Timing Of Menopause Research Articles

Quantitative bias analysis for epidemiological associations of perfluoroalkyl substance serum concentrations and early onset of menopause

An association between increased serum concentrations of perfluoroalkyl substances (PFAS) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and early menopause has been reported (Knox et al., 2011; Taylor et al., 2014). This association may be explained by the fact that women who underwent menopause no longer excrete PFAS through menstruation. Our objective was to assess how much of the epidemiologic association between PFAS and altered timing of menopause might be explained by reverse causality. We extended a published population life-stage physiologically-based pharmacokinetic (PBPK) model of PFOS and PFOA characterized by realistic distributions of physiological parameters including age at menopause. We then conducted Monte Carlo simulations to replicate the Taylor population (Taylor et al., 2014) and the Knox population (Knox et al., 2011). The analysis of the simulated data overall showed a pattern of results that was comparable to those reported in epidemiological studies. For example, in the simulated Knox population (ages 42–51) the odds ratio (OR) for menopause in the fifth quintile of PFOA compared to those in the first quintile was 1.33 (95% CI 1.26–1.40), whereas the reported OR was 1.4 (95% CI 1.1–1.8). Using our model structure, a substantial portion of the associations reported can be explained by pharmacokinetics.

Early Menopause Is a Risk Factor for CVD

Menopause begins at a mean age of 51 and is associated with a rapid rise in likelihood of cardiovascular disease (CVD; including coronary heart disease [CHD] and stroke). To evaluate associations between timing of menopause and CVD as well as all-cause mortality, investigators performed a systematic review and meta-analysis of observational studies (cohort, case-control, and …

Length ofFMR1repeat alleles within the normal range does not substantially affect the risk of early menopause

STUDY QUESTIONIs the length of FMR1 repeat alleles within the normal range associated with the risk of early menopause?SUMMARY ANSWERThe length of repeat alleles within the normal range does not substantially affect risk of early menopause.WHAT IS KNOWN ALREADYThere is a strong, well-established relationship between length of premutation FMR1 alleles and age at menopause, suggesting that this relationship could continue into the normal range. Within the normal range, there is conflicting evidence; differences in ovarian reserve have been identified with FMR1 repeat allele length, but a recent population-based study did not find any association with age at menopause as a quantitative trait.STUDY DESIGN, SIZE, DURATIONWe analysed cross-sectional baseline survey data collected at recruitment from 2004 to 2010 from a population-based, prospective epidemiological cohort study of >110 000 women to investigate whether repeat allele length was associated with early menopause.PARTICIPANTS/MATERIALS, SETTING, METHODWe included 4333 women from the Breakthrough Generations Study (BGS), of whom 2118 were early menopause cases (menopause under 46 years) and 2215 were controls. We analysed the relationship between length of FMR1 alleles and early menopause using logistic regression with allele length as continuous and categorical variables. We also conducted analyses with the outcome age at menopause as a quantitative trait as well as appropriate sensitivity and exploratory analyses.MAIN RESULTS AND THE ROLE OF CHANCEThere was no association of the shorter or longer FMR1 allele or their combined genotype with the clinically relevant end point of early menopause in our main analysis. Likewise, there were no associations with age at menopause as a quantitative trait in our secondary analysis.LIMITATIONS, REASONS FOR CAUTIONWomen with homozygous alleles in the normal range may have undetected FMR1 premutation alleles, although there was no evidence to suggest this. We estimate minor dilution of risk of early menopause from the likely inclusion of some women with menopause at over 45 years in the early menopause cases due to age-rounding bias in self-reports.WIDER IMPLICATIONS OF THE FINDINGSThere is no robust evidence in this large study that variation within the normal range of FMR1 repeat alleles influences timing of menopause in the general population, which contradicts findings from some earlier, mainly smaller studies. The FMR1 CGG repeat polymorphism in the normal range is unlikely to contribute to genetic susceptibility to early menopause.STUDY FUNDING/COMPETING INTEREST(S)We thank Breast Cancer Now and The Institute of Cancer Research for funding the BGS. The Institute of Cancer Research acknowledges NHS funding to the NIHR Biomedical Research Centre. The study was funded by the Wellcome Trust (grant number 085943). There are no competing interests.TRIAL REGISTRATION NUMBERNot applicable.

