Without trials comparing Genotropin with other somatropin products in adults with GHD, we undertook a literature search to identify and describe systematic reviews that would provide information relevant to the evaluation of the efficacy and harms of somatropin in this population. Eight systematic reviews covering most of the clinically important outcomes in adults with GHD were identified.15–22 The studies included in these reviews consisted of randomized and non-randomized trials, as well as observational studies. Five reviews included placebo-controlled RCTs exclusively.17,19–22 One systematic review assessed the clinical effectiveness and safety in elderly patients (> 60 years) exclusively.18 The number of included studies in each review ranged from 8 to 54. Use of somatropin was compared with no treatment or placebo, or a before–after treatment comparison was carried out in these studies. Outcome measures that were examined included health-related quality of life (HRQoL), body composition, lipid profile, BMD, exercise capacity, muscle strength and safety. Meta-analysis was performed in six of the eight systematic reviews.16,17,19–22 All of the reviews treated the various somatropin products collectively without differentiating among them. Only one review specified the somatropin agents that were examined.17 The systematic reviews included in this review are summarized in .
a. Critical Appraisal of the Systematic Reviews
The methodological quality of the included systematic reviews was evaluated using the “assessment of multiple systematic reviews.”23
Overall, the systematic reviews were conducted using acceptable methods to identify, extract, appraise, and summarize studies. Limitations included restriction to English-language publication only,15,16 uncertainty as to whether grey literature searching was performed,15,16,18–21 failure to assess the methodological quality of the included studies,16,18,19 and lack of assessments for publication bias.15,18,20,21 Conflict of interest and funding sources were reported in all but one review (Maison et al. 200422). Results of the critical appraisal are summarized in below.
Critical Appraisal of Systematic Reviews.
b. Summary of Key Characteristics of the Included Studies in the Systematic Reviews
The Appelman-Dijkstra et al., review15 included 23 prospective studies, of which 11 had a control arm. No RCTs were identified by the review authors. The number of patients in the individual studies ranged from 10 to 13,983 (patient cohorts overlapped among some of these studies), and the treatment duration ranged from 4 to 15 years. Different doses of somatropin were used in each study, with a mean dose ranging from 0.3 mg to 0.8 mg per day. Dose titrations were determined according to body weight or IGF-1 levels according to the normal age and sex-related range. At baseline, patients ranged from 27 to 65 years of age. The vast majority of patients had adult-onset GHD.
The meta-analysis performed by Xue et al.16 included 20 prospective studies evaluating effects of somatropin on BMD of total body, femoral neck, and spine. It is unclear how many RCTs were included. The numbers of patients in the individual studies ranged from 12 to 128, and treatment duration ranged from six months to 15 years. Different doses of somatropin were used in studies employing dosage adjustment according to body weight, body surface area, or IGF-1 levels. Age at baseline ranged from 17 to 74 years. Pooled standardized mean difference with 95% confidence interval (CI, using either fixed-effect or random-effect models, depending on heterogeneity among the included studies) were used to analyze the effects of somatropin therapy on BMD. The methodological quality of the included studies was not examined, although the authors stated that publication bias was not detected.
The meta-analysis by Hazem et al.17 included the largest number of studies. Data on body composition and HRQoL from 54 placebo-controlled RCTs with more than 3,400 patients were synthesized. The numbers of patients in the individual studies ranged from 10 to 171, and the treatment duration ranged from 3 to 24 months. This was the only review that specified the type of somatropin products assessed. Genotropin, Humatrope, Nutropin and Norditropin were evaluated, and Genotropin was the most frequently investigated study drug. Different doses of somatropin were used in studies employing dosage adjustment according to age, sex, body weight, body surface area, and IGF-1 levels. The dose of Genotropin in this review ranged from 0.4 mg to 1.8 mg per day (assuming 80 kg body weight). Age at baseline ranged from 18 to 79 years. Random-effect models were used to generate pooled relative risk (RR) or weighted mean difference (WMD); subgroup analyses were performed to seek explanations for inconsistency in results across trials. The methodological quality of the included studies was described as fair using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. Significant publication biases for the outcomes of lean body mass and carpal tunnel syndrome were detected using funnel plots. The overall effects of somatropin versus placebo were reported, instead of individual effects of each somatropin product.
