after reaching the adult height, after 1–3 months GH therapy will be discontinued. Patients with isolated GH-deficiency or patients with 1 (besides GH) pituitary hormone deficiencies in the presence of a normal IGF-1 level (against the background of somatropin withdrawal) and not having molecular genetic confirmation of the diagnosis need re- evaluation. Patients with two or more (besides GH) pituitary hormone deficiencies, acquired hypothalamic-pituitary lesions due to operations on the pituitary and irradiation of the hypothalamic-pituitary area (if the IGF-1 level is low against somatropin withdrawal), specific pituitary/ hypothalamic structural defect on MRI, gene defects of the GH-IGF-I system do not need re- evaluation.

If GH deficiency is confirmed, treatment with somatropin is resumed at metabolic doses of 0.01—0.003 mg/kg/day under the control of the IGF-I level in the blood (measurement 1 time in 6 months), the indicator should not exceed the upper limit of the reference value for the corresponding age and floor.

hypopituitarism, growth hormone deficiency, central hypothyroidism, central hypocortisolism, central hypogonadism, growth hormone, somatropin, consensus

1. Российская академия медицинских наук, Министерство здравоохранения и социального развития РФ, Российская ассоциация эндокринологов. Диагностика и лечение соматотропной недостаточности у детей. Национальный Консенсус. — М. 2005. [Russian Academy Of Medical Sciences, Ministry Of Health And Social Development Of The Russian Federation, Russian Association Of Endocrinologists. Diagnostika i lechenie somatotropnoy nedostatochnosti u detey. Natsional’nyy Konsensus. Moscow. 2005. (In Russ.)].

2. Growth Hormone Research S. 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. 2000;85(11):3990-3993. doi: https://doi.org/10.1210/jcem.85.11.6984

3. Molitch ME, Clemmons DR, Malozowski S, et al. Evaluation and treatment of adult growth hormone deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(6):1587-1609. doi: https://doi.org/10.1210/jc.2011-0179

4. Нагаева Е.В. Федеральные клинические рекомендации по диагностике и лечению гипопитуитаризма у детей и подростков. // Проблемы эндокринологии. — 2013. — Т. 59. — № 6. — С. 27-43. [Nagaeva EV. Clinical guidelines on diagnostics and treatment of hypopituitarism in children and adolescences. Problems of Endocrinology. 2013;59(6):27-43. (In Russ.)]. doi: https://doi.org/10.14341/probl201359627-43

5. Grimberg A, Divall SA, Polychronakos C, et al. Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency. Horm Res Paediatr. 2016;86(6):361-397. doi: https://doi.org/10.1159/000452150

6. Дедов И.И., Петеркова В.А. Детская эндокринология. — Москва: Универсум Паблишинг; 2006. [Dedov II, Peterkova VA. Detskaya Endokrinologiya. Moscow: Universum Publishing; 2006. (In Russ.)].

7. Rose SR, Ross JL, Uriarte M, et al. The advantage of measuring stimulated as compared with spontaneous growth hormone levels in the diagnosis of growth hormone deficiency. N Engl J Med. 1988;319(4):201-207. doi: https://doi.org/10.1056/Nejm198807283190403

8. Secco A, Di Iorgi N, Napoli F, et al. The glucagon test in the diagnosis of growth hormone deficiency in children with short stature younger than 6 years. J Clin Endocrinol Metab. 2009;94(11):4251-4257. doi: https://doi.org/10.1210/Jc.209-0779

9. Butenandt O, Kunze D. Growth velocity in constitutional delay of growth and development. Journal of Pediatric Endocrinology and Metabolism. 2010;23(1-2). doi: https://doi.org/10.1515/Jpem.2010.23.1-9.12

10. Saggese G, Cesaretti G, Giannessi N, et al. Stimulated Growth hormone (GH) secretion in children with delays in pubertal development before and after the onset of puberty: relationship with peripheral plasma GH-releasing hormone and somatostatin levels. J Clin Endocrinol Metab. 1992;74(2):272-278. doi: https://doi.org/10.1210/jcem.74.2.1346143

11. Martinez AS, Domene HM, Ropelato MG, et al. Estrogen priming effect on growth hormone (GH) provocative test: a useful tool for the diagnosis of GH deficiency. J Clin Endocrinol Metab. 2000;85(11):4168-4172. doi: https://doi.org/10.1210/jcem.85.11.6928

12. Marin G, Domene Hm, Barnes Km, et al. The effects of estrogen priming and puberty on the growth hormone response to standardized treadmill exercise and arginine-insulin in normal girls and boys. J Clin Endocrinol Metab. 1994;79(2):537-541. doi: https://doi.org/10.1210/jcem.79.2.8045974

13. Gone EN, Kandemir N, Ozon A, Alikasifoglu A. Final heights of boys with normal growth hormone responses to provocative tests following priming. J Pediatr Endocrinol Metab. 2008;21(10). doi: https://doi.org/10.1515/jpem.2008.21.10.963