Lessons from Genome-Wide Association Studies in Reproductive Medicine: Menopause.

In recent years, common genetic variants have been identified by genome-wide association studies (GWASs) that have led to the detection of 44 genetic loci associated with approximately 6% of common variation in age at natural menopause. In the latest GWAS, doubling the sample size to approximately 70,000 women more than doubled the number of signals identified, from 17 to 56. In addition, low-frequency coding variants (< 5% minor allele frequency), with relatively large effect sizes, have been identified in two genes, by analyzing genome-wide exome data. GWAS has been very successful in identifying novel biological pathways involved in reproductive aging. Approximately two-thirds of the loci reported so far include genes involved in DNA damage response (DDR), highlighting the importance of this pathway in determining oocyte reserve. In addition, GWAS demonstrates that the hypothalamic-pituitary axis is involved in menopause timing as well as puberty timing, showing the first genetic link between timing of the start and end of reproductive life. Genetic variants have been used to explore the causal relationships between menopause timing and breast cancer. These studies demonstrate that for a 1 year increase in menopause age, there is a 6% increase in breast cancer risk, a value approximately double the estimate from epidemiological studies. Prolonged exposure to estrogen during reproductive life is the likely mechanism, rather than a direct effect of DDR variants on cancer risk. Further work is needed to determine the mechanism for the effect of each variant identified by GWAS and more variants will undoubtedly be discovered as sample sizes increase, denser single nucleotide polymorphism arrays and reference genomes are used, and populations from diverse ethnic groups are studied.

Exploring Black-White Differences in the Relationship Between Inflammation and Timing of Menopause.

Understanding the biosocial context of menopausal timing offers insight into social and health inequalities. Prior research on inflammatory chronic conditions suggests that inflammation may predict how early women experience menopause. We explore the ability of black race to moderate the overall relationship between chronic inflammation and timing of menopause. We use data from the National Social Life, Health, and Aging Project on inflammation, age of last menstruation, and race as well as relevant social and medical covariates. We conduct event history modeling to predict age at menopause by inflammatory biomarker levels. Using interaction analysis, we investigate whether being black may shape the overall relationship between inflammation status and menopause timing. Our analyses find no significant statistical interactions between black race and inflammation in predicting menopausal onset. However, we do identify independent correlational relationships between inflammation and black race (r = 0.136) and between menopausal timing and black race (r = -0.129) as well as inflammation (r = -0.138) that emerge as significant in corresponding regression models. We conclude that race probably does not moderate associations between inflammation and menopause. Yet, we also note that the original parameter estimate for black race's impact on menopausal onset (HR = 1.29, p < 0.05) becomes non-significant in a model that includes inflammation (HR = 1.06, p < 0.01). To translate our findings into policy and practice implications, we present alternate conceptualizations of black-white disparity in the inflammation-menopause relationship and recommend future research using mediation modeling.

Hypertension and age at onset of natural menopause in Korean postmenopausal women: Results from the Korea National Health and Nutrition Examination Survey (2008–2013)

ObjectivesMenopause is a natural phenomenon of aging, although the timing and management of menopause can significantly affect a woman’s quality of life. It is therefore important to identify measures to ensure a healthy menopause. We set out to investigate the association between hypertension and early menopause in Korean women. Study designThis cross-sectional study was based on 2008–2013 data from the Korea National Health and Nutrition Examination Survey (KNHANES). Of the 53,829 participants surveyed, 13,584 women were selected. We analyzed the contents of the health interview, health examination, and nutrition survey. Main outcome measureThe main outcome was defined based on hazard ratios (HR) to identify the effects of hypertension on age at onset of menopause. ResultsAmong postmenopausal women (n=6650), the mean age at onset of menopause was 50.4 years. Premenopausal hypertension was statistically significantly associated with age at menopause, oral contraceptive usage, household income, education level, occupation, marital status and smoking and drinking habits. With lower age at diagnosis of hypertension, HRs for menopause tended to be higher, and hypertension diagnosed before age 40 years conferred a statistically significantly higher HR (Model 1, HR=2.32, 95% CI=1.87–2.88; Model 2, HR=2.31, 95% CI=1.86–2.86; Model 3, HR=2.23, 95% CI=1.80–2.77; Model 4, HR=2.00, 95% CI=1.52–2.63). ConclusionPremature menopause is strongly associated with lifestyle factors, in combination with incomplete management of chronic diseases. Our findings support the hypothesis that younger age at diagnosis of hypertension is associated with younger age at onset of menopause in Korean women.

