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Original Studies |
Endocrine Unit, Division of Pediatrics, Department of Reproductive Medicine and Pediatrics, University of Pisa, Santa Chiara Hospital, I-56125 Pisa, Italy
Address correspondence and requests for reprints to: Giovanni Federico, M.D., Clinica Pediatrica, Università di Pisa, Ospedale S. Chiara, Via Roma 67, I-56125 Pisa, Italy.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Several lines of evidence show that conventional doses of r-hGH in GH-deficient patients do not increase total pubertal growth over that gained by normal children, indicating that the height deficit cumulated at the onset of puberty cannot be recovered during puberty (7, 11). In general, children with isolated GHD (IGHD) start puberty spontaneously at a later age than normal; when it starts, however, it progresses faster than normal, possibly shortening the period of pubertal growth and resulting in a reduced pubertal growth spurt (11). Thus, the conclusion is that the higher the height before puberty, the better the final height may be (12). This is confirmed by children with gonadotropin deficiency associated to GHD, in whom pubertal development is induced by the administration of sex hormones, usually at a later age than in those with IGHD. This permits them to reach a better statural growth before the start of puberty and a final height greater than that observed in IGHD (11).
Studies in children with precocious puberty have shown that GnRH agonists (GnRHa) are effective in stopping pubertal development and leading to an improvement in final height (13). Thus, a possible strategy for improving final height in children with IGHD might be to add GnRHa to r-hGH to delay pubertal development and, thus, prolong the period of growth, a condition that is reminiscent, at least in some respects, of what naturally occurs in patients with GHD + gonadotropin deficiency.
Previous studies in which GnRHa was used led to different results in the effectiveness of the therapy (14, 15, 16, 17, 18, 19). Most of them were short-term studies evaluating the changes of predicted adult height (PAH) during the administration of the combined therapy (14, 15, 16, 17).
Here, we report the results on final height reached by 14 selected girls with IGHD, who were given GnRHa with r-hGH when they were in early puberty. The results were compared with those observed in a group of patients with IGHD who were given conventional substitutive r-hGH therapy.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Because the only patients with IGHD to reach their final height
during treatment with GnRHa with r-hGH were girls, the present study is
concerned only with them. We enrolled 24 girls with IGHD who were
taking r-hGH substitutive therapy (0.1 IU/kg·day sc at bedtime) from
2.1 ± 0.5 yr, on average (Table 1
).
The diagnosis of IGHD was based on insufficient hGH response (peak,
<10 µg/L) to two provocative tests (administration of
L-dopa and insulin-induced hypoglycemia) and after the
exclusion of other identifiable systemic, genetic, nutritional, or
psychological causes of short stature.
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5.0 µg/L). They did not show any associated deficiency of other
pituitary hormones. The secretory response of the hormone to the same
stimuli was reevaluated at final height, within 1 month after
r-hGH administration was stopped. The peak of circulating hGH was still
subnormal (5.4 ± 1.9 µg/L; range, 2.0–8.5 µg/L) in all, with
14 of the girls having partial GHD.
These girls were selected because of their growth response to r-hGH
with an accelerated progression of bone age (BA), without any
improvement in PAH and with a deteriorating height-BA SD
score when they entered puberty (Table 1
). During the first 2 yr of
r-hGH they grew 14.4 ± 1.7 cm, a value comparable with 15.2
± 1.4 cm/2 yr (P = not significant), which was the
cumulative growth response to the hormone predicted by the method of
Ranke et al. (20) in the same 2 yr. A growth
response to r-hGH like this may be due, at least in part, to the
presence of partial GHD in some of them, their reduced MPH
(Table 1), and to the relatively late age at which the treatment
was started. These factors, which are growth predictors in the
Ranke’s prediction model (20), are known to influence
growth response to r-hGH (20, 21, 22).
These findings prompted us to offer them the addition of GnRHa to r-hGH administration to slow pubertal development. On the basis of these findings, the Ethics Committee of the Faculty of Medicine of our University considered it ethically correct to give GnRHa in addition to r-hGH to these girls and approved our study protocol, which set out the decision to administer GnRHa for 2 yr. The decision was taken to avoid any unwanted side effects resulting from suppressing pubertal development for too long, including psychological disturbance. Thereafter, the girls were switched to r-hGH alone until they reached their final height, defined as a height gain of less than 1.0 cm in the preceding year, with a BA of 16.0 yr or higher.