The Kokshoorn et al. review18 included 11 prospective studies (two of them were placebo-controlled RCTs) enrolling patients older than 60 years. The numbers of elderly patients in the individual studies ranged from 10 to 135 (patient cohorts overlapped among some of these studies), and the treatment duration ranged from six months to 10 years. The two included RCTs recruited 34 and 31 patients, respectively, and the treatment durations ranged from 6 months to 12 months. Different doses of somatropin were used in each study, with a mean dose ranging from 0.16 mg to 0.5 mg per day. Doses titrations were based on clinical response, body weight, or IGF-1 levels. The methodological quality of the included studies was not assessed, nor was publication bias.
The meta-analysis by Rubeck et al.19 included 15 double-blind placebo-controlled RCTs evaluating the clinical effects of somatropin on exercise capacity and muscle strength. The numbers of patients in the individual studies ranged from 9 to 38, and the treatment duration ranged from 3 to 12 months. The mean age at baseline ranged from 20 to 49 years. Different doses of somatropin were used in each study, with a mean dose ranging from 5 mcg/kg to 24 mcg/kg per day. The quality of the included studies was not reported, although the authors indicated that publication bias was unlikely in this review.
Widdowson and Gibney conducted a meta-analysis in 200821 to evaluate the effects of somatropin on exercise performance. It included 11 double-blind, placebo-controlled RCTs. The numbers of patients in the individual studies ranged from 10 to 55, and the treatment duration ranged from 6 to 18 months. Different doses of somatropin were used in each study, with a mean dose ranging from 3.3 mg to 15.7 mg per week. The mean age of patients at baseline ranged from 24 to 49 years. The methodological quality of the included studies was not reported, although the authors indicated that quality assessment had been performed. Data analysis was carried out using a fixed-effect model.
Widdowson and Gibney conducted another meta-analysis in 201020 to investigate the effects of somatropin on muscle strength in adults with GHD. Eight double-blind, placebo-controlled studies were included. The numbers of patients in the individual studies ranged from 14 to 35, and the treatment duration ranged from 3 to 12 months. The mean age of patients at baseline ranged from 29 to 49 years. Different doses of somatropin were used in each study, with a mean dose ranging from 3.3 mg to 13.3 mg per week. The methodological quality of the included studies was not reported, although the authors indicated that quality assessment had been performed. The methods for data synthesis were the same as the Widdowson and Gibney 2008 review.
Maison et al. conducted a meta-analysis of blinded placebo-controlled RCTs of somatropin on cardiovascular risk factors, such as blood pressure, blood glucose, lipid profile and body composition.22 Thirty-seven trials (36 double-blind and 1 single-blind) were included. The numbers of patients in the individual studies ranged from 8 to 166, and the treatment duration ranged from 3 to 12 months.
The vast majority of the patients had adult-onset GHD. The mean age of patients at baseline ranged from 24 to 50 years. Different doses of somatropin were used in each study, with a mean dose ranging from 0.1 IU/kg to 0.56 IU/kg per week. The quality of the included studies was assessed based on study design, randomization method, blinding, and statistical methods. The authors indicated that the studies were generally of good quality, without providing further details, and that publication bias was unlikely. Global effect sizes for each outcome were calculated based on standardized effect sizes for each study. Random-effect models were adopted. The effects of the somatropin dose, treatment duration, percentage of patients with adult-onset GHD, and study design on overall estimates were assessed through stratification or meta-regression.
c. Summary of Efficacy Outcomes
Health-Related Quality of Life
HRQoL data were reported in two of the included systematic reviews.15,17 The main findings are shown in .
Findings on HRQoL From Systematic Reviews.
Three questionnaires of HRQoL assessment were adopted in these reviews.
The Quality of Life–Assessment of Growth Hormone Deficiency in Adults (QoL–AGHDA) is a patient self-reported, condition-specific instrument for adults with GHD that can be used in clinical trials or for routine patient assessment. The questionnaire consists of 25 items with a Yes/No response format. A score of 1 is given to each “Yes” answer, and the total score is the sum of the individual scores for all 25 items. A higher total score represents poorer quality of life. The dimensions of the questionnaire are memory and concentration, friendships, social activities, mood, sleep, energy, work (paid or unpaid), confidence/self-esteem, family life, and expectations. The reliability, internal consistency, and construct validity of the QoL–AGHDA were described as good in a pharmaceutical company–sponsored study.24 A minimal clinically important difference (MCID) for QoL–AGHDA was not identified in the literature.
