Growth hormone (GH) has been in use since the late 1950s. It initially was extracted from human cadaveric pituitary glands. In April 1985, use of cadaveric GH was banned in this country because of its association with Creutzfeldt-Jakob disease. The long latent period of the Creutzfeldt-Jakob prion infection means the disease should be included in the differential diagnosis for adult patients presenting with dementia if there is a history of GH treatment before 1985. Currently used GH products are produced by recombinant DNA technology and have not been associated with Creutzfeldt-Jakob disease.
Growth hormone is approved by the Food and Drug Administration for treatment of GH deficiency, Turner syndrome, chronic renal failure before transplantation, Prader-WUli syndrome, short stature in children bora small for gestational age, AIDS wasting, idiopathic short stature, and adult GH deficiency.
In children, the response to GH usually decreases after the first year of treatment. However, growth should proceed at least at the normal growth velocity for age while on GH treatment If growth is slower than normal, several factors should be considered, including poor compliance, improper preparation of GH for administration, incorrect injection technique, subclinical hypothyroidism, chronic disease, glucocorticoid therapy, history of irradiation to spine, and epiphyseal fusion. Presence of anti-GH antibodies, common in patients with GHgene deletions and exceedingly rare in others, and incorrect diagnosis of GH deficiency as a cause for growth retardation should also be considered.1
The most prevalent adverse effects of GH treatment were observed during the early years of its use. The effects occurred in adults treated with doses higher than currently used doses. The most common side effects include, in order of frequency, edema, arthralgia, myalgia, paresthesias, and carpal tunnel syndrome. Most symptoms resolve within 1 to 2 months after discontinuation of therapy or with dose diminution.2
With the approval of GH for idiopathic short stature, the number of children receiving this therapy very likely will increase significantly. In general, GH is considered a low-risk, relatively safe drug. However, several side effects may cause significant concerns in some patients and need to be monitored closely.
Diabetes and Insulin Resistance
Cutfield et al.3 studied data derived from the Pharmacia-organized international surveillance program of children and adolescents who received GH treatment for a mean of longer than 2 years between 1986 and 1997. Among the 23,333 GH-treated children, the incidence of type 1 diabetes mellitus was comparable to the general population. The risk of type 2 diabetes mellitus was sixfold higher in children treated with GH compared with an age- and sex-matched untreated population. A significant increase in type 2 diabetes mellitus was particularly evident during adolescence.
However, this population included patients with Turner syndrome (with and without oxandrolone treatment), PraderWilli syndrome, and intrauterine growth retardation. These patients are known to be prone to insulin resistance and are at a higher risk for developing diabetes. On the other hand, the diagnostic criteria for glucose intolerance used in this paper were the American Diabetes Association criteria. Compared with the World Health Organization criteria, the American Diabetes Association criteria detect only half of patients with glucose intolerance.4
Cutfield3 concluded that the incidence of type 1 diabetes mellitus is not increased in patients receiving GH treatment and that the incidence of type 2 diabetes mellitus is increased only in patients who are predisposed to this condition. Until further data are available, checking hemoglobin AIc, fasting plasma glucose, and insulin levels before starting GH therapy and at regular intervals thereafter is recommended. This is especially important in high-risk patients, including patients with obesity, Turner syndrome, intrauterine growth retardation, and Prader- WiUi syndrome.
LaFranchi et al.5 evaluated thyroid function tests, lipid profile, and growth velocity in GH-deficient children started on GH treatment Twenty-five percent of these patients had decreased thyroxine (T4) levels and increased cholesterol levels in association with decreased growth velocity. After initiation of L-thyroxine (LT4) treatment, growth rates unproved.
Two other studies showed decreased free thyroxine (FT4) and reverse triiodothyronine levels and increased triiodothyronine (T3) and T3/T4 ratio.6'7 Only one patient in each study developed a FT4 level below the normal range. In one patient, the level normalized within a few months while remaining on GH treatment, despite not receiving thyroxine supplementation.
