eMedicine Specialties > Pediatrics: General Medicine > Endocrinology
Hyposomatotropism: Treatment & Medication
Updated: Jul 2, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
Replacement dosages of recombinant human growth hormone (rhGH)
For patients with hyposomatotropism, effective replacement dosages of rhGH are 0.175-0.75 mg/kg/wk, and therapy should be individualized. Dividing the weekly dose into 6 or 7 daily subcutaneous injections is more effective than dividing the total dose into 3 doses administered on alternate days.
Height outcome
In the authors' personal experience in treating patients with GH deficiency (GHD) starting at younger than 4 years, the patient's final height may exceed the target height.
The patient's final height is best correlated with his or her pretreatment chronologic age. It is also related to the height standard deviation score and to the child's predicted adult height, duration of therapy, and birth length. In many studies, the final height was closely correlated with the height standard deviation score, the patient's age at onset of puberty, weight, and serum concentrations of GH binding protein (indicators of GH receptor mass).
Early recognition of GHD is essential for an optimal outcome in terms of height.
Patterns of growth during childhood
Growth during childhood follows predictable patterns.
- Before birth - Prenatal growth averages 1.2-1.5 cm each week.
- Infancy and childhood - Growth velocity increases to 15 cm (approximately 6 inches) per year over the first 2 years and then slows to 6 cm (approximately 2 inches) per year until puberty.
- Puberty - A second peak in growth velocity occurs during puberty. This peak occurs earlier but is lower in magnitude and is shorter in girls than in boys. Characteristics of the Pubertal Peak of Growth Velocity in Girls and Boys
Open table in new window
[ CLOSE WINDOW ]Table
Characteristic Girls Boys Mean age at peak height velocity, y 11.5 13 Magnitude, cm/y 8.5 9.5 Duration, y 5 6 Characteristic Girls Boys Mean age at peak height velocity, y 11.5 13 Magnitude, cm/y 8.5 9.5 Duration, y 5 6
In children who are receiving rhGH therapy, growth velocity usually exceeds reference values in the first few years. Therefore, suspect partial GH resistance or noncompliance if suboptimal growth velocity is observed at the beginning of rhGH therapy.
Treatment principles
- Monitor patients with visits every 3 months.
- Conduct physical examination.
- Perform funduscopy to exclude pseudotumor cerebri.
- Pubertal staging should be performed during each visit because gonadal steroids have a notable effect on skeletal maturation.
- Monitor patients by measuring their height in centimeters and weight in kilograms.
- Obtain interim histories.
- Monitor medical therapy.
- Adjust drug dosages by weight, and monitor patients for adverse effects of therapy (see Medication).
- For patients whose condition does not respond well to weight-based therapy, some clinicians advocate titrating dosages according to insulinlike growth factor (IGF)-1 levels. The goal is to maintain an IGF-1 value in the upper quartile for the child's age and sex.
- Bone age can be used to determine the remaining growth potential for patients with GHD who are approaching their final height. Bone ages have no proven role in monitoring GH therapy.
Surgical Care
- Brain tumors and/or secondary hydrocephalus indicate a need for consultation with a neurosurgeon.
- A pediatric surgeon may be consulted to address cleft lip repair, cleft palate repair, and/or cosmetic reconstruction of the facies in a patient with long-standing GHD.
Consultations
Consultations with the specialists listed below may aid in the care of patients with hyposomatotropism.
- Neurosurgeon
- Plastic surgeon
- Radiation oncologist
- Neurooncologist
- Psychologist
- Nutritionist
Medication
Growth hormone (GH) extracted from cadaveric pituitary glands was used to treat hypopituitarism in children for more than 30 years until 1985, when recombinant human GH (rhGH) became commercially available. Cadaveric hGH was effective. However, complications associated with its use were an inadequate supply, variable biopotencies, and the transmission of Creutzfeldt-Jakob disease.
rhGH and novel treatment modalities
Widespread production of rhGH has increased worldwide use of rhGH. Dosing of rhGH remains arbitrary to some degree.
- In the United States, the customary starting dosage is 0.3 mg/kg/wk given subcutaneously divided in 7 nightly injections.
- In Japan and in many European countries, the customary dosage is approximately 0.025 mg/kg/d or 0.15 mg/kg/wk (50% of the US dose).
With respect to nomenclature and conversion,
3 IU of rhGH = 1 mg of rhGH.
In children who have completely GH deficient, rhGH typically accelerates linear growth to 10-12 cm/y during the first year of therapy and to 7-9 cm/y in the second and third years.