Events in Early Life are Associated with Female Reproductive Ageing: A UK Biobank Study.

The available oocyte pool is determined before birth, with the majority of oocytes lost before puberty. We hypothesised that events occurring before birth, in childhood or in adolescence (‘early-life risk factors’) could influence the size of the oocyte pool and thus the timing of menopause. We included cross-sectional data from 273,474 women from the UK Biobank, recruited in 2006–2010 from across the UK. We analysed the association of early menopause with events occurring before adulthood in 11,781 cases (menopause aged under 45) and 173,641 controls (menopause/pre-menopausal at ≥45 years), in models controlling for potential confounding variables. Being part of a multiple birth was strongly associated with early menopause (odds ratio = 1.42, confidence interval: 1.11, 1.82, P = 8.0 × 10−9, fully-adjusted model). Earlier age at menarche (odds ratio = 1.03, confidence interval: 1.01, 1.06, P = 2.5 × 10−6) and earlier year of birth were also associated with EM (odds ratio = 1.02, confidence interval: 1.00, 1.04, P = 8.0 × 10−6). We also confirmed previously reported associations with smoking, drinking alcohol, educational level and number of births. We identified an association between multiple births and early menopause, which connects events pre-birth, when the oocyte pool is formed, with reproductive ageing in later life.

MANAGEMENT OF ENDOCRINE DISEASE: Long-term outcomes of the treatment of central precocious puberty.

GnRH analogues (GnRHa) are the treatment of choice for central precocious puberty (CPP), with the main objective to recover the height potential compromised by the premature fusion of growth cartilages. The aim of this review was to analyze long-term effects of GnRHa on height, body weight, reproductive function, and bone mineral density (BMD) in patients with CPP, as well as the potential predictors of outcome. Because randomized controlled trials on the effectiveness and long-term outcomes of treatment are not available, only qualified conclusions about the efficacy of interventions can be drawn. GnRHa treatment appears to improve adult height in girls with CPP, especially if diagnosed before the age of 6, whereas a real benefit in terms of adult height is still controversial in patients with the onset of puberty between 6 and 8 years of age. No height benefit was shown in patients treated after 8 years. Gonadal function is promptly restored in girls after cessation of treatment, and reproductive potential appears normal in young adulthood. Data are conflicting on the long-term risk of polycystic ovarian syndrome in both treated and untreated women. Fat mass is increased at the start of treatment but normalizes thereafter, and GnRHa itself does not seem to have any long-term effect on BMI. Similarly, analogue treatment does not appear to have a negative impact on BMD. Owing to the paucity of data available, no conclusions can be drawn on the repercussions of CPP and/or its treatment on the timing of menopause and on the health of the offspring.

Abstract P163: Are Coronary Artery Disease and Type 2 Diabetes Causally Related to Age of Menopause?

