**4. Discussion**

Many reports have shown that obesity occurs at a high frequency among children with CPP. (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) Feuillan et al. reported that the mean BMI of 18 girls with precocious puberty due to hypothalamic hamartoma (HH) and 32 with ICPP was higher than normal before GnRHa treatment (Feuillan et al., 1999), and Arrigo et al. reported that 23.6% of the 101 girls with ICPP that they studied were obese before the start of therapy. (Arrigo et al., 2004) Our results confirm that obesity is a common problem in children with CPP in Japan. Indeed, in this study, a quarter of our patients were found to be obese according to both BMI and POW before the start of therapy. Moreover, the BMI SDS for CA and BA were higher than zero in more than half of the patients at the baseline. Since the prevalence of obesity in girls in later childhood is 14.3% in Japan (http://www.iotf.org/documents/iotfsocplan251006.pdf), the above figure indicates that the prevalence of obesity in children with CPP is unusually high.

Although several reports have stated that obesity is a common problem in girls with CPP, as mentioned above, the reason why so many girls with CPP have an increased BMI is unclear. A decrease in lean body mass and an increase in fat mass leads to obesity. Chiumello et al. suggested that girls with CPP undergo a shortened period of prepubertal lean mass development and so possess an insufficient lean body mass, leading to obesity. (Chiumello et al., 2000) Recently, Arrigo et al. hypothesized that the pre-treatment increase in BMI is caused pubertal hormonal changes and secondary changes in body fat rather than CPP itself, as in their series they found that the suppression of pituitary-gonadal axis function was accompanied by a significant decrease in excess weight (Arrigo et al., 2004). However, our results showed that the suppression of the pituitary-gonadal axis did not bring about a significant change in excess weight, as described below. Furthermore, as for the number of patients whose BMI SDS for CA was higher than zero, it decreased from 14 (77.8%) to 9 (50%) after correcting for BA, and the mean BMI SDS for CA (1.07±0.32) also decreased to 0.33±0.25 after correcting for BA at the start of treatment. Moreover, Oostdijk et al. reported that the BMI SDS for CA of CPP patients was higher than that of the reference population, whereas their BMI SDS for bone age (BA) was normal at the start of treatment. (Oosdijk et al., 1996) Taken together, the BMI of children with CPP might be appropriate for the onset of adolescence, even though they are indicated to be overweight by BMI calculations. Therefore, it is reasonable to suggest that the pre-treatment overweightness observed in CPP girls is due to pubertal hormonal changes and secondary changes in body fat, rather than being a cause of their CPP.

As for the progression of baseline overweightness in CPP patients, the available data in the literature are very inconsistent; however, many reports have suggested that obesity progresses in this group (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, Traggiai et al., 2005). Oostdijk et al. treated 31 girls with CPP with triptorelin for a mean period of 3.4 years. (Oosdijk et al., 1996) The mean BMI SDS for CA at the start of treatment was higher than that of the reference population, and it did not change significantly during treatment. However, the mean BMI SDS for BA at the start of treatment was normal and increased during treatment. Boot et al. treated 32 girls and 2 boys with CPP or early puberty with leuprolide-acetate for 2 years. (Boot et al., 1998) Their lean tissue mass SDS decreased significantly during treatment, whereas their fat mass SDS and percentage body fat SDS

Many reports have shown that obesity occurs at a high frequency among children with CPP. (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) Feuillan et al. reported that the mean BMI of 18 girls with precocious puberty due to hypothalamic hamartoma (HH) and 32 with ICPP was higher than normal before GnRHa treatment (Feuillan et al., 1999), and Arrigo et al. reported that 23.6% of the 101 girls with ICPP that they studied were obese before the start of therapy. (Arrigo et al., 2004) Our results confirm that obesity is a common problem in children with CPP in Japan. Indeed, in this study, a quarter of our patients were found to be obese according to both BMI and POW before the start of therapy. Moreover, the BMI SDS for CA and BA were higher than zero in more than half of the patients at the baseline. Since the prevalence of obesity in girls in later childhood is 14.3% in Japan (http://www.iotf.org/documents/iotfsocplan251006.pdf), the above figure indicates that

