Abstract
Context
Premature adrenarche (PA) is linked to prematurity, small for gestational age (SGA), and rapid weight gain. Understanding these factors is important for early identification and management of PA.
Objective
To evaluate the impact of prematurity, SGA, obesity, and rapid weight gain on the development of PA in Turkish girls.
Design
A retrospective review of medical records from girls diagnosed with PA between 2015 and 2020.
Subjects and methods
A total of 104 girls diagnosed with PA were included. Clinical data, including birth weight, gestational age, body mass index (BMI), and hormone levels (DHEA-S), were analyzed. The relationships between PA and prematurity, SGA, obesity, and rapid weight gain (delta weight SDS) were assessed.
Results
Of the 104 patients, 14.4% were born prematurely, 28.8% were SGA, and 30.5% were overweight or obese. A positive correlation was observed between delta weight SDS and DHEA-S levels (r=0.523, p<0.01). While obesity was not significantly associated with elevated DHEA-S levels, rapid weight gain was a key factor.
Conclusions
Prematurity and SGA are significant risk factors for PA, with rapid weight gain playing a critical role. Monitoring weight gain in SGA and premature infants is essential to mitigate PA-related risks.
Keywords: rapid weight gain, SGA, premature adrenarche, obesity, prematurity
INTRODUCTION
Premature adrenarche (PA) is a clinical condition characterized by the early activation of adrenal androgen secretion before the onset of normal puberty. It is commonly observed in girls and manifests as signs such as pubic hair growth, axillary hair, and body odor, which are typically seen during puberty (1). In the absence of pathological conditions such as late-onset congenital adrenal hyperplasia (CAH) and virilizing tumors, premature adrenarche is considered a benign condition (2). However, given its association with long-term complications such as insulin resistance, metabolic syndrome, and polycystic ovary syndrome (PCOS), the pathophysiology and risk factors of premature adrenarche should be well understood (3).
The cause of premature adrenarche has yet to be fully clarified. While some studies suggest that inadequate fetal growth, early adiposity gain, and childhood obesity increase the risk of premature adrenarche (3), there is no clear consensus due to inconsistent findings across studies (4-7).
Several risk factors have been implicated in the development of early adrenarche, including obesity, prematurity, small for gestational age (SGA), and early adiposity rebound. Obesity is associated with increased insulin resistance during childhood, which may trigger early androgen secretion. Meanwhile, prematurity and SGA, particularly when coupled with rapid weight gain and catch-up growth, are also considered potential risk factors for premature adrenarche (8-11). However, the relationship between PA and these risk factors remains incompletely understood, necessitating further research.
In this study, we aimed to evaluate the clinical and laboratory findings of Turkish girls with premature adrenarche and assess the impact of potential risk factors such as obesity, low birth weight, rapid postnatal weight gain, and gestational age on the early onset of adrenarche. This study provides valuable insights into these associations, which may guide early interventions and help prevent long-term health risks, such as metabolic syndrome and polycystic ovary syndrome, though further research is needed to confirm these associations.
METHODS
In this retrospective study, children diagnosed with premature adrenarche at the pediatric endocrinology outpatient clinics of two tertiary care centers, Mardin State Hospital and Hitit University Faculty of Medicine Pediatric Endocrinology Clinics, between 2015 and 2020 were reviewed. Girls with pubic and/or axillary hair before the age of 8 years were included in the study. Children with breast development or any signs of virilization, including clitoromegaly, hirsutism, or deepening of the voice, were excluded.
Patients with advanced bone age and/or basal 17OH progesterone levels >2 ng/dl underwent standard-dose ACTH stimulation testing to exclude congenital adrenal hyperplasia (CAH). In the standard-dose ACTH stimulation test, peak 17OHP levels >40 ng/mL, 12-40 ng/mL, and 6-12 ng/mL were considered classical CAH, non-classical CAH, and heterozygous 21-hydroxylase deficiency, respectively (12). Those with peak 17 OH progesterone <6 ng/ml in the stimulation test were considered normal (12). Non-classical congenital adrenal hyperplasia was detected in two of the 39 patients who underwent the ACTH stimulation test, and these patients were excluded from the study.
