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Gonadotropin-Releasing Hormone Agonist Treatment of Girls with Constitutional Short Stature and Normal Pubertal Development

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Gonadotropin-Releasing Hormone Agonist Treatment of Girls with Constitutional Short Stature and Normal Pubertal Development 0021-972X/96/$03.00/0 Vol. 81, No. 9 Journal of Clmcal Endocrinology and Metabolism Printed in U.S.A. Copyright 0 1996 by The Endocrine Society Gonadotropin-Releasing Hormone Agonist Treatment of Girls with Constitutional Short Stature and Normal Pubertal Development JEAN-CLAUDE CAREL, FRlkDliRIQUE HAY, RliGIS COUTANT, DANIlkLE RODRIGUE, AND JEAN-LOUIS CHAUSSAIN Downloaded from https://academic.oup.com/jcem/article/81/9/3318/2651102 by guest on 23 September 2021 INSERM U-342 and Department of Pediatric Endocrinology, University of Paris V, Hbpital Saint Vincent de Paul, Paris, France ABSTRACT interruption of treatment, bone age was 14.9 2 1.3 yr (~13.5 yr in all GnRH agonists have been proposed to improve final height in patients), height was 149.1 k 4 cm, and final height prognosis was patients with constitutional short stature. We treated 31 girls, aged 150.6 2 3.6 cm. Final height prognosis was 1 2 2.3 cm greater than 11.9 i 1 yr (mean t- SD), with short stature, recent pubertal onset and pretreatment height prognosis (P < 0.02) and 1.2 k 2.2 cm below the predicted final height of 155 cm or less with depot triptorelin. During height predicted at the end of the treatment (P < 0.01). No major the 23 2 4 months of treatment, bone age progression was 0.6 ? 0.3 side-effect was observed. Height SD score decreased during treatment bone age yr/yr, and growth velocity declined from 7 k 2 to 4 2 0.8 with GnRH agonist from -2.3 ? 0.9 to -2.7 -C 0.7 SD score (P < cm/yr (P < 0.0001). Height prognosis, calculated by the Bayley-Pin- 0.0001). We conclude that 2 yr of depot triptorelin-induced pubertal neau method, progressed from 149.6 k 3.4 to 151.8 2 4 cm at the end delay has a limited effect on near-final height in girls with constitu- of treatment (+2.2 t 2.6 cm; P < 0.0001). When treatment was tional short stature and that the growth benefit observed does not interrupted, growth velocity slightly increased to 4.6 ? 1.6 cm/yr, and currently justify the use of GnRH agonists, given their cost and po- bone age maturation was accelerated: 1.3 2 0.4 bone age yr/yr during tential side-effects. (J Clin Endocrinol Metab 81: 33183322, 1996) the first posttreatment year. At the last visit, 26 k 9 months after LJBERTY IS associated with increased growth velocity of the fourth treatment year. However, no follow-up after P and bone maturation, leading to fusion of growth cessation of treatment was presented. plates and achievement of final height. Extreme abnormal- We initiated an open trial of long acting GnRH agonist in ities of pubertal timing can affect final height. Premature girls with constitutional short stature, and we report here the exposure to sexual steroids in situations such as precocious results of 31 patients who have reached final or near-final puberty or congenital adrenal hyperplasia is associatedwith height. a reduction of final height, averaging, in the case of preco- cious puberty, 2 SD (-10 cm) (1,2). Conversely, gonadotropin Subjects and Methods deficiency (idiopathic or Kallmann’s syndrome) is associated Patients with prolonged statural growth and a 3-cm increment in final Thirty-one girls were included with the following criteria: height -1 height. However, this increment is attributable to patients SD or less, height prognosis of 155 cm or less, recent pubertal onset treated after age 18 yr, i.e. after 5 yr of pubertal delay (3). defined by breast development (B2-B3) of less than 12-month duration, Several reports have documented the ability of treatment chronological age of 9-14 yr, bone age less than 12.5 yr, and pubertal with GnRH agonist to increase final height in patients with response of LH to GnRH (8). Preliminary data for nine patients have been previously reported (9). central precocious puberty (2, 4-6). However, genetic growth potential is not always fully restored (5), and some Treatment reports have suggested that the benefit on final height might be insignificant in patients with pubertal onset occurring Patients were treated with depot triptorelin (Decapeptyl, Ipsen-Bio- tech, France; 3.75 mg every 28 days) as previously described (10). Ad- close to the normal age of puberty (2). equate suppression of the gonadotroph was assessed clinically by the Given their action on final height in precocious puberty, interruption of pubertal development and suppressed LH response to GnRH agonists are candidates for increasing final height in GnRH. The planned treatment duration was 2 yr, but varied from 15-30 constitutional short stature. Municchi et al. (7) treated pa- months. After the end of treatment, growth and bone age were assessed every 6-12 months, and in most patients, a GnRH test was performed tients with short stature with deslorelin in a double blind 6-12 months after interruption of treatment. Data were analyzed in trial. Their preliminary data, concerning 16 patients, indi- patients followed for at least 12 months after discontinuation of the cated a 7.2-cm increase in predicted adult height at the end treatment who had reached a bone age of 13.5 yr or more. Methods Received September 5, 1995. Revision received February 15, 1995. Rerevision received February 20, 1995. Accepted February 21, 1995. Bone age was evaluated by two of us (J.