Indications of younger age at menarche in Greek adolescents but no relation to body mass index

Indications of younger age at menarche in Greek adolescents but no relation to body mass index | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Indications of younger age at menarche in Greek adolescents but no relation to body mass index Anastasia Papageorgiou, Evangelia Charmandari, Vasiliki Efthymiou, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3030151/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Apr, 2024 Read the published version in Hormones → Version 1 posted 6 You are reading this latest preprint version Abstract Purpose This study aimed to present recent trends in the pubertal timing of a Greek female sample. Methods Data were collected retrospectively from medical records of healthy females aged 6–18 years who attended a tertiary Adolescent Friendly Health Center over a 5-year period (2016–2020) and included gestational age, birth weight, age of thelarche and/or pubarche and/or menarche along with corresponding anthropometric, hormonal, and biochemical measurements. Results Data from 298 girls’ medical records were included in the analysis. Median age at menarche and thelarche was 12 and 9 years respectively, while mean age at pubarche 8.97 years. The mean interval between pubertal onset and menarche was 1.99 years. Mean body mass index (BMI) at menarche and thelarche was 20.99 kg/m 2 and 18.90 kg/m 2 respectively. Mean weight at menarche was 49.6 kg, whereas the mean height difference between thelarche and menarche was 19.17cm. Among participants, 6.3% had premature menarche, while 24.0% had premature thelarche. Birth weight was moderately correlated with BMI at thelarche/pubarche (r s =0.334, p = 0.005). Birth weight and BMI at thelarche/pubarche were not predictive of premature menarche or premature thelarche. Median (interquartile range, IQR) levels at menarche vs. thelarche were higher for insulin-like growth factor-1 [358.00(140.50) vs. 176.00(55.00) ng/ml], follicle stimulation hormone [5.65(3.14) vs. 3.10(4.23) mIU/ml], testosterone [25.50(31.00) vs. 13.00(21.00) ng/dl], dehydroepiandrosterone sulfate [117.00(112.50) vs. 46.40(51.90) µg/dl] and insulin [17.40(15.05) vs. 8.47(4.97) µIU/ml]. Conclusion The timing of pubertal stages in the Greek female sample studied followed the recent international downward trends. Younger age at menarche was not related to body mass index. menarche thelarche pubarche adolescents Greece pubertal timing pubertal stages puberty Introduction Worldwide, the timing of female puberty has attracted considerable interest among professionals over time. Excess adipose tissue in childhood is a determinant for sexual maturation in girls and, thus, can affect the process of growth and puberty.[ 1 – 3 ] Child and adolescent obesity has been recognized as a predisposing factor for later life comorbidities such as hypertension, dyslipidemia, coronary heart disease as well as diabetes mellitus type 2 and metabolic syndrome.[ 3 ] The observed changes in normative onset of thelarche and menarche are related to childhood body mass index (BMI), whereas cardiovascular disease is related to extremely early age of menarche.[ 2 ] [ 4 ] Premature menarche is also considered a risk factor for breast cancer, depression, type 2 diabetes mellitus and overall morbidity.[ 4 , 5 ] According to latest studies, several other determinants, apart from childhood BMI seem to have an effect on the timing of puberty, and these include birth weight, stress, climate conditions, socioeconomic factors, endocrine disruptors and epigenetics. [ 6 , 7 ] Potential mechanisms of hypothalamic-pituitary-gonadal axis (HPG) activation in earlier thelarche are mostly related to insulin resistance and hyperinsulinemia, androgen hypersecretion and leptin.[ 3 ] Data from various studies over the last decades have shown a clear secular trend toward earlier onset of puberty and menarche, both in developed and developing countries. A recent study referring to the American population, showed that there is a substantial decline in the median age at menarche from 12.1 years in 1995 to 11.9 years during the period 2013–2017. [ 8 ] In Greece, research on the timing of female sexual maturation has not been published recently. Pantsiotou et al. have published longitudinal data from 307 girls during the period 1990–1997 and showed that the median (p25-p75) age at the onset of puberty was 10.0 (9.2–10.6) years, mean (± SD) age at peak height velocity was 11.2 (± 0.1) years and mean (± SD) age at menarche was 12.14 (± 0.08) years.[ 9 ] In another study of young women in Greece, higher childhood height and BMI were shown to accelerate menarche. [ 10 ] Going back in time, mean menarcheal age of Greek girls was 12.4 years in 1979, 12.27 years in 1996 and 12.29 in 2006. [ 11 ] Recent data regarding the timing of onset of thelarche and menarche in contemporary Greek girls, as well as correlations with anthropometric and hormonal measurements are lacking. This study aimed to show recent trends in the pubertal timing of a Greek female sample who presented to a tertiary adolescent friendly health center over a 5-year period. Methods Data were collected retrospectively from the medical records of all girls who were assessed at the Center for Adolescent Medicine and UNESCO Chair in Adolescent Health Care of the Medical School, National and Kapodistrian University of Athens at the Aghia Sophia Children’s Hospital in Athens, Greece, over a 5-year period, from January 2016 to December 2020. The study protocol was approved by the hospital’s Scientific and Ethics Committee (protocol number 9222/17.05.2021). Data Collection Data from females’ records were included in the study if they pertained to: i) Greek females aged 6–18 years and ii) the age of thelarche and/or pubarche and/or menarche, anthropometric data from growth curves, and birth details. Records of girls who were diagnosed with any condition that could have affected the progression of puberty (i.e. congenital adrenal hyperplasia, hypothyroidism, growth hormone deficiency, etc.) or data regarding the period post-treatment for pubertal induction or delay, were excluded. The cut-offs of 8 years and 10 years were used for premature thelarche (defined as breast development before this age) and menarche (defined as first menstrual period) respectively. Anthropometric data included gestational age, birth weight, length, head circumference at birth, height and weight at thelarche, height and weight at pubarche, height and weight at menarche, as well as bone age at thelarche/menarche, where available. Hormonal and biochemical measurements that corresponded to each pubertal stage were also recorded and included parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], calcium (Ca), phosphate (P), insulin-like growth factor 1 (IGF-1), cortisol, luteinizing hormone (LH), follicle stimulation hormone (FSH), estradiol (E2), prolactin (PRL), thyroid-stimulating hormone (TSH), free thyroxine (fT4), triiodothyronine (T3), testosterone, dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), Δ4-androstendione, 17-hydroxyprogesterone (17ΟΗPg), sex hormone-binding globulin (SHBG), insulin, glucose, glycated hemoglobin (HbA1c), total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and lipoprotein a (Lpa). Statistical analysis Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) for Windows, Version 25.0 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). The level of statistical significance was set at a two-sided p = 0.05. Data are expressed as mean ± standard deviation (SD), or as median value and interquartile range (IQR). The threshold of 8 years was used to define premature thelarche or pubarche. The cut-off of 10 years was used to define premature menarche. BMI was calculated as body weight (kg) divided by the square of height (m 2 ). Spearman and Pearson’s correlation coefficients were calculated to examine the associations between age at thelarche, age at menarche and anthropometric measurements. Simple linear regression models were used in cases of continuous dependent variables. Logistic regression analysis was performed to estimate the odds ratio (OR) for binary characteristics, such as premature thelarche and menarche. Analysis of variance (ANOVA) and the Kruskal-Wallis test were used to evaluate the differences in parameters related to the stages of thelarche, menarche, and pubarche. Results Data from 298 girls were included in the study (Table 1 ). Median birth weight of the sample was 3,050 gr, median gestational age 38 weeks, median body length at birth 50 cm and median head circumference 34 cm. Median/mean ages at thelarche, pubarche and menarche were median (Mdn) 9 years (IQR 2.05), mean (M) 8.97 years (SD 1.95) and Mdn 12 years (IQR 1.59) respectively. Mean bone age at thelarche was 9.48 years whereas mean bone age at pubarche was 9.65 years. The mean interval between pubertal onset and menarche was 1.99 years. At the onset of puberty, mean body weight was 34.80 kg and median body height was 135 cm. Mean weight at menarche was 49.6kg. Mean height at menarche was 154.39 cm, whereas the mean height difference between thelarche and menarche was 19.17 cm. The mean BMI at the onset of puberty was 18.90 kg/m 2 while the mean BMI at menarche was 20.99 kg/m 2 . Among participants, 6.3% presented with premature menarche and 24.0% presented with premature thelarche. Table 1 Anthropometric measurements at sexual maturation stages of the study sample. Total sample Birth weight (g) 3050.00 (610.00) Body length (cm) 50.00 (2.00) Head circumference (cm) 34.00 (1.50) Gestational age (weeks) 38.00 (2.00) Height at pubertal onset (cm) 135.00 (11.00) Weight at pubertal onset (kg) * 34.80 ± 8.37 BMI at pubertal onset (kg/m 2 ) * 18.90 ± 3.35 Age at thelarche (years) 9.00 (2.05) Age at pubarche (years) * 8.97 ± 1.95 Age at menarche (years) 12.00 (1.59) Age at onset of puberty * 8.93 ± 1.88 Bone age at thelarche * 9.48 ± 1.28 Bone age at pubarche * 9.65 ± 1.29 Height at menarche (cm) * 154.39 ± 7.46 Weight at menarche (kg) * 49.60 ± 10.03 BMI at menarche (kg/m 2 ) * 20.99 ± 3.44 Height difference between thelarche-menarche (cm) * 19.17 ± 3.41 Interval between pubertal onset and menarche (years) * 1.99 ± 1.05 g; grams, cm; centimeters, kg; kilograms, m; meters, ΒΜΙ; body mass index. Values are referred as median (interquartile rage - IQR) or as *mean ± standard deviation. Age at menarche was strongly correlated to the age at pubertal onset ( r s =0.832, p < 0.001) and the age at pubarche ( r s =0.861, p < 0.001). The age at pubertal onset was strongly correlated to the age at pubarche ( r s =0.817, p < 0.001). Birth weight was correlated to gestational age ( r s =0.572, p < 0.001) and moderately correlated to BMI at thelarche/pubarche ( r s =0.334, p = 0.005) (Table 2 ). Table 2 Correlations between study variables. Correlations r (p-value) Age at pubertal onset Gestational age Age at menarche Birth weight Interval between onset of puberty and menarche Age at pubarche ΒΜΙ at thelarche/ pubarche Age at pubertal onset 1 Gestational age -0.093 1 Age at menarche 0.832 *** 0.143 1 Birth weight -0.146 0.572 *** 0.003 1 Interval between onset of puberty and menarche -0.254 † 0.031 0.330 0.226 1 Age at pubarche 0.817 *** -0.067 0.861 *** -0.097 -0.159 1 ΒΜΙ at thelarche/ pubarche -0.003 † 0.061 -0.167 0.334 ** 0.384 † 0.052 1 ΒΜΙ; body mass index. Values are referred as Spearman correlation or as †Pearson correlation coefficient. *** p < 0.001, ** p < 0.01 Simple logistic regression models did not demonstrate statistically significant results for premature menarche or for premature thelarche with independent variables BMI at thelarche/pubarche and birth weight, as shown in Table 3 . Table 3 Simple logistic regression models for premature menarche and thelarche. Dependent variable: Premature Menarche β p Odds Ratio (95% CI) ΒΜΙ at thelarche/pubarche 0.073 0.810 1.076 (0.592–1.957) Birth weight 0.001 0.602 1.000 (0.999–1.001) Dependent variable: Premature Thelarche β p Odds Ratio (95%CI) ΒΜΙ at thelarche/pubarche 0.013 0.878 1.013 (0.860–1.193) Birth Weight 0.001 0.206 1.001 (1.001–1.002) ΒΜΙ; body mass index, CI; confidence interval Differences in hormonal and biochemical parameters at thelarche, pubarche and menarche are presented in Table 4 . Statistically significant differences were observed in FSH ( p < 0.001), DHEA-S ( p < 0.001), testosterone ( p = 0.002), 17OHPg ( p = 0.049), SHBG ( p = 0.037), insulin ( p = 0.001) and phosphate ( p = 0.003) levels. Post-hoc analysis showed differences in menarche vs. pubarche and menarche vs. thelarche (lower levels of phosphate and SHBG in menarche vs. pubarche/thelarche, in contrast to the higher levels of the other parameters in menarche vs. pubarche/thelarche). Significant differences were also found in IGF-1 ( p = 0.029), total cholesterol ( p = 0.004), and calcium ( p = 0.002), with lower levels of calcium and total cholesterol and higher levels of IGF-1 in menarche than in thelarche. Moreover, fT4 levels ( p = 0.011) were lower in menarche than in pubarche. Table 4 Participants’ hormonal and biochemical parameters at thelarche, pubarche and menarche. Parameters Thelarche Pubarche Menarche p PTH (pg/ml) 34.95 (20.72) 59.40 (45.00) 42.90 (30.70) 0.176 25(OH)D (ng/ml) 25.00 (10.40) 23.20 (7.50) 22.90 (3.40) 0.100 Ca (mg/dl) 9.90 (0.36) 9.60 (0.80) 9.60 (0.60) 0.002 P (mg/dl) * 4.96 ± 0.40 5.11 ± 0.45 4.56 ± 0.71 0.003 IGF-1 (ng/ml) 176.00 (55.00) 183.25 (171.00) 358.00 (140.50) 0.029 Cortisol (µg/dl) 12.40 (5.15) 13.40 (5.82) 15.50 (6.90) 0.362 FSH (mIU/ml) 3.10 (4.23) 1.75 (2.88) 5.65 (3.14) < 0.001 E2 (pg/ml) * 33.00 ± 13.84 27.50 ± 19.57 48.94 ± 27.65 0.214 PRL (ng/ml) 10.90 (10.72) 11.00 (13.44) 11.25 (8.42) 0.929 TSH (µIU/ml) 2.31 (1.72) 2.40 (1.41) 2.39 (1.52) 0.961 Τ3 (ng/ml) 1.56 (0.38) 1.74 (0.00) 1.29 (0.21) 0.403 fT4 (pmol/l) * 15.13 ± 2.11 16.48 ± 2.77 13.72 ± 3.76 0.011 Testosterone (ng/dl) 13.00 (21.00) 13.50 (14.50) 25.50 (31.00) 0.002 DHEA-S (µg/dl) 46.40 (51.90) 56.50 (49.70) 117.00 (112.50) < 0.001 DHEA (ng/ml) 2.70 (0.80) 3.00 (0.70) 3.80 (2.50) 0.455 17OHPg (ng/ml) 0.93 (0.50) 0.68 (0.66) 1.11 (0.74) 0.049 SHBG (nmol/l) 70.30 (44.58) 71.30 (66.30) 52.60 (34.50) 0.037 Insulin (µIU/ml) 8.47 (4.97) 9.08 (4.46) 17.40 (15.05) 0.001 Glucose (mg/dl) 85.00 (9.00) 85.00 (8.50) 89.00 (13.00) 0.087 HbA1c (%) 5.30 (0.35) 5.30 (0.30) 5.25 (0.21) 0.828 Total Cholesterol (mg/dl) * 167.43 ± 22.15 168.49 ± 27.63 150.19 ± 29.21 0.004 Triglycerides (mg/dl) 60.00 (20.00) 60.00 (47.00) 65.00 (30.00) 0.852 HDL (mg/dl) * 62.56 ± 15.73 62.66 ± 14.54 57.78 ± 13.86 0.213 LDL (mg/dl) 89.00 (25.50) 94.00 (30.45) 79.00 (32.00) 0.262 Lpa (nmol/l ) 8.20 (8.40) 8.37 (22.42) 73.50 (133.00) 0.592 PTH; parathyroid hormone, 25(OH)D; 25-hydroxy-vitamin D, Ca; calcium, P; phosphate, IGF-1; insulin-like growth factor 1, FSH; follicle stimulation hormone, E2; estradiol, PRL; prolactin, TSH; thyroid-stimulating hormone, T3; triiodothyronine, fT4; free thyroxine, DHEA-S; dehydroepiandrosterone sulfate, DHEA; dehydroepiandrosterone, 17ΟΗPg; 17-hydroxyprogesterone, SHBG; sex hormone-binding globulin, HbA1c; glycated hemoglobin, HDL; high-density lipoprotein, LDL; low-density lipoprotein and Lpa ; lipoprotein a. Values are referred as median (interquartile range) and p -value of Kruskal-Wallis test or as * mean ± standard deviation and p -value of analysis of variance (ANOVA). Discussion Mean menarcheal age can be assessed using different methods of scientific research, retrospective, prospective, or status quo. It can be elicited by a parent, adolescent, or remembered by an adult and this method has been proven reliable enough to be used in a study. During the last 70 years, there has been a decrease in menarcheal age, which is smaller than the decrease in thelarcheal age. In other words, girls present menarche earlier than the previous half of the century, but most notable is the fact that they present even earlier thelarche. In a systematic review concerning white-Caucasian women of different nationalities, the mean age at menarche fluctuated between 11.96 and 12.93 years.[ 2 ] Futhermore, girls from the northern part of Europe experience menarche earlier than girls from southern Europe. [ 2 ] Martinez et al. (2020) with reference to the American population for the years 2013–2017 compared to 1995, reported a decrease in median age at menarche from 12.1 to 11.9 years [ 8 ], which coincides with our findings in the Greek sample (median menarcheal age 12 years, IQR 1.59). Pereira et al. (2019) reported a mean age at menarche of 11.9 years and median age at thelarche of 9.2 years in girls in Chile. [ 12 ] Le-Ha et al. in 2018 estimated a slightly higher average age at menarche of 12.7 years (95% CI 12.6–12.8). [ 13 ] An older survey from 2014 found a median age at menarche 12.77 years for white-Caucasian women and 12.17 years for Afro-American women [ 14 ] while an even lower mean menarcheal age of 11.52 years was reported by Barcellos et al. a few years ago in Brazil. [ 15 ] Over the past four decades, the pubertal stages of the Greek female adolescent population seem to follow the international secular trends. More specifically, in 1979, Dacou-Voutetakis et al. found that mean age at menarche was 12.5 years for girls living in Athens whereas Mantzagriotis and Meimaridis reported a median menarcheal age of 12.59 years from a national sample around the same period. [ 16 ] In 1996 a mean menarcheal age of 12.27 years (with a median value of 12.1 years) for school-aged girls living in Athens was reported and, later, in 2006 mean menarcheal age of Greek girls was 12.29.[ 11 ] Historically, in 1970, Frisch et al. hypothesized that there is a threshold of approximately 48 kg for menarche to commence. Currently, various studies support in part this controversial hypothesis, interpreting it in the context of percentage of body fat and leptin levels to activate the hypothalamic–pituitary–gonadal axis.[ 17 ] In line with this hypothesis, we found mean body weight at menarche 49.6 kg. In our study, the median age at thelarche was 9 years, which is consistent with the data from international studies. [ 14 , 18 ] This phenomenon of earlier thelarche over the last 40 years has been described in various studies from the USA. As part of the NHANES III (Third National Health and Nutrition Examination Study) between 1988–1994, Sun et al. reported that median age of breast development for non-Hispanic white girls was approximately 10.4 years, while for non-Hispanic black girls was approximately 9.5 years, profoundly earlier than previous registrations.[ 19 ] In the same context and period, another survey from Herman-Giddens et al. reported a mean age at thelarche for Caucasian girls of 9.96 years.[ 20 ] Even more recent studies claim that a greater percentage of girls aged 7–8 years old in USA have breast development [ 21 ], whereas in Europe, specifically in Denmark, an almost 12 months decrease in the mean age at thelarche over a period of 15 years has been reported.[ 22 ] A systematic review published lately with meta-analysis of international data mentioned that mean thelarcheal age presents a fall of 0.24 years, almost 3 months, for every decade from 1977 to 2013.[ 23 ] Age at menarche was not correlated to the age at thelarche in our study, although data from other studies show such a correlation.[ 24 ] The prevalence of premature thelarche in our sample was 24.0% which is relatively high and does not align with current data about thelarche worldwide of around 10% for white-Caucasian women. [ 21 ] We can assume that this reflects the greater proportion of girls with signs of early puberty seeking expertise advise in a tertiary Adolescent Medicine Center. Finally, 6.3% of our sample presented premature menarche. In our study, birth weight was positively correlated with BMI at thelarche/pubarche, but not with menarcheal age. According to the scientific literature of the last two decades, birth weight, as an index of intrauterine growth, has been correlated to earlier onset of puberty and/or menarche. A possible explanation for the association between smaller birth size and an earlier age at menarche could be the fact that the rapid transition from one nutritional condition to the other may act as a stimulus for advancement of growth tempo and induction of puberty in order to magnify the reproductive potential. Moreover, in 2013, another study found that earlier menarche at 10 or 11 years was related to low birth weight. [ 25 ] Lastly, birth weight and the pattern of growth in early childhood have been related to adrenarche, meaning that obese children undergo adrenarche earlier. A prospective cohort study in 2007 showed that both very low birth weight and childhood BMI (8 years old) are related to the age at menarche. More specifically, it was found that menarche occurs earlier in girls with a history of very low birth weight but also with a greater childhood BMI, indicating that these factors act synergistically. [ 1 ] BMI at thelarche/pubarche was not correlated to the age at menarche in our study. Nevertheless, a body of research supports this association. The systematic review by Kaplowitz supports the correlation between adiposity levels and earlier puberty based on data claiming - but not proving - etiological relationship. [ 26 ] In 2017, another study revealed that obese and overweight girls underwent onset of puberty 3.5 months earlier than girls of normal weight. [ 27 ] Finally, a German study has shown that there is no cut-off value of BMI for the achievement of menarche, as in the Frisch hypothesis, but there is a clear linear inverse relation between age at onset of menarche and body mass index standard deviation score (BMI-SDS).[ 28 ] It is interesting that research is focused on the relationship between precocious puberty and obesity in girls, however the question of whether higher levels of adipose tissue predispose girls to earlier onset of puberty or, inversely, whether earlier activation of the HPG axis and precocious puberty leads to an estrogen-dependent rise in adipose tissue, still exists. Childhood BMI, adult BMI, and age at menarche could be interrelated with hormonal changes, which, in turn, can be related to specific metabolic predisposition at the population level. The secular decrease in the age of menarche, as well as the rising prevalence of overweight/obesity in different countries worldwide, can share a common underlying etiology. In this study, we also compared hormonal and biochemical parameters between thelarche and menarche. IGF-1 levels were higher in the perimenarcheal period than in thelarche, while the opposite was observed for SHBG. This observation is consistent with findings from other studies, as IGF-1 is involved in the growth and puberty mechanisms and its levels seem to rise as puberty advances. On the other hand, levels of SHBG tend to be lower during female puberty, and this is partially explained by androgens’ suppression. FT4 levels gradually decrease as puberty advances, as described by a large community-based study in school-age children.