Woman's Reproductive Lifespan Research Articles

Diet, menopause and the risk of ovarian, endometrial and breast cancer.

Menopause, the permanent cessation of the menstrual cycle, marks the end of a woman's reproductive lifespan. In addition to changes in sex hormone levels associated with menopause, its timing is another predictor of future health outcomes such as duration of the presence of vasomotor symptoms (VMS) and the risk of hormone-related cancers. With ageing of the population, it is estimated that worldwide 1·2 billion women will be menopausal by the year 2030. Previously the effects of reproductive factors (e.g. parity, age at menarche, pregnancy) and socio-demographic factors on intermediate and long-term health outcomes of menopause have been widely documented. However, little is known about whether diet could have an impact on these. Therefore, we review current evidence on the associations of diet with menopause, presence of VMS and the risk of hormone-related cancers such as ovarian, endometrial and breast cancer. Dietary factors could influence the lifespan of the ovaries and sex-hormones levels, hence the timing of natural menopause. Few studies reported an association between diet, in particular soya consumption, and a reduced risk of VMS. Sustained oestrogen exposure has been associated with a higher risk of hormone-related cancers and thus high-fat and meat diets have been linked with an increased risk of these cancers. However, to better understand the mechanistic pathways involved and to make stronger conclusions for these relationships, further studies investigating the associations of dietary intakes and dietary patterns with menopause, presence of VMS and the risk of hormone-related cancers are required.

Prepregnancy counseling: Committee Opinion No. 762

The goal of prepregnancy care is to reduce the risk of adverse health effects for the woman, fetus, and neonate by working with the woman to optimize health, address modifiable risk factors, and provide education about healthy pregnancy. All those planning to initiate a pregnancy should be counseled, including heterosexual, lesbian, gay, bisexual, transgender, queer, intersex, asexual, and gender nonconforming individuals. Counseling can begin with the following question: "Would you like to become pregnant in the next year?" Prepregnancy counseling is appropriate whether the reproductive-aged patient is currently using contraception or planning pregnancy. Because health status and risk factors can change over time, prepregnancy counseling should occur several times during a woman's reproductive lifespan, increasing her opportunity for education and potentially maximizing her reproductive and pregnancy outcomes. Many chronic medical conditions such as diabetes, hypertension, psychiatric illness, and thyroid disease have implications for pregnancy outcomes and should be optimally managed before pregnancy. Counseling patients about optimal intervals between pregnancies may be helpful to reduce future complications. Assessment of the need for sexually transmitted infection screening should be performed at the time of prepregnancy counseling. Women who present for prepregnancy counseling should be offered screening for the same genetic conditions as recommended for pregnant women. All patients should be routinely asked about their use of alcohol, nicotine products, and drugs, including prescription opioids and other medications used for nonmedical reasons. Screening for intimate partner violence should occur during prepregnancy counseling. Female prepregnancy folic acid supplementation should be encouraged to reduce the risk of neural tube defects.

ACOG Committee Opinion No. 762 Summary: Prepregnancy Counseling.

The goal of prepregnancy care is to reduce the risk of adverse health effects for the woman, fetus, and neonate by working with the woman to optimize health, address modifiable risk factors, and provide education about healthy pregnancy. All those planning to initiate a pregnancy should be counseled, including heterosexual, lesbian, gay, bisexual, transgender, queer, intersex, asexual, and gender nonconforming individuals. Counseling can begin with the following question: "Would you like to become pregnant in the next year?" Prepregnancy counseling is appropriate whether the reproductive-aged patient is currently using contraception or planning pregnancy. Because health status and risk factors can change over time, prepregnancy counseling should occur several times during a woman's reproductive lifespan, increasing her opportunity for education and potentially maximizing her reproductive and pregnancy outcomes. Many chronic medical conditions such as diabetes, hypertension, psychiatric illness, and thyroid disease have implications for pregnancy outcomes and should be optimally managed before pregnancy. Counseling patients about optimal intervals between pregnancies may be helpful to reduce future complications. Assessment of the need for sexually transmitted infection screening should be performed at the time of prepregnancy counseling. Women who present for prepregnancy counseling should be offered screening for the same genetic conditions as recommended for pregnant women. All patients should be routinely asked about their use of alcohol, nicotine products, and drugs, including prescription opioids and other medications used for nonmedical reasons. Screening for intimate partner violence should occur during prepregnancy counseling. Female prepregnancy folic acid supplementation should be encouraged to reduce the risk of neural tube defects.

ACOG Committee Opinion No. 762: Prepregnancy Counseling.