The medical records of 104 cases diagnosed with premature adrenarche were retrospectively reviewed. Birth weight (BW), gestational age, age at onset of symptoms, height, body weight, and bone age at the time of diagnosis were recorded. The pubertal characteristics of the patients were evaluated according to the Tanner-Marshall staging system, while bone age was evaluated using the Greulich and Pyle bone atlas (13,14). Bone age progression was calculated by subtracting calendar age from bone age (1).
Patients born before 37 weeks of gestation were classified as preterm. Birth weights were converted to standard deviation scores (SDS) according to Turkish growth charts, adjusted for gestational age and sex (15). Children with birth weights below the 10th percentile for gestational age were classified as small for gestational age (SGA). Delta weight SDS was calculated by subtracting the birth weight SDS from the weight SDS at diagnosis, representing the change in weight standard deviation score from birth to diagnosis (16). Children with a history of SGA were compared with those who had normal birth weights for gestational age, and preterm births were compared with those born at term.
Body mass index (BMI) was calculated using the formula: weight/height2. Height, weight, and BMI SD scores were calculated according to the standards for Turkish children (15). Those with a BMI SD >1 were classified as overweight, those with a BMI SD >2 as obese, and those with a BMI ≤1 as normal weight. Patients were divided into two groups: normal weight and overweight/obese. The two groups were compared with respect to age at presentation, age at symptom onset, anthropometric characteristics, and laboratory data.
Hormone analyses
The laboratory data, which includes measurements of DHEA-S and 17-OHP, were obtained from the patients' medical records. DHEA-S levels were measured using immunochemiluminescence (ICMA), while 17 OHP levels were measured using radioimmunoassay (RIA). A serum DHEA-S level greater than 40 µg/dl was considered the laboratory criterion for adrenarche (12). A DHEA-S level of at least 124 μg/dl was classified as 'exaggerated adrenarche' (17). The group with exaggerated adrenarche was compared to the others in terms of age at presentation, age at symptom onset, anthropometric characteristics, and laboratory data.
Statistical analysis
Statistical analyses of the data obtained in this study were performed using IBM SPSS Statistics (version 22.0. Armonk, NY: IBM Corp.). The Kolmogorov-Smirnov test was used to assess the normality of data distribution. Descriptive statistics for continuous variables were reported as mean ± standard deviation (SD) for normally distributed data and median (interquartile range) for non-normally distributed data. Student's t-test was used for normally distributed parameters, and the Mann-Whitney U test was used for non-normally distributed parameters when comparing groups. Statistical significance was set at p < 0.05. For categorical data, descriptive statistics were presented as numbers and percentages. Spearman's or Pearson’s correlation coefficient, depending on the data distribution, was used to evaluate relationships between numerical variables.
Ethical considerations
The study was approved by the Ethics Board of the Hitit University Medical Faculty (Date: 06/01/2021; No: 377) and was conducted in accordance with the Helsinki Declaration. As this was a retrospective study, informed consent was waived.
RESULTS
We analyzed clinical and laboratory data from 104 patients with premature adrenarche. The patients' age at the time of evaluation was 7.04±0.89 years, and the age at the onset of complaints was 6.5±1.04 years. The bone age was 7.56±1.1 years, the mean ΔBA/ΔCA value was 1.07±0.15 and bone age was greater than + 2 SD in 24% of patients. In the presented data, the most frequent complaint was the development of pubic hair (69.4%, n=75). Additionally, 9.3% (n=10) of all cases presented with axillary hair only, while 21.3% (n=23) presented with both pubic and axillary hair. Physical examination revealed stage 2 pubic hair in 80 cases (74.1%), stage 3 pubic hair in 20 cases (18.5%), and axillary hair in 59 cases (54.6%) according to Tanner staging. All patients presented with stage 1 thelarche. The mean BMI SDS and height SDS were 0.56±1.15 and 0.43±1.04, respectively. Overweight was observed in 19.4% (n=20), while obesity was observed in 11.1% (n=12) of the cases.