Background: Women who enter the menopause at a younger age, are at an increased risk of cardiovascular disease (CVD) and type 2 diabetes (T2D) in later life. However, we have previously reported that development of an unfavourable cardiovascular risk profile premenopausally accelerates the onset of menopause. Furthermore, we reported that women who were diagnosed with diabetes at a very young age also reached menopause earlier. Hence, the direction of the relationship between coronary heart disease (CHD), T2D and the onset of menopause is unclear, and whether the associations are causal is also unclear. Hypothesis: In this study we hypothesize that CHD and/or T2D are causally related to the age of menopause, and studied this using genetic risk scores for CHD and T2D. Methods: Single nucleotide polymorphisms which had previously reached genome-wide significance for CHD and T2D were, individually and as a genetic risk score, tested for an association with age at natural menopause in over 50,000 women from three large consortia: the ITMAT/Broad/CARe (IBC) consortium, the ReproGen consortium, and the EPIC-InterAct consortium. From these consortia all women with a known age at natural menopause between 40 and 60 years were included. We used the genotyping array of the IBC consortium for the selection of the SNPs. The IBC array is a gene-centric genotyping array developed for replication and fine mapping and incorporates about 50K SNPs that capture information on 2000 genetic regions related to cardiovascular, inflammatory, and metabolic regions. The selected SNPs were also requested for analyses in the other two consortia. A total of 18 single nucleotide polymorphisms for CHD and 28 for T2D were selected. In the EPIC-InterAct study we used these SNPs to calculate unweighted individual level genetic risk scores. Results: No statistically significant associations were found for any of the CHD SNPs, nor for the T2D SNPs, nor for the genetic risk scores. Conclusions: Previous findings that women with an increased risk of CHD or T2D also have an increased risk of entering the menopause at younger ages, could not be supported by our data. Furthermore, the association between cardiometabolic disease and earlier timing of menopause does not seem to be causal. However, this finding does not exclude the possibility that the reverse association can be causal.

Early menopause does not influence left ventricular diastolic dysfunction: A clinical observational study in healthy subjects

BackgroundThe prevalence of left ventricular diastolic dysfunction (LVDD) sharply increases in women after their 50s and may contribute to the high prevalence of diastolic heart failure in elderly women. A decrease in estrogen levels after menopause is postulated to be one of the mechanisms responsible for this phenomenon. However, there is a paucity of data on the relationship between the timing of menopause and the progression of LVDD in the clinical setting; thus, we investigated this relationship in healthy postmenopausal women. MethodsWe enrolled 115 women and divided them into two groups according to median menopause age: 61 who experienced menopause at ≤50 years (early menopause group), and 54 who experienced menopause at >50 years (late menopause group). We compared the echocardiographic and clinical characteristics between the two groups. ResultsThere were no significant differences in LV diastolic parameters (mitral E/A, p=0.561; e’, p=0.052; E/e’, p=0.081; DCT, p=0.082; prevalence of LVDD class, p=0.801), as well as other echocardiographic parameters and clinical characteristics between the two groups. Multivariate linear regression analysis showed that the independent determinants of LVDD were age and body mass index, but not the timing of menopause. ConclusionsEarly menopause did not influence the progression of LVDD in postmenopausal women. The sharp progression of LVDD in elderly women is complex and probably influenced by multiple factors.

Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health.

