Iron intake in relation to ovarian reserve among women seeking infertility treatment.

STUDY QUESTION: Is there an association between iron intake and ovarian reserve among women seeking fertility care? SUMMARY ANSWER: Supplemental iron intake above 45 mg/day is associated with lower ovarian reserve among women seeking fertility care. WHAT IS KNOWN ALREADY: Although the literature regarding iron intake in relation to ovarian reserve is scant and inconsistent, some evidence suggests that iron may have gonadotoxic effects. STUDY DESIGN, SIZE, DURATION: This observational study included 582 female participants attending the Massachusetts General Hospital Fertility Center (2007-2019) enrolled in the Environment and Reproductive Health (EARTH) Study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Iron intake was estimated using a validated food frequency questionnaire. Markers of ovarian reserve included antral follicle count (AFC) (assessed via transvaginal ultrasound) and Day 3 FSH, both obtained during the course of an infertility evaluation. MAIN RESULTS AND THE ROLE OF CHANCE: Participants had a median age of 35 years and median total iron intake of 29 mg/day. Total iron intake was inversely related to AFC and this association was driven by intake of supplemental iron. Compared to women with a supplemental iron intake of ≤20 mg/day, women consuming 45-64 mg/day of supplemental iron had a 17% (-35%, 0.3%) lower AFC and women consuming ≥65 mg/day of supplemental iron had a 32% (-54%, -11%) lower AFC after adjusting for potential confounders (P, linear trend = 0.003). Similarly, in a multivariable-adjusted analysis, Day 3 FSH levels were 0.9 (0.5, 1.3) IU/ml higher among women with a supplemental iron intake of ≥65 mg/day when compared to women with a supplemental iron intake of ≤20 mg/day (P, linear trend = 0.02). LIMITATIONS, REASONS FOR CAUTION: Iron intake was estimated using a method that relies on self-report and we had no biomarkers of iron status in our participants; only 36 women consumed ≥45 mg/day of supplemental iron. WIDER IMPLICATIONS OF THE FINDINGS: Since all study participants were seeking fertility treatment, our findings may not apply to women in the general population. Although our findings are consistent with studies of women with iron overload, given the paucity of literature on this topic, it is essential that this question is revisited in studies designed to better understand the dose-response relation of this association across the entire distribution of ovarian reserve and the risk-benefit balance of pre-conceptional iron supplementation given its many positive effects on pregnancy outcomes. STUDY FUNDING/COMPETING INTEREST(S): The project was funded by Grants R01ES022955, R01ES033651, R01ES009718, P30ES000002, and P30DK046200 from the National Institutes of Health. N.J.-C. was supported by a Fulbright Scholarship. N.J.-C., M.M., L.M.-A., E.O.-P., S.W., I.S., and J.E.C. declare no conflict of interest related to the work in the manuscript. R.H. has received grants from the National Institute of Environmental Health Sciences. TRIAL REGISTRATION NUMBER: N/A.

Association between intake of soft drinks and testicular function in young men.

STUDY QUESTION: Is intake of sugar-sweetened beverages (SSB) or artificially sweetened beverages (ASB) associated with testicular function in young men? SUMMARY ANSWER: Among young men unaware of their semen quality and reproductive hormone levels, intake of SSBs was associated with lower sperm concentration, lower total sperm count, and a lower ratio of serum inhibin-B/FSH. WHAT IS KNOWN ALREADY: SSBs may adversely impact testicular function, but results are not consistent across studies. Moreover, the associations of ASB, energy-drinks or fruit juices with testicular function are unclear. STUDY DESIGN, SIZE, DURATION: Young healthy men and unselected for fertility status men enrolled in a cross-sectional study between 2008 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 2935 young (median age: 19 years) men enrolled in the study. Intake of SSBs, ASBs, fruit juices, and energy-drinks was assessed with a validated food frequency questionnaire. Testicular function was assessed through conventional semen quality parameters (semen volume, sperm concentration, total count, motility and morphology), testicular volume assessed with ultrasound, and serum reproductive hormone concentrations (total testosterone, free testosterone, E2, inhibin-B, LH, FSH, sex hormone-binding globulin) were measured. MAIN RESULTS AND THE ROLE OF CHANCE: In multivariable-adjusted analyses, men in the highest category of SSB intake (median: 1.1 servings (∼220 ml)/day) had a 13.2 million/ml lower median sperm concentration (95% CI: -21.0, -5.5) than non-consumers. A similar pattern was observed with total sperm count (-28 million (95% CI: -48, -9)), serum inhibin-B (-12 pg/ml (95% CI: -21, -4)), and inhibin-B/FSH ratio (-9 (95% CI: -18, 0)). The adjusted median difference in sperm concentration and inhibin-B associated with increasing SSB intake by 1 serving (∼200ml)/day at the expense of water was -3.4 million sperm/ml (95% CI: -5.8, -1.0) and -7 pg/ml (95% CI: -11, -3), respectively. LIMITATIONS, REASONS FOR CAUTION: Inferring causality is limited owing to the cross-sectional design. We adjusted for a number of potential confounders but cannot exclude that unmeasured lifestyle and behavior associated with soft drink intake is associated with testicular function in these young men. WIDER IMPLICATIONS OF THE FINDINGS: In the largest study to date, intake of SSBs was associated with lower sperm concentration, total sperm count, and serum inhibin-B/FSH ratio, consistent with a direct suppressive effect of SSB intake on testicular function among otherwise healthy men, potentially affecting fertility. However, the observed association between higher SSB intake and lower semen quality does not necessarily imply a decrease in fertility. STUDY FUNDING/COMPETING INTEREST(S): Supported by research from the Danish Council for Strategic Research (2101-08-0058), Independent Research Fund Denmark (8020-00218B), European Union (212844), the Kirsten and Freddy Johansen's Foundation (95-103-72087), the Research Fund of the Capital Region of Denmark (A6176), and the NIH (P30DK046200). The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Vitamin D status is not associated with reproductive parameters in young Spanish men.

BACKGROUND: Relatively low sperm count was reported among young Spanish men in 2013. Several potential culprits have been suggested as explanations for reported trends in sperm counts in Western men, including lifestyles. Although controversial, some studies suggest that semen parameters, such as low sperm motility or abnormal morphology, may be associated with low serum vitamin D levels. OBJECTIVES: To evaluate associations between semen parameters and reproductive hormones and serum 25-hydroxyvitamin D (25OHD) status in young Spanish men and to examine these associations in relation to dietary intake of vitamin D. MATERIALS AND METHODS: This cross-sectional study includes 198 university students recruited in 2010-2011 in southern Spain, who provided samples of blood and semen and food frequencies. Semen quality was evaluated by measuring volume, concentration, sperm counts, motility, and morphology, according to the WHO guidelines. Serum samples were analyzed for total 25OHD and reproductive hormones, including FSH, LH, testosterone, inhibin B, and estradiol. Dietary vitamin D intake was assessed using a validated food frequency questionnaire. Associations with semen quality and reproductive hormones were examined using linear regression, adjusting for potential confounders. RESULTS: Almost all men had adequate levels of serum vitamin D - only three men (1.5%) were vitamin D deficient (<30 nmol/L) and 17% were insufficient (<50 nmol/L). However, dietary vitamin D intakes were relatively low (below recommended 600 IU/day in 99% of men). Neither dietary intake nor serum vitamin D levels were associated with any sperm parameter or any reproductive hormone (all p ≥ 0.09). DISCUSSION: We did not observe an association between vitamin D status and any reproductive parameter in our study population. CONCLUSIONS: Our results suggest that serum vitamin D levels are sustained in Spanish men despite low dietary intake and therefore low vitamin D does not explain the poor semen quality previously observed in these young Spanish men.

Semen parameters on the day of oocyte retrieval predict low fertilization during conventional insemination IVF cycles.

PURPOSE: Poor fertilization during