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Address all correspondence and requests for reprints to: David K. Stephure, M.D., Department of Pediatrics, University of Calgary, Alberta Children’s Hospital, 1820 Richmond Road SW, Calgary, Alberta, Canada T2T 5C7. E-mail: david.stephure{at}calgaryhealthregion.ca.
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Abstract |
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Methods: One hundred fifty-four girls with Turner syndrome, aged 7–13 yr, were randomly assigned to one of two groups: 1) GH by sc injection six times per week (0.30 mg/kg·wk), and 2) control (C), no GH treatment. Both cohorts received standardized sex steroid replacement starting at a chronological age of 13 yr. Subjects were followed until protocol completion, defined as height velocity less than 2 cm/yr and bone age 14 yr or greater. A subsequent protocol addendum requested follow-up safety and efficacy assessment in all patients at least 1 yr after the last core protocol visit.
Results: One hundred four patients completed the study (61 GH, 43 C), and 50 withdrew (15 GH, 35 C). At protocol completion, mean heights were 147.5 ± 6.1 (GH) and 141.0 ± 5.4 cm (C), respectively (P < 0.001). Of those who completed the protocol, 59 (40 GH, 19 C) had height data at least 1 yr after protocol completion; in that group, mean heights were 149.0 ± 6.4 (GH) and 142.2 ± 6.6 cm (C), respectively (P < 0.001). At protocol completion and follow-up, the mean height gain due to GH, estimated by analysis of covariance, was +7.2 cm (confidence interval 6.0, 8.4) and +7.3 cm (confidence interval 5.4, 9.2), respectively (both P < 0.001).
Conclusions: This is the first evidence from a randomized, controlled trial to adult height that GH supplementation with induction of puberty at a near physiological age increases the adult height of girls with Turner syndrome.
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Introduction |
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More recently the adult height attained after GH supplementation was reported by numerous groups. Compared with the height predicted or projected at the beginning of treatment and/or to the height attained by historical control groups of patients with Turner syndrome, GH supplementation was estimated to have no effect on adult height in some studies (4, 5), a dramatic effect in others [mean +16.9 cm in a study in The Netherlands (6)], and a moderate effect in most (7, 8). Factors contributing to wide variability in estimated effectiveness include methodological difficulties in predicting or projecting adult height (9, 10), questionable appropriateness of using historical controls (11), patient selection biases, and differences in treatment protocols (age of initiation of GH therapy, dosing regimen, adjuvant therapies). Specifically, delaying estrogen replacement well beyond the physiological age of thelarche was suggested as a way to maximize any effect of GH on adult height (12).
A few protocols have included an untreated control group for the first 12–18 months (3, 13), but maintenance of such a group to adult height was not planned or was abandoned. Therefore, the results from a randomized controlled study of GH supplementation on adult height in Turner syndrome have not been published. In 1989 a randomized, controlled trial of GH supplementation combined with standardized sex steroid replacement was initiated in Canada to examine the effects of GH supplementation on adult height and psychosocial functioning in patients with Turner syndrome. We report the results of an analysis of adult height in those subjects who completed the core study protocol and in a subset of those, who had at least 1 yr of follow-up beyond protocol completion. Effects on psychosocial functioning will be published separately.
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Patients and Methods |
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Eligible subjects were stratified for height relative to chronological age at entry and randomly assigned to recombinant human GH (Humatrope, Eli Lilly Canada Inc., Toronto, Ontario, Canada) by daily sc injection six times weekly (0.30 mg/kg·wk, maximum weekly dose 15 mg) (GH group) or no GH treatment [control group (C)[. Girls with primary ovarian failure received standardized sex steroid replacement as follows: ethinyl estradiol (Schering Canada Inc., Montreal, Quebec, Canada) 2.5 µg/d at age 13 yr, 5.0 µg/d at age 14 yr, and 20 µg on d 1–24 with medroxyprogesterone acetate 10 mg on d 15–24 of each month at age 15 yr and thereafter. Subjects returned for follow-up every 3 months until study completion. Routine hematology, biochemistry, and thyroid function studies were monitored every 3 months (every 6 months in control subjects after the first year of study). Bone age, interpreted by a central reader using the method of Greulich and Pyle (15), was obtained annually. Protocol completion criteria required annualized height velocity less than 2 cm/yr and bone age 14 yr or greater.
