| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Editorial |
Department of Pediatric Endocrinology and Institut National de la Santé et de la Recherche Médicale Unité 561 Groupe hospitalier Cochin–Saint Vincent de Paul and Université Paris V 75014 Paris, France
Address all correspondence and requests for reprints to: Prof. Jean-Claude Carel, Pediatric Endocrinology and Institut National de la Santé et de la Recherche Médicale Unité 561, Groupe hospitalier Cochin–Saint Vincent de Paul, 82 av Denfert Rochereau, 75014 Paris, France. E-mail: carel{at}paris5.inserm.fr.
Short stature is a hallmark of Turner syndrome, with an estimated mean loss of 20 cm associated with X chromosome aneuploidy (1). Studies of this condition have increased our understanding of the role of sex chromosomes in growth regulation and led to the discovery of the SHOX gene (1). Early attempts to increase stature by treatment with extracted GH gave variable results. In the mid 1980s, clinical trials of recombinant GH in Turner syndrome (2, 3) demonstrated a dose-dependent growth-promoting effect and led to the approval of GH use for Turner syndrome (2, 3). However, although more than 10,000 patients have now been treated with GH, few studies have considered the impact of treatment on adult height. Analyses based on comparison with historical controls have shown variable estimates of gains in mean height, ranging from minimal in a study by Canadian investigators (4) to up to 17 cm for high doses of GH (5). In the absence of randomized studies including an untreated control group, a recent systematic review concluded that "there is little evidence on the effects of GH on final height" (6).
The long-awaited Canadian randomized control trial published in this issue of The Journal of Clinical Endocrinology and Metabolism (7) is a major milestone after years of uncertainty, and its investigators should be congratulated on its straightforward design and careful follow-up. They randomly assigned 154 children to treatment with GH or no treatment and both groups were observed until adult height was reached. They were able to follow 61 of 76 treated patients and 43 of 78 controls to adult height and observed a 7.2 cm difference between the two groups, with a 95% confidence interval of 6.0–8.4 cm. The dose used (42 µg/kg·d) corresponds to 78% and 84% of the upper limit of the dose range recommended for Turner syndrome in the United States and in Europe. The mean duration of treatment was 5.7 yr, and puberty was induced pharmacologically at a chronological age of 13 yr. A key issue in the interpretation of long-term results for GH treatment is the identification of bias due to the involuntary selection of good responders, who tend to stay in the trials vs. poor responders who tend to be lost to follow-up, resulting in the overestimation of height gain (8). In the Canadian trial, the proportion of patients followed to adult height was high, and the data were analyzed carefully to rule out such bias. Such a high level of evidence has rarely been achieved for other pediatric GH indications: results are only available for controlled trials with untreated (or placebo) control groups for idiopathic short stature (9) and, to a lesser extent, for children born small for gestational age (10).
The story of GH treatment for Turner syndrome does not stop here, and several points should now be considered. First, this study demonstrates that long-term GH treatment increases adult height in patients with Turner syndrome and gives a realistic estimate of height gains. As patients in the trial resembled the "average patient" in large post-marketing databases (11) in terms of age, height, and GH dose, results of the Canadian trial can be generalized to clinical practice. The magnitude of height gain differs considerably between individuals, and the most important factor associated with adult height was age at treatment initiation, which accounted for 1.5 cm/yr. In this trial, age at initiation of treatment ranged from 7–13 yr, translating to a mean height gain of 11.7–2.7 cm. This raises the issue of whether GH should be used if only a minor effect can be anticipated. The results of this trial can at least help doctors make realistic estimates of expected height gains and to discuss them prior to initiation of therapy with their patients and families.
Second, the aim of increasing height in patients with Turner syndrome is to improve well-being and quality of life. However, height is not validated as a surrogate measure for quality of life and most studies have failed to demonstrate an effect of height on psychosocial parameters in adults and adolescents (12). Our analysis of a population-based cohort of patients with Turner syndrome treated in France in the 1990s showed normal perceived health-related quality of life and lower self-esteem than for the general population (13). In this large patient sample, we detected no influence of height on any of the psychosocial parameters studied, including health-related quality of life, self-esteem, or social adjustment. In contrast, when young adults were asked to give their opinion of the treatment they had received, the opinion was favorable in 88%, neutral in 9%, and negative in 3%. When asked to estimate the minimal gain they thought would make GH treatment worthwhile, the figure was above 8 cm in 64% of cases. Thus, two thirds of our patients treated with GH would not consider treatment to have been "worthwhile" based on the mean results of the Canadian trial and many other studies. Furthermore, those with the highest expectations had a significantly lower perceived health-related quality of life than other patients, showing that unrealistic expectations concerning the benefits of GH treatment could result in treatment doing more harm than good. However, assessment of the influence of GH treatment on psychosocial outcome was indirect in our study and results from the Canadian trial will allow a direct comparison between treated and untreated patients.
