Associations between birthweight and preterm birth and the ages at menarche and menopause.

BACKGROUND: Women who reach menarche and menopause at earlier ages have been shown to be at increased risk for numerous conditions including cardiovascular disease, cancer, depression, and obesity; however, risk factors for earlier ages of menarche and menopause are not fully understood. Therefore, we aimed to perform a retrospective investigation of the associations between a personal birthweight and/or being born preterm and the age of and menarche and menopause and related events in the Women's Health Initiative, a large, racially and ethnically diverse cohort of postmenopausal women. METHODS: At study entry, women reported their birthweight by category (< 6 lbs., 6-7 lbs. 15 oz, 8-9 lbs. 15 oz, or ≥ 10 lbs.) and preterm birth status (4 or more weeks premature). Ages at events related to menarche and menopause were also self-reported. Linear regression and logistic regression models were used to estimate unadjusted and adjusted effect estimates (ß) and odds ratios (OR), respectively (n ≤ 86,857). Individuals born preterm were excluded from all birthweight analyses. RESULTS: After adjustments, individuals born weighing < 6lbs. were more likely to reach natural menopause at an earlier age (adjusted ß=-0.361, SE = 0.09, P = < 0.001) and have a shorter reproductive window (adjusted ß = -0.287, SE = 0.10, p < 0.004) compared to individuals weighing 6-7 lbs. 15 oz. Individuals born preterm were also more likely to reach natural menopause at an earlier age (adjusted ß=-0.506, SE = 0.16, P = 0.001) and have a shorter reproductive window (adjusted ß = -0.418, SE = 0.17, p < 0.006). CONCLUSIONS: These findings raise concerns that, as more preterm and low birthweight individuals survive to adulthood, the prevalence of earlier-onset menarche and menopause may increase. Clinical counseling and interventions aimed at reducing the incidence of preterm and low birthweight births, as well as intensification of lifestyle modifications to reduce CVD risk among women with these early-life risk factors, should be prioritized.

Relationship between early age at menarche, older age at menopause and subtypes of breast cancer: a scoping review.

Objective: To determine the relationship between early age at menarche, late age at menopause with specific subtypes of breast cancer (BC). Methods: A literature search was conducted in Embase, Lilacs, PubMed, Scopus, and Scielo databases, following the Joanna Briggs Institute scoping review protocol and answering the question "How early age at menarche or late age at menopause are related to different breast cancer subtypes?". Results: A number of 4,003 studies were identified, of which 17 were selected. Most of the included articles found a clear relationship between early menarche, late menopause and some subtypes of BC, mainly, PR+, ER+, luminal, and HER-2 tumors. However, some studies have found a contradictory relationship and one study didn't find any relationship between them. Conclusion: A relationship between early age at menarche and advanced age at menopause was observed with some subtypes of breast cancer, since other factors must be considered in its understanding.

Small for gestational age and age at menarche in a contemporary population-based U.S. sample.

Children born small for gestational age (SGA) may be at risk for earlier puberty and adverse long-term health sequelae. This study investigates associations between SGA and age at menarche using secondary data on 1,027 female children in a population-based U.S. birth cohort that over-sampled non-marital births, which in the U.S. is a policy-relevant population. SGA was defined as <10th percentile of weight for gestational age compared to the national U.S. distribution. We estimated unadjusted and adjusted Ordinary Least Squares (OLS) models of associations between SGA and age at menarche in years, as well as unadjusted and adjusted logistic regression models of associations between SGA and early menarche (before age 11). SGA was not significantly associated with earlier age at menarche, even when adjusting for maternal sociodemographic characteristics, prenatal smoking, and maternal pre-pregnancy overweight and obesity. Similarly, SGA was not significantly associated with the odds of menarche occurring before age 11. However, maternal non-Hispanic Black race-ethnicity, Hispanic ethnicity, and pre-pregnancy obesity all had independent associations with average earlier age at menarche and menarche before age 11. Thus, maternal risk factors appear to play more influential roles in determining pubertal development.

Exploring the impact of women-specific reproductive factors on phenotypic aging and the role of life's essential 8.