Fourteen of the 24 girls, and their parents, accepted the treatment
with the combined therapy and were administered GnRHa [long-acting
D-Trp-6-GnRH (Decapeptyl)] at a dosage of 60 µg/kg im
every 28 days in association with r-hGH at the same dosage. The
combined therapy lasted 1.9 ± 0.9 yr, on average (range, 1.6–2.4
yr; 78% of the patients took the GnRHa for 1.9 yr or more); the girls
then continued r-hGH alone (3.1 ± 0.7 yr, on average), and the
study was stopped at a BA of 16.2 ± 0.3 yr (Table 2).
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). Before entering the study, the girls were evaluated for height, which was measured five times by the same observer (S.B.) with a Harpenden’s stadiometer; MPH according to Tanner (23); BA according to Greulich and Pyle’s method (24), by a single observer (G.F.) who was not aware of the patient’s treatment status; and PAH according to Bayley and Pinneau (25). Pubertal staging was calculated by the standards of Marshall and Tanner (26). The follow-up included detailed clinical visits at 6-month intervals, together with blood test screening to assess metabolic, hepatic, renal, hematological, and thyroid function and the levels of estradiol and gonadotropins (these last were obtained without an acute GnRH test) in the GnRHa-treated girls, whereas BA and PAH were reevaluated yearly.
The girls and their parents were informed about the side effects of the treatment, including the GnRHa-induced delay of pubertal development. The children’s parents gave informed consent for the study.
Hormonal assays
Circulating levels of LH, FSH, and estradiol were assayed in duplicate, using commercial kits. LH and FSH serum levels were determined by an immunoradiometric-coated tube assay (DiaSorin, Inc. s.r.l., Saluggia, Italy). The detection limit of the assay was 0.5 IU/L for both gonadotropins; the intra- and interassay variations were 6.7% and 1.4% for LH and 2.2% and 6.3% for FSH, respectively.
Circulating values of estradiol were assayed by antibody-coated tube RIA (Orion Diagnostica, Espoo, Finland). The detection limit of the method was 10.0 pmol/L; the intra- and interassay variations were 7.2% and 9.6%, respectively.
Statistical analysis
Data are expressed as mean ± SD, unless stated otherwise. Statistical differences among the groups were analyzed using the unpaired and paired t test. A P less than 0.05 was considered significant. Statistical elaboration was performed by the SPSS for Windows software package (release 6.1, 1994; SPSS, Inc., Chicago, IL).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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and
Fig. 1).
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). As expected, BA progressed faster in the latter patients
during the same study period (2.6 ± 0.4 yr), in comparison with
the girls treated with the combined therapy (1.4 ± 0.2 yr;
P < 0.001) who had a significantly reduced BA (Table 2). During GnRHa administration the girls grew at a rate similar to
controls in the same study period (Fig. 2) and GnRHa-treated patients, who were,
on average, 1.7 cm taller than controls before GnRHa, became 2.0 cm
taller when the combined therapy was stopped. As a result, height-BA
SD score improved significantly during GnRHa
administration, a finding that was not evident in controls (Fig. 1)
despite the increase in height-chronological age (CA)
SD score (Table 2). Similarly, during the
combined therapy, we observed a significant improvement in PAH (Table 2
and Fig. 1) that was modest in controls.
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and Fig. 2). Thus, it seemed that the gain in
height obtained in girls administered with the combined therapy during
the whole treatment period, from the start of the agonist to final
height, was due mostly to the statural gain attained after the agonist
was stopped (Fig. 2).