Although several reports have stated that obesity is a common problem in girls with CPP, as mentioned above, the reason why so many girls with CPP have an increased BMI is unclear. A decrease in lean body mass and an increase in fat mass leads to obesity. Chiumello et al. suggested that girls with CPP undergo a shortened period of prepubertal lean mass development and so possess an insufficient lean body mass, leading to obesity. (Chiumello et al., 2000) Recently, Arrigo et al. hypothesized that the pre-treatment increase in BMI is caused pubertal hormonal changes and secondary changes in body fat rather than CPP itself, as in their series they found that the suppression of pituitary-gonadal axis function was accompanied by a significant decrease in excess weight (Arrigo et al., 2004). However, our results showed that the suppression of the pituitary-gonadal axis did not bring about a significant change in excess weight, as described below. Furthermore, as for the number of patients whose BMI SDS for CA was higher than zero, it decreased from 14 (77.8%) to 9 (50%) after correcting for BA, and the mean BMI SDS for CA (1.07±0.32) also decreased to 0.33±0.25 after correcting for BA at the start of treatment. Moreover, Oostdijk et al. reported that the BMI SDS for CA of CPP patients was higher than that of the reference population, whereas their BMI SDS for bone age (BA) was normal at the start of treatment. (Oosdijk et al., 1996) Taken together, the BMI of children with CPP might be appropriate for the onset of adolescence, even though they are indicated to be overweight by BMI calculations. Therefore, it is reasonable to suggest that the pre-treatment overweightness observed in CPP girls is due to pubertal hormonal changes and secondary changes in body fat, rather than

As for the progression of baseline overweightness in CPP patients, the available data in the literature are very inconsistent; however, many reports have suggested that obesity progresses in this group (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, Traggiai et al., 2005). Oostdijk et al. treated 31 girls with CPP with triptorelin for a mean period of 3.4 years. (Oosdijk et al., 1996) The mean BMI SDS for CA at the start of treatment was higher than that of the reference population, and it did not change significantly during treatment. However, the mean BMI SDS for BA at the start of treatment was normal and increased during treatment. Boot et al. treated 32 girls and 2 boys with CPP or early puberty with leuprolide-acetate for 2 years. (Boot et al., 1998) Their lean tissue mass SDS decreased significantly during treatment, whereas their fat mass SDS and percentage body fat SDS

the prevalence of obesity in children with CPP is unusually high.

**4. Discussion** 

being a cause of their CPP.

increased. In addition, their mean BMI SDS was higher than zero at the baseline and increased during treatment. Chiumello et al. treated 14 girls and 2 boys with CPP with leuprolide and triptorelin for at least 1 year. (Chiumello et al., 2000) They concluded that fat mass is increased by GnRHa therapy and that this could lead to obesity; therefore, they suggested that CPP patients undergo a shortened period of pubertal lean mass development and that while the progression of puberty in these patients is associated with increases in fat and lean mass, only the latter is blocked by the "menopausal effect" or the GnRHa therapy itself. van der Sluis et al., who belong to the same group as Boot, reported 47 patients (36 girls and 11 boys) with CPP or early puberty who received leuprolide-acetate for a mean period of 2.7 years. (van der Sluis et al., 2002) In this cohort, BMI SDS increased significantly during treatment, whereas lean body mass decreased significantly during treatment, and percentage body fat increased. Paterson et al. reported 46 girls with CPP or early puberty who received goserelin for a mean period of 1.6 years. (Paterson et al., 2004) In this group, there was a marked increase in BMI following treatment. On average, the girls were fatter than the general population before treatment (BMI SDS: 0.93) and were significantly fatter (BMI SDS: 1.2) than the general population after the completion of therapy. Before treatment, 19 (41%) girls were overweight (BMI > 85th centile), 13 (28%) of whom were obese (BMI > 95th centile), which rose to 27 (59%) overweight patients, of whom 18 (39%) were obese, after the completion of therapy. Wacharasindhu et al. treated 10 Thai girls with CPP for a period of 1 year and reported that their percentage fat values increased significantly. (Wacharsindhu et al., 2006) So far, this is the only report in an Oriental population.