STUDY QUESTIONHow does a genetic variant in the FSHB promoter, known to alter FSH levels, impact female reproductive health?SUMMARY ANSWERThe T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) results in longer menstrual cycles and later menopause and, while having detrimental effects on fertility, is protective against endometriosis.WHAT IS KNOWN ALREADYThe FSHB promoter polymorphism (rs10835638; c.-211G>T) affects levels of FSHB transcription and, as a result, circulating levels of FSH. FSH is required for normal fertility and genetic variants at the FSHB locus are associated with age at menopause and polycystic ovary syndrome (PCOS).STUDY DESIGN, SIZE, DURATIONWe used cross-sectional data from the UK Biobank to look at associations between the FSHB promoter polymorphism and reproductive traits, and performed a genome-wide association study (GWAS) for length of menstrual cycle.PARTICIPANTS/MATERIALS, SETTING, METHODSWe included white British individuals aged 40–69 years in 2006–2010, in the May 2015 release of genetic data from UK Biobank. We tested the FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) for associations with 29, mainly female, reproductive phenotypes in up to 63 350 women and 56 608 men. We conducted a GWAS in 9534 individuals to identify genetic variants associated with length of menstrual cycle.MAIN RESULTS AND THE ROLE OF CHANCEThe FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; MAF 0.16) was associated with longer menstrual cycles [0.16 SD (c. 1 day) per minor allele; 95% confidence interval (CI) 0.12–0.20; P = 6 × 10−16], later age at menopause (0.13 years per minor allele; 95% CI 0.04–0.22; P = 5.7 × 10−3), greater female nulliparity [odds ratio (OR) = 1.06; 95% CI 1.02–1.11; P = 4.8 × 10−3] and lower risk of endometriosis (OR = 0.79; 95% CI 0.69–0.90; P = 4.1 × 10−4). The FSH-lowering T allele was not associated with other female reproductive illnesses or conditions in our study and we did not replicate associations with male infertility or PCOS. In the GWAS for menstrual cycle length, only variants near the FSHB gene reached genome-wide significance (P < 5 × 10−9).LIMITATIONS, REASONS FOR CAUTIONThe data included might be affected by recall bias. Cycle length was not available for 25% of women still cycling (1% did not answer, 6% did not know and for 18% cycle length was recorded as ‘irregular’). Women with a cycle length recorded were aged over 40 and were approaching menopause; however, we did not find evidence that this affected the results. Many of the groups with illnesses had relatively small sample sizes and so the study may have been under-powered to detect an effect.WIDER IMPLICATIONS OF THE FINDINGSWe found a strong novel association between a genetic variant that lowers FSH levels and longer menstrual cycles, at a locus previously robustly associated with age at menopause. The variant was also associated with nulliparity and endometriosis risk. These findings should now be verified in a second independent group of patients. We conclude that lifetime differences in circulating levels of FSH between individuals can influence menstrual cycle length and a range of reproductive outcomes, including menopause timing, infertility, endometriosis and PCOS.STUDY FUNDING/COMPETING INTEREST(S)None.TRIAL REGISTRATION NUMBERNot applicable.

Large-Scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility, and BRCA1-Mediated DNA Repair

ABSTRACT: Menopause timing has a major impact on infertility and risk of disease. Younger age at natural (nonsurgical) menopause (ANM) is associated with a higher risk of osteoporosis, cardiovascular disease, and type 2 diabetes and a lower risk of breast cancer. Late menopause is associated with a higher risk of breast cancer. It is well known that the age at which women go through menopause is partly determined by genes, but the underlying mechanisms are poorly understood. Genome-wide association studies have identified 18 common genetic variants associated with ANM. These variants explain less than 5% of the variation in ANM compared with the 21% explained by all common variants on genome-wide association study arrays. This genome-wide association study was the collaborative effort of researchers from 177 institutions worldwide. The study was designed to investigate genetic variants associated with timing of menopause among a population of approximately 70,000 women of European ancestry. A dual strategy was used to identify both common and, for the first time, low-frequency coding variants associated with ANM. The causal relationship between ANM and breast cancer was investigated using a Mendelian randomization approach. Combined analysis identified 1208 single-nucleotide polymorphisms (SNPs) of a total of approximately 2.6 million that reached the genome-wide significance threshold for association with ANM. Forty-four regions with common variants were identified; among these 44 loci were 2 rare low-frequency missense alleles of large effect. A majority of ANM SNPs were enriched in DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal relationship between delayed ANM and breast cancer risk; there was approximately 6% increase in risk per year; P = 3 × 10-14); increased risk with delayed menopause appeared to be mediated primarily by prolonged sex hormone exposure in a woman’s lifetime, not DDR mechanisms. This is the first study to confirm the link between early and late menopause and breast cancer risk using genetic information. Age at natural menopause genetic variants influence breast cancer risk primarily through variation in menopause timing. Although carrying higher numbers of ANM-increasing variants and enrichment in DDR genes are associated with a modest increase in breast cancer risk, the major mechanism for increased risk appears to be prolonged estrogen and/or progesterone exposure due to delayed menopause.

