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Objective: The aim of this study was to explore the impact of growth hormone (GH) therapy on the onset and progression of puberty in girls with idiopathic short stature., Methods: This study included 541 girls aged between 4.5 and 10.6 years who were receiving GH treatment, monitored over a 22-year follow-up period. Of these, 126 girls have been followed up to the onset of menarche. The participants were divided into two groups: a ISS control group ( n  = 66) and a group receiving daily GH treatment at a dose of 0.15 iu/kg ( n  = 60). We assessed the pubertal development and GH usage of these girls every three months., Results: (1) There was no significant difference in the onset of puberty between the growth hormone (GH) treatment group and the control group; however, the average duration of puberty was longer in the treatment group compared to the control group. (2) During puberty, there were no significant differences in height growth between the treated and untreated groups. (3) The duration of GH treatment showed a significant negative correlation with the age at onset of gonadal development and the age at menarche in females within the treatment group., Conclusion: GH treatment does not seem to accelerate the onset of puberty but may extend its duration, without significantly impacting height growth during puberty. Additionally, longer GH treatment duration is linked to earlier gonadal development and menarche in females.

Objectives: To understand possible predictors of the onset of menses after gonadotropin-releasing hormone agonist treatment cessation in girls with central precocious puberty (CPP)., Methods: This exploratory post hoc analysis of a phase 3 and 4 trial of girls with CPP treated with once-monthly intramuscular leuprolide acetate examined onset of menses after treatment completion using a time-to-event analysis. Pretreatment and end-of-treatment chronologic age (CA), bone age (BA)/CA ratio, and Tanner breast stage; pretreatment menses status; and end-of-treatment BA and body mass index (BMI) were studied as potential factors influencing the onset of menses., Results: Median time to first menses after stopping treatment was 18.3 months among 35 girls (mean age at onset of treatment, 6.8 years) examined. Of 26 girls experiencing menses, 11 (42 %) menstruated at 16-21 months after stopping treatment. Most girls with pretreatment BA/CA≥1.4 started menstruating very close to 18 months after stopping treatment; those with less advanced BA/CA experienced menses at 9-18 months. End-of-treatment BA/CA≥1.2 was associated with a quicker onset of menses (14.5 vs. 18.5 months for BA/CA<1.2, p=0.006). End-of-treatment BA≥12 years predicted longer time to menses. No relationship with time to menses was observed for pretreatment menarche status, pretreatment or end-of-treatment Tanner breast stage (<3/≥3) or CA (<6/≥6 or ≤11/>11), or end-of-treatment BMI percentiles (<85.6/≥85.6 and <92.6/≥92.6)., Conclusions: Pretreatment menarche status or CA do not appear to predict onset of menses, but pre- and end-of-treatment BA/CA may be helpful in anticipating time to first menses after stopping treatment., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Longer-acting gonadotropin-releasing hormone analogs (GnRHa) have been widely used for central precocious puberty (CPP) treatment. However, the follow-up of patients after this treatment are still scarce. Our aim was to describe anthropometric, metabolic, and reproductive follow-up of CPP patients after treatment with leuprorelin acetate 3-month depot (11.25 mg)., Methods: Twenty-two female patients with idiopathic CPP were treated with leuprorelin acetate 3-month depot (11.25 mg). Their medical records were retrospectively evaluated regarding clinical, hormonal, and imaging aspects before, during, and after GnRHa treatment until adult height (AH)., Results: At the diagnosis of CPP, the mean chronological age (CA) was 8.2 ± 1.13 year, and mean bone age (BA) was 10.4 ± 1.4 year. Mean height SDS at the start and the end of GnRHa treatment was 1.6 ± 0.8 and 1.3 ± 0.9, respectively. The mean duration of GnRHa treatment was 2.8 ± 0.8 year. Mean predicted adult heights (PAH) at the start and the end of GnRH treatment was 153.2 ± 8.6 and 164.4 ± 7.3 cm, respectively (p<0.05). The mean AH was 163.2 ± 6.2 cm (mean SDS: 0.1 ± 1). All patients were within their target height (TH) range. There was a decrease in the percentage of overweight and obesity from the diagnosis until AH (39-19% p>0.05). At the AH, the insulin resistance and high LDL levels were identified in 3/17 patients (17.6%) and 2/21 patients (9.5%), respectively. The mean CA of menarche was 12.2 ± 0.5 years. At the AH, PCOS was diagnosed in one patient (4.8%)., Conclusions: Long-term anthropometric, metabolic, and reproductive follow-up of patients with CPP treated with longer-acting GnRHa revealed effectivity, safety, and favorable outcomes., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Little is known about the estrogen exposure measurement and mutual effect of age at menarche and age at menopause in the risk of cardiovascular disease (CVD) events., Objectives: To evaluate estrogen exposure measurement and describe mutual effect of age at menarche and age at menopause in the risk of CVD events., Search Strategy: Systematic review of literature in PubMed, Embase and Web of Science for studies published up to 28 June 2020., Selection Criteria: Observational studies related to estrogen exposure measurement, including mutual effect of age at menarche and age at menopause and risk of CVD events., Data Collection and Analysis: Synthesis of evidence was conducted by reviewing individual estimates, followed by meta-analysis. The study received no external funding., Main Results: A total of 75 studies were included in synthesis of evidence, of which 17 studies were included in meta-analysis. Reproductive lifespan (age at menopause - age at menarche), endogenous estrogen exposure and total estrogen exposure were used for estrogen exposure measurement. Reproductive lifespan was by far the most commonly used method for estrogen exposure measurement. A shorter reproductive lifespan was associated with a higher risk of CVD events; the pooled relative risk (95% CI) was 1.31 (1.25-1.36) for stroke events. Robust epidemiological studies with measurement of estrogen exposure and associated health risk would strengthen the evidence., Conclusions: Reproductive lifespan was the most commonly used method for estrogen exposure measurement in epidemiological studies. A shorter reproductive lifespan was associated with a higher risk of CVD events, particularly stroke., Tweetable Abstract: A systematic review and meta-analysis found that women with a shorter reproductive lifespan have a higher risk of stroke events., (© 2020 John Wiley & Sons Ltd.)

Objective: To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known., Methods: Clinical, laboratory, and genetic data were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the available data to study the impact of gender, puberty, and pregnancy on disease onset and deterioration., Results: We found that disease onset early in life was common in both sexes but there was also a second peak in females around the time of puberty. Further, pregnancy had a negative impact with 10 of 14 women (71%) experiencing disease onset or deterioration during pregnancy., Interpretation: Gender clearly influences the expression of POLG disease. While onset very early in life was common in both males and females, puberty in females appeared associated both with disease onset and increased disease activity. Further, both disease onset and deterioration, including seizure aggravation and status epilepticus, appeared to be associated with pregnancy. Thus, whereas disease activity appears maximal early in life with no subsequent peaks in males, both menarche and pregnancy appear associated with disease onset or worsening in females. This suggests that hormonal changes may be a modulating factor., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Migraine affects 959 million people worldwide,1 with the highest prevalence being in women of childbearing age. The interplay between female hormones and migraine can be a challenging area to navigate since issues relating to pregnancy, contraception and the menopause are often out of the neurology comfort zone. This review aims to help the neurologist to manage women with migraine, from menarche to menopause., Competing Interests: Competing interests: SKA received speaker’s fees and participated in advisory boards for Novartis, Teva and Eli-Lilly., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Previous studies have examined the association between blood lead levels and pubertal timing in adolescent girls; however, the evidence is lacking on the role of lead exposure during sensitive developmental periods on sexual maturation., Objectives: To examine the association of prenatal and early childhood lead exposure with pubertal stages among 264 boys and 283 girls aged 9.8-18.0 years in Mexico City., Methods: We measured maternal bone lead (a proxy for cumulative fetal exposure to lead from maternal bone stores mobilized during pregnancy) at 1 month postpartum. Blood lead was measured annually from 1 to 4 years. Pubertal stage was assessed by a pediatrician. We examined the association between lead and pubertal stages of breast, pubic hair and genitalia using ordinal regression. Age at menarche was evaluated using Cox proportional-hazard models., Results: Multivariate models showed that maternal patella lead and early childhood blood lead were inversely associated with breast growth (patella OR = 0.72, 95% CI: 0.51-1.00; blood OR = 0.70, 95% CI: 0.53-0.93) in girls. Girls with maternal patella lead in the 3rd tertile and child blood lead in the 2nd tertile had a later age at menarche compared with girls in the 1st tertile (patella HR = 0.60, 95% CI: 0.41-0.88; blood HR = 0.65, 95% CI 0.46-0.91). Additionally, early childhood blood lead was negatively associated with pubic hair growth (OR = 0.68, 95% CI: 0.51-0.90) in girls. No associations were found in boys., Conclusions: These data suggest that higher prenatal and early childhood exposure to lead may be associated with delayed pubertal development in girls but not boys. Our findings are consistent with previous analyses and reinforce the reproductive effects of lead for girls., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Animal and cross-sectional epidemiological studies suggest that prenatal lead exposure is related to delayed menarche, but this has not been confirmed in longitudinal studies. We analyzed this association among 200 girls from Mexico City who were followed since the first trimester of gestation. Maternal blood lead levels were analyzed once during each trimester of pregnancy, and daughters were asked about their first menstrual cycle at a visit between the ages of 9.8 and 18.1 years. We estimated hazard ratios (HRs) and 95% confidence intervals (CI) for probability of menarche over the follow-up period using interval-censored Cox models, comparing those with prenatal blood lead level ⩾5 µg/dl to those with prenatal blood lead <5 µg/dl. We also estimated HRs and 95% CI with conventional Cox regression models, which utilized the self-reported age at menarche. In adjusted analyses, we accounted for maternal age, maternal parity, maternal education, and prenatal calcium treatment status. Across trimesters, 36-47% of mothers had blood lead levels ⩾5 µg/dl. Using interval-censored models, we found that during the second trimester only, girls with ⩾5 µg/dl prenatal blood lead had a later age at menarche compared with girls with prenatal blood lead levels <5 µg/dl (confounder-adjusted HR=0.59, 95% CI 0.28-0.90; P=0.05). Associations were in a similar direction, although not statistically significant, in the conventional Cox regression models, potentially indicating measurement error in the self-recalled age at menarche. In summary, higher prenatal lead exposure during the second trimester could be related to later onset of sexual maturation.

