Genetic determinants of age at menarche: does the LIN28B gene play a role? A narrative review.

Menarche, the first menstrual period marking the onset of female reproduction, is a milestone of female puberty. The timing of menarche determines the timing of later phases of pubertal maturation in girls and has major implications for health later in life, including behavioral and psychosocial disorders during adolescence and fertility problems and increased risk for certain diseases in adulthood. Over the last few decades, a continuous decline in age at menarche has been noted, with environmental factors contributing to this change in the timing of menarche. However, a genetic component of age at menarche and pubertal onset has been strongly suggested by studies in families and twins wherein up to approximately 80% of the variance in puberty onset can be explained by heritability. Gene association studies have revealed several genetic loci involved in age at menarche, among which LIN28B has emerged as a key regulator of female growth and puberty. LIN28B, a human homolog of Lin28 of C. elegans, is a known RNA-binding protein that regulates let-7 microRNA biogenesis. Genome-wide association studies have identified the association of polymorphisms in the LIN28B gene with age at menarche in several population cohorts worldwide. In this paper, we review the genetic factors contributing to age of menarche, with particular focus on the identified polymorphisms in LIN28B gene.

Causal effects of female reproductive features on nonalcoholic fatty liver disease: A mendelian randomization study.

BACKGROUND AND AIMS: Epidemiological evidence on the associations between female reproductive features and nonalcoholic fatty liver disease (NAFLD) is conflicting. To explore their causalities, we conducted a Mendelian randomization (MR) study. METHODS: Summary-level data were obtained, and univariable MR was performed to explore the causalities between female reproductive features and NAFLD. And we performed multivariable MR and MR mediation analysis to explore the mediation effects of educational attainment (EA) and body mass index (BMI) for these associations. Sensitivity analyses were performed to evaluate pleiotropy and heterogeneity. RESULTS: There were causal effects of age at menarche (AAMA) (odds ratio [OR]: 0.817, 95% confidence interval [CI]: 0.736-0.907, per year-increase), age at first birth (AFB) (OR: 0.851, 95%CI: 0.791-0.926, per year-increase) and age at first sexual intercourse (AFS) (OR: 0.676, 95%CI: 0.511-0.896, per standard deviation-increase) on NAFLD risk. Besides, the causal effects were also observed on NAFLD phenotypes including liver fat content (LFC) and alanine aminotransferase (ALT). Further mediation analysis showed that BMI mediated partial proportion of effects of AAMA and AFS on NAFLD/ALT, AFB on NAFLD/LFC/ALT, while EA mediated partial proportion of effects of AFB on NAFLD/LFC/ALT, and AFS on NAFLD/ALT. CONCLUSIONS: This study provided convincing evidence that early AAMA, AFB, and AFS were risk factors for NAFLD. Reproductive health education, obesity management, and education spread might be the beneficial strategies for NAFLD prevention.

Exploring the Effects of Age at Menarche and Pregnancy on Myopia.

PURPOSE: Associations between age at menarche and myopia have been observed in studies that included older women. Furthermore, pregnancy-related hormone surges in young women are associated with short-term changes in refractive error, although the long-term effects are less known. This study explored associations of age at menarche and parity with refractive error and ocular biometry in young women, and the relationship between age at menarche and refractive error in middle-aged adults for comparison. METHODS: Community-based young women underwent eye examinations at 20 and 28 years old. Information on age at menarche and parity were collected prospectively. The older cohort underwent an eye examination and information on age at menarche was self-reported retrospectively. Cross-sectional associations between age at menarche and myopia were explored in both cohorts. Associations between parity and 8-year longitudinal change in refractive error measures were explored in the young cohort. RESULTS: The cross-sectional analyses comprised 429 young (age 18-22) and 1,818 older (age 46-69) women. No associations were found between age at menarche and myopia or ocular biometry measures in either cohort. The longitudinal analysis (n = 269 women) revealed that for each pregnancy carried to full term, there rate of lens thickening increased by 0.004 mm/year (95% CI = 0.002-0.007). No other associations between parity and refractive error or ocular biometry were found. CONCLUSION: There is no association between age at menarche and myopia or its related measures. While pregnancy was associated with thicker lens in the long term, there is no lasting effect on refractive error.