The study found that the mean gestational age of the 104 children was 38.4±1.5 weeks, with a birth weight of 2849±579 grams. Among the 104 patients, 15 (14.4%) were preterm (<37 weeks gestation) and 30 (28.8%) were SGA. The delta weight SDS was 1.35 ± 1.44.
The birth weight and birth weight SDS of the small for gestational age (SGA) group were lower than those of the appropriate for gestational age (AGA) group. However, the delta weight SDS was higher. The catch-up rate in patients with SGA was 93%. The height SDS and BMI SDS of the SGA group were lower compared to the AGA group. Additionally, the obesity rate was 13% in the SGA group, while it was 38% in the AGA group. No other differences in characteristics were observed between the two groups. In the premature group, birth week, birth weight, and birth weight SDS were lower, while the delta weight SDS and DHEA-S levels were higher than in the non-premature group. Approximately half of the cases in the premature group had exaggerated adrenarche (Table 2).
Table 2.
Comparison of SGA and Prematurity
| SGA | Prematurity | |||||
|---|---|---|---|---|---|---|
| Yes (n=30) | No (n=74) | p-value | Yes (n=15) | No (n=89) | p-value | |
| Age at evaluation, years (mean, SD) | 7.2±0.73 | 7.1±1.02 | 0.463a | 7.14± 0.77 | 7.16± 0.97 | 0.523a |
| The age of onset of complaint (mean, SD) | 6.6± 1.11 | 6.6±1.1 | 0.704a | 6.6±0.72 | 6.6± 1.15 | 0.152a |
| Gestational age, week (mean, SD) | 38.3±1.3 | 38.5±1.6 | 0.627a | 35.3±1.04 | 38.9±0.89 | <0.001a |
| Birth weight, g (mean, SD) | 2237±395 | 3061±485 | <0.001a | 1963± 434 | 2969± 483 | <0.001a |
| Birth weight SDS (mean, SD) | -2.38±0.74 | -0.12±0.73 | <0.001a | -1.42± 1.64 | -0.67± 1.16 | <0.05a |
| ∆Weight SDS (mean, SD) | 2.25±1.64 | 0.98±1.17 | <0.001a | 1.9±2.6 | 1.2± 1.1 | <0.001a |
| Prematurity (n, %) | 4(%13.3) | 11(%14.8) | 0.840b | - | - | |
| SGA (n, %) | - | - | 4(%26.6) | 26(%29.2) | 0.262b | |
| Weight SDS (mean, SD) | 0.06±1.09 | 0.85±1.13 | <0.05a | 0.48±1.50 | 0.65±1.11 | 0.080a |
| Height SDS (mean, SD) | 0.00±0.96 | 0.59±0.99 | <0.05a | 0.38±1.31 | 0.43±0.97 | 0.605a |
| BMI SDS (mean, SD) | 0.03±1.13 | 0.70±1.09 | <0.05a | 0.36±1.42 | 0.53±1.09 | 0.129a |
| Overweight/obesity (>1 SDS) (n, %) | 4(%13.3) | 28(%37.8) | <0.05b | 4(%26.6) | 28(31.4) | 0.484b |
| BA, years (mean, SD) | 7.5±0.68 | 7.64±1.25 | 0.618a | 7.7±0.92 | 7.5± 1.14 | 0.265a |
| BA-CA, years (mean, SD) | 0.25±0.88 | 0.52±0.99 | 0.194a | 0.62±0.92 | 0.42±0.97 | 0.454a |
| DHEA-S (mean, SD) | 91.5±50.8 | 91.0±47.7 | 0.963a | 144.2±74.0 | 82.2± 36.26 | <0.001a |
| Exaggerated adrenarche (n, %) | 7(%23.3) | 12(%16.2) | 0.395b | 7(%46.6) | 12(%13.4) | <0.05b |
a) Mann-Whitney U-test for independent samples; b) Chi-square. ∆Weight SDS: Weight SDS minus Birth Weight SDS. BMI: Body Mass Index. BA: Bone Age, BA-CA: bone age (years, months) minus chronological age (years, months).