In contrast, some authors have reported no change throughout the observation period. (Palmert et al., 1999, Herger et al., 1999, Pasuquino et al., 2008) For example, Heger et al. treated 50 girls with CPP with depot triptorelin for a mean period of 4.4 years and reported that their BMI SDS values at pretreatment, at the end of treatment, and at final height were not significantly different. (Herger et al., 1999) Palmert et al. treated 96 girls and 14 boys with CPP with deslorelin or histrelin for 36 months. (Palmert et al., 1999) Among the girls, multiple regression analysis indicated that the BMI SDS for CA at the pretherapy visit was the greatest predictor of the BMI SDS for CA at the end of treatment. They concluded that the administration of GnRHa did not influence the progression of adolescent CPP patients toward obesity. Pasquino et al. reported 87 girls with CPP who received depot triptorelin for a mean period of 4.2 years. (Pasuquino et al., 2008) Their BMI increased markedly during treatment, but their BMI SDS for CA did not change significantly. In addition, 14.3% of the girls were overweight and 9.1 % were obese at the start of therapy, and both categories contained 11.7% of patients at the discontinuation of treatment. Although the patients' overall BMI increased, they remained in the same BMI centile and had the same BMI SDS throughout the treatment period. Regression analysis showed that the BMI SDS for CA at the end of treatment was positively correlated with the BMI SDS for CA at the start of treatment. As a result, they concluded that GnRHa treatment did not result in a significant BMI increase.

On the other hand, Arrigo et al. reported 101 girls with CPP who received decapeptyl depot for over 2 years. (Arrigo et al., 2004) As described above, a quarter of the girls were classified as obese at the start of therapy, and only 4% of them were still obese at the end of therapy. BMI SDS did not increase in any of the patients during the therapy period. In fact, both the mean BMI SDS and obesity prevalence significantly decreased during the treatment period. This is the only report to state that BMI and the prevalence of obesity decreased during GnRHa therapy.

Standard Gonadotropin-Suppressive Therapy in Japanese Girls with

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Palmert MR, Mansfield MJ., Crowley Jr WF., Crigler Jr JF., Crawford JD., & Boepple PA.

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Bone mineral density and body composition in Thai precocious puberty girls

In our study, although on the whole BMI increased, the SDS for both CA and BA remained the same throughout the treatment period. Moreover, POW also changed little during the therapeutic period, as reported by Chiumello (who described it as relative body weight) (Chiumello et al., 2000). It should be noted that we used a small amount of GnRHa in relation to body weight in accordance with the standard treatment protocol used in Japan, as described above (we used 2.5mg or less) and were able to control CPP. In the reports from Western countries in which the same leuprolide acetate drug was used, a dose of 3.75mg was used from the first stage onwards, and all showed a significant increase in BMI during treatment (Boot et al., 1998, Chiumello et al., 2000, van der Sluis et al., 2002). The doses used in other reports were also larger than the dose that is usually administered in Japan.

In this study, regression analysis showed that the BMI SDS for both CA and BA during treatment were positively correlated with those observed at the start of treatment, as reported by Pasquino et al. (Pasuquino et al., 2008) and Palmert (Palmert et al., 1999). Therefore, we consider that the initial BMI SDS is a predictor of BMI SDS at subsequent visits.

Taken together, the administration of GnRHa according to the standard Japanese protocol does not seem to influence the progression of children with CPP towards obesity. One possible reason for this is the suitability of the standard gonadotropin-suppressive therapy administered to girls with CPP in Japan, although racial differences might also be relevant.

#### **5. Conclusion**

In conclusion, the standard gonadotropin-suppressive therapy protocol used to treat girls with ICCP or ICEP in Japan does not adversely affect body composition, at least when administered for up to 2 years.