BACKGROUND: Aging is an inevitable biological process. Accelerated aging renders adults more susceptible to chronic diseases and increases their mortality rates. Previous studies have reported the relationship between lifestyle factors and phenotypic aging. However, the relationship between intrinsic factors, such as reproductive factors, and phenotypic aging remains unclear. METHODS: This study utilized data from the National Health and Nutrition Examination Survey (NHANES), spanning from 1999 to 2010 and 2015-2018, with 14,736 adult women. Random forest imputation was used to handle missing covariate values in the final cohort. Weighted linear regression was utilized to analyze the relationship between women-specific reproductive factors and PhenoAgeAccel. Considering the potential impact of menopausal status on the results, additional analyses were conducted on premenopausal and postmenopausal participants. Additionally, the Life's Essential 8 (LE8) was used to investigate the impact of healthy lifestyle and other factors on the relationship between women-specific reproductive factors and PhenoAgeAccel. Stratified analyses were conducted based on significant interaction p-values. RESULTS: In the fully adjusted models, delayed menarche and gynecological surgery were associated with increased PhenoAgeAccel, whereas pregnancy history were associated with a decrease. Additionally, early or late ages of menopause, first live birth, and last live birth can all negatively impact PhenoAgeAccel. The relationship between women-specific reproductive factors and PhenoAgeAccel differs between premenopausal and postmenopausal women. High LE8 scores positively impacted the relationship between certain reproductive factors (age at menarche, age at menopause, age at first live birth, and age at last live birth) and phenotypic age acceleration. Stratified analysis showed significant interactions for the following variables: BMI with age at menarche, pregnancy history, and age at menopause; ethnicity with age at menopause, age at first live birth, and parity; smoking status with use of contraceptive pills and gynecologic surgery; hypertension with use of contraceptive pills, pregnancy history, and age at menopause. CONCLUSION: Delayed menarche, gynecological surgery, and early or late ages of menopause, first live birth, and last live birth are associated with accelerated phenotypic aging. High LE8 score may alleviate the adverse effects of reproductive factors on phenotypic aging.

Menstrual pattern in polycystic ovary syndrome and hypothalamic-pituitary-ovarian axis immaturity in adolescents: a systematic review and meta-analysis.

OBJECTIVE: To analyze differences in the menstrual pattern, age at menarche, and body mass index (BMI) in adolescents with Hypothalamic-Pituitary-Ovarian (HPO) axis immaturity and Polycystic Ovary Syndrome (PCOS) through a systematic review and meta-analysis. METHODS: The PubMed, EMBASE, Web of Science, Virtual Health Library, Scopus databases were searched using combinations of descriptors. Study quality was assessed using the Newcastle-Ottawa Scale. For data analysis, the results were grouped into PCOS group and NPCOS group (HPO axis immaturity). We performed a meta-analysis of raw data and the inverse variance method, employing the standardized mean difference, of the age at menarche and BMI of adolescents. RESULTS: Participants totaled 1,718 from nine selected studies. The meta-analysis showed that the PCOS group had a higher BMI than the NPCOS group (SMD 0.334; CI95% 0.073 - 0.595; p = .012). The degree of heterogeneity of the studies was approximately 40%. No significant difference in age at menarche (SMD - 0.027; CI95% -0.227 - 0.172; p = 0.790) and menstrual patterns was found, but amenorrhea was described only in adolescents with PCOS. CONCLUSIONS: The main characteristic in menstrual pattern that differentiated PCOS patients from girls with HPO axis immaturity was amenorrhea. Also, the BMI of PCOS patients was nearly one third higher than that of adolescents with HPO axis immaturity.

Female reproductive histories and the risk of chronic obstructive pulmonary disease.

BACKGROUND: Female reproductive factors may influence the development of chronic obstructive pulmonary disease (COPD) through the female hormonal environment, but studies on this topic are limited. This study aimed to assess whether age at menarche, number of children, infertility, miscarriage, stillbirth and age at natural menopause were associated with the risk of COPD. METHODS: Women from three cohorts with data on reproductive factors, COPD and covariates were included. Cause specific Cox regression models were adjusted for birth year, race, educational level, body mass index and pack years of smoking, stratified by asthma, and incorporating interaction between birth year and time. Between cohort differences and within cohort correlations were taken into account. RESULTS: Overall, 2 83 070 women were included and 10 737 (3.8%) developed COPD after a median follow-up of 11 (IQR 10-12) years. Analyses revealed a U shaped association between age at menarche and COPD (≤11 vs 13: HR 1.17, 95% CI 1.11 to 1.23; ≥16 vs 13: HR 1.24, 95% CI 1.21 to 1.27). Women with three or more children (3 vs 2: HR 1.14, 95% CI 1.12 to 1.17; ≥4 vs 2: HR 1.34, 95% CI 1.28 to 1.40), multiple miscarriages (2 vs 0: HR 1.28, 95% CI 1.24 to 1.32; ≥3 vs 0: HR 1.36, 95% CI 1.30 to 1.43) or stillbirth (1 vs 0: HR 1.38, 95% CI 1.25 to 1.53; ≥2 vs 0: HR 1.67, 95% CI 1.32 to 2.10) were at a higher risk of COPD. Among postmenopausal women, earlier age at natural menopause was associated with an increased risk of COPD (<40 vs 50-51: HR 1.69, 95% CI 1.63 to 1.75; 40-44 vs 50-51: HR 1.42, 95% CI 1.38 to 1.47). CONCLUSIONS: Multiple female reproductive factors, including age at menarche, number of children, miscarriage, stillbirth, and age at natural menopause were associated with the risk of COPD.