[ 29 ] Moreover, FSH levels are higher and its final product estradiol being the core hormone of female puberty reflects the advance of this process and the growing ovarian volume, as its levels rise in the systematic circulation. From the scope of lipids, it has been shown that pubertal progression as depicted from height growth could be associated with lower total cholesterol levels, in both sexes. In a large cohort, Kouda et al. found that height velocity was inversely associated with dynamic changes in serum lipids during puberty, which is in accordance with our results.[ 30 ] Νo significant differences were observed in HDL, LDL, triglycerides, Lpa and 25(OH)D between the pubertal stages. This study has some limitations. The sample size of the study was relatively small, not nationally representative and was derived from an adolescent population attending a tertiary Center. Therefore, the results cannot be generalized. Additionally, socio-economic, environmental, and other confounding factors were not taken into consideration. Future prospective studies of general adolescent population samples are needed to explore the influence of socioeconomic and environmental exposures on the timing of thelarche and menarche, and thus on the tempo of puberty in Greek adolescents. Conclusion In summary, results indicate younger age at menarche of Greek adolescents but no relation to body mass index. The timing of pubertal stages in the Greek female sample studied followed the international downward trends of recent decades. Whether earlier attainment of pubertal stages is mediated by obesity, endocrine disruptors, or other factors remains to be elucidated in larger, population-based prospective studies in the future. Abbreviations 17-hydroxyprogesterone (17ΟΗPg), 25-hydroxyvitamin D [25(OH)D], analysis of variance (ANOVA), body mass index (ΒΜΙ), body mass index standard deviation score (BMI-SDS), calcium (Ca), centimeters (cm), confidence interval (CI), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), estradiol (E2), follicle stimulation hormone (FSH), free thyroxine (fT4), glycated hemoglobin (HbA1c), grams (g), high-density lipoprotein (HDL), hypothalamic-pituitary-gonadal axis (HPG), insulin-like growth factor 1 (IGF-1), interquartile range (IQR), kilograms (kg), lipoprotein a (Lpa), luteinizing hormone (LH), low-density lipoprotein (LDL), mean (M), median (Mdn), meters (m), odds ratio (OR), parathyroid hormone (PTH), phosphate (P), prolactin (PRL), sex hormone-binding globulin (SHBG), standard deviation (SD), statistical package for social sciences (SPSS), third National Health and Nutrition Examination Study (NHANES III), thyroid-stimulating hormone (TSH), triiodothyronine (T3), United Nations Educational, Scientific and Cultural Organization (UNESCO) Declarations Contributors Statement Dr Anastasia Papageorgiou conceptualized and designed the study, collected the data, carried out the initial analyses and drafted the initial manuscript. Professor Dr Evangelia Charmandari and Professor Dimitrios Vlachakis supervised data collection, and critically reviewed and revised the manuscript for important intellectual content. Vasiliki Efthymiou carried out the final analyses, and critically reviewed and revised the manuscript. Professor Dr Flora Bacopoulou conceptualized and designed the study, coordinated and supervised data collection, analysis of the data and interpretation of data, and critically reviewed and revised the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of this work. Compliance with Ethical Standards Conflict of Interest : The authors have no relevant financial or non-financial interests to disclose. Funding/Support: No funding was secured for this study. Ethical Approval: This research study was conducted retrospectively from data obtained for clinical purposes. Information is anonymized and the submission does not include images that may imply identification. Ethical approval was waived by the hospital’s Scientific and Ethics Committee (protocol number 9222/17.05.2021) in view of the study’s retrospective nature and all the procedures being performed were part of the routine care. References Sloboda DM, Hart R, Doherty DA, Pennell CE, Hickey M: Age at menarche: Influences of prenatal and postnatal growth. The Journal of clinical endocrinology and metabolism 2007;92:46-50. https://doi.org/10.1210/jc.2006-1378 Yermachenko A, Dvornyk V: Nongenetic determinants of age at menarche: a systematic review. BioMed research international 2014;2014:371583. https://doi.org/10.1155/2014/371583 Shalitin S, Kiess W: Putative Effects of Obesity on Linear Growth and Puberty. Hormone Research in Paediatrics 2017;88:101-110. https://doi.org/10.1159/000455968 Ley SH, Li Y, Tobias DK, Manson JE, Rosner B, Hu FB, Rexrode KM: Duration of Reproductive Life Span, Age at Menarche, and Age at Menopause Are Associated With Risk of Cardiovascular Disease in Women. Journal of the American Heart Association 2017;6 https://doi.org/10.1161/jaha.117.006713 Lee JJ, Cook-Wiens G, Johnson BD, Braunstein GD, Berga SL, Stanczyk FZ, Pepine CJ, Bairey Merz CN, Shufelt CL: Age at Menarche and Risk of Cardiovascular Disease Outcomes: Findings From the National Heart Lung and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation. Journal of the American Heart Association 2019;8:e012406. https://doi.org/10.1161/jaha.119.012406 Parent AS, Franssen D, Fudvoye J, Gérard A, Bourguignon JP: Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents. Frontiers in neuroendocrinology 2015;38:12-36. https://doi.org/10.1016/j.yfrne.2014.12.004 Livadas S, Chrousos GP: Molecular and Environmental Mechanisms Regulating Puberty Initiation: An Integrated Approach. Frontiers in endocrinology 2019;10:828. https://doi.org/10.3389/fendo.2019.00828 Martinez GM: Trends and Patterns in Menarche in the United States: 1995 through 2013-2017. National health statistics reports 2020:1-12. Pantsiotou S, Papadimitriou A, Douros K, Priftis K, Nicolaidou P, Fretzayas A: Maturational tempo differences in relation to the timing of the onset of puberty in girls. Acta paediatrica (Oslo, Norway : 1992) 2008;97:217-220. https://doi.org/10.1111/j.1651-2227.2007.00598.x Georgiadis E, Mantzoros CS, Evagelopoulou C, Spentzos D: Adult height and menarcheal age of young women in Greece. Annals of human biology 1997;24:55-59. https://doi.org/10.1080/03014469700004772 Papadimitriou A, Fytanidis G, Douros K, Bakoula C, Nicolaidou P, Fretzayas A: Age at menarche in contemporary Greek girls: evidence for levelling-off of the secular trend. Acta paediatrica (Oslo, Norway : 1992) 2008;97:812-815. https://doi.org/10.1111/j.1651-2227.2008.00806.x Pereira A, Corvalan C, Merino PM, Leiva V, Mericq V: Age at Pubertal Development in a Hispanic-Latina Female Population: Should the Definitions Be Revisited? Journal of pediatric and adolescent gynecology 2019;32:579-583. https://doi.org/10.1016/j.jpag.2019.08.008 Le-Ha C, Beilin LJ, Burrows S, Huang RC, Hickey M, Mori TA, Hart RJ: Age at menarche and childhood body mass index as predictors of cardio-metabolic risk in young adulthood: A prospective cohort study. PloS one 2018;13:e0209355. https://doi.org/10.1371/journal.pone.0209355 Cabrera SM, Bright GM, Frane JW, Blethen SL, Lee PA: Age of thelarche and menarche in contemporary US females: a cross-sectional analysis. Journal of pediatric endocrinology & metabolism : JPEM 2014;27:47-51. https://doi.org/10.1515/jpem-2013-0286 Barcellos Gemelli IF, Farias EDS, Souza OF: Age at Menarche and Its Association with Excess Weight and Body Fat Percentage in Girls in the Southwestern Region of the Brazilian Amazon. Journal of pediatric and adolescent gynecology 2016;29:482-488. https://doi.org/10.1016/j.jpag.2016.02.011 Papadimitriou A, Chiotis D, Tsiftis G, Hatzisimeon M, Maniati M, Krikos X, Tzonou A, Dacou-Voutetakis C: Secular growth changes in the Hellenic population in the twentieth century. Hormones (Athens, Greece) 2002;1:245-250. https://doi.org/10.14310/horm.2002.1174 Bandini LG, Must A, Naumova EN, Anderson S, Caprio S, Spadano-Gasbarro JI, Dietz WH: Change in leptin, body composition and other hormones around menarche--a visual representation. Acta paediatrica (Oslo, Norway : 1992) 2008;97:1454-1459. https://doi.org/10.1111/j.1651-2227.2008.00948.x Biro FM, Greenspan LC, Galvez MP, Pinney SM, Teitelbaum S, Windham GC, Deardorff J, Herrick RL, Succop PA, Hiatt RA, Kushi LH, Wolff MS: Onset of breast development in a longitudinal cohort. Pediatrics 2013;132:1019-1027. https://doi.org/10.1542/peds.2012-3773 Sun SS, Schubert CM, Chumlea WC, Roche AF, Kulin HE, Lee PA, Himes JH, Ryan AS: National estimates of the timing of sexual maturation and racial differences among US children. Pediatrics 2002;110:911-919. https://doi.org/10.1542/peds.110.5.911 Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG, Hasemeier CM: Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics 1997;99:505-512. https://doi.org/10.1542/peds.99.4.505 Biro FM, Galvez MP, Greenspan LC, Succop PA, Vangeepuram N, Pinney SM, Teitelbaum S, Windham GC, Kushi LH, Wolff MS: Pubertal assessment method and baseline characteristics in a mixed longitudinal study of girls. Pediatrics 2010;126:e583-590. https://doi.org/10.1542/peds.2009-3079 Aksglaede L, Sørensen K, Petersen JH, Skakkebaek NE, Juul A: Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics 2009;123:e932-939. https://doi.org/10.1542/peds.2008-2491 Eckert-Lind C, Busch AS, Petersen JH, Biro FM, Butler G, Bräuner EV, Juul A: Worldwide Secular Trends in Age at Pubertal Onset Assessed by Breast Development Among Girls: A Systematic Review and Meta-analysis. JAMA pediatrics 2020;174:e195881. https://doi.org/10.1001/jamapediatrics.2019.5881 Biro FM, Pajak A, Wolff MS, Pinney SM, Windham GC, Galvez MP, Greenspan LC, Kushi LH, Teitelbaum SL: Age of Menarche in a Longitudinal US Cohort. Journal of pediatric and adolescent gynecology 2018;31:339-345. https://doi.org/10.1016/j.jpag.2018.05.002 D'Aloisio AA, DeRoo LA, Baird DD, Weinberg CR, Sandler DP: Prenatal and infant exposures and age at menarche. Epidemiology 2013;24:277-284. https://doi.org/10.1097/ede.0b013e31828062b7 Kaplowitz PB: Link between body fat and the timing of puberty. Pediatrics 2008;121 Suppl 3:S208-217. https://doi.org/10.1542/peds.2007-1813f Holmgren A, Niklasson A, Nierop AF, Gelander L, Aronson AS, Sjöberg A, Lissner L, Albertsson-Wikland K: Pubertal height gain is inversely related to peak BMI in childhood. Pediatric research 2017;81:448-454. https://doi.org/10.1038/pr.2016.253 Bau AM, Ernert A, Schenk L, Wiegand S, Martus P, Grüters A, Krude H: Is there a further acceleration in the age at onset of menarche? A cross-sectional study in 1840 school children focusing on age and bodyweight at the onset of menarche. European journal of endocrinology 2009;160:107-113. https://doi.org/10.1530/eje-08-0594 Marwaha RK, Tandon N, Desai AK, Kanwar R, Sastry