A study of association between early menarche and anxiety in undergraduate students.

Background: Anxiety has been reported to be one of the most common epidemics in recent years. The present study focused on understanding the association between early menarche and the prevalence of anxiety and anxiety symptoms among adult undergraduate students. Methods: This was an observational, case-control study. The sample included 146 young female adults aged more than or equal to 18 years pursuing the Bachelor of Medicine and Bachelor of Surgery (MBBS) and Bachelor of Dental Sciences (BDS). Using an online questionnaire, participants were asked to recall and enter the age at which they attained menarche. We used the Generalized Anxiety Disorder 7- Item Questionnaire (GAD-7) to measure the severity of their present anxiety symptoms. Results: The results showed a significant increase in anxiety symptoms in participants who had early menarche compared to those who did not have early menarche. The mean score on the GAD-7 Questionnaire for the cases was 9.93 and the control group was 6.89. The GAD-7 scores among the cases group were significantly higher in the GAD-7 scores than in the control group. Conclusions: This study concluded that early menarche is associated with higher anxiety levels in young adults.

Estimated timing of the first menstrual period and dietary and nutritional correlates of menarche among urban school-going adolescents in four sub-Saharan African sites.

Characterizing the timing of menarche and the factors that are associated with it is important for understanding a population's reproductive health needs and long-term health trajectories. We estimated the age at the menstrual onset among adolescent girls and the association between dietary and nutritional factors and menarche in four sub-Saharan African urban sites. We used cross-sectional school-based data from 2307 female adolescents aged 10-14 years collected by the Africa Research, Implementation Science, and Education (ARISE) Network in Ouagadougou, Burkina Faso; Addis Ababa, Ethiopia; Khartoum, Sudan; and Dar es Salaam, Tanzania. Logit models were used to estimate the median age at menarche at each site. Associations between menarche and BMI-for-age, stunting, dietary quality and food insecurity across settings were assessed using Poisson regression models adjusted for country and school levels. The estimated median age at menarche was 13.1 years (95% confidence interval: 12.7, 13.5) in Ouagadougou; 12.9 (12.6, 13.2) in Addis Ababa; 13.3 (12.7, 13.6) in Khartoum; and 13.2 (12.3, 14.0) in Dar es Salaam. Between 18% and 49% of the girls in each setting had already menstruated. Based on the pooled multivariable models, underweight participants were 42% less likely (adjusted prevalence ratio [PR] 0.58 [0.44, 0.77]) to have experienced menarche in comparison to normal-weight individuals. The likelihood of experiencing menarche increased for overweight [PR 1.47 (1.30,1.66)] and obese [PR 1.57 (1.35,1.82)] in comparison to normal-weight girls. Those stunted were 47% less likely to have experienced menarche [PR 0.53 (0.41, 0.69)] than their nonstunted counterparts. A lower likelihood of menarche among those experiencing moderate/severe hunger when compared to those with no/little hunger was also observed (PR 0.78 [0.63,0.96]). No evidence of association with dietary quality was found. Further research is needed to strengthen the body of evidence and inform evidence-based initiatives in low- and middle-income settings.

Age at Menarche and Its Association With Adult-Onset Metabolic Syndrome and Related Disorders in Women: A Cross-Sectional Study of a Nationally Representative Sample Over 10 Years.