Background: The age of menarche has been associated with metabolic and cardiovascular disease, as well as cancer risk. The decline in menarcheal age over the past century may be partially attributable to increased exposure to endocrine disrupting chemicals (EDCs)., Methods: We assessed the influence of 26 phenol and phthalate biomarkers on the timing of menarche in a longitudinal cohort of Chilean girls. These EDCs were quantified in urine collected prior to the onset of breast development (Tanner 1; B1), and during adolescence (Tanner 4; B4). Multivariable accelerated failure time (AFT) models were used to analyze associations between biomarker concentrations and the age of menarche adjusting for body mass index (BMI) Z-score and maternal education, accounting for within-subject correlation., Results: Several biomarkers were significantly associated with the age at menarche; however, these associations were dependent on the timing of biomarker assessment. A log(ng/ml) increase in B1 concentrations of di(2-ethylhexyl) phthalate biomarkers was associated with later menarche (hazard ratio (HR): 0.77; 95% CI: 0.60, 0.98), whereas higher B1 concentrations of 2,5-dichlorophenol and benzophenone-3 were associated with earlier menarche (HR: 1.13; 95% CI: 1.01, 1.27; HR: 1.17; 95% CI: 1.06, 1.29, respectively). Elevated B4 concentrations of monomethyl phthalate were similarly associated with earlier menarche (HR: 1.30; 95% CI: 1.10, 1.53). The impact of monoethyl phthalate and triclosan concentrations on pubertal timing were significantly modified by BMI Z-score. Higher monoethyl phthalate and triclosan concentrations were associated with earlier menarche among overweight or obese girls, but not among those that were normal weight., Conclusions: This study identifies modulation of sexual maturation by specific EDC biomarkers in Latina girls.

Adolescence is an important developmental period of childhood. Good health and adequate nutrition consisting major food constituents and trace elements like zinc are fundamental for optimal sexual maturation. To determine the relationship between zinc levels and pattern of breast and pubic hair development, as well as menarcheal age of female SCA children aged 6-18 years and their matched controls with hemoglobin genotype AA. Cross sectional, case-control study. Information on biodata, age at menarche, medical and drug history as well as 24-hour dietary recall was documented using interviewer administered questionnaire. Sexual maturation was assessed using Tanner staging and zinc levels determined using Atomic absorption spectrophotometer. Eighty-one subjects were compared with 81 controls. There was significant delay in the mean age of attainment of various Tanner stages of breast and pubic hair in the subjects. Mean age of 14.81 ± 1.07 years at menarche in subjects was significantly higher than 12.62 ± 1.18 years in controls (p = 0.001). Serum zinc of 58.01 ± 10.58 µg/dl in subjects was significantly lower than 68.37 ± 8.67 µg/dl in controls (p = 0.001). Serum zinc levels were found to have a significant positive relationship with stages of sexual maturation and mean age at menarche. Reduced serum zinc in children with SCA was associated with delayed sexual maturation.

Background: Tobacco smoke contains known hormonally active chemicals and reproductive toxicants. Several studies have examined prenatal maternal smoking and offspring age at menarche, but few examined earlier pubertal markers, nor accounted for exposure during childhood. Our objective was to examine pre- and postnatal smoke exposure in relation to timing of early pubertal events., Methods: An ethnically diverse cohort of 1239 girls was enrolled at age 6-8 years old for a longitudinal study of puberty at three US sites. Girls participated in annual or semi-annual exams to measure anthropometry and Tanner breast and pubic hair stages. Prenatal and current tobacco smoke exposures, as well as covariates, were obtained from parent questionnaire. Cotinine was measured in urine collected at enrollment. Using accelerated failure time models, we calculated adjusted time ratios for age at pubertal onset (maturation stages 2 or higher) and smoke exposure., Results: Girls with higher prenatal (≥5 cigarettes per day) or secondhand smoke exposure had earlier pubic hair development than unexposed (adjusted time ratio: 0.92 [95% CI = 0.87, 0.97] and 0.94 [95% CI = 0.90, 0.97], respectively). Including both exposures in the same model yielded similar associations. Higher urinary cotinine quartiles were associated with younger age at breast and pubic hair onset in unadjusted models, but not after adjustment., Conclusions: Greater prenatal and childhood secondhand smoke exposure were associated with earlier onset of pubic hair, but not breast, development. These exposures represent modifiable risk factors for early pubertal development that should be considered for addition to the extensive list of adverse effects from tobacco smoke.

Background: Evidence from experimental studies suggests that atrazine and its analytes alter the timing of puberty in laboratory animals. Such associations have not been investigated in humans., Objective: To determine the association between in utero exposure to atrazine analytes and earlier menarche attainment in a nested case-control study of the population-based Avon Longitudinal Study of Parents and Children., Methods: Cases were girls who reported menarche before 11.5 years while controls were girls who reported menarche at or after 11.5 years. Seven atrazine analyte concentrations were measured in maternal gestational urine samples (sample gestation week median (IQR): 12 (8-17)) during the period 1991-1992, for 174 cases and 195 controls using high performance liquid chromatography-tandem mass spectrometry. We evaluated the study association using multivariate logistic regression, adjusting for potential confounders. We used multiple imputation to impute missing confounder data for 29% of the study participants., Results: Diaminochlorotriazine (DACT) was the most frequently detected analyte (58%>limit of detection [LOD]) followed by desethyl atrazine (6%), desethyl atrazine mercapturate (3%), atrazine mercapturate (1%), hydroxyl atrazine (1%), atrazine (1%) and desisopropyl atrazine (0.5%). Because of low detection of other analytes, only DACT was included in the exposure-outcome analyses. The adjusted odds of early menarche for girls with DACT exposures≥median was 1.13 (95% Confidence Interval [95% CI]:0.82, 1.55) and exposure

Perfluoroalkyl substances (PFAS), chemicals used to make products stain and stick resistant, have been linked to health effects in adults and adverse birth outcomes. A growing body of literature also addresses health effects in children exposed to PFAS. This review summarizes the epidemiologic evidence for relationships between prenatal and/or childhood exposure to PFAS and health outcomes in children as well as to provide a risk of bias analysis of the literature. A systematic review was performed by searching PubMed for studies on PFAS and child health outcomes. We identified 64 studies for inclusion and performed risk of bias analysis on those studies. We determined that risk of bias across studies was low to moderate. Six categories of health outcomes emerged. These were: immunity/infection/asthma, cardio-metabolic, neurodevelopmental/attention, thyroid, renal, and puberty onset. While there are a limited number of studies for any one particular health outcome, there is evidence for positive associations between PFAS and dyslipidemia, immunity (including vaccine response and asthma), renal function, and age at menarche. One finding of note is that while PFASs are mixtures of multiple compounds few studies examine them as such, therefore the role of these compounds as complex mixtures remains largely unknown., Competing Interests: The authors declare no conflict of interest.