Because of these findings, monitoring of FT4 every 3 to 6 months is reasonable during GH treatment. If FT4 levels become low, LT4 supplementation should be considered. Because FT4 may normalize without LT4 treatment, a repeat FT4 determination may be performed before treatment with LT4. Individuals with multiple pituitary hormone deficiencies may be at greatest risk of thyroid stimulating hormone deficiency, which may be unmasked during GH treatment. Because infants require normal levels of thyroid hormones for brain development, low FT4 levels in infants should be corrected promptly.
In 1995, Malozowski et al.8 reported 10 cases of pancreatitis in GH-treated patients. The first patient had pseudohypoparathyroidism in association with GH deficiency and was receiving thyroxine, vitamin D, and GH. The patient developed nausea, vomiting, severe abdominal pain, and elevated Upase and amylase levels after the sixth dose of GH. Symptoms resolved when GH therapy was discontinued. After 3 weeks, GH was restarted and pancreatitis redeveloped (positive dechallenge/rechallenge test). The patient improved and did not develop symptoms while off GH. The patient's sister also had pseudohypoparathyroidism and was treated with GH; she did not develop symptoms of pancreatitis. The mechanism by which GH can cause pancreatitis is unknown. However, if a patient receiving GH develops abdominal pain, pancreatitis should be included in the differential diagnosis. Five of the six patients who developed pancreatitis had other predisposing factors, including chronic renal insufficiency, DM, and valproic acid treatment. Pancreatitis improved despite the continuation of GH in one patient.
Salerno et al.9 studied 78 patients receiving GH, six of whom developed transient benign hypertransaminasemia persisting approximately 6 months. Five of these patients had multiple pituitary hormone deficiency. Other replacement hormones, such as hydrocortisone, might have played a role. Three of these patients had increased levels of creatine kinase, suggesting muscular rather than hepatic damage. This study failed to include a control group of children in whom liver function studies were obtained at a similar frequency over a similar period of time.
Benign lntracranial Hypertension and Retinal Changes
Benign intracranial hypertension (BIH) is a rare condition in children. Some causes include obesity and treatment with specific drugs. Endocrine causes are usually related to significant changes in hormone levels during a short period of time. For example, beginning treatment with a high dose of levothyroxine in a child with newly diagnosed, severe hypothyroidism or sudden withdrawal of steroids in a child with Gushing syndrome, may cause BIH.10
The FDA reported 23 cases of benign intracranial hypertension associated with GH treatment in 22 children and one adult.11 Growth hormone was used for treatment of various conditions, such as chronic renal failure, GH deficiency, Turner syndrome, Prader-Willi syndrome, and constitutional delay of growth and development. In most of these patients, BIH was noted within 8 weeks of initiating GH treatment and, in others, between 2 and 60 months. After the publication of this FDA report, more cases were reported.
GH treatment should be discontinued promptly if a GH-treated patient develops visual symptoms, headaches, and vomiting. Patients should have an ophthalmologic evaluation, and other causes of increased intracranial pressure should be ruled out by neuroimaging. Benign intracranial hypertension did not recur in any of the reported cases after GH treatment was restarted, suggesting an adaptive mechanism. With GH treatment, GH levels in cerebrospinal fluidrise. Choroid plexi have high concentrations of IGF-I receptors. Increases in GH levels in cerebrospinal fluid may cause an increase in cerebrospinal fluid production.10
Koller et al.12 reported that of 1,670 patients with renal disorders who were undergoing GH treatment, 15 developed intracranial hypertension with papilledema. Mean duration of onset of GH treatment before papilledema developed was 13 weeks. None of the patients were symptomatic. Therefore, funduscopic evaluation should be a routine part of physical examination in patients receiving GH treatment, especially patients with renal disorders.