An interim analysis performed in 1996 for regulatory purposes contributed to approval of GH for treatment of short stature due to Turner syndrome in the United States and Canada. The Data Monitoring Board for the study subsequently made recommendations that led to the following initiatives: 1) in 1997, in support of intent-to-treat analyses, an attempt was made to contact and obtain height measurements on all patients who had completed the protocol or had withdrawn (1997 follow-up data); 2) analyses of patients who had completed the protocol were updated and were presented in abstract form in 1998 (16); and 3) a formal addendum was initiated in 1998 to assess long-term safety and efficacy (addendum follow-up data), requiring a visit at least 1 yr after the last core protocol visit. The two sources of follow-up data allow comparison of true adult height with protocol-defined adult height and an assessment of the potential for bias due to differences between patients who completed the protocol vs. those who withdrew.
The main analyses presented here are of all patients who completed the core protocol and patients who both completed the core protocol and participated in the formal addendum follow-up. All patients are analyzed as members of the group to which they were randomized, including 10 control patients who withdrew from the core protocol and received GH before follow-up assessment. Data are reported as mean ± 1 SD unless stated otherwise. Differences between groups at baseline and end point for characteristics such as age and duration of therapy were assessed by one-way ANOVA or Fisher’s exact test, as appropriate. Age-specific and adult height SD scores (SDS; height SD score) and the change in height SD scores at protocol completion and follow-up relative to baseline (
height SD score) were calculated according to published standards for girls with Turner syndrome (1). At protocol completion and follow-up, differences in height variables between groups were assessed using an analysis of covariance (ANCOVA) model with explanatory variables of treatment, baseline height SDS, baseline height SDS by treatment interaction, baseline age, and baseline age by treatment interaction. Explanatory variables were removed from the model when not significant; design factors were always retained. This is not the a priori model defined in the protocol but has greater explanatory power. The a priori model and supportive analyses of protocol-complete and intent-to-treat populations, including analyses of available follow-up data on patients who withdrew from the protocol, led to very similar efficacy estimates and statistical inferences.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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. One hundred four girls completed the protocol (GH 61, C 43) and 50 withdrew from participation (GH 15, C 35). A common reason for withdrawal was by patient decision within 6 months of randomization (GH 3, C 16).
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Efficacy analysis
Baseline characteristics and efficacy results are summarized in Table 1. There were no statistically significant differences between the GH and C groups at baseline. At protocol completion and addendum follow-up, the GH and C groups were comparable for bone age and duration of follow-up.
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depicts the individual heights at baseline, protocol completion, and follow-up. At protocol completion, 17 of 61 GH recipients (27.9%) exceeded the 90th percentile for adult women with Turner syndrome, compared with one of the 43 controls (2.3%). The corresponding numbers at follow-up were 14 of 40 (GH, 35.0%) and 2 of 19 (C, 10.5%). At follow-up, 100% of GH recipients (40/40) had increased height SDS, compared with 47.4% of controls (9/19).
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Estimates of efficacy, based on ANCOVA models, were consistent at protocol completion and follow-up. The difference in adult height due to GH, estimated by ANCOVA, was +7.2 cm [95% confidence interval (CI) 6.0–8.5 cm] at protocol completion and +7.3 cm (95% CI 5.3–9.2 cm) at follow-up, each P < 0.001, compared with control patients. Expressed in adult height SDS, this height difference was +1.1 SD (95% CI 0.9–1.3 SD at protocol completion, 0.7–1.4 SD at follow-up, each P < 0.001, compared with control patients).
Figure 3 shows, at most recent available height for all patients who completed the protocol, the change in age-specific height SDS from baseline vs. baseline age. In the ANCOVA model of Table 1
, applied to most recent height data of all patients who completed the protocol, the benefit of each year of earlier GH initiation on height SDS was +0.22 SD (P < 0.001, 95% CI 0.10–0.33 SD) or +1.5 cm/yr, i.e. girls who began GH at an earlier age had greater increase in height, although this age effect is highly variable between patients.
