Prevalence of vitamin D deficiency in girls with idiopathic central precocious puberty

Abstract

The relationship between vitamin D deficiency and idiopathic central precocious puberty (ICPP) has been recently documented. In this study, 280 girls diagnosed with ICPP and 188 normal puberty control girls of similar ages were enrolled and retrospectively studied. The ICPP group had significantly lower serum 25-hydroxyvitamin D (25[OH]D) levels than the control group. Furthermore, a nonlinear relationship was found between serum 25[OH]D and ICPP, and a cut-off point for serum 25[OH]D was found at 31.8 ng/ml for ICPP with and without adjusting the different confounding factors. Girls with serum 25[OH]D≥31.8 ng/ml had a lower odds ratio (unadjusted: OR 0.36, 95% CI 0.15 to 0.83, P <0.05; height and weight adjusted: OR 0.44, 95% CI 0.18 to 1.08, P = 0.072; BMI adjusted: OR 0.36, 95% CI 0.16 to 0.84, P <0.05). The ICPP subjects with 25[OH]D deficiency had a higher body mass index (BMI) than the subjects from the two other subgroups. Correlation analysis showed that vitamin D level is correlated with BMI and some metabolic parameters in the ICPP group. Our study suggested that vitamin D status may be associated with ICPP risk and may have a threshold effect on ICPP.

Keywords

idiopathic central precocious puberty / threshold effects / vitamin D status

Introduction

Vitamin D plays a crucial role in bone and mineral metabolism. Existing evidence suggested that 25[OH]D level are associated with many disorders, including immune dysfunction, obesity [¹,²], metabolic syndrome, insulin resistance [³], infection [⁴], cancers, and cardiovascular abnormalities [⁵,⁶]. Moreover, vitamin D is suggested to have a regulatory role in reproduction function [⁷,⁸].

Idiopathic central precocious puberty (ICPP) is marked by relatively high luteinizing hormone (LH) levels and a high LH/follicle-stimulating hormone (FSH) peak ratio in gonadotropin-releasing hormone (GnRH) stimulation tests, combined with advanced bone age (BA). However, the mechanisms underlying ICPP remain unclear. Several studies have indicated a correlation between vitamin D status and the timing of menarche [⁹,¹⁰] and central precocious puberty (CPP) [¹¹]. Moreover, studies have proven the correlation between obesity and vitamin D deficiency [¹²,¹³], as well as precocious puberty [¹⁴,¹⁵]. However, the nature of the relationship between the serum level of vitamin D and the risk of precocious puberty in girls has not been investigated.

In the present study, we compared 280 girls with ICPP and 188 normal girls of similar ages to explore the serum vitamin D levels in these girls, as well as its relationship with the risk of ICPP.

Materials and methods

Subjects

Girls diagnosed with ICPP in our hospital from 2014 to 2016 were included in our study. To avoid seasonal variations, only patients diagnosed from June to August were studied. Finally, 280 girls diagnosed with ICPP and 188 normal girls of similar ages (6–10 years) were enrolled. The ICPP subjects were diagnosed according to the 2015 guidelines of the Chinese Medical Association [¹⁶]: (1) secondary sex characteristics in girls before the age of 8 years or menarche under age of 10 years; (2) liner growth acceleration; (3) BA levels higher than chronological age of more than one year; (4) enlarged uterus, at least one ovarian volume greater than 1 ml, and more than one ovarian follicle’s diameter greater than 4 mm upon ultrasound; (5) HPG axis activation: confirmed by peak LH response to the GnRH stimulation test, with cut-off level considered as peak LH≥5 mIU/ml and LH/FSH peak ratio>0.6. Exclusion criteria include: (1) history of identified etiology; (2) taking medications known to affect the reproductive axis or had used hormonal medications before diagnosis; (3) blood and imaging evaluation of liver, renal, thyroid, adrenal, and pituitary diseases showed peripheral or organic CPP or other types of precocious puberty; (4) MRI evaluation of the hypothalamus and pituitary gland showed brain tumor; (5) girls under 6 years were excluded to avoid the influence of “mini-puberty.” In the present study, serum 25-hydroxyvitamin D (25[OH]D) <20 ng/ml, 20 ng/ml≤25[OH]D<30 ng/ml and≥30 ng/ml were considered as deficiency, insufficiency, and sufficiency status of vitamin D, respectively [¹⁷,¹⁸].