Aspectos clínicoepidemiológicos de pacientes con cáncer de mama del Policlínico 28 de septiembre / Clinical-Epidemiological Aspects of Patients with Breast Cancer and from the Policlínico 28 de Septiembre of Santiago de Cuba

Introducción: El cáncer de mama es considerado como un serio problema de salud pública por la alta prevalencia tanto en países desarrollados como en desarrollo. Son escasos los estudios clínico-epidemiológicos actualizados en el área de salud del Policlínico 28 de septiembre relacionados con dicha entidad clínica. Objetivo: Caracterizar desde el punto de vista clínico y epidemiológico a pacientes con cáncer de mama del área de salud perteneciente al Policlínico 28 de septiembre. Métodos: Estudio descriptivo en una serie de 35 mujeres mayores de 30 años con diagnóstico confirmado de cáncer de mama. Las variables estudiadas comprendieron edad, antecedentes familiares de cáncer de mama, factores de riesgo generales y hormonales, signos y síntomas clínicos, resultados de estudio ecográfico y diagnóstico histopatológico. Se utilizó el porcentaje como medida de resumen. Resultados: El 42,8 por ciento de la muestra objeto de estudio estuvo comprendido en el grupo de edad de 40-49 años. El 65,7 por ciento del total de mujeres tenía antecedentes familiares de cáncer de mama. La menarquía precoz (54,2 por ciento) y la nuliparidad (48,5 por ciento) representaron los factores de riesgo de mayor incidencia. El 57,1 por ciento de las lesiones diagnosticadas correspondieron a carcinomas en estadío I y IIa. Conclusiones: El cáncer de mama constituye un serio problema de salud en mujeres mayores de 30 años pertenecientes al Policlínico 28 de septiembre del municipio Santiago de Cuba(AU)

Introduction: Breast cancer is considered a serious public health concern due to its high prevalence in both developed and developing countries. There are few updated clinical-epidemiological studies carried out in the health area of the Policlínico Docente 28 de Septiembre related to this clinical entity. Objective: To characterize, from the clinical and epidemiological point of view, the patients with breast cancer and from the health area belonging to the Policlínico Docente 28 de Septiembre. Methods: A descriptive study was carried out with a series of 35 women aged more than 30 years and with a confirmed diagnosis of breast cancer. The variables studied included age, family history of breast cancer, general and hormonal risk factors, clinical signs and symptoms, ultrasound findings and histopathological diagnosis. Percentage was used as summary measure. Results: 42.8 percent of the study sample was in the age group 40-49 years old. Of the total number of women, 65.7 percent had a family history of breast cancer. Early menarche (54.2 percent) and nulliparity (48.5 percent) represented the risk factors with the highest incidence. 57.1 percent of the diagnosed lesions corresponded to stage I and IIA carcinomas. Conclusions: Breast cancer is a serious health problem in women older than 30 years and belonging to the Policlínico Docente 28 de Septiembre, of Santiago de Cuba Municipality(AU)

Menstrual Dysfunction in Adolescents with Chronic Illness: A Systematic Review.

