Metabolome-wide Mendelian randomization for age at menarche and age at natural menopause.

BACKGROUND: The role of metabolism in the variation of age at menarche (AAM) and age at natural menopause (ANM) in the female population is not entirely known. We aimed to investigate the causal role of circulating metabolites in AAM and ANM using Mendelian randomization (MR). METHODS: We combined MR with genetic colocalization to investigate potential causal associations between 658 metabolites and AAM and between 684 metabolites and ANM. We extracted genetic instruments for our exposures from four genome-wide association studies (GWAS) on circulating metabolites and queried the effects of these variants on the outcomes in two large GWAS from the ReproGen consortium. Additionally, we assessed the mediating role of the body mass index (BMI) in these associations, identified metabolic pathways implicated in AAM and ANM, and sought validation for selected metabolites in the Avon Longitudinal Study of Parents and Children (ALSPAC). RESULTS: Our analysis identified 10 candidate metabolites for AAM, but none of them colocalized with AAM. For ANM, 76 metabolites were prioritized (FDR-adjusted MR P-value ≤ 0.05), with 17 colocalizing, primarily in the glycerophosphocholines class, including the omega-3 fatty acid and phosphatidylcholine (PC) categories. Pathway analyses and validation in ALSPAC mothers also highlighted the role of omega and polyunsaturated fatty acids levels in delaying age at menopause. CONCLUSIONS: Our study suggests that metabolites from the glycerophosphocholine and fatty acid families play a causal role in the timing of both menarche and menopause. This underscores the significance of specific metabolic pathways in the biology of female reproductive longevity.

The Effects of Lifetime Estrogen Exposure on Breast Epigenetic Age.

BACKGROUND: Estrogens are thought to contribute to breast cancer risk through cell cycling and accelerated breast aging. We hypothesize that lifetime estrogen exposure drives early epigenetic breast aging observed in healthy women. In this study, we examined associations between hormonal factors and epigenetic aging measures in healthy breast tissues. METHODS: We extracted DNA from breast tissue specimens from 192 healthy female donors to the Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center. Methylation experiments were performed using the Illumina EPIC 850K array platform. Age-adjusted regression models were used to examine for associations between factors related to estrogen exposure and five DNA methylation-based estimates: Grim age, pan-tissue age, Hannum age, phenotypic age, and skin and blood clock age. RESULTS: Women were aged 19-90 years, with 95 premenopausal, and 97 nulliparous women. The age difference (Grim age - chronologic age) was higher at earlier ages close to menarche. We found significant associations between earlier age at menarche and age-adjusted accelerations according to the Grim clock, the skin and blood clock, and between higher body mass index (BMI) and age-adjusted accelerations in the Grim clock, Hannum clock, phenotypic clock, and skin and blood clock. CONCLUSIONS: Earlier age at menarche and higher BMI are associated with elevations in DNA methylation-based age estimates in healthy breast tissues, suggesting that cumulative estrogen exposure drives breast epigenetic aging. IMPACT: Epigenetic clock measures may help advance inquiry into the relationship between accelerated breast tissue aging and an elevated incidence of breast cancer in younger women.

Age at menopause in India: A systematic review.

BACKGROUND AND AIMS: Menopause is a physiological process in nature and hence, variations in the age of menopause are not expected. Hence, the study was conducted with an objective to calculate the reliable estimates of age at menopause for India, and understand the differentials in women's age at menopause throughout the country. METHODS: A total of 202 studies of age at menopause, covering the period 2009-2020, were accessed from PubMed database and Google. Of these only ten studies met the selection criteria for this paper, which is that the data for these studies must be collected from house-to-house surveys. RESULTS: The average age at menopause in India, with minimal publication bias, is 46.6 years (95% CI: 44.83, 48.44). In one study slightly above 1.96 Standard Deviation, was observed, as ascertained by Funnel Plot and Egger's test. The mean age ranged from a minimum of 44.69 years (95% CI: 35.01, 54.37) to a maximum of 48.95 (95% CI: 42.29, 55.61) years. Furthermore, the age at menopause did not exhibit any significant variation by age at menarche, although the association was positive. CONCLUSIONS: The age at menopause showed positive association with age at menarche. In India, during the period 2009-2020, it was 46.6 years, which significantly lower than the age in some developed countries. The differences may be methodological since no information was found regarding the distribution of age at menopause in the studies that were considered for meta-analysis.