A, Narang A, Singh S, Bhadra K, Mani K: The evolution of thyroid function with puberty. Clinical endocrinology 2012;76:899-904. https://doi.org/10.1111/j.1365-2265.2011.04305.x Kouda K, Nakamura H, Fan W, Takeuchi H: Negative relationships between growth in height and levels of cholesterol in puberty: a 3-year follow-up study. International Journal of Epidemiology 2003;32:1105-1110. https://doi.org/10.1093/ije/dyg207 Cite Share Download PDF Status: Published Journal Publication published 22 Apr, 2024 Read the published version in Hormones → Version 1 posted Editorial decision: Major revisions 25 Jul, 2023 Reviewers agreed at journal 22 Jun, 2023 Reviewers invited by journal 17 Jun, 2023 Editor invited by journal 16 Jun, 2023 Editor assigned by journal 12 Jun, 2023 First submitted to journal 09 Jun, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3030151","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":210722711,"identity":"39c8e5f7-75c8-4134-b7e5-dc980669dc8a","order_by":0,"name":"Anastasia Papageorgiou","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-8009-9693","institution":"National and Kapodistrian University of Athens School of Medicine: Ethniko kai Kapodistriako Panepistemio Athenon Iatrike Schole","correspondingAuthor":true,"prefix":"","firstName":"Anastasia","middleName":"","lastName":"Papageorgiou","suffix":""},{"id":210722712,"identity":"dc01f6d2-6d1d-4508-b88d-1007b00b318c","order_by":1,"name":"Evangelia Charmandari","email":"","orcid":"","institution":"National and Kapodistrian University of Athens School of Medicine: Ethniko kai Kapodistriako Panepistemio Athenon Iatrike Schole","correspondingAuthor":false,"prefix":"","firstName":"Evangelia","middleName":"","lastName":"Charmandari","suffix":""},{"id":210722713,"identity":"165ef2e1-0c76-4769-8a1d-2b96a4d03374","order_by":2,"name":"Vasiliki Efthymiou","email":"","orcid":"","institution":"National and Kapodistrian University of Athens School of Medicine: Ethniko kai Kapodistriako Panepistemio Athenon Iatrike Schole","correspondingAuthor":false,"prefix":"","firstName":"Vasiliki","middleName":"","lastName":"Efthymiou","suffix":""},{"id":210722714,"identity":"a7ced140-c36f-4dda-8e96-652f536da45b","order_by":3,"name":"Dimitrios Vlachakis","email":"","orcid":"","institution":"National and Kapodistrian University of Athens School of Medicine: Ethniko kai Kapodistriako Panepistemio Athenon Iatrike Schole","correspondingAuthor":false,"prefix":"","firstName":"Dimitrios","middleName":"","lastName":"Vlachakis","suffix":""},{"id":210722715,"identity":"91ed78b5-db4d-4aef-8eea-6cd05c7df395","order_by":4,"name":"Flora Bacopoulou","email":"","orcid":"","institution":"National and Kapodistrian University of Athens School of Medicine: Ethniko kai Kapodistriako Panepistemio Athenon Iatrike Schole","correspondingAuthor":false,"prefix":"","firstName":"Flora","middleName":"","lastName":"Bacopoulou","suffix":""}],"badges":[],"createdAt":"2023-06-06 15:21:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3030151/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3030151/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s42000-024-00557-8","type":"published","date":"2024-04-22T23:36:20+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":55696589,"identity":"c0dc0a2b-bb27-458d-bb5c-75a8a64ae1a3","added_by":"auto","created_at":"2024-05-02 01:46:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":578092,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3030151/v1/38dabf33-5d10-4828-aebc-0d8941b83175.pdf"}],"financialInterests":"","formattedTitle":"Indications of younger age at menarche in Greek adolescents but no relation to body mass index","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWorldwide, the timing of female puberty has attracted considerable interest among professionals over time. Excess adipose tissue in childhood is a determinant for sexual maturation in girls and, thus, can affect the process of growth and puberty.[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Child and adolescent obesity has been recognized as a predisposing factor for later life comorbidities such as hypertension, dyslipidemia, coronary heart disease as well as diabetes mellitus type 2 and metabolic syndrome.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] The observed changes in normative onset of thelarche and menarche are related to childhood body mass index (BMI), whereas cardiovascular disease is related to extremely early age of menarche.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Premature menarche is also considered a risk factor for breast cancer, depression, type 2 diabetes mellitus and overall morbidity.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] According to latest studies, several other determinants, apart from childhood BMI seem to have an effect on the timing of puberty, and these include birth weight, stress, climate conditions, socioeconomic factors, endocrine disruptors and epigenetics. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Potential mechanisms of hypothalamic-pituitary-gonadal axis (HPG) activation in earlier thelarche are mostly related to insulin resistance and hyperinsulinemia, androgen hypersecretion and leptin.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Data from various studies over the last decades have shown a clear secular trend toward earlier onset of puberty and menarche, both in developed and developing countries. A recent study referring to the American population, showed that there is a substantial decline in the median age at menarche from 12.1 years in 1995 to 11.9 years during the period 2013\u0026ndash;2017. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIn Greece, research on the timing of female sexual maturation has not been published recently. Pantsiotou et al. have published longitudinal data from 307 girls during the period 1990\u0026ndash;1997 and showed that the median (p25-p75) age at the onset of puberty was 10.0 (9.2\u0026ndash;10.6) years, mean (\u0026plusmn;\u0026thinsp;SD) age at peak height velocity was 11.2 (\u0026plusmn;\u0026thinsp;0.1) years and mean (\u0026plusmn;\u0026thinsp;SD) age at menarche was 12.14 (\u0026plusmn;\u0026thinsp;0.08) years.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] In another study of young women in Greece, higher childhood height and BMI were shown to accelerate menarche. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Going back in time, mean menarcheal age of Greek girls was 12.4 years in 1979, 12.27 years in 1996 and 12.29 in 2006. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Recent data regarding the timing of onset of thelarche and menarche in contemporary Greek girls, as well as correlations with anthropometric and hormonal measurements are lacking.\u003c/p\u003e \u003cp\u003eThis study aimed to show recent trends in the pubertal timing of a Greek female sample who presented to a tertiary adolescent friendly health center over a 5-year period.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e Data were collected retrospectively from the medical records of all girls who were assessed at the Center for Adolescent Medicine and UNESCO Chair in Adolescent Health Care of the Medical School, National and Kapodistrian University of Athens at the Aghia Sophia Children\u0026rsquo;s Hospital in Athens, Greece, over a 5-year period, from January 2016 to December 2020. The study protocol was approved by the hospital\u0026rsquo;s Scientific and Ethics Committee (protocol number 9222/17.05.2021).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData Collection\u003c/h2\u003e \u003cp\u003eData from females\u0026rsquo; records were included in the study if they pertained to: i) Greek females aged 6\u0026ndash;18 years and ii) the age of thelarche and/or pubarche and/or menarche, anthropometric data from growth curves, and birth details. Records of girls who were diagnosed with any condition that could have affected the progression of puberty (i.e. congenital adrenal hyperplasia, hypothyroidism, growth hormone deficiency, etc.) or data regarding the period post-treatment for pubertal induction or delay, were excluded. The cut-offs of 8 years and 10 years were used for premature thelarche (defined as breast development before this age) and menarche (defined as first menstrual period) respectively.\u003c/p\u003e \u003cp\u003eAnthropometric data included gestational age, birth weight, length, head circumference at birth, height and weight at thelarche, height and weight at pubarche, height and weight at menarche, as well as bone age at thelarche/menarche, where available. Hormonal and biochemical measurements that corresponded to each pubertal stage were also recorded and included parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], calcium (Ca), phosphate (P), insulin-like growth factor 1 (IGF-1), cortisol, luteinizing hormone (LH), follicle stimulation hormone (FSH), estradiol (E2), prolactin (PRL), thyroid-stimulating hormone (TSH), free thyroxine (fT4), triiodothyronine (T3), testosterone, dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), Δ4-androstendione, 17-hydroxyprogesterone (17ΟΗPg), sex hormone-binding globulin (SHBG), insulin, glucose, glycated hemoglobin (HbA1c), total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and lipoprotein a (Lpa).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using the Statistical Package for Social Sciences (SPSS) for Windows, Version 25.0 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). The level of statistical significance was set at a two-sided \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05. Data are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), or as median value and interquartile range (IQR). The threshold of 8 years was used to define premature thelarche or pubarche. The cut-off of 10 years was used to define premature menarche. BMI was calculated as body weight (kg) divided by the square of height (m\u003csup\u003e2\u003c/sup\u003e). Spearman and Pearson\u0026rsquo;s correlation coefficients were calculated to examine the associations between age at thelarche, age at menarche and anthropometric measurements. Simple linear regression models were used in cases of continuous dependent variables. Logistic regression analysis was performed to estimate the odds ratio (OR) for binary characteristics, such as premature thelarche and menarche. Analysis of variance (ANOVA) and the Kruskal-Wallis test were used to evaluate the differences in parameters related to the stages of thelarche, menarche, and pubarche.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eData from 298 girls were included in the study (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Median birth weight of the sample was 3,050 gr, median gestational age 38 weeks, median body length at birth 50 cm and median head circumference 34 cm. Median/mean ages at thelarche, pubarche and menarche were median (Mdn) 9 years (IQR 2.05), mean (M) 8.97 years (SD 1.95) and Mdn 12 years (IQR 1.59) respectively. Mean bone age at thelarche was 9.48 years whereas mean bone age at pubarche was 9.65 years. The mean interval between pubertal onset and menarche was 1.99 years. At the onset of puberty, mean body weight was 34.80 kg and median body height was 135 cm. Mean weight at menarche was 49.6kg. Mean height at menarche was 154.39 cm, whereas the mean height difference between thelarche and menarche was 19.17 cm. The mean BMI at the onset of puberty was 18.90 kg/m\u003csup\u003e2\u003c/sup\u003e while the mean BMI at menarche was 20.99 kg/m\u003csup\u003e2\u003c/sup\u003e. Among participants, 6.3% presented with premature menarche and 24.0% presented with premature thelarche.