Growth hormone deficiency medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]
Overview
Growth hormone (GH) is indicated for children with GH deficiency whose epiphyses are open. The dose for children is between 0.16 and 0.24 mg/kg/week, divided into once daily injections. Serum levels of insulin-like growth factor I (IGF-I) should be measured several weeks after beginning GH treatment or making a dose adjustment. GH side effects include headaches, Idiopathic intracranial hypertension, Slipped capital femoral epiphysis, worsening of existing scoliosis, Pancreatitis, and Gynecomastia. There is a possible role for GH in cancer risk.
Medical Therapy
Children treatment
Indications[1]
- Treatment with Growth hormone (GH) is indicated for children with GH deficiency whose epiphyses are open.
- Treatment should be continued until linear growth ceases or even beyond.
Dosing
- The dose for children is between 0.16 and 0.24 mg/kg/week, divided into once daily injections.
- The dose for patients with severe GH deficiency is 20 micrograms/kg/day.
Dosing during puberty[2]
- A temporary increase in GH dose is preferred if the patient failed to respond to normal doses.
- Although, effective treatment with GH before puberty is more efficacious than efforts to treat patients during puberty.
Monitoring
- Serum levels of insulin-like growth factor I (IGF-I) should be measured several weeks after beginning GH treatment or making a dose adjustment.
- This helps to avoid very high IGF-I levels, which are thought to be associated with some of the drug's toxicity as recommended in guidelines from the Pediatric Endocrine Society (PES):[3]
- If the IGF-I level is below this target range, increase the dose of GH because GH is unlikely to be efficacious if IGF-I levels are very low.
- If the IGF-I level is above this target range, we reduce the GH dose to prevent GH toxicity.
- For patients with multiple pituitary hormone deficiencies, adrenal and thyroid function should be reassessed a few months after initiation of GH therapy.[3]
Duration of therapy
- Treatment is continued at least until linear growth decreases to less than 2.0 to 2.5 cm.[3]
- More than two-thirds of patients have normal results when retested for GH deficiency as adults.
- It is important to repeat the GH stimulation test during the transition period to determine if they will require ongoing therapy.
- If GH is administered at an early age, patients can achieve adult height.[4]
- Patients heights should be rechecked every four to six months to determine if the growth response is adequate.
- During the initial growth period, the 75th percentile curve for height velocity is an appropriate target to define an adequate growth response to GH.
Effect of treatment
Growth
Bone mass
- Children with GH deficiency have low bone mass compared with control children.
- To maximize bone mass, it is important to consider the continuation of GH treatment even after linear growth has ceased until full skeletal.[6]
- GH therapy increases bone mass.[7]Without adequate GH replacement, GH deficiency can be associated with low bone mass during adulthood.[8]
ADVERSE EFFECTS OF GROWTH HORMONE THERAPY
Treatment of children with recombinant human GH has generally been safe.[9][10]
Acute effects
- Headaches which usually are benign.
- Idiopathic intracranial hypertension (formerly known as pseudotumor cerebri), increased intraocular pressure usually resolves with discontinuation of GH therapy. Treatment can often be resumed at a lower dose without the return of symptoms back up to standard doses.[11]
- Slipped capital femoral epiphysis: routine monitoring is recommended for suggestive symptoms such as hip and/or knee pain, and changes in gait. This condition usually requires surgical pinning of the capital femoral epiphysis.[12]
- Worsening of existing scoliosis.[13]
- Pancreatitis
- Gynecomastia
- Increase in the growth and pigmentation of nevi, without malignant degeneration.[14]
- Carpal tunnel syndrome, edema, and arthralgia are more common in adults undergoing GH treatment but are unusual in children.
- Most usually occur soon after therapy is initiated, and some of these effects are probably caused by sodium and water retention.
- Neutralizing antibodies against GH may be formed resulting in loss of efficacy.[15]
- Development of insulin resistance and disorders of glucose intolerance may occur in children receiving GH therapy.[16]
Chronic effects
- There is a possible role for GH in cancer risk especially prostate cancer.[17][18]
- GH therapy does not increase the risk of leukemia or other cancers compared with the general population.[19]
- However, a lack of association with cancer was also found in other studies.[20]
- For patients with a primary cancer diagnosis that led to the GH treatment, recombinant GH was associated with a modest increase in risk for secondary cancer.[19]
- The increased risk was significant for a variety of secondary cancers including bone, melanoma, kidney, brain, thyroid cancer and leukemia.
- Cancer mortality increased with GH dose and duration of treatment.