Duration of estrogen exposure during reproductive years, age at menarche and age at menopause, and risk of cardiovascular disease events, all-cause and cardiovascular mortality: a systematic review and meta-analysis.

BACKGROUND: Little is known about the estrogen exposure measurement and mutual effect of age at menarche and age at menopause in the risk of cardiovascular disease (CVD) events. OBJECTIVES: To evaluate estrogen exposure measurement and describe mutual effect of age at menarche and age at menopause in the risk of CVD events. SEARCH STRATEGY: Systematic review of literature in PubMed, Embase and Web of Science for studies published up to 28 June 2020. SELECTION CRITERIA: Observational studies related to estrogen exposure measurement, including mutual effect of age at menarche and age at menopause and risk of CVD events. DATA COLLECTION AND ANALYSIS: Synthesis of evidence was conducted by reviewing individual estimates, followed by meta-analysis. The study received no external funding. MAIN RESULTS: A total of 75 studies were included in synthesis of evidence, of which 17 studies were included in meta-analysis. Reproductive lifespan (age at menopause - age at menarche), endogenous estrogen exposure and total estrogen exposure were used for estrogen exposure measurement. Reproductive lifespan was by far the most commonly used method for estrogen exposure measurement. A shorter reproductive lifespan was associated with a higher risk of CVD events; the pooled relative risk (95% CI) was 1.31 (1.25-1.36) for stroke events. Robust epidemiological studies with measurement of estrogen exposure and associated health risk would strengthen the evidence. CONCLUSIONS: Reproductive lifespan was the most commonly used method for estrogen exposure measurement in epidemiological studies. A shorter reproductive lifespan was associated with a higher risk of CVD events, particularly stroke. TWEETABLE ABSTRACT: A systematic review and meta-analysis found that women with a shorter reproductive lifespan have a higher risk of stroke events.

Comparison of PCOS phenotypes in adolescent and young adult Mediterranean women with possible PCOS.

PURPOSE: During adolescence, PCOS features are supposed to be in evolution. Because of this, the diagnosis of PCOS in adolescence is often unclear and few studies have compared adolescent and adult PCOS phenotype distribution and features. The aim is to compare phenotypes in adolescents and young adults with PCOS. METHODS: 109 girls aged from 13 to 19 years were retrospectively studied. All patients had a gynecological age > 2 years. 63 patients were adolescents (3-5 years beyond menarche) while 46 patients were young adults (6-9 years beyond menarche). Diagnosis of different PCOS phenotypes (A, B, C, D) was made according to the Rotterdam criteria. Clinical data (menstrual cycles, BMI, presence of hirsutism), androgen circulating levels (total testosterone, androstenedione, dehydroepiandrosterone sulphate) and ovarian morphology by ultrasound were assessed. RESULTS: 109 patients presented PCOS according to the Rotterdam criteria. Phenotype A was by far the most common phenotype (73.4%) followed by phenotype B (21.1%). Only few patients had phenotype C (4.6%) or phenotype D (0.9%). When patients were divided in two groups (adolescent and young adult patients), no significant difference in prevalence and features of the different phenotypes was observed. CONCLUSION: In this cohort of adolescent and young adult women with PCOS, the progression of age does not change the prevalence and the features of main PCOS phenotypes. It suggests that the Rotterdam criteria might be used also in adolescents, at least in those with 2 or more years of gynecological age, for the diagnosis of PCOS.

Reproductive health in women with type 2 diabetes mellitus.

As type 2 diabetes mellitus (T2DM) reaches epidemic proportions in the developed world and the age at diagnosis decreases, more women of reproductive age are being affected. In this article, we provide a synoptic view on potential mechanisms and relevant factors underlying menstrual cycle disorders and fertility issues in women with T2DM. The article discusses the function of the hypothalamic-pituitary-ovarian (HPO) axis, the central role of the hypothalamus in the homeostasis of this system, the central modulators of the axis, and the peripheral metabolic signals involved in neuroendocrine control of reproduction. The available literature on the relationship between T2DM and the female reproductive lifespan, menstrual cycle disorders, fertility issues, and gestational health in women with T2DM are also discussed. The data so far indicate that there is a "U-shaped" relationship between menarche, menopause, and T2DM, both early and late menarche/menopause being risk factors for T2DM. Hyperglycemia and its consequences may be responsible for the effects of T2DM on reproductive health in women, but the exact mechanisms are not as yet fully understood; thus, more studies are needed in order to identify factors causing disruption of the HPO axis.

