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Can Some Growth Hormone (GH)-Deficient Children Benefit from Combined Therapy with Gonadotropin-Releasing Hormone Analogs and GH? Results of a Retrospective Study

Unité d’Endocrinologie, Hôpital des Enfants, 31026 Toulouse, France

Address all correspondence and requests for reprints to: Dr. M. Tauber, Hopital des Enfants, 330 avenue de Grande Bretagne, BP3119, 31026 Toulouse, France. E-mail: tauber.mt{at}chu-toulouse.fr.

Abstract

Recombinant GH (rGH) treatment does not invariably correct height deficits in GH-deficient children once puberty has begun. The addition of GnRH analogs (GnRHa) to delay puberty has been advocated, but published results are few and sometimes conflicting.

We retrospectively compared GH-deficient children treated with rGH and GnRHa for at least 1 yr after entering puberty and having attained their final height (n = 23) with a matched control group treated only with rGH. Overall, combined therapy did not significantly increase final height relative to rGH alone. However, the shortest girls at the onset of puberty (<25th percentile) benefited more than the tallest (>75th percentile) in both final height relative to predicted height and pubertal catch-up growth.

In the control group, patients having experienced intrauterine growth retardation (IUGR) attained a lower mean final height than patients without IUGR (difference significant in boys, but not in girls). In the combined therapy group, IUGR did not affect the final height of either sex.

Our results suggest that two populations might benefit most from combined GnRHa and rGH therapy: girls particularly short at the onset of puberty and patients who had experienced IUGR. Further prospective studies are required to confirm these preliminary hypothesis.

MANY GH-DEFICIENT (GHD) children treated with recombinant human GH (rGH) fail to reach a final height within the target range (1, 2, 3), and the best therapeutic strategy to adopt to improve the final height of such patients is still a matter of debate (3, 4). Delay in starting treatment (5) and pronounced height deficit at the onset of puberty may be factors contributing to these unsatisfactory results.

The height gained during puberty represents 14–17% of the total growth (3), and final height has been shown to be closely correlated with height at the onset of puberty (6). When the predicted final height calculated at the onset of puberty is low, one strategy for achieving a more satisfactory final height is to optimize catch-up growth by lengthening the pubertal process, thereby enhancing the total pubertal height gain (7, 8). In theory, combined treatment with GnRH analogs and rGH should slow the rate of bone maturation by delaying puberty while maintaining a satisfactory growth rate, as shown in children with precocious puberty (9, 10, 11, 12). By prolonging the duration of growth before epiphyseal fusion, the final height can be increased. This combination treatment is often used in clinical practice (13), but has not yet been validated and needs further assessment. Unfortunately, few prospective studies have investigated combination therapy in GHD children, and these have generally involved small numbers of children treated with different therapeutic regimens (7, 14, 15). Moreover, few data are available on the final heights obtained (13, 16, 17, 18). The objective of this study was to compare the growth of patients with idiopathic GH deficiency (GHD) treated from the onset of puberty with a combination of GH and LHRH analogs and with rGH alone, respectively, by a retrospective analysis of registry data.

Patients and Methods

Patients and protocol

Of the 392 children with idiopathic GHD in our registry who had started rGH treatment in our unit between 1990 and 1993, we selected those treated from the onset of puberty with a combination of GH and GnRH analogs for at least 1 yr. Only patients who had completed their treatment and who had attained their final height were retained for analysis. The selected children were paired with children treated with rGH only, matching for gender, height, and bone age at the onset of puberty, pubertal development, target height, and history of intrauterine growth retardation (IUGR).

GHD was confirmed by either two stimulation tests showing peak plasma GH levels below 10 µg/liter, or one stimulation test showing a peak plasma GH level below 10 µg/liter and a 24-h integrated GH concentration less than 2.5 µg/ml·min. The stimulation tests involved the administration of glucagon and betaxolol, insulin, or arginine and L-dopa. Complete GHD and partial GHD were defined by GH levels at diagnosis below 5 µg/liter and between 5–10 µg/liter, respectively.

