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Growth Disorders: Evaluation, Treatment
The following is a synopsis of growth-promoting therapies.
Reviewed By Steven D. Chernausek, MD
This discussion was taken from the syllabus and Dr. Chernausek's Meet-The-Experts session presented during the American Association of Clinical Endocrinologists 18th Annual Meeting & Clinical Congress in Houston.
Human growth hormone (hGH) is the most abundant hormone produced in the pituitary, comprising up to 25% of the gland's dry weight. Children generally tolerate treatment with hGH well, and it yields few adverse effects over short- or intermediate-term treatment.1,2
GROWTH HORMONE
GH use can be considered replacement therapy for growth hormone deficiency (GHD) or pharmacologic therapy. In the latter, a patient is using hGH to overcome relative GH or insulin-like growth factor (IGF) insensitivity and to stimulate growth-promoting pathways that, for some reason, are attenuated by a disease process or normal variation. Few studies have systematically evaluated multiple doses in various conditions. Therefore, recommended doses typically reflect the dose used during clinical trials for the condition in question, rather than the optimal regimen (Table 1). An individual with recently acquired GHD should be started on a dose that mimics daily production—approximately 0.6 mg/m2/day in the prepubertal period, increasing twofold during puberty.3 A child with a non-GHD condition will need a higher dose that can be adjusted based on expected response, age, and degree of short stature.
A patient will increase his or her growth velocity at least 2 cm/year over baseline. When this does not occur, the physician should consider the following: (1) Is the patients compliant with the medical regimen? (2) Is the diagnosis correct and the dose appropriate? (3) Has another condition such as inadequate nutrition or hypothyroidism developed? A trial at a higher hGH dose with monitoring of circulating IGF-1 is reasonable if no explanation is found.
Safety. Adverse events associated with hGH treatment are listed in Table 2. HGH is well tolerated, and complications rarely arise in children. Some patients develop antibodies to hGH, but these rarely affect the response. The exception is in patients with a GH gene deletion who develop high titers that neutralize administered hGH. Scoliosis and slipped capital femoral epiphysis have been reported in association with hGH. Intracranial hypertension is a rare complication that typically responds to a brief period of withdrawal of hGH treatment.
The possible role of hGH in de novo neoplasm formation or in the growth of existing tumors has been of concern.4 Data indicate that hGH and IGF-1 promote tumor growth. Some epidemiological studies reveal that higher-than-average circulating levels of IGF-1 are associated with an increased incidence of breast and prostate cancers in adults. Generally, preexisting malignancies should be inactive and treatment complete before instituting hGH. For patients with craniopharyngioma and other central nervous system tumors, treatment with hGH does not appear to cause recurrence.5 Administration of hGH may increase the risk of a second primary malignancy, frequently a meningioma.6 In that the increased risk is low, most children with bona fide GHD and adequately treated stable neoplasms should be offered treatment. The risk of tumor formation in otherwise normal short or GHD children given hGH is extremely low.
Monitoring. Patients should be examined every 3 to 6 months, to measure IGF-1 once or twice annually, and to determine skeletal age radiographically every 1 to 3 years depending on the age and treatment phase. Monitor growth velocity and interpret it in light of the patient's diagnosis, pubertal status, bone age, and degree of growth retardation. Unless there is a risk for diabetes, measures of carbohydrate homeostasis are not routinely measured .
The Growth Hormone & IGF Research Society recommends that circulating IGF-1 be monitored as part of ongoing surveillance and adjustments to avoid IGF-1 concentrations above normal.7 In GHD, use all parameters to assess the adequacy of hGH replacement, including growth rate, skeletal maturation, and IGF-1 concentration. Monitoring IGF-1 is also helpful for detecting noncompliance. When both the growth velocity and circulating IGF-1 are lower than expected, noncompliance is often the problem.
RECOMBINANT HUMAN IGF-1
IGF-1 was originally recognized as "sulfation factor," the putative mediator of hGH's growth-promoting actions in cartilage. However, it was quickly recognized that its growth regulatory role involves most organs and tissues. IGF-1 is structurally homologous with insulin and possesses both insulin-like and growth-promoting properties. These features have been exploited therapeutically—there is improved glycemic control in type 2 diabetes patients—but only the treatment of short stature is approved at this time.
Clinical use. Initial clinical trials in the 1990s examined the response in children with hGH insensitivity syndrome (GHIS, Laron syndrome), a condition commonly due to defects of the GH receptor.8-10 Studies involving a modest number of patients demonstrated safety and efficacy, which led to approval of rhIGF for a condition termed severe primary IGF deficiency.11 This is defined as height and circulating IGF-1 level both below -3 standard deviations for age and sex accompanied by normal hGH secretion and nutritional status.
