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Results of Long-Term Follow-Up after Treatment of Central Precocious Puberty with Leuprorelin Acetate: Evaluation of Effectiveness of Treatment and Recovery of Gonadal Function. The TAP-144-SR Japanese Study Group on Central Precocious Puberty

Department of Endocrinology and Metabolism (T.T., N.M.), National Center for Child Health and Development, Tokyo 157-8535; Department of Pediatrics (H.N.), Graduate School of Medicine, Chiba University, Chiba, Chiba 260-8670; Department of Pediatrics (K.F.), Asahikawa Medical College, Asahikawa 078-8510; Division of Endocrinology and Metabolism (K.T.), Kanagawa Children’s Medical Center, Yokohama 232-8555; Department of Clinical Nursing and Pediatrics (K.O.), Faculty of Medicine, University of Yamanashi, Yamanashi 409-3898; Department of Pediatrics (M.S.), School of Medicine, Toho University, Tokyo 143-8540; and Department of Obstetrics and Gynecology (K.K.), Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan

Address all correspondence and requests for reprints to: Toshiaki Tanaka, Department of Endocrinology and Metabolism, National Center for Child Health and Development, 2-10-1, Okura, Setagaya, Tokyo, 157-8535, Japan. E-mail: tanaka-t{at}ncchd.go.jp.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We evaluated the effect of leuprorelin treatment on adult height (AH) and followed recovery of reproductive function in 63 girls and 13 boys with central precocious puberty (CPP). Mean treatment durations were 3.8 ± 2.0 and 4.1 ± 2.5 yr, and posttreatment follow-up durations were 3.5 ± 1.3 and 2.6 ± 1.1 yr for girls and boys, respectively. AH was 154.5 ± 5.7 cm for girls, and 89.5% of girls reached AH within their target height range. For boys, AH was 163.2 ± 13.0 cm, and 90.9% reached target height range. It appeared that the Bayley-Pinneau method, modified for Japanese children, using a table for advanced bone age (BA), overestimated AH in CPP; and this method, using a table for average BA and projected height for BA, was suitable for prediction of AH in CPP.

Menarche or remenarche occurred in 96.8% of girls at the age of 13.1 ± 1.5 yr. Of 11 girls who contributed urine samples, all seven idiopathic and two organic cases were considered to have ovulation. Serum testosterone levels reached normal adult level in all boys.

In conclusion, long-term leuprorelin treatment for children with CPP improved AH and had no adverse effects on recovery of reproductive function.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE OBJECTIVES OF treatment for children with central precocious puberty (CPP) are to avoid psychosocial problems caused by early pubertal development and to normalize adult height (AH). Long-term GnRH analog administration induces persistent suppression of the hypothalamic-pituitary-gonadal axis and reduction of sexual hormones to prepubertal levels (1, 2). GnRH analog administration effectively arrests further development of secondary sex characteristics, slows bone age (BA) maturation, increases pubertal height gain, and is believed to eventually improve AH prognosis (3, 4). Recently, several investigators have reported that improvement in AH above pretreatment predicted AH (PAH) was obtained after long-term GnRH analog treatment (5, 6, 7, 8). However, the accuracy of PAH methods remains controversial, because they are based on the auxological data from normally growing children.

Although it has been reported that gonadal function almost fully recovers after the cessation of GnRH analog administration, little information is available regarding ovulation in girls (7, 9, 10).

Since 1989, we have followed children with CPP who enrolled in two prospective clinical trials (phase II and phase III) that investigate the effects of leuprorelin acetate depot on CPP (4, 11, 12, 13) and have now obtained AH measurements for 76 children (63 girls and 13 boys). In this report, we present AH results of long-term follow-up after leuprorelin acetate treatment, evaluate the effectiveness of treatment using target height (TH) and PAH methods, and demonstrate good recovery of reproductive function, particularly of ovulation in girls.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Children with CPP were enrolled in this prospective clinical trial at 35 study sites of the TAP-144-SR Study Group. The diagnosis of CPP was based on the early occurrence of secondary pubertal signs, advanced BA, accelerated growth rate, pubertal LH and FSH responses in the GnRH test and pubertal sex steroid levels. Peak LH greater than 6 mIU/ml in both boys and girls and ratio of peak LH/peak FSH greater than 0.8 in boys and 0.5 in girls were judged as showing pubertal responses (14, 15). The study protocol was approved by the Institutional Review Board of each study site, and the study was conducted in accordance with the guidelines of the Declaration of Helsinki. Written consent was obtained from the patients and their parents before enrollment of patients.