Families should be informed about the possibility of headaches at initiation of GH treatment. If there is an increase in the frequency or the severity of headaches, the physician should be informed. Once GH treatment is suspended and the symptoms of BIH have resolved, GH may be restarted at one-fourth the previous dose and increased slowly while intra-cranial pressure is measured for signs or symptoms of increase.13
Prepubertal Gynecomastia and Premature Thelarche
In boys, breast development is common in newborns and adolescents. It is uncommon in prepubertal boys. Malozowski et al.14 reported 22 cases of prepubertal gynecomastia in GH-treated patients between the ages of 2 and 12. Most cases were noted 2 weeks to 7 months after initiation of therapy, but in some cases, gynecomastia developed up to 8 years after GH was started. Gynecomastia may be unilateral or bilateral and is unassociated with breast discharge. None of the reported patients had elevated serum levels of estrogen, testosterone, or prolactin. In one patient, the dechallenge/rechallenge test was positive. In five patients, the gynecomastia caused by GH regressed while the patients were still on therapy.
The mechanism underlying GH treatment-induced gynecomastia is unknown. Growth hormone might be stimulating the breast growth through GH receptors, lactogenic receptors, or IGF-I production. Findings indicate GH-induced prepubertal gynecomastia is self-limited and benign.15 However, breast examinations should be a part of routine physical examination in patients receiving GH treatment.
Premature thelarche has also been reported in GH-treated girls as young as age 5. The duration of GH treatment ranged between 2 months and 60 months. These patients had prepubertal gonadotropi and estradiol levels.16
Arthralgia, myalgia, and carpal tunnel syndrome may occur occasionally in children treated with GH. However, these symptoms are more common in the GHtreated adult population.2 Peripheral edema is also more common in GH-treated adults than GH-treated children. However, peripheral edema is quite common in GH-treated children with Turner syndrome, perhaps because of the frequent abnormalities in lymphatic development.
Slipped capital femoral epiphysis has been associated with hypothyroidism and GH deficiency. Turner syndrome, obesity, and chronic renal failure are other risk factors for this disorder. Among the patients with slipped capital femoral epiphysis and GH deficiency, approximately 92% develop this problem during or after GH supplementation.17 Any child receiving GH treatment who complains of knee pain, hip pain, or manifesting limp must be evaluated carefully for this disorder.
Children with chronic renal failure are more likely to develop osteodystrophies and, therefore, should have x-rays of the hips before GH is initiated. In patients with chronic renal failure treated with recombinant human GH, serial radiographs and serum calcium, phosphorus, alkaline phosphatase, and parathroid hormone levels should be obtained to monitor renal osteodystrophy, slipped capital femoral epiphysis, and avascular necrosis.18
A study by Wang et al.19 concluded GH treatment in children contributes to rapid progression of scoliosis. In one patient, discontinuation of GH was associated with stabilization of scoliosis. Unlike the general population, mere was a strong male predominance of scoliosis in GH-treated children. Kyphosis also is more common in the setting of GH treatment. Therefore, back examination should be a routine part of the physical examination in children receiving GH treatment
Growui Hormone Antibody Formation
Growth hormone preparations result in antibody formation in 10% or less of children receiving GH treatment. One group studied the frequency of GH antibody formation in 23,000 specimens from more than 5,000 patients treated with GH.20 Only 0.04% of these patients (two patients) had growth deceleration associated with high levels of GH-binding antibodies or growth-attenuating antibodies. Most GH antibodies are not neutralizing and do not interfere with growth velocity. Non-compliance, inadequate dosing, under-nutrition, and comorbid illnesses including hypothyroidism should be considered in patients receiving GH treatment who have decreased growth velocity. If these are ruled out, antibodies should be studied. If studies for GH antibodies are positive, another GH preparation should be considered.20 One patient who developed antibodies to methionyl human GH in association with growth deceleration manifested significant growth acceleration after changing to a methionyl-free GH preparation.21
One study found four males between ages 17 and 25 treated with GH for nonGH-deficient short stature who were later diagnosed with hypergonadotropic hypogonadism.22 The problem with this study is the small sample size.