The onset of puberty was defined by the following characteristics: acceleration of growth velocity, Tanner stage II secondary sexual characteristics, LH/FSH ratio greater than 1 measured during the LHRH test, testosterone level above 50 ng/dl for boys, uterine length greater than 36 mm, and ovarian volume more than 2 cm³ on pelvic ultrasonography. We did not use estradiol at this time because of lack of reliability of our local assay. Bone age was determined on x-rays of the left hand and wrist according to the method of Greulich and Pyle (19). The predicted adult height was calculated using the Bailey-Pinneau method (20), and the genetic target height (midparental height) was calculated according to Tanner (21) as the mean of the parents’ heights ± 6.5 cm. Standard deviation scores (SDS) for growth retardation were calculated according to Sempé and Pedron (22). Final height was defined by a bone age greater than 16 yr in boys and greater than 14 yr in girls, associated with a growth velocity of less than 2 cm/yr. The height gain at puberty was defined as the difference between height at the start of treatment with GnRHa and final height on combination therapy, and the difference between height at the onset of puberty and final height in the children receiving rGH only. IUGR was defined as a birth length more than 2 SD less than the normal length for the gestational age, according to the tables published by Usher and MacLean (23).

All children had received treatment with one of the recombinant GHs available on the French market administered in six injections per week at a dose of 0.20–0.23 mg/kg·wk. In the group treated with combination therapy, GnRHa (D-triptorelin, Decapeptyl, Laboratoire Ipsen, France) was administered every 4 wk according to body weight (3 mg for a body weight >30 kg, 1.5 mg for a body weight <30 kg). GnRHa was initiated either at the same time or subsequent to starting rGH treatment.

Statistical analysis

Data are expressed as the mean ± SD unless stated otherwise. The means were compared using t test on paired series (Wilcoxon’s test) and the Mann-Whitney test on nonpaired series. The correlation between pairs of variables was studied using linear regression. Statistical analyses were performed using StatView 4.5 software (Abacus Concepts, Inc., Berkeley, CA).

Results

Patients characteristics

We identified 23 children (14 females and 9 males) from the register who had been treated with combined rGH and GnRHa for at least 1 yr from the onset of puberty, and who had reached their final height. GnRHa treatment was prescribed for rapidly progressive puberty or, in the case of rapid bone age progression, worsening of the adult height prognosis. The children had been followed up every 3 or 6 months in the out-patient clinic. The control group treated with rGH alone also included 23 children (14 females and 9 males).

All of the children displayed partial or complete idiopathic GHD. Partial deficit was predominant in both treatment groups, accounting for 65% of the patients in the combination therapy group and 78% in the group receiving rGH only. Baseline data are presented in Table 1. Treatment with GnRHa was prescribed either at the same time as rGH (n = 13) or after initiating rGH treatment (n = 10). The mean ages at GnRHa initiation for the girls and boys were 11.7 ± 1.3 and 13.0 ± 0.9 yr, respectively. The mean GnRHa treatment duration was 17 ± 6 months (range, 12–38 months). The girls had started rGH treatment at a slightly younger age than the boys (11.5 ± 1.5 vs. 12.0 ± 2.4 yr in the combination therapy group and 11.5 ± 1.6 vs. 12.8 ± 1.0 yr in the group receiving rGH alone).

At the onset of treatment, the pubertal status of the patients was similar and scored at Tanner stage II or above in the two groups. In the group treated with rGH alone, puberty progressed significantly during the 12-month period. In the group also receiving GnRHa, a clear decrease in LH and FSH during the LHRH test was observed in both sexes after 1 yr of treatment as well as a drop in the testosterone level in boys below 50 ng/dl, the upper limit of prepubertal values in our assay. In girls, echography did not show an increase in uterine length and ovarian volume in the combined treatment group, in contrast to the group treated with rGH alone (Table 2). In children receiving the combination treatment, a bone age gain of 8 months was observed over a 17-month period, corresponding to a 55% reduction in expected bone maturation. No slowing of bone maturation was noted in those receiving rGH alone during the same period.

Combined GnRHa-rGH therapy did not significantly increase final height relative to rGH alone (Table 1). With combination therapy, the final height SDS was -1.8 ± 0.5 for girls and -1.9 ± 0.5 for boys vs. -1.8 ± 0.8 for both girls and boys in the group receiving rGH alone.