Of 106 enrolled patients, 76 (63 girls and 13 boys) for whom AH was determined were included in analysis. Patient characteristics are summarized in Table 1. Forty-eight patients had idiopathic CPP (mean age, 8.2 ± 2.2 yr), and 24 had organic CPP (mean age, 7.8 ± 2.3 yr). Hypothalamic hamartoma was observed in 10 patients (mean age, 7.4 ± 2.0 yr); hydrocephalus in four; astrocytoma in three; and microcephalia, suprasellar germinoma, pineal cyst, pineal hamartoma, cerebral infarction, arachnoid cyst, and nuclear jaundice in one patient each. The other patients had sex hormone-induced CPP with congenital adrenal hyperplasia (n = 2), testicular cancer (n = 1), or nonclassical 3ß-hydroxysteroid dehydrogenase deficiency (n = 1).

Patients were treated with a depot formulation of leuprorelin acetate [D-Leu (6)-[des-Gly (10)-NH₂]-GnRH ethylamide acetate, Takeda Pharmaceutical Co. Ltd., Osaka, Japan] given sc every 4 wk at an initial dose of 10, 30, or 90 µg/kg (5, 63, and 8 children, respectively). Initial dose varied because 21 children were initially enrolled in phase II trial (dose-finding study), which compared effect on secondary sex characteristics between three doses (11). Fifty-five children initially enrolled in the phase III trial received an initial dose of 30 µg/kg. The dosage was adjusted in the case of inadequate gonadal suppression. Treatment was discontinued at the age of pubertal onset in normal Japanese children or at the wish of a patient’s family. Concurrent treatment with GH was not allowed.

Methods

Height was measured with a stadiometer at each study site. Height SD score (SDS) was calculated according to the standard height table for Japanese children. One experienced physician estimated all of BA in this study using the modified Tanner-Whitehouse 2 (TW-2) method (radius-ulna-short bone) standardized for Japanese children (16). She was informed of the sex and chronological age (CA) of each individual patient at the time of estimation of BA. PAH at the start of treatment was determined by three different methods: PAH based on the Bayley-Pinneau method (17) modified for Japanese children (18) using a table for advanced BA (PAH-BPad) or using a table for average BA (PAH-BPav), and that based on the projected height SDS for BA (PAH-phSD) (19). The Bayley-Pinneau method modified for Japanese children is standardized for the use of the modified TW-2 method for Japanese children (16, 18). TH was calculated as midparent height minus 6.5 cm for girls and midparent height plus 6.5 cm for boys. TH ranges (TH ± 8 cm for girls and TH ± 9 cm for boys) were calculated using parental height adjusted for Japanese data. AH was defined as height velocity less than 1 cm/yr and/or BA surpassing 14 yr for girls and 15 yr for boys as determined by the modified TW-2 method for Japanese children. AH was determined after a mean posttreatment follow-up period of 3.5 ± 1.3 yr for girls and 2.6 ± 1.1 yr for boys.

Plasma levels of estradiol and testosterone were measured by RIA. In girls who underwent daily urine sample collection during a menstrual cycle, urine levels of LH, FSH (determined by time-resolved fluorescence immunoassay or chemiluminescent enzyme immunoassay), estradiol (by RIA), and pregnanediol (by gas chromatography) were measured. When peak pregnanediol level was more than 1 mg/g Cr, a patient was considered to have an ovulatory menstrual cycle. Biphasic basic body temperature, LH surge greater than 5 IU/g Cr, and estradiol level greater than 10 µg/g Cr provided ancillary evidence of the occurrence of an ovulation. In two girls, basic body temperature was measured every morning during one menstrual cycle.

Statistics

Values are expressed as mean ± SD. Student’s t test for paired samples with Bonferroni adjustment for multiple comparisons or repeated-measures ANOVA were performed when appropriate. Correlations between two parameters were determined by Pearson’s correlation coefficient analysis. Stepwise multiple regression analysis was performed to determine correlations between AH or height gain and clinical factors. Findings of P < 0.05 were considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
AH, TH, and PAH

AH, TH, and PAH, determined by the three methods at the start and end of treatment, are shown in Table 2. Of 57 girls and 11 boys for whom TH was available, 51 girls (89.5%) and 10 boys (90.9%) reached AH within their TH range. AH was higher than TH in 34 girls (59.6%) and three boys (27.3%). No significant difference was observed between AH and TH either for girls or boys.