In contrast, a study by the National Institutes of Health did not find evidence of testicular dysfunction in 49 boys treated with GH or placebo for idiopathic short stature.23 A Danish study by Juul et al.24 also failed to confirm such an effect in 13 young males with childhood-onset GH deficiency receiving either placebo or GH treatment The GH-treated patients and placebo-treated patients had similar LH and FSH responses to gonadotrophinreleasing hormone and similar testosterone responses to human chorionic gonadotropin.
Possible increased incidence of de novo cancers and recurrence of previous cancers are two major concerns regarding the risk of neoplasia in GH-treated children.
There are concerns regarding neoplasm induction from GH treatment because IGF- 1 is a mitogenic and antiapoptotic peptide. On the other hand, in a state of GH deficiency, natural killercell activity decreases. Growth hormone might therefore have an inhibitory role on tumor metastatsis.25
There have been concerns that GH treatment may increase the risk of skin cancer. The effect of GH on pigmented nevi is hard to assess. In untreated children, frequency and progression of pigmented nevi have not been reported.26 Some of the underlying conditions for which patients require GH treatment, such as Turner syndrome and prior radiation therapy, are also risk factors for development of pigmented nevi. As of 1996, 17 cases with increased number and size of pigmented nevi were reported. Seven of these cases were children with non-GH risk factors such as Turner syndrome, previous radiation, and Gorlin syndrome. Among six patients who had biopsies, none had malignant transformation.25,26
Melanoma risk is not associated with acquired melanocytic nevi size but with atypical or dysplastic histologie characteristics. The possible association of nevi with underlying conditions should be kept in mind while treating patients with GH. If changes are noted in previously known nevi with or without associated lymphadenopathy, careful examination by an experienced pediatrie dermatologist is warranted.
Japanese studies conclude that in children without any predisposing factors, the risk of developing leukemia is not greater in GH-treated patients than in the general population.27 Other predisposing factors may include Down's syndrome, Fanconi's anemia, and previous radiation or chemotherapy.
Recurrence of Central Nervous System Tumors
Recent studies show that GH treatment in survivors of central-system tumors does not increase the risk of tumor recurrence.28·29 Both of these studies included large numbers of GH recipients. However, long-term follow up is warranted. It is recommended that GH should be started at least 1 year after a tumor-free period.
Long-term Cancer Risk
A recent study in the United Kingdom concluded the risk of death from colorectal cancer and Hodgkin's disease is increased in patients treated in childhood with GH (confidence interval of 1.3 to 38.8 and 1 to 28.7, respectively).30 This increased risk is based on two patients with each of the tumors.
Several epidemiological studies link higher IGF-I and lower IGF-BP-3 levels with increased risk for breast, prostate, and colorectal cancer.31'33 Therefore, adjustment of GH doses to avoid high levels of IGF-I, especially when IGF-BP3 levels are not elevated, seems prudent.
Sudden Death in Patients With Prader-Willi
Seven fatalities were reported as of April 2003 among patients with PraderWiIIi receiving GH treatment.34 All of these patients had one or more respiratory risk factors including severe obesity, history of sleep apnea, or unidentified respiratory infection. Male patients with Prader-Willi may be at higher risk than female patients. All patients with Prader-Willi syndrome receiving GH treatment should be evaluated carefully for sleep apnea, and effective weight control measures need to be taken. Until further data are available, a conservative approach seems prudent in initiating GH treatment in patients with Prader-Willi at risk for respiratory compromise.
Lipoatrophy rarely may be seen at the side of GH injection. Therefore, alternating injection sites is recommended.
In most patients, increase in height as a result of GH injection increases serfesteem, hi others, daily GH administration may be a major Stressor and may contribute to dysfunctional behavior.
Sleep Apnea and Hypertrophy of the Adenoids and Tonsils
The National Cooperative Growth Study35 did not report any cases of clinically detectable sleep apnea. The study, however, reported four of 145 patients treated with recombinant GH developed sleep apnea.
