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    Drugs & Diseases > Pediatrics: General Medicine

    Hyposomatotropism (Growth Hormone Deficiency) Medication

    Updated: Jan 24, 2019
    • Author: Sunil Kumar Sinha, MD; Chief Editor: Robert P Hoffman, MD  more...
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    Medication

    Medication Summary

    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/yr during the first year of therapy and to 7-9 cm/yr in the second and third years.

    Several novel treatment modalities for GHD have emerged, as folows:

    • 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/day, whereas girls have a bell-shaped dose-response curve, with maximal effect at 0.05 mg/kg/day. 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:

    1. 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.

    2. 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.

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    rhGHs

    Class Summary

    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.

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    IGFs

    Class Summary

    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.

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