Assisted reproductive technology treatment and risk of multiple sclerosis - a Danish cohort study.

OBJECTIVE: To compare the incidence of multiple sclerosis (MS) among women who had undergone assisted reproductive technology (ART) treatment with the women who had conceived a child without previous ART treatment. DESIGN: A register-based nationwide cohort study. PATIENT(S): Women with a first ovarian stimulation cycle before in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) (i.e., ART treatment) recorded in the Danish IVF register between 1996 and 2018; and women recorded in the Danish Medical Birth Register with the birth of their first child where date of conception is between 1996 and 2018. The cohort was observed until March 10, 2021. INTERVENTION(S): Mainly included IVF, ICSI, and fresh embryo transfer with hormone stimulation. MAIN OUTCOME MEASURES: A diagnosis of MS recorded in the Danish Multiple Sclerosis Registry. Crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were calculated. RESULTS: A total of 585,716 women were included in the cohort of which 63,791 (11%) were exposed to at least one initiated IVF or ICSI cycle during the study period. Cycles with oocyte donation were excluded. The median follow-up time for the entire cohort was 12.4 years (Q1-Q3= 6.6-18.1). Compared with women conceiving without previous ART, ART treated women were older (31.8 years vs. 27.5 years), more often had a university degree (45% vs. 36%), and more often had received other fertility treatments than IVF or ICSI before cohort entry (26% vs. 3%). We found no association between incident MS and exposure to ART compared with non-ART pregnancy (aHR=1.08; 95 % CI, 0.93-1.25). An analysis following intention-to-treat principle on a propensity score matched sub cohort confirmed our results. In subgroup analysis including all ART cycles among the ART treated women, we found no increased risk of MS within 2 years of ART cycle start for successful ART cycles (pregnancy) compared with failed ART cycles (no pregnancy) (aHR=1.01; 95% CI, 0.58-1.76). We found a non-significant trend toward increased risk of MS with increasing numbers of ART cycles although based on small numbers. CONCLUSION(S): Women treated with ART do not seem to be at increased risk of developing MS compared with the women not exposed to ART.

Maternal Serum α-Fetoprotein Levels during Pregnancy and Testicular Cancer in Male Offspring: A Cohort Study within a Danish Pregnancy Screening Registry.

Testicular cancer is believed to originate from disruptions of normal androgen-estrogen balance in-utero. α-fetoprotein (AFP) may modify fetal response to estrogens via estrogen interaction. In a cohort study, we investigated the association between circulating maternal pregnancy AFP and testicular cancer risk in offspring. Of the 56,709 live-born males from a pregnancy screening registry in 1980-1995, our study included 50,519 singleton males with available second trimester blood samples from their mothers and complete covariate ascertainment. Testicular cancer diagnoses and covariate data were obtained from nationwide Danish health registries. Cox regression and Kaplan-Meier analyses estimated the prospective risk of testicular cancer (all, seminoma, nonseminoma) by AFP multiples of the median. During follow-up, 163 (0.3%) of the included males developed testicular cancer, of which 89 (54.6%) were nonseminomas. Maternal serum AFP levels greater than/equal to the median were associated with a relative risk of testicular cancer close to unity (RR 1.04, 95% CI 0.76; 1.41) compared to AFP below the median. Associations differed by type of testicular cancer (RRseminoma 0.81, 95% CI 0.51; 1.29, RRnonseminoma 1.31, 95% CI 0.85; 2.02). On balance, our findings do not support that serum AFP in pregnancy can be used as a predictor of testicular cancer in offspring.

Male childlessness as independent predictor of risk of cardiovascular and all-cause mortality: A population-based cohort study with more than 30 years follow-up.