STUDY OBJECTIVE: Menstrual dysfunction can impact both the physical and emotional health of young people.1 Multiple chronic diseases have been associated with menstrual dysfunction in adults2; however, there is little research in adolescents, despite nonadherence and suboptimal illness control in this group. We aimed to identify the impact of chronic illness on the age of menarche and the menstrual cycle in adolescents. METHODS: Studies were extracted of female adolescents aged 10-19 who had a chronic physical illness. Data included outcomes on age of menarche and/or menstrual cycle quality. Exclusion criteria aimed to exclude diseases where menstrual dysfunction was a known part of the disease pathophysiology (ie, polycystic ovarian syndrome)3 or in which medications were used that directly impacted gonadal function.4 A literature search (to January 2022) was performed on the EMBASE, PubMed, and Cochrane library databases. Two widely used modified quality analysis tools were used. RESULTS: Our initial search netted 1451 articles, of which 95 full texts were examined and 43 met the inclusion criteria. Twenty-seven papers focused on type 1 diabetes (T1D), with 8 papers examining adolescents with cystic fibrosis and the remaining studying inflammatory bowel disease, juvenile idiopathic arthritis, coeliac disease, and chronic renal disease. Metanalysis of 933 patients with T1D vs 5244 controls demonstrated a significantly later age of menarche in T1D (by 0.42 years; P ≤ .00001). There was also a significant association between higher HbA1c and insulin dose (IU/kg) and later age of menarche. Eighteen papers reviewed other aspects of menstruation, including dysmenorrhea, oligomenorrhoea, amenorrhea, and ovulatory function, with variable findings. CONCLUSION: Most studies were small and in single populations. Despite this, there was evidence of delayed menarche and some evidence of irregular menses in those with cystic fibrosis and T1D. Further structured studies are needed to evaluate menstrual dysfunction in adolescents and how it relates to their chronic illness.

[Epidemiology and clinical features of patients with breast cancers hospitalized in the Department of Oncology in Fianarantsoa, Madagascar from 2011 to 2018]. / Aspects épidémio-cliniques des cancers du sein au Service d´Oncologie de Fianarantsoa, Madagascar de 2011 à 2018.

INTRODUCTION: we conducted the first epidemiological study of patients with breast cancers living in Fianarantsoa. The purpose of this study was to describe the epidemiology and clinical features of these patients in the Department of Oncology Fianarantsoa. METHODS: we conducted a retrospective and descriptive study in the Department of Oncology at the University Hospital Center of Tambohobe over a period of 8 years (2011-2018). All patients with breast cancer diagnosed based on cytological and/or histological examination were included. The parameters studied were: age, occupation, a family history of breast cancer, menarche, menopause, parity, use of oral contraceptives, smoking, circumstances leading to detection, breast symptoms, signs of locoregional and distant spread, tumour site and stage of the disease. RESULTS: the study included 62 patients with an average age of 52.83 ± 10.47 years. Housewives accounted for 39% (n = 24) of cases. No patient had an early menarche. Late menopause had occurred in 6.45% (n = 4) of patients and a family history of breast cancer was found in 8.06% (n = 5) of patients. Chewing tobacco was used by 17.74% (n = 11) of patients. Patients reporting breast symptoms accounted for 95.2% (n = 59). Breast cancers had affected the upper outer quadrant in 53.23% (n = 33) of cases. Stage III breast cancer was diagnosed in 55% (n = 34) of cases and stage IV in 32% (n = 20) of cases. CONCLUSION: in patients diagnosed with cancer at an advanced stage, risk factors for breast cancer were little observed.

Association of the Age at Menarche with Site-Specific Cancer Risks in Pooled Data from Nine Cohorts.

The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31-39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer. Over a median 10 years of follow-up, 60,968 women were diagnosed with a first primary incident cancer. Inverse linear associations were observed for seven of 19 cancers studied. Each additional year in the age at menarche was associated with reduced risks of endometrial cancer (HR = 0.91; 95% CI, 0.89-0.94), liver cancer (HR = 0.92; 95% CI, 0.85-0.99), melanoma (HR = 0.95; 95% CI, 0.93-0.98), bladder cancer (HR = 0.96; 95% CI, 0.93-0.99), and cancers of the colon (HR = 0.97; 95% CI, 0.96-0.99), lung (HR = 0.98; 95% CI, 0.96-0.99), and breast (HR = 0.98; 95% CI, 0.93-0.99). All but one of these associations remained statistically significant following adjustment for baseline body mass index. Similarities in the observed associations between menarche and seven cancers suggest shared underlying causes rooted early in life. We propose as a testable hypothesis that early exposure to sex hormones increases mid-life cancer risks by altering functional capacities of stem cells with roles in systemic energy balance and tissue homeostasis. SIGNIFICANCE: Age at menarche is associated with risk for seven cancers in middle-aged women, and understanding the shared underlying causal pathways across these cancers may suggest new avenues for cancer prevention.

The Influence of Prepubertal Onset of Type 1 Diabetes and Age of Menarche on Polycystic Ovary Syndrome Diagnosis.