AH was positively correlated with height SDS for CA at the start of treatment (girls, r = 0.66, P < 0.01; boys, r = 0.69, P < 0.01), height SDS for BA at the start of treatment (girls, r = 0.35, P < 0.01; boys, r = 0.83, P < 0.01) and mean growth velocity during treatment (girls, r = 0.32, P < 0.05; boys, r = 0.57, P < 0.05). Stepwise regression analysis revealed that height SDS for CA, height SDS for BA at start of treatment, and mean growth velocity during treatment influenced AH for girls (r = 0.83, R² = 0.69).

When height gain was defined as the difference between AH and PAH-phSD at the start of treatment, height gain was positively correlated with mean growth velocity during treatment (girls, r = 0.59, P < 0.01; boys, r = 0.81, P < 0.01), treatment period (girls, r = 0.58, P < 0.01; boys, r = 0.28, P = 0.35), and change in BA during treatment (girls, r = 0.41, P < 0.01; boys, r = 0.58, P = 0.05) and negatively correlated with CA at the start of treatment (girls, r = –0.73, P < 0.01; boys, r = –0.47, P = 0.11) and BA at the start of treatment (girls, r = –0.40, P < 0.01; boys, r = –0.45, P = 0.12) for both girls and boys. Stepwise multiple regression analysis revealed that both CA and BA at the start of treatment, treatment period, and mean growth velocity during treatment influenced height gain for girls (r = 0.82, R² = 0.66). Stepwise multiple regression analysis was not performed for boys because of the small number of subjects.

Reproductive function

Menarche, including remenarche, was observed after the end of treatment in 61 girls (96.8%). Age at menarche was 13.1 ± 1.5 yr (range 10.4–16.8 yr). For 13 girls in whom menarche already had occurred before the start of treatment, mean age at remenarche was 12.7 ± 1.3 yr (range 11.0–15.3 yr). Duration between last injection of leuprorelin and menarche was 17.5 ± 11.2 months (median, 14.7; range 3.6–62.8 months). Among these patients, a regular menstrual cycle was observed in 53 girls. For two girls for whom menarche was not observed after the end of treatment, ages at last observation were 14.6 and 14.9 yr, and posttreatment follow-up durations were 36.6 and 50.1 months, respectively. One of these girls (age, 14.6 yr) had hypothalamic hamartoma, and the other (age, 14.9 yr) had a diencephalohypophysial disorder due to brain tumor.

When the girls were divided into a menarche group and a remenarche group, the duration from the last injection was significantly shorter in the remenarche group than in the menarche group, as shown in Fig. 1.

View larger version (14K): [in this window] [in a new window]   FIG. 1. Occurrence of menarche or remenarche after cessation of GnRH analog treatment.

View larger version (21K): [in this window] [in a new window]   FIG. 2. A typical pattern of urinary hormone levels in a girl with ovulation.

View larger version (20K): [in this window] [in a new window]   FIG. 3. Urinary hormone levels in a girl with anovulatory menstruation.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Because it is well known that AH in untreated patients with CPP is significantly shorter than TH, by approximately 3.5–10 cm (3, 20, 22, 23, 24), improvement of AH within TH range is one of the major objectives of treatment for CPP. In our study, 90% of girls and of boys reached AH within TH range, and AH did not significantly differ from TH. Treatment with leuprorelin appears to be effective for improvement of AH.

One of the indicators of therapeutic effects is the difference between AH after treatment and PAH at the start of treatment. The Bayley-Pinneau method has been used to determine PAH for patients with CPP in various studies (5, 6, 7). However, the accuracy of PAH methods should be evaluated carefully using clinical data, because the Bayley-Pinneau method is based on auxological data from normally growing children. We therefore evaluated the usefulness of PAH-BPad, PAH-BPav, and PAH-phSD in our study. If treatment for CPP is judged to be effective, PAH at the start of treatment should be significantly shorter than AH after treatment.

Because the number of boys in our study was small and some boys had started GnRH analog treatment at a very late BA, when efficacy of treatment had not been expected, we evaluated the effectiveness of PAH methods only for girls. There was no significant difference between PAH-BPad and AH after treatment, suggesting that treatment was not effective in improving AH. On the other hand, PAH-BPav was significantly shorter than AH. Because long-term treatment with leuprorelin was judged to be effective, the Bayley-Pinneau method using a table for advanced BA might be thought to overestimate PAH.