The goal of prepregnancy care is to reduce the risk of adverse health effects for the woman, fetus, and neonate by working with the woman to optimize health, address modifiable risk factors, and provide education about healthy pregnancy. All those planning to initiate a pregnancy should be counseled, including heterosexual, lesbian, gay, bisexual, transgender, queer, intersex, asexual, and gender nonconforming individuals. Counseling can begin with the following question: "Would you like to become pregnant in the next year?" Prepregnancy counseling is appropriate whether the reproductive-aged patient is currently using contraception or planning pregnancy. Because health status and risk factors can change over time, prepregnancy counseling should occur several times during a woman's reproductive lifespan, increasing her opportunity for education and potentially maximizing her reproductive and pregnancy outcomes. Many chronic medical conditions such as diabetes, hypertension, psychiatric illness, and thyroid disease have implications for pregnancy outcomes and should be optimally managed before pregnancy. Counseling patients about optimal intervals between pregnancies may be helpful to reduce future complications. Assessment of the need for sexually transmitted infection screening should be performed at the time of prepregnancy counseling. Women who present for prepregnancy counseling should be offered screening for the same genetic conditions as recommended for pregnant women. All patients should be routinely asked about their use of alcohol, nicotine products, and drugs, including prescription opioids and other medications used for nonmedical reasons. Screening for intimate partner violence should occur during prepregnancy counseling. Female prepregnancy folic acid supplementation should be encouraged to reduce the risk of neural tube defects.

Anti-Müllerian hormone as a predictor of reproductive potential.

Anti-Müllerian hormone (AMH), a marker of ovarian reserve, declines over a woman's reproductive lifespan. AMH is highly correlated with a woman's age and number of primordial ovarian follicles, and has been shown to predict time to menopause in women in their 40s. For these reasons, it was assumed that AMH levels could predict a woman's reproductive potential or serve as a 'fertility test'. Recently, studies have sought to determine the association between AMH and fertility. Although a small, prospective, time-to-pregnancy study of 98 women suggested that an AMH level less than 0.7 ng/ml was associated with lower day-specific probabilities of conception, the follow-up, larger cohort did not identify an association with AMH and fecundability. Women with AMH values less than 0.7 ng/ml had similar pregnancy rates after 12 cycles of attempting to conceive as women with normal AMH values after adjusting for age. Four additional studies, including a secondary analysis of the NICHD EAGER trial including over 1200 women confirmed these findings. Although AMH is a marker of ovarian reserve, existing literature does not support the use of AMH as a marker of reproductive potential in the general population.

Studying the relationship between a woman's reproductive lifespan and age at menarche using a Bayesian multivariate structured additive distributional regression model.

Studies addressing breast cancer risk factors have been looking at trends relative to age at menarche and menopause. These studies point to a downward trend of age at menarche and an upward trend for age at menopause, meaning an increase of a woman's reproductive lifespan cycle. In addition to studying the effect of the year of birth on the expectation of age at menarche and a woman's reproductive lifespan, it is important to understand how a woman's cohort affects the correlation between these two variables. Since the behavior of age at menarche and menopause may vary with the geographic location of a woman's residence, the spatial effect of the municipality where a woman resides needs to be considered. Thus, a Bayesian multivariate structured additive distributional regression model is proposed in order to analyze how a woman's municipality and year of birth affects a woman's age of menarche, her lifespan cycle, and the correlation of the two. The data consists of 212,517 postmenopausal women, born between 1920 and 1965, who attended the breast cancer screening program in the central region of Portugal.

