Expectation bias with respect to growth hormone therapy in Turner syndrome.

Abstract

More than 10 years ago, preliminary reports indicated that high-dose growth hormone therapy was beneficial in treating short stature in girls with Turner syndrome (1, 2). In previous reports, with lower doses of growth hormone and suboptimal therapeutic regimens i.e. three times weekly vs daily, and intramuscular vs subcutaneous injection, no growth promoting effect was demonstrated (3, 4). Until recently, the positive effects of growth hormone therapy were documented by increased growth velocities, improved height predictions and/or a gain in actual height, when height during therapy was compared with ‘projected height’ using Turner syndrome specific growth charts (5, 6). The positive results were viewed with cautious optimism. It was generally stated that further studies were needed to document the effects of different therapeutic regimens on bone maturation, long-term growth and final height. In several studies bone age advanced significantly more than chronological age during high-dose growth hormone therapy alone or in combination with oxandrolone or estrogens (7–9). Bone age accelerates especially at younger ages, so it is suggested that the optimal age of starting growth promoting therapies is 9 years (7). This recommendation contradicts the general observation in patients with ‘classical’ growth hormone deficiency, that an earlier start of therapy significantly improves adult height. Today, results on long-term growth and adult height are available. The results vary from study to study indicating major improvements in adult height and overt psychosocial benefit in some (9–11) or minor, insignificant height gains and little changes in the psychosocial status in other clinical trials (12, 13). It is a major disadvantage of all published studies that changes in growth velocity and adult height have been compared with historical controls only, thus not accounting for a possible normal acceleration of growth in untreated Turner syndrome patients. The presently available data are encouraging, though still controversial. Optimism still prevails and will hopefully be substantiated after all ongoing clinical trials, including the data from the two randomized clinical trials initiated in Canada (14) and the US (15), have published their final results. In addition, it is necessary to establish whether a psychosocial benefit is obtained during, at the end of, and years after therapy with or without a documented effect of growth hormone therapy on adult height. A bias in favor of the publication of positive and statistically significant results is well documented in clinical medicine (16). It should be avoided by reporting the results of all ongoing trials with growth promoting therapies in Turner syndrome. This is especially important, since concerns have been raised about bias in industry-supported clinical research, about data presented in the absence of peer review (14) and the pressure in favor of treatment exerted by parental groups. Many questions still remain, so that additional prospective and randomized clinical trials with psychosocial guidance are required to evaluate, for example, bone age development in patients and controls, to document a possible normal acceleration of growth in untreated patients, and to determine final height in treatment and control groups (17). The major determinant of randomized clinical trials is the assessment of the psychosocial well-being in treated and untreated girls with Turner syndrome. The effects should be assessed during therapy and at the time when adult height is reached. Furthermore, long-term evaluations should be performed several years after therapy, when the enthusiasm and positive reinforcement of the therapeutic intervention by physicians and parents have waned. It will be necessary to assess the importance of a ‘minor’ or ‘major’ increase in adult height during the routine of everyday adult life and with the knowledge that adult stature for many patients is still far from being ‘normal’. In the coming years we, hopefully, will be able to justify the long and expensive treatments whose potential long-term risks still remain uncertain. More than 10 years ago, large clinical trials of growth hormone therapy were started in girls with Turner syndrome. Hopefully it will not take another 10 years until randomized, prospective and controlled clinical trials are initiated to find the necessary answers to the many remaining questions.