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAnthropometric measurements at sexual maturation stages of the study sample.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal sample\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight (g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3050.00 (610.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody length (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.00 (2.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHead circumference (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.00 (1.50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age (weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38.00 (2.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight at pubertal onset (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e135.00 (11.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight at pubertal onset (kg)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.80\u0026thinsp;\u0026plusmn;\u0026thinsp;8.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI at pubertal onset (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.90\u0026thinsp;\u0026plusmn;\u0026thinsp;3.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at thelarche (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.00 (2.05)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at pubarche (years)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.97\u0026thinsp;\u0026plusmn;\u0026thinsp;1.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at menarche (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.00 (1.59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at onset of puberty \u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.93\u0026thinsp;\u0026plusmn;\u0026thinsp;1.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone age at thelarche\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.48\u0026thinsp;\u0026plusmn;\u0026thinsp;1.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone age at pubarche\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.65\u0026thinsp;\u0026plusmn;\u0026thinsp;1.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight at menarche (cm)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e154.39\u0026thinsp;\u0026plusmn;\u0026thinsp;7.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight at menarche (kg)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49.60\u0026thinsp;\u0026plusmn;\u0026thinsp;10.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI at menarche (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20.99\u0026thinsp;\u0026plusmn;\u0026thinsp;3.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight difference between thelarche-menarche (cm)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19.17\u0026thinsp;\u0026plusmn;\u0026thinsp;3.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterval between pubertal onset and menarche (years)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.99\u0026thinsp;\u0026plusmn;\u0026thinsp;1.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eg; grams, cm; centimeters, kg; kilograms, m; meters, ΒΜΙ; body mass index.\u003c/p\u003e \u003cp\u003eValues are referred as median (interquartile rage - IQR) or as *mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAge at menarche was strongly correlated to the age at pubertal onset (\u003cem\u003er\u003c/em\u003e\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e=0.832, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and the age at pubarche (\u003cem\u003er\u003c/em\u003e\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e=0.861, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The age at pubertal onset was strongly correlated to the age at pubarche (\u003cem\u003er\u003c/em\u003e\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e=0.817, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Birth weight was correlated to gestational age (\u003cem\u003er\u003c/em\u003e\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e=0.572, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and moderately correlated to BMI at thelarche/pubarche (\u003cem\u003er\u003c/em\u003e\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e=0.334, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCorrelations between study variables.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorrelations\u003c/p\u003e \u003cp\u003er (p-value)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge at pubertal onset\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGestational age\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAge at menarche\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBirth weight\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eInterval between onset of puberty and menarche\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAge at pubarche\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eΒΜΙ at thelarche/ pubarche\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at pubertal onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.093\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at menarche\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.832\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.572\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterval between onset of puberty and menarche\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.254\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.031\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.330\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.226\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at pubarche\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.817\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.861\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.097\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.159\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΒΜΙ at thelarche/ pubarche\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.003\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.334\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.384\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003eΒΜΙ; body mass index.\u003c/p\u003e \u003cp\u003eValues are referred as Spearman correlation or as \u0026dagger;Pearson correlation coefficient.\u003c/p\u003e \u003cp\u003e\u003csup\u003e***\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, **\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSimple logistic regression models did not demonstrate statistically significant results for premature menarche or for premature thelarche with independent variables BMI at thelarche/pubarche and birth weight, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSimple logistic regression models for premature menarche and thelarche.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDependent variable: Premature Menarche\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eβ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOdds Ratio (95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΒΜΙ at thelarche/pubarche\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.073\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.810\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.076 (0.592\u0026ndash;1.957)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.602\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.000 (0.999\u0026ndash;1.001)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDependent variable: Premature Thelarche\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eβ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOdds Ratio (95%CI)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΒΜΙ at thelarche/pubarche\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.878\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.013 (0.860\u0026ndash;1.193)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth Weight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.206\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.001 (1.001\u0026ndash;1.002)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eΒΜΙ; body mass index, CI; confidence interval\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eDifferences in hormonal and biochemical parameters at thelarche, pubarche and menarche are presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Statistically significant differences were observed in FSH (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), DHEA-S (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), testosterone (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002), 17OHPg (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.049), SHBG (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037), insulin (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) and phosphate (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) levels. Post-hoc analysis showed differences in menarche vs. pubarche and menarche vs. thelarche (lower levels of phosphate and SHBG in menarche vs. pubarche/thelarche, in contrast to the higher levels of the other parameters in menarche vs. pubarche/thelarche). Significant differences were also found in IGF-1 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029), total cholesterol (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004), and calcium (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002), with lower levels of calcium and total cholesterol and higher levels of IGF-1 in menarche than in thelarche. Moreover, fT4 levels (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) were lower in menarche than in pubarche.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eParticipants\u0026rsquo; hormonal and biochemical parameters at thelarche, pubarche and menarche.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThelarche\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePubarche\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMenarche\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePTH (pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.95 (20.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59.40 (45.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42.90 (30.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.176\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25(OH)D (ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.00 (10.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.20 (7.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.90 (3.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCa (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.90 (0.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.60 (0.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.60 (0.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP (mg/dl)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.96\u0026thinsp;\u0026plusmn;\u0026thinsp;0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIGF-1 (ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176.00 (55.