Physiological but not pharmacological growth hormone tests predict adult height

The history of GH research demonstrates two major trends in medicine. One approach was to define the disease and to search for its cure; these days drugs are awaiting new indications to be discovered. Observing the natural model of acromegaly where excessive amounts of GH result in tall stature, it made sense for researchers that excessive GH supplementation would improve final height of normal short children. The increased mortality during GH therapy in critically ill patients in whom, theoretically, the anabolic effect of GH was expected to help recovery is a warning that theories do not always fit into reality (Takala et al. , 1999). The other trend is the slow movement of medicine from an art to a science (to evidence-based medicine). Most previous GH trials in short children were not controlled. The work of Raddeti et al . (2003) in this issue is very important as it tries to evaluate the ultimate benefit of GH therapy on final height in a controlled, unbiased way. The researchers tried to control for GH ‘abundance’ spectrum in both treated and untreated patients (both spontaneous and stimulated GH). They also controlled for the familial, genetic growth potential. Raddeti et al . (2003) evaluated the benefit of GH therapy in both GH-deficient and nonGH-deficient children. The problem is how to define GH deficiency? The diagnosis of GH deficiency is still problematic because it is based on a nonphysiologic ‘gold standard’, i.e. the GH artificial pharmacological stimulation. These tests represent the maximal blood level after the administration of various standard stimuli (Fraiser, 2003). The first normative data for this gold standard were derived from healthy young adults and later from ‘normal short children’, who by all means cannot be regarded as a perfect control group. These tests are not controlled for age, pubertal status, body mass index (BMI), or for a specific pharmacological agent, despite welldocumented evidence that all these factors affect the magnitude of GH response (Zadik et al. , 1990). The variability of the results was noticeable even before the shift from radioimmunoassay (RIA) to ‘nonradioactive tests’ (Reiter et al. , 1998). None of these factors are considered while evaluating the GH status of a short slowly growing patient. According to the art of medicine, if the maximal response to a pharmacological stimulus is under the ‘golden border of 10 μ g / l’, the patient is granted GH therapy because it is believed that this patient will have a significantly better final height prognosis. Ignoring the physiological secretion of GH as an important diagnostic tool, although difficult and expensive to perform, was proven wrong. It directly relates to growth velocity (Hindmarsh et al. , 1987). Both physiological secretion of GH and pretreatment growth velocity are the best markers for the short-term growth response to GH (Zadik et al ., 1992). Indeed, by using the physiological secretion of GH as a diagnostic tool, a new indication for GH therapy was identified, i.e. neuro-secretory-dysfunction (Spiliotis et al. , 1984). In a controlled trial, the effectiveness of GH therapy on final height was demonstrated in children with a subnormal physiological secretion, as compared to their untreated counterparts (Zadik et al. , 1992). All these clues were sporadic and did not give the whole picture. Raddeti et al . (2003) added a missing piece to this clinical puzzle. A drawback in Raddeti et al . ’s (2003) study is the traditional artificial grouping of the children to GH-sufficient and -insufficient patients. Is there convincing evidence to say that a maximal GH response to stimulation of 10·1 μ g/l is GH-sufficient and 9·9 is GH-deficient? We are talking about a continuum of a GH secretory spectrum and a spectrum of growth response to GH therapy. This is a multiple regression equation where some of the factors are not known yet, i.e. the receptor and postreceptor events that affect growth and are ignored as previously the physiological GH secretion was not taken into account.