CONTEXT: Higher prevalence of polycystic ovary syndrome (PCOS) in women with type 1 diabetes (T1DM) is linked to exogenous insulin, especially when diabetes is diagnosed before puberty. OBJECTIVE: The study evaluates the impact of prepubertal onset of T1DM and insulin therapy on PCOS diagnosis and phenotypic characteristics in women with T1DM. DESIGN, SETTING, AND PATIENTS: We studied 83 women with T1DM (age 26 ± 5 years, BMI 24 ± 3 kg/m2) 36 with premenarchal (PM) onset of T1DM [17 with PCOS diagnosed (PCOS+PM) and 19 without PCOS (noPCOS+PM)] and 47 women with postmenarchal onset of T1DM [24 with PCOS (PCOS-noPM) and 23 without PCOS (noPCOS-noPM)]. OUTCOME MEASUREMENTS: Clinical examination, assessment of serum sex hormones, glycated hemoglobin (HbA1c) and ultrasonographic evaluation of the ovaries were performed in all women. RESULTS: Applying Rotterdam criteria, 49% of women with T1DM were diagnosed with PCOS. There were no differences in hormonal profile and ovarian parameters between PCOS+PM and PCOS-noPM. Women with T1DM+PM had higher insulin dose/24 h and U/kg bw/24 h than T1DM-noPM (P-values = 0.014 and 0.001, respectively). Both PCOS+PM and noPCOS+PM groups had higher insulin dose U/kg bw/24 h in comparison to PCOS-noPM (P-values = 0.004 and = 0.006, respectively). In multivariable logistic regression analysis, age of menarche [odds ratio (OR): 0.672; 95% confidence interval (CI): 0.465-0.971] and HbA1c (OR: 0.569; 95% CI: 0.383-0.846) were associated with the diagnosis of PCOS. CONCLUSIONS: There were no differences in the prevalence of PCOS between T1DM+PM and T1DM-noPM; however, earlier menarche might have an influence on PCOS diagnosis in women with T1DM.

Association of Female Reproductive Factors With Incidence of Fracture Among Postmenopausal Women in Korea.

Importance: Although estrogen level is positively associated with bone mineral density, there are limited data on the risk of fractures after menopause. Objective: To investigate whether female reproductive factors are associated with fractures among postmenopausal women. Design, Setting, and Participants: This population-based retrospective cohort study used data from the Korean National Health Insurance Service database on 1 272 115 postmenopausal women without previous fracture who underwent both cardiovascular and breast and/or cervical cancer screening from January 1 to December 31, 2009. Outcome data were obtained through December 31, 2018. Exposures: Information was obtained about reproductive factors (age at menarche, age at menopause, parity, breastfeeding, and exogenous hormone use) by self-administered questionnaire. Main Outcomes and Measures: Incidence of any fractures and site-specific fractures (vertebral, hip, and others). Results: Among the 1 272 115 participants, mean (SD) age was 61.0 (8.1) years. Compared with earlier age at menarche (≤12 years), later age at menarche (≥17 years) was associated with a higher risk of any fracture (adjusted hazard ratio [aHR], 1.24; 95% CI, 1.17-1.31) and vertebral fracture (aHR, 1.42; 95% CI, 1.28-1.58). Compared with earlier age at menopause (<40 years), later age at menopause (≥55 years) was associated with a lower risk of any fracture (aHR, 0.89; 95% CI, 0.86-0.93), vertebral fracture (aHR, 0.77; 95% CI, 0.73-0.81), and hip fracture (aHR, 0.88; 95% CI, 0.78-1.00). Longer reproductive span (≥40 years) was associated with lower risk of fractures compared with shorter reproductive span (<30 years) (any fracture: aHR, 0.86; 95% CI, 0.84-0.88; vertebral fracture: aHR, 0.73; 95% CI, 0.71-0.76; and hip fracture: aHR, 0.87; 95% CI, 0.80-0.95). Parous women had a lower risk of any fracture than nulliparous women (aHR, 0.96; 95% CI, 0.92-0.99). Although breastfeeding for 12 months or longer was associated with a higher risk of any fractures (aHR, 1.05; 95% CI, 1.03-1.08) and vertebral fractures (aHR, 1.22; 95% CI, 1.17-1.27), it was associated with a lower risk of hip fracture (aHR, 0.84; 95% CI, 0.76-0.93). Hormone therapy for 5 years or longer was associated with lower risk of any factures (aHR, 0.85; 95% CI, 0.83-0.88), while use of oral contraceptives for 1 year or longer was associated with a higher risk of any fractures (aHR, 1.03; 95% CI, 1.01-1.05). Conclusions and Relevance: The findings of this cohort study suggest that female reproductive factors are independent risk factors for fracture, with a higher risk associated with shorter lifetime endogenous estrogen exposure. Interventions to reduce fracture risk may be needed for women at high risk, including those without osteoporosis.