Several novel treatment modalities for GHD have emerged:
- Oral GH secretagogs
- Growth hormone-releasing hormone
- Oral liquid formulations of rhGH
- Depot GH (administered once or twice a month)
Evaluation of most of these modalities remains incomplete at this time. Depot rhGH had been approved for use in GHD but was subsequently removed from the market. Data from clinical trials reported to date suggest that the depot form is less effective for stimulating growth than the daily form. This result was also found with clinical use.
Children with GHD have dramatic and clearly distinguishable responses to rhGH treatment compared with children given placebo. Data regarding the potential benefits of high doses are still being collected. The dose response of rhGH is nonlinear.
A double-blind, placebo-controlled, crossover trial of rhGH therapy in adults with GHD suggested sex-related differences in GH responsiveness. An identical dose of rhGH per body surface area was administered to men and women. With treatment, men had less basal body fat, as well as higher basal levels of serum insulinlike growth factor (IGF)-1, greater basal lean body mass, enhanced lowering of cholesterol levels, and more increases in markers of bone metabolism than did the women. These sex-related differences in the response to rhGH treatment resemble differences found in children.
Of interest, boys have a linear dose-response curve, with maximal effects observed with dosages of 0.1 mg/kg/d, whereas girls have a bell-shaped dose-response curve, with maximal effect at 0.05 mg/kg/d. This evidence suggests that estrogen and testosterone play a role in regulating the secretion and action of GH. As a result, optimal dosing strategies for the treatment of GHD may differ in boys and girls.
The dosage of rhGH may be a valuable parameter for optimizing the response to therapy. In patients who are receiving GH replacement, serum IGF-1 and insulinlike growth factor binding protein-3 (IGFBP-3) concentrations should be monitored carefully, for 2 reasons:
- IGF-1 and IGFBP-3 are direct biomarkers of tissue responsiveness to rhGH therapy. The standard of practice in adults with GHD is titrating the dosage of rhGH to maintain serum growth-factor levels within an age-appropriate reference range; this approach may become standard practice in pediatric patients. Some have proposed mathematical prediction models that can be used to predict the growth response to a specific dosage and to guide the pediatric endocrinologist in modifying therapy when a patient's observed growth falls short of the predicted outcome.
- Monitoring of growth factors is useful for evaluating compliance and for assessing risk. Results of several studies have linked high serum IGF-1 levels to an increased risk of cancer in otherwise healthy patients. Although the data did not indicate a causal relationship, further consideration of this issue is warranted, as is monitoring of IGF-1 and IGFBP-3 levels during rhGH therapy. Individually defined treatment is the goal in patients with GHD. The ability to adjust rhGH dosing on the basis of clinical and biochemical information provides an ideal strategy.
GnRH agonists
Gonadal steroids are important mediators of bone development. When normal or precocious puberty limits the response to GH, delaying puberty with an analog of luteinizing hormone-releasing hormone may be appropriate. However, this strategy in pubertal patients has not led to documented enhancements in final heights.
Nevertheless, the younger the age of pubertal onset, the lower the patient's final height. As a result, leuprolide has been used in patients with fast-tempo puberty or in those in whom GHD was diagnosed late. In a recent multicenter trial in pubertal children (predominantly boys) with GHD, high-dose rhGH 0.7 mg/kg/wk increased near-final heights, without a change in the safety profile. Both of these therapeutic strategies require further study.
GHRH ghrelin is a synthetic form of an identified endogenous ligand for the GH-secretagogue receptor. Ghrelin is involved in a novel system for regulating GH release. It is an acylated peptide with a molecular weight of 3300 Da. Intravenously administered ghrelin stimulated GH release in primary pituitary cell cultures and serum GH in rats. Furthermore, ghrelin strongly stimulates GH release in humans. These characteristics make this peptide a possible therapeutic tool for the future.
rhGHs
These agents are used to treat GHD, chronic renal failure, Turner syndrome, Prader-Willi syndrome, AIDS-wasting syndrome, small size for gestational age with failure to catch up, idiopathic short stature, and short gut syndrome.
Somatropin (Saizen, Genotropin, Humatrope, Norditropin, Tev-Tropin, Nutropin, Valtropin for EMEA-regulated markets)
Polypeptide hormone of recombinant DNA origin. Has 191 amino acid residues, and molecular weight of approximately 22,125 Da. Synthesized in strain of Escherichia coli modified by adding the human GH gene.