- For children with cancer, guidelines suggest a 12-month period after completion of cancer-directed therapy to confirm that the cancer was eradicated before initiating GH therapy.
Transition of GH treatment from childhood to adults[21]
- The transition period between childhood treatment and adults treatment begins in late puberty and ends with full adult maturation.
- Children treated with GH should be retested near the time of reaching the adult height to determine if they have persistence of GHD.
- Patients with idiopathic GHD usually do not need GH treatment anymore, children with organic causes of GHD usually are found to have GHD on retesting.
- Retesting involves measurement of IGF-I and stimulation with insulin-induced hypoglycemia or arginine.
- Most studies have shown the benefit of GH treatment in young adults with GHD in body composition, especially the achievement of peak bone mass.
Adult-type GH deficiency treatment
Treatment protocol
- GH is administered by subcutaneous injection once a day, usually in the evening.
- The goal should be to start with low doses and increase gradually until the serum IGF-1 concentration is normal.
- The eventual goal is to find the GH dose that maintains the serum IGF-1 concentration within the middle of the age-adjusted normal range.[22]
- If side effects occur or the serum IGF-1 concentration increases to above normal at any dose, the dose should be decreased.
Dosing
The starting dose should be 2 to 5 mcg/kg body weight once daily.
Duration of therapy
- Treatment should be continued indefinitely.[23]
- Stopping the treatment causes an increase in C-reactive protein and increases in both LDL and HDL cholesterol but improved insulin sensitivity and decreased glycated hemoglobin (A1C).[24]
Monitoring
- Measurement of serum IGF-1 is probably the best single test of the adequacy of GH treatment.[25]
- We suggest measuring a serum IGF-1 two months after starting therapy.
- GH treatment should increase the serum IGF-1 concentration to within, but not higher than, the age-specific range of normal to avoid over replacement.
- Once serum IGF-1 is in the normal range, we suggest repeating it every 6 to 12 months.
- If IGF-1 is ever above normal, the GH dose should be decreased by 1 to 2 mcg/kg increments and serum IGF-1 should be repeated every two months until it returns to the normal range.
References
- ↑ Albertsson-Wikland K (1987). "The effect of human growth hormone injection frequency on linear growth rate". Acta Paediatr Scand Suppl. 337: 110–6. PMID 3481175.
- ↑ Allen DB (1999). "Issues in the transition from childhood to adult growth hormone therapy". Pediatrics. 104 (4 Pt 2): 1004–10. PMID 10506252.
- ↑ 3.0 3.1 3.2 Grimberg A, DiVall SA, Polychronakos C, Allen DB, Cohen LE, Quintos JB; et al. (2016). "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. 86 (6): 361–397. doi:10.1159/000452150. PMID 27884013.
- ↑ Reiter EO, Price DA, Wilton P, Albertsson-Wikland K, Ranke MB (2006). "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. 91 (6): 2047–54. doi:10.1210/jc.2005-2284. PMID 16537676.
- ↑ Carel JC, Ecosse E, Nicolino M, Tauber M, Leger J, Cabrol S; et al. (2002). "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. 325 (7355): 70. PMC 117125. PMID 12114235.
- ↑ Conway GS, Szarras-Czapnik M, Racz K, Keller A, Chanson P, Tauber M; et al. (2009). "Treatment for 24 months with recombinant human GH has a beneficial effect on bone mineral density in young adults with childhood-onset GH deficiency". Eur J Endocrinol. 160 (6): 899–907. doi:10.1530/EJE-08-0436. PMID 19324976.
- ↑ Bonjour JP, Theintz G, Buchs B, Slosman D, Rizzoli R (1991). "Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence". J Clin Endocrinol Metab. 73 (3): 555–63. doi:10.1210/jcem-73-3-555. PMID 1874933.
- ↑ Holmes SJ, Economou G, Whitehouse RW, Adams JE, Shalet SM (1994). "Reduced bone mineral density in patients with adult onset growth hormone deficiency". J Clin Endocrinol Metab. 78 (3): 669–74. doi:10.1210/jcem.78.3.8126140. PMID 8126140.
- ↑ Saenger P, Attie KM, DiMartino-Nardi J, Hintz R, Frahm L, Frane JW (1998). "Metabolic consequences of 5-year growth hormone (GH) therapy in children treated with GH for idiopathic short stature. Genentech Collaborative Study Group". J Clin Endocrinol Metab. 83 (9): 3115–20. doi:10.1210/jcem.83.9.5089. PMID 9745413.
- ↑ Carel JC, Butler G (2010). "Safety of recombinant human growth hormone". Endocr Dev. 18: 40–54. doi:10.1159/000316126. PMID 20523016.