Reproductive Health of Women: An Attempt to Define Prevention of Breast Cancer

Background. On the evidence-based information of breast cancer as a preventable disease, an attempt is made for definition of primary, non-chemical prevention of the epidemic breast cancer. The battle over healthcare reform, besides other priorities, is revolving around women’s issues and health protection too. Aim. To add to the knowledge and to advance the tested concept of the potential for primary (non-chemical) prevention of breast cancer as an epidemic disease. Ultimately, to present from a medical point of view the attempted definition of a preventive contraception against the epidemic breast cancer. Justification. The number of cases and the incidence of breast cancer is in a steady increase worldwide and in our country, Macedonia, (with more than 800 cases, or 76.2 crude rate per 100,000 female population, in 2008), followed by great losses and expenses in human lives, individual and familial sufferings and disasters, and material resources. It could be assessed that no healthcare reform could be achieved successfully as long as the half of the population, women of all ages, is threatened by a real risk of breast cancer as an epidemic disease. The changes in the biological micro-environment and ecosystem of the intimate (sexual) woman-man relations, which is still unknown, reflect gravely upon the health and lives of people, especially women of all ages. Primary (non-chemical) prevention of breast cancer is neither mentioned nor considered in the ongoing debate of healthcare reform, in the scientific literature, and at the conference meeting. Evidence and Discussion. The results of the initial field study and other ecological and experimental studies showed and corroborated the evidence that the mass condomization of women’s sexuality is the root cause of the perplexing emergence and rapid rise of the breast cancer epidemic all over the world along with the occurrence of the AIDS epidemic, after 1981. Prevention of breast cancer rather than programs of mass mammographic screening for early detection of cases of the disease are discussed. The views on contraception and marriage of the main religious denominations in the Western world, which were relevant to the aim of this study, are briefly presented. The negative consequences of screening of the disease and the recent debate of questioning the breast screening programs is discussed.Conclusion. From a medical standpoint, to achieve the suggested primary prevention of the breast cancer epidemic it is necessary to eliminate completely the barrier devices and methods of contraception, the condom use and withdrawal practice. Instead of use of barrier methods, a replacement is to be done by shifting to use of other, non-barrier methods and techniques for fertility-control and family-planning purposes during the reproductive life-span of women, which include: abstention, rhythm, IUDs, OC pills, and tubal ligation.

Adult Stem Cells in the Pathogenesis and Treatment of Endometriosis

The human endometrium is a dynamic tissue that undergoes approximately 400 cyclical episodes of proliferation, differentiation, shedding, and regeneration in a woman's reproductive lifespan. The regenerative capacity of human endometrium is likely mediated by adult stem cells. At the cellular level, endometrial mesenchymal stem/stromal cells, located in both the functionalis and basalis layers, support regeneration of the stromal vascular compartment and epithelial progenitor cells, postulated to reside in the basalis epithelium, likely regenerate the glands. Bone marrow adult stem cells, including endothelial progenitor cells, may also participate. Endometriosis can be considered an endometrial proliferative disorder due to dysregulation of the cellular and molecular regenerative processes. Endometriosis is primarily thought to occur via retrograde menstruation of endometrial debris. It is postulated that endometrial stem/progenitor cells, which have been identified in menstrual blood, are shed into the peritoneal cavity where they adhere to pelvic organs and initiate endometriotic lesions. The homing of bone-marrow-derived adult stem cells to endometriotic lesions is thought to drive progression of the disease. New drug therapies are urgently required for the treatment of endometriosis due to frequent disease recurrence with current surgical or medical treatments. Medications directly targeting endometrial stem/progenitor cells during menstruation, or following surgery, or targeting bone marrow cell trafficking, are potential targets for future therapies to manage disease initiation and progression. In this review, we will summarize the current literature on adult stem cell contributions to the development of endometriosis and will then examine the current potential therapies that may target endometrial stem/progenitor cells.

Oocytes are more resistent to oxidative stress than embryos

Reactive oxygen species (ROS) are a major cause of aging in all tissues studied, including reproductive tissues. Recent studies demonstrate extensive DNA damage repair capacity in oocytes (1), and genetic variation in DNA damage repair pathways is associated with reproductive lifespan in women (2). We hypothesized that MII oocytes are more resistant to oxidative stress than other stages of development.

Fertility: The Role of mTOR Signaling and KIT Ligand

Activation of a limited pool of diminishing ovarian follicles determines women's reproductive lifespan. A recent rodent study describes the role of mTOR signaling and KIT ligand in granulosa cells of primordial follicles for follicle activation and for reproductive lifespan regulation.

A comparison of self-reported oral contraceptive use and automated pharmacy data in perimenopausal and early postmenopausal women

PurposeOral contraceptive (OC) use can occur throughout a woman's reproductive life span with the potential for long-term impacts on health. To assess potential measurement error in prior OC use, this study compared level of agreement between self-reported prior OC use and pharmacy dispensing data in perimenopausal and/or early postmenopausal women. MethodsThe study's 1399 women (ages, 45–59 years) were participants in a population-based case-control study of the association between OC use and fracture risk. Episodes of lifetime self-reported OC use (in months) were collected, by telephone interview, for January 1, 2008 through November 25, 2012. Pharmacy fills, back to 1980, were collected from automated data. Agreement was measured using the prevalence-adjusted and bias-adjusted kappa index. ResultsThe number of women with OC pharmacy fills was 11% to 45% higher than those who reported OC use during each time period. Between-measures agreement was better for more recent use. Prevalence-adjusted and bias-adjusted kappa index values ranged from 0.88 (95% confidence interval, 0.85–0.90) within 5 years from the reference date to 0.65 (95% confidence interval, 0.59–0.71) within 15 to 20 years. ConclusionsFor studies designed to assess the long-term effects of OC use, the current results are reassuring in noting moderate agreement between self-reported OC use and pharmacy data for up to 15 to 20 years before the interview.

