Puberty in girls with Prader-Willi syndrome: cohort evaluation and clinical recommendations in a Latin American tertiary center.

Introduction: Prader-Willi syndrome (PWS) is a genetic disorder characterized by hypothalamic-pituitary deficiencies including hypogonadism. In girls with PWS, hypogonadism can present early in childhood, leading to genital hypoplasia, delayed puberty, incomplete pubertal development, and infertility. In contrast, girls can present with premature activation of the adrenal axis leading to early pubarche and advanced bone age. We aim to evaluate the progression of puberty and adrenarche signals in girls with PWS. Methodology: A longitudinal retrospective cohort study included girls with PWS followed at a Pediatric Endocrinology Outpatient Clinic in a Tertiary University Hospital in Sao Paulo, Brazil from 2002 to 2022. Data collected via chart review included clinical information on birth history, breast and pubic hair Tanner stages, presence of genital hypoplasia, age at menarche, regularity of menstrual cycles, body mass index (BMI) z-score, final height, age of initiation of estrogen replacement and growth hormone replacement, as well as results for PWS genetic subtype; biochemical investigation (LH, FSH, estradiol, DHEA-S); radiographic bone age and pelvic ultrasound. Results: A total of 69 girls were included in the study and the mean age of puberty onset was 10.2 years in those who started puberty after the age of 8 years. Breast Tanner stage IV was reached by 29.1% girls at a mean age of 14.9 years. Spontaneous menarche was present in 13.8% and only one patient had regular menstrual cycles. Early adrenarche was seen in 40.4% of cases. Conclusion: Our study demonstrated in a large sample that girls with PWS often present with delayed onset of puberty despite frequent premature adrenarche. Based on our results, we suggest an estrogen replacement protocol for girls with PWS to be started at the chronological age or bone age of 12-13 years, taking into consideration the uterus size. Further prospective studies are needed.

Pelvic ultrasound and pubertal attainment in girls with sexual precocity: the pivotal role of uterine volume in predicting the timing of menarche.

Introduction: Among girls assessed for pubertal precocity, pelvic ultrasound (pUS) may represent a pivotal tool to predict the time expected to elapse between sonographic assessment and the onset of menarche (TUS-M). Accordingly, the present analysis is meant to define the statistical relationship between sonographic parameters and TUS-M, in order to identify the most reliable predictor of the timing of menarche. Methods: Retrospective, multicenter analysis. Girls assessed for sexual precocity and showing sonographic and clinical findings consistent with pubertal onset upon referral were considered eligible. Patients treated with GnRH analogues were excluded and only those who had subsequently achieved complete and spontaneous pubertal attainment and for whom the exact date of menarche was available were included. Overall, we enrolled 184 girls from five tertiary care Italian Centers. Results: The time elapsed (months) between baseline endocrine assessment and spontaneous achievement of menarche showed a negative statistically significant correlation (p<0.0001) with LH (r:-0.61), FSH (r:-0.59), estradiol (r:-0.52) and stimulated LH values (r:-0.58). Among pUS parameters, ovarian volume (r:-0.17 left, -0.30 right) and uterine body-to-cervix ratio (r:-0.18) poorly correlated with TUS-M, while uterine diameters (r:-0.61 longitudinal, -0.64 anteroposterior) and volume (r:-0.70) achieved a highly statistical significance (p<0.0001). Uterine volume (UV) showed a negative logarithmic relationship with TUS-M and represented the most reliable predictor of the timing of menarche in uni- and multivariable analyses (p <0.001). ROC analyses identified the UV thresholds that best predict the onset of menarche within 18, 12 and 6 months, respectively: 3.76, 6.02 and 8.80 ml. Conclusion: The logarithm of UV shows the best statistical performance in predicting the timing of menarche in girls assessed for pubertal precocity. Accordingly, we developed a user-friendly online application that provides clinicians with an estimation of the months expected to elapse before menarche, based on the UV recorded upon pUS.