-L.C. and J.-CC.) according Address all correspondence and requests for reprints to: Dr. Jean- to the method of Greulich and Pyle (ll), and height prognosis was Claude Carel, INSERM U-342, Hapital Saint Vincent de Paul, 82 avenue calculated by the method of Bayley-Pinneau (12). Methods for measure- Denfert Rochereau, 75014 Paris, France. E-mail: [email protected]. ment of plasma estradiol and gonadotropins were previously described 3318 GnRH AGONISTS AND SHORT STATURE 3319 (13). Informed consent was given by the patients and their families to 0.6 ? 0.3 bone age yr/yr of treatment (Fig. 2). This reduction participate in the protocol, which was approved by the local ethical of bone age maturation resulted in a 2.2 + 2.6 cm increase in committee. height prognosis at the end of treatment (Table 1 and Fig. 2; Statistics P < 0.0001). Although the treatment was planned to last 24 months, its average duration was 23 -C 4 months. Eight pa- Statistical tests were performed with the Statview- software (Abacus tients decided to interrupt the treatment before completing Concept, Berkeley, CA). Results are expressed as the mean i SD. Paired t tests were used. the 2-yr protocol, mainly becauseof poor growth velocity (2.7 2 2 cm / yr during the portion of the second year of treatment Results they completed). Their data have been maintained in the The initial characteristics of the 31 patients are described present analysis on the basis of the intention to treat. How- in Table 1. The patients were carefully evaluated to rule out ever, removal of these eight patients from the analysis would Downloaded from https://academic.oup.com/jcem/article/81/9/3318/2651102 by guest on 23 September 2021 defined causes of growth retardation; the peak plasma GH not affect the conclusions of our study (not shown). In three in response to a pharmacological stimulation test exceeded patients, treatment was slightly prolonged to 26, 27, and 30 10 ng/mL in all cases(mean GH peak, 22.1 ? 6.5 ng/mL). months, because of poor compliance with the schedule of When appropriate, other investigations ruled out defined out-patient visits. causes of short stature; a karyotype was performed in 5 The patients were followed for an additional 26 +- 9 patients with features suggestive of Turner’s syndrome, a months after interruption of treatment. Clinical pubertal de- jejunal biopsy was performed in 2 patients with abdominal velopment resumed in all patients, and a pubertal LH re- complaints compatible with celiac disease, and bone x-rays sponse to GnRH was documented in 23 patients 9.1 + 7 were performed in 2 patients with hyperlordosis clinically months after interruption of treatment (Table 2). Although suggestive of hypochondroplasia. All of these investigations bone age at the end of treatment was 11.8 + 0.6 yr, no clear were normal. Birth length adjusted for gestational age was growth spurt was observed (Fig. 1); growth velocity was 4.6 -1.8 t 1.2 SD, and a history of intrauterine growth retarda- t 1.6 cm/yr during the first posttreatment year, 1 ? 0.3 tion (IUGR; birth length, less than -2 SD) was found in 46% cm/yr more than that during the last year of treatment (P < (13 of 28) of the patients (12). Target height, calculated from 0.01). In contrast, bone age maturation was markedly in- midparental height, was 7.8 cm (1.4 SD) below the average creased, averaging 1.3 ? 0.4 bone age yr/yr during the first height of French women (14), indicating a genetic participa- posttreatment year and 1.5 + 0.3 bone age yr / yr during the tion in the short stature of our patients. A GnRH test was entire follow-up period (both P < 0.0001 VS. bone age pro- performed in 29 of 31 patients before treatment and con- gression during treatment; Fig. 2). Growth after interruption firmed the onset of pubertal development, with LH peak of treatment (difference between heights at last visit and at values greater than 5 IU/L in all cases (Table 2). the end of treatment) was inversely correlated with bone age As expected, treatment with GnRH agonist was associated at the end of treatment (r = 0.73; P < 0.0001).
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