The prevalence of metabolic syndrome (MetS) as well as related social costs and efforts is increasing. The purpose of this study was to investigate the association between age at menarche and the risk of MetS, obesity, diabetes, and cardiovascular disease (CVD) in women over 30 years, using data from the Korean National Health and Nutrition Examination Survey (2010-2020). The analysis of 30 916 participants showed that early menarche (before 11 years) significantly increased the risk of obesity, diabetes, and MetS compared with the median age of 14 years. Late menarche (after 17 years) was also linked to MetS and related disorders. The relationship between age at menarche (at <10 years and >19 years) and the risk of MetS and related disorders exhibited a reversed J-shaped (し) pattern characterized by a pronounced increased risk among those who experience early menarche, whereas the increased risk associated with late menarche was less consistent. These results will help to decrease the risk of MetS and related disorders by enabling early intervention in early and late menarche age groups.

Functional ovulatory menstrual health literacy amongst adolescent females in Western Australia.

STUDY OBJECTIVE: To assess the knowledge of ovulation and menstruation of adolescent females in Western Australia. METHODS: A validated adolescent ovulatory menstrual health literacy questionnaire was used in a cross-sectional study, which included an open-response question inviting participants' reflections. RESULTS: Participants (n=297) were from two single sex and seven co-educational schools of varied socio-educational advantage. Mean chronological age was 15 years and mean gynaecological age was two years. The prevalence of dysmenorrhoea was 69%. Primary sources of information included mothers (91%), friends (61%) and, for post-menarcheal participants (n=274), mobile applications (52%). Most adolescents enjoyed finding out information about ovulatory menstrual health, and understood the information given to them. However, participants' knowledge of ovulation, menstruation and their occurrence in the cycle were low. Attendance at a single sex or Catholic school or use of mobile applications did not confer a knowledge advantage overall (p<0.05), except for knowing the meaning of cervical mucus. Thematic content analysis of open-ended responses resulted in five themes, including normality, menstrual flow, charting, ovulation and dysmenorrhoea. CONCLUSION: Inadequate functional ovulatory menstrual health literacy hampers progression to acquiring complete health literacy. This has negative implications for progressing towards the interactive and critical ovulatory menstrual health literacy domains, which include providing an accurate menstrual history when engaging with healthcare providers.

Feasibility of Early Surgical Treatment for Adolescent Patients with Prolactinoma: A Case Report and Literature Review.

Background and Objectives: Prolactinomas are the most common pituitary adenomas, comprising 30-50% of such tumors. These adenomas cause hyperprolactinemia, leading to decreased fertility, reduced energy and libido, and galactorrhea. Diagnosing and treating prolactinomas in adolescents present unique challenges, as symptoms may be confused with age-related developmental variations. This case report explores the outcomes of early surgical intervention in an adolescent with a prolactinoma. Materials and Methods: A 14-year-old female presented delayed menarche and absent pubertal development. Initial evaluation revealed hyperprolactinemia (228.37 ng/mL) with normal estradiol levels. Initial management through observation was adopted, but persistent amenorrhea and severe headaches prompted further investigation. Magnetic resonance imaging revealed a cystic pituitary mass with apoplexy. Due to concerns regarding delayed puberty and the need for rapid normalization of prolactin levels, the patient underwent transsphenoidal surgery. Results: After operation, prolactin levels normalized, menarche occurred within three months, and secondary sexual characteristics developed within eight months. Pathology confirmed a pituitary adenoma with a high Ki-67 index (15%). Conclusions: Early surgical intervention for prolactinomas in adolescents can achieve successful biochemical remission and resolution of endocrine symptoms. Adolescents, particularly those with a high Ki-67 index and potential resistance to dopamine agonists, may benefit from prompt surgical management, resulting in improved clinical outcomes and complete tumor resection.

Neighbourhood environment and early menarche among adolescent girls of five countries.