Comparison of predicted and final height

Different relationships between predicted and final heights were observed in girls and boys. In both treatment groups the mean final height of the girls was significantly higher than the mean predicted height, whereas this was not observed in boys (Table 1). To determine whether initial height might have influenced the final outcome, we selected the shortest girls (defined by an initial height <25th percentile of the study population) and the tallest girls (defined by an initial height >75th percentile) at the time of initiating GnRHa treatment and compared their mean final heights relative to their predicted heights in both treatment groups (Table 3). The mean final height of the smallest girls was 7.5 ± 1.8 cm greater than the predicted height at initiation of GnRHa treatment vs. 1.0 ± 4.8 cm in the group receiving rGH alone. In contrast, in the tallest girls, the mean final height was only 4.1 ± 4.4 cm greater than the predicted height at the start of GnRHa treatment vs. 4.4 ± 1.9 cm in the control group (Table 3). Due to the small sample size, this analysis was not possible for the boys.

Pubertal height gain was measured by subtracting the height at the onset of puberty (or the start of treatment with GnRHa) from the final height attained. In girls, but not in boys, a significant difference in pubertal height gain was seen between the two treatment groups (Table 3); the gain was significantly higher in the combination therapy group than in the group receiving rGH only (22.9 ± 5.9 vs. 19.7 ± 6.9 cm; P < 0.04). When the girls were analyzed according to their initial height on starting treatment, a greater pubertal height gain was observed in the smallest girls than in the tallest girls (25.2 ± 5.1 vs. 21.7 ± 7.6 cm), but the difference was not significant. It is worth pointing out that the height gain during puberty in the group of shortest girls receiving the combined therapy was significantly higher than that in the group of shortest girls treated with rGH alone (25.2 ± 5.1 vs. 16.5 ± 4.7 cm; P < 0.04; Table 3). In contrast, the difference between the two treatment groups was not significant for the tallest girls.

Influence of IUGR

We also compared the mean final height achieved by boys and girls in both treatment groups according to whether they had a history of IUGR. Due to the methodology used in this study, involving matching of the children, the prevalence of IUGR was obviously similar in both groups for both sexes. Thirteen of 23 children (56.5%; 9 girls and 4 boys) in the combination therapy group and 12 of 23 children (8 girls and 4 boys) in the group receiving only GH had a history of IUGR.

In the group treated with rGH alone, the boys who had experienced IUGR were shorter, with a mean final height of 160.1 ± 4.5 cm compared with 168.2 ± 1.2 cm (P < 0.03) in boys with no history of IUGR. The girls in this treatment group also showed a small difference in mean final height depending on whether they had experienced IUGR (150.2 ± 5.6 vs. 154.3 ± 6.3 cm), but this was nonsignificant (Table 4). In contrast, in the combined therapy group, no significant difference in final heights was observed in relation to IUGR for either boys or girls; patients who had experienced IUGR were not smaller than those without a history of IUGR.

In this retrospective survey no adverse effect induced by rGH or GnRHa was notified, and the delayed pubertal development was well tolerated.

Discussion

There is abundant evidence that a height deficit observed at the onset of puberty cannot be consistently recovered despite rGH treatment. In a study of 674 children with GHD treated with biosynthetic GH, even though height SDS increased during puberty, the target adult height was not attained (3). This disappointing result emphasizes the need for optimizing prepubertal growth. Increasing GH dosage during puberty could be an alternative (24, 25) to GnRHa treatment. The use of GnRHa in GHD children to delay the progression of puberty has been also proposed, but few results have been published (7, 13, 14, 15, 16, 17, 18). Most of these studies reported a gain in predicted adult height rather than in final height on combined therapy, but the results are sometimes conflicting. Furthermore, these studies generally involved small cohorts of children, without a control group in the majority of cases, and give no data on final height. Only 3 prospective studies (16, 17, 18) and 1 retrospective study (13) provide data on final height or near final height. In the prospective studies, a total of 66 GH-deficient children were enrolled, of whom 33 received combined treatment; the other children (control group) received only rGH therapy. The results indicated a benefit of the combination therapy in comparison with rGH treatment alone, with an increase in final height SDS compared with predicted adult height. However, in only one study (18) did patients (all were girls) treated with combined therapy reach a final height significantly higher than their mean predicted height.