Body Mass Index and Hypertension as Mediators of the Association Between Age at Menarche and Subclinical Atherosclerosis: A Sex-Specific Mendelian Randomization Analysis.

BACKGROUND: Early age at menarche (AAM) has been associated with a higher risk of carotid artery intima-media thickness (cIMT), an indicator of subclinical vascular disease, albeit the mechanisms underlying this association remain elusive. A better understanding of the relationship between AAM, modifiable cardiometabolic risk factors, and subclinical atherosclerosis may contribute to improved primary prevention and cardiovascular disease treatment. We aimed to investigate the putative causal role of AAM on cIMT, and to identify and quantify the potentially mediatory effects of cardiometabolic risk factors underlying this relationship. METHODS AND RESULTS: We conducted linkage disequilibrium score regression analyses between our exposure of interest, AAM, our outcome of interest, cIMT and potential mediators of the AAM-cIMT association to gauge cross-trait genetic overlap. We considered as mediators the modifiable anthropometric risk factors body mass index (BMI), systolic blood pressure (SBP), lipid traits (total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), and glycemic traits (fasting glucose). We then leveraged the paradigm of Mendelian randomization to infer causality between AAM and cIMT, and to identify whether cardiometabolic risk factors served as potential mediators of this effect. Our analyses showed that genetically predicted AAM was inversely associated with cIMT, BMI, SBP, and triglycerides, and positively associated with high-density lipoprotein, low-density lipoprotein, and total cholesterol. We showed that the effect of genetically predicted AAM on cIMT may be partially mediated through BMI (20.1% [95% CI, 1.4% to 38.9%]) and SBP (13.5% [95% CI, 0.5%-26.6%]). Our cluster-specific Mendelian randomization revealed heterogeneous causal effect estimates of age at menarche on BMI and SBP. CONCLUSIONS: We highlight supporting evidence for a potential causal association between earlier AAM and cIMT, and almost one third of the effect of AAM on cIMT may be mediated by BMI and SBP. Early intervention aimed at lowering BMI and hypertension may be beneficial in reducing the risk of developing subclinical atherosclerosis due to earlier age at menarche.

Reproductive history is associated with functional disabilities and symptoms in women with knee osteoarthritis: a case-control study.

OBJECTIVES: Studies that have examined the correlation between reproductive history and knee osteoarthritis (KOA) have had heterogeneous findings. We aimed to investigate the reproductive history and its relationship with pain and physical dysfunction in women with KOA. This case-control study, comprising 204 women aged 50 and older with and without KOA recruited through random cluster sampling, was executed from February 2018 to October 2018 in the health centers of Tabriz City. The reproductive history questionnaire was completed for the subjects in two groups. Pain intensity and functional dysfunction caused by KOA were evaluated using the Visual analogue scale and the Western Ontario and McMaster index, respectively. RESULTS: The women's age of menarche in the case group was significantly lower (p = 0.031), and the number of pregnancies (p = 0.017) and the average duration of breastfeeding (p = 0.039) were substantially higher than those of the control group. Older age at the first menstruation (OR = 0.851) was a protective factor, and higher parity (OR = 8.726) was a risk factor for KOA. In the women with KOA, the younger age of the mother at the birth of the first alive baby and the longer duration of breastfeeding were associated with higher pain intensity and functional disorders.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Association between 25-hydroxyvitamin D concentrations and pubertal timing: 6-14-year-old children and adolescents in the NHANES 2015-2016.