In a recent population-based study, an elevated risk of the Metabolic syndrome (MetS) and type 2 diabetes was found in childless men compared to those who have fathered one or more children. Therefore, by using a larger cohort of more than 22 000 men from the Malmo Preventive Project (MPP) we aimed to expand our observations in order to evaluate the metabolic profile of childless men and to evaluate if childlessness is an additional and independent predictor of major adverse cardiovascular events (MACE), mortality and incident diabetes when accounting for well-known biochemical, anthropometric, socio-economic and lifestyle related known risk factors. Logistic regression was used to assess risk of MACE, diabetes and MetS at baseline. Multivariate Cox regression was used to evaluate the risks of MACE and mortality following the men from baseline screening until first episode of MACE, death from other causes, emigration, or end of follow-up (31st December 2016) adjusting for age, family history, marital status, smoking, alcohol consumption, educational status, body mass index, prevalent diabetes, high blood lipids, increased fasting glucose and hypertension. Childless men presented with a worse metabolic profile than fathers at the baseline examination, with elevated risk of high triglycerides, odds ratio (OR) 1.24 (95%CI: 1.10-1.42), high fasting glucose OR 1.23 (95%CI: 1.05-1.43) and high blood pressure, OR 1.28 (95%CI: 1.14-1.45), respectively. In the fully adjusted prospective analysis, childless men presented with elevated risk of cardiovascular mortality, HR: 1.33 (95% CI: 1.18-1.49) and all-cause mortality, HR 1.23 (95%CI: 1.14-1.33), respectively. In conclusion, these results add to previous studies showing associations between male reproductive health, morbidity and mortality. Male childlessness, independently of well-known socio-economic, behavioral and metabolic risk factors, predicts risk of cardiovascular disease and mortality. Consequently, this group of men should be considered as target population for preventive measures.

Semen quality among young healthy men taking protein supplements.

OBJECTIVE: To study the association between use of protein supplements (PS) and semen quality among young men. DESIGN: Cross-sectional study. SETTING: Not applicable PATIENT(S): We used data from the Fetal Programming of Semen Quality (FEPOS) cohort, which is a subsample of 778 men whose mothers enrolled in the Danish National Birth Cohort 1996-2002. INTERVENTION(S): Semen samples were collected from April 2017 to March 2019. Relative difference in semen characteristics according to self-reported PS use was estimated with negative binomial regression adjusting for lifestyle factors including exercise, body mass index, and use of anabolic steroids, and maternal and paternal factors potentially confounding the association between PS and semen quality. MAIN OUTCOME MEASURE(S): Negative binomial regression yielded the best fit and was used to estimate the percent difference with 95% confidence intervals in semen volume, sperm concentration, total sperm count, proportions of progressive, nonprogressive, and immotile sperm, and percentage of morphologically normal sperm in former and current users of PS relative to never users. RESULT(S): PS was used currently by 28% and formerly by 24% of participants. PS use was not associated with reduced semen quality in terms of semen volume, sperm concentration, total sperm count, morphology, or motility in either crude or adjusted analyses. CONCLUSION: This study showed no association between use of PS and semen quality characteristics. Still, we encourage others to repeat the study, as even a small harmful effect would have a large impact on the population level because of the widespread use of PS among young men.

Evaluation, Treatment, and Insurance Coverage for Couples With Male Factor Infertility in the US: A Cross-Sectional Analysis of Survey Data.

OBJECTIVE: To characterize the evaluation, treatment, and insurance coverage among couples with male factor infertility in the United States. MATERIALS AND METHODS: A cohort of 969 couples undergoing fertility treatment with a diagnosis of male factor infertility were identified from an online survey. The proportion of men that were seen/not seen by a male were compared. Insurance coverage related to male factor was also assessed. RESULTS: Overall, 98.0% of the men reported at least one abnormal semen parameter. Of these, 72.0% were referred to a male fertility specialist with the majority being referred by the gynecologist of their female partner. As part of the male evaluation, 72.2% had blood hormone testing. Of the 248 men who were not recommended to see a male fertility specialist, 96.0% had an abnormal semen analysis including 7.6% who had azoospermia. Referral to a male fertility specialist was largely driven by severity of male factor infertility rather than socioeconomic status. Insurance coverage related to male factor infertility was poor with low coverage for sperm extractions (72.9% reported 0-25% coverage) and sperm freezing (83.7% reported 0-25% coverage). CONCLUSION: Although this cohort includes couples with abnormal semen parameters, 28% of the men were not evaluated by a male fertility specialist. In addition, insurance coverage for services related to male factor was low. These findings may be of concern as insufficient evaluation and coverage of the infertile man could lead to missed opportunities for identifying reversible causes of infertility/medical comorbidities and places an unfair burden on the female partner.

Male factor infertility and risk of death: a nationwide record-linkage study.