INTRODUCTION: We aim to investigate the relationship between individuals' perceptions of their neighbourhood environment and early menarche. METHODS: This was a retrospective cohort study of 7,486 girls of Ethiopia, India, South Korea, the United Kingdom (UK), and the United States (US), born in 1997-2011 was analysed. Early menarche was defined as being below the 10th to 20th percentiles in each cohort, considering the varying distributions across countries. Perceived neighbourhood environments were assessed based on the responses for neighbourhood pollution, safety, and recreational facilities. We calculated the relative risk (RR) of early menarche for unfavourable environment. RESULTS: The mean age at menarche was lowest in South Korea (10.6 years) and highest in Ethiopia (13.7 years). Unfavourable environment was associated with higher risk of early menarche overall (RR = 1.34, 95% confidence interval [CI]:1.09-1.65) and each country (3.03, 95% CI: 1.15-7.96 in Ethiopia; 1.99, 95% CI: 0.97-4.10 in India, 1.23, 95% CI: 0.67-2.27 in Korea; 1.26, 95% CI: 0.96-1.64 in the UK). Specifically, pollution (1.29, 95% CI: 1.03-1.62) and low safety (1.19, 95% CI: 1.60-1.88) were associated with early menarche. CONCLUSIONS: Our finding highlights the potential role of perceived neighbourhood environment in the timing of puberty.

Associations of urinary heavy metals with age at menarche, age at menopause, and reproductive lifespan: A cross-sectional study in U.S. women.

Female reproductive timing and lifespan, with a close relation to long-term health outcomes, have been altered in U.S. women over the past decades. However, epidemiologic evidence of the potential causes was lacking. On the basis of 1981 naturally postmenopausal women from the National Health and Nutrition Examination Survey 1999-2020, this study aimed to investigate the associations of urinary heavy metals with age at menarche, age at menopause, and reproductive lifespan. Multivariate generalized linear regression and addictive models were used for single metal exposure analysis, and weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were employed for mixed exposures. In the fully adjusted model, higher urinary antimony concentration was associated with earlier age at menarche of 0.137 years, while higher concentrations of cadmium, cesium, lead, antimony, and thallium were associated with delayed age at menopause of 0.396-0.687 years. Additionally, urinary barium, cesium, lead, antimony, and thallium levels were associated with longer reproductive lifespan ranging between 0.277 and 0.713 years. Both WQS and BKMR models showed significantly positive associations of metal mixtures with age at menopause (ß: 0.667, 95 % CI: 0.120-1.213) and reproductive lifespan (ß: 0.686, 95 % CI: 0.092-1.280), with cadmium and lead identified as principal contributors. In conclusion, heavy metal exposures were associated with reproductive timing and lifespan of U.S. women, highlighting the need for further prevention and intervention strategies.

Timing of menarche and pubertal growth patterns using the QEPS growth model.

Objectives: To explore the timing of menarche, postmenarcheal growth, and to investigate the impact of various variables on menarcheal age and postmenarcheal and pubertal growth. Study Design: This longitudinal community population-based study analyzed pubertal growth and menarcheal age in 793 healthy term-born Swedish girls, a subset of the GrowUp1990Gothenburg cohort. The timing of menarche and postmenarcheal growth was related to variables from the Quadratic-Exponential-Pubertal-Stop (QEPS) growth model, birth characteristics, and parental height. Multivariable models were constructed for clinical milestones; at birth, age 7 years, pubertal growth onset, and midpuberty. Results: Menarche aligned with 71.6% (18.8) of the QEPS model's specific pubertal growth function, at a mean age of 13.0 (1.3) years, ranging from 8.2 to 17.2 years. Postmenarcheal growth averaged 8.0 (4.9) cm, varying widely from 0.2 to 31.1 cm, decreasing with later menarche. Significant factors associated with menarcheal age included height at 7 years, childhood body-mass index, parental height, and QEPS-derived pubertal growth variables. Multivariable models demonstrated increasing explanatory power for each milestone, explaining 1% of the variance in menarcheal age at birth, 8% at age 7 years, 44% at onset of pubertal growth, and 45% at midpuberty. Conclusions: This study underscores the strong link between pubertal growth and age at menarche. Data available at start of puberty explain 44% of the variation in menarcheal age, apparent on average 3.2 years before menarche. In addition, the study shows a previously seldom noticed wide variation in postmenarcheal height gain from 0.2 to 31.1 cm.