Background: The association between 25(OH)D and pubertal timing has not been well studied. The aim of this study was to assess the relationship between 25(OH)D levels and pubertal timing in children. Methods: Participants aged 6-14 years who had available nutritional and serum sex hormone (total testosterone (TT) and estradiol (E2)) information (n =1318) were included. We conducted a cross-sectional analysis of the associations between 25(OH)D and sex steroid hormones among children in the National Health and Nutrition Examination Survey, 2015-2016. Puberty was indicated by high levels of steroid hormones (TT≥50 ng/dL in men, E2≥20 pg/ml in women) or menarche. Results: Serum 25(OH)D and pubertal status showed the same trend in both males and females. In the male population, the OR values of serum 25(OH)D between 50 and <75 and ≥75 nmol/L were 0.52 (0.25, 1.08) and 0.64 (0.23, 1.75), respectively, compared with serum 25(OH)D<50 nmol/L. The OR of serum 25(OH)D ≥50 nmol/L compared with <50 nmol/L was 0.54 (0.26, 1.10), and the P value was statistically significant (P=0.048). In the female population, when the serum 25(OH)D concentration was <50 nmol/L, the ORs corresponding to a serum 25(OH)D concentration between 50 and <75 and ≥75 nmol/L were 0.53 (0.29, 0.98) and 0.50 (0.19, 1.30), respectively. The OR of serum 25(OH)D≥50 nmol/L compared with <50 nmol/L was 0.52 (0.19, 0.96), and the P value was statistically significant (P=0.037). Conclusions: A lower 25(OH)D level was associated with earlier puberty in both girls and boys. There was a negative association between 25(OH)D concentrations and pubertal timing.

Early Puberty Trend during the COVID-19 Pandemic in Singapore: A Retrospective Review in a Single Tertiary Centre.

Objectives: We aimed to study the trend of referrals for precocious puberty during the COVID-19 pandemic compared to pre-COVID years, explore the differences in the demographic and clinical features, and evaluate the contributing factors. Methodology: The cases referred for assessment of PP from 2018-2021 to our endocrine centre were grouped into pre-COVID (2018-2019) and COVID (2020-2021) years. Cases fulfilling the diagnosis of PP included the onset of thelarche <8 years in females and 4 ml testicular volume <9 years in males. The PP was further differentiated as Isolated Thelarche (IST) and Central Precocious Puberty (CPP). Early menarche was defined as menarche <10 years old. Results: There were more referrals for PP and more diagnosed as CPP during the COVID-19 pandemic, predominantly among females. There were more endocrine tests done and more cases received treatment. None of the abnormal magnetic resonance imaging (MRI) pituitary findings required surgical intervention. The body mass index (BMI) was found to be positively associated with the risk of getting CPP with a crude-odd ratio (COR) of 1.8, P <0.001, and early menarche (COR 2.1, P <0.001). Conclusion: We found a significant increase in the referrals of PP and diagnosis of CPP during the COVID-19 pandemic. Higher BMI was found to be associated with CPP and early menarche.

Does timing of sexual debut following menarche among female youth in Uganda matter? A discrete time analysis.

BACKGROUND: The burden of early sexual engagement among youth is enormous. It directly raises the risk of sexually transmitted infections(STIs) and indirectly contributes to unintended pregnancy, unsafe abortion, premature childbirth, and psychosocial issues. The aim of this paper was to estimate the timing of sexual debut and examine the factors influencing the timing of first sexual intercourse following menarche among female youth aged between 15 and 24 in Uganda. METHOD: Self-reported data were extracted from the 2016 Uganda Demographic and Health Survey (UDHS), with a sub-sample of 7964 female youth from the individual woman file. Kaplan-Meier survival curves, decrement life-table analysis, and the discrete-time logit model were used to examine the timing of sexual debut and associated factors. RESULTS: 67.4% of the female youth had experienced first sexual initiation. Overall, the meantime to sexual debut was 4.4 years and the median time was 4.3 years, and all the female youth had experienced first sexual initiation by the end of the twelfth year following menarche. Significant factors found to influence the timing of sexual initiation include having higher education level (OR = 0.724: 95% CI = 0.59-0.89; p = 0.003), residing in the Northern region (OR = 0.877:95% CI = 0.79-0.97, p = 0.012), being employed (OR = 1.085: 95% CI = 1.01-1.16; p = 0.021), and being literate (OR = 1.155; 95% CI = 1.07-1.25; p < 0.001). CONCLUSIONS: These findings are expected to be central in the bid to delay first sexual intercourse. Also they shed light on some of the factors associated with the timing of sexual debut which may be addressed at community level for non-school going youth and in schools, as school based prevention sexual and reproductive health programs. The findings highlight the need for future studies to collect more data to explore further the linkage between time to first debut since menarche and, mass media, religion, type of residence, and wealth index.

