**1. Introduction**

304 Sex Steroids

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of tibolone (5 mg/day) vs combined continuous estrogen/progestagen in post menopausal women]," *Revista Medica de Chile*, vol. 131, no. 10, pp. 1151-1156,

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> Estrogen deprivation, for instance after ovariectomy or natural menopause, is associated with significant bone loss in adult women. (Lindsay, 1995) Gonadotropin-releasing hormone agonist (GnRHa) inhibits hypothalamo-pituitary-gonadal hormone secretion and gradually reduces the estrogen level. (Wacharawsindhu et al., 2006) Consequently, decreases in bone mineral density, which are also observed after ovariectomy and natural menopause, have been observed during GnRHa therapy in women with endometriosis and men with benign prostatic hyperplasia. (Goldray et al., 1993) Moreover, women who were treated with this analog showed body composition changes, including a decrease in lean mass and an increase in fat mass, which resemble the body changes that occur during the menopause. (Revila et al., 1998)

> Meanwhile, GnRHa has also been the treatment of choice for central precocious puberty (CPP) since the mid-1980s. (Crowley et al., 1981) Many of the previous studies on the auxological effects of GnRHa treatment on CPP have focused on assessing the patient's final height, whereas much less attention has been paid to changes in their weight and body composition. (Arrigo et al., 2004)

> However, concern has been expressed that CPP might be associated with increases in body mass index (BMI) both at the initial presentation and during GnRHa treatment (Boot et al., 1998) and that individuals with the condition are prone to developing obesity. This concern is supported by adult cases that were treated with GnRHa, as described above.

> On the other hand, it is well known that BMI and percentage body fat increase during puberty. Consequently, gonadotropin-suppressive therapy can theoretically halt the progression to obesity by inhibiting pubertal development.

> Recently, there have been many reports about the changes in body composition that occur in children with CPP who are treated with GnRHa (Wacharsindhu et al., 2006, Arrigo et al., 2004, Boot et al., 1998, Feuillan et al.,1999, Palmert et al., 1999, Chiumello et al., 2000, van der Sluis et al., 2002, Paterson et al., 2004, Oosdijk et al., 1996, Traggiai et al., 2005, Herger et al., 1999, Pasuquino et al., 2008). Some reports have shown that obesity occurs at a high frequency among children with CPP (Arrigo et al., 2004, Feuillan et al., 1999, Palmert et al.,

Standard Gonadotropin-Suppressive Therapy in Japanese Girls with

method of Greulich and Pyle (Greulich & Pyle, 1959).

**2.3 Statistical analysis** 

**3. Results** 

threshold was set at p < 0.05.

**3.1 Prevalence of obesity** 

patients (27.8%) at the baseline.

**3.2 BMI and POW during follow-up** 

**16.5**

Fig. 1. Changes in BMI during GnRHa therapy

**17.5**

**18.5**

**BMI (kg/m2)**

**19.5**

which was also true after 2 years treatment.

Idiopathic Central Precocious or Early Puberty Does Not Adversely Affect Body Composition 307

incomplete suppression, the dose of leuprolide acetate was increased to 150 g/kg. Bone age (BA) was assessed by one investigator using an x-ray of the left hand, according to the

For statistical purposes, the Wilcoxon test was used when appropriate in order to estimate the significance of differences between groups. The correlations between individual values were examined using Pearson's test. All values are given as the mean ± S.E. The significance

In our recent study of 18 girls with CPP or early puberty, five girls (27.8%) were diagnosed with obesity because their BMI values were higher than the 95th centile (Inokuchi, 2009) at the initiation of therapy. Moreover, the BMI standard deviation score (SDS) for chronological age (CA) was higher than zero in 14 (77.8%) patients, and the mean BMI SDS for CA was 1.07±0.32 at the baseline. Even when it was corrected for bone age (BA), the BMI SDS was still higher than zero in 9 (50.0%) patients, and the mean BMI SDS was 0.33±0.25 at the baseline. On the other hand, the POW was higher than 20% (indicating obesity) in 5

The mean BMI was significantly increased after 1 year and increased further afterwards (Fig.1). BMI was higher than the 95th centile in 5 patients (27.8%) at the initiation of therapy,

**Start 6 mo 1 y 2 y**

\*

\*

1999, Chiumello et al., 2000, van der Sluis et al., 2002, Paterson et al., 2004). However, most of these reports studied populations in Western countries, and almost none investigated Asian children (Wacharsindhu et al., 2006). Furthermore, in these studies, GnRHa was administered at higher doses (Boot et al., 1998, Chiumello et al., 2000, van der Sluis et al., 2002) than are used in the standard gonadotropin-suppressive therapy protocol that is currently in operation in Japan. With some exceptions, all these reports showed that obesity is aggravated during GnRHa therapy (Wacharsindhu et al., 2006, Boot et al., 1998, Chiumello et al., 2000, van der Sluis et al., 2002, Paterson et al., 2004, Oosdijk et al., 1996, http://www.iotf.org/documents/iotfsocplan251006.pdf). Therefore, we assessed the effects of the standard gonadotropin-suppressive therapy protocol that is currently used in Japan on body composition in order to review the optimal dose of GnRHa.

The aims of the present study were to prospectively evaluate whether obesity occurs at a high frequency among Japanese children with CPP and to longitudinally evaluate the body composition of Japanese children with CPP before and during GnRHa therapy.