Nutritional status and age at menarche in Amazonian students

Abstract Objectives: Age at menarche (MA) is a proxy for biological maturation and a parameter of socioeconomic changes. Worldwide, anticipation of menarche is associated with nutritional transition and excess weight. The objective of this study was to evaluate the MA in Amazonian students and its association with nutritional status, ethnicity, and socioeconomic level. Methods: Cross-sectional study with 1,017 students aged 6 to 17 living in the city of Manaus, Brazil. MA was analyzed by status quo and recall; its association with body mass index (BMI), race, socioeconomic status, and adult height was examined. Results: 559 (51.9%) participants had already experienced menarche. In 91.7%, menarche occurred between 10 and 14 years of age; the mean age at the onset of menarche was 11.9 years. Overweight (11.6 years) and obese (11.4 years) participants reached menarche earlier than those with normal weight (12 years) and lean (12.7 years) participants. The associations between MA and nutritional status showed that overweight and obesity are risk factors for the early occurrence of menarche. MA was not associated with socioeconomic status/parental education or race. However, excess weight was associated with earlier MA in all races and social classes. The adult height was slightly lower in girls with menarche before 12 years old (157.9 vs 159.4 cm). Conclusion: Regardless of socioeconomic level or ethnicity, excess weight was associated with earlier menarche in Amazonian students.

Delayed menarche in children and adolescents with type 1 diabetes mellitus: a systematic review and meta-analysis.

Several studies have reported an association between age at menarche and the onset of type-1 diabetes mellitus (T1DM). This review compared the age at menarche in patients who had menarche after T1DM diagnosis with that of patients who were healthy and/or had menarche before T1DM diagnosis. Searches were conducted using four databases. The outcome was the age at menarche of patients who had menarche after T1DM diagnosis and patients who were healthy and/or had menarche before T1DM diagnosis. A qualitative analysis was performed using the JBI (Joanna Briggs Institute) Critical Appraisal. Quantitative analysis of the mean differences was performed using Revman 5.4 tool. A total of 1952 studies were obtained from the initial search. The final results were 13 articles that met the inclusion criteria for the qualitative assessment and eight for the quantitative assessment. Eight studies included 1030 patients who had menarche after being diagnosed with T1DM and 1282 patients who were healthy and/or had menarche before T1DM diagnosis. The meta-analysis showed a cumulative effect on a mean difference of 0.87 (95% CI: 0.75; 0.99, p-value < 0.00001), indicating a later age at menarche in patients who had menarche after T1DM diagnosis. The age at menarche was later in patients who had menarche after T1DM diagnosis compared to healthy subjects and those who had menarche beforehand.

Relationship between age at menarche and breast cancer in individuals, as well as in first-degree kin and estrogen receptor status: a Mendelian randomization study.

Target: We executed a Mendelian randomization (MR) investigation employing two distinct cohorts of genetic instrumental variables to elucidate the causal nexus between age at menarche (AAM) and the incidence of disparate breast cancer (BC) subtypes, in addition to the incidence of BC among first-degree kin. Methods: We aggregated statistical data pertaining to AAM and BC from various consortia representing a homogenous population cohort. MR analysis was conducted employing inverse variance weighted (IVW) methodology as the principal approach, complemented by weighted median and MR-Egger regression techniques for an exhaustive evaluation. To evaluate the presence of pleiotropy, we applied the MR-Egger intercept test, MR-PRESSO, and leave-one-out sensitivity analysis. Results: Upon exclusion of confounding SNP, an increment of one standard deviation in AAM was inversely correlated with the incidence of BC. (odds ratio [OR] 0.896, 95% confidence interval [CI] 0.831-0.968)/(OR 0.998, 95% CI 0.996-0.999) and estrogen receptor-positive (ER+) BC incidence (OR 0.895, 95% CI 0.814-0.983). It was also associated with reducing the risk of maternal BC incidence (OR 0.995, 95% CI 0.990-0.999) and sibling BC incidence (OR 0.997, 95% CI 0.994-0.999). No significant association was found between AAM and estrogen receptor-negative (ER-) BC incidence (OR 0.936, 95% CI 0.845-1.037). Conclusion: Our study substantiated the causal relationship between a delayed AAM and a diminished risk of BC in probands, as well as in their maternal progenitors and siblings. Furthermore, the analysis suggests that AAM exerts a considerable potential causal influence on the risk of developing Luminal-a/b subtype of BC.