STUDY QUESTION: What is the risk of death among men with oligospermia, unspecified male factor and azoospermia in the years following fertility treatment? SUMMARY ANSWER: No significantly elevated risk was observed among men with oligospermia and unspecified male factor, while an increased risk was found among men with azoospermia. WHAT IS KNOWN ALREADY: Previous studies have shown associations between male factor infertility and risk of death, but these studies have relied on internal reference groups and the risk of death according to type of male infertility is not well characterized. STUDY DESIGN, SIZE, DURATION: In this prospective record-linkage cohort study, we identified men who had undergone medically assisted reproduction (MAR) between 1994 and 2015. Data was linked to the Danish causes of death register and sociodemographic registers through personal identification numbers assigned to all Danish citizens at birth. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men that had undergone MAR in Denmark (MAR Cohort; n = 64 563) were identified from the Danish IVF register, which includes data on whether infertility was due to male factor. For each man in the MAR cohort, five age-matched men who became fathers without fertility treatment were selected from the general population (non-MAR fathers; n = 322 108). Men that could not adequately be tracked in the Danish CPR register (n = 1259) and those that were censored prior to study entry (n = 993) were excluded, leaving a final population of 384 419 men. Risk of death was calculated by Cox regression analysis with age as an underlying timeline and adjustments for educational attainment, civil status and year of study entry. The risk of death was compared among men with and without male factor infertility identified from the IVF register (internal comparisons) as well as to the non-MAR fathers (external comparison). MAIN RESULTS AND THE ROLE OF CHANCE: The risk of death between the MAR cohort (all men, regardless of infertility) and the non-MAR fathers was comparable [hazard ratio (HR), 1.07; 95% CI, 0.98-1.15]. When the MAR cohort was limited to infertile men, these men were at increased risk of death [HR, 1.27; 95% CI, 1.12-1.44]. However, when stratified by type of male factor infertility, men with azoospermia had the highest risk of death, which persisted when in both the internal [HR, 2.30; 95% CI, 1.54-3.41] and external comparison [HR, 3.32; 95% CI, 2.02-5.40]. No significantly elevated risk of death was observed among men with oligospermia [HR, 1.14; 95% CI, 0.87-1.50] and unspecified male factor [HR, 1.10; 95% CI, 0.75-1.61] compared with the non-MAR fathers. The same trends were observed for the internal comparison. LIMITATIONS, REASONS FOR CAUTION: Duration of the follow-up was limited and there is limited generalizability to infertile men who do not seek fertility treatment. WIDER IMPLICATIONS OF THE FINDINGS: Using national health registers, we found an increased risk of death among azoospermic men while no increased risk was found among men with other types of infertility. For the azoospermic men, further insight into causal pathways is needed to identify options for monitoring and prevention. STUDY FUNDING/COMPETING INTEREST(S): This study is part of the ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS. C.G.'s research stay at Stanford was funded by grants from the University of Copenhagen, Kong Christian den Tiendes Fond, Torben og Alice Frimodt Fond and Julie Von Müllen Fond. M.E. is an advisor for Sandstone and Dadi. All other authors declare no conflict of interests. TRIAL REGISTRATION NUMBER: Not relevant.

Risk of hospitalization for early onset of cardiovascular disease among infertile women: a register-based cohort study.

STUDY QUESTION: Is female infertility predictive of a woman's future risk of early cardiovascular disease (CVD)? SUMMARY ANSWER: Female infertility does not seem to be predictive of early CVD during a mean follow-up of 9 years. WHAT IS KNOWN ALREADY: Associations between infertility and comorbidity have been found in several studies, but data on the association between female infertility and risk of CVD are scarce and inconclusive. STUDY DESIGN, SIZE, DURATION: In this nationwide cohort study, we included 87 221 women registered in the Danish National IVF register, undergoing medically assisted reproduction (MAR) between 1st of January 1994 and 31st of December 2015. The cohort was followed for incident hospitalization due to CVD in the Danish National Patient Register from enrollment to 31 December 2015. Women with a history of CVD prior to enrollment were excluded. Cox proportional hazard models with age as the underlying time scale were used to estimate hazard ratios (HR) with 95% CI of CVD among women with an infertility diagnosis, compared to women without an infertility diagnosis. All analyses were adjusted for educational attainment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Female infertility and the reason for infertility was diagnosed and registered in the IVF register by specialists in Danish public and private fertility clinics since 1st of January 1994. In our cohort, 53 806 women (61.7%) were diagnosed with female factor infertility, while 33 415 (38.3%) did not have a female factor infertility diagnosis and made up the reference group. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 686 (1.3%) infertile women were hospitalized for CVD compared to 250 (0.7%) among women without an infertility diagnosis during a mean follow-up time of 9 years. We found no increased risk of early CVD in our analyses (adjusted HR 0.98, 95% CI: 0.85;1.14). Likewise, analyses stratified by specific infertility diagnosis, showed no risk difference. LIMITATIONS, REASONS FOR CAUTION: We were unable to adjust for confounding parameters such as body mass index, cigarette smoking or alcohol consumption. These results may not be generalizable to infertile women who do not seek out fertility treatment, or infertile women with other lifestyle characteristics than Danish women. WIDER IMPLICATIONS OF THE FINDINGS: Diagnosing female infertility or the time of MAR does not seem to be a window of opportunity where early screening for cardiovascular disease risk factors can have a prophylactic potential. STUDY FUNDING/COMPETING INTEREST(S): This study is part of the ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS. None of the authors declare any conflict of interest.