Recent studies demonstrated that determination of PAH by the Bayley-Pinneau method, using a table for advanced BA, overestimated AH in untreated patients with CPP (24, 25). Kauli et al. (24) reported that PAH-BP in untreated CPP patients was significantly higher than actual AH (difference, 5.6 cm) when the Bayley-Pinneau table for accelerated BA was used. They concluded that the table for average BA was more appropriate for AH prediction of children with CPP because PAH-BPav did not differ from actual AH in patients without any treatment. In patients treated with GnRH analog, they reported that no significant difference was found between AH and PAH-BPad but that AH was significantly higher than PAH-BPav. Mul et al. (26) reported similar results. Our results are similar to those by Kauli et al. (24).

The Bayley-Pinneau method that we used was the modified method for Japanese children (18). Our results demonstrate that this modified method is as useful as the original Bayley-Pinneau method used in Western countries.

In addition, we demonstrated the usefulness of PAH-phSDS, which is based on the hypothesis that height SDS for BA in childhood is preserved in AH. Because BA advance is progressive in untreated CPP patients, PAH-phSDS will progressively decrease if patients do not receive any treatment for CPP. Therefore, when AH after treatment is equal to or greater than PAH-phSDS at the start of treatment, improvement of AH can be considered to have been obtained by treatment. In the present study, AH was significantly greater than pretreatment PAH-phSDS for girls, and PAH-phSDS was comparable with PAH-BPav, indicating the usefulness of PAH-phSDS as well as PAH-BPav in patients with CPP.

Determination of factors that influence the therapeutic effect of GnRH analog administration is very important for identifying groups of patients who will benefit from treatment. Klein et al. (5) reported that height gain was positively correlated with duration of treatment and height SDS for CA at the start of treatment, and negatively correlated with age at onset of puberty and age at the start of treatment. Mul et al. (26) reported that a model including BA at the start and end of treatment, CA at the start of treatment, and BA advance at the end of treatment could explain 48.9% of variance in the results of multiple regression analysis. Arrigo et al. (27) reported that BA/CA at the start of treatment was the only significant variable in the results of stepwise regression analysis. In the present study, stepwise multiple regression analysis for girls showed that CA and BA at the start of treatment, treatment duration, and average growth rate during treatment mainly affected height gain. This finding suggests that patients who were younger and had advanced BA at the start of treatment had greater gain in height. Our results also suggested that longer treatment and higher growth velocity during treatment contributed to greater height gain, as Klein et al. (5) reported. Because it has been reported that continuing treatment beyond BA of 12–12.5 yr (13, 27) or beyond CA of 11 yr does not improve AH (28), an earlier start of GnRH analog treatment might be important in obtaining longer treatment duration in accelerated progressive forms of precocious puberty.

Reproductive function

It has been reported that the hormonal suppression induced by GnRH analog is reversible (7, 21). We observed menarche, including remenarche, after the end of treatment in 61 of 63 girls (96.8%). Jay et al. (9) found that, of a total of 46 subjects, 44 (96%) had attained menarche by completion of their study. Feuillan et al. (10) reported that all idiopathic CPP and CPP with hypothalamic hamartoma began spontaneous menses 17.6 ± 11.0 months and 20.5 ± 16.3 months after the cessation of GnRH analog, respectively. In the present study, the mean time interval between cessation of GnRH analog treatment and the start of spontaneous menarche was 17.5 ± 11.2 months, an interval compatible with that reported by Feuillan et al. The age at menarche of 13.1 ± 1.5 yr was significantly higher than that of normal Japanese girls, 12.24 ± 0.92 yr (n = 226).

When the patients were divided into remenarche and menarche groups, the remenarche group was found to have started menstruation with a shorter duration after the last injection of leuprorelin than the menarche group. In the remenarche group, uteri appeared to be more mature than in the menarche group. This finding might be useful for predicting the time of occurrence of menarche after the treatment.

We established a method of evaluation of ovulation by measuring urinary gonadotropins, estradiol, and pregnanediol. As shown in Fig. 2, patterns of urinary hormone levels were identical with those of daily serum sampling: estrogen surge, gonadotropin surge, and elevation of pregnanediol as an index of progesterone secretion and corpus luteal function. Our results demonstrated the usefulness of urinary hormone sampling for assessment of ovulation. Of 11 girls for whom investigation of ovulation using urine samples was performed, all idiopathic cases appeared to have ovulatory menstrual cycles, but two of four organic cases were considered to have anovulatory menstruation. It is possible that their organic disorders (pineal cyst and suprasellar germinoma) affected ovulation.