Association of puberty timing with type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Emerging studies have investigated the association between puberty timing, particularly age at menarche (AAM), and type 2 diabetes. However, whether this association is independent of adiposity is unclear. We aimed to systematically review published evidence on the association between puberty timing and type 2 diabetes (T2D) or impaired glucose tolerance (IGT), with and without adjustment for adiposity, and to estimate the potential contribution of puberty timing to the burden of T2D in the United Kingdom (UK). METHODS AND FINDINGS: We searched PubMed, Medline, and Embase databases for publications until February 2019 on the timing of any secondary sexual characteristic in boys or girls in relation to T2D/IGT. Inverse-variance-weighted random-effects meta-analysis was used to pool reported estimates, and meta-regression was used to explore sources of heterogeneity. Twenty-eight observational studies were identified. All assessed AAM in women (combined N = 1,228,306); only 1 study additionally included men. In models without adjustment for adult adiposity, T2D/IGT risk was lower per year later AAM (relative risk [RR] = 0.91, 95% CI 0.89-0.93, p < 0.001, 11 estimates, n = 833,529, I2 = 85.4%) and higher for early versus later menarche (RR = 1.39, 95% CI 1.25-1.55, p < 0.001, 23 estimates, n = 1,185,444, I2 = 87.8%). Associations were weaker but still evident in models adjusted for adiposity (AAM: RR = 0.97 per year, 95% CI 0.95-0.98, p < 0.001, 12 estimates, n = 852,268, I2 = 51.8%; early menarche: RR = 1.19, 95% CI 1.11-1.28, p < 0.001, 21 estimates, n = 890,583, I2 = 68.1%). Associations were stronger among white than Asian women, and in populations with earlier average AAM. The estimated population attributable risk of T2D in white UK women due to early menarche unadjusted and adjusted for adiposity was 12.6% (95% CI 11.0-14.3) and 5.1% (95% CI 3.6-6.7), respectively. Findings in this study are limited by residual and unmeasured confounding, and self-reported AAM. CONCLUSIONS: Earlier AAM is consistently associated with higher T2D/IGT risk, independent of adiposity. More importantly, this research has identified that a substantial proportion of T2D in women is related to early menarche, which would be expected to increase in light of global secular trends towards earlier puberty timing. These findings highlight the need to identify the underlying mechanisms linking early menarche to T2D/IGT risk.

Branched-Chain and Aromatic Amino Acids Are Associated With Insulin Resistance During Pubertal Development in Girls.

PURPOSE: Cross-sectional studies in children show branched-chain and aromatic amino acids are associated with insulin resistance, but whether these associations persist from childhood to adulthood is not known. This study aimed to assess whether circulating amino acids associate with insulin resistance during pubertal development. METHODS: This was a 7.5-year longitudinal study from childhood to early adulthood. A total of 396 nondiabetic Finnish girls aged 11.2 ± .8 years at baseline participated in the study which was conducted at the Health Science Laboratory, University of Jyväskylä. Serum concentrations of glucose and insulin were determined by enzymatic photometric methods and amino acids by nuclear magnetic resonance spectroscopy. Insulin resistance was determined by the homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: All amino acids were positively associated with HOMA-IR both before and after menarche (p < .05 for all), except for histidine. Branched-chain amino acids and aromatic amino acids showed the strongest associations, the magnitude of correlation coefficients being similar before and after menarche (R2 = .064-.171). After adjusting for body mass index z-score and height, the associations between branched-chain amino acids and aromatic amino acids and HOMA-IR remained significant both before and after menarche. CONCLUSIONS: Branched-chain amino acids and aromatic amino acids associate with insulin resistance during pubertal development, independent of adiposity. Further studies are needed to determine whether changes in amino acid metabolism link pubertal hyperinsulinemia to accelerated physiological growth and/or heightened cardiometabolic risk later in life.