Association of early menarche with breast tumor molecular features and recurrence.

BACKGROUND: Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear. METHODS: We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses' Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952). RESULTS: Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN α and IFN γ ). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (ß = 0.082 [0.02-0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18-2.85] and HER2-enriched, OR = 2.32 [1.46-3.69]), and PAM50 risk of recurrence score (ß = 4.81 [1.71-7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10-2.25]). CONCLUSIONS: Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies.

Early Menarche as a Protective Factor Against Cardiovascular Events: A Systematic Review and Meta-analysis.

BACKGROUND: Women are often neglected in cardiovascular health prevention. Age at menarche (AAM) has been linked to cardiovascular (CVD) disease in women and is potentially identified as one of the significant CVD risk factor. However, there is still limited comprehensive evidence addressing this issue. This systematic review and meta-analysis aimed to investigate how early menarche affects the outcome of all-cause mortality, CVD mortality, total cardiovascular disease event, stroke (ischemic, hemorrhagic, and total stroke), and coronary heart disease (CHD). METHOD: The Cochrane Library, MEDLINE, Embase, ScienceDirect, and Google Scholar databases were searched from March 2013 to March 2023 for cohorts investigating the effect of early onset of menarche on CVD events with a minimum follow-up period of 5 years. Studies that observed specific population and/or included women with a history of CVD at baseline were excluded. The Newcastle-Ottawa scale was used for risk of bias assessment for each cohort included. The data were presented as dichotomous measure using risk ratios. I2 statistics were utilized to evaluate the heterogeneity of presented data. RESULTS: Thirteen cohorts included 18 626 799 female patients with ages ranging from 43 to 62.6 years. These reported 6 estimates each for CHD (5 483 298 patients) and all-cause mortality (1 595 878 patients), 5 estimates each for total stroke (2 941 321 patients) and CVD mortality (1 706 742 patients), 4 estimates each for total CVD events (3 988 311 patients) and ischemic stroke (2 434 580 patients), and 1 estimate for hemorrhagic stroke (66 104 patients). Our study found that events of CHD were significantly lower in early menarche (RR 0.57; 95% CI 0.41-0.78; P <.00001), as well as total stroke (RR 0.51; 95% CI 0.35-0.73; P =.0003), CVD mortality (RR 0.47; 95% CI 0.22-0.98; P =.04), total CVD events (RR 0.44; 95% CI 0.25-0.76; P =.003), ischemic stroke (RR 0.31; 95% CI 0.15-0.61; P <.0008), and hemorrhagic stroke (RR 0.12; 95% CI 0.07-0.20; P <.00001); and insignificantly higher in all-cause mortality (RR 0.90, 95% CI 0.76-1.06, P =.20). CONCLUSION: In our study, cardiovascular events are lower in women with early menarche; hence, the later age of menarche is a potential risk factor to be considered when assessing CVD risk in a patient. However, our sample characteristics were heterogenous, and we did not consider other female hormonal factors that might potentially contribute to the CVD outcomes observed; thus, further studies are needed to clarify.

Association between depression and young-onset dementia in middle-aged women.

BACKGROUND: Dementia is associated with older adults; however, it can also affect younger individuals, known as young-onset dementia (YOD), when diagnosed before the age of 65 years. We aimed to conduct a retrospective cohort study involving middle-aged women to investigate the association between premorbid depression and YOD development. METHODS: We included 1.6 million women aged 40-60 years who underwent health checkups under the Korean National Health Insurance Service and investigated the association between depression and YOD. RESULTS: Women with depression had a significantly higher risk of developing YOD than women without depression. Among premenopausal women, those with depression had a 2.67-fold increased risk, whereas postmenopausal women with depression had a 2.50-fold increased risk. Late age at menarche (> 16 years) and young age at menopause (< 40 years) was associated with an increased risk of YOD. CONCLUSIONS: Depression in middle-aged women is a significant risk factor for the development of YOD. Understanding the role of reproductive factors can aid in the development of targeted therapeutic interventions to prevent or delay YOD.

