Background Information of the Condition
Growth hormone (GH) is synthesized and released from the anterior pituitary gland. GH releasing hormone stimulates GH secretion and somatostatin inhibits it. After peaking in puberty, endogenous GH secretion declines by about 14% per decade (Fisker, S et al 2005). Adults with GH deficiency include those with childhood-onset GH deficiency, those who have had injury to the hypothalamus or pituitary, or had pituitary tumors, pituitary surgery, or radiotherapy (Toogood, A. 2005). An estimated 3 in 10,000 adults have GH deficiency (Toogood, A. 2005).
GH deficiency in adults is associated with lack of energy, lack of interest in sexual activity, emotional lability, abnormal body composition (increased fat mass, decreased lean body mass, increased abdominal fat), decreased exercise capacity, decreased bone mineral density, thin and dry skin, serum lipid abnormalities, reduced insulin sensitivity, abnormal cardiovascular risk factors, and poor quality of life.
Drug (Product Monograph)
Category: Nutropin (generic name: somatropin) is a synthesized recombinant human GH.
Mechanism of Action: Nutropin is identical in protein structure to pituitary-derived human GH and has similar effects in terms of pharmacokinetics, stimulation of growth and other actions. GH stimulates skeletal, organ, and cell growth, and has a regulatory role in protein, carbohydrate, lipid, mineral, and connective tissue metabolism.
Indications: For the replacement of endogenous GH in patients with adult GHD who have peak GH levels ≤ 5μg/L and were GH deficient since childhood or as an adult
Dose: Daily subcutaneous injection should not exceed 0.006 mg/kg/day. It may be increased to a maximum of 0.025 mg/kg/day in individuals’ ≤ 35 years, and a maximum of 0.0125 mg/kg/day in individuals > 35 years of age. Lower doses may be required in older or overweight individuals.
Methodology of Systematic Review
In double blind randomized controlled trials (DBRCTs), does Nutropin provide a therapeutic advantage in terms of mortality, morbidity or improvement in quality of life over other synthesized recombinant human GH or placebo in the treatment of adult patients with GH deficiency?
DBRCTs in adult patients with GH deficiency will be critically appraised. Health outcomes will be assessed according to the following hierarchy – all cause mortality, non-fatal serious adverse events, quality of life, withdrawals due to adverse events, efficacy as measured by changes in exercise endurance and muscle strength, and other adverse events.
Databases searched were MEDLINE (1966 to June 2006), EMBASE (1988-June 2006), and the Cochrane database (issue 2, 2006).
No DB RCT was identified comparing Nutropin to other synthesized recombinant human GH. Three DBRCTs (Baum, HB et al 1998, Hoffman, AR et al 2004, and Underwood, LE et al 2003) compared Nutropin to placebo in patients with GH deficiency. Data from Underwood et al 2003 trial was not included since the trial included patients with bone age ≥ 14 years but did not report on outcome measures separately in patients’ ≥ 18 years age.
Results by trial:
Hoffman et al 2004, is a 12-month trial in 171 adult men and women (mean age ranging from 46 to 50 years) with adult onset GH deficiency comparing initial dose of rhGH (Nutropin) or placebo given subcutaneously once daily. Nutropin was administered at 0.0125 mg/kg/day for the first month and then increased to 0.025mg/kg/day as tolerated [7(8%) subjects received 0.025mg/kg/day between month 1 and 3, but no patient continued this dose through month 12]. If adverse events occurred, the dose could be reduced to 0.00625mg/kg/day. If adverse events persisted for 3 months or more at this dose, the patient could be discontinued from the study at the discretion of the investigator. Dose reductions occurred in 21% of patients primarily because of edema. At 12 months, 79% of patients remained on a dose of 0.0125mg/kg/day. A single primary outcome was not identified. Multiple outcomes were evaluated including reduction in proportion of body mass composed of fat, an increase in thigh muscle strength and endurance, and improved quality of life and there was no significant difference between GH and placebo groups.