Previous women's health practitioners and researchers have postulated that some women are particularly sensitive to hormonal changes occurring during reproductive events. We hypothesize that some women are particularly sensitive to hormonal changes occurring across their reproductive lifespan. To evaluate this hypothesis, we reviewed findings from the existing literature and findings from our own lab. Taken together, the evidence we present shows a recurring pattern of hormonal sensitivity at predictable but different times across the lifespan of some women (i.e., menarche, the premenstrual phase, hormonal contraceptive use, pregnancy, the postpartum period, and menopause). These findings provide support for the hypothesis that there is a subgroup of women who are more susceptible to physical, psychological, and sexual symptoms related to hormonal shifts or abrupt hormonal fluctuations that occur throughout the reproductive lifespan. We propose that this pattern reflects a Hormonal Sensitivity Syndrome., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Estrogen replacement therapy in Turner syndrome should theoretically mimic the physiology of healthy girls. The objective of this study was to describe final height and bone mineral density (BMD) in a group of 17 Turner syndrome patients (group E) who started their ethinyl estradiol therapy with an ultra-low dosage (1-5 ng/kg/day) from 9.8-13.7 years. The subjects in group E had been treated with GH 0.35 mg/kg/week since the average age of 7.4 years. The 30 subjects in group L, one of the historical groups, were given comparable doses of GH, and conjugated estrogen 0.3125 mg/week ∼0.3125 mg/day was initiated at 12.2-18.7 years. The subjects in group S, the other historical group, were 21 patients who experienced breast development and menarche spontaneously. Final height (height gain < 2 cm/year) in group E was 152.4 ± 3.4 cm and the standard deviation (SD) was 2.02 ± 0.62 for Turner syndrome. The final height in group L was 148.5 ± 3.0 cm with a SD of 1.30 ± 0.55, which was significantly different from the values for group E. The volumetric BMD of group S (0.290 ± 0.026 g/cm 3 ) was significantly different from that of group L or E (0.262 or 0.262 g/cm 3 as a mean, respectively). This is the first study of patients with Turner syndrome where estrogen was administered initially in an ultra-low dose and then increased gradually. Our estrogen therapy in group E produced good final height but not ideal BMD.

To study potential environmental influences on puberty in girls, we investigated urinary biomarkers in relation to age at menarche. Phenols and phthalates were measured at baseline (6-8 years of age). Menarche was ascertained over 11 years for 1051 girls with menarche and biomarkers. Hazards ratios were estimated from Cox models adjusted for race/ethnicity and caregiver education (aHR, 95% confidence intervals [CI] for 5th vs 1st quintile urinary biomarker concentrations). 2,5-Dichlorophenol was associated with earlier menarche (aHR 1.34 [1.06-1.71]); enterolactone was associated with later menarche (aHR 0.82 [0.66-1.03]), as was mono-3-carboxypropyl phthalate (MCPP) (aHR 0.73 [0.59-0.91]); the three p-trends were <0.05. Menarche differed by 4-7 months across this range. Enterolactone and MCPP associations were stronger in girls with below-median body mass index. These analytes were also associated with age at breast development in this cohort. Findings from this prospective study suggest that some childhood exposures are associated with pubertal timing., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Blepharophimosis syndrome (BPES) is an autosomal dominant genetic condition resulting from heterozygous mutations in the FOXL2 gene and clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure. The distinction between the two forms is critical for female patients, as it may allow to predict fertility and to plan an appropriate therapy. Identifying an underlying causative mutation is not always predictive of the clinical type of BPES since genotype-phenotype correlations are not yet fully delineated. Here, we describe the clinical and hormonal phenotypes of three female patients with BPES type 1 from two novel families, correlate their phenotypes with identified mutations, and investigate the effects of hormone replacement therapy (HRT)., Methods: Clinical, biochemical, and genetic evaluation were undertaken in all the patients and genotype-phenotype correlation was analyzed. The effects of substitutive hormonal therapy on secondary sexual characteristics development and induction of menarche were evaluated., Results: All patients presented with primary amenorrhea or other signs of ovarian dysfunction. Two distinct mutations, a missense p.H104R change and an in-frame p.A222&#95;A231dup10 duplication in the FOXL2 gene were identified. Observed phenotypes were not in accordance with the prediction based on the current genotype-phenotype correlations. HRT significantly improved secondary sexual characteristics development, as well as the induction of menarche., Conclusions: This study highlights the importance of early recognition of BPES and emphasizes the need of personalized therapy and follow-up in female patients carrying distinct FOXL2 mutations.

Background: Early menarche has been linked to risk of several chronic diseases. Prospective research on whether the intake of soft drinks containing caffeine, a modulator of the female reproductive axis, is associated with risk of early menarche is sparse., Objective: We examined the hypothesis that consumption of caffeinated soft drinks in childhood is associated with higher risk of early menarche., Design: The National Heart, Lung, and Blood Institute Growth and Health Study recruited and enrolled 2379 (1213 African American, 1166 Caucasian) girls aged 9-10 y (from Richmond, CA; Cincinnati, OH; and Washington, DC) and followed them for 10 y. After exclusions were made, there were 1988 girls in whom we examined prospective associations between consumption of caffeinated and noncaffeinated sugar- and artificially sweetened soft drinks and early menarche (defined as menarche age <11 y). We also examined associations between intakes of caffeine, sucrose, fructose, and aspartame and early menarche., Results: Incident early menarche occurred in 165 (8.3%) of the girls. After adjustment for confounders and premenarcheal percentage body fat, greater consumption of caffeinated soft drinks was associated with a higher risk of early menarche (RR for 1 serving/d increment: 1.47; 95% CI: 1.22, 1.79). Consumption of artificially sweetened soft drinks was also positively associated with risk of early menarche (RR for 1 serving/d increment: 1.43; 95% CI: 1.08, 1.88). Consumption of noncaffeinated soft drinks was not significantly associated with early menarche (RR for 1 serving/d increment: 0.88; 95% CI: 0.62, 1.25); nor was consumption of sugar-sweetened soft drinks (RR for 1 serving/d increment: 1.15; 95% CI: 0.95, 1.39). Consistent with the beverage findings, intakes of caffeine (RR for 1-SD increment: 1.22; 95% CI: 1.08, 1.37) and aspartame (RR for 1-SD increment: 1.20; 95% CI: 1.10, 1.31) were positively associated with risk of early menarche., Conclusion: Consumption of caffeinated and artificially sweetened soft drinks was positively associated with risk of early menarche in a US cohort of African American and Caucasian girls., (© 2015 American Society for Nutrition.)

Objective: We examined the associations between childhood passive smoking exposure and age at menarche in women who had never smoked in southern China., Methods: Among 30,518 participants in Guangzhou Biobank Cohort Study (GBCS) from 2003-2008, 20,061 women who had never smoked and had complete outcome data were included. Childhood passive smoking exposure was defined as living with 1 or more smokers in the same household during childhood. Data on the number of smokers in the household and frequency of exposure (density and frequency) were also obtained. Age at menarche was measured as a continuous variable., Results: 11,379 (56.7%) participants were exposed to passive smoking during childhood. Compared to those with no passive smoking exposure during childhood, those with exposure ≥ 5 days/week had menarche 0.19 year (95% confidence interval (CI): 0.13-0.25) earlier on average. Those exposed to more than two smokers had menarche 0.38 year earlier (95% CI: 0.29-0.47). Childhood exposure was associated with early age at menarche (≤ 13 vs. >13 years), with an adjusted odds ratio of 1.34 (95% CI: 1.21-1.48) for high density, and 1.17 (95% CI: 1.09-1.26) for high frequency of exposure., Conclusion: Childhood passive smoking exposure was associated with earlier age at menarche, with a dose-response relationship in Chinese women who had never smoked. If causal, the results support the promotion of smoking cessation in families with children, particularly young girls.