Association between type 2 diabetes, alcohol intake frequency, age at menarche, and gallbladder cancer: a two-sample Mendelian randomization study.

Background: Gallbladder cancer (GBC) is a rare malignancy of the digestive tract, characterized by a remarkably poor prognosis. Currently, there is a controversy on the relationship between type 2 diabetes (T2D) and GBC. Additionally, no definitive conclusions were established regarding the causal relationships between alcohol intake frequency (AIF), age at menarche (AAM) and GBC. The objective of this study was to elucidate the causal association between T2D, AIF, AAM, and GBC. Methods: Single-nucleotide polymorphisms (SNPs) associated with exposures and outcomes were sourced from the Integrative Epidemiology Unit (IEU) Open Genome-Wide Association Study (GWAS) database. Specifically, the data of GBC comprised 907 East Asians (pathological results of all cases were registered into Biobank Japan) and 425,707 SNPs; T2D comprised 655,666 Europeans with 5,030,727 SNPs; AIF comprised 462,346 Europeans and 9,851,867 SNPs; AAM comprised 243,944 Europeans and 9,851,867 SNPs. The measurement of exposure traits is collected uniformly from the UK Biobank (UKB) database and presented in the form of standard deviation (SD) or the logarithmic form of the odds ratio (logOR). We employed a two-sample Mendelian randomization (MR) analysis to discern the causalities between T2D, AIF, AAM, and GBC. Sensitivity analyses were conducted to identify and address potential heterogeneity, horizontal pleiotropy, and outliers. Results: Our findings indicated that T2D reduced GBC risk [odds ratio (OR) =0.044; 95% confidence interval (CI): 0.004-0.55; P=0.015, inverse variance-weighted (IVW)]. However, no causal relationship was observed between AIF (OR =0.158; 95% CI: 5.33E-05 to 466.84; P=0.65, IVW), AAM (OR =0.19; 95% CI: 0.0003-140.34; P=0.62, IVW), and GBC. Sensitivity analysis revealed no evidence of horizontal pleiotropy, heterogeneity, or outliers, suggesting the robustness and reliability of our conclusions. Conclusions: T2D emerged as a potentially protective factor against GBC, whereas neither AIF nor AAM demonstrated a causal relationship with GBC risk. Regulation of glucose metabolism may be one of the methods for preventing GBC.

Female Reproductive Factors and Risk of Mild Cognitive Impairment and Dementia: The HUNT Study.

BACKGROUND: More women are living with dementia than men worldwide and there is a need to investigate causes for this female preponderance. While reproductive factors have been investigated as risk factors, the results are conflicting. We aim to clarify this using a large cohort with a long observation time, adjusting for multiple health and lifestyle variables and encompassing a wider range of cognitive impairment. OBJECTIVE: To study the association between menopause age, menarche age and risk of and risk of mild cognitive impairment (MCI) and dementia. SETTING: The Trøndelag Health study (HUNT), a longitudinal population health study in Norway (1984-2019). PARTICIPANTS: Women who were ≥70 years in 2017-2019 were assessed for cognitive impairment. MEASUREMENTS: Data on menopause age and menarche age were obtained from questionnaires. Diagnosis of MCI or dementia was set using a standardised procedure by a diagnostic group of nine physicians. Multinomial logistic regression was used to study the association between menopause age, menarche age and risk of MCI and dementia with adjustment for birth year, education, smoking, ApoE4, number of children, diabetes, body mass index, alcohol use and physical inactivity. RESULTS: We evaluated 5314 women where 900 (16.9%) had dementia, and 1747 (32.8%) had MCI. Multiple adjusted relative risk ratio (RRR) and 95% confidence intervals (CI) for dementia were: 0.96(95%CI 0.95-0.98) (p<0.001) for menopause age, 0.97(95%CI 0.94-0.99) (p=0.007) for natural menopause age (excluding hysterectomy and/or oophorectomyp<55 years) and 0.97(95%CI 0.95-0.99) (pp<0.001) for reproductive span (menopause age minus menarche age). Menopause age p<45years was associated with a 56% higher risk compared to mean menopause age 50 years. We found no significant associations between menarche age and dementia and no associations with MCI. CONCLUSIONS: Older menopause age and longer reproductive span corresponding to longer oestrogen exposure were associated with a lower dementia risk. Future studies should explore therapeutical options to offset this risk in women.