Physical examinations and laboratory parameters

Physical examinations were conducted by a professionally trained pediatric endocrinologist. Heights and weights were measured by standard methods as in previous studies [¹⁹]. Secondary sexual characteristics, including the evaluation of breast development, were examined via visual inspection and palpation, and the distribution of pubic hair was examined via visual examination. BA was confirmed based on left hand radiograph according to Greulich and Pyle’s standards [²⁰].

All laboratory parameters were measured in the Department for Clinical Laboratory and Centre for the Diagnosis of Genetic Metabolic Diseases Laboratory (Tongji Hospital, Huazhong University of Science and Technology). After undergoing overnight fasting, blood samples were obtained from the subjects from the left elbow vein, standing at 4 °C for 30 min. Plasma was then isolated after centrifugation (2400 g, 5 min). Serum 25[OH]D was measured by electrochemiluminescence (Roche e602). Serum LH, FSH, Estradiol (E2), and Testosterone (T) concentrations were measured by chemiluminescence (Access 2 Immunoassay system, Beckman Coulter, #81600N, USA). Serum insulin-like growth factor 1 (IGF-1) was determined by chemiluminescence (IMMULITE 2000 systems analyzer, Siemens Diagnostic, Inc. Flanders, NJ, 07836, USA). Serum total cholesterol (T-Cho) and triglyceride (TG) were measured using standard enzymatic methods (Cobas 8000 modular analyzer series, Roche, German). High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were determined directly (Cobas 8000 modular analyzer series, Roche, German). Apolipoprotein A1 (ApoA1) and apolipoprotein B (apoB) were measured using the immunoturbidimetric method (Randox Laboratories Ltd., UK). Fasting blood glucose (FBG) was evaluated using the hexokinase method (BioSino Bio-Technology and Science Inc., normal range: 4.11–6.05 mmol/L). Fasting serum insulin levels (FINS) were evaluated by a chemiluminescence assay (Access 2 Immunoassay system, Beckman Coulter, #81600N, USA). The HOMA-IR index, as the product of FINS (mIU/ml) and FBG (mmol/L) divided by 22.5 [²¹], was an indicator used to assess insulin resistance.

Statistical analysis

We performed unpaired two-tailed Student’s t-test to examine two-group differences and one-way analysis of variance (ANOVA) with the post hoc test of Bonferroni for multiple comparisons for data of normal distribution. The Mann–Whitney and Kruskal–Wallis tests were used for two-group and multiple group comparisons of non-normally distributed data, respectively. Chi-square test was used for comparisons of the prevalence of vitamin D status between the two groups. The relationship between 25[OH]D and the risk of ICPP was then explored using the smoothing plot through generalized additive model (GAM). A two-piecewise linear regression model was applied to examine the threshold effect of the 25[OH]D on the risk of ICPP. An inflection of 25[OH]D, at which the relationship between the risk of ICPP and 25[OH]D level began to change, was determined by moving the trial inflection point along a pre-defined interval to detect the point that revealed the model with the most likelihood. Multivariate binary logistic regression was applied to calculate the odds ratio depending on 25[OH]D levels. Multiple linear regression was used to estimate the relationships between the 25[OH]D and the parameters in the ICPP group after adjusting for age. Results presented as`c±SD, or median (interquartile range) as appropriate, a P value<0.05 was considered significant. All analyses were performed using Empower (R) (www.empowerstats.com, X&Y solutions, Inc., Boston, MA, USA) and R (http://www.R-project.org).

Results

The clinical characteristics of the two groups are shown in Table 1. A total of 280 girls with ICPP and 188 control girls of similar ages were enrolled. The average age of all the subjects was 8.47±0.85 years, and the average 25[OH]D level was 20.01±6.81 ng/ml. Approximately 91.7% of the subjects did not reach the sufficient status. Compared with the control group, the girls with ICPP had significantly lower mean levels of 25[OH]D (19.36±6.15 vs. 20.98±7.60, P<0.05). Furthermore, the ICPP group had significantly higher height and weight and more advanced BA than the control group. The results did not show significant differences between the born weight, BMI, BMI-SDS, and height-SDS of the two groups. Moreover, the prevalent 25[OH]D status of the two groups was compared. Out of the 188 subjects of the control group, 164 (87.2%) did not reach 25[OH]D sufficiency, whereas 24 (12.8%) subjects were reported to have sufficient 25[OH]D. Out of the 280 subjects in the ICPP group, the concentration of 25[OH]D was below 30 ng/ml in 261 (93.2%) and sufficient 25[OH]D was observed in 19 (6.8%) subjects. A significant difference in the proportion of 25[OH]D status (insufficiency and sufficiency) was found between the two groups (c² = 4.82, P<0.05).