Association between reproductive variables and metabolic syndrome in chinese community elderly women

ObjectiveThis study aimed to evaluate the association between reproductive variables and metabolic syndrome (MetS) among Chinese community elderly women. MethodsWe conducted a cross-sectional study in a Beijing urban district. A two-stage stratified clustering sampling method was used and 1251 elderly women were included. ResultsThe prevalence of MetS was 65.1% in this population. Women with MetS had younger menarche age, a greater number of years after menopause, higher gravidity and parity. The prevalence of MetS showed an increasing trend for tertiles of years after menopause (p=0.002) and number of children (p<0.001), while decreasing trend for menarche age (p=0.021). Logistic regression showed ORs of age at menarche, years after menopause and number of children for MetS were 0.94, 1.40, and 1.36 for second and 0.63, 1.58, and 1.75 for last tertiles. ConclusionThere is strong association between reproductive variables and higher risk of MetS. Simple information on timing of menarche and menopause could help identify women who may have higher risk of getting MetS and take early action to prevent related chronic diseases.

Early age at natural menopause and risk of cardiovascular and all-cause mortality: A meta-analysis of prospective observational studies

Menopause is defined as the permanent cessation of menstruation because of loss of ovarian follicular function. Menopause is a marker of the end of a woman's reproductive life. The age at menopause varies in different ethnic populations [ [1] Baber R.J. East is east and West is west: perspectives on the menopause in Asia and the West. Climacteric. 2014; 17: 23-28 Crossref PubMed Scopus (19) Google Scholar ]. Menopause between the ages of 40 and 45 years is usually described as early menopause [ [2] Miro F. Parker S.W. Aspinall L.J. Coley J. Perry P.W. Ellis J.E. Sequential classification of endocrine stages during reproductive aging in women: the FREEDOM study. Menopause. 2005; 12: 281-290 Crossref PubMed Scopus (34) Google Scholar ], while occurring before the age of 40 years is defined as premature menopause [ [3] Luborsky J.L. Meyer P. Sowers M.F. Gold E.B. Santoro N. Premature menopause in a multi-ethnic population study of the menopause transition. Hum. Reprod. 2003; 18: 199-206 Crossref PubMed Scopus (302) Google Scholar ]. Early or premature menopause can be naturally spontaneous or induced by medical interventions including chemotherapy or bilateral oophorectomy. Some epidemiologic studies [ 4 Snowdon D.A. Kane R.L. Beeson W.L. Burke G.L. Sprafka J.M. Potter J. et al. Is early natural menopause a biologic marker of health and aging?. Am. J. Public Health. 1989; 79: 709-714 Crossref PubMed Scopus (279) Google Scholar , 5 Cooper G.S. Sandler D.P. Age at natural menopause and mortality. Ann. Epidemiol. 1998; 8: 229-235 Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar , 6 Jacobsen B.K. Knutsen S.F. Fraser G.E. Age at natural menopause and total mortality and mortality from ischemic heart disease: the Adventist Health Study. J. Clin. Epidemiol. 1999; 52: 303-307 Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar , 7 Mondul A.M. Rodriguez C. Jacobs E.J. Calle E.E. Age at natural menopause and cause-specific mortality. Am. J. Epidemiol. 2005; 162: 1089-1097 Crossref PubMed Scopus (184) Google Scholar , 8 Cooper G.S. Baird D.D. Weinberg C.R. Ephross S.A. Sandler D.P. Age at menopause and childbearing patterns in relation to mortality. Am. J. Epidemiol. 2000; 151: 620-623 Crossref PubMed Scopus (49) Google Scholar , 9 Jacobsen B.K. Heuch I. Kvale G. Age at natural menopause and all-cause mortality: a 37-year follow-up of 19,731 Norwegian women. Am. J. Epidemiol. 2003; 157: 923-929 Crossref PubMed Scopus (208) Google Scholar , 10 Amagai Y. Ishikawa S. Gotoh T. Kayaba K. Nakamura Y. Kajii E. Age at menopause and mortality in Japan: the Jichi Medical School Cohort Study. J. Epidemiol. 2006; 16: 161-166 Crossref PubMed Scopus (44) Google Scholar , 11 Hong J.S. Yi S.W. Kang H.C. Jee S.H. Kang H.G. Bayasgalan G. et al. Age at menopause and cause-specific mortality in South Korean women: Kangwha Cohort Study. Maturitas. 2007; 56: 411-419 Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar , 12 Tom S.E. Cooper R. Wallace R.B. Guralnik J.M. Type and timing of menopause and later life mortality among women in the Iowa Established Populations for the Epidemiological Study of the Elderly (EPESE) cohort. J. Womens Health (Larchmt). 2012; 21: 10-16 Crossref PubMed Scopus (21) Google Scholar , 13 Li S. Rosenberg L. Wise L.A. Boggs D.A. LaValley M. Palmer J.R. Age at natural menopause in relation to all-cause and cause-specific mortality in a follow-up study of US black women. Maturitas. 2013; 75: 246-252 Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar , 14 Wu X. Cai H. Kallianpur A. Gao Y.T. Yang G. Chow W.H. et al. Age at menarche and natural menopause and number of reproductive years in association with mortality: results from a median follow-up of 11.2 years among 31,955 naturally menopausal Chinese women. PLoS One. 2014; 9: e103673 Crossref PubMed Scopus (57) Google Scholar , 15 Jacobsen B.K. Heuch I. Kvale G. Age at natural menopause and stroke mortality: cohort study with 3561 stroke deaths during 37-year follow-up. Stroke. 2004; 35: 1548-1551 Crossref PubMed Scopus (46) Google Scholar ] suggested that women who experienced early natural menopause or premature menopause were at increased risk of all-cause mortality. However, findings from these studies are conflicting. Therefore, we conducted this meta-analysis on all available prospective studies to quantitatively evaluate the early age at natural menopause and risk of cardiovascular or all-cause mortality.