Table 1.
Basic Clinical and Laboratory Characteristics
| (n=104) | |
|---|---|
| Age at evaluation, years (mean, SD) | 7.04±0.89 |
| The age of onset of complaint | 6.5±1.04 |
| Gestational age, week (mean,SD) | 38.4±1.5 |
| Birth weight, g (mean, SD) | 2849±579 |
| Birth weight SDS (mean, SD) | -0.78±1.26 |
| ∆Weight SDS (mean, SD) | 1.35 ± 1.44 |
| Prematurity (n, %) | 15 (%14.4) |
| SGA (n, %) | 30 (%28.8) |
| First clinical sign | |
| Pubarche (n, %) | 75 (%69.4) |
| Axillary hair (n, %) | 10 (%9.3) |
| Pubarche + Axillary hair (n, %) | 23 (%21.3) |
| Weight SDS (mean, SD) | 0.64±1.20 |
| Height SDS (mean, SD) | 0.43±1.04 |
| BMI SDS (mean, SD) | 0.56±1.15 |
| Normal BMI (≤ 1 SDS) (n, %) | 72 (%69.5) |
| Overweight or obesity (>1 SDS) (n, %) | 32 (%30.5) |
| BA, years (mean, SD) | 7.56±1.1 |
| BA-CA, years (mean, SD) | 0.45±0.96 |
| DHEA-S (mean, SD) | 91.8±48.1 |
| Exaggerated adrenarche (n, %) | 20 (%19.4) |
∆Weight SDS: Weight SDS minus Birth Weight SDS. BMI: Body Mass Index BA: Bone Age. BA-CA: bone age (years, months) minus chronological age (years,months).
The overweight/obese group had a lower age of presentation compared to the normal BMI group. As expected, weight and BMI SDSs were higher in the overweight/obese group. Additionally, the overweight/obese group was taller than the normal weight group. Although bone age progression was higher in the overweight/obese group, there was no difference in mean bone age between the two groups. DHEA-S and 17 OH progesterone levels were similar between the two groups. Only four of 32 overweight/obese cases were SGA (12.5%). Although SGA rates were significantly higher in the normal group, there was no difference between the two groups in terms of prematurity rates (refer to Table 3).
Table 3.
Comparison of BMI SDS and DHEA-s levels
| Overweight/Obesity | Exaggerated Adrenarche | |||||
|---|---|---|---|---|---|---|
| Yes (n=32) | No (n=72) | p-value | Yes (n=19) | No (n=85) | p-value | |
| Age at evaluation, years (mean, SD) | 6.75±1.26 | 7.33±0.70 | <0.05a | 7.34±0.83 | 7.11±0.97 | 0.334a |
| The age of onset of complaint (mean, SD) | 6.27±1.34 | 6.78±0.94 | 0.110a | 6.74±0.86 | 6.60±1.15 | 0.619a |
| Gestational age, week (mean, SD) | 38.7±1.39 | 38.3±1.64 | 0.252a | 37.6±1.8 | 38.6±1.4 | <0.05a |
| Birth weight, g (mean, SD) | 3031±667 | 2732±536 | 0.080a | 2437±743 | 2910±520 | <0.05a |
| Birth weight SDS (mean, SD) | -0.38±1.43 | -0.95±1.14 | <0.05a | -1.4±1.5 | -0.6±1.1 | <0.05a |
| ∆Weight SDS | 2.31±1.63 | 0.92±1.11 | <0.05a | 2.12±2.15 | 1.17±1.17 | <0.05a |
| Prematurity (n, %) | 4(%12.5) | 11(15.2) | 0.484b | 7(%36.8) | 8(%9.4) | <0.05b |
| SGA (n, %) | 4(%12.5) | 26(%36) | <0.05b | 7(%36.8) | 23(%27) | 0.279b |
| Weight SDS (mean, SD) | 1.96±0.71 | 0.03±0.78 | <0.05a | 0.71±1.34 | 0.60±1.14 | 0.724a |
| Height SDS (mean, SD) | 0.98±0.85 | 0.17±0.99 | <0.05a | 0.42±0.90 | 0.42±1.04 | 0.986a |
| BMI SDS (mean, SD) | 1.84±0.55 | -0.07±0.77 | <0.05a | 0.57±1.40 | 0.49±1.08 | 0.791a |