In all boys, serum testosterone levels were elevated to normal adult level after the end of treatment.

No severe adverse drug reaction was observed during leuprorelin treatment. Long-term leuprorelin treatment appeared to be well tolerated in terms of safety and reversibility of reproductive function.

	Acknowledgments

 
We thank the following members of the TAP-144-SR Study Group on Central Precocious Puberty: A. Okuno, K. Yano, Y. Ito, Department of Pediatrics, Asahikawa Medical College School of Medicine; Y. Igarashi, E. Ogawa, I. Fujiwara, Department of Pediatrics, Tohoku University School of Medicine; M. Kojima, Department of Internal Medicine, Ohara Medical Center, Ohara General Hospital; W. Abo, T. Hatasawa, Department of Pediatrics, Aomori Prefectural Center Hospital; N. Moriya, Department of Pediatrics, Yamagata University School of Medicine; R. Tanaka, T. Tamura, H. Okazaki, Department of Neurosurgery, Niigata University School of Medicine; N. Koda, Department of Metabolism and Endocrinology, Saitama Children’s Medical Center; T. Yasuda, Y. Kobayashi, Department of Pediatrics, Chiba University School of Medicine; H. Inomata, Department of Pediatrics, Ichihara Hospital, Teikyo University School of Medicine; K. Fujiwara, Department of Neurosurgery, Tokyo Metropolitan Bokuto Hospital; A. Miyata, Department of Pediatrics, Tokyo Metropolitan Fuchu Hospital; M. Murata, H. Matsuoka, Department of Pediatrics, Dai-Ni Hospital, Tokyo Women’s Medical College School of Medicine; M. Anzo, T. Kamimaki, Department of Pediatrics, Keio University School of Medicine; M. Ishikawa, Division of Endocrinology and Metabolism, National Children’s Hospital; Y. Ohyama, Department of Pediatrics, Kitasato University School of Medicine; H. Maesaka, M. Adachi, Division of Endocrinology and Metabolism, Kanagawa Children’s Medical Center; E. Tokuhiro, Department of Pediatrics, Odawara City Hospital; Y. Nakagomi, Department of Pediatrics, Yamanashi Medical University; Y. Igarashi, H. Ogawa, Department of Pediatrics, Hamamatsu University School of Medicine; M. Ogawa, Department of Pediatrics, Nagoya University School of Medicine; J. Yoshida, K. Saito, Department of Neurosurgery, Nagoya University School of Medicine; M. Nagasaka, Department of Neurosurgery, Aichi Prefecture Colony Central Hospital; K. Yasuda, H. Daido, T. Mune, Department of Internal Medicine III, Gifu University School of Medicine; Y. Shigematsu, A. Nakai, Department of Pediatrics, Fukui Medical School Faculty of Medicine; S. Okada, K. Inui, H. Tsukamoto, Department of Pediatrics, Osaka University Medical School; Y. Kobayashi, H. Higashino, Department of Pediatrics, Kansai Medical University School of Medicine; Y. Nishi, Department of Pediatrics, Japan Red Cross Hiroshima Atomic Bomb Hospital; T. Kurashige, K. Araki, T. Okada, Department of Pediatrics, Kochi Medical School; S. Miyazaki, T. Kuno, Department of Pediatrics, Saga Medical School Faculty of Medicine; Y. Tsuji, M. Yoshimoto, E. Kinoshita, Department of Pediatrics, Nagasaki University School of Medicine; and E. Tamanaha, Department of Pediatrics, Nakagami Hospital.

	Footnotes

 
Financial disclosure: This study was conducted as phases II, III, and IV trial of leuprorelin acetate and was financially supported by Takeda Pharmaceutical Company, Ltd.

First Published Online December 14, 2004

Abbreviations: AH, Adult height; BA, bone age; CA, chronological age; CPP, central precocious puberty; PAH, predicted AH; PAH-BPad, PAH based on the Bayley-Pinneau method for advanced BA; PAH-BPav, PAH based on the Bayley-Pinneau method for average BA; PAH-phSD, PAH based on projected height SDS for BA; SDS, SD score; TH, target height; TW-2, Tanner-Whitehouse 2.

Received September 21, 2004.

Accepted November 23, 2004.

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