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e183.25 (171.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e358.00 (140.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.029\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCortisol (\u0026micro;g/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.40 (5.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.40 (5.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15.50 (6.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.362\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFSH (mIU/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.10 (4.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.75 (2.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.65 (3.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eE2 (pg/ml)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33.00\u0026thinsp;\u0026plusmn;\u0026thinsp;13.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.50\u0026thinsp;\u0026plusmn;\u0026thinsp;19.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e48.94\u0026thinsp;\u0026plusmn;\u0026thinsp;27.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.214\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePRL (ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.90 (10.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.00 (13.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.25 (8.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.929\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSH (\u0026micro;IU/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.31 (1.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.40 (1.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.39 (1.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.961\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΤ3 (ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.56 (0.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.74 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.29 (0.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.403\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efT4 (pmol/l)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.13\u0026thinsp;\u0026plusmn;\u0026thinsp;2.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.48\u0026thinsp;\u0026plusmn;\u0026thinsp;2.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.72\u0026thinsp;\u0026plusmn;\u0026thinsp;3.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.011\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTestosterone (ng/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.00 (21.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.50 (14.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.50 (31.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDHEA-S (\u0026micro;g/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46.40 (51.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56.50 (49.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e117.00 (112.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDHEA (ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.70 (0.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.00 (0.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.80 (2.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.455\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17OHPg (ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.93 (0.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.68 (0.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.11 (0.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.049\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSHBG (nmol/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70.30 (44.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71.30 (66.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52.60 (34.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.037\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInsulin (\u0026micro;IU/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.47 (4.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.08 (4.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.40 (15.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucose (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85.00 (9.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85.00 (8.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e89.00 (13.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.087\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHbA1c (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.30 (0.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.30 (0.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.25 (0.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.828\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Cholesterol (mg/dl)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e167.43\u0026thinsp;\u0026plusmn;\u0026thinsp;22.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e168.49\u0026thinsp;\u0026plusmn;\u0026thinsp;27.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e150.19\u0026thinsp;\u0026plusmn;\u0026thinsp;29.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriglycerides (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.00 (20.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.00 (47.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65.00 (30.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.852\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDL (mg/dl)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.56\u0026thinsp;\u0026plusmn;\u0026thinsp;15.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.66\u0026thinsp;\u0026plusmn;\u0026thinsp;14.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57.78\u0026thinsp;\u0026plusmn;\u0026thinsp;13.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.213\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDL (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89.00 (25.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94.00 (30.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e79.00 (32.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.262\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLpa (nmol/l )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.20 (8.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.37 (22.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73.50 (133.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.592\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003ePTH; parathyroid hormone, 25(OH)D; 25-hydroxy-vitamin D, Ca; calcium, P; phosphate, IGF-1; insulin-like growth factor 1, FSH; follicle stimulation hormone, E2; estradiol, PRL; prolactin, TSH; thyroid-stimulating hormone, T3; triiodothyronine, fT4; free thyroxine, DHEA-S; dehydroepiandrosterone sulfate, DHEA; dehydroepiandrosterone, 17ΟΗPg; 17-hydroxyprogesterone, SHBG; sex hormone-binding globulin, HbA1c; glycated hemoglobin, HDL; high-density lipoprotein, LDL; low-density lipoprotein and Lpa ; lipoprotein a.\u003c/p\u003e \u003cp\u003eValues are referred as median (interquartile range) and \u003cem\u003ep\u003c/em\u003e-value of Kruskal-Wallis test or as \u003csup\u003e*\u003c/sup\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation and \u003cem\u003ep\u003c/em\u003e-value of analysis of variance (ANOVA).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eMean menarcheal age can be assessed using different methods of scientific research, retrospective, prospective, or status quo. It can be elicited by a parent, adolescent, or remembered by an adult and this method has been proven reliable enough to be used in a study. During the last 70 years, there has been a decrease in menarcheal age, which is smaller than the decrease in thelarcheal age. In other words, girls present menarche earlier than the previous half of the century, but most notable is the fact that they present even earlier thelarche. In a systematic review concerning white-Caucasian women of different nationalities, the mean age at menarche fluctuated between 11.96 and 12.93 years.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Futhermore, girls from the northern part of Europe experience menarche earlier than girls from southern Europe. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eMartinez et al. (2020) with reference to the American population for the years 2013\u0026ndash;2017 compared to 1995, reported a decrease in median age at menarche from 12.1 to 11.9 years [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], which coincides with our findings in the Greek sample (median menarcheal age 12 years, IQR 1.59). Pereira et al. (2019) reported a mean age at menarche of 11.9 years and median age at thelarche of 9.2 years in girls in Chile. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] Le-Ha et al. in 2018 estimated a slightly higher average age at menarche of 12.7 years (95% CI 12.6\u0026ndash;12.8). [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] An older survey from 2014 found a median age at menarche 12.77 years for white-Caucasian women and 12.17 years for Afro-American women [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] while an even lower mean menarcheal age of 11.52 years was reported by Barcellos et al. a few years ago in Brazil. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eOver the past four decades, the pubertal stages of the Greek female adolescent population seem to follow the international secular trends. More specifically, in 1979, Dacou-Voutetakis et al. found that mean age at menarche was 12.5 years for girls living in Athens whereas Mantzagriotis and Meimaridis reported a median menarcheal age of 12.59 years from a national sample around the same period. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] In 1996 a mean menarcheal age of 12.27 years (with a median value of 12.1 years) for school-aged girls living in Athens was reported and, later, in 2006 mean menarcheal age of Greek girls was 12.29.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Historically, in 1970, Frisch et al. hypothesized that there is a threshold of approximately 48 kg for menarche to commence. Currently, various studies support in part this controversial hypothesis, interpreting it in the context of percentage of body fat and leptin levels to activate the hypothalamic\u0026ndash;pituitary\u0026ndash;gonadal axis.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] In line with this hypothesis, we found mean body weight at menarche 49.6 kg.\u003c/p\u003e \u003cp\u003eIn our study, the median age at thelarche was 9 years, which is consistent with the data from international studies. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] This phenomenon of earlier thelarche over the last 40 years has been described in various studies from the USA. As part of the NHANES III (Third National Health and Nutrition Examination Study) between 1988\u0026ndash;1994, Sun et al. reported that median age of breast development for non-Hispanic white girls was approximately 10.4 years, while for non-Hispanic black girls was approximately 9.5 years, profoundly earlier than previous registrations.[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] In the same context and period, another survey from Herman-Giddens et al. reported a mean age at thelarche for Caucasian girls of 9.96 years.