| Overweight/obesity (>1 SDS) (n, %) | - | - | 6(%31.6) | 26(%30.6) | 0.933b | |
| BA, years (mean, IQR) | 7.5±1.53 | 7.6±0.88 | 0.820a | 8.0±0.79 | 7.5±1.15 | 0.032a |
| BA-CA, years (mean, SD) | 0.81±1.20 | 0.28±0.79 | <0.05a | 0.69±1.14 | 0.39±0.92 | 0.231a |
| DHEA-S (mean, SD) | 88.4±48.4 | 92.3±48.7 | 0.706a | 173.0±42.7 | 72.8±25.1 | <0.005a |
| Exaggerated adrenarche (n, %) | 6(%18.8) | 13(%18.1) | 0.566b | - | - | |
a) Mann-Whitney U-test for independent samples; b) Chi-square. ∆Weight SDS: Weight SDS minus Birth Weight SDS. BMI: Body Mass Index. BA: Bone Age BA-CA: bone age (years, months) minus chronological age (years, months).
Of the 104 children examined, 68 (65%) were overweight/obese and/or had a history of SGA and/or prematurity. Among the children who were of normal weight at diagnosis, 36% (26/72) had a history of SGA and 15% (10/72) were premature. Additionally, 50% (36/72) of the children had a history of prematurity and/or SGA. The delta weight SDS was compared between the group with obesity/overweight or a history of SGA and/or prematurity, and the group with normal weight and no history of SGA and/or prematurity. The delta weight SDS was found to be 1.8 in the group with obesity/overweight or SGA and/or prematurity, while it was 0.4 in the other group (p<0.005).
The mean DHEA-S level was 91.8±48.1 µg/dl. Out of 104 participants, 19.4% had a DHEA-S level above 124 µg/dl, which was considered an exaggerated adrenarche. There was no significant difference in age at presentation and age at onset of complaints between the two groups with and without exaggerated adrenarche. However, the exaggerated adrenarche group had lower birth weight, birth weight SDS, and gestational age, but higher delta weight SDS. Additionally, the rates of prematurity were higher in the exaggerated adrenarche group (Table 3).
The age at onset of complaints was negatively correlated with BMI SDS (r=-0.204 p=0.038) and bone age advancement (r=-0.349, p=0.000). DHEA-S levels were positively correlated with chronological age (r=0.275, p=0.005), bone age (r=0.413, p=0.000), and bone age advancement (r=0.201, p=0.041) but negatively correlated with gestational age (r=-0.343, p=0.002). While bone age advancement was negatively correlated with gestational age (r= -0.238, p=0.032), it was positively correlated with BMI SDS (r=0.287, p=0.003). BMI SDS was positively correlated with delta weight SDS (r=0.523, p=0.000) but not with bone age or DHEA-S levels. In addition, delta weight SDS was positively correlated with DHEA-S and bone age advancement but negatively correlated with birth weight SDS (r=-0.554, p=0.000) and gestational age (r= -0.227, p=0.045).
DISCUSSION
In this retrospective study evaluating the clinical and laboratory findings of Turkish children diagnosed with premature adrenarche, prematurity and SGA rates were found to be higher than the average rates in Turkey, where prematurity is observed in 11.1% of pregnancies and the rate of low birth weight is 8% (18).