- ↑ Youngster I, Rachmiel R, Pinhas-Hamiel O, Bistritzer T, Zuckerman-Levin N, de Vries L; et al. (2012). "Treatment with recombinant human growth hormone during childhood is associated with increased intraocular pressure". J Pediatr. 161 (6): 1116–9. doi:10.1016/j.jpeds.2012.05.024. PMID 22727870.
- ↑ Darendeliler F, Karagiannis G, Wilton P (2007). "Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a safety update from the KIGS database". Horm Res. 68 Suppl 5: 41–7. doi:10.1159/000110474. PMID 18174706.
- ↑ Blethen SL, Allen DB, Graves D, August G, Moshang T, Rosenfeld R (1996). "Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience". J Clin Endocrinol Metab. 81 (5): 1704–10. doi:10.1210/jcem.81.5.8626820. PMID 8626820.
- ↑ Bourguignon JP, Piérard GE, Ernould C, Heinrichs C, Craen M, Rochiccioli P; et al. (1993). "Effects of human growth hormone therapy on melanocytic naevi". Lancet. 341 (8859): 1505–6. PMID 8099381.
- ↑ Pitukcheewanont P, Schwarzbach L, Kaufman FR (2002). "Resumption of growth after methionyl-free human growth hormone therapy in a patient with neutralizing antibodies to methionyl human growth hormone". J Pediatr Endocrinol Metab. 15 (5): 653–7. PMID 12014526.
- ↑ Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB; et al. (2000). "Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment". Lancet. 355 (9204): 610–3. doi:10.1016/S0140-6736(99)04055-6. PMID 10696981.
- ↑ Giovannucci E, Pollak M (2002). "Risk of cancer after growth-hormone treatment". Lancet. 360 (9329): 268–9. doi:10.1016/S0140-6736(02)09561-2. PMID 12147365.
- ↑ Swerdlow AJ, Cooke R, Albertsson-Wikland K, Borgström B, Butler G, Cianfarani S; et al. (2015). "Description of the SAGhE Cohort: A Large European Study of Mortality and Cancer Incidence Risks after Childhood Treatment with Recombinant Growth Hormone". Horm Res Paediatr. 84 (3): 172–83. doi:10.1159/000435856. PMC 4611066. PMID 26227295.
- ↑ 19.0 19.1 Swerdlow AJ, Cooke R, Beckers D, Borgström B, Butler G, Carel JC; et al. (2017). "Cancer Risks in Patients Treated With Growth Hormone in Childhood: The SAGhE European Cohort Study". J Clin Endocrinol Metab. 102 (5): 1661–1672. doi:10.1210/jc.2016-2046. PMID 28187225.
- ↑ Raman S, Grimberg A, Waguespack SG, Miller BS, Sklar CA, Meacham LR; et al. (2015). "Risk of Neoplasia in Pediatric Patients Receiving Growth Hormone Therapy--A Report From the Pediatric Endocrine Society Drug and Therapeutics Committee". J Clin Endocrinol Metab. 100 (6): 2192–203. doi:10.1210/jc.2015-1002. PMC 5393518. PMID 25839904.
- ↑ Molitch ME (2011). "Growth hormone treatment in adults with growth hormone deficiency: the transition". J Endocrinol Invest. 34 (2): 150–4. doi:10.3275/7483. PMID 21270511.
- ↑ Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R; et al. (2016). "Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 101 (11): 3888–3921. doi:10.1210/jc.2016-2118. PMID 27736313.
- ↑ Appelman-Dijkstra NM, Claessen KM, Roelfsema F, Pereira AM, Biermasz NR (2013). "Long-term effects of recombinant human GH replacement in adults with GH deficiency: a systematic review". Eur J Endocrinol. 169 (1): R1–14. doi:10.1530/EJE-12-1088. PMID 23572082.
- ↑ Filipsson Nyström H, Barbosa EJ, Nilsson AG, Norrman LL, Ragnarsson O, Johannsson G (2012). "Discontinuing long-term GH replacement therapy--a randomized, placebo-controlled crossover trial in adult GH deficiency". J Clin Endocrinol Metab. 97 (9): 3185–95. doi:10.1210/jc.2012-2006. PMID 22791760.
- ↑ de Boer H, Blok GJ, Popp-Snijders C, Stuurman L, Baxter RC, van der Veen E (1996). "Monitoring of growth hormone replacement therapy in adults, based on measurement of serum markers". J Clin Endocrinol Metab. 81 (4): 1371–7. doi:10.1210/jcem.81.4.8636336. PMID 8636336.