This study was performed to evaluate whether treatment with a lutenizing hormone-releasing hormone agonist (LHRHa) increases adult height in short adolescents with normally timed puberty. There were 32 girls and 18 boys with a mean predicted adult height of more than 3 SDS below the population mean who were administered an LHRHa or a placebo in a randomized double-blind fashion; 26 subjects received the medication and 24 were given placebo. There were a variety of growth limiting disorders, but principally idiopathic short stature. Three patients were also treated with growth hormone (GH) because they had a peak GH after stimulation of less than 7µg/l. The treatment was started at approximately 12-13 years of age; mean bone age was 11.5-13.2 years, and mean Tanner stages were 2.8 to 3.2 in the two groups, respectively. The mean duration of the LHRHa treatment group was 3.5 years, and that of the placebo group was 2.1 years. Adult height was measured when the bone age exceeded 16 years in girls and 17 years in boys, and when the growth rate was less than 1.5 cm per year. Forty-seven subjects were followed until they attained full adult height.

At the end of the study, those treated with LHRHa were older and taller than those who received placebo (20 vs 18 years of age; and -2.2 vs -3.0 SD below the 50^th percentile, respectively). Treatment with LHRHa resulted in a mean increase of 0.6 SDS in height (4.2 cm) over the initial predicted adult height in these short patients. The gain in height among the LHRHa treated group was independent of sex, concomitant GH treatment or presence of growth limiting syndromes (Figure). However, added GH treatment produced an apparent additive effect on growth (+ 0.4 SDS). The principal adverse event of this treatment was a decrease in bone accretion, with reduced bone mineral density below that attained in the placebo group. There were no apparent lasting effects on secondary sexual characteristics. The authors concluded that LHRHa increases adult height, but because of resulting decreased bone mineral density, it should not be routinely employed to augment adult height.

 

Yanovski JA, et al. New Eng J Med 2003; 348:908-917.

 

First Editor’s Comment: This very well controlled study clearly showed that there may be a small increment achieved in adult height (mean of 4.2 cm) with LHRHa treatment of short stature patients. Previous studies have also shown that there is a small gain in adult height with such therapy.^1,2  However, in this study the medication was given for more prolonged periods (mean 3.5 years) and it resulted in a significant reduction of bone mineral density. This is not surprising, since bone accretion at the time of adolescence is greatly dependent on the presence of adequate pubertal hormones which are suppressed by LHRHa. Of great concern is that this deficit persisted even after the LHRHa treatment ceased. It would have been of interest to ascertain calcium intake and determine if some of these detrimental effects could have been counteracted by an increased ingestion of this mineral. I agree with the authors that LHRHa treatment for augmentation purposes to increase height should not be routinely prescribed. The average cost of such treatment  is $10,000 to $15,000 per year, and this should also be kept in mind.

 

Fima Lifshitz, MD

References

 

1.   Carel JC, et al. J Clin Endocrinol Metab 1996;81:3318-3322.

2.   Lindner D, et al. Eur J Pediatr 1993;152:393-396.

 

Second Editor’s Comment: While the current study may not be ideal in terms of the present approach to inhibition of hypothalamic-pituitary-gonadal function with LHRHa, it is unlikely that similar investigations will be conducted in the future. Furthermore, the preponderance of girls with intrinsic short stature (32/50) without gonadal dysgenesis is the reverse of that encountered in general pediatric endocrine experience. Thus, present data serve for future recommendations.  This writer agrees with the conclusion of the authors and that of the first editor’s comment; namely that routine administration of LHRHa is not to be recommended for subjects with intrinsic short stature.  It is of interest that the increase in adult height was greatest in patients who received both GH and LHRHa.  Nevertheless, in the absence of data demonstrating significant educational, social, and occupational benefit of relatively small increases in adult stature, such efforts cannot be routinely supported.

 

Allen W. Root, MD

 

Reference

 

1.   Carel JC, et al. J Clin Endocrinol Metab 2002;87:4111-4117.