Objective: To evaluate the long-term efficacy of triptorelin 3.75 mg subcutaneously every 6 weeks on the final height in girls with idiopathic central precocious puberty (ICPP)., Methods: Forty females with ICPP received triptorelin 3.75 mg every 6 weeks subcutaneously in our hospital from 2002 to December 2010 and reached their final heights were enrolled. These patients were treated with triptorelin alone (group A, n=17) or triptorelin+recombinant human growth hormone (rhGH) (group B, n=23). Height, weight, annual growth velocity (GV), sexual development, predicted adult height (PAH), and adverse effects were observed. Bone age (BA) and height standard deviation score (SDS) were monitored yearly., Results: Final adult heights (FAHs) were 159.81±1.20 cm and 161.01±1.02 cm in group A vs. group B, which exceeded target height (THt) by 1.51±1.04 cm, 4.86±0.94 cm, respectively. The values of (FAH-THt), (FAH-PAH posttreatment) showed significant difference between the two groups (p<0.05). FAH was positively correlated with Ht SDS-BA at the end of treatment, THt, course of rhGH treatment, and age of menarche (r2=0.66). Body mass index (BMI) increased after treatment in group B. However, there was no significant tendency of increase compared with healthy children at the same age. Ages of menarche and time to menarche from discontinuation were 11.74±0.16 vs. 12.18±0.15 years and 17.41±1.69 vs. 14.71±1.04 months in two groups., Conclusion: The FAH was improved effectively by triptorelin 3.75 mg subcutaneously every 6 weeks, and more height gain could be achieved when rhGH was used concomitantly. BMI maintained steadily and ovarian function restored quickly after treatment discontinuation with the age of menarche similar to that of normal children. Neither significant side effect nor polycystic ovary syndrome was observed.

Study Question: Is sugar-sweetened beverage (SSB) consumption associated with age at menarche?, Summary Answer: More frequent SSB consumption was associated with earlier menarche in a population of US girls., What Is Known Already: SSB consumption is associated with metabolic changes that could potentially impact menarcheal timing, but direct associations with age at menarche have yet to be investigated., Study Design, Size, Duration: The Growing up Today Study, a prospective cohort study of 16 875 children of Nurses' Health Study II participants residing in all 50 US states. This analysis followed 5583 girls, aged 9-14 years and premenarcheal at baseline, between 1996 and 2001. During 10 555 person-years of follow-up, 94% (n = 5227) of girls reported their age at menarche, and 3% (n = 159) remained premenarcheal in 2001; 4% (n = 197) of eligible girls were censored, primarily for missing age at menarche., Participants/materials, Setting, Methods: Cumulative updated SSB consumption (composed of non-carbonated fruit drinks, sugar-sweetened soda and iced tea) was calculated using annual Youth/Adolescent Food Frequency Questionnaires from 1996 to 1998. Age at menarche was self-reported annually. The association between SSB consumption and age at menarche was assessed using Cox proportional hazards regression., Main Results and the Role of Chance: More frequent SSB consumption predicted earlier menarche. At any given age between 9 and 18.5 years, premenarcheal girls who reported consuming >1.5 servings of SSBs per day were, on average, 24% more likely [95% confidence interval (CI): 13, 36%; P-trend: <0.001] to attain menarche in the next month relative to girls consuming ≤2 servings of SSBs weekly, adjusting for potential confounders including height, but not BMI (considered an intermediate). Correspondingly, girls consuming >1.5 SSBs daily had an estimated 2.7-month earlier menarche (95% CI: -4.1, -1.3 months) relative to those consuming ≤2 SSBs weekly. The frequency of non-carbonated fruit drink (P-trend: 0.03) and sugar-sweetened soda (P-trend: 0.001), but not iced tea (P-trend: 0.49), consumption also predicted earlier menarche. The effect of SSB consumption on age at menarche was observed in every tertile of baseline BMI. Diet soda and fruit juice consumption were not associated with age at menarche., Limitations, Reasons for Caution: Although we adjusted for a variety of suspected confounders, residual confounding is possible. We did not measure SSB consumption during early childhood, which may be an important window of exposure., Wider Implications of the Findings: More frequent SSB consumption may predict earlier menarche through mechanisms other than increased BMI. Our findings provide further support for public health efforts to reduce SSB consumption., Study Funding/competing Interests: The Growing up Today Study is supported by grant R03 CA 106238. J.L.C. was supported by the Breast Cancer Research Foundation; Training Grant T32ES007069 in Environmental Epidemiology from the National Institute of Environmental Health Sciences, National Institutes of Health; and Training Grant T32HD060454 in Reproductive, Perinatal and Pediatric Epidemiology from the National Institute of Child Health and Human Development, National Institutes of Health. A.L.F. is supported by the American Cancer Society, Research Scholar Grant in Cancer Control. K.B.M. was supported in part by the National Cancer Institute at the National Institutes of Health (Public Health Service grants R01CA158313 and R03CA170952). There are no conflicts of interest to declare., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To clarify the impact of body mass index (BMI) on luteinizing hormone (LH) secretion in response to gonadorelin (GnRH) stimulation testing in girls diagnosed with idiopathic central precocious puberty (ICPP)., Methods: Retrospective single-center cohort study was carried out in 865 confirmed ICPP girls who underwent GnRH stimulation tests. Pubertal development according to Tanner, sex hormone parameters, and LH secretion in response to GnRH-stimulation was compared., Results: Around 609 girls were of normal weight (70.4%), while 168 children (19.4%) were overweight, and 88 (10.2%) were obese. Peak LH levels after GnRH were much higher in the normal-weight group, with a median of 9.1 mIU ml(-1) (interquartile 5.2-13.1), compared with the median peak LH in the overweight and obese groups (8.5 mIU ml(-1), interquartile 5.3-11.6, and 6.2 mIU ml(-1), interquartile 5.3-11.0, respectively P < 0.001 for all comparisons). Peak LH/FSH ratio was also lower in the obese group (median 0.6, interquartile 0.68-0.90) compared with the normal-weight (median 0.8, interquartile 0.61-1.11) and overweight (median 0.8, interquartile 0.64-0.92) groups., Conclusions: Higher BMI is associated with lower LH response to GnRH-stimulation testing in girls with ICPP. It is recommended that BMI should be considered when interpreting GnRH-stimulation tests., (© 2015 The Obesity Society.)

Serenoa repens, commonly known as saw palmetto, is the sole species currently classified in the genus Serenoa. The plant is a low shrubby palm that is native of West Indies, and it grows in the coastal lands of North America and other European mediterranean countries. Its fruits contain high concentrations of fatty acids and phytosterols. S. repens extracts have been studied for the symptomatic treatment of benign prostatic hyperplasia. Recently, they have been proposed to treat androgenic alopecia and other hair disorders. We report a new case of hot flashes in a 10-year-old girl using a food supplement containing the extract of S. repens for the treatment of hirsutism. When the girl discontinued the treatment, the hot flashes stopped. A 'rechallenge' of the supplement was tried and symptoms reappeared. About 4 months after starting therapy, the girl experienced menarche. Exposure to the plant-derived product could be responsible for the appearance of menarche. In our opinion, use of phytotherapeutic agents in pediatric patients should be associated to a better evaluation of benefit/risk profile taking in account the physiological changes that occurs at different ages in this subgroup of population., (© 2015 S. Karger AG, Basel.)