Furthermore, a nonlinear relationship between the serum 25[OH]D and groups was found (Fig. 1). Above the inflection point (31.8 ng/ml), the risk of ICPP decreased (unadjusted: OR 0.67, 95% CI 0.45 to 1.00, P<0.05; height and weight adjusted: OR 0.67, 95% CI 0.42 to 1.06, P = 0.09; BMI adjusted: OR 0.67, 95% CI 0.45 to 1.00, P<0.05) as the level of serum 25[OH]D increased. Below the inflection point, the change in serum 25[OH]D was not associated with the change in ICPP risk (unadjusted: OR 0.99, 95% CI 0.45 to 1.00, P = 0.37; age, height, and weight adjusted: OR 1.00, 95% CI 0.96 to 1.03, P = 0.84; age and BMI adjusted: OR 0.99, 95% CI 0.95 to 1.02, P = 0.42). The inflection point did not change with and without adjusted different confounding factors (Table 2). Furthermore, girls with serum 25[OH]D≥31.8 ng/ml had lower odds ratio (unadjusted: OR 0.36, 95% CI 0.15 to 0.83, P<0.05; age, height, and weight adjusted: OR 0.44, 95% CI 0.18 to 1.08, P = 0.072; BMI and age adjusted: OR 0.36, 95% CI 0.16 to 0.84, P<0.05) than girls with serum 25[OH]D lower than 31.8 ng/ml (Table 3).

The subjects in the ICPP group were further divided into three subgroups according to the serum 25[OH]D status with the clinical characteristics and laboratory parameters compared (Table 4). The subjects with ICPP with25[OH]D deficiency were significantly older, taller, and had greater BMI than the other two subgroups. The basal LH and basal FSH in the 25[OH]D deficiency group were higher than the other two groups, with statistical significance. No difference was found in BA, born weight, BMI, BMI-SDS, BA-CA, and height SDS. For sex hormones and metabolic index, no difference was found in the other parameters between the groups, except for a slight increase of T presented in the 25[OH]D deficiency group.

The association between 25[OH]D and several parameters of ICPP group was analyzed with adjusted age (Table 5). 25[OH]D was negatively associated with basal FSH (β −0.58, 95% CI −0.93 to −0.24, P = 0.0011), BA (β −0.80, 95% CI −1.57 to −0.03, P = 0.042), weight (β −0.18, 95% CI −0.29 to −0.06, P = 0.0037), BMI (β −0.42, 95% CI −0.73 to −0.11, P = 0.0077), and BMI-SDS (β −0.67, 95% CI −1.20 to −0.14, P = 0.014). 25[OH]D was positively associated with HDL (β 3.58, 95% CI 0.65 to 6.51, P = 0.017) and apoA1 (β 5.32, 95% CI 1.48 to 9.16, P = 0.007).

Discussion

In our study, the ICPP group had significantly lower serum 25[OH]D levels and higher prevalence of 25[OH]D insufficiency than the control group. A nonlinear relationship between serum 25[OH]D level and the risk of ICPP was found. The results suggest that 31.8 ng/ml may be an inflection point because high serum 25[OH]D level (above 31.8 ng/ml) is associated with low risk for ICPP. Serum 25[OH]D concentration lower than 20 ng/ml has been recommended as vitamin D deficiency by the Institute of Medicine (IOM) and serum 25[OH]D of 30 ng/ml has been recommended as a desirable level [¹⁷,²²]. Even though the discussion on 25[OH]D insufficiency and deficiency in children has yet to reach a consensus [²³,²⁴], the inflection point of 31.8 ng/ml found in our study is close to the desirable level of serum vitamin D.

We have different confounding factors adjusted in the analysis of the threshold effect of 25[OH]D on ICPP. The inflection point did not change with or without adjusted different confounding factors. However, the results did not reach significance when height and weight were adjusted, which can be due to the relatively small number of participants in our study. Thus, we acknowledge the need for a study at a larger scale, with increased participating subjects, for further confirmation. Moreover, we noticed that a relatively high risk of ICPP remained below the inflection point (31.8 ng/ml), which indicated a potential risk of vitamin D insufficiency to ICPP. Also, girls with serum 25[OH]D that is higher than 31.8 ng/ml had lower odds ratio of ICPP. The present study is the first to examine the threshold effect of vitamin D to girls with ICPP.