The Nottingham Health Profile (NHP) is a self-administered, generic questionnaire that measures perceived health problems — social, physical, and mental. It consists of two parts. Part I (NHP I) has 38 statements measuring six dimensions of health: physical mobility (8 statements), sleep (5 statements), energy (3 statements), pain (8 statements), social isolation (5 statements) and emotional reactions (9 statements). Respondents are required to answer “Yes” or “No.” The final score for each dimension is measured on a range from 0 to 100, with higher scores indicating poorer health. Part II of NHP (NHP II) provides a general estimate of social functioning perceived to be affected by individual health status. NHP II consists of one statement for each of the following seven areas: jobs around the home, paid employment, family relationships, sex life, holidays, hobbies/interests, and social life. Respondents are required to answer with “Yes” or “No.”25,26 The reliability and validity of NHP have not been evaluated in adult patients with GHD.
The Psychological General Well-Being Index (PGWBI) is a generic, self-administered questionnaire commonly used in adults with GHD to measure psychological well-being. PGWBI assesses six affective states (positive well-being, general health, depressed mood, self-control, and vitality) using 22 questions. The score for each question ranges from 0 to 5 (maximum total score is 110), or 1 to 6 in some studies (resulting in a total score of between 22 and 132). Higher scores indicate higher levels of psychological well-being. It is important to be aware of the different scoring algorithms, as they may affect the interpretation of the overall score.27 The validity and reliability of this HRQoL questionnaire have been evaluated in adult- or childhood-onset GHD. An MCID for PGWBI was not identified in the literature.
In the Appelman-Dijkstra et al. review,15 four non-RCTs with 2,197 patients reported HRQoL results. Treatment duration in these studies ranged from 4 to 10 years. Compared with no treatment or healthy controls, somatropin therapy was associated with improved overall psychological well-being, energy, and emotional reaction in one study (instrument not specified); another study reported higher energy levels with somatropin therapy (measured with NHP); the third study reported increase in vitality score (measured with PGWB); and the fourth study reported an improved QoL–AGHDA score in the first year of treatment, and a sustained improvement or regression to country-specific mean thereafter. The authors concluded that HRQoL improved during long-term somatropin therapy, particularly within the first year of treatment. However, no detailed HRQoL data were reported in this review.
The Hazem et al. review17 also reported findings on HRQoL from 16 RCTs with treatment duration of 3 to 18 months. The HRQoL assessment questionnaires adopted included, but were not limited to, NHP, PGWBI, AGHDA, Beck Depression Index, General Health Questionnaire, General Well-being Questionnaire (GWBI) and SF-36. In 9 out of 16 studies, patients on somatropin therapy showed significant improvements from baseline in at least one subsection of general health, energy levels, the mood subsections, emotional reaction, and psychological distress. Five out of 16 studies reported no difference in HRQoL between somatropin and placebo. One study reported significant deterioration in physical activity, energy, and general health in the placebo group, but not in the somatropin group. However, two studies reported significant improvement in pain and social isolation with placebo compared with the somatropin group. The authors concluded that most trials of this review demonstrated improvement in HRQoL in somatropin-treated patients.
Presentation of HRQoL data was heterogeneous, and meta-analysis was not feasible in either review. In summary, some studies (RCTs and non-RCTs) have shown benefits of somatropin on certain dimensions of quality of life; however, benefits were not consistently observed.
Exercise Capacity
Two meta-analyses reported summary results for the effect of somatropin therapy on exercise capacity ().19,21 Significant benefits of somatropin replacement on exercise capacity were identified. In the Widdowson and Gibney 2008 review, the summary effect size for somatropin versus placebo was 0.34 for maximal oxygen uptake (VO2 max), 0.4 for maximum power output, and 0.32 for overall combined variable set. All values were statistically significant. In the Rubeck et al. review, aerobic exercise capacity was measured as either VO2 maximum, total work performed, or exercise time. A significant 8.9% increase in aerobic exercise capacity was observed with somatropin therapy versus placebo.
Findings on Exercise Capacity From Systematic Reviews.
Muscle Strength
One systematic review and two meta-analyses reported results on muscle strength (). Summary effect sizes or WMDs between somatropin therapy and placebo were reported.15,19,20 The Appelman-Dijkstra et al. review narratively reported its findings without data synthesis, and indicated that somatropin improved muscle strength during the first five years of treatment, but these effects were not sustained after prolonged follow-up. The Widdowson and Gibney 2010 review indicated that there was no statistically significant beneficial effect of somatropin therapy on muscle strength. The Rubeck et al. review failed to show a convincing effect of GH replacement on muscle strength.
Findings on Muscle Strength From Systematic Reviews.
Lipid Profile
Three systematic reviews and meta-analyses15,18,22 examined the lipid profile in patients treated with somatropin ().