Racial and Sociodemographic Differences of Semen Parameters Among US Men Undergoing a Semen Analysis.

OBJECTIVE: To characterize sociodemographic differences in semen parameters among US men undergoing a semen analysis. MATERIALS AND METHODS: Men who provided a semen sample were identified from insurance claims between 2007 and 2016. Differences in semen parameters were characterized according to age, race, education, and region. Mean semen parameters and proportions of men with suboptimal parameters were compared and risks of oligospermia and azoospermia were assessed by logistic regression. RESULTS: Of the 7263 men included, most men were white (55.1%), Hispanic (20.2%), or Asian (10.2%). Asians had the highest mean semen concentrations (69.2 × 106/mL), whereas blacks had the lowest (51.3 × 106/mL). Men from the Midwest were more likely to have oligospermia (odds ratio [OR] 1.62; 95% confidence interval [CI] 1.34-1.94), whereas men from the West were less likely (OR 0.82; 95% CI 0.82-0.94) when compared with men from South. An association between education and sperm concentration was observed. For example, men with a high school diploma or less were more likely to have oligospermia (OR 1.09; 95% CI 0.95-1.26), whereas men with at least a bachelor degree were less likely (OR 0.87; 95% CI 0.76-1.0) when compared with men with less than a bachelor degree. CONCLUSION: As we observed differences in semen quality based on sociodemographic factors, these findings may have clinical implications as relying on a single reference value when guiding infertile couples may be problematic given these variations. Further work is warranted to understand the etiology of such differences and determine if different normative reference values may apply for different populations.

Risk of metabolic disorders in childless men: a population-based cohort study.

OBJECTIVE: To study whether male childlessness is associated with an increased risk of metabolic disorders such as metabolic syndrome (MetS) and diabetes. DESIGN: A population-based cohort study. SETTING: Not applicable. PARTICIPANTS: 2572 men from the population-based Malmö Diet and Cancer Cardiovascular Cohort. INTERVENTIONS: None. MAIN OUTCOME MEASURES: From cross-sectional analyses, main outcome measures were ORs and 95% CIs for MetS and diabetes among childless men. In prospective analyses, HRs and 95% CI for diabetes among childless men. RESULTS: At baseline, in men with a mean age of 57 years, the prevalence of MetS was 26% and 22% among childless men and fathers, respectively. Similarly, we observed a higher prevalence of diabetes of 11% among childless men compared with 5% among fathers. In the cross-sectional adjusted analyses, childless men had a higher risk of MetS and diabetes, with ORs of 1.22 (95% CI 0.87 to 1.72) and 2.12 (95% CI 1.34 to 3.36) compared with fathers. In the prospective analysis, during a mean follow-up of 18.3 years, we did not see any increase in diabetes risk among childless men (HR 1.02 (0.76 to 1.37)). CONCLUSION: This study provides evidence of an association between male childlessness and a higher risk of MetS and diabetes. However, as these associations were found in cross-sectional analyses, reverse causation cannot be excluded.

Mortality in Women Treated With Assisted Reproductive Technology-Addressing the Healthy Patient Effect.