The duration of combined treatment with rGH and GnRH varied in published studies from 1 yr to more than 5 yr (16). In our study the mean duration of treatment was 17 months (range, 12–38 months), as our criterion for interrupting treatment with GnRHa was a bone age between 11–12 yr in girls and between 13–14 yr in boys. In fact, the optimal time point for interruption of such a treatment has not been clearly determined, and although some researchers continue it for a long time, we have long believed that this treatment should be discontinued early enough to avoid blunting the pubertal spurt. It has been demonstrated that discontinuing the treatment late had a negative impact on the growth spurt, assessed both directly and on the basis of bone age (9). The duration of GH treatment in the group treated with the combination therapy was also obviously longer than that in the group treated with rGH alone, as the result of the treatment was to delay the onset of puberty.

In our study the addition of GnRHa to rGH treatment for at least 1 yr from the onset of puberty did not significantly improve the final height attained by either boys or girls in comparison with the control group. On comparing final height and predicted height, we observed that in both treatment groups the final height of girls, but not of boys, was significantly greater than the predicted height at the onset of puberty, and their final heights were close to the target height. Overall, girls receiving either combined therapy or rGH alone were taller than their mean predicted heights at the onset of puberty by 4.7 and 3.2 cm, respectively, with a greater height gain noted in the combined therapy group. This difference cannot be explained by the lower number of partial GHD in the combined therapy group, as we did not reported better results in complete GHD than in partial GHD in a previous study (26). A similar difference between girls and boys was observed in a study comparing the effects of combined treatment with rGH and GnRHa in a mixed group of normal and GHD children (13). The difference between the sexes and the slightly better results in girls may be due to the faster epiphyseal fusion in girls, driven by estrogens. However, Tanaka et al. (16) reported that combination treatment appeared to be more effective in boys than girls.

When we analyzed subgroups of patients according to their height at the onset of puberty, we found that the shortest girls (<25th percentile of the study population) benefited more than the tallest girls (>75th percentile) with respect to both gain in final height and catch-up growth during puberty. This result cannot be explained by the overlapping with the effect of IUGR, as this situation is comparable in both groups, i.e. shortest and tallest girls. Although these subgroups were small, preventing any definitive conclusion from being drawn, the findings of this study corroborate those of Saggese et al. (18), who advocates this treatment for the shortest girls, with a predicted height of less than 153 cm (-2 SDS). Mericq et al. (17) also observed better results in very short GHD children treated late (with a mean chronological age of 14.3 yr at treatment initiation) with the combination therapy group compared with GH only.

The incidence of IUGR was high in our selected group of children (56.5%), and consequently the control group, matched for IUGR, is not perfectly representative of GHD children treated with rGH. This high incidence could be due to the high prevalence of advanced puberty in IUGR patients (27). Interestingly, whereas we observed no difference in the final height of children of either gender in the group receiving the combination therapy according to whether they had a history of IUGR, the final height of boys with a history of IUGR who received rGH therapy alone was significantly lower than the final height of boys without a history of IUGR in this treatment group. The girls with a history of IUGR receiving rGH alone also reached a shorter final height than girls with no history of IUGR in this treatment group, although the difference was not significant. The benefit of the combination GnRHa-rGH has been clearly shown in GHD children secondary to cerebrospinal fluid irradiation (28), who exhibited advanced puberty as did the patients in our study who had experienced IUGR.

Conclusion

Some studies have shown that administering GnRHa with recombinant human GH may lead to an improvement in the final height of GHD children, but published results are few and sometimes conflicting. A central issue is the selection of the patients likely to benefit from such a combined therapy. Although we did not find that administration of GnRHa in combination with rGH resulted in a clear overall positive effect on the final height of GHD children in comparison with rGH treatment alone, the results of our study suggest that two populations might benefit particularly from combined GnRHa-rGH replacement therapy. As already reported by some researchers, a beneficial effect on the shortest girls at the onset of puberty was observed in our study. Interestingly, we found that another population, GHD children of either sex with a history of IUGR, might also benefit from such a combination therapy. Further prospective studies are required to confirm these preliminary results in this particular group of patients who already benefit from treatment with recombinant human GH.

Footnotes

Abbreviations: GHD, GH deficient, GH deficiency; GnRHa, GnRH analog; IUGR, intrauterine growth retardation; rGH, recombinant GH; SDS, SD score(s).

Received June 25, 2002.

Accepted December 9, 2002.

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