Factors affecting bone maturation in Chinese girls aged 4–8 years with isolated premature thelarche

Abstract

Background: In isolated premature thelarche (IPT) girls, bone age (BA) is considered consistent with chronological age. However, some IPT girls confirmed by gonadotropin-releasing hormone (GnRH) stimulation test could show another trend. We analysed BA and possible potentiating factors in a selected group of girls aged 4-8 years with IPT. Methods: IPT girls confirmed by GnRH stimulation test aged 4-8 years hospitalized from January 2015 to April 2018 at Shenzhen Children's Hospital were included in this retrospective study. They were divided into two groups with advanced BA of 2 years as the cutoff. Body mass index (BMI) and hormone levels were the main outcome measures, and regression analysis was used to identify independent risk factors. IPT girls were divided into subgroups according to the levels of BMI standard deviation score (SDS), insulin-like growth factor-1 (IGF-1) SDS and dehydroepiandrosterone sulfate (DHEAS) SDS for comparisons of advanced BA. Results: Overall, 423 subjects were included and classified into the advanced BA group (48.7%, n = 206) and control group (51.3%, n = 217). The advanced BA group had significantly higher BMI SDS, serum DHEAS SDS, IGF-1 SDS, androstenedione and fasting insulin and significantly lower sex hormone binding globulin (all p < 0.001). Serum IGF-1 SDS (OR = 1.926, p<0.001), BMI SDS (OR = 1.427, p = 0.001) and DHEAS SDS (OR = 1.131, p = 0.005) were independent risk factors for significantly advanced BA. In the multiple linear regression model, serum IGF-1 SDS, BMI SDS and DHEAS SDS were the strongest predictors of advanced BA, accounting for 19.3% of the variance. According to BMI, 423 patients were classified into three groups: normal weight (56.03%, n = 237), overweight (19.15%, n = 81) and obesity (24.82%, n = 105). The proportion of advanced BA in obesity group was significantly higher than those of normal weight and overweight groups (χ 2 = 18.088, p<0.001). In the subgroup with normal weight, higher serum IGF-1 SDS (p = 0.009) and DHEAS SDS (p = 0.003) affected BA advancement independent of BMI SDS. Conclusions: Girls with IPT confirmed by GnRH stimulation test aged 4-8 years might have significantly advanced BA. Obesity was highly associated with advanced BA. Age-specific serum IGF-1 SDS and DHEAS SDS were risk factors for BA advancement independent of BMI.

An Approach to the Evaluation and Management of the Obese Child With Early Puberty

“…In the assessment of children with early puberty, significantly (> 2 years) advanced BA typically favors CPP over benign variants, although such advancement can occasionally be seen in girls with both isolated premature thelarche [ 60 ] and premature adrenarche [ 61 , 62 ]. In these benign variants, as in the population studies discussed above, higher BMI Z-scores are associated with more advanced BA [ 60-62 ].…”

“…In the assessment of children with early puberty, significantly (> 2 years) advanced BA typically favors CPP over benign variants, although such advancement can occasionally be seen in girls with both isolated premature thelarche [ 60 ] and premature adrenarche [ 61 , 62 ]. In these benign variants, as in the population studies discussed above, higher BMI Z-scores are associated with more advanced BA [ 60-62 ]. Thus, perhaps not surprisingly, obesity not only blurs the distinction between bone ages seen among prepubertal vs pubertal children, but it can also confound the distinction of CPP from benign variants of early development.…”

“…As discussed above, BA may have limited discriminatory value in the diagnosis of CPP in obese girls; however, it remains an important tool for predicting height outcomes, which may impact counseling and treatment decisions [ 9 , 36 ]. BA advancement can be significant in obese girls, which raises concern around the possibility of compromised adult height [ 60 , 61 ]. However, differences in prepubertal growth between obese and nonobese children may mitigate this risk.…”

“…Regarding the mechanism for BA advancement in obesity, dehydroepiandrosterone sulfate (DHEAS) may play a role as higher DHEAS levels are often found in obese children. Increased adrenal androgen production, with subsequent aromatization to estrogens, may be a key driver of bone maturation and as such, a strong predictor of BA advancement [ 60 , 61 , 108 , 109 ]. Therefore, some have recommended measuring DHEAS as an additional part of assessment for accelerated growth and BA advancement in obese individuals with early puberty [ 110 ].…”

Association between phthalate exposure and accelerated bone maturation in Chinese girls with early puberty onset: a propensity score-matched case–control analysis

“…Shorter height may influence their physical and mental health from childhood to adulthood 2 ; thus, significantly accelerated bone maturation, which could lead to impaired final adult height, is a social health issue that deserves attention. However, children with considerably advanced BA (BA-CA ≥ 2 years) have been observed in different populations: approximately 10% of healthy prepubescent Chinese children (unpublished observations by our research team); up to 21% of healthy children in the United States 3 ; and 48.7% of girls with isolated premature thelarche, who should not have significantly advanced BA 4 , 5 . Moreover, a long-term trend of overall accelerated bone maturation in children has been observed in many countries 3 , 6 – 10 .…”