Context: The optimal approach to estrogen replacement in girls with Turner syndrome has not been determined., Objective: The aim of the study was to assess the effects of an individualized regimen of low-dose ethinyl estradiol (EE2) during childhood from as early as age 5, followed by a pubertal induction regimen starting after age 12 and escalating to full replacement over 4 years., Design: This study was a prospective, randomized, double-blind, placebo-controlled clinical trial., Setting: The study was conducted at two US pediatric endocrine centers., Subjects: Girls with Turner syndrome (n = 149), aged 5.0-12.5 years, were enrolled; data from 123 girls were analyzable for pubertal onset., Intervention(s): Interventions comprised placebo or recombinant GH injections three times a week, with daily oral placebo or oral EE2 during childhood (25 ng/kg/d, ages 5-8 y; 50 ng/kg/d, ages >8-12 y); after age 12, all patients received escalating EE2 starting at a nominal dosage of 100 ng/kg/d. Placebo/EE2 dosages were reduced by 50% for breast development before age 12 years, vaginal bleeding before age 14 years, or undue advance in bone age., Main Outcome Measures: The main outcome measures for this report were median ages at Tanner breast stage ≥2, median age at menarche, and tempo of puberty (Tanner 2 to menarche). Patterns of gonadotropin secretion and impact of childhood EE2 on gonadotropins also were assessed., Results: Compared with recipients of oral placebo (n = 62), girls who received childhood low-dose EE2 (n = 61) had significantly earlier thelarche (median, 11.6 vs 12.6 y, P < 0.001) and slower tempo of puberty (median, 3.3 vs 2.2 y, P = 0.003); both groups had delayed menarche (median, 15.0 y). Among childhood placebo recipients, girls who had spontaneous breast development before estrogen exposure had significantly lower median FSH values than girls who did not., Conclusions: In addition to previously reported effects on cognitive measures and GH-mediated height gain, childhood estrogen replacement significantly normalized the onset and tempo of puberty. Childhood low-dose estrogen replacement should be considered for girls with Turner syndrome.

Context: Estrogen is critical for bone formation and growth in women. Estrogen exposures occur throughout life, including prenatally, and change with reproductive events, such as menarche and menopause., Objective: The objective of this study was to investigate the association between age at menarche, age at menopause, and years of menstruation with incidence of osteoporosis and assess the impact of prenatal exposure to diethylstilbestrol (DES), a synthetic estrogen, on such associations., Design, Setting, and Participants: Participants were 5573 women in the National Cancer Institute Combined Cohort Study of DES (1994-2006). Data on reproductive history and medical conditions were collected through questionnaires at baseline in 1994 and subsequently in 1997, 2001, and 2006. Age-stratified Cox regression models were used to calculate multivariable incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Effect measure modification by prenatal DES exposure was assessed using cubic restricted spline regression models., Main Outcome Measure: Osteoporosis was the main outcome measure., Results: The IRRs for osteoporosis incidence with age at menarche less than 11 years and age at menopause of 50 years or younger were 0.82 (CI 0.59, 1.14) and 0.61 (CI 0.40, 0.92), respectively. Fewer than 25 years of menstruation was associated with an increased incidence of osteoporosis (IRR 1.80; CI 1.14, 2.86) compared with 35 years or more of menstruation. Associations were stronger among women who had not been prenatally exposed to DES., Conclusions: Our data support the hypothesis that lifetime cumulative exposure to estrogens is protective against osteoporosis. Furthermore, prenatal exposure to estrogen appears to modify these associations, although the mechanism by which this occurs is unknown.

Purpose: Dental sealant materials may intraorally release their components, including bisphenol-A (BPA), but long-term health effects are uncertain. The New England Children's Amalgam Trial (NECAT) found that composite restorations were associated with psychosocial, but not neuropsychological or physical, outcomes. The previous analysis did not consider sealants and preventive resin restorations (PRRs), which were routinely placed. The purpose of this analysis was to examine sealant/PRR exposure in association with psychosocial and other health outcomes., Methods: NECAT recruited 534 six- to 10-year-olds and provided dental care during a five-year follow-up. Annually, examiners conducted psychosocial and neuropsychological tests and measured body mass index (BMI) and fat percentage (BF%). Associations between surface years (SY) of sealants/PRRs and outcomes were tested using multivariable models., Results: Cumulative exposure level to sealants and/or PRRs was not associated with psychosocial assessments (eg, total problems: Child Behavior Checklist, 10-SY β=-0.2 ± 0.3, P=.60) or neuropsychological tests (eg, full-scale IQ, 10-SY β=0.1 ± 0.2, P=.60). There were no associations for changes in BMI-for-age z-score (P=.40), BF% (girls 10-SY β=-0.2 ± 0.3; boys 10-SY β=-0.1 ± 0.3), or menarche (10-SY hazard ratio=0.91, 95% confidence interval=0.83-1.01, P=.08)., Conclusions: This study showed no associations between exposure level of dental sealants or PRRs and behavioral, neuropsychological, or physical development in children over 5-years.

Study Question: Does prenatal exposure to perfluoroalkyl substances (PFASs) have long-term effects on female reproductive function?., Summary Answer: Our results suggest an association between in utero exposure to perfluorooctanoic acid (PFOA) and delay in age of menarche., What Is Known Already: Previous cross-sectional studies have reported possible effects of PFASs on female reproduction including reduced fecundity, delayed puberty and accelerated age at menopause. Only limited data exist from follow-up studies on long-term implications of prenatal exposure to PFASs., Study Design, Size, Duration: In this study we used data from a Danish population-based cohort established in 1988-1989. Of 1212 eligible pregnant women, 965 participated. Follow-up was initiated in 2008 on the female offspring at ∼20 years of age. Three hundred and sixty seven (84%) daughters answered a questionnaire and 267 (61%) daughters furthermore attended clinical examinations which were conducted in 2008-2009., Participants/materials, Setting, Methods: The final study population consisted of 343 daughters of which 254 had attended the clinical examinations and 89 had answered the questionnaire only. Levels of PFASs in maternal serum from pregnancy week 30 were used as a measure of prenatal exposure and related to age of menarche, menstrual cycle length, levels of reproductive hormones and follicle number of the daughters. Data were divided into three groups according to tertiles of maternal concentrations of PFASs (low, medium, high)., Main Results and the Role of Chance: In adjusted regression analyses, daughters exposed to higher levels of PFOA in utero had a 5.3 (95% confidence interval: 1.3; 9.3) months later age of menarche compared with the reference group of lower PFOA. Crude (P = 0.05) and adjusted (P = 0.01) trend tests also indicated a relationship between higher prenatal PFOA exposure and delay of menarche., Limitations, Reasons for Caution: We did not measure the exact amount of PFASs to which the daughters had been exposed prenatally. Instead we used PFAS concentrations in maternal serum as surrogates. However, PFASs are efficiently transferred to the fetus via placenta. Information on age of menarche was collected retrospectively but the time interval for recall in our study was relatively short (2-10 years). The remaining outcome measures depended on participation in clinical examination which reduced the number of observations leading to limited statistical power and risk of selection bias., Wider Implications of the Findings: Since PFASs can be detected in humans all over the world, effects of prenatal exposure on female reproductive function later in life may have wide health implications., Study Funding/competing Interest(s): The study was supported by the Danish Council for Independent Research (271-05-0296, 09-065631), the Danish Ministry of Interior and Health (0-302-02-18/5), the Danish Council for Strategic Research (09-067124 (Centre for Fetal Programming), 09-063072, 2101-06-0005), the Novo Nordisk Foundation, the Aarhus University Research Foundation, the Frimodt-Heineke Foundation, the Foundation of Maria Dorthea and Holger From, the Beckett-Foundation, the Research Grant of Organon and the Foundation of Lily Benthine Lund. There are no competing interests., Trial Registration Number: Not applicable.

In a recently published prospective study, Villamor et al. found increased risk of early menarche in vitamin D-deficient girls compared to vitamin D-sufficient girls in Bogota, Columbia. The association was not fully explained by differences in body mass index-for-age z-scores. The mechanism for the association, if real, has not been elucidated, but could potentially involve vitamin D receptor polymorphisms. Early menarche and vitamin D deficiency are both associated with poor health outcomes, and further exploration of their association is important for women's health., (© 2013 International Life Sciences Institute.)