#### **6. References**


with precocious puberty: Long term follow-up comparing girls with hypothalamic hamartoma to those with idiopathic precocious puberty. J Clin Endocrinol Metab Vol.84, No.1, pp. 44-49


312 Sex Steroids

In our study, although on the whole BMI increased, the SDS for both CA and BA remained the same throughout the treatment period. Moreover, POW also changed little during the therapeutic period, as reported by Chiumello (who described it as relative body weight) (Chiumello et al., 2000). It should be noted that we used a small amount of GnRHa in relation to body weight in accordance with the standard treatment protocol used in Japan, as described above (we used 2.5mg or less) and were able to control CPP. In the reports from Western countries in which the same leuprolide acetate drug was used, a dose of 3.75mg was used from the first stage onwards, and all showed a significant increase in BMI during treatment (Boot et al., 1998, Chiumello et al., 2000, van der Sluis et al., 2002). The doses used in

In this study, regression analysis showed that the BMI SDS for both CA and BA during treatment were positively correlated with those observed at the start of treatment, as reported by Pasquino et al. (Pasuquino et al., 2008) and Palmert (Palmert et al., 1999). Therefore, we

Taken together, the administration of GnRHa according to the standard Japanese protocol does not seem to influence the progression of children with CPP towards obesity. One possible reason for this is the suitability of the standard gonadotropin-suppressive therapy administered to girls with CPP in Japan, although racial differences might also be relevant.

In conclusion, the standard gonadotropin-suppressive therapy protocol used to treat girls with ICCP or ICEP in Japan does not adversely affect body composition, at least when

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after discontinuation of gonadotropin-releasing hormone analog treatment of girls

other reports were also larger than the dose that is usually administered in Japan.

consider that the initial BMI SDS is a predictor of BMI SDS at subsequent visits.

**5. Conclusion** 

**6. References** 

administered for up to 2 years.

Vol.45, pp. 642-646

370-372

of Endocrinology Vol.150, pp. 533-537

Endocrinol Metab V13: 791-794


**1. Introduction** 

**16** 

*Japan* 

**Hormone Therapy for the** 

Tomoki Sumida and Akiko Ishikawa *Department of Oral & Maxillofacial Surgery,* 

*Ehime University School of Medicine* 

**Salivary Gland Tumor (MSGT)** 

**Treatment of Patients with Malignant** 

Malignant salivary gland tumors (MSGTs) account for 2-6% of all head and neck cancers (Glisson et al., 2004; Milano et al., 2007). Despite their rarity, MSGTs have been of great interest because of their wide variety of pathological features and high rates of metastasis, which result in poor prognoses. Surgical resection followed by radiation therapy is the primary therapy for this malignancy. Adjuvant therapy is reserved for the management of local recurrence no longer amenable to additional local therapy and for metastasis. Based on studies of other types of tumors, particularly breast cancer, the expression and function of sex steroid hormone receptors in cancer have been extensively studied and the findings applied to diagnosis and treatment (Clarke & Sutherland, 1990; Kester et al., 1997). Although a number of studies have been published, the rationale for hormone therapy of MSGTs remains controversial because of disparate results and an insufficient number of cases. However, some recent studies have shown that certain salivary gland neoplasms are similar to breast cancer, not only in terms of their pathological features, but also at the molecular level (Pia-Foschini, 2003; Wick et al., 1998; Yoshimura et al., 2007). Here, we shed light on the biological similarity between MSGTs and certain types of breast cancer, and describe the

potential use of hormone and additional therapies for MSGTs.

**2. The role of sex steroid hormone receptors in cancer therapy** 

The function of sex steroid hormone receptors in breast cancer has been extensively studied and the findings applied to diagnosis and treatment (Clarke & Sutherland, 1990; Kester et al., 1997) Estrogen stimulates cell proliferation of breast epithelial cells, and the close relationship between the expression of estrogen receptor (ER) and the prognosis of breast cancer has been well characterized (Ma et al., 2009). Progesterone levels fluctuate during the menstrual cycle and regulate cell proliferation and differentiation; however, less is known regarding its role in breast cancer (Jeng et al., 1992; Sutherland et al., 1988; van der Burg et al., 1992) We have previously reported that introducing progesterone receptor (PR) into hormone-independent breast cancer cells significantly suppresses their proliferative and invasive activities upon progesterone treatment (Sumida et al., 2004). Several drugs, such as