14. Kelly A, Tang R, Becker S, Stanley CA. Poor specificity of low growth hormone and cortisol levels during fasting hypoglycemia for the diagnoses of growth hormone deficiency and adrenal insufficiency. Pediatrics. 2008;122(3):E522-E528. doi: https://doi.org/10.1542/peds.2008-0806

15. Root AW, Dana K, Lippe B. Treatment of growth hormone-deficient infants with recombinant human growth hormone to near-adult height: patterns of growth. Horm Res Paediatr. 2011;75(4):276-283. doi: https://doi.org/10.1159/000322881

16. Reiter EO, Price DA, Wilton P, et al. Effect of growth hormone (GH) treatment on the near-final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database. J Clin Endocrinol Metab. 2006;91(6):2047-2054. doi: https://doi.org/10.1210/jc.2005-2284

17. Carel JC. Adult height after long-term treatment with recombinant growth hormone for idiopathic isolated growth hormone deficiency: observational follow up study of the French population based registry. BMJ. 2002;325(7355):70-70. doi: https://doi.org/10.1136/bmj.325.7355.70

18. Radetti G, Buzi F, Paganini C, et al. Treatment of GH-deficient children with two different GH doses: effect on final height and cost-benefit implications. Eur J Endocrinol. 2003;148(5):515-518. doi: https://doi.org/10.1530/eje.0.1480515

19. Juul A, Bernasconi S, Clayton PE, et al. European audit of current practice in diagnosis and treatment of childhood growth hormone deficiency. Horm Res. 2002;58(5):233-241. doi: https://doi.org/10.14341/probl201359627-43

20. Sas TC, De Ridder MA, Wit JM, et al Adult height in children with growth hormone deficiency: a randomized, controlled, growth hormone dose-response trial. Horm Res Paediatr. 2010;74(3):172-181. doi: https://doi.org/10.1159/000281323

21. Kristrom B, Aronson AS, Dahlgren J, et al. Growth hormone (GH) dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with GH deficiency or idiopathic short stature. J Clin Endocrinol Metab. 2009;94(2):483-490. doi: https://doi.org/10.1210/jc.2008-1503

22. Mauras N, Attie KM, Reiter EO, et al. High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: s randomized, multicenter trial. Genentech, Inc., Cooperative Study Group. J Clin Endocrinol Metab. 2000;85(10):3653-3660. doi: https://doi.org/10.1210/jcem.85.10.6906

23. Bell J, Parker Kl, Swinford Rd, Et Al. Long-term safety of recombinant human growth hormone in children. J Clin Endocrinol Metab. 2010;95(1):167-177. doi: https://doi.org/10.1210/jc.2009-0178

24. Darendeliler F, Karagiannis G, Wilton P. Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a safety update from the KIGSs database. Horm Res. 2007;68 Suppl 5:41-47. doi: https://doi.org/10.1159/000110474

25. Malozowski S, Tanner LA, Wysowski DK, et al. Benign intracranial hypertension in children with growth hormone deficiency treated with growth hormone. J Pediatr. 1995;126(6):996-999. doi: https://doi.org/10.1016/s0022-3476(95)70232-6

26. Cohen P, Bright GM, Rogol AD, et al. Effects of dose and gender on the growth and growth factor response to GH in GH-deficient children: implications for efficacy and safety. J Clin Endocrinol Metab. 2002;87(1):90-98. doi: https://doi.org/10.1210/jcem.87.1.8150

27. Mostoufi-Moab S, Isaacoff EJ, Spiegel D, et al. Childhood cancer survivors exposed to total body irradiation are at significant risk for slipped capital femoral epiphysis during recombinant growth hormone therapy. Pediatr Blood Cancer. 2013;60(11):1766-1771. doi: https://doi.org/10.1002/pbc.24667

28. Vedi A, Neville K, Johnston K, et al. Slipped capital femoral epiphyses after total body irradiation. Pediatr Blood Cancer. 2014;61(6):1140. doi: https://doi.org/10.1002/pbc.24895

29. Carel JC, Ecosse E, Landier F, et al. Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE Study. J Clin Endocrinol Metab. 2012;97(2):416-425. doi: https://doi.org/10.1210/jc.2011-1995

30. Savendahl L, Maes M, Albertsson-Wikland K, Et Al. Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: preliminary report of 3 countries participating in the EU SAGhE Study. J Clin Endocrinol Metab. 2012;97(2):E213-2E17. doi: https://doi.org/10.1210/jc.2011-2882

31. Wilton P, Mattsson AF, Darendeliler F. Growth hormone treatment in children is not associated with an increase in the incidence of cancer: experience from KIGS (Pfizer International Growth Database). J Pediatr. 2010;157(2):265-270. doi: https://doi.org/10.1016/j.jpeds.2010.02.028