Study Question: Does in utero exposure to constituents of cigarette smoke have a programming effect on daughters' age of menarche and markers of long-term reproductive health?, Summary Answer: In utero exposure to constituents of cigarette smoke was associated with earlier age of menarche and--to a lesser extent--changes in the testosterone profile of the young women., What Is Known Already: Studies observe potential effects of in utero exposure to constituents of cigarette smoke on the intrauterine formation of female gonads, but the consequences on long-term reproductive health in daughters remain unclear., Study Design, Size and Duration: A prospective cohort study was designed using data from 965 pregnant women enrolled prior to a routine 30th-week antenatal examination at a midwifery practice in Denmark from 1988 to 1989 and a follow-up of their 19-21-year-old daughters in 2008., Participants/materials, Setting and Methods: The pregnant women provided information on lifestyle factors during pregnancy, including the exact number of cigarettes smoked per day during the first and the second trimesters. A total of 438 eligible daughters were asked to complete a web-based questionnaire on reproductive health and subsequently invited to participate in a clinical examination during 2008. Of the 367 daughters (84%) who answered the questionnaire, 267 (61%) agreed to further examination. Information on menstrual pattern was provided at examination, blood samples were drawn to be analyzed for serum levels of reproductive hormones [FSH, LH, estradiol (E(2)), sex hormone-binding globulin, anti-Müllerian hormone, dehydroepiandrosterone-sulphate (DHEAS), free testosterone and free E(2)] and number of follicles (2-9 mm) were examined by transvaginal ultrasound. The daughters were divided into three exposure groups according to the level of maternal smoking during first trimester [non-exposed (reference), low-exposed (mother smoking >0-9 cigarettes/day) and high-exposed (mother smoking ≥ 10 cigarettes/day)]. Data were analyzed by multiple regression analyses in which we adjusted for potential confounders. Both crude and adjusted test for trend were carried out using maternal smoking during the first trimester as a continuous variable., Main Results and the Role of Chance: We observed an inverse association between in utero exposure to constituents of cigarette smoke and age of menarche (P = 0.001). Daughters exposed to >0-9 cigarettes/day debuted with -2.7 [95% confidence interval (CI) -5.2 to -0.1] percentage earlier age of menarche, whereas daughters exposed to ≥ 10 cigarettes/day had -4.1 (95% CI: -6.6 to -1.5) percentage earlier age of menarche corresponding to 6.5 (95% CI: -10.7 to -2.2) months. There was a non-significant tendency towards lower levels of testosterone and DHEAS with increasing in utero exposure to constituents of cigarette smoke but no associations with follicle number, cycle length or serum levels of the other reproductive hormones were observed., Limitations and Reasons for Caution: We collected information on age of menarche retrospectively but the recall time was relatively short (2-10 years) and the reported values were within the normal range of Caucasians. Analyses of reproductive hormones are presented only for the group of daughters who were non-users of hormonal contraceptives because users were excluded, leaving only a low number of daughters available for the analyses (n = 75), as reflected in the wide CIs. The analyses of hormones were further adjusted for menstrual phase at time of clinical examination (follicular, ovulation and luteal phase) because blood samples were not collected on a specific day of the menstrual cycle., Wider Implications of the Findings: This study supports the limited evidence of an inverse association between maternal smoking during pregnancy and age of menarche and further addresses to what extent reproductive capacity and hormones may be programmed by maternal smoking during pregnancy. A trend toward earlier maturation of females is suggested to have implications on long-term reproductive function., Study Funding/competing Interest(s): Supported by a scholarship from The Lundbeck Foundation (R93-A8476). No conflict of interest declared.

Resin-based composite dental restoration materials may release bisphenol-A, an endocrine-disrupting chemical. Using secondary analysis of a randomized clinical safety trial of amalgam vs. composites, we tested the hypothesis that dental restoration materials affect children's growth. Children (N = 218 boys, N = 256 girls) aged 6 to 10 yrs at baseline with ≥ 2 decayed posterior teeth were randomized to amalgam or composites (bisphenol-A-diglycidyl-dimethacrylate composite for permanent teeth, urethane-dimethacrylate compomer for primary teeth) for treatment of posterior caries throughout follow-up. Primary outcomes for this analysis were 5-year changes in BMI-for-age z-scores, body fat percentage (BF%), and height velocity; exploratory analyses (n = 113) examined age at menarche. Results showed no significant differences between treatment assignment and changes in physical development in boys [(composites vs. amalgam) BF%, 4.9 vs. 5.7, p = 0.49; (BMI-z-score) 0.13 vs. 0.25, p = 0.36] or girls (8.8 vs. 7.7, p = 0.95; 0.36 vs. 0.21, p = 0.49). Children with more treatment on primary teeth had greater increases in BF% regardless of material type. Girls assigned to composites had lower risk of menarche during follow-up (hazard ratio = 0.57, 95% CI 0.35-0.95). Overall, there were no significant differences in physical development over 5 years in children treated with composites or amalgam. Additional studies examining these restoration materials in relation to age at menarche are warranted (clinicaltrials.gov number NCT00065988).

Objectives: To evaluate short-term secular change in menarche and associations with blood lead level in Polish girls between 1995 and 2007., Methods: Menarcheal status of school girls 7-16 years from villages in southwestern Poland was surveyed in 1995, 2001, 2004, and 2007. Blood lead was sampled in 1995 and 2007. Median ages and variance statistics for menarche were estimated with probit analysis. Associations between blood lead level and menarcheal status in 1995 and 2007 were analyzed with logistic regression using blood lead level as an independent binary variable: 2.00-5.00 and ≥5.10 μg/dl., Results: Median ages at menarche declined slightly from 1995 (13.36 ± 0.06 years) to 2001 (13.20 ± 0.04 years), was stable in 2004 (13.20 ± 0.05 years), and declined to 2007 (12.81 ± 0.05 years). Blood lead levels declined from 6.57 ± 0.13 μg/dl in 1995 to 4.24 ± 0.14 μg/dl in 2007. With age, height, and BMI controlled, probability of attaining menarche was not associated with blood lead in 1995, but was decreased with increased blood lead in 2007 (OR 0.31, 95% CI 0.09-1.06, P = 0.057)., Conclusion: Ages at menarche and blood lead levels declined between 1995 and 2007. Higher blood lead levels were not associated with menarche in 1995, suggesting that nutritional and health conditions and perhaps somewhat unstable social and economic conditions in the 1980s and early 1990s may have masked the influence of lead on sexual maturation. Elevated blood lead was associated with the probability of later menarche in 2007, although the association was of borderline (P = 0.06)., (Copyright © 2012 Wiley Periodicals, Inc.)

Objectives: To perform systematic assessment of ovarian reserve markers using a combination of tests in juvenile systemic lupus erythematosus (JSLE) patients without amenorrhoea., Methods: Twenty-seven consecutive JSLE female patients and 13 healthy controls without amenorrhoea were evaluated for 6 months. Ovarian reserve was assessed during early follicular phase by serum levels of follicle stimulating hormone (FSH), luteinising hormone (LH), estradiol, inhibin A, inhibin B and anti-Mullerian hormone (AMH). Ovarian size was measured by abdominal ultrasonography. Demographic data, disease activity, damage and treatment were also analysed., Results: The median of current age was similar in JSLE patients and controls (16.5 vs. 15years, p=0.31) with a significantly higher age at menarche (13 vs. 12years, p=0.03). A trend of lower median total antral follicle count was observed in JSLE compared to controls (9 vs. 14.5, p=0.062) with similar median of other ovarian reserve parameters (p>0.05). Further evaluation of patients treated with cyclophosphamide and those without this treatment revealed a higher median FSH levels (6.4 vs. 4.6 IU/L, p=0.023). Inhibin B, AMH levels and ovarian volume were also lower but did not reach statistical significance (10.8 vs. 27.6 pg/mL, p=0.175; 0.6 vs. 1.5 ng/mL, p=0.276; 3.4 vs. 5 cm3, p=0.133; respectively). LH (2.7 vs. 2.9 IU/L, p=0.43), estradiol (50 vs. 38 pg/mL, p=0.337) and inhibin A (1.1 vs. 0 pg/mL, p=0.489) levels were comparable in both groups., Conclusions: Our study suggests that ovarian reserve after cyclophosphamide treatment may be hampered in spite of the presence of menstrual cycles emphasising the relevance of gonadal protection during the use of this alkylating agent.

Female gender and hormones have been associated with disease activity in multiple sclerosis (MS). We investigated age at menarche, use of oral contraceptives and pregnancy in relation to progression of disability in relapsing onset and progressive onset MS. We conducted a cross-sectional survey among individuals with MS, registered by the Flemish MS Society in Belgium. A time-to-event analysis and Cox proportional hazard regression were performed with time to Expanded Disability Status Score (EDSS) of 6 (requires a cane) as outcome measure. Hazard ratios for the time from onset and the time from birth were adjusted for age at onset and immunomodulatory treatment. Data on 973 women with definite MS were collected. In the relapsing onset group, women with at least two pregnancies had a reduced risk to reach EDSS 6 compared with nulliparous women. In the progressive onset group, later age at menarche was associated with a reduced risk to reach EDSS 6, whereas oral contraceptive use was associated with a higher risk of reaching EDSS 6. Our study corroborates the association of pregnancies with a reduced progression of disability in relapsing onset MS. In progressive onset MS, a slower progression was found in women with a later onset of menarche and a more rapid progression occurred when women reported the use of oral contraceptives.