Ovarian Dermoid Cyst Trajectory in Premenarchal Girls.

STUDY OBJECTIVE: Mature ovarian dermoid cysts (ODCs) are the most common benign ovarian tumors diagnosed in children. However, there is minimal data on management of ODCs in premenarchal patients. This study assesses characteristics associated with expectant (EM) vs surgical (SM) management in premenarchal patients and the growth rate of ODCs in EM patients at a single institution. METHODS: Forty-four premenarchal patients, either post-surgical with pathologically-confirmed ODC or having radiologic findings consistent with ODCs, were included. Data collected included demographics, cyst characteristics, imaging findings, presence of symptoms, surgical procedure performed, and ovarian torsion occurrence. RESULTS: Patient age at diagnosis was similar between groups (SM: 8.8 vs EM: 8.0, P = .55). At presentation, 36 patients (82%) underwent SM and 8 (18%) underwent EM. There was a significant difference in cyst size between groups (SM: 8.9 cm vs EM: 3.6 cm, P = .004). Of SM patients, 30% underwent oophorectomy vs cystectomy, with a significant difference in ODC size between procedures (11.8 cm vs 7.7 cm, P = .016). Of EM patients, 75% had at least one and 60% had three follow-up ultrasounds, with average follow-up timeframes of 3.7 and 27 months respectively. Average yearly ODC growth rate for the latter group was 0.8 cm. CONCLUSION: The average yearly growth rate of ODCs in premenarchal patients within our institution was slower than in older cohorts, and both age and cyst size played significant roles in determining surgical procedure. Continued study on EM in premenarchal ODCs will help define parameters for recommending SM vs EM in this population.

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.

Exploratory Study into the Classification Agreement between Self-Reported Age of Menarche and Calculated Maturity Offset in Adolescent Girls: A Two-Year Follow-Up Study.

Menarche is a significant pubertal event influencing girls' participation in physical activity. As menarche is a sensitive matter, a non-invasive substitute is needed to help classify girls' maturity status and provide physical literacy to them in this regard. The objective of this exploratory study was to investigate the classification agreement between self-reported age of menarche and calculated maturity offset in adolescent girls from South Africa by making use of various statistical methods. Fifty-eight girls, n = 13 pre- and n = 45 post-menarche (Status Quo method) aged 13.51 ± 3.51 years at baseline, were analyzed (2010-2012). Independent t-testing, cross-tabulation, Roc Curve statistics and logistic regression were used to analyze the classification agreement between markers. All four statistical methods revealed the potential to categorize different maturity groups through the maturity offset equation, although the accuracy declined with increased age. A realized power of 0.92 was found for the group in the first year of the study, with a gradual and significant decline over time. Cross-tabs showed a significant moderate predictive effectiveness (Chi-square = 0.042) during T1, closer to PHV (13.51 years) although also declining significantly with increased age (T2, 14.51 years) beyond PHV (Chi-square = 0.459). Although positive results were found, caution must be used when using maturity offset equations in different homogenic populations due to their unique growth characteristics.

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.