The ovarian response to controlled stimulation in IVF cycles may be predictive of the age at menopause.

Can the number of oocytes retrieved in IVF cycles be predictive of the age at menopause? The number of retrieved oocytes can be used as an indirect assessment of the extent of ovarian reserve to provide information on the duration of the reproductive life span in women of different ages. Menopause is determined by the exhaustion of the ovarian follicular pool. Ovarian reserve is the main factor influencing ovarian response in IVF cycles. As a consequence the response to ovarian stimulation with the administration of gonadotrophins in IVF treatment may be informative about the age at menopause. In the present cross-sectional study, participants were 1585 infertile women from an IVF clinic and 2635 menopausal women from a more general population. For all infertile women, the response to ovarian stimulation with gonadotrophins was recorded. For menopausal women, relevant demographic characteristics were available for the analysis. A cubic function described the relationship between mean numbers of oocytes and age, with all terms being statistically significant. From the estimated residual distribution of the actual number of oocytes about this mean, a distribution of the age when there would be no oocytes retrieved following ovarian stimulation was derived. This was compared with the distribution of the age at menopause from the menopausal women, showing that menopause occurred about a year later. The retrieved oocyte data were from infertile women, while the menopausal ages were from a more general population. In the present study, we have shown some similarity between the distributions of the age when no retrieved oocytes can be expected after ovarian stimulation and the age at menopause. For a given age, the lower the ovarian reserve, the lower the number of retrieved oocytes would be and the earlier the age that menopause would occur. This work was supported by a grant from the Italian Ministry of Health (GR-2009-1580036). There are no conflicts of interest.

Approaches to identify genetic variants that influence the risk for onset of fragile X-associated primary ovarian insufficiency (FXPOI): a preliminary study.

Fragile X-associated primary ovarian insufficiency (FXPOI) is due to an X-linked mutation that results from the expansion of a CGG repeat sequence located in the 5′ untranslated region of the FMR1 gene (premutation, PM). About 20% of women who carry the PM have cessation of menses before age 40, a clinical condition known as premature ovarian failure (POF). This leads to a 20-fold increased risk over women in the general population. Thus, this single gene mutation has a major effect on reducing a woman's reproductive life span. Based on survival analysis of about 1300 women, we showed that the mean age at menopause among PM carriers is reduced compared with noncarriers, even after removing women who reported POF. This suggests that the majority of women with the PM, not just a subset, experience ovarian insufficiency earlier than noncarriers. To better understand the underlying mechanism of the PM and to identify genes that modify the variable expressivity of FXPOI, we conducted two pilot studies. The first focused on five common variants known to reduce age at menopause. We genotyped these SNPs in 72 women with a PM who experienced menopause and found a significant association with the total SNP risk burden and age at menopause. This suggests that these SNPs influence onset of FXPOI, after adjusting for the effect of the PM allele. In the second approach, we conducted whole genome sequencing on 10 PM carriers, five with onset of FXPOI prior to age 30 and five who experienced menopause after age 47 years. Although only a pilot study, we describe our preliminary approach to identify potential variants that may play a role in modifying onset of FXPOI and potentially play a role in idiopathic primary ovarian insufficiency. The overarching goal of both approaches is to identify predictor variants that may identify women predisposed to early onset FXPOI and to further identify genes involved in defining a woman's reproductive life span.

Genomic Markers of Ovarian Reserve

Ovarian reserve and its utilization, over a reproductive life span, are determined by genetic, epigenetic, and environmental factors. The establishment of the primordial follicle pool and the rate of primordial follicle activation have been under intense study to determine genetic factors that affect reproductive lifespan. Much has been learned from transgenic animal models about the developmental origins of the primordial follicle pool and mechanisms that lead to primordial follicle activation, folliculogenesis, and the maturation of a single oocyte with each menstrual cycle. Recent genome-wide association studies on the age of human menopause have identified approximately 20 loci, and shown the importance of factors involved in double-strand break repair and immunology. Studies to date from animal models and humans show that many genes determine ovarian aging, and that there is no single dominant allele yet responsible for depletion of the ovarian reserve. Personalized genomic approaches will need to take into account the high degree of genetic heterogeneity, family pedigree, and functional data of the genes critical at various stages of ovarian development to predict women's reproductive life span.