Obesity is one of the most investigated parameters in the etiology of premature adrenarche, and much of the blame is ascribed to it. In most previous studies in the literature, the rates of overweight and obesity were found to be higher than in the normal population, and it has been suggested that rapid weight gain and obesity may trigger premature adrenarche (5,19). Racial differences have also been identified, with much higher obesity rates being reported for some races, while the rates in others differ little from those of the general population (20). In our study, the rate of overweight/obesity was 30.5%, which is slightly higher than the Turkey average (30.5% & 24.5%) (21), but lower than in many studies (5,19). In addition, unlike in many studies, no relationship was found between obesity and DHEA-S levels in our study (5). In our study, the lack of a significant relationship between obesity and DHEA-S levels suggests that rapid weight gain may play a more important role in the development of PA. Obesity is known to be associated with other long-term complications, such as metabolic syndrome and insulin resistance. However, our findings suggest that rapid weight gain, rather than obesity itself, may play a more critical role in triggering adrenal androgen secretion and the development of premature adrenarche.
Prematurity, and particularly SGA, are two important conditions investigated in the etiology of premature adrenarche. In our study, unlike obesity, the rates of SGA and prematurity were found to be higher compared not only to the general population in Turkey but also to many other studies on premature adrenarche (7,18, 22). DHEA-S levels were higher in the premature and SGA cases than in other cases, and an inverse relationship was identified between DHEA-S and gestational week.
When the entire cohort (SGA, premature, and term-AGA births) was evaluated, the rate of overweight and obesity was found to be 30%. However, when only term and normal birth weight children were considered, this rate increased to 47%. This indicates that nearly half of the children born term-AGA and followed up with a diagnosis of premature adrenarche are either overweight or obese. Therefore, the lower rates of overweight and obesity observed in our study compared to other studies can be attributed to the higher number of SGA and premature children in our cohort. Additionally, when the SGA and premature group was evaluated separately, a high rate of catch-up growth was observed. While babies born at normal weight become overweight or obese with rapid weight gain, in SGA and premature infants, rapid weight gain and catch-up growth normalize the weight. In fact, the common feature of all these risk factors seems to be rapid weight gain. It has also been proposed that rapid weight gain, independent of obesity, may trigger adrenal androgen secretion (23,24).
One of the key strengths of this study is the detailed analysis of a large cohort of patients. The comprehensive evaluation of multiple risk factors, including prematurity, SGA, obesity, and rapid weight gain, provides a broad perspective on the etiology of PA. The use of standardized and reliable methods for hormonal and anthropometric measurements enhances the accuracy of the findings. However, the retrospective design of the study carries the risk of bias and incomplete data collection. Additionally, the fact that the study is based on data from only two centers limits the generalizability of the results. The small sample size within the prematurity and SGA groups may also reduce the statistical power of the conclusions. Furthermore, the relationship between obesity and DHEA-S levels needs to be explored more thoroughly in light of conflicting findings in the literature. Despite these limitations, the study offers valuable insights into the role of prematurity, SGA, and rapid weight gain in the development of PA, contributing important information for clinical practice.
In conclusion, this study identified a higher prevalence of prematurity and SGA in Turkish children with premature adrenarche compared to the general population. While obesity has often been implicated as a key factor in the etiology of premature adrenarche, our findings suggest that in this cohort, rapid weight gain, particularly in children born SGA or prematurely, may play a more significant role. The lack of a clear relationship between obesity and DHEA-S levels further highlights the potential influence of other factors, such as early catch-up growth, in the development of premature adrenarche. Future studies should aim to explore the underlying genetic and environmental mechanisms contributing to these findings. Clinically, children exhibiting rapid weight gain, whether AGA, SGA, or premature, should be closely monitored to mitigate long-term metabolic risks associated with premature adrenarche.
Conflict of interest
The authors declare that they have no conflict of interest.
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