This study examines the timing of menarche in relation to infant-feeding methods, specifically addressing the potential effects of soy isoflavone exposure through soy-based infant feeding. Subjects were participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Mothers were enrolled during pregnancy and their children have been followed prospectively. Early-life feeding regimes, categorised as primarily breast, early formula, early soy and late soy, were defined using infant-feeding questionnaires administered during infancy. For this analysis, age at menarche was assessed using questionnaires administered approximately annually between ages 8 and 14.5. Eligible subjects were limited to term, singleton, White females. We used Kaplan-Meier survival curves and Cox proportional hazards models to assess age at menarche and risk of menarche over the study period. The present analysis included 2920 girls. Approximately 2% of mothers reported that soy products were introduced into the infant diet at or before 4 months of age (early soy). The median age at menarche [interquartile range (IQR)] in the study sample was 153 months [144-163], approximately 12.8 years. The median age at menarche among early soy-fed girls was 149 months (12.4 years) [IQR, 140-159]. Compared with girls fed non-soy-based infant formula or milk (early formula), early soy-fed girls were at 25% higher risk of menarche throughout the course of follow-up (hazard ratio 1.25 [95% confidence interval 0.92, 1.71]). Our results also suggest that girls fed soy products in early infancy may have an increased risk of menarche specifically in early adolescence. These findings may be the observable manifestation of mild endocrine-disrupting effects of soy isoflavone exposure. However, our study is limited by few soy-exposed subjects and is not designed to assess biological mechanisms. Because soy formula use is common in some populations, this subtle association with menarche warrants more in-depth evaluation in future studies., (Published 2011. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Hyperandrogenemia is associated with several clinical disorders in which both reproductive dysfunction and metabolic changes may coexist [i.e. polycystic ovary syndrome (PCOS), obesity and congenital adrenal hyperplasia]. Moreover, there is growing evidence that the elevated levels of circulating androgens in obese girls may lead to an increased neuroendocrine drive to the reproductive axis, similar to that associated with PCOS., Methods: To test whether androgen exposure in the childhood and adolescent period could lead to pubertal alterations in LH secretory patterns, female rhesus monkeys received subcutaneous testosterone implants prepubertally beginning at 1 year of age, maintaining a 3.7-fold increase (P = 0.001) in circulating testosterone levels over cholesterol-implant controls (n = 6/group) into the post-pubertal period. In early adulthood, pulsatile secretion of LH was measured over 12 h during the early follicular phase of a menstrual cycle, and responsiveness of the pituitary to gonadotrophin-releasing hormone was determined. In addition, ultrasounds were performed to assess ovarian morphology and glucose tolerance testing was performed to assess insulin sensitivity., Results: The timing of menarche was similar between groups. Testosterone-treated animals had a significantly greater LH pulse frequency during the early follicular phase compared with controls (P = 0.039) when measured at 5 years of age. There was a larger LH response to GnRH when testosterone-treated animals were 4 years of age (P = 0.042), but not when the animals were 5 years old (P = 0.57). No differences were seen in insulin sensitivity or ovarian morphology, and the groups showed similar rates of ovulation in early adulthood., Conclusions: Exposure to increased levels of androgens over the course of pubertal development appears to trigger physiological changes in the neural drive to the reproductive axis that resemble those of obese hyperandrogenemic girls in early adulthood and are characteristic of PCOS.

Background: Leptin deficiency leads to midluteal-phase defect or reduced testicular volume in adults, despite normal gonadotropin levels. All children documented to date with leptin deficiency were prepubertal with physiologically low gonadotropins prior to therapy. A direct effect of leptin on pubertal development in a leptin-naive adolescent has not yet been shown., Methods: In 2010, we reported the first connatal leptin-deficient adolescent girl with clinically and chemically proven hypogonadotropic hypogonadism. In this study, we evaluated the effect of recombinant methionyl human leptin substitution., Results: Initially, the patient had prepubertal basal and stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, low growth hormone and insulin-like growth factor 1 (IGF1) levels and no pulsatile secretion of LH and FSH. After 11 weeks of therapy, basal and stimulated LH and FSH levels rose to pubertal values and nocturnal pulsatility was initiated. After 76 weeks of therapy, menstruation occurred at the age of 16.3 years. Pulsatile nocturnal growth hormone secretion, stimulated growth hormone secretion and IGF1 values also normalized., Conclusion: We describe here the first adolescent with hypogonadotropic hypogonadism due to connatal leptin deficiency. Leptin substitution led to a rapid induction of gonadotropin secretion and menarche. These data are further proof of the concept that leptin is needed for a timely maturation of the hypothalamic/pituitary/gonadal axis., (Copyright © 2012 S. Karger AG, Basel.)

Background/aims: With rising cure rates of childhood cancer, side effects of treatment are attracting increasing interest. The present analysis evaluates the influence of tumor localization, radiotherapy and chemotherapy on the age of menarche., Methods: 4,689 former pediatric oncology patients, diagnosed 1980-2004, were contacted in collaboration with the German Childhood Cancer Registry., Results: 1,036 out of 1,461 female participants reported their age at menarche and had an oncological diagnosis before menarche. The median age at menarche was 13 years, compared to 12.8 years in the German general population. A significant delay of menarche was seen in patients with pituitary radiation doses of ≥30 Gy (mean 13.6 years, SD 2.2) compared to <30 Gy (mean 12.5 years, SD 1.4, p = 0.05). Patients with additional spinal radiation were even older at menarche (mean 14.4 years, SD 2.5). Pelvic and pelvic-near radiation significantly delayed onset of menarche (mean 14.0 years, SD 1.9 and mean 14.3, SD 2.6, respectively, p < 0.001). Only some chemotherapeutic agents (carboplatin/cisplatin, etoposide) were associated with a menarcheal delay of <1 year., Conclusion: Overall, female childhood cancer survivors showed a normal menarcheal age. Pituitary radiation dosage of ≥30 Gy, spinal and pelvic radiotherapy were associated with a moderate delay in the occurrence of menarche., (Copyright © 2012 S. Karger AG, Basel.)

Background: Long-term outcome data of central precocious puberty (CPP) girls treated with gonadotropin-releasing hormone analogue (GnRHa) are conflicting., Aim: To assess long-term outcome of girls with idiopathic CPP (iCPP) treated with GnRHa., Methods: We compared adult height (AH), body mass index (BMI) and time of menarche in GnRHa-treated (n = 47) and untreated (n = 11) girls with iCPP., Results: There were no differences in age, bone age, height, weight and BMI z-scores, predicted adult height (PAH) at the time of diagnosis and target height between the two groups. Mean (SD) age of GnRHa-treated girls was 8.5 (1.0) years at the start of treatment. Mean (SD) AH of the treated group was greater [158.6 (5.2) vs. 154.8 (5.6) cm], p < 0.05. AH gain over pre-treatment PAH in the treated group was 4.7 cm. BMI z-score of treated girls was 1.26 (0.95) before the treatment initiated and returned to normal [0.16 (1.0)] at the time of AH reached. Menstruation occurred at 0.9 (0.5) years following GnRHa discontinuation with regular pattern., Conclusions: Long-term GnRHa therapy has a modest beneficial effect on adult height gain in girls with iCPP. No detrimental effects on increasing BMI and hypothalamic-pituitary-gonadal axis reactivation are demonstrated.