Early Menstrual Factors Are Associated with Adulthood Cardio-Metabolic Health in a Survey of Mexican Teachers.

Objectives To evaluate whether age at menarche and time to menstrual regularity were related to cardio-metabolic risk factors in Mexican women. Methods The study population comprised 54,921 women from the 2008-2010 wave of the Mexican Teacher's Cohort. A modified Poisson approach was used; exposures were age at menarche and time to menstrual regularity (< 1 year vs. ≥1 year), and outcomes were prevalent obesity, type 2 diabetes, high blood pressure, and high cholesterol. Results Mean (SD) age of women was 42.1 (7.6) years, and mean (SD) menarcheal age was 12.5 (1.5) years. Compared to women with menarche age 13 years, those with menarche < 9 years had a 65% (95% CI 43-90%); 27% (95% CI 4-55%); and 23% (95% CI 1-49%) higher prevalence of obesity, high blood pressure, and high cholesterol, respectively. For diabetes, there was a U-shaped association; compared to menarche age 13 years, those with menarche < 9 years had an 89% higher prevalence of diabetes (95% CI 39-156%), and those with menarche ≥ 17 years had a 65% higher prevalence (95% CI 16-134%). Among women with regular cycles (n = 43,113), a longer time to menstrual regularity was associated with diabetes (PR = 1.11 with 95% CI 1.02-1.22), high blood pressure (PR = 1.11 with 95% CI 1.06-1.17), and high cholesterol (PR = 1.09 with 95% CI 1.04-1.14). Conclusions for practice Mexican women with earlier and later ages at menarche and/or longer time to menstrual regularity may have higher risk of cardio-metabolic disease in adulthood.

Relationship between umbilical cord sex hormone binding globulin, sex steroids, and age at menarche: a prospective cohort study.

OBJECTIVE: To study the role of the prenatal environment in regulating reproductive development by measuring the prospective association between umbilical cord concentrations of sex hormone binding globulin (SHBG; principal regulator of sex steroid activity), bioavailable sex steroids, and age at menarche. DESIGN: Prospective population-based cohort. SETTING: Not applicable. PATIENT(S): In 286 female members of the Western Australian Pregnancy (Raine) cohort, concentrations of SHBG and steroids (estrogens: estrone, estradiol, estriol and estetrol [E4]; androgens: total testosterone, Δ4-androstenedione, androstenedione and dehydroepiandrosterone) were measured by liquid chromatography-tandem mass spectrometry from archived umbilical cord blood samples collected at birth. Bioavailable concentrations of testosterone and estradiol were calculated along with total composite measures of androgen and estrogen bioactivity. SHBG was measured by ELISA. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Age of menarche was calculated from date of menarche, collected prospectively by questionnaire sent home with participants at the year 10 follow-up. RESULT(S): Higher maternal education, higher body mass index, and the presence of antepartum hemorrhage were all significantly associated with earlier age at menarche. The bioavailable sex steroid measures accounted for 8.3% of the variance in age at menarche. Further, both SHBG and E4 concentrations accounted for a significant proportion of unique variance in age at menarche. CONCLUSION(S): Lower SHBG and higher E4 concentrations in umbilical cord blood were associated with earlier age at menarche. These results suggest that the prenatal sex steroid environment contributes toward pubertal development and age at menarche.

The hormonal sensitivity hypothesis: A review and new findings.

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

Reproductive Factors and Incidence of Heart Failure Hospitalization in the Women's Health Initiative.

