The results of this prospective, longitudinal study show that leuprolide acetate 1-month depot effectively suppressed the advanced growth rate and rate of bone maturation in females with CPP who were naïve to treatment with GnRHa, similar to the effects observed in previous studies [20–24]. After discontinuation of study drug, a small increase in growth rate was observed during the first year post-treatment, suggesting the occurrence of a limited pubertal growth spurt. Furthermore, on average, patients in this study population reached adult height of the standard normal population after treatment with leuprolide acetate 1-month depot.
Using the Bayley-Pinneau method at baseline to predict the adult height of our study population, adult heights were on average 4.0 cm greater than PAH at onset of treatment with leuprolide acetate among female patients. This is consistent with previous studies using depot GnRHa for CPP, which have demonstrated that females between the ages of 6-8 years have a moderate height increase that ranges from 4.5 cm to 7.2 cm [6, 25]. While studies have failed to show benefit if treatment is begun after age 8 years , this does not take into account subsequent diminution of growth potential without treatment. Some studies suggest that the Bayley-Pinneau method may over-predict adult height among those with advanced skeletal age by several centimeters at baseline [2, 7, 27]. The 30 patients who had adult heights in this study had a mean HtSDS of -0.1, which indicates that their mean height was within the range of target heights equivalent to that of the normal population. Twenty-four of the 29 patients with target heights reached their target height range.
Similar to previous studies (11, 15, 19, 21, 22, 26-28), we used multiple linear regression to identify factors that may affect height gain from baseline and from the end of treatment and final adult height in females with CPP. Factors having significant correlation by multiple linear regression analyses (Tables 2, 3, and 4) are discussed below.
Factors Influencing Adult Height
The two factors that explained 82% of the variability in adult height were HtSDS score at baseline and average growth rate during treatment. Both were positively correlated and similarly identified as positive factors in a previous study in determining patients who may benefit the most with regard to height gain from leuprolide acetate 1-month depot therapy . The positive correlation between growth rate during treatment and adult height highlights the importance of monitoring the level of growth rate suppression during treatment Adequate growth rates during treatment were associated with positive final growth outcomes in our study population. The growth rates observed in this study (5-6 cm/year during the first 72 weeks of therapy and 4-4.5 cm/year from week 72 to week 192) were similar to growth rates observed in normal prepubertal children of these ages. Unlike prior reports and common expectations, CA at onset of therapy did not predict height outcome. This is likely related to the diversity of age at onset of puberty.
Factors Influencing Height Gain Over PAH at Baseline
In the multiple linear regression for height gain over PAH at baseline, the advancement of BA over CA at baseline was a strong positive predictor, and time to treatment from onset of CPP was a strong negative predictor. This indicates that the greater the advancement of BA over CA at baseline and the shorter the interval between onset of CPP and the initiation of treatment, the greater the height gain (defined as adult height minus predicted mature height at baseline). This observation is similar to results reported by Mul et al. . Overall, the advancement of BA over CA at baseline and the time to treatment from onset of CPP accounted for 41% of the variability in height gain. The finding that advancement in BA at the onset of therapy is a positive predictor of height gain over PAH may seem inconsistent with the previously described inverse relationship of BA at onset of therapy and adult height . Because subjects with a more advanced BA have a lower PAH at the onset of therapy, halting advancement of BA during GnRHa therapy appears to result in a greater gain in height than the initial predicted height. This would explain the positive predictor of height gain, but not actual adult height. Hence, there appears to be a greater "gain back" growth potential among those in this study having more advanced BAs at onset of therapy.
Factors Influencing Height Gain After Stopping Therapy
The duration of therapy had a negative association with the height gain after stopping therapy. Previous studies have shown no association between duration of therapy and height gain after therapy [20, 25]. The negative correlation between BA at baseline and height gain after stopping therapy is expected, and was observed by Brito et al . The two factors of treatment duration and BA at baseline explain 72% of the variance in height gain after treatment. The univariate analysis showing a correlation between ΔBA/ΔCA and growth after therapy does not persist with the multiple linear regression analyses; hence, this is not a major factor. The difference in the results between the univariate and multiple linear regression analyses might be explained by the considerable variation in BAs. At the onset of therapy, BA would be expected to continue to advance until typical pubertal BA is reached. The ratio, therefore, may reflect considerable variation.
In summary, treatment with leuprolide acetate 1-month depot increased adult height over the PAH. In addition, the HtSDS was equivalent to that of the normal population, indicating that these patients had on average nearly achieved the height of their peers without CPP. Overall, treatment with leuprolide acetate 1-month depot preserved adult height potential and resulted in clinically meaningful height gains over PAH. The results of this study confirm that in females, early initiation of treatment from the onset of CPP results in the greatest increase in height. In addition, female patients with the greatest advance in BA experience the most height gain over PAH with GnRHa treatment, and maintaining growth rates within that of normal prepubertal children during GnRHa treatment may result in the highest adult height outcome.