In previous studies, investigators have reported reduced mortality among women undergoing assisted reproductive technology (ART) treatment, possibly related to selection of healthy women into ART treatment. Our aim in this study was to explore the impact of relevant selection factors on the association between ART treatment and mortality and to explore effect modification by parity. Women treated with ART in fertility clinics in Denmark during 1994-2009 (n = 42,897) were age-matched with untreated women from the background population (n = 204,514) and followed until December 31, 2010. With adjustment for relevant confounders, the risk of death was lower among ART-treated women during the first 2 years after ART treatment (hazard ratio (HR) = 0.68, 95% confidence interval (CI): 0.63, 0.74), but there was no apparent difference after 10 years (HR = 0.92, 95% CI: 0.79, 1.07). Having children prior to ART treatment was associated with markedly reduced mortality (HR = 0.45, 95% CI: 0.38, 0.53), possibly due to better health among fertile women. While the frequencies of previous medical and psychiatric diagnoses among ART-treated and untreated women were similar, differences in disease severity could explain the reduced mortality among ART-treated women, as poor prognosis would make initiation of ART treatment unlikely. The survival advantage among ART-treated women is likely a selection phenomenon rather than a biological phenomenon.

Male factor infertility and risk of multiple sclerosis: A register-based cohort study.

BACKGROUND: Gender, possibly due to the influence of gonadal hormones, is presumed to play a role in the pathogenesis of multiple sclerosis (MS), but no studies have evaluated whether male infertility is associated with MS. OBJECTIVE: To study the association between male factor infertility and prevalent as well as incident MS. METHOD: Our cohort was established by linkage of the Danish National in vitro fertilization (IVF) registry to The Danish Multiple Sclerosis Registry and consisted of 51,063 men whose partners had undergone fertility treatment in all public and private fertility clinics in Denmark between 1994 and 2015. RESULTS: With a median age of 34 years at baseline, 24,011 men were diagnosed with male factor infertility and 27,052 did not have male factor infertility and made up the reference group. Men diagnosed with male factor infertility had a higher risk of prevalent (odds ratio (OR) = 1.61, 95% confidence interval (95% CI) 1.04-2.51) and incident MS (hazard ratio (HR) = 1.28, 95% CI 0.76-2.17) when compared to the reference group. CONCLUSION: This nationwide cohort study has shown, for the first time, an association between male infertility and MS which may be due to underlying common etiologies such as hypogonadism, shared genetics, or a joint autoimmune component.

Natural history of pain associated with melanoma surgery.

INTRODUCTION: After excision of a primary malignant melanoma (MM), treatment of stage IB or higher MM consists of sentinel lymph node biopsy (SLNB). If malignant cells are identified, a complete lymph node dissection (CLND) can be performed. OBJECTIVE: To determine the natural history of pain and sensory changes after MM surgery. METHODS: We prospectively followed 39 patients (29 SLNB-only, 2 CLND-only, and 8 CLND preceded by SLNB) from before inguinal or axillary surgery through 6 months after surgery on measures of pain intensity, sensory symptoms, allodynia, and questionnaires of anxiety, depression, and catastrophizing. RESULTS: No patient had pain preoperatively. Ten days after surgery, 35% had surgical site pain after SLNB-only compared with 90% after CLND (P < 0.003); clinically meaningful pain (Visual Analogue Scale ≥ 30 mm/100 mm) was reported by 3% of patients after SLNB-only compared with 40% after CLND (P < 0.001). At 6 months, all SLNB-only patients were pain-free. By contrast, 4 of 7 in the SLNB + CLND group still had pain (P < 0.002). At 6 months, symptoms of altered sensation or numbness were reported by 32% and 42% of SLNB-only patients, and by 67% and 67% of patients undergoing CLND surgery (both P > 0.05). CONCLUSION: Acute pain is more common after CLND surgery. Undergoing SLNB followed by more invasive CLND surgery may increase the likelihood of pain at 6 months. Persistent sensory symptoms typical of those associated with nerve injury are more common after CLND. Surgery for MM is a good model for studying the natural history of postsurgical pain and sensory changes.

Risk of diabetes according to male factor infertility: a register-based cohort study.