BACKGROUND: Reproductive factors reflective of endogenous sex hormone exposure might have an effect on cardiac remodeling and the development of heart failure (HF). OBJECTIVES: This study examined the association between key reproductive factors and the incidence of HF. METHODS: Women from a cohort of the Women's Health Initiative were systematically evaluated for the incidence of HF hospitalization from study enrollment through 2014. Reproductive factors (number of live births, age at first pregnancy, and total reproductive duration [time from menarche to menopause]) were self-reported at study baseline in 1993 to 1998. We employed Cox proportional hazards regression analysis in age- and multivariable-adjusted models. RESULTS: Among 28,516 women, with an average age of 62.7 ± 7.1 years at baseline, 1,494 (5.2%) had an adjudicated incident HF hospitalization during an average follow-up of 13.1 years. After adjusting for covariates, total reproductive duration in years was inversely associated with incident HF: hazard ratios (HRs) of 0.99 per year (95% confidence interval [CI]: 0.98 to 0.99 per year) and 0.95 per 5 years (95% CI: 0.91 to 0.99 per 5 years). Conversely, early age at first pregnancy and nulliparity were significantly associated with incident HF in age-adjusted models, but not after multivariable adjustment. Notably, nulliparity was associated with incident HF with preserved ejection fraction in the fully adjusted model (HR: 2.75; 95% CI: 1.16 to 6.52). CONCLUSIONS: In post-menopausal women, shorter total reproductive duration was associated with higher risk of incident HF, and nulliparity was associated with higher risk for incident HF with preserved ejection fraction. Whether exposure to endogenous sex hormones underlies this relationship should be investigated in future studies.

Bivariate Genome-Wide Association Study Implicates ATP6V1G1 as a Novel Pleiotropic Locus Underlying Osteoporosis and Age at Menarche.

OBJECTIVE: Age at menarche (AAM) is determined by the overall duration of endocrine-tissue sex hormone exposure levels. Osteoporosis, the most common metabolic bone disease, is characterized primarily by reduced bone mineral density (BMD) and an increased risk of low trauma fractures. Bone was an endocrine organ regulating the synthesis and secretion of sex steroid hormones. The mutual dependence between bone and gonads underscore the importance of genetic approaches to identify novel pleiotropic genetic factors coregulating BMD and AAM. In this study, we performed a bivariate genome-wide association study (GWAS) to explore novel ethnic common loci and/or genes that may influence both AAM and BMD. METHODS: We analyzed genotyping data available for 826 unrelated Chinese subjects using genome-wide human genotyping arrays. After quality control, a total of 702 413 single-nucleotide polymorphisms (SNPs) were tested for association using a bivariate linear regression model. The interesting SNPs were replicated in three independent cohorts including 1728 unrelated Caucasians, 709 African-Americans, and 408 Hispanic-Americans. RESULTS: We found four SNPs (rs10817638, rs7851259, rs10982287, and rs4979427), located upstream of the ATP6V1G1 gene, were bivariately associated with hip BMD-AAM (P = 4.90 × 10(-7), P = 1.07 × 10(-6), P = 1.28 × 10(-5), and P = 5.42 × 10(-5), respectively). These four SNPs were replicated in African-Americans, with corresponding values of P = 1.95 × 10(-2), P = 3.18 × 10(-2), P = 2.57 × 10(-2), and P = 3.64 × 10(-2), respectively. rs10817638 and rs10982287 were further replicated in Caucasians (P = 1.76 × 10(-2) and P = 9.42 × 10(-3), respectively) and Hispanic-Americans (P = 8.37 × 10(-3) and P = 1.52 × 10(-3), respectively). Meta-analyses yielded stronger association signals for rs10817638 and rs10982287 with combined values of P = 3.02 × 10(-9) and P = 3.49 × 10(-9), respectively. CONCLUSIONS: Our study implicated ATP6V1G1 as a novel pleiotropic gene underlying variation of both BMD and AAM. The findings enhance our knowledge of genetic associations between BMD and AAM and provide a rationale for subsequent functional studies of these implicated genes in the pathophysiology of diseases/traits, such as osteoporosis and AAM.

Determinación de la relación 2-hidroxiestrona/16x-hidroxiestrona en la orina de mujeres mexicanas como indicador de riesgo a cáncer de mama y su relación con otros factores de riesgo / Determination of 2-hydroxyestrone/16x-hydroxyestrone ratio in urine of Mexican women as a risk indicator for breast cancer and its relationship with other risk factors