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Of patients who reached age 13 yr during the core protocol (71 GH, 52 C), 13 patients (9 GH, 4 C) were noted by investigators to have secondary sexual characteristics without hormone replacement. Change in height SDS from baseline to latest available height for patients with such findings was +1.1 SD (GH) and +0.2 SD (C) and for those without +1.2 SD (GH) and +0.1 SD (C). The small sample size of this population precludes any formal conclusions regarding differential effect of GH supplementation in girls with sufficient ovarian function to enter puberty without sex steroid replacement therapy.
It is naturally a concern whether those patients who completed both the protocol and the follow-up addendum are representative of the overall study population. In addition to follow-up data collected for patients who completed the protocol, follow-up data beyond the discontinuation visit were obtained for 70% of patients who withdrew from the protocol (from Fig. 1, 13 of 15 GH, 22 of 35 C). Figure 4 summarizes the latest available data on all 154 patients randomized in the study. The available data on patients who had addendum follow-up, 1997 follow-up only, or core protocol data only suggest that there is no inherent difference in these groups, aside from nature of follow-up. Two GH patients lost height SD by the time of follow-up but in both cases had participated in the study for less than 7 months. Seven control patients who withdrew from the study had height gain at follow-up of more than +1 SD; in all but one case, these patients had received GH therapy after leaving the study.
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Adverse events and safety
In 138 patients for whom postbaseline data are available, a significant difference in treatment emergent adverse events between GH (n = 74) and C (n = 64) subjects was noted as follows: 1) surgical procedures (37 GH, 17 C, P = 0.005); 2) otitis media (35 GH, 17 C, P = 0.014); 3) ear disorder (15 GH, 4 C, P = 0.024); 4) joint disorder (10 GH, 2 C, P = 0.036); 5) respiratory disorder (8 GH, 1 C, P = 0.037); 6) sinusitis (14 GH, 4 C, P = 0.041); and 7) goiter (0 GH, 4 C, P = 0.044). Death from ruptured aortic aneurysm occurred in a single control subject. Two GH recipients withdrew because of an adverse event, one because of elevated transaminase levels and one because of intracranial hypertension. After protocol completion, there was no significant difference in auditory acuity (conductive or neurosensory) between groups (data not shown). There were no significant between-group differences in change from baseline to end point in fasting blood glucose, hemoglobin A1c, serum T4, or TSH (data not shown).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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). Even in the nonrandomized studies that have reported very positive mean outcomes, a small proportion of patients were found not to respond to GH supplementation at all (12). The reason for the uniformly positive height outcome in the present study is unclear but may relate to greater adherence to treatment in patients who complete randomized, controlled trials (17). The pubertal induction protocol allowed thelarche and menarche to occur about 2 SD beyond the mean age of occurrence of these important milestones of adolescence. This sex steroid replacement protocol may have a positive impact on psychosocial adaptation and bone health, two important challenges for patients living with Turner syndrome (18, 19). Whereas we began sex steroid replacement at a younger age than in some other published studies (4, 5, 6, 7, 8, 9), our patients experienced similar magnitude of height gain from GH therapy. Our results and those of a recent observational study (20) with a very low initial dose of ethinyl estradiol do not support the practice of delaying pubertal induction further, especially in those girls who request age-appropriate feminization.
The GH recipients had significantly more ear disorders, otitis media, and surgical procedures (mostly ear, nose, and throat surgeries) than the control patients. Possible explanations for these observations could include an increase in the size of tonsils and adenoids with GH treatment (21) or a reporting bias due to the unblinded design of the present study. Given the heavy burden that hearing loss represents for many adult women with Turner syndrome (22), formal audiometry was undertaken in this study starting in 1998; there were no differences in auditory acuity between GH and control patients. The increase in joint disorders observed in the GH group has also been observed in dose-titration studies in GH-deficient adults (23).
The impact of age at initiation of GH treatment on adult height remains controversial, with some studies suggesting that earlier is better (13, 24) and some finding no effect (20). Our own results show a significant, although variable advantage to starting at 7–8 yr rather than at 12–13 yr (Fig. 3). Our study design cannot distinguish between an effect of age of initiation, total duration of GH therapy, or duration of GH therapy before starting sex steroid replacement. Whether starting earlier than age 7 yr would result in a greater gain in adult height remains to be demonstrated. In one study (25), GH accelerated bone maturation in very young children with Turner syndrome. In addition, young children with Turner syndrome do not yet perceive their height as a problem and may not easily accept daily injections (26). Analyses of the effect of baseline height SDS on change in height SDS due to GH therapy were inconclusive.