Findings on Lipid Profile From Systematic Reviews.
Inconsistent results were reported in the Appelman-Dijkstra et al. review, which assessed long-term lipid metabolism based on data from 10 studies involving 827 patients: 7 out of 10 studies reported favourable changes with somatropin therapy, while another 3 did not find changes in lipid profile after somatropin administration. No numerical data were provided in this review. The Kokshoorn et al. review presented consistent results favouring somatropin for total cholesterol (TC) and low-density lipoprotein (LDL) in elderly patients, but inconsistent results were reported for high-density lipoprotein (HDL). The Maison et al. review reported that somatropin significantly lowered TC and LDL. Overall, the effects of somatropin on lipid profile were inconsistent, although the systematic reviews were more likely to report lower TC and LDL with treatment.
Bone Mineral Density
Two systematic reviews reported effects of somatropin therapy on BMD. In the Appelman-Dijkstra et al. review,15 results were inconsistent across the five non-RCTs that reported this outcome: BMD increased in three studies, while in another two studies, no differences were detected in BMD when somatropin was compared with no treatment, or a before–after treatment comparison was conducted. Two cases of bone fracture were reported in one study with 15 years’ treatment duration ().
Findings on Bone Mineral Density From Systematic Reviews.
In the meta-analysis by Xue et al., the standardized mean differences in BMD were statistically significant between somatropin therapy and placebo or no treatment, on all three sites of interest (total body, spine, and femoral neck).
Body Composition
Four reviews reported results regarding body composition.15,17,18,22 In the Appelman-Dijkstra et al. review, most of the included studies reported increased lean body mass and decreased total body fat with somatropin therapy. The Hazem et al. review of RCTs reported statistically significant increases in lean body mass and decreased body fat mass after somatropin therapy. The Maison et al. review of RCTs also indicated favourable effects of somatropin on body composition. Inconsistent results for body composition were reported in elderly patients in the Kokshoorn et al. review: somatropin had no impact on body composition in two trials, but had small effects on lean body mass and body fat in another four trials ().
Findings on Body Composition From Systematic Reviews.
d. Summary of Safety Outcomes
Mortality
Only one systematic review reported long-term (five to six years’ study duration) mortality in adult patients with GHD.15 Conflicting results were reported: according to data from three observational studies, increases in overall, cardiovascular or cerebrovascular-related, and infection-related mortality were observed in the study population after long-term somatropin therapy, compared with the general population; yet inconsistent findings were reported in other studies (). Data from one study showed that treatment with somatropin was not associated with a higher risk of malignancy-related death.
Findings on Mortality from Systematic Reviews.
Glucose Metabolism
Two systematic reviews reported the impacts of somatropin on glucose metabolism (). The Appelman-Dijkstra et al. review examined the long-term effects (5 to 10 years) of somatropin therapy on glucose metabolism. Elevated glucose levels in somatropin-treated patients were reported in some but not all studies in this review. The Maison et al. review reported statistically significantly elevated glucose levels with 2 to 18-month somatropin therapy compared with placebo.
Findings on Glucose Metabolism From Systematic Reviews.
Hypertension
Three systematic reviews assessed the impact of somatropin therapy on blood pressure in adults with GHD ().15,18,22 The Appelman-Dijkstra et al. review reported that long-term treatment with somatropin had no effects on systolic blood pressure, while it may lower diastolic blood pressure. Effects of somatropin therapy were inconsistent in elderly patients enrolled in the included trials in the Kokshoorn et al. review. A statistically significant change in diastolic blood pressure was related to the use of somatropin in the Maison et al. review.
Findings on Blood Pressure From Systematic Reviews.
Adverse events, serious adverse events, withdrawal due to adverse events and harms of special interest, such as change in IGF-1 levels and tumour occurrence, were not evaluated in any of the included systematic reviews.
In summary, eight systematic reviews assessing the effects of somatropin in adults with GHD were included in this review. All reviews except the Appelman-Dijkstra et al. review included RCTs, and five included placebo-controlled RCTs exclusively. Statistically significant improvements in exercise capacity were reported in somatropin-treated patients, compared with placebo. Conflicting results were reported for the outcomes of HRQoL, muscle strength, change in lipid profile, BMD, and body composition. Since an MCID is not available for the employed HRQoL assessment tools or other outcomes, and numerical estimates were rarely reported in the reviews, the clinical relevance of the observed improvements is unclear. Data for safety of somatropin were scarce and inconsistently reported.
