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A study of the effect of GH and GnRH on final adult height

by Maria Vogiatzi, M.D.

Children with CAH are frequently tall before puberty, but complete their growth prematurely and are ultimately short as adults. This growth pattern can be caused by elevated adrenal androgens that result in bone age (BA) advancement and fusion of the epiphysis (growth plates in the bones). Despite treatment with steroids, adrenal suppression may not be perfect, allowing androgen levels to rise, leading to bone age advancement. When the bone plates are completely fused, growth is finished in the child. Furthermore, over-treatment with steroids can result in growth deceleration (slowing of the rate of growth). An additional problem can be early puberty, which frequently occurs in CAH and may contribute to advanced bone age (BA) and eventually to short adult height. The combination of these factors (advanced bone age, early puberty and slow growth rate) lead to a short adult height prediction in many children with CAH.

This article summarizes the results of a study that used growth hormone (GH) in combination with gonadotropin-releasing hormone (GnRH) analogue to improve the final height in children with CAH. In addition to GH and GnRH, all children continued their standard therapy with steroid replacement and florinef, as needed, with the goal of maintaining satisfactory suppression of adrenal steroids. GH was used to improve growth rate that could be decreased because of steroid therapy. GnRH analogues are medications that suppress puberty as long as they are being administered. The most common medication in this group is Lupron^®, an FDA approved medication for the treatment of precocious puberty. In this study, Lupron was given to children with early puberty to prevent advancement of BA. A previous study in CAH looked at the effect of Lupron alone on final height and failed to show a positive outcome. This result was contributed to the growth deceleration that is usually seen with Lupron therapy. Therefore, this study examined the combination of GH and Lupron therapy.

Approximately 30 children with CAH, both with the classical and nonclassical form of the disease, enrolled in the study that was conducted at the New York Presbyterian Hospital/ Weill Medical College. The results of the first two years of therapy in the first 20 enrolled children (13 boys and 7 girls) were reported in 2001. Changes in growth rate, BA advancement and height prediction in the group of children who were treated with GH and Lupron (treatment group) were compared to those of children who were treated only with steroids in the past by the same investigator (control group). For statistical analysis, each child of the treatment group was matched at the start of the study with a child in the control group for type of CAH (classical vs. nonclassical), age, BA, sex and stage of puberty.

The average age of the children at the beginning of the study was 8.6 years in both groups. The average BA was 11.8 years for both groups. The predicted adult height was just below the 3rd percentile in the treatment group and a little above the 3rd percentile in the control group. GH therapy was started first and Lupron was added with the onset of puberty.  Twelve children of the 20 enrolled were not in puberty at the start of the study and remained prepubertal during the study. Therefore, they were treated with GH alone. The rest of the children received combined GH and Lupron treatment.

Growth rate increased by the end the first year of the study. At the end of two years, growth rate was higher in the treatment group compared to the control group, and BA progression was much slower in the children who received Lupron. Predicted height improved significantly with each year of the therapy, so that at the end of the two years the gain was 11cm (or 4.3in.) in average over the initial height prediction. This corresponds to an improvement of predicted final height from just below the 3rd percentile to close to the 25th percentile. On the contrary, predicted height remained the same in the control group, close to the 5th percentile.

The study was continued to determine if the beneficial effects of GH and Lupron therapy were temporary or could be sustained until final height, and a report on the final height of the first 14 children (8 boys and 6 girls) was published this summer. Their final height was compared to that of children who were treated only with steroids (control group). As in the first report, each child of the treatment group was matched at the start of the study with a child in the control group for type of CAH, age, BA, sex and stage of puberty.

This paragraph summarizes the growth characteristics and outcome of these 14 treated children and their controls. For simplicity, the results, which are reported here, refer to the average values for each group.  The age of the treated children at the beginning of therapy was 9.7 years, their bone age was 12.5 years and their predicted final height was close to the 5th percentile. The children in the control group had the same growth parameters at baseline. In the first year of the therapy, the growth rate of the experimental group was a little more than one inch faster than the control group. In the following years, growth rate slightly decreased for the experimental group but remained higher than that of the untreated children. The change in BA did not differ between groups, or otherwise, was not affected by the therapy.

The treated children reached a final height between the 25th and 50th percentile in contrast to close to the 5th percentile for the control group. Final height in treated boys averaged 67.5 inches and treated girls averaged 64.5 inches. In contrast, the final height of untreated boys and girls was 64 inches and 62 inches respectively. The treated group, as a whole, improved their height by 2.9 inches compared to their initial height prediction. However, the final height in the control group was practically the same with their initial height prediction. Length of therapy was approximately 4.5 years.

Comparisons were also made between the final height of each group and their corresponding target height. Target height is an adjusted average of the height of both mother and father and reflects the genetic potential of the child. The treated group reached a final height that was one inch shorter than its target height. Contrary, the control group’s final height was about 3.6 inches shorter than its target. Both groups had similar target heights.

These studies are the first to show that GH therapy, combined with Lupron in case of early puberty, improves the height potential and final height of children with CAH. The treatment had excellent short-term results that could be sustained until the end of growth. There were not reported adverse effects except pain at the injection site with Lupron. As the rest of the children of this study complete their growth, we will gain additional information about the long term efficacy and safety profile of this therapy.

Despite treatment with steroids, children with CAH have significant difficulties reaching their genetic potential in terms of height. GH therapy, combined with Lupron in case of early puberty, can be an attractive alternative option for those children with CAH, who despite treatment with steroids, suffer from an advanced BA, and therefore, are projected to have a poor final height. Otherwise, not all children with CAH are candidates for this therapy. It can be considered, however, for those who continue to have low predicted final height despite steroid therapy. It is of interest that the studies included a number of children with non-classical CAH: 12 out the 20 children in the first report and 5 out of the 14 in the second report. The children with NCAH have a milder disease, but also tend to present late in childhood, and may experience significant BA advancement before the diagnosis is established. However, the form of the disease did not appear to affect the response to the GH therapy

Beyond the medical outcome, problems with the GH and Lupron therapy include its high cost, difficulties obtaining approval by the insurance and the intensity of the treatment. GH therapy requires a daily injection, once at bedtime, that is very similar to insulin injection in terms of administration. It is typically a lengthy therapy ( i.e. until the child reaches near adult height). Lupron is given monthly as an intramuscular injection that is frequently painful. In order to be most effective, it is recommended that GH treatment begin before puberty and continue until the bone age shows fusion of growth plates. In general, the longer the GH therapy is, the more significant is the effect on final height.

Finally, the response to the GH/ GnRH analogue therapy was quite variable. Factors that may influence the outcome, such as adrenal control or type of CAH, could not be identified. This speaks to the fact that there are multiple, still poorly defined factors, that may affect growth overall and response to GH therapy, and represents a challenge for all those who care for these children. The answer to this challenge lies in continuous commitment to research that can lead to a better understanding of the disease and its impact on growth.

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