The third issue is whether the increment in adult height could be increased by adjusting the dose or duration of treatment. GH treatment has a dose-dependent effect (5, 14), but the dose-dependence curve is not a straight line (5, 14); instead, it tends to reach a plateau, raising cost-effectiveness and safety issues. Starting treatment earlier is limited by the age at which Turner syndrome is diagnosed. Furthermore, the influence of age at start of treatment on adult height identified by the Canadian study cannot be extrapolated to children under the age of 7 yr. Trials in young patients are underway and adult height data will be required for clear conclusions to be drawn. The optimal age for initiation of estrogen therapy in patients with Turner syndrome is debated, and results of the Canadian study were obtained with low dose estrogen replacement started at the near physiological age of 13 yr. Thus, these results as well as others do not support the practice of further delaying estrogen therapy (15, 16).
The final issue is the safety profile of GH treatment in Turner syndrome. Overall, the safety profile of this treatment is good, with precautions related to risks of intracranial hypertension, type 2 diabetes, impaired glucose tolerance, and slipped capital epiphyses (17). However, two randomized controlled trials have demonstrated a doubling in the risk of otitis media with GH treatment (7, 18). Although recurrent otitis in childhood has not been formally linked to otological complications and deafness in adults, it should be noted that otological conditions were one of the strongest predictors of health-related quality of life in young adults in our study (13). Otological follow-up should be particularly rigorous in patients with Turner syndrome on GH treatment, and more research into the natural history of otological problems in Turner syndrome patients is required. The other major safety concern is the theoretical potential of GH to increase cancer risk. Published data have suggested that the frequency of colon cancer or Hodgkin disease might be increased by GH treatment (19). In the general population, higher IGF-I levels are associated with increased risk of cancers (20), particularly for colon cancer. In Turner syndrome, there is debate as to whether the risk of colon cancer is higher than that for the general population (1, 21). IGF-I levels increase during GH treatment and, when high GH doses are used, supraphysiological IGF-I levels are recorded (5). There is therefore a need for GH dose adaptation based on a careful monitoring of IGF-I levels and for long-term follow-up studies for the early detection of bowel neoplasms.
In summary, the Canadian study provides essential information for clinicians, patients with Turner syndrome, and their families. However, the situation remains complex for clinicians who can now give a reasonably precise estimate of adult height with and without treatment but must put the height gain into perspective, given the lack of evidence for a beneficial psychosocial effect and the need for long-term safety studies. In any case, clinicians should emphasize health priorities other than height in Turner syndrome.
Acknowledgments
The author thanks Jean-Louis Chaussain, Paul Czernichow, Judy Ross, and Guy Van Vliet for helpful comments.
Footnotes
The author acknowledges the support of Ministère de la Santé, Programme Hospitalier de Recherche Clinique AOM98009
Received April 18, 2005.
Accepted April 18, 2005.
References
This article has been cited by other articles:
 |
|
 |
|
  M. L. Davenport, B. J. Crowe, S. H. Travers, K. Rubin, J. L. Ross, P. Y. Fechner, D. F. Gunther, C. Liu, M. E. Geffner, K. Thrailkill, et al. Growth Hormone Treatment of Early Growth Failure in Toddlers with Turner Syndrome: A Randomized, Controlled, Multicenter Trial J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3406 - 3416. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A M Solomon and P M G Bouloux Modifying muscle mass - the endocrine perspective. J. Endocrinol., November 1, 2006; 191(2): 349 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Carel, C. Elie, E. Ecosse, M. Tauber, J. Leger, S. Cabrol, M. Nicolino, R. Brauner, J.-L. Chaussain, and J. Coste Self-Esteem and Social Adjustment in Young Women with Turner Syndrome--Influence of Pubertal Management and Sexuality: Population-Based Cohort Study J. Clin. Endocrinol. Metab., August 1, 2006; 91(8): 2972 - 2979. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Soriano-Guillen, J. Coste, E. Ecosse, J. Leger, M. Tauber, S. Cabrol, M. Nicolino, R. Brauner, the StaTur Study Group, J.-L. Chaussain, et al. Adult Height and Pubertal Growth in Turner Syndrome after Treatment with Recombinant Growth Hormone J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5197 - 5204. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