Background: Polybrominated diphenyl ethers (PBDEs), widely used as flame retardants since the 1970s, have exhibited endocrine disruption in experimental studies. Tetra- to hexa-BDE congeners are estrogenic, while hepta-BDE and 6-OH-BDE-47 are antiestrogenic. Most PBDEs also have antiandrogenic activity. It is not clear, however, whether PBDEs affect human reproduction., Objectives: The analysis was designed to investigate the potential endocrine disruption of PBDEs on the age at menarche in adolescent girls., Methods: We analyzed the data from a sample of 271 adolescent girls (age 12-19 years) in the National Health and Nutrition Examination Survey (NHANES), 2003-2004. We estimated the associations between individual and total serum BDEs (BDE-28, -47, -99, -100, -153, and -154, lipid adjusted) and mean age at menarche. We also calculated the risk ratios (RRs) and 95% confidence intervals (CI) for menarche prior to age 12 years in relation to PBDE exposure., Results: The median total serum BDE concentration was 44.7ng/g lipid. Higher serum PBDE concentrations were associated with slightly earlier ages at menarche. Each natural log unit of total BDEs was related to a change of -0.10 (95% CI: -0.33, 0.13) years of age at menarche and a RR of 1.60 (95% CI: 1.12, 2.28) for experiencing menarche before 12 years of age, after adjustment for potential confounders., Conclusion: These data suggest high concentrations of serum PBDEs during adolescence are associated with a younger age of menarche., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To study the effects of early metformin treatment on menarche, height, and polycystic ovary syndrome (PCOS) markers. Low-birthweight (LBW) girls with precocious pubarche (PP) are at risk for an early menarche (<12 years), an adult stature below target level, and PCOS. Hyperinsulinemic insulin resistance is thought to be a key factor., Design: Open-label, randomized study., Setting: University hospital., Patient(s): Thirty-eight LBW-PP girls., Intervention(s): At age 8 years, girls were randomly assigned to remain untreated or to receive metformin for 4 years; subsequently, both subgroups were followed without treatment until each girl was postmenarcheal., Main Outcome Measure(s): Age at menarche, height, weight, endocrine-metabolic state (fasting blood), body composition (by absorptiometry), abdominal fat (subcutaneous vs. visceral), and hepatic adiposity (by magnetic resonance imaging)., Result(s): At last assessment, girls in each subgroup were on average 2 years beyond menarche; the mean growth velocity was below 2 cm/years. Age at menarche was 11.4 ± 0.1 years in untreated girls and 12.5 ± 0.2 years in metformin-treated girls; the latter girls were taller and much leaner (with less visceral and hepatic fat) and had more favorable levels of circulating insulin, androgens, and lipids., Conclusion(s): Early metformin therapy (age ∼ 8-12 years) suffices to delay menarche; to augment postmenarcheal height; to reduce total, visceral, and hepatic adiposity; and to curb the endocrine-metabolic course of LBW-PP girls away from adolescent PCOS., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Central precocious puberty (CPP) is defined as pubertal development caused by activation of the hypothalamic-pituitary-gonadal axis before 8 years of age in girls and 9 years in boys. Failure to recognize and/or treat this condition can result in short adult stature., Objective: To determine the etiology, clinical presentation and near-final height (NFH) of Thai children with CPP with or without gonadotropin-releasing hormone analog (GnRHa) treatment., Methods: In a longitudinal observational study, 73 CPP patients who attended Songklanagarind Hospital between 1995 and 2009 were followed up every 3-6 months until they attained their NFH., Results: The etiologies observed were idiopathic CPP, hypothalamic hamartoma and central nervous system diseases. The mean age at time of diagnosis was 6.4 +/- 2.9 years. Bone age was on average 4 years more advanced than chronological age. Of the 52 patients who reached their NFH during the study, 32 were treated with GnRHa and 20 were not. The mean age at menarche was significantly greater for GnRHa-treated than for untreated girls (11.6 +/- 0.8 vs 10.1 +/- 1.1 years, p < 0.001). The median NFH of GnRHa-treated girls was 152.4 +/- 5.2 cm, which was significantly greater than the 144.4 +/- 5.0 cm for untreated girls (p < 0.001)., Conclusion: GnRHa treatment can preserve the genetic height potential of children with CPP.

Background/aims: Untreated girls with Turner syndrome (TS) have growth failure, and adult height is, on average, 20 cm less than predicted height. Treatment with growth hormone (GH) is now standard of care. The objective of this study was to investigate the benefit of adding oxandrolone (Ox) to GH in a long-term, randomized, placebo (Pl)-controlled prospective trial to near adult height in TS., Methods: prospective, randomized, Pl-controlled study: 76 girls with TS (ages 10-14.9 years) were randomized to receive Ox (0.06 mg/kg/day) or Pl in combination with GH (0.35 mg/kg/week, daily) over 2 years. Auxologic data, breast and pubic hair Tanner stages, and hormone and lipid levels were measured. Subjects who chose to continue were followed in a 2-year double-blind extension, also received estrogen therapy (years 3, 4), and had dual-energy X-ray absorptiometry evaluation of bone density (years 3, 4)., Results: at year 4, the change in absolute height and height SDS was greater in the GH/Ox versus GH/Pl group [26.2 ± 6.7 vs. 22.2 ± 5.1 cm, analysis of covariance (ANCOVA) p < 0.001; 1.8 ± 0.9 vs. 1.2 ± 0.7 standard deviation scores, ANCOVA p < 0.001]. Bone mineral density (BMD) of the wrist (0.51 ± 0.17 vs. 0.54 ± 0.05 g/cm(2)) and spine (0.91 ± 0.34 vs. 0.96 ± 0.13 g/cm(2)) in the GH/Ox versus GH/Pl groups was similar after 4 years. Breast development was slower in the GH/Ox versus GH/Pl group [year 4: Tanner stage 2.9 ± 1.3 (Ox) vs. 4.1 ± 1.3 (Pl), p = 0.003], and menarche was approximately 1 year later., Conclusions: the addition of Ox to GH at mean age 12.0 ± 1.7 year augmented height gain after 4 years of treatment, slowed breast development and did not affect BMD in girls with TS. Whether initiation of Ox prior to initiation of pubertal development would optimize height gain without impeding breast development will require further study., (2010 S. Karger AG, Basel.)

Introduction: Polyfluoroalkyl chemicals (PFCs) are commercially synthesized chemicals used in consumer products. Exposure to certain PFCs is widespread, and some PFCs may act as endocrine disruptors. We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) in the United Kingdom to conduct a nested case-control study examining the association between age at menarche, and exposure to PFCs during pregnancy., Methods: Cases were selected from female offspring in the ALSPAC who reported menarche before the age of 11.5 years (n = 218), and controls were a random sample of remaining girls (n = 230). Serum samples taken from the girls' mothers during pregnancy (1991-1992) were analyzed using on-line solid-phase extraction coupled to isotope dilution high-performance liquid chromatography-tandem mass spectrometry for 8 PFCs. Logistic regression was used to determine association between maternal serum PFC concentrations, and odds of earlier age at menarche., Results: PFOS and PFOA were the predominant PFCs (median serum concentrations of 19.8 ng/mL and 3.7 ng/mL). All but one PFC were detectable in most samples. Total PFC concentration varied by number of births (inverse association with birth order; p-value < 0.0001) and race of the child (higher among whites; p-value = 0.03). The serum concentrations of carboxylates were associated with increased odds of earlier age at menarche; concentrations of perfluorooctane sulfonamide, the sulfonamide esters and sulfonates were all associated with decreased odds of earlier age at menarche. However, all confidence intervals included the null value of 1.0., Conclusions: ALSPAC study participants had nearly ubiquitous exposure to most PFCs examined, but PFC exposure did not appear to be associated with altered age at menarche of their offspring., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: We assessed whether exposure to prenatal smoking or alcohol accelerates age of menarche (AOM) in offspring., Methods: We studied a Danish cohort of 3169 singleton females born in April 1984-April 1987. Linear regressions were conducted to examine associations between prenatal smoking or alcohol exposure and offspring's AOM on: (i) the daughters who provided data on both month and the year of menarche (n= 1634) and (ii) the entire sample that provided at least the year of menarche (n= 3169). We also examined associations between only pre-pregnancy smoking or childhood exposure to smoking and AOM. The full model was adjusted for maternal pre-pregnancy body mass index, maternal age at childbirth, parental socio-economic status, parity, consumption of milk products during pregnancy and marital status., Results: Among those who provided both year and month, AOM was accelerated by 2.8 months (95% CI in months: -5.3, -0.4) among those exposed to 10+ cigarettes/day throughout pregnancy and by 4.1 months (95% CI in months: -7.7, -0.5) among those with mothers who quit smoking sometime during pregnancy, compared with the unexposed group after adjustment for covariates. Similar, but much weaker, associations were observed among girls whose mothers smoked 1-9 cigarettes/day throughout pregnancy or whose fathers smoked compared with their unexposed counterparts after adjustment for covariates [-0.8 months (95% CI: -2.6, 1.0)]. No associations were observed between AOM and only pre-pregnancy smoking or only childhood exposure or prenatal alcohol exposure., Conclusions: Our study indicates that heavy smoking throughout the pregnancy may be important in prenatal programming of AOM.