La relación 2-hidroxiestrona/16α-hidroxiestrona urinaria (RMEO), se ha propuesto en diversas poblaciones del mundo como indicador de riesgo a cáncer de mama (CM), sin embargo, en la población mexicana, nunca se ha determinado. Objetivo: Determinar la RMEO en mujeres mexicanas y establecer su relación con factores de riesgo para CM. Material y Métodos: Estudio transversal analítico de 142 mujeres premenopáusicas y 42 posmenopáusicas. Se determinó la RMEO con el estuche ESTRAMETTM y se relacionó con factores de riesgo para CM. Se realizaron correlaciones y regresiones lineales. Resultados: La mediana de la RMEO fue 0.90 (RIC: 0.64-1.18). El índice de masa corporal (IMC) y la menarca temprana contribuyeron en 5.4% de su variabilidad (F=5.17; p<0.000). IMC participó en 6.1% de la variabilidad de 2-hidroxiestrona en mujeres premenopáusicas (F=4.40; p<0.000) y 18.1% en posmenopáusicas (F=8.85; p<0.000). Conclusión: La RMEO fue ≈50% menor que lo reportado para otras poblaciones e inversamente proporcional al IMC (AU)

The urinary ratio 2-hydroxyoestrone/16α-hydroxyoestrone (URME), has been proposed in various populations on the world as a risk indicator for breast cancer (BC), however in the Mexican population has never been determined. Objective: To determine URME Mexican women and establish its relationship with risk factors for BC. Material and Methods: Cross-sectional study of 142 premenopausal and 42 posmenopausal women. The URME was determined with the kit ESTRAMETTM and was related to risk factors for BC. Correlations and linear regressions were performed. Results: The median URME was 0.90 (RIQ 0.64-1.18). The body mass index (BMI) and early menarche contribute 5.4% of their variability (F=5.17; p<0.000). IMC participated in 6.1% of the variability of 2-hydroxyoestrone in premenopausal (F=4.40; p<0.000) and 18.1% in posmenopausal women (F=8.85; p<0.000). Conclusion: The URME was ≈50% lower than reported for other populations and inversely proportional to BMI (AU)

Age at menarche and non-alcoholic fatty liver disease.

BACKGROUND & AIMS: The goal of this study was to examine the association between age at menarche and non-alcoholic fatty liver disease (NAFLD) in Korean women and to explore whether any observed associations were mediated by adult adiposity. METHODS: A cross-sectional study was performed for 95,183 Korean women, aged 30 or older, who underwent a regular health screening examination between March 2011 and April 2013. Information regarding age at menarche was collected using standardized, self-administered questionnaires. The presence of fatty liver was determined using ultrasonographic findings. Poisson regression models with robust variance were used to evaluate the association between age at menarche and NAFLD. RESULTS: Of the 76,415 women evaluated in this study, 9601 had NAFLD. Age at menarche was inversely associated with the prevalence of NAFLD. In a multivariable-adjusted model, the prevalence ratios (95% CIs) for NAFLD comparing menarche at <12, 12, 14, 15, and 16-18 years to menarche at 13 years were 1.31 (1.18-1.45), 1.05 (0.97-1.13), 0.93 (0.87-0.99), 0.87 (0.82-0.93), and 0.78 (0.73-0.84), respectively (p for trend <0.001). Adjusting for adult BMI or percent fat mass (%) substantially reduced these associations; however, they remained statistically significant. The association between age at menarche and NAFLD was modified by age. CONCLUSIONS: We identified an inverse association between age at menarche and NAFLD in a large sample of middle-aged women. This association was partially mediated by adiposity. The findings of this study suggest that obesity prevention strategies are needed in women who undergo early menarche to reduce the risk of NAFLD.

Puberty-related changes in cortisol, dehydroepiandrosterone, and estradiol-17ß secretions within the first hour after waking in premenarcheal girls.

OBJECTIVE: The onset of menstruation is the hallmark of female pubertal development. The present study determined whether pubertal girls experience adrenocortical and ovarian steroid secretions within their first waking hour before getting their period, similar to those observed in adult females with regular cycles. METHODS: Cortisol, dehydroepiandrosterone (DHEA), and estradiol-17ß concentrations were measured in saliva samples collected after awakening (0, 30, and 60 min after awakening) from 158 normal premenarcheal pubertal girls and 69 adult females with regular menstrual cycles. The girls were subgrouped according to self-reported Tanner breast (B) and pubic hair (PH) stages (B1PH1, B2PH1, B2PH2, B3PH1, and B3PH2). RESULTS: All the subgroups showed a similar pattern of cortisol secretion. However, cortisol levels were higher in girls at B3PH1 and at B3PH2 than other subgroups. DHEA secretion showed a similar pattern across the groups examined. The largest increase in DHEA levels occurred between B1PH1 and B2PH1 stages, and further increased with pubertal progression. DHEA levels in girls at B3PH2 were approximately one half of the adult value. Estradiol-17ß profiles in girls at B3PH1 and B3PH2 differed from those of other subgroups of girl. A sharp increase in estradiol-17ß levels after awakening which observed in adult females emerged in girls at B3PH1 and B3PH2. However, the estradiol-17ß levels did not reach adult values until B3PH2 stage. CONCLUSIONS: The progression of female puberty includes an increase in the levels of adrenocortical and ovarian steroid secretions and a gain of adult female-like patterns of estradiol-17ß secretion within their first waking hour.