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] Even more recent studies claim that a greater percentage of girls aged 7\u0026ndash;8 years old in USA have breast development [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], whereas in Europe, specifically in Denmark, an almost 12 months decrease in the mean age at thelarche over a period of 15 years has been reported.[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] A systematic review published lately with meta-analysis of international data mentioned that mean thelarcheal age presents a fall of 0.24 years, almost 3 months, for every decade from 1977 to 2013.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eAge at menarche was not correlated to the age at thelarche in our study, although data from other studies show such a correlation.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] The prevalence of premature thelarche in our sample was 24.0% which is relatively high and does not align with current data about thelarche worldwide of around 10% for white-Caucasian women. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] We can assume that this reflects the greater proportion of girls with signs of early puberty seeking expertise advise in a tertiary Adolescent Medicine Center. Finally, 6.3% of our sample presented premature menarche.\u003c/p\u003e \u003cp\u003eIn our study, birth weight was positively correlated with BMI at thelarche/pubarche, but not with menarcheal age. According to the scientific literature of the last two decades, birth weight, as an index of intrauterine growth, has been correlated to earlier onset of puberty and/or menarche. A possible explanation for the association between smaller birth size and an earlier age at menarche could be the fact that the rapid transition from one nutritional condition to the other may act as a stimulus for advancement of growth tempo and induction of puberty in order to magnify the reproductive potential. Moreover, in 2013, another study found that earlier menarche at 10 or 11 years was related to low birth weight. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] Lastly, birth weight and the pattern of growth in early childhood have been related to adrenarche, meaning that obese children undergo adrenarche earlier. A prospective cohort study in 2007 showed that both very low birth weight and childhood BMI (8 years old) are related to the age at menarche. More specifically, it was found that menarche occurs earlier in girls with a history of very low birth weight but also with a greater childhood BMI, indicating that these factors act synergistically. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eBMI at thelarche/pubarche was not correlated to the age at menarche in our study. Nevertheless, a body of research supports this association. The systematic review by Kaplowitz supports the correlation between adiposity levels and earlier puberty based on data claiming - but not proving - etiological relationship. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] In 2017, another study revealed that obese and overweight girls underwent onset of puberty 3.5 months earlier than girls of normal weight. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] Finally, a German study has shown that there is no cut-off value of BMI for the achievement of menarche, as in the Frisch hypothesis, but there is a clear linear inverse relation between age at onset of menarche and body mass index standard deviation score (BMI-SDS).[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIt is interesting that research is focused on the relationship between precocious puberty and obesity in girls, however the question of whether higher levels of adipose tissue predispose girls to earlier onset of puberty or, inversely, whether earlier activation of the HPG axis and precocious puberty leads to an estrogen-dependent rise in adipose tissue, still exists. Childhood BMI, adult BMI, and age at menarche could be interrelated with hormonal changes, which, in turn, can be related to specific metabolic predisposition at the population level. The secular decrease in the age of menarche, as well as the rising prevalence of overweight/obesity in different countries worldwide, can share a common underlying etiology.\u003c/p\u003e \u003cp\u003eIn this study, we also compared hormonal and biochemical parameters between thelarche and menarche. IGF-1 levels were higher in the perimenarcheal period than in thelarche, while the opposite was observed for SHBG. This observation is consistent with findings from other studies, as IGF-1 is involved in the growth and puberty mechanisms and its levels seem to rise as puberty advances. On the other hand, levels of SHBG tend to be lower during female puberty, and this is partially explained by androgens\u0026rsquo; suppression. FT4 levels gradually decrease as puberty advances, as described by a large community-based study in school-age children.[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] Moreover, FSH levels are higher and its final product estradiol being the core hormone of female puberty reflects the advance of this process and the growing ovarian volume, as its levels rise in the systematic circulation. From the scope of lipids, it has been shown that pubertal progression as depicted from height growth could be associated with lower total cholesterol levels, in both sexes. In a large cohort, Kouda et al. found that height velocity was inversely associated with dynamic changes in serum lipids during puberty, which is in accordance with our results.[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] Νo significant differences were observed in HDL, LDL, triglycerides, Lpa and 25(OH)D between the pubertal stages.\u003c/p\u003e \u003cp\u003eThis study has some limitations. The sample size of the study was relatively small, not nationally representative and was derived from an adolescent population attending a tertiary Center. Therefore, the results cannot be generalized. Additionally, socio-economic, environmental, and other confounding factors were not taken into consideration. Future prospective studies of general adolescent population samples are needed to explore the influence of socioeconomic and environmental exposures on the timing of thelarche and menarche, and thus on the tempo of puberty in Greek adolescents.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, results indicate younger age at menarche of Greek adolescents but no relation to body mass index. The timing of pubertal stages in the Greek female sample studied followed the international downward trends of recent decades. Whether earlier attainment of pubertal stages is mediated by obesity, endocrine disruptors, or other factors remains to be elucidated in larger, population-based prospective studies in the future.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e17-hydroxyprogesterone (17\u0026Omicron;\u0026Eta;Pg), 25-hydroxyvitamin D [25(OH)D], analysis of variance (ANOVA), body mass index (\u0026Beta;\u0026Mu;\u0026Iota;), body mass index standard deviation score (BMI-SDS), calcium (Ca), centimeters (cm), confidence interval (CI), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), \u0026nbsp;estradiol (E2), follicle stimulation hormone (FSH), free thyroxine (fT4), glycated hemoglobin (HbA1c), grams (g), high-density lipoprotein (HDL), hypothalamic-pituitary-gonadal axis (HPG), insulin-like growth factor 1 (IGF-1), interquartile range (IQR), kilograms (kg), lipoprotein a (Lpa), luteinizing hormone (LH), low-density lipoprotein (LDL), mean (M), median (Mdn), meters (m), odds ratio (OR), parathyroid hormone (PTH), phosphate (P), prolactin (PRL), sex hormone-binding globulin (SHBG), standard deviation (SD), statistical package for social sciences (SPSS), third National Health and Nutrition Examination Study (NHANES III), thyroid-stimulating hormone (TSH), triiodothyronine (T3), United Nations Educational, Scientific and Cultural Organization (UNESCO)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eContributors Statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr Anastasia Papageorgiou conceptualized and designed the study, collected the data, carried out the initial analyses and drafted the initial manuscript.\u003c/p\u003e\n\u003cp\u003eProfessor Dr Evangelia Charmandari and Professor Dimitrios Vlachakis supervised data collection, and critically reviewed and revised the manuscript for important intellectual content.\u003c/p\u003e\n\u003cp\u003eVasiliki Efthymiou carried out the final analyses, and critically reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eProfessor Dr Flora Bacopoulou conceptualized and designed the study, coordinated and supervised data collection, analysis of the data and interpretation of data, and critically reviewed and revised the manuscript for important intellectual content.\u003c/p\u003e\n\u003cp\u003eAll authors approved the final manuscript as submitted and agreed to be accountable for all aspects of this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with Ethical Standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConflict of Interest\u003c/em\u003e\u003cem\u003e:\u0026nbsp;\u003c/em\u003eThe authors have no relevant financial or non-financial interests to disclose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding/Support:\u0026nbsp;\u003c/em\u003eNo funding was secured for this study.\u003cem\u003e\u003cbr\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthical Approval:\u0026nbsp;\u003c/em\u003eThis research study was conducted retrospectively from data obtained for clinical purposes. Information is anonymized and the submission does not include images that may imply identification. Ethical approval was waived by the hospital\u0026rsquo;s Scientific and Ethics Committee (protocol number 9222/17.05.2021) in view of the study\u0026rsquo;s retrospective nature and all the procedures being performed were part of the routine care.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSloboda DM, Hart R, Doherty DA, Pennell CE, Hickey M: Age at menarche: Influences of prenatal and postnatal growth. The Journal of clinical endocrinology and metabolism 2007;92:46-50. https://doi.org/10.1210/jc.2006-1378\u003c/li\u003e\n\u003cli\u003eYermachenko A, Dvornyk V: Nongenetic determinants of age at menarche: a systematic review. BioMed research international 2014;2014:371583. https://doi.org/10.1155/2014/371583\u003c/li\u003e\n\u003cli\u003eShalitin S, Kiess W: Putative Effects of Obesity on Linear Growth and Puberty. Hormone Research in Paediatrics 2017;88:101-110. https://doi.org/10.1159/000455968\u003c/li\u003e\n\u003cli\u003eLey SH, Li Y, Tobias DK, Manson JE, Rosner B, Hu FB, Rexrode KM: Duration of Reproductive Life Span, Age at Menarche, and Age at Menopause Are Associated With Risk of Cardiovascular Disease in Women. Journal of the American Heart Association 2017;6 https://doi.org/10.1161/jaha.117.006713\u003c/li\u003e\n\u003cli\u003eLee JJ, Cook-Wiens G, Johnson BD, Braunstein GD, Berga SL, Stanczyk FZ, Pepine CJ, Bairey Merz CN, Shufelt CL: Age at Menarche and Risk of Cardiovascular Disease Outcomes: Findings From the National Heart Lung and Blood Institute-Sponsored Women\u0026apos;s Ischemia Syndrome Evaluation. Journal of the American Heart Association 2019;8:e012406. https://doi.org/10.1161/jaha.119.012406\u003c/li\u003e\n\u003cli\u003eParent AS, Franssen D, Fudvoye J, G\u0026eacute;rard A, Bourguignon JP: Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents. Frontiers in neuroendocrinology 2015;38:12-36. https://doi.org/10.1016/j.yfrne.2014.12.004\u003c/li\u003e\n\u003cli\u003eLivadas S, Chrousos GP: Molecular and Environmental Mechanisms Regulating Puberty Initiation: An Integrated Approach. Frontiers in endocrinology 2019;10:828. https://doi.org/10.3389/fendo.2019.00828\u003c/li\u003e\n\u003cli\u003eMartinez GM: Trends and Patterns in Menarche in the United States: 1995 through 2013-2017. National health statistics reports 2020:1-12.