STUDY QUESTION: Is male factor infertility associated with an increased risk of developing diabetes? SUMMARY ANSWER: The study provides evidence that male factor infertility may predict later occurrence of diabetes mellitus with the risk being related to the severity of the underlying fertility problem. WHAT IS KNOWN ALREADY: Previous cross-sectional studies have shown an increased prevalence of comorbidities among infertile men when compared to controls. STUDY DESIGN, SIZE, DURATION: In this prospective cohort study, 39 516 men who had since 1994 undergone fertility treatment with their female partner were identified from the Danish national IVF register, which includes data on assumed cause of couple infertility (male/female factor, mixed and unexplained infertility) and type of fertility treatment. With a median follow-up time of 5.6 years, each man was followed for diabetes occurrence from enrollment until 31 December 2012 using the National Diabetes Register (NDR). Men with a history of diabetes prior to their fertility diagnosis were excluded. Hazard ratios (HR) were estimated by Cox proportional hazard models with age as the underlying time scale. In addition to analyzing the data for the entire IVF registration period (1994-2012), separate analyses were performed for men identified from the first (1994-2005) and second (2006-2012) IVF registration period owing to heterogeneity in the reporting of male factor infertility in these two time periods, because the reason for male factor infertility was not available from the first register. PARTICIPANTS/MATERIALS, SETTING, METHODS: Male factor infertility was identified from the variable 'yes' or 'no' from the first IVF register and through a diagnosis code (e.g. oligospermia, azoospermia) from the second IVF register. The reference group was men with male factor infertility (='no') and those with normal semen quality or sterilized men. Of the included men, 18 499 (46.8%) had male factor infertility and 21 017 (53.2%) made up the reference group. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 651 (1.6%) diabetes cases were identified during the follow-up period. The adjusted HR's for diabetes risk among men with male factor infertility when compared to the reference group were HR = 1.08 (95% CI: 0.89, 1.31) and HR = 1.45 (95% CI: 1.06, 1.97) for the first and second IVF registration period, respectively. When assessing the effects of individual causes of male factor infertility, the adjusted HR's for men with oligospermia, azoospermia and aspermia were HR = 1.44 (95% CI: 1.01, 2.06), HR = 2.10 (95% 1.25, 3.56) and HR = 3.20 (95% CI 1.00, 10.31), respectively. LIMITATIONS, REASONS FOR CAUTION: We found no increased risk among men identified from the first IVF register, which may be related to exposure misclassification as the reason for male factor infertility was not available from this time period. The NDR does not distinguish between type 1 and type 2 diabetes. WIDER IMPLICATIONS OF THE FINDINGS: These findings support previous studies that a man's reproductive and somatic health are closely intertwined and highlight the importance for further monitoring of these men. Further, implementation of diabetes screening may be especially relevant among aspermic and azoospermic men. STUDY FUNDING/COMPETING INTERESTS: This article is part of the ReproUnion collaborative study, co-financed by the European Union, Intereg V Öresund-Kattegat-Skagerrak. None of the authors declare any conflict of interest. TRIAL REGISTRATION NUMBER: None.

Changing trends in reproductive/lifestyle factors in UK women: descriptive study within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

OBJECTIVE: There has been considerable interest in the impact of reproductive factors on health but there are little data on how these have varied over time. We explore trends in reproductive/lifestyle factors of postmenopausal British women by analysing self-reported data from participants of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). DESIGN: Prospective birth cohort analysis. SETTING: Population cohort invited between 2001 and 2005 from age-sex registers of 27 Primary Care Trusts in England, Wales and Northern Ireland and recruited through 13 National Health Service Trusts. PARTICIPANTS: 202 638 postmenopausal women aged 50-74 years at randomisation to UKCTOCS between April 2001 and October 2005. INTERVENTIONS: Women were stratified into the following six birth cohorts (1925-1929, 1930-1934, 1935-1939, 1940-1944, 1945-1949, 1950-1955) based on year of birth. Self-reported data on reproductive factors provided at recruitment were explored using tabular and graphical summaries to examine for differences between the birth cohorts. OUTCOME MEASURES: Trends in mean age at menarche and menopause, use of oral contraceptives, change in family size, infertility treatments, tubal ligation and hysterectomy rates. RESULTS: Women born between 1935 and 1955 made up 86% of the cohort. Median age at menarche decreased from 13.4 for women born between 1925 and 1929 to 12.8 for women born between 1950 and 1955. Increased use of the oral contraceptives, infertility treatments and smaller family size was observed in the younger birth cohorts. Tubal ligation rates increased for those born between 1925 and 1945, but this increase did not persist in subsequent cohorts. Hysterectomy rates (17-20%) did not change over time. CONCLUSIONS: The trends seen in this large cohort are likely to reflect the reproductive history of the UK female postmenopausal population of similar age. Since these are risk factors for hormone-related cancers, these trends are important in understanding the changing incidence of these cancers. TRIAL REGISTRATION NUMBER: International Standard Randomised Controlled Trial Number: 22488978.

The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis.

BACKGROUND: More than 20 years ago, it was hypothesized that exposure to prenatal and early postnatal environmental xenobiotics with the potential to disrupt endogenous hormone signaling might be on the causal path to cryptorchidism, hypospadias, low sperm count and testicular cancer. Several consensus statements and narrative reviews in recent years have divided the scientific community and have elicited a call for systematic transparent reviews. We aimed to fill this gap in knowledge in the field of male reproductive disorders. OBJECTIVE AND RATIONALE: The aim of this study was to systematically synthesize published data on the risk of cryptorchidism, hypospadias, low sperm counts and testicular cancer following in utero or infant exposure to chemicals that have been included on the European Commission's list of Category 1 endocrine disrupting chemicals defined as having documented adverse effects due to endocrine disruption in at least one intact organism. SEARCH METHODS: A systematic literature search for original peer reviewed papers was performed in the databases PubMed and Embase to identify epidemiological studies reporting associations between the outcomes of interest and exposures documented by biochemical analyses of biospecimens including maternal blood or urine, placenta or fat tissue as well as amnion fluid, cord blood or breast milk; this was followed by meta-analysis of quantitative data. OUTCOMES: The literature search resulted in 1314 references among which we identified 33 papers(28 study populations) fulfilling the eligibility criteria. These provided 85 risk estimates of links between persistent organic pollutants and rapidly metabolized compounds (phthalates and Bisphenol A) and male reproductive disorders. The overall odds ratio (OR) across all exposures and outcomes was 1.11 (95% CI 0.91-1.35). When assessing four specific chemical subgroups with sufficient data for meta-analysis for all outcomes, we found that exposure to one of the four compounds, p,p'-DDE, was related to an elevated risk: OR 1.35 (95% CI 1.04-1.74). The data did not indicate that this increased risk was driven by any specific disorder. WIDER IMPLICATIONS: The current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classified as endocrine disruptors but the evidence is limited. Future epidemiological studies may change the weight of the evidence in either direction. No evidence of distortion due to publication bias was found, but exposure-response relationships are not evident. There are insufficient data on rapidly metabolized endocrine disruptors and on specific exposure-outcome relations. A particular data gap is evident with respect to delayed effects on semen quality and testicular cancer. Although high quality epidemiological studies are still sparse, future systematic and transparent reviews may provide pieces of evidence contributing to the narrative and weight of the evidence assessments in the field.

Use and perceived efficacy of complementary and alternative medicines after discontinuation of hormone therapy: a nested United Kingdom Collaborative Trial of Ovarian Cancer Screening cohort study.

OBJECTIVE: Given that the Women's Health Initiative reported in 2002 increased risks of breast cancer and cardiovascular events with hormone therapy (HT) use and many women discontinued use, we assessed the use and perceived efficacy of complementary and alternative medicines (CAMs) for menopausal symptom relief after discontinuation of HT. METHODS: Postmenopausal women aged 50 to 65 years within the United Kingdom Collaborative Trial of Ovarian Cancer Screening who were willing to take part in a secondary study were mailed a survey to evaluate menopausal symptom management. Use and perceived efficacy of CAMs for relief of vasomotor symptoms (VMS) upon discontinuation of HT were examined. RESULTS: The survey was sent to 15,000 women between July 2 and July 9, 2008. Seventy-one percent (10,662 of 15,000) responded, and 10,607 women with complete data were included. Ever use of HT was reported by 60.2% (6,383 of 10,607). At survey completion, 79.3% (5,060 of 6,383) had discontinued HT, with 89.7% (4,540 of 5,060) of the latter reporting using one or more CAMs for VMS relief. About 70.4% (3,561 of 5,060) used herbal remedies, with evening primrose oil (48.6%; 2,205 of 4,540) and black cohosh (30.3%;1,377 of 4,540) being most commonly used. Exercise was used by 68.2% (3,098 of 4,540), whereas other behavioral/lifestyle approaches were less frequently reported (13.9%; 629 of 4,540). Contrarily, more women (57%-72%) rated behavioral/lifestyle approaches as effective compared with herbal remedies (28%-46%; rating ≥4 on a "helpfulness" scale from 1-10). Among medical treatments, selective serotonin reuptake inhibitors were used by 10% and rated effective by 72.1%. CONCLUSIONS: Although more women use over-the-counter medicines, behavioral/lifestyle approaches seem to provide better relief of VMS. There is a pressing need for better evidence-based lay information to support decision-making on CAM use for relief of VMS.