Central precocious puberty (CPP) is identified by the attainment of breast and testicle development prior to the age of 8 years in girls and 9 years in boys. Early development of secondary sexual characteristics are driven by the premature activation of the hypothalamic-pituitary-gonadal axis [1,2]. Gonadotropin-releasing hormone analogs (GnRHa) treatment for CPP have been established as a gold-standard since the early 1980s [3]. GnRHa continuously stimulating the pituitary gonadotrophs leads it to desensitization and decreases the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) [4]. As such, GnRHa treatment postpones development of puberty and elongates the duration of growth and one maturation, thus, height potential is preserved [3].

Although the efficacy of GnRHa is well known, the long-term side effects remain controversial, especially in association with obesity and metabolic syndrome [5,6]. Many previous studies have reported that GnRHa treatment is associated with changes in weight and body composition in precocious pubertal girls [7]. In obese or altered energy balance, metabolic modulators such as leptin and ghrelin regulate kisspeptin neuron [8]. Then kisspeptin neurons stimulate GnRH secretion and gonadal steroid production. In the treatment of GnRHa, obesity may affect gonadotropin suppression, and this feedback may affect the clinical finding as BA advancement and height outcome. However, few studies have reported the effect of obesity on the GnRHa treatment outcome.

Therefore, we aimed to investigate the effect and the clinical course of GnRHa treatment in obese girls compared to girls of normal weight with CPP.

In the current study we compared the clinical course and treatment effect between normal weight and overweight/obese girls during GnRHa treatment for CPP and GnRHa treatment improved the height outcome and delayed progression of bone maturation in both normal weight girls and obese girls with CPP. GnRHa treatment efficacy was not affected by the obesity in female CPP patients. The BMI SDS significantly increased only in normal weight female CPP patients during long-term GnRHa treatment.

The number of CPP patients is increasing worldwide, and in Korea [14,15]. As the report of the Health Insurance Review and Assessment Service, CPP patients increased annually about 44.4% from 2006 to 2010 in Korea [16]. In addition, a marked increase of obesity prevalence in childhood has been observed around the world [17,18]. Many studies have been performed to investigate the association between precocious puberty and obesity [19]. A Swedish longitudinal study reported that an increase of BMI in childhood was associated with an earlier timing of pubertal onset, by as much as 0.7 years in girls and 0.6 years in boys [20]. Since recent reports have primarily focused on whether GnRHa treatment has increased BMI or not, we investigated the clinical parameters to evaluate whether the obesity affects the treatment outcome in CPP girls.

In this study, the overall course of treatment in both groups was similar. We found that BA-CA in both groups significantly decreased during follow-up. It means that GnRHa also worked well in postponing bone maturity in the overweight/obesity group. Both groups similarly revealed distinct improvement of PAH and height SDS for BA. At the end of treatment, PAH increased 1.61±2.87 cm vs. 1.86±3.01 cm in the normal weight and overweight/obese groups, respectively, compared to the beginning of treatment. Near adult height of 46 patients showed height gain of 2.26±3.70 cm in the normal weight group and 2.72±3.85 cm in the overweight/obese group, respectively, compared to their baseline PAH. Near adult height was comparable to their MPH, although gain of height is smaller than that of previous other studies. Thus, it is considered that GnRHa treatment can be effective in height outcome in our study. According to previous study about GnRHa treatment effects in obese CPP girls, Yoon et al. [21] reported that PAH SDS significantly increased in overweight/obesity group compared to in the normal weight group, and BA–CA similarly decreased in both groups during 1-year of GnRHa treatment in CPP girls.

We performed a multiple regression analysis and compared the factors predicting ΔPAH in both groups, respectively. Our results suggest that greater baseline BA and height SDS for BA and growth velocity for the first year of treatment indicate good growth outcomes, regardless of the treatment group. However, body weight and BMI did not exhibit any statistical correlation with PAH at the end of treatment. Obesity did not contribute significantly to the height outcome. In previous other studies, Partsch et al. [22] reported that initial BA advancement and treatment duration were factors that explained 68% of height gain. Other studies found that MPH, CA, pretreatment height, height at the end of treatment, and growth rate during treatment were factors influencing near final height [23,24].

Several previous studies have evaluated alterations in BMI before and after GnRHa treatment in CPP. Whether GnRHa treatment affects BMI and aggravates obesity remain controversial [25]. Shiasi Arani and Heidari [26] reported that girls treated for CPP revealed no change in BMI compared with girls not treated for CPP, during 1 year of follow up. In contrast, Paterson et al. [27] reported a marked increase in mean BMI SDS after treatment from 0.93 to 1.2 in girls with early puberty and CPP. On the other hand in our study, BMI SDS significantly increased in the normal weight group only during GnRHa treatment. The reasons explaining an increase in BMI SDS in normal weight group are unclear. Paterson et al. [27] found that the mean BMI SDS returned to the pretreatment state 3 years after finishing GnRHa treatment course, suggesting that the weight increase was a transient phenomenon. Wolters et al. [28] explained the beneficial effect of GnRHa on weight status by reducing sex hormones that lead to weight gain through increase in body fat and muscle mass during GnRHa treatment. However, this is insufficient to account for the difference in the impact of GnRHa on weight status between overweight and normal weight children. In our study, 19 of the normal weight groups showed increased BMI and they were turned into overweight or obese at the end of treatment, whereas, 89 patients maintained normal weight persistently. Patients who turned into overweight/obesity revealed higher BMI SDS at baseline and more increase in BMI SDS compared to patients with normal BMI SDS at the end of treatment (0.51 vs. -0.01, P<0.001 and 0.74 vs. 0.23, P<0.001, respectively). On the other hand, overweight/obese patients at baseline showed a tendency to maintain their BMI SDS, and this finding is consistent with that in previous studies [28,29]. Pich et al. [30] reported that obese patients may have tendency to recognize their obese status and modify risk factors such as diet, sleep and physical activity. However, our study cannot investigate these factors. A prospective further study is warranted to confirm the tendency.

The strength of our study is that all subjects were had CPP, except for those in early puberty and that they were separated into 2 groups; namely overweight and normal weight girls. However, in our retrospective study, there were some limitations. There were no clinical measures of body adiposity, such as waist circumference, skinfold thickness or dual-energy x-ray absorptiometry. Although BMI is a valid tool to determine obesity, it has limitations as an indirect measure of fat mass. A long-term follow-up following discontinuation of GnRHa treatment is lacking in our study. To confirm the effects of obesity on the treatment outcome, additional analysis of the final height, BMI SDS and menarche age is required.

In conclusion, obese girls with CPP had an improved height outcome similar to normal weight girls during GnRHa treatment. Obesity may not affect the efficacy of GnRHa in girls with CPP.