Relationships between biomarkers of inflammation, ovarian steroids, and age at menarche in a rural Polish sample.

OBJECTIVES: To test the hypothesis that life history trade-offs between maintenance and reproductive effort would be evident through inverse associations between levels of a biomarker of inflammation [C-reactive protein (CRP)], and ovarian hormones. Associations between CRP and age at menarche were also explored. METHODS: Urinary CRP, salivary progesterone, and estradiol were measured over one menstrual cycle from rural Polish women (n = 25), representing a natural fertility sample. Age of menarche was assessed through interview recall methods. We used minimum second-order Akaike Information Criteria as a means of multiple regression model selection, and repeated measures ANOVA to test cycle-dependent hypotheses. RESULTS: Comparisons of individuals in high and low CRP tertiles revealed that those with high CRP had significantly lower progesterone (luteal P = 0.03, mid luteal P = 0.007) but not estradiol (follicular P = 0.21, luteal P = 0.15) concentrations through the menstrual cycle. However, when the age at menarche was included in the analysis, both age at menarche and urinary CRP were negatively associated with estradiol (R(2) = 0.44, P = 0.0007). Age at menarche and estradiol were the strongest negative predictors of CRP (R(2) = 0.52, P = 0.0001). CONCLUSIONS: Inflammation itself may suppress ovarian function, or indicate immune challenges that lead to ovarian suppression. The timing of menarche may also influence adult inflammatory sensitivity and ovarian hormone concentrations. This lends support to existing models of trade-offs between maintenance and reproduction in women.

Intake of dairy products, calcium, magnesium, and phosphorus in childhood and age at menarche in the Tehran Lipid and Glucose Study.

PURPOSE: Studies indicate that milk intake is associated with insulin-like growth factor 1 (IGF-1) concentrations and height in childhood, whether milk and other dairy products promote puberty remains unclear. This study aimed to investigate influences of pre-pubertal intakes of milk, yogurt and cheese on menarcheal age in Tehranian girls. The associations of total dietary calcium (Ca), magnesium (Mg), and phosphorus (P) with menarcheal age were also examined. METHODS: This prospective study was conducted on 134 pre-pubertal girls, aged 4-12 years at baseline, who participated in the Tehran Lipid and Glucose Study (TLGS), and were followed for a median of 6.5 years. Dietary intakes were determined at initiation of the study using two non-consecutive 24-h dietary recalls and the age of menarche was documented during the follow-up. Logistic regression was used to calculate the risk of reaching menarche ≤ 12 years according to pre-pubertal levels of dairy or mineral intakes. RESULTS: The risk of earlier menarche was higher in girls with higher intakes of milk [OR: 2.28 (95% CI: 1.03-5.05)], Ca [OR: 3.20 (95%CI: 1.39-7.42)], Mg [OR: 2.43 (95% CI: 1.12-5.27)] and P [OR: 3.37 (95 % CI: 1.44-7.87) after controlling for energy and protein intake, interval between the age at study initiation and the age of menarche, and maternal age at menarche (Model 1). Girls in the middle tertile of cheese intakes had a lower risk of reaching menarche ≤ 12 years than those in the lowest tertile after controlling for covariates in model 1. These associations remained significant after further adjustment of BMI Z-score at baseline. The relationship of Ca, Mg, and P with menarche remained after further adjustment for height Z-score at baseline, whereas the association between milk and cheese intakes became non-significant. CONCLUSIONS: Pre-pubertal intake of milk, but not cheese and yogurt, may hasten age at menarche.