Prepubertal Internalizing Symptoms and Timing of Puberty Onset in Girls.

Stressful environments have been associated with earlier menarche. We hypothesized that anxiety, and possibly other internalizing symptoms, are also associated with earlier puberty in girls. The Lessons in Epidemiology and Genetics of Adult Cancer From Youth (LEGACY) Girls Study (2011-2016) included 1,040 girls aged 6-13 years at recruitment whose growth and development were assessed every 6 months. Prepubertal maternal reports of daughter's internalizing symptoms were available for breast onset (n = 447), pubic hair onset (n = 456), and menarche (n = 681). Using Cox proportional hazard regression, we estimated prospective hazard ratios and 95% confidence intervals for the relationship between 1 standard deviation of the percentiles of prepubertal anxiety, depression, and somatization symptoms and the timing of each pubertal outcome. Multivariable models included age, race/ethnicity, study center, maternal education, body mass index percentile, and family history of breast cancer. Additional models included maternal self-reported anxiety. A 1-standard deviation increase in maternally reported anxiety in girls at baseline was associated with earlier subsequent onset of breast (hazard ratio (HR) = 1.22, 95% confidence interval (CI): 1.09, 1.36) and pubic hair (HR = 1.15, 95% CI: 1.01, 1.30) development, but not menarche (HR = 0.94, 95% CI: 0.83, 1.07). The association of anxiety with earlier breast development persisted after adjustment for maternal anxiety. Increased anxiety in young girls may indicate risk for earlier pubertal onset.

Delayed age at menarche in chronic respiratory diseases.

OBJECTIVE: Age at menarche (AAM) is an important indicator of physiological development in women, and delayed AAM has been associated with chronic illnesses. We investigated predictive factors at diagnosis that influence AAM in adolescents with chronic respiratory diseases. STUDY DESIGN: AAM was assessed in 1207 northern Italian female aged 11-24 (1062 healthy, 98 with asthma and 47 with cystic fibrosis [CF]). AAM was defined by recall and status quo methods. We studied anthropometric data, metabolic status, diagnosis parameters, presence of irregular menses. Clinical data of subjects with chronic respiratory illness were compared with that of healthy adolescents. RESULTS: Mean AAM for healthy adolescents was 12.49 ± 1.2 years. Mother's AAM was positively associated with that of their daughters (P < .001). BMI was negatively correlated with AAM (P < .001). 69% of healthy adolescents referred regular menses. AAM in the different groups was 12.79 ± 3.0 years for patients with asthma (P < .05 vs healthy) and 13.24 ± 1.44 years for adolescents with CF (P < .0001 vs healthy). In the asthmatic group, 57% of the patients referred regular menses, and no significant differences were found between AAM and control of the disease (ACT test). In the CF group, no correlation was found between the type of CFTR mutation or FEV1% and AAM. 53% of the patients with CF referred regular menses. CONCLUSIONS: AAM in patients with CF and asthma was significantly higher than in healthy adolescents, and menses abnormalities were observed in the last two groups. Inflammation influences the reproductive function in chronic respiratory disease.

Pubertal Development: What's Normal/What's Not.

Onset of puberty, as defined by breast stage 2, appears to be starting at younger ages since the 1940s. There is an ongoing controversy regarding what is normative, as well as what is normal, and the evaluation that is deemed necessary for girls maturing before 8 years of age. There are potential implications of earlier pubertal timing, including psychosocial consequences during adolescence, as well as longer term risks, such as breast cancer and cardiometabolic risks. There are additional consequences derived from slower pubertal tempo, for age of menarche has not decreased as much as age of breast development; these include longer interval between sexual initiation and intentional childbearing, as well as a broadened window of susceptibility to endocrine-related cancers.

Timing of menarche and abnormal hippocampal connectivity in youth at clinical-high risk for psychosis.