Adult
Pediatric
0.3 mg/kg/wk IM/SC divided in 7 nightly doses or 0.05 mg/kg/d
Glucocorticoids may decrease growth-promoting effects; carefully adjust glucocorticoid replacement dose in pediatric patients with coexisting corticotropin deficiency to avoid growth inhibition; increases cytochrome P450 (CYP)–mediated antipyrine clearance in humans (may alter clearance of compounds metabolized by CYP liver enzymes
Documented hypersensitivity; evidence of active neoplastic activity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Closely monitor for malignant transformation of skin lesions, insulin resistance (acanthosis nigricans), diabetes mellitus (polyuria, polydipsia, nocturia, enuresis), hypothyroidism, slipped capital femoral epiphysis (limp, knee, or hip pain), and pseudotumor cerebri (symptoms of increased intracranial pressure); begin therapy only when intracranial lesions are inactive and at least 1 y after antitumoral therapy; discontinue if tumoral growth is evident; do not use to promote growth in children with fused epiphyses
IGFs
These agents are indicated for long-term treatment of severe primary IGF deficiency.
Mecasermin (Increlex), mecasermin rinfabate (Iplex)
Recombinant IGF-1 and IGF-1 with equimolar binding protein-3 (IGFBP-3). Indicated for long-term treatment of growth failure in children with severe primary IGF-1 deficiency (ie, basal IGF-1 and height standard deviation scores of -3 or lower, normal or elevated GH value). IGF-1 essential for normal growth of children's bones, cartilage, and organs, as it stimulates glucose, fatty acids, and amino acid uptake into tissues. IGF-1 is principal hormone for statural growth and directly mediates GH effect. Primary IGF deficiency characterized by lack of IGF-1 production despite normal or elevated GH concentrations.
Adult
Contraindicated
Pediatric
<2 years: Not established
≥2 years:
Mecasermin: 0.04-0.08 mg/kg SC bid initially with meal or snack; if tolerated after 1 wk, may increase by 0.04 mg/kg/dose; not to exceed 0.12 mg/kg bid; once daily dosing may be equally effective; must be administered with food
Mecasermin rinfabate: 0.5 mg/kg SC qd initially; increase to therapeutic dosage range of 1-2 mg/kg qd; administer with meal or snack
Individualize dosage and adjust downward if hypoglycemia occurs
Data limited; caution when coadministering other drugs that alter blood glucose levels
Documented hypersensitivity; closed epiphyses; active or suspected neoplasia; IV administration
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Common adverse effects include hypoglycemia, lipohypertrophy, and tonsillar hypertrophy; contains benzyl alcohol (associated with neurotoxicity in neonates); must be administered with meal or snack to avoid hypoglycemic effect (preprandial glucose monitoring recommended); as with GH administration, intracranial hypertension with papilledema may develop and cause visual changes, headache, nausea, or vomiting; rapid growth may cause progression of slipped capital femoral epiphysis and scoliosis; administration of protein substance may cause local or systemic reaction (eg, flushing, hypotension or hypertension, rash, dyspnea)
More on Hyposomatotropism |
| Overview: Hyposomatotropism |
| Differential Diagnoses & Workup: Hyposomatotropism |
 Treatment & Medication: Hyposomatotropism |
| Follow-up: Hyposomatotropism |
| Multimedia: Hyposomatotropism |
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Further Reading
Keywords
deficient secretion of pituitary growth hormone, deficient secretion of pituitary somatotropin, growth hormone, GH, human growth hormone, hGH, somatotropin, human pituitary growth hormone, human pituitary-derived growth hormone, pit-hGH, growth hormone deficiency in children, growth hormone deficiency, GHD in children, GHD, GH deficiency in children, GH deficiency, growth hormone inadequacy in children, growth hormone inadequacy
recombinant human growth hormone, rhGH, growth hormone-releasing hormone, GHRH, somatotropin-releasing factor, SRF, somatomedin deficiency , pituitary adenylate cyclase activating polypeptide, PACAP, pituitary-specific transcription factor-1, Pit-1, prophet of Pit-1, PROP1, HESX1, insulinlike growth factor, IGF, insulinlike growth factor-1, IGF-1, IGF deficiency, insulinlike growth factor deficiency, insulinlike growth factor binding protein, IGFBP, thyroid-stimulating hormone, thyroid hormone, sex steroids, treatment, diagnosis