Mortality and non-fatal serious adverse events were not reported. 14 subjects withdrew from the GH group due to adverse events [edema (2), arthritis (1), arthritis-like symptoms (4), carpal tunnel syndrome(3), increasing suprasellar mass (2), abnormal glucose tolerance (1), and Graves disease(1)] and 4 patients in the placebo group (ARI = 11.8%, NNH = 8). Significant increase in arthralgia was reported in men (ARI = 24%, NNH = 4), and edema in women (ARI = 30%, NNH = 3) receiving GH as compared to placebo. Statistically significant improvements were observed in surrogate outcomes such as total cholesterol and low density lipoprotein (p < 0.05) the clinical significance of which is not known.
Baum et al 1998 is an 18-month trial in 40 men (median age 51 years) with adult onset GH deficiency comparing initial dose of rhGH (Nutropin) 10 µg/kg/day or placebo given subcutaneously once daily. Serum IGF-1 levels were measured at week 1 and month 1, 3, 6 and 12 and if they were elevated the GH dose was reduced by 25%. The mean dose received at study completion was 4 + 2µg/kg/day. 37/40 (93%) of patients had undergone surgery, radiation, chemotherapy or a combination there of and 38/40 (95%) were receiving adrenal, thyroid and /or gonadal hormone replacement therapy. A single primary outcome was not identified. Multiple outcomes were evaluated including various psychometric testing for cognitive function as well as sense of well being and quality of life scores. 6/40 (15%) withdrew from the study -5 from the GH group (1 each due to seizure, tachycardia, or cerebrovascular accident, and 2 due to non medical reasons) and 1 from the placebo group (due to pneumonia). Mortality and serious adverse events were not reported. Chronic low-dose GH replacement is not associated with significant alterations in cognitive function or quality of life. There is inadequate reporting of all adverse events. GH-related adverse events were reported in 3 patients (2 patients developed edema and one patient developed myalgia).
A systematic review by a UK National Health Service Health Technology Assessment (Bryant et al 2002) reports on the clinical effectiveness and cost-effectiveness of growth hormone in adult patients with childhood onset or adult onset GH deficiency. Seventeen randomized controlled trials reporting quality of life scores were included. The review concludes that the effectiveness of GH on mortality or morbidity is not known. GH has no significant effect compared to placebo on quality of life scores. There was a significant increase in short-term adverse events: edema (NNH – 5 to 16) and arthralgia (NNH – 5 to 10) across trials. They recommend that long-term adverse events need to be studied particularly cancer rates and glucose regulation.
Critical appraisal Issues:
Two trials of 12 and 18 months in duration did not identify a single primary outcome measure. They did not report on mortality and non-fatal serious adverse events. There was poor reporting of total adverse events in the GH group as compared to placebo. There is inadequate information regarding long-term effects of GH.
- No double blind randomized trial was identified comparing Nutropin to other synthesized recombinant human GH products, therefore there is insufficient evidence that it provides a therapeutic advantage vs. other synthesized recombinant human GH in the treatment of adults with childhood- or adult-onset growth hormone deficiency.
- There is insufficient evidence from published double-blind randomized controlled trials that Nutropin as compared to placebo provides a therapeutic advantage in terms of mortality, morbidity or quality of life.
- Fisker S, Andersen M, Orskov H. Diagnosis of growth hormone deficiency. Frontiers of Hormone Research, 33:68-85, 2005.
- Nutropin Product Monograph. Roche Pharmaceuticals, 2005.
- Toogood A. Safety and efficacy of growth hormone replacement therapy in adults. Expert Opinion in Drug Safety, 4(6): 1069-1082, 2005.
- Baum HBA, Katznelson L, Sherman JC, Biller BMK et al. Effects of physiological growth hormone (GH) therapy on cognition and quality of life in patients with adult-onset GH deficiency. Journal of Clinical Endocrinology & Metabolism, 83(9): 3184-3189, 1998.
- Hoffman AR, Kuntze JE, Baptista J, Baum HBA, et al. Growth hormone (GH) replacement therapy in adult-onset GH deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial. Journal of Clinical Endocrinology & Metabolism, 89(5): 2048-2056, 2004.
- Underwood LE, Attie KM, Baptista J, et al. Growth hormone (GH) dose-response in young adults with childhood-onset GH deficiency: a two-year, multicenter, multiple-dose, placebo-controlled study. Journal of Clinical Endocrinology & Metabolism, 88(11): 5273-5280, 2003.