Temporal trend of age at menarche in Korean females born between 1927 and 2004: a population-based study.

Backgrounds: The age at menarche has decreased worldwide. Previous studies on Korean adolescents have reported a downward trend in age at menarche. This study aimed to investigate the current trends in age at menarche among Korean adolescents using nationally representative data. Materials and methods: The study used data from the Korea National Health and Nutrition Examination Survey 2007-2021. A total of 50,730 females born between 1927 and 2004 with information on age at menarche were included. The trend in age at menarche was analyzed according to 15 birth-year groups (with 5-year intervals) using quantile regression analysis. Results: The mean age at menarche decreased from 16.92 ± 0.06 years for females born before 1935 to 12.45 ± 0.04 years for females born between 2000 and 2004 (p <.001). According to the percentile group of age at menarche, mean menarche age decreased by -0.071 years per year (95% confidence interval [CI], -0.072 to -0.070) in total, -0.050 years per year (95% CI, -0.052 to -0.048) in the 3rd percentile group, -0.088 years per year (95% CI, -0.091 to -0.085) in the 97th percentile group (p <.001 for all). A decreasing trend of age at menarche was more prominent in the obesity group (-0.080 years per year, 95% CI, -0.082 to -0.078) compared to the non-obesity group (-0.069 years per year, 95% CI, -0.071 to -0.068) (p <.001 for both). Conclusion: Ongoing downward trend in age at menarche was observed in Korean females born until 2004, decreasing by 0.71 years per decade. The downward trend was faster in individuals with a higher percentile of age at menarche and in those with obesity.

Maternal exposure to polycyclic aromatic hydrocarbons during pregnancy and timing of pubertal onset in a longitudinal mother-child cohort in rural Bangladesh.

BACKGROUND: In experimental studies, several polycyclic aromatic hydrocarbons (PAHs) have shown endocrine disrupting properties, but very few epidemiological studies have examined their impact on pubertal development and results have been heterogenous. OBJECTIVE: To explore if maternal PAH exposure during pregnancy was associated with the offspring's timing of pubertal onset. METHODS: We studied 582 mother-daughter dyads originating from a population-based cohort in a rural setting in Bangladesh. Maternal urinary samples, collected in early pregnancy (on average, gestational week 8), were analyzed for monohydroxylated metabolites of phenanthrene (1-OH-Phe, Σ2-,3-OH-Phe, and 4-OH-Phe), fluorene (Σ2-,3-OH-Flu), and pyrene (1-OH-Pyr) using liquid chromatography with tandem mass spectrometry (LC-MS/MS). The girls were interviewed on two separate occasions concerning date of menarche, as well as breast and pubic hair development according to Tanner. Associations were assessed using Kaplan-Meier analysis and multivariable-adjusted Cox proportional hazards regression or ordered logistic regression. RESULTS: In early pregnancy, the mothers' median urinary concentrations of Σ1-,2-,3-,4-OH-Phe, Σ2-,3-OH-Flu, and 1-OH-Pyr were 3.25 ng/mL, 2.0 ng/mL, and 2.3 ng/mL respectively. At the second follow-up, 78 % of the girls had reached menarche, and the median age of menarche was 12.7 ± 0.81 years. Girls whose mothers belonged to the second and third quintiles of ΣOH-Phe metabolites had a higher rate of menarche, indicating a younger menarcheal age (HR 1.39; 95 % CI 1.04, 1.86, and HR 1.41; 95 % CI 1.05, 1.88, respectively), than girls of mothers in the lowest quintile. This trend was not observed in relation to either breast or pubic hair development. None of the other maternal urinary PAH metabolites or the sum of all thereof in early pregnancy were associated with age at menarche or pubertal stage. CONCLUSIONS: Indications of non-monotonic associations of prenatal phenanthrene exposure with the daughters' age of menarche were found, warranting further investigation.