Genetics of the ovarian reserve.

Primordial follicles or non-growing follicles (NGFs) are the functional unit of reproduction, each comprising a single germ cell surrounded by supporting somatic cells. NGFs constitute the ovarian reserve (OR), prerequisite for germ cell ovulation and the continuation of the species. The dynamics of the reserve is determined by the number of NGFs formed and their complex subsequent fates. During the reproductive lifespan, the OR progressively diminishes due to follicle atresia as well as recruitment, maturation, and ovulation. The depletion of the OR is the major determining driver of menopause, which ensues when the number of primordial follicles falls below a threshold of ∼1,000. Therefore, genes and processes involved in follicle dynamics are particularly important to understand the process of menopause, both in the typical reproductive lifespan and in conditions like primary ovarian insufficiency, defined as menopause before age 40. Genes and their variants that affect the timing of menopause thereby provide candidates for diagnosis of and intervention in problems of reproductive lifespan. We review the current knowledge of processes and genes involved in the development of the OR and in the dynamics of ovarian follicles.

Molecular insights into the aetiology of female reproductive ageing.

As age at pubertal onset declines and age at first pregnancy increases, the mechanisms that regulate female reproductive lifespan become increasingly relevant to population health. The timing of menarche and menopause can have profound effects not only on fertility but also on the risk of diseases such as type 2 diabetes mellitus, cardiovascular disease and breast cancer. Genetic studies have identified dozens of highly penetrant rare mutations associated with reproductive disorders, and also ∼175 common genetic variants associated with the timing of puberty or menopause. These findings, alongside other functional studies, have highlighted a diverse range of mechanisms involved in reproductive ageing, implicating core biological processes such as cell cycle regulation and energy homeostasis. The aim of this article is to review the contribution of such genetic findings to our understanding of the molecular regulation of reproductive timing, as well as the biological basis of the epidemiological links between reproductive ageing and disease risk.