The "estrogen hypothesis" suggests that estrogen is a protective factor against psychotic disorders such as schizophrenia. Although the precise protective mechanisms are still unclear, one potential explanation lies in the role that increased estrogens play in mediating hippocampal plasticity, as this may reduce hippocampal dysconnectivity that is characteristically observed in psychosis. In support of this view, later age at menarche- less available estrogen during critical early adolescent development- is related to earlier onset of psychosis and increased symptom severity. Furthermore, if estrogens have protective effects, then we should see this effect in the psychosis risk period in those at clinical high-risk (CHR) for psychosis - i.e., individuals showing attenuated symptoms at imminent risk for transitioning to a psychotic diagnosis. This study examined whether earlier age at menarche would result in more normative hippocampal connectivity in CHR youth; menarche is an easily assessed, developmental marker associated with the availability of estrogens. Resting-state connectivity was examined in sixty female participants (26 CHR and 34 healthy control; age 12-21) using a cross-sectional approach; hippocampal connectivity was found to relate to age at menarche. Later age at menarche in the CHR group related to increased hippocampal dysconnectivity to the occipital cortex (a region with a neurotrophic response to estrogen) compared to the controls. Results suggest that earlier availability of estrogens may have neuroprotective effects on hippocampal plasticity. Findings have relevance for understanding sex differences and etiology, as well as guiding novel treatments.

Isolated premature menarche in two siblings with Neurofibromatosis type 1.

Objectives Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder, caused by mutation in NF1. The condition is typified by the development of benign and malignant tumours in both the central nervous system and peripheral tissues. Isolated menarche is a sub-classification of incomplete isosexual precocious puberty typified by menarche in girls with no other features of pubertal development. The effects of NF1 on pubertal timing are poorly understood, we report two siblings with NF1 and apparent abnormal pubertal development. Case Presentation Two siblings were referred to the tertiary paediatric endocrinology clinic at 6 and 7 years of age with recurrent, cyclical vaginal bleeding. There was a strong family history of NF1, the mother of the siblings and two brothers were also diagnosed at a young age. On examination both patients were prepubertal at presentation. Both siblings underwent a gonadotrophin releasing hormone test, which revealed a follicle-stimulating hormone dominant (prepubertal) response. The features were suggestive of isolated premature menarche as no other cause was identified. The elder sibling established menarche and developed signs of consonant pubertal development at 12 years of age. The younger sibling remains under regular follow-up. Conclusions NF1 has previously been associated with alterations in pubertal timing. We report, for the first time, two siblings with NF1 who presented with isolated menarche.

Gut microbiome associations with breast cancer risk factors and tumor characteristics: a pilot study.

OBJECTIVE: To investigate the association between gut microbiome with breast tumor characteristics (receptor status, stage and grade) and known breast cancer risk factors. METHODS: In a pilot cross-sectional study of 37 incident breast cancer patients, fecal samples collected prior to chemotherapy were analyzed by 16S ribosomal RNA (rRNA) gene-based sequencing protocol. Alpha diversity and specific taxa by tumor characteristics and breast cancer risk factors were tested by Wilcoxon rank sum test, and by differential abundance analysis, using a zero-inflated negative binomial regression model with adjustment for total counts, age and race/ethnicity. RESULTS: There were no significant alpha diversity or phyla differences by estrogen/progesterone receptor status, tumor grade, stage, parity and body mass index. However, women with human epidermal growth factor receptor 2 positive (HER2+) (n = 12) compared to HER2- (n = 25) breast cancer showed 12-23% lower alpha diversity [number of species (OTU) p = 0.033, Shannon index p = 0.034], lower abundance of Firmicutes (p = 0.005) and higher abundance of Bacteroidetes (p = 0.089). Early menarche (ages ≤ 11) (n = 11) compared with later menarche (ages ≥ 12) (n = 26) was associated with lower OTU (p = 0.036), Chao1 index (p = 0.020) and lower abundance of Firmicutes (p = 0.048). High total body fat (TBF) (> 46%) (n = 12) compared to lower (≤ 46%) TBF was also associated with lower Chao 1 index (p = 0.011). There were other significant taxa abundance differences by HER2 status, menarche age, as well as other tumor and breast cancer risk factors. CONCLUSIONS AND RELEVANCE: Further studies are needed to identify characteristics of the human microbiome and the interrelationships between breast cancer hormone receptor status and established breast cancer risk factors.

The association between second to fourth digit ratio, reproductive and general health among women: findings from an Israeli pregnancy cohort.