32. Albertsson-Wikland K, Martensson A, Savendahl L, et al. Mortality is not increased in recombinant human growth hormone-treated patients when adjusting for birth characteristics. J Clin Endocrinol Metab. 2016;101(5):2149-2159. doi: https://doi.org/10.1210/jc.2015-3951

33. Sklar CA, Mertens AC, Mitby P, et al. Risk of disease recurrence and second neoplasms in survivors of childhood cancer treated with growth hormone: a report from the childhood cancer survivor study. J Clin Endocrinol Metab. 2002;87(7):3136-3141. doi: https://doi.org/10.1210/jcem.87.7.8606

34. Karavitaki N, Warner JT, Marland A, et al. GH replacement does not increase the risk of recurrence in patients with craniopharyngioma. Clin Endocrinol (Oxf). 2006;64(5):556-560. doi: https://doi.org/10.1111/j.1365-2265.2006.02508.x

35. Boulware SD, Caprio S, et al. Decreased insulin sensitivity and compensatory hyperinsulinemia after hormone treatment in children with short stature. J Clin Endocrinol Metab. 1997;82(10):3234-3238. doi: https://doi.org/10.1210/jcem.82.10.4302

36. Bareille P, Azcona C, Matthews DR, et al. Lipid profile, glucose tolerance and insulin sensitivity after more than four years of growth hormone therapy in non-growth hormone deficient adolescents. Clin Endocrinol (Oxf). 1999;51(3):347-353. doi: https://doi.org/10.1046/j.1365-2265.1999.00765.x

37. Burgers AM, Biermasz NR, Schoones JW, et al. Metaanalysis and dose-response metaregression: circulating insulin-like growth factor I (IGF-I) and mortality. J Clin Endocrinol Metab. 2011;96(9):2912-2920. doi: https://doi.org/10.1210/jc.2011-1377

38. Cutfield WS, Wilton P, Bennmarker H, et al. Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. Lancet. 2000;355(9204):610-613. doi: https://doi.org/10.1016/s0140-6736(99)04055-6

39. Dahlgren J. Metabolic benefits of growth hormone therapy in idiopathic short stature. Horm Res Paediatr. 2011;76 Suppl 3:56-58. doi: https://doi.org/10.1159/000330165

40. Loche S, Bizzarri C, Maghnie M, et al. Results of early reevaluation of growth hormone secretion in short children with apparent growth hormone deficiency. J Pediatr. 2002;140(4):445-449. doi: https://doi.org/10.1067/mpd.2002.122729

41. Maghnie M, Strigazzi C, Tinelli C, et al. Growth hormone (GH) deficiency (GHD) of childhood onset: reassessment of GH status and evaluation of the predictive criteria for permanent GHD in young adults. J Clin Endocrinol Metab. 1999;84(4):1324-1328. doi: https://doi.org/10.1210/jcem.84.4.5614

42. Hartman ML, Crowe BJ, Biller BM, et al. Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency? J Clin Endocrinol Metab. 2002;87(2):477-485. doi: https://doi.org/10.1210/jcem.87.2.8216

43. Toogood AA, Beardwell CG, Shalet SM. The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism. Clin Endocrinol (Oxf). 1994;41(4):511-516. doi: https://doi.org/10.1111/j.1365-2265.1994.tb02583.x

44. Attanasio AF, Howell S, Bates PC, et al. Confirmation of severe GH deficiency after final height in patients diagnosed as GH deficient during childhood. Clin Endocrinol (Oxf). 2002;56(4):503-507. doi: https://doi.org/10.1046/j.1365-2265.2002.01515.x

45. Secco A, Di Iorgi N, Napoli F, et al. Reassessment of the growth hormone status in young adults with childhood-onset growth hormone deficiency: reappraisal of insulin tolerance testing. J Clin Endocrinol Metab. 2009;94(11):4195-4204. doi: https://doi.org/10.1210/jc.2009-0602

46. Maghnie M, Aimaretti G, Bellone S, et al. Diagnosis of GH deficiency in the transition period: accuracy of insulin tolerance test and insulin-like growth factor-I measurement. Eur J Endocrinol. 2005;152(4):589-596. doi: https://doi.org/10.1530/eje.1.01873

47. Quigley CA, Zagar AJ, Liu CC, et al. United States multicenter study of factors predicting the persistence of GH deficiency during the transition period between childhood and adulthood. Int J Pediatr Endocrinol. 2013;2013(1):6. doi: https://doi.org/10.1186/1687-9856-2013-6

48. Banerjee I, Tudorancea A, Scanlon MF, Gregory JW. Are factors at diagnosis of growth hormone deficiency in childhood associated with persistence of growth hormone deficiency into adult life? J Pediatr Endocrinol Metab. 2005;18(10). doi: https://doi.org/10.1515/jpem.2005.18.10.943