Circulating Serotonin as Bone Remodelling Marker in Women

The bone remodelling represents a physiological reparative process which is constant into the human body. The underlying aspects include osteoclasts activity (for instance areas of bone are resorbed) and osteoblasts activity that fill with new bone the resorbed zones (bone formation). Normally there is a balance between these two mechanisms. By this continuum a major contribution to the quality of bone is achieved[1,2]. The bone turnover is influenced by age: in time resorption become more pronounced that bone formation causing a net loss of bone, and thus damaging the skeleton integrity. In women a secondary factor is essential: the timing of menopause and the consecutive exposure to estrogens deficiency[2,3]. Overall the bone quality suffers by affecting the micro-architecture, decreasing the mineralisation and increasing the cortical porosity[3,4]. The process of remodelling is best assessed by bone markers levels. They are biochemical parameters with blood or urinary assay that offer to the clinician a rapid and facile clue regarding the bones turnover status (see Figure 1)[5,6]. They predict the fracture risk especially in some menopausal population but the references levels still vary so a specific pattern cannot actually be predicted[5,6]. Some persons with menopausal osteoporosis may have normal bone markers while others display a high status of bone turnover bio-markers. The data regarding the correlation to bone mineral density as assessed by central DXA (Dual Energy X-Ray Absorptiometry) are heterogeneous but usually in subjects with osteoporosis higher bone resorbtion markers are found compare to control group[7]. Overall the biochemical markers are not recommended for the diagnosis of osteoporosis by any guideline. They may become useful in follow-up the patients who started anti-osteoporotic drugs especially if they had a high values at the beginning of therapy[5,6,7]. An extended usefulness is seen in clinical trials in order to express the medication effects. However the routine use in not recommended and the intra-individual variations are difficult to “translate” in everyday practice[5,6,7].

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ~70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two harbouring additional rare missense alleles of large effect. We found enrichment of signals in/near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses revealed a major association with DNA damage-response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomisation analyses supported a causal effect of later ANM on breast cancer risk (~6% risk increase per-year, P=3×10−14), likely mediated by prolonged sex hormone exposure, rather than DDR mechanisms.

Does prolapse equal hysterectomy? The role of uterine conservation in women with uterovaginal prolapse

Hysterectomy has historically been a mainstay in the surgical treatment of uterovaginal prolapse, even in cases in which the removal of the uterus is not indicated. However, uterine-sparing procedures have a long history and are now becoming more popular. Whereas research on these operations is underway, hysteropexy for the treatment of prolapse is not as well studied as hysterectomy-based repairs. Compared with hysterectomy and prolapse repair, hysteropexy is associated with a shorter operative time, less blood loss, and a faster return to work. Other advantages include maintenance of fertility, natural timing of menopause, and patient preference. Disadvantages include the lack of long-term prolapse repair outcomes and the need to continue surveillance for gynecological cancers. Although the rate of unanticipated abnormal pathology in this population is low, women who have uterine abnormalities or postmenopausal bleeding are not good candidates for uterine-sparing procedures. The most studied approaches to hysteropexy are the vaginal sacrospinous ligament hysteropexy and the abdominal sacrohysteropexy, which have similar objective and subjective prolapse outcomes compared with hysterectomy and apical suspension. Pregnancy and delivery have been documented after vaginal and abdominal hysteropexy approaches, although very little is known about outcomes following parturition. Uterine-sparing procedures require more research but remain an acceptable option for most patients with uterovaginal prolapse after a balanced and unbiased discussion reviewing the advantages and disadvantages of this approach.

Anti-mullerian hormone (AMH) is associated with natural menopause in a population-based sample: The CARDIA Women's Study

ObjectiveAMH is associated with menopausal timing in several studies. In contrast to prior studies that were restricted to women with regular cycles, our objective was to examine this association in women with either regular or irregular menstrual cycles. MethodsCARDIA is a longitudinal, population-based study that recruited adults ages 18–30 when it began in 1985–1986. AMH was measured in serum stored in 2002–2003. Natural menopause was assessed by survey in 2005–2006 and 2010–2011. ResultsAmong 716 premenopausal women, median [25th, 75th] AMH was 0.77 [0.22–2.02]ng/dL at a median age of 42 [39–45] years. Twenty-nine percent of the women (n=207) reported natural menopause during 9 years of follow up. In fully adjusted discrete-time hazard models, a 0.5ng/dL AMH decrement was associated with higher risk of menopause (p<0.001). Hazard ratios varied with time since AMH measurement. The HR (95% CI) for menopause was 8.1 (2.5–26.1) within 0–3 years and 2.3 (1.7–3.3) and 1.6 (1.3–2.1) for 3–6 and 6–9 years, respectively. When restricted to women with regular menses, results were similar (e.g., HR=6.1; 95% CI: 1.9–20.0 for 0–3 years). ConclusionAMH is independently associated with natural menopause. AMH appears most useful in identifying women at risk of menopause in the near future (within 3 years of AMH measurement).