Accelerating Ovarian Age: Cancer Treatment in the Premenopausal Woman

The reproductive sequelae of cancer treatments may provide an important model of accelerated ovarian aging. Tens of thousands of women treated for cancer each year experience infertility and early menopause as a result of treatment. A spectrum of reproductive compromise commonly ranges from immediate menopause at the time of cancer treatment to the less proximate outcome of early menopause in the years to decades after treatment. A woman's reproductive lifespan can be shortened after chemotherapy or radiation because such treatments likely decrease the number of viable eggs after treatment. This acceleration in the decline of the number of follicles leads to increased rates of not only infertility and miscarriage but also early menopause, which represents the most extreme form of accelerated ovarian aging. The degree of reproductive impairment is dependent on chronologic age and the diagnosis or treatment. The variation in outcomes that persist may be partially explained by pretreatment ovarian reserve. Establishing the use of clinical predictors such as ovarian reserve markers to effectively anticipate such outcomes is an obvious and important keystone in the foundation of cancer survivorship research. An improved understanding of cancer treatment's ability to accelerate follicle death, decrease fecundability, and initiate an earlier menopause could provide a clinically relevant, time-shortened, and reproducible snapshot into the basic biology of ovarian aging.

Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study

Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study? We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry. Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations. A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM. SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses. We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends. Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings. The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.

Vanishing returns on the investment that is the ovarian reserve

Vanishing returns on the investment that is the ovarian reserve

Genetic variation and reproductive timing: African American women from the Population Architecture using Genomics and Epidemiology (PAGE) Study.

Age at menarche (AM) and age at natural menopause (ANM) define the boundaries of the reproductive lifespan in women. Their timing is associated with various diseases, including cancer and cardiovascular disease. Genome-wide association studies have identified several genetic variants associated with either AM or ANM in populations of largely European or Asian descent women. The extent to which these associations generalize to diverse populations remains unknown. Therefore, we sought to replicate previously reported AM and ANM findings and to identify novel AM and ANM variants using the Metabochip (n = 161,098 SNPs) in 4,159 and 1,860 African American women, respectively, in the Women’s Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) studies, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study. We replicated or generalized one previously identified variant for AM, rs1361108/CENPW, and two variants for ANM, rs897798/BRSK1 and rs769450/APOE, to our African American cohort. Overall, generalization of the majority of previously-identified variants for AM and ANM, including LIN28B and MCM8, was not observed in this African American sample. We identified three novel loci associated with ANM that reached significance after multiple testing correction (LDLR rs189596789, p = 5×10−08; KCNQ1 rs79972789, p = 1.9×10−07; COL4A3BP rs181686584, p = 2.9×10−07). Our most significant AM association was upstream of RSF1, a gene implicated in ovarian and breast cancers (rs11604207, p = 1.6×10−06). While most associations were identified in either AM or ANM, we did identify genes suggestively associated with both: PHACTR1 and ARHGAP42. The lack of generalization coupled with the potentially novel associations identified here emphasize the need for additional genetic discovery efforts for AM and ANM in diverse populations.

Menopause and lead body burden among US women aged 45–55, NHANES 1999–2010

BackgroundEnvironmental factors in menopause have received limited attention. Lead is a known reproductive toxicant associated with delayed puberty in girls that may also affect menopause. MethodsThe odds of menopause among US women aged 45–55 were estimated in the National Health and Nutrition Examination Survey, 1999–2010, in relation to quartiles of blood lead. Women still menstruating (n=2158) were compared to women with natural menopause (n=1063). Logistic regression models included age, race/ethnicity, current hormone use, poverty, smoking and where available, bone density or bone alkaline phosphatase. ResultsLead levels (ug/dL) were higher in menopausal women, geometric mean (standard error)=1.71 (0.04) vs. 1.23 (0.02). Adjusted odds of menopause and 95% confidence intervals for lead quartiles (lowest quartile referent) were 1.7 (1.0–2.8), 2.1 (1.2–3.6), and 4.2 (2.5–7.0) respectively. Results adjusting for bone markers were generally similar but had less precision. ConclusionsBlood lead was associated with natural menopause in US women even after adjustment for bone turnover. This raises concern that lead exposure, even at low levels, may shorten women's reproductive lifespan.

How genes influence a woman's reproductive lifespan: the impact of the FMR1 gene on age at menarche

How genes influence a woman's reproductive lifespan: the impact of the FMR1 gene on age at menarche