The ratio between the length of second and fourth digits (2D:4D) is a putative biomarker for prenatal testosterone and estrogen exposure. The aim of the study was to examine the association between 2D:4D and women's general and reproductive health. This analysis was conducted within a prospective pregnancy cohort study. The study population included 187 women. 2D:4D was measured directly in both hands using a digital caliper. Multivariable linear and logistic models were used to study the associations between digit ratio and the studied health characteristics. Mean age of the participants was 30.7 ± 4.9 years. The mean age at menarche was 12.9 ± 1.4 years. Right hand 2D:4D mean ± SD was 0.965 ± 0.03. Left hand 2D:4D mean ± SD was 0.956 ± 0.03. An association was found between right 2D:4D and age at menarche, with older age in women with 2D:4D ≥ mean versus 2D:4D < mean (13.2 ± 1.5 and 12.8 ± 1.3 respectively, b = 0.48, 95%CI:0.06-0.91) while controlling for ethnicity. Higher 2D:4D was also associated with heavier menses bleeding and dysmenorrhea. There is an association between 2D:4D and sub optimal reproductive characteristics, including later age at menarche, heavier menses bleeding and dysmenorrhea. These findings support the association between the intrauterine period and reproductive characteristics. Further studies are required to support our findings.

Pubertad en pacientes con hiperplasia adrenal congénita por déficit de 21hidroxilasa y asignación femenina / Puberty in patients with congenital adrenal hyperplasia due to a 21-hydroxylase deficit and female assignment

RESUMEN Introducción: En la hiperplasia adrenal congénita el aumento de los niveles de andrógenos suprarrenales en las pacientes no tratadas o mal controladas, puede alterar el inicio y/o la progresión puberal (progresión puberal/progresiones puberales?). Objetivos: Describir las características puberales de pacientes con hiperplasia adrenal congénita asignadas como femeninas e identificar si existe asociación entre elementos relacionados con la enfermedad y el inicio y progresión puberales. Métodos: Se incluyeron todas las pacientes con diagnóstico de hiperplasia adrenal congénita asignadas como femeninas, que fueron atendidas en el INEN de enero 2000 a mayo 2019. Resultados: Fueron estudiadas 47 pacientes, con una media de edad de 14,76 ± 7,04 años. Se comprobó un predominio de las formas clínicas clásicas en 25 pacientes (53,19 por ciento), de ellas 11 (23,40 por ciento) fueron formas virilizantes simples, 14 (29,78 por ciento) perdedoras de sal y 22 (46,80 por ciento) formas no clásicas. El inicio del vello pubiano fue a una edad promedio de 7,78 ± 3,2 años. El comienzo de la telarquia resultó en una media de 10,09 ± 2,4 años y la menarquia a los 12,2 ± 2,3 años como promedio. De las 29 pacientes que ya habían menstruado 16 (55,2 por ciento) presentaban irregularidades menstruales. El tiempo entre el inicio puberal y la menarquia fue de 3,4 años en las formas no clásicas, 5,6 años en las perdedoras de sal y 7,0 años en las virilizantes simples. La edad al diagnóstico, la edad de inicio del tratamiento y la dosis de esteroides empleada se relacionaron con algunos aspectos puberales. Conclusiones: El diagnóstico oportuno y el ajuste cuidadoso del esquema esteroideo, constituyen pilares importantes en el inicio y progresión puberales, y en la consecución de ciclos ovulatorios regulares que aseguren desde la adolescencia, un inicio y desarrollo puberales normales y en edades reproductivas, la optimización de la fertilidad(AU)

ABSTRACT Introduction: In the congenital adrenal hyperplasia, the increased levels of adrenal androgens in patients untreated or poorly controlled can alter the start and/or pubertal progression (pubertal progression/pubertal progressions). Objectives: To describe the pubertal characteristics of patients with congenital adrenal hyperplasia assigned as females and to identify whether there is an association between elements related to the disease and the pubertal onset and progression. Methods: There were included all patients diagnosed with congenital adrenal hyperplasia assigned as females that were attended at the National Institute of Endocrinology from January 2000 to May 2019. Results: 47 patients were studied, with an average age of 14.76 ± 7.04 years. It was found a predominance of classic clinical forms in 25 patients (53.19 percent, of which 11 (23.40 percent) had simple virilization forms, 14 (29.78 percent) were salt-losers and 22 (46.80 percent) had non-classical forms. The onset of the pubic hair was at an average age of 7.78 ± 3.2 years. The beginning of the thelarche resulted in an average of 10.09 ± 2.4 years and menarche at the 12.2 ± 2.3 years on average. Of the 29 patients who had menstruated, 16 (55.2 percent) presented menstrual irregularities. The time between the puberty onset and menarche was 3.4 years in the non-classical forms, 5.6 years in the salt-losers, and 7.0 years in the simple virilizations. The age at initial diagnosis treatment and the dose of steroids used were related to some pubertal aspects. Conclusions: Early diagnosis and careful adjustment of the steroid scheme are important pillars in the pubertal onset and progression, the achievement of regular ovulatory cycles, and with it, in the optimization of fertility(AU)