This study highlights that vitamin D status in 6- to 8-year-old girls with CPP is similar to that in control group (prepubertal girls), whereas PTH concentrations were significantly higher in girls with CPP compared to those in control individuals. Furthermore, our data revealed that girls with CPP also maintain seasonal variations in 25(OH)D and PTH concentrations, as it occurs in the control group. It should be noted that this is the first report that simultaneously analyzes vitamin D status and PTH concentrations in girls with CPP.

Vitamin D and PTH are well known because of their role in bone metabolism and calcium homeostasis. Their biological functions are widely complementary, contributing to the normal bone mass acquisition. The major physiologic function of vitamin D is to enhance the absorption of dietary calcium and phosphate, and to increase tubular reabsorption of calcium [1, 3]. On the other hand, under physiological conditions, PTH promotes bone mineralization through the effect on osteoblasts. During hypovitaminosis D or hypocalcemic phases, PTH concentrations increase and the osteoclast becomes its main target cell in bone; in this way, it activates bone resorption. The two processes do not occur independently, and the increase in bone resorption is accompanied by stimulation of osteoblast activity via a series of paracrine and autocrine mechanisms that result in an increase in bone turnover [22]. PTH concentrations are currently used as the best markers of bone turnover [9]. In accordance to several authors [4, 6, 7, 23, 24], we found a negative correlation between PTH and 25(OH)D concentrations, and this would be consistent with the physiological feedback mechanism of vitamin D on PTH secretion.

In contrast to other studies, we found no association between vitamin D status and CPP characteristics (clinical data, and basal and stimulated gonadopropins). To a large extent, this disagreement is possibly due to methodological reasons, since the sample in this study was entirely made up of Caucasian girls and, furthermore, all those overweight/obese girls have been excluded (cutaneous pigmentation and overweight/obesity have been associated with hypovitaminosis D) [25,26,27,28]. On the other hand, we cannot define a vitamin D status in a concrete population without referring to seasonal variations since, as it occurred in this study, the maximum concentration of 25(OH)D usually corresponds to the summer period, being significantly lower in the rest of the seasons of the year [4, 8, 29]. In this case, there was sufficient homogeneity in the seasonal distribution among the participants included in this study (CPP and control groups). However, previous studies that evaluated a possible association between vitamin D status and timing of puberty in girls have several limitations, since either they did not refer to race or season of the year in which the sample was collected [12,13,14], or did not include a group control [15]. In other words, this study allows us to analyze the results obtained avoiding confounding factors.

There is evidence that vitamin D has some effects on female fertility. VDR has been shown to be expressed in ovarian cells, indicating a role in steroidogenesis of sex hormones [10, 11]. In addition, VDR and 1α-hydroxylase are expressed in the endometrium, suggesting that it is an extra renal site of vitamin D synthesis and vitamin D action [30]. There are several studies that suggest that vitamin D status could contribute to hormonal dysregulation in patients with POCS; and it is even pointed out that vitamin D supplementation may be useful to improve fertility and metabolic alterations in women with POCS [31, 32]. Recent studies have reported that vitamin D is involved in ovarian steroidogenesis by modulating the expression of the 3β-hydroxy steroid dehydrogenase enzymes [33]; therefore, it could be suggested that a situation of hypovitaminosis D could rather condition a deficiency of gonadal steroids and, consequently, a delayed puberty. Experimental studies have revealed that peripubertal vitamin D sufficiency is important for an appropriate pubertal transition and maintenance of normal female reproductive physiology [34]. In this sense, it was expected that vitamin D status in girls with CPP were similar to that of the control group, as we found in this study. In addition, it should be remembered that we found no association between vitamin D status and CPP characteristics.

The main innovation of this study would be the fact that PTH concentrations in girls aged 6–8 years with CPP are increased in relation to the control group. And, curiously, it should be noted that our finding that PTH concentrations remained significantly increased throughout the year in the CPP group compared to the control group, even with seasonal variations. In addition, it can be said that PTH concentrations were also significantly higher—independent of vitamin D status—in girls with CPP with respect to the control group. Our data support the hypothesis that the high levels of PTH found in girls with CPP do not represent, as it is commonly assumed, an increase secondary to hypovitaminosis D.

During growth, the shape and structure of bones are continuously modified and renovated by modeling and remodeling processes. Maintaining normal bone turnover is important to achieve optimal peak bone mass and to optimize growth. This apposition-reabsorption process involves a positive balance during childhood and adolescence until the maximum peak of bone mass is acquired in the third decade of life, then moving to a neutral balance [35]. PTH concentrations are currently considered the best available marker of bone turnover. It is interesting to note that it has been reported that, in healthy children and adolescents, PTH concentrations increase significantly in girls in the age group of 8–10 years, whereas in boys it is significantly increased in the age groups of 10–12 years, leading to the hypothesis of a relationship between PTH concentrations and pubertal and bone growth spurt [9]. That is, the increase of PTH concentrations in these age groups, and with a clear sexual dimorphism, could be considered as a physiological characteristic of the pubertal period and, in this case, of pubertal precocity. There was a strong correlation between PTH concentrations and bone age in CPP group. Thus, these results support our working hypothesis that girls with precocious puberty might have elevated PTH concentrations as it appears to occur in the chronologically normal pubertal period. However, there is controversy regarding the relationship between vitamin D and bone turnover markers. In compliance with several studies [4, 6, 7, 23, 24], we found a negative correlation between the concentrations of PTH and 25(OH)D, and several authors have suggested that vitamin D deficiency could contribute through hyperparathyroidism secondary to accelerated bone turnover. However, we found that PTH concentrations were also significantly higher, regardless of vitamin D status, in girls with CPP compared to the control group; therefore, this hypothesis seems unreliable.

This study has some limitations. Unfortunately, bone alkaline phosphatase values as markers of bone turnover were not determined in the participants included in this study. It would have been very interesting to analyze its possible correlation with PTH concentrations, pubertal development and vitamin D status. Another limitation is that it would have been very suitable to have been able to compare the results obtained in this study with an additional group of girls with physiological pubertal development.

As a conclusion, vitamin D status in 6- to 8-year-old girls with CPP is similar to that in prepubertal girls, and we did not find any correlation between vitamin D status and CPP characteristics. Additionally, PTH concentrations were significantly higher in girls with CPP compared to those in control individuals, and could be considered as a physiological characteristic of the pubertal period and, in this case, of pubertal precocity.