\u003c/li\u003e\n\u003cli\u003ePantsiotou S, Papadimitriou A, Douros K, Priftis K, Nicolaidou P, Fretzayas A: Maturational tempo differences in relation to the timing of the onset of puberty in girls. Acta paediatrica (Oslo, Norway : 1992) 2008;97:217-220. https://doi.org/10.1111/j.1651-2227.2007.00598.x\u003c/li\u003e\n\u003cli\u003eGeorgiadis E, Mantzoros CS, Evagelopoulou C, Spentzos D: Adult height and menarcheal age of young women in Greece. Annals of human biology 1997;24:55-59. https://doi.org/10.1080/03014469700004772\u003c/li\u003e\n\u003cli\u003ePapadimitriou A, Fytanidis G, Douros K, Bakoula C, Nicolaidou P, Fretzayas A: Age at menarche in contemporary Greek girls: evidence for levelling-off of the secular trend. Acta paediatrica (Oslo, Norway : 1992) 2008;97:812-815. https://doi.org/10.1111/j.1651-2227.2008.00806.x\u003c/li\u003e\n\u003cli\u003ePereira A, Corvalan C, Merino PM, Leiva V, Mericq V: Age at Pubertal Development in a Hispanic-Latina Female Population: Should the Definitions Be Revisited? Journal of pediatric and adolescent gynecology 2019;32:579-583. https://doi.org/10.1016/j.jpag.2019.08.008\u003c/li\u003e\n\u003cli\u003eLe-Ha C, Beilin LJ, Burrows S, Huang RC, Hickey M, Mori TA, Hart RJ: Age at menarche and childhood body mass index as predictors of cardio-metabolic risk in young adulthood: A prospective cohort study. PloS one 2018;13:e0209355. https://doi.org/10.1371/journal.pone.0209355\u003c/li\u003e\n\u003cli\u003eCabrera SM, Bright GM, Frane JW, Blethen SL, Lee PA: Age of thelarche and menarche in contemporary US females: a cross-sectional analysis. Journal of pediatric endocrinology \u0026amp; metabolism : JPEM 2014;27:47-51. https://doi.org/10.1515/jpem-2013-0286\u003c/li\u003e\n\u003cli\u003eBarcellos Gemelli IF, Farias EDS, Souza OF: Age at Menarche and Its Association with Excess Weight and Body Fat Percentage in Girls in the Southwestern Region of the Brazilian Amazon. Journal of pediatric and adolescent gynecology 2016;29:482-488. https://doi.org/10.1016/j.jpag.2016.02.011\u003c/li\u003e\n\u003cli\u003ePapadimitriou A, Chiotis D, Tsiftis G, Hatzisimeon M, Maniati M, Krikos X, Tzonou A, Dacou-Voutetakis C: Secular growth changes in the Hellenic population in the twentieth century. Hormones (Athens, Greece) 2002;1:245-250. https://doi.org/10.14310/horm.2002.1174\u003c/li\u003e\n\u003cli\u003eBandini LG, Must A, Naumova EN, Anderson S, Caprio S, Spadano-Gasbarro JI, Dietz WH: Change in leptin, body composition and other hormones around menarche--a visual representation. Acta paediatrica (Oslo, Norway : 1992) 2008;97:1454-1459. https://doi.org/10.1111/j.1651-2227.2008.00948.x\u003c/li\u003e\n\u003cli\u003eBiro FM, Greenspan LC, Galvez MP, Pinney SM, Teitelbaum S, Windham GC, Deardorff J, Herrick RL, Succop PA, Hiatt RA, Kushi LH, Wolff MS: Onset of breast development in a longitudinal cohort. Pediatrics 2013;132:1019-1027. https://doi.org/10.1542/peds.2012-3773\u003c/li\u003e\n\u003cli\u003eSun SS, Schubert CM, Chumlea WC, Roche AF, Kulin HE, Lee PA, Himes JH, Ryan AS: National estimates of the timing of sexual maturation and racial differences among US children. Pediatrics 2002;110:911-919. https://doi.org/10.1542/peds.110.5.911\u003c/li\u003e\n\u003cli\u003eHerman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG, Hasemeier CM: Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics 1997;99:505-512. https://doi.org/10.1542/peds.99.4.505\u003c/li\u003e\n\u003cli\u003eBiro FM, Galvez MP, Greenspan LC, Succop PA, Vangeepuram N, Pinney SM, Teitelbaum S, Windham GC, Kushi LH, Wolff MS: Pubertal assessment method and baseline characteristics in a mixed longitudinal study of girls. Pediatrics 2010;126:e583-590. https://doi.org/10.1542/peds.2009-3079\u003c/li\u003e\n\u003cli\u003eAksglaede L, S\u0026oslash;rensen K, Petersen JH, Skakkebaek NE, Juul A: Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics 2009;123:e932-939. https://doi.org/10.1542/peds.2008-2491\u003c/li\u003e\n\u003cli\u003eEckert-Lind C, Busch AS, Petersen JH, Biro FM, Butler G, Br\u0026auml;uner EV, Juul A: Worldwide Secular Trends in Age at Pubertal Onset Assessed by Breast Development Among Girls: A Systematic Review and Meta-analysis. JAMA pediatrics 2020;174:e195881. https://doi.org/10.1001/jamapediatrics.2019.5881\u003c/li\u003e\n\u003cli\u003eBiro FM, Pajak A, Wolff MS, Pinney SM, Windham GC, Galvez MP, Greenspan LC, Kushi LH, Teitelbaum SL: Age of Menarche in a Longitudinal US Cohort. Journal of pediatric and adolescent gynecology 2018;31:339-345. https://doi.org/10.1016/j.jpag.2018.05.002\u003c/li\u003e\n\u003cli\u003eD\u0026apos;Aloisio AA, DeRoo LA, Baird DD, Weinberg CR, Sandler DP: Prenatal and infant exposures and age at menarche. Epidemiology 2013;24:277-284. https://doi.org/10.1097/ede.0b013e31828062b7\u003c/li\u003e\n\u003cli\u003eKaplowitz PB: Link between body fat and the timing of puberty. Pediatrics 2008;121 Suppl 3:S208-217. https://doi.org/10.1542/peds.2007-1813f\u003c/li\u003e\n\u003cli\u003eHolmgren A, Niklasson A, Nierop AF, Gelander L, Aronson AS, Sj\u0026ouml;berg A, Lissner L, Albertsson-Wikland K: Pubertal height gain is inversely related to peak BMI in childhood. Pediatric research 2017;81:448-454. https://doi.org/10.1038/pr.2016.253\u003c/li\u003e\n\u003cli\u003eBau AM, Ernert A, Schenk L, Wiegand S, Martus P, Gr\u0026uuml;ters A, Krude H: Is there a further acceleration in the age at onset of menarche? A cross-sectional study in 1840 school children focusing on age and bodyweight at the onset of menarche. European journal of endocrinology 2009;160:107-113. https://doi.org/10.1530/eje-08-0594\u003c/li\u003e\n\u003cli\u003eMarwaha RK, Tandon N, Desai AK, Kanwar R, Sastry A, Narang A, Singh S, Bhadra K, Mani K: The evolution of thyroid function with puberty. Clinical endocrinology 2012;76:899-904. https://doi.org/10.1111/j.1365-2265.2011.04305.x\u003c/li\u003e\n\u003cli\u003eKouda K, Nakamura H, Fan W, Takeuchi H: Negative relationships between growth in height and levels of cholesterol in puberty: a 3-year follow-up study. International Journal of Epidemiology 2003;32:1105-1110. https://doi.org/10.1093/ije/dyg207\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"hormones","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"HORM","sideBox":"Learn more about [Hormones](https://www.springer.com/journal/42000)","snPcode":"42000","submissionUrl":"https://www.editorialmanager.com/horm/default2.aspx","title":"Hormones","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"menarche, thelarche, pubarche, adolescents, Greece, pubertal timing, pubertal stages, puberty","lastPublishedDoi":"10.21203/rs.3.rs-3030151/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3030151/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThis study aimed to present recent trends in the pubertal timing of a Greek female sample.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eData were collected retrospectively from medical records of healthy females aged 6\u0026ndash;18 years who attended a tertiary Adolescent Friendly Health Center over a 5-year period (2016\u0026ndash;2020) and included gestational age, birth weight, age of thelarche and/or pubarche and/or menarche along with corresponding anthropometric, hormonal, and biochemical measurements.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eData from 298 girls\u0026rsquo; medical records were included in the analysis. Median age at menarche and thelarche was 12 and 9 years respectively, while mean age at pubarche 8.97 years. The mean interval between pubertal onset and menarche was 1.99 years. Mean body mass index (BMI) at menarche and thelarche was 20.99 kg/m\u003csup\u003e2\u003c/sup\u003e and 18.90 kg/m\u003csup\u003e2\u003c/sup\u003e respectively. Mean weight at menarche was 49.6 kg, whereas the mean height difference between thelarche and menarche was 19.17cm. Among participants, 6.3% had premature menarche, while 24.0% had premature thelarche. Birth weight was moderately correlated with BMI at thelarche/pubarche (r\u003csub\u003es\u003c/sub\u003e=0.334, p\u0026thinsp;=\u0026thinsp;0.005). Birth weight and BMI at thelarche/pubarche were not predictive of premature menarche or premature thelarche. Median (interquartile range, IQR) levels at menarche vs. thelarche were higher for insulin-like growth factor-1 [358.00(140.50) vs. 176.00(55.00) ng/ml], follicle stimulation hormone [5.65(3.14) vs. 3.10(4.23) mIU/ml], testosterone [25.50(31.00) vs. 13.00(21.00) ng/dl], dehydroepiandrosterone sulfate [117.00(112.50) vs. 46.40(51.90) \u0026micro;g/dl] and insulin [17.40(15.05) vs. 8.47(4.97) \u0026micro;IU/ml].\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe timing of pubertal stages in the Greek female sample studied followed the recent international downward trends. Younger age at menarche was not related to body mass index.\u003c/p\u003e","manuscriptTitle":"Indications of younger age at menarche in Greek adolescents but no relation to body mass index","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-06-21 04:25:59","doi":"10.21203/rs.3.rs-3030151/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2023-07-25T07:06:09+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2023-06-22T05:55:34+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-06-17T09:42:16+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Hormones","date":"2023-06-16T12:13:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-06-12T09:45:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"Hormones","date":"2023-06-09T14:39:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"hormones","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"HORM","sideBox":"Learn more about [Hormones](https://www.springer.com/journal/42000)","snPcode":"42000","submissionUrl":"https://www.editorialmanager.com/horm/default2.aspx","title":"Hormones","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c6c2c2e5-31b2-4feb-a14c-1069ec493331","owner":[],"postedDate":"June 21st, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-05-01T23:36:20+00:00","versionOfRecord":{"articleIdentity":"rs-3030151","link":"https://doi.org/10.1007/s42000-024-00557-8","journal":{"identity":"hormones","isVorOnly":false,"title":"Hormones"},"publishedOn":"2024-04-22 23:36:20","publishedOnDateReadable":"April 22nd, 2024"},"versionCreatedAt":"2023-06-21 04:25:59","video":"","vorDoi":"10.1007/s42000-024-00557-8","vorDoiUrl":"https://doi.org/10.1007/s42000-024-00557-8","workflowStages":[]},"version":"v1","identity":"rs-3030151","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3030151","identity":"rs-3030151","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}