Two of these patients had obstructive apnea, and two others had mixed-sleep apnea. None of these patients had risk factors such as pharyngitis or sinusitis predisposing to upper-airway obstruction. Two of these patients had markedly higher IGF-I levels compared with agematched controls. In these patients, the mechanism of obstructive sleep apnea may be simitar to that hi acromegalie patients. Fjtcess GH induces macroglossia and bony and son tissue enlargement in the hypopharyngeal area. The third patient was an 8-year-old female with a history of two renal transplants who was receiving immunosuppressive therapy including prednisone. She had a bone mass index of 37.
Only one of the four patients had a positive dechaUenge/rechaUenge test for adenoid and tonsillar hypertrophy with GH. Despite the limitations of this study, snoring, sleep apnea, and daytime somnolence should be determined hi follow up of GH-treated patients.
Acutely Ill Patients
Takala et al.36 studied the effects of GH in critically ill adults and concluded high doses increased mortality and prolonged the length of hospital stay. This could be due to altered immune mechanisms. Therefore, until further data are available, if children receiving GH treatment are admitted to the hospital for an acute illness, GH treatment should be discontinued during the time of hospital stay.
In general, GH is a safe medication. Patients overwhelmingly enjoy its benefits. Infrequently, its side effects produce worrisome problems. Knowledge of these effects may allow families to choose treatment more judiciously and may allow physicians to detect adverse effects at an early stage.
1. Rosenfeld R, Cohen P. Disorders of growth hormone/insulin-like growth factor secretion and action. In: Sperling MA, ed. Pediatrie Endocrinology. Philadelphia, PA: W.B. Saunders-,2002.
2. Ghaiib H, QxA DM, Saenger PH, et al. American Association of Clínica] Endocrinologiste medical guidelines for clinical practice for growth hormone use in adults and children - 2003 update. EndocrPract 2003;9(1):64-76
3. Cutfield W, 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.
4. Jeffcoatee W. Can grwoth hormone therapy cause diabetes? Lancei. 2000;355(9204):589-590.
5. LaFranchi S, Manna CE, Illingwortb DR. Effect of growth hormone replacement on development of hypothyriodism and hyperlipidemia. J Pedicar. 1985:106(4):588-593.
6. Wyatt DT, Gesundheit N, Sherman B. Changes in thyroid hormone levels during growth bormone therapy in initially euthyroid patients: lack of need tor tfayroxine supplementation. J Clin Endocrino! Metab. l998;83(10):3493-3497.
7. Portes ES, Oliveira JH. MacCagnan P. Abucham J. Changes in serum thyroid hormones levels and their mechanisms during long-term growth hormone (GH) replacement therapy in GH deficient children. Clin Endocrinol (Oxf). 2000;53(2):183-189.
8. Malozowski S, Hung W, Scott DC, Stadel BV. Acute pancreatitis associated with growth hormone therapy for short stature. N Engl J Med. 1995;332(6):40 1-402.
9. Salerno M, Di Maio S, Ferri P, et al. Liver abnormalities during growth hormone treatment. J Pediatr Gastmenteml Natr. 2000;3 1(2): 149-151.
10. Crock PA, McKenzie JD, Nicoli AM, et al. Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand Acta Paediatr. 1998;87(4):381-386.
11. Malozowski S, Tanner LA, Wysowski D, Fleming GA. Growth hormone, insulin-like growth factor I, and benign intracranial hypertension. N Eng J Med 1993;329(9):665-666.
12. Koller EA, Stadel BV, Malozowski S. Papilledema in 15 renally compromised patients treated with a growth hormone. Pediatr Nephrol. 1997;11(4):451-454.
13. Malozowski S. Growth Hormone, insulin-like growth factor. 1, and benign intracranial hypertension. N Engl J Med. 1993;329(9):665-666.
14. Malozowski S, Stadel B. Prepubertal gynecomastia during growth hormone therapy. J Pediatr. 1995;126(4):659-661.
15. Malozowski S, Stadel BV. Prepubertal gynecomastia during growth hormone therapy. J Pediatr. 1995;126(4):659-661.
16. Carvalho LR, Munura LY, Amhold IJ, Mendonca BB. Premature thelarche in girls after growth hormone therapy. J Pediatr. 2001;138(3):448449.