Safety. Compared to hGH, there is much less experience with rhIGF-1 as a therapeutic agent. Table 3 lists adverse events reported in clinical trials. Hypoglycemia is the most common and has been a persistent concern. Many of the patients given rhIGF-1 have spontaneous hypoglycemia due to their underlying condition (GHIS). Symptomatic hypoglycemia due to rhIGF-1 can be largely avoided when adequate calories are consumed along with the injection. IGF-1 may lead to lymphoid tissue overgrowth. Tonsillectomy and/or adenoidectomy along with tympanostomy tube placement are needed in some patients. Intracranial hypertension can also occur. Too few patients have been treated, however, to accurately judge the incidence of intracranial hypertension during rhIGF-1 treatment.
Monitoring. There must be periodic assessment of safety and efficacy by interim history and physical findings. There is no demonstrated utility of measurement of circulating IGF-1 during treatment. Home blood glucose monitoring is not formally recommended, but can be helpful in some situations. Signs/symptoms of tonsillar/adenoidal hypertrophy should prompt audiometry and other measures. Symptoms of headache, nausea, changes in visual status, and/or irritability might indicate intracranial hypertension
SEX STEROIDS
Androgens were the first growth-promoting hormones used clinically. They stimulate bone growth directly and increase hGH-secretion. Today, androgens are primarily used to treat constitutional delay of growth and adolescence or as an adjunct to hGH.
Clinical use. Testosterone is frequently administered as a long-acting therapy at monthly intervals. A reasonable starting dose is
50 mg/month, with increases every 3 to 6 months. Transcutaneous preparations are more expensive, and the dosing for pubertal induction or growth promotion is not established. Oxandrolone is a nonaromatizable androgen administered orally at 0.05 to 0.1 mg/kg/day. Because it is not metabolized to estrogen, it may produce less bone age advancement. Administering estrogens at very-low (subfeminizing) dose may promote growth without untoward skeletal maturation, but the data are limited.12 At present, it is hard to recommend any estrogen regimen as yielding a significant net gain in height.
Safety. Intramuscular testosterone given to males in the adolescent age range at doses recommended is safe. Oxandrolone is generally safe for both boys and girls if dosing is kept at recommended levels. It reduces insulin sensitivity and could result in carbohydrate intolerance in susceptible individuals.13 Estrogens occasionally cause hyperlipidemia and rarely induce thrombosis.
Monitoring. Patients should undergo periodic assessment of skeletal age. Lipid profiles should be obtained in those with risk factors beginning estrogen therapy.
GnRH AGONISTS, AROMATASE INHIBITORS
Adult height may be increased by delaying puberty with a gonadotropin-releasing hormone (GnRH) agonist or by reducing estrogen, the main hormone driving skeletal maturation, with an aromatase inhibitor. Neither treatment is approved for height augmentation, but there are several reports of clinical trials that document the effects. When puberty is blocked completely with GnRH superagonists, the growth rate slows because of the lack of sex steroid exposure. Yanovski et al14 conducted a randomized trials of GnRH agonist in short, but otherwise normal children. There was about a 5-cm gain with 3 years of therapy.
Aromatase inhibition might allow the beneficial growth effects of androgens while negating the growth plate maturation of estrogens. Data on aromatase inhibitors are sparse but suggestive. Studies show that treatment slows skeletal maturation; however, growth is sustained, implying that end height will be increased.15 The effect on final height remains to be determined, however.
Clinical use. GnRH superagonists are administered as daily injections, intranasally, or in a depot form by injection or implantation. They are extremely effective at suppressing pitutitary gonadotrophin secretion, but treatment may need to be individualized for dose and frequency. When puberty is far advanced, any therapy is unlikely to increase stature.
Clinical trials published of aromatase inhibitors enrolled only boys because the therapy may induce ovarian cysts in girls. Although results are encouraging, using aromatase inhibitors for improving height should be considered experimental at this time because of the small number of patients treated and the scant data on final height.
Safety. There has been concern that such interventions might lead to decreased bone mineral acquisition. There is no evidence at this time that indicates this would be clinically significant. Most of the adverse events associated with GnRH superagonists consist of local site reactions. Aromatase inhibitors appear well tolerated, but the experience is limited in the pediatric population. Testosterone levels increase substantially due to the reflex increase in gonadotrophin secretion. The significance of this is unknown.
Monitoring. When using GnRH superagonists, it is important that pituitary suppression be verified at treatment initiation and periodically thereafter. Skeletal maturation should be determined at least annually. It is premature to discuss monitoring for aromatase inhibition given the experimental nature of its use.
Steven D. Chernausek, MD, is the Children's Medical Research Institute Edith Kinney Gaylord Chair – Diabetes, Oklahoma City. He may be reached at Steven-Chernausek@ouhsc.edu.
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