At the end of the study period, patients of both groups reached a BA
that corresponded to 99.6% of the complete linear growth
(Table 2). Thus, the actual height reached by all the girls studied
could be considered as final height and was significantly higher in the
patients given the combined therapy than in those treated with r-hGH
alone (Table 2). Finally, whereas controls reached a final height
similar to their MPH, girls administered with GnRHa achieved a final
height that was significantly higher than their MPH (Table 2).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). To our knowledge, only two recent controlled studies, one by Meriq et al. (19) and the other one by Tanaka et al. (18), reported the effect of the addition of GnRHa to r-hGH on near final height or final height in GH-deficient patients. Both studies reported a positive effect of the combined therapy on the statural growth of such patients. Meriq et al. (19) compared the near final height obtained by 5 girls and 2 boys treated with the combined therapy with that reached by 10 controls, 5 girls, and 5 boys treated with r-hGH alone. All the patients were treatment naïve, and the study lasted 3 yr, on average. Because the results are reported for the whole treatment group, it is not possible to know the growth of girls during the combined therapy. However, during the first 2 yr of combined therapy, the patients, as a group, grew about 13 cm, on average, a value that was similar to that observed in our series. The patients of Meriq et al. (19) grew 4.4 cm more, on average, during the third year of combined therapy, reaching a near final height that was -1.3 ± 0.5 SD score with a gain of 1.3 ± 0.1 SD score over the controls treated with r-hGH alone. Our girls grew about 10.9 cm after the GnRHa was stopped and until they reached their final height, a 3-yr period during which they were given r-hGH alone. The difference between our results and those of Meriq et al. (19) may reflect the remaining growth potential at the BA (14 yr) chosen to define near final height, as suggested by the authors themselves (19), the younger age of our patients, their smaller growth delay when the combined treatment was started, and perhaps the different treatment protocol used.
Tanaka et al. (18) examined the final height in a group of GH-deficient patients treated with (eight boys and four girls) or without (seven boys and six girls) GnRHa in addition to r-hGH. The authors reported a greater, even if not significant, growth in the girls treated with the combined therapy in comparison with controls treated with r-hGH alone. During the administration of the GnRHa the girls grew 13.4 ± 5.4 cm, a value that was similar to that observed in our own patients (13.7 ± 2.7 cm). The girls treated by Tanaka et al. (18) with the combined therapy reached a final height or predicted final height that was less, although not significantly, than what we observed in our series. Perhaps the small number of female patients included in the study by Tanaka et al. (18) affected the results reported by these authors, preventing them from detecting a significant improvement in the final height or in the height prediction in the GnRHa-treated girls over the controls. We did not observe any adverse effect induced by GnRHa, there was no disproportion of the body segments (data not shown), and also the delayed pubertal development was well tolerated by the girls, as shown by the fact that none of them dropped out of the study.
A central point is the selection of patients who may benefit from the combined therapy. Tanaka et al. (18, 27) proposed to treat girls entering puberty shorter than 125 cm and with a projected height SD score for BA below -1.5, with this therapy. According to the authors, 5 yr of combined therapy would permit them to reach at least 150 cm, which is the minimum height desired by these patients in Japan.
Based on the results we obtained in our girls administered with the combined therapy or with r-hGH alone, we tentatively propose the following selection criteria for the therapy with r-hGH+GnRHa: GH-deficient girls entering puberty without showing any r-hGH-induced improvement in PAH that remains 153 cm or less, with a deteriorating height-BA SD score under r-hGH, and with a height SD score of 2.0 or less. A PAH of 153 cm was chosen on the basis that a final height of 153 cm represents the height in the 3rd percentile of the Italian population (28) and that it is also the average height attained by our girls treated with r-hGH alone. In keeping with Tanaka et al. (18), the treatment should be started at a BA between 10.5 and 12 yr.
In summary, we found that in our selected girls the administration of the GnRHa in combination with r-hGH gave a clear, positive effect on final height in comparison with the r-hGH alone. In particular, whereas girls treated with r-hGH appropriate for dose and number of injections reached a final height that was into the range of their MPH, those administered with the GnRHa for 2 yr grew significantly more. This result indicates that slowing pubertal development in selected girls may improve final height, allowing them to grow above their MPH and close to the normal values for age.
Interestingly, a recent study (29) reported that the combined therapy also had a significant positive effect on the final height of girls with idiopathic short stature. A 4-yr period of treatment allowed them to grow significantly above their target height and 4.6 cm, on average, above the control girls administered with r-hGH alone. The effect of the combined therapy on final height in this series was slightly less than in ours, possibly reflecting the less favorable auxological and the different endocrinological characteristics of those girls.
Although our results on final height in girls with IGHD support those by other authors on near final height or final height obtained on a smaller number of girls with GHD, such a therapy must be still considered as experimental and requires a larger number of controlled studies to determine its role in GHD patients.
Received August 30, 2000.
Revised January 19, 2001.
Accepted January 22, 2001.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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