17. Loder RT, Wittenberg B, DeSilva G. Slipped capita) femoral epiphysis associated with endocrine disorders. J Pediatr Orthop. 1995;15(3):349-356.
18. Watkins SL. Is severe renal osteodystrophy a contraindication for recombinant human growth hormone treatment? Pediatr Nephrol. 1996;10(3):351-354.
19. Wang ED, Dmmmond DS. Dormans JP, et al. Scoliosis in patients beated with growth hormone. J Pediatr Orthop. 1997; 17(6):708-711.
20. Blethen SL, Alien DB, Graves D. Satety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. J CUn Endocrinoi Metab. 1996;81(5):1704-1710.
21. Pitttkcheewanont P, Schwarzbach L, Kaufinan FR. Resumption of growth after methionyKree human growth hormone therapy in a panent wiib neutralizing antibodies to metbionyl human growth hormone. J Pediatr Endocrinoi Metab. 2002;15(5):653-657.
22. BerteDoni S, BarooceUi GL Viacava P, et at Can growth Donnone treatment in boys without growth hormone deficiency impair testicular function? J Pediatr 1999;135(3):367-370.
23. Leschek EW, Troendle JF, Yanovski JA. et al. Effect of growth hormone treatment on testicular function, puberty, and adrenarche in boys with non-growth hormone-deficient short stature: a randomized, double-blind, placebo-controlled trial. J Pediatr. 2001;138(3):406-410.
24. Juul A, Andersson AM, Pedersen SA, et al. Effects of growth hormone replacement therapy on IGF-related parameters and on the pituitary-gonadal axis in GH-deficient makes. A doubleblind, placebo-controlled crossover study. Harm Res. 1998;496):269-278.
25. Alien DB. Safety of growth hormone therapy: current topics. J Pediatr. 1996;128(5 Pt 2):S8S13.
26. Wyatt D. Melanocytic nevi in children treated with growth hormone. Pediatrics. 1999;104(4 Pt 2): 1045-1049.
27. Nishi Y, Tanaka T, Takano K, et al. Recent status in the occurrence of leukemia in growth hormone-treated patients in Japan. GH Treatment Study Committee of the Foundation for Growth Science, Japan. J Clin Endocrinoi Metab. 1999;84(6):1961-1965.
28. 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 Endocrinoi Metab. 2002;87(7):3 136-3 141.
29. Swerdlow AJ, Reddingius RE, Higgins CD, et al. Growth hormone treatment of children with brain tumors and risk of tumor recurrence. J Clin Endocrinoi Metab, 2000;85(!2):4444-4449.
30. Swerdlow AJ, Higgins CD, Adlard P, Preece MA. Risk of cancer in patients treated with human pituitary growth hormone in the UK, 1959-85: a cohort study. Lancet. 2002;360(9329):273-277.
31. Hankinson SE, Willett WC, Coklitz GA, et al. Circulating concentrations of IGF-I and risk of breast cancer. Lancet. 1998;35I(9113):13731375.
32. Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma IGF-I and prostate cancer risk: aprospective study. Science, 1998;279(5350):563-566.
33. Sandhu MS, Dunger DB, Giovannucci EL. Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer. J Nati Cancer Inst. 2002:94(13);72-980.
34. US Food and Drug Administration. 2003 safety alert genotropin (somatropin [rDNA origin] for injection). Available at http://www jda.gov/inedwatchSAFETY/2003/genotropm.htm. Last accessed January 23, 2004.
35. Gerani JM, Garibaldi U Myers SE, et al. Sleep apea in patients receiving growth hormone. Clin Pediatr(Phila). l997J6(6)J2l-326.
36. Takala J, Ruokonen E, Webster NR, et aL Inceased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999-341(11):785-792.