Several studies in animals and humans indicated that vitamin D plays a role in sexual maturation and female reproduction. Early animal studies showed that vitamin D deficiency leads to overall reduction in the reproductive capacity of female rats by directly regulating aromatase gene expression [²⁵,²⁶]. Maternal vitamin D deficiency programs reproductive dysfunction in adult female offspring through adverse effects on the hypothalamic function [⁷]. Another recent study in rodents demonstrated that peripubertal vitamin D sufficiency is important for an appropriately timed pubertal transition and maintenance of normal female reproductive physiology [²⁷]. In humans, the VDR gene polymorphism at the ApaI site is significantly associated with having an earlier onset of menarche [²⁸]. A prospective study followed a random sample of 242 girls (mean age 8.8±1.6 years old) for a median of 30 months and concluded that vitamin D deficiency is associated with earlier menarche [⁹]. Furthermore, the level of 25[OH]D was significantly lower in girls with precocious puberty than normal control subjects. Girls with precocious puberty have high risk for vitamin D deficiency, thereby suggesting an association between serum 25[OH]D levels and precocious puberty [¹¹]. In the present study, low vitamin D levels were observed among girls with ICPP compared with the control group. Further analyses showed significant differences in vitamin D prevalence. Mechanistic explanations of vitamin D deficiency affecting early menarche or puberty initiation are speculative; previous studies have indicated that compared with control groups with sufficient vitamin D levels, peripubertal girls with vitamin D deficiency have highly rapid development of adiposity [²⁹]. The aforementioned study indicated that vitamin D status could indirectly affect the timing of menarche through its effect on obesity [¹¹]. In our comparison between ICPP and normal control groups, we found significantly high weight in girls with ICPP; however, no difference existed in BMI and BMI-SDS. In this study, we found a negative correlation between vitamin D and BMI, BMI-SDS, and weight, as well as positive correlation with HDL and ApoA1 in the group with ICPP. As such, the decreased levels of vitamin D deficiency as precocious puberty develops may be related to obesity and obesity-induced metabolic disorders; even though some studies have reported that children with obesity are highly likely to enter puberty, vitamin D deficiency has been found to be prevalent among them [³⁰]. One study ascribed an inverse association between higher body fat and low vitamin D concentration to the sequestration of fat-soluble vitamin D within the increased adipose tissue [³¹]. Low vitamin D levels may be associated with insulin resistance, considering that vitamin D directly regulates insulin secretion by binding to pancreatic β-cell VDRs, and indirectly affects pancreatic β-cell function by regulating extracellular calcium concentrations [³²]. One study recently reported an inverse correlation between serum 25[OH]D levels and HOMA-IR, TG, and LDL in Korean adolescents aged 12–13 years [³³]. Another study reported that vitamin D levels are inversely correlated with insulin-like growth factor-1 (IGF-1) [³⁴], thereby suggesting that vitamin D may influence the onset of puberty by affecting IGF-1 levels [³⁵]. The relationship between vitamin D and IGF-1 axis has been documented [³⁶]. Even though we did not find a significant difference of IGF-1 between the different subgroups of the ICPP group, and although the correlation between vitamin D and IGF-1 was not significant in the correlation analysis, we did observe a trend of change in IGF-1 between vitamin D classified groups (that is, the level of vitamin D increases as the level of IGF-1 decreases). This result indicated a link between vitamin D and IGF-1 to a certain degree. The lack of significance may be attributed to the relatively small number of the subjects and the function of the hypothalamic-pituitary-growth hormone axis (HPGH axis) to be relatively less affected in ICPP. The serum level of leptin was not monitored in our study; however, the fact that increased leptin levels induced by excess body fat may inhibit the renal synthesis of the active form of vitamin D [³⁷] could be another reason leading to obesity-related vitamin D deficiency.

However, we need to acknowledge several limitations in the present study. First, serum vitamin D concentration considerably varies among people. This one-center based study may lead to possible sample size and selection biases. Second, we only used BMI and BMI-SDS to determine the state of obesity of the subjects and did not evaluate other indexes, including body fat percentage and waist circumference, which could be more sensitive in evaluating body fat. Third, male subjects were not used in our study because precocious puberty in boys is mainly caused by peripheral causes and data on ICPP boys are difficult to collect on a large scale.

In summary, our study provides evidence to support the potential correlation between vitamin D status and the risk of ICPP. The current study suggested a threshold effect of serum vitamin D level. We are unable to determine a clear causal mechanism between vitamin D status and puberty setup and development; however, this study first proposed the threshold effects of vitamin D status on girls with ICPP. Future studies in vitro and in vivo with an increased scale are needed to further elucidate the role of vitamin D in neuroendocrine functions and its role in sexual maturation.

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