Statistical modeling leads to consistent estimation, at protocol completion and follow-up, of height gain due to GH therapy. However, patients continued to grow after protocol completion. Accordingly, age-specific height SDSs and adult height SDSs differ at time of completion. The follow-up data resolve this issue by examining patients when growth has either ceased or is extremely slow. At follow-up, we see that the age-specific and adult SDSs are the same. Moreover, our control patient population was very similar to the standards established by Lyon et al. (1) in attained height SDS (–0.1 ± 1.0, Turner adult) and the mean; control patients attained their projected height SD ( = 0.0 ± 0.5). This is one reason we believe that the patients who participated in the addendum follow-up accurately represent the overall study population. These observations show that, for the most accurate evaluation of the impact on adult height of therapies for short stature, studies should follow patients until cessation of growth, even if treatment is stopped earlier.
In summary, we report the first conclusive evidence, based on a randomized, controlled trial to adult height, of a positive impact of GH supplementation on the adult height of Turner syndrome patients. The benefits of GH supplementation need to be balanced against the cost of therapy and the need for daily sc injections over a period of many years. The differences in the magnitude of the height gain observed in our study and those reported by others may reflect differences in study design, patient selection, duration of GH supplementation, GH dosage, concurrent anabolic steroid administration, or timing and dosage of estrogen replacement. The impact of GH on psychosocial adaptation and adult health outcomes in these patients requires further study. In conclusion, GH supplementation with induction of secondary sexual characteristics at a near physiological age increased the mean adult height of girls with Turner syndrome. Patients and parents should establish with their physician realistic expectations of GH supplementation. The results of the present analysis provide a strong justification to offer the option of GH supplementation to school-age girls with Turner syndrome and an accurate estimate of what can be expected from this intervention.
Steering and Writing Committees: D. K. Stephure (Chairman and Principal Investigator 1994 to present) (University of Calgary); G. Anglin (Statistics) (Eli Lilly Canada Inc.); J. Chipman (Eli Lilly & Co.); D. Daneman (University of Toronto); H. J. Dean (University of Manitoba); H. J. Guyda (McGill University); F. J. Holland (Principal Investigator 1989–1994) (McMaster University); C. Quigley (Eli Lilly & Co.); G. Van Vliet (University of Montreal).
Writing Committee: D. K. Stephure (University of Calgary), G. Anglin (Eli Lilly Canada Inc.), G. Van Vliet (University of Montreal).
Data Monitoring Board: J. G. Hall (Chairman) (University of British Columbia); M. A. Preece (Institute of Child Health); W. Taylor (McMaster University).
Bone Age Interpretation: A. Daneman, B. Riley (University of Toronto).
The following investigators and academic institutions also participated in this research: S. R. Salisbury (Dalhousie University); J. A. Curtis (Memorial University); F. Szots (Laval University); R. D. Barnes, L. Legault, C. Polychronakos, C. Rodd (McGill University); A. B. MacMillan, J. A. Vander Meulen (McMaster University); D. S. Alexander (Queens University); R. M. Couch, E. E. McCoy (University of Alberta); D. Metzger, H. F. Kitson, L. L. Stewart, W. J. Tze (University of British Columbia); S. P. Taback (University of Manitoba); R. Collu, C. L. Deal, C. Huot (University of Montreal); K. A. Faught, M. L. Lawson, S. E. Muirhead (University of Ottawa); T. B. Best, G. A. Bruce (University of Saskatoon); K. Khoury (University of Sherbrooke); J. D. Bailey, R. M. Ehrlich, K. Perlman, J. Rovet (University of Toronto); B. C. Boulton (University of Victoria); C. L. Clarson, M. R. F. Jenner (University of Western Ontario).
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Acknowledgments |
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Footnotes |
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1 A listing of The Canadian Growth Hormone Advisory Committee appears in the Appendix. 
Abbreviations: ANCOVA, Analysis of covariance; C, control group; CI, confidence interval; SDS, SD score.
This work was supported by Eli Lilly Canada, Inc.
Received November 8, 2004.
Accepted March 14, 2005.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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