Strong evidence supports the use of estradiol therapy for the treatment of vaginal inflammation: a two-way Mendelian randomization study.

OBJECTIVE: Nowadays, there has been limited Mendelian randomization (MR) research focusing on the causal relationship between estradiol and vaginitis. Therefore, this study conducted a two-way MR study to clarify the causal effect and related influencing factors between them. METHODS: All genetic datasets were obtained using publicly available summary statistics based on individuals of European ancestry from the IEU GWAS database. MR analysis was performed using MR-Egger, weighted median (WM) and inverse variance weighted (IVW) methods to assess the causal relationship between exposure and outcome and to validate the findings by comprehensively evaluating the effects of pleiotropic effects and outliers. RESULTS: MR analysis revealed no significant causal relationship between estradiol and vaginitis risk. There was a negative correlation between estradiol and age at menarche (IVW, OR: 0.9996, 95% CI: 0.9992-1.0000, P = 0.0295; WM, OR: 0.9995, 95% CI: 0.9993-0.9998, P = 0.0003), and there was a positive correlation between age at menarche and vaginitis (IVW, OR: 1.5108, 95% CI: 1.1474-2.0930, P = 0.0043; MR-Egger, OR: 2.5575, 95% CI: 1.7664-9.6580, P = 0.0013). Estradiol was negatively correlated with age at menopause (IVW, OR: 0.9872, 95% CI: 0.9786-0.9959, P = 0.0041). However, there was no causal relationship between age at menopause and vaginitis (P > 0.05). In addition, HPV E7 Type 16, HPV E7 Type 18, and Lactobacillus had no direct causal effects on estradiol and vaginitis (P > 0.05). Sensitivity analyses revealed no heterogeneity and horizontal pleiotropy. CONCLUSION: When estrogen levels drop, it will lead to a later age of menarche, and a later age of menarche may increase the risk of vaginitis, highlighting that the longer the female reproductive tract receives estrogen stimulation, the stronger the defense ability is formed, and the prevalence of vaginitis is reduced. In conclusion, this study indirectly supports an association between reduced level of estrogen or short time of estrogen stimulation and increased risk of vaginitis.

Association between BMI and age at menarche or spermarche among both sexes: Findings from six successive national surveys in China.

Background: To explore trends of the association between body mass index (BMI) and age at menarche or spermarche and its urban-rural disparities from 1995 to 2019. Methods: A total of 912 753 children and adolescents - including 519 940 9-18 years old girls and 392 813 11-18 years old boys - were involved in six successive cross-sectional surveys conducted across 30 provinces in China from 1995 to 2019. Data on menarche and spermarche was collected using the status quo method, where same-gender physicians conducted face-to-face interviews to determine if children and adolescents had experienced their first menstrual cycle or ejaculation (yes/no). The median age at menarche or spermarche was estimated by probit analysis. Anthropometric measurements measured the height and weight of the study subjects. Children and adolescents were classified into thinness, normal range of weight, overweight, and obesity. t test was used to compare the differences in BMI between premenarchal and postmenarchal girls or prespermarcheal and postspermarcheal boys. Logistic regression was used to explore the associations between BMI/nutritional status and menarche or spermarche stratified by urban or rural residency status. Results: From 1995 to 2019, BMI in all age groups growth over time, and the values of BMI among children and adolescents under 15 who had menarche or spermarche were more significant than those without menarche or spermarche. In 2019, for girls, thinness was associated with delayed menarche (odds ratio (OR) = 0.26; 95% confidence interval (CI) = 0.24-0.28), while overweight (OR = 1.99; 95% CI = 1.85-2.14) and obesity (OR = 2.20; 95% CI = 1.92-2.53) was associated with advanced menarche. For boys, thinness was associated with delayed spermarche (OR = 0.71; 95% CI = 0.65-0.78), overweight was associated with advanced spermarche (OR = 1.08; 95% CI = 1.01-1.15) while obesity had no association with spermarche. The OR between BMI and menarche in 1995 was 1.35 (95% CI = 1.33-1.37), which decreased to 1.19 (95% CI = 1.18-1.20) by 2019. The OR between BMI and spermarche in 1995 was 1.10 (95% CI = 1.09-1.11), which decreased to 1.02 (95% CI = 1.02-1.03) by 2019. The trends by urban-rural stratification were consistent with the total sample. Conclusions: We have established a dose-response relationship between BMI and menarche in girls, whereas the association appears to be nonlinear in boys, and the associations were diminishing. Similar findings were observed in both urban and rural areas. Considering the dual adverse effects of obesity and early puberty on health, the results of this study suggest that sexual health education should be strengthened, especially among obese girls. Further research on the influencing factors and biological mechanisms of early puberty will be beneficial.

A causal examination of the correlation between hormonal and reproductive factors and low back pain.

Background: The relationship between hormonal fluctuations in the reproductive system and the occurrence of low back pain (LBP) has been widely observed. However, the causal impact of specific variables that may be indicative of hormonal and reproductive factors, such as age at menopause (ANM), age at menarche (AAM), length of menstrual cycle (LMC), age at first birth (AFB), age at last live birth (ALB) and age first had sexual intercourse (AFS) on low back pain remains unclear. Methods: This study employed Bidirectional Mendelian randomization (MR) using publicly available summary statistics from Genome Wide Association Studies (GWAS) and FinnGen Consortium to investigate the causal links between hormonal and reproductive factors on LBP. Various MR methodologies, including inverse-variance weighted (IVW), MR-Egger regression, and weighted median, were utilized. Sensitivity analysis was conducted to ensure the robustness and validity of the findings. Subsequently, Multivariate Mendelian randomization (MVMR) was employed to assess the direct causal impact of reproductive and hormone factors on the risk of LBP. Results: After implementing the Bonferroni correction and conducting rigorous quality control, the results from MR indicated a noteworthy association between a decreased risk of LBP and AAM (OR=0.784, 95% CI: 0.689-0.891; p=3.53E-04), AFB (OR=0.558, 95% CI: 0.436-0.715; p=8.97E-06), ALB (OR=0.396, 95% CI: 0.226-0.692; p=0.002), and AFS (OR=0.602, 95% CI: 0.518-0.700; p=3.47E-10). Moreover, in the reverse MR analysis, we observed no significant causal effects of LBP on ANM, AAM, LMC and AFS. MVMR analysis demonstrated the continued significance of the causal effect of AFB on LBP after adjusting for BMI. Conclusion: Our study explored the causal relationship between ANM, AAM, LMC, AFB, AFS, ALB and the prevalence of LBP. We found that early menarche, early age at first birth, early age at last live birth and early age first had sexual intercourse may decrease the risk of LBP. These insights enhance our understanding of LBP risk factors, offering valuable guidance for screening, prevention, and treatment strategies for at-risk women.

Factors influencing menstrual regularity among female workers: a cross-sectional analysis study.

BACKGROUND: Regularity of menstrual cycles is an important indicator of women's health and fertility, and female workers are exposed to several factors, such as sleep disorders, stress, and shift work, that affect their menstrual regularity. This makes it necessary to comprehensively identify the determinants of menstrual regularity. Therefore, this study identified the factors affecting menstrual regularity among female workers from physiological, psychological, and situational dimensions based on the theory of unpleasant symptoms. METHODS: This was a secondary analysis of the 2010-2012 Korea National Health and Nutrition Examination Survey and utilized the data of 2418 female workers. Based on the theory of unpleasant symptoms, physiological factors included age, age at menarche, childbirth experience, body mass index, and sleep duration. Psychological factors included stress level, depressive mood, and suicidal ideation. Situational factors included education level, household income, consumption of alcohol, engagement in smoking, and work schedule. The χ²-test and hierarchical logistic regression analysis were performed, reflecting the complex sample design. RESULTS: Age at menarche, childbirth experience, and body mass index among physiological factors and education level and work schedule among situational factors were found to be related to menstrual regularity. A higher risk of menstrual irregularities was found among those who had given birth (versus those who had not), had a high age at menarche (versus those with a low age at menarche), were obese (versus those who had a normal body mass index), had elementary school-level or lesser educational achievements (versus those with college graduate-level or higher educational achievements), and who had a shift work schedule (versus those with a fixed schedule). CONCLUSIONS: Intervention is needed for female workers who have these risk factors, and special attention must be paid to female workers who have a shift work schedule. Additionally, since body mass index can be controlled, intervention concerning body mass index is necessary to reduce menstrual irregularity.

Effects of growth hormone therapy on the onset and progression of pubertal development in girls with idiopathic short stature.

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.

Menarche and Time to Cycle Regularity Among Individuals Born Between 1950 and 2005 in the US.

Importance: Early menarche is associated with adverse health outcomes. Trends toward earlier menarche have been observed in the US, but data remain limited on differences by sociodemographic factors and body mass index (BMI). Time from menarche to cycle regularity is another understudied early-life characteristic with health implications. Objectives: To evaluate the temporal trends and disparities in menarche and time to regularity and explore early-life BMI as a mediator. Design, Setting, and Participants: This ongoing cohort study enrolled participants from an ongoing mobile application-based US cohort from November 14, 2019, to March 20, 2023. Exposures: Birth year (categorized as 1950-1969, 1970-1979, 1980-1989, 1990-1999, and 2000-2005). Main Outcomes and Measures: Main outcomes were age at menarche and time to regularity, which were self-recalled at enrollment. In addition, early (aged <11 years), very early (aged <9 years), and late (aged ≥16 years) age at menarche was assessed. Results: Among the 71 341 female individuals who were analyzed (mean [SD] age at menarche, 12.2 [1.6] years; 2228 [3.1%] Asian, 3665 [5.1%] non-Hispanic Black, 4918 [6.9%] Hispanic, 49 518 [69.4%] non-Hispanic White, and 8461 [11.9%] other or multiple races or ethnicities), 5223 were born in 1950 to 1969, 12 226 in 1970 to 1979, 22 086 in 1980 to 1989, 23 894 in 1990 to 1999, and 7912 in 2000 to 2005. The mean (SD) age at menarche decreased from 12.5 (1.6) years in 1950 to 1969 to 11.9 (1.5) years in 2000 to 2005. The number of individuals experiencing early menarche increased from 449 (8.6%) to 1223 (15.5%), the number of individuals experiencing very early menarche increased from 31 (0.6%) to 110 (1.4%), and the number of individuals experiencing late menarche decreased from 286 (5.5%) to 137 (1.7%). For 61 932 participants with reported time to regularity, the number reaching regularity within 2 years decreased from 3463 (76.3%) to 4075 (56.0%), and the number not yet in regular cycles increased from 153 (3.4%) to 1375 (18.9%). The magnitude of the trend toward earlier menarche was greater among participants who self-identified as Asian, non-Hispanic Black, or other or multiple races (vs non-Hispanic White) (P = .003 for interaction) and among participants self-rated with low (vs high) socioeconomic status (P < .001 for interaction). Within a subset of 9865 participants with data on BMI at menarche, exploratory mediation analysis estimated that 46% (95% CI, 35%-61%) of the temporal trend in age at menarche was explained by BMI. Conclusions and Relevance: In this cohort study of 71 341 individuals in the US, as birth year increased, mean age at menarche decreased and time to regularity increased. The trends were stronger among racial and ethnic minority groups and individuals of low self-rated socioeconomic status. These trends may contribute to the increase in adverse health outcomes and disparities in the US.

Mammographic density mediates the protective effect of early-life body size on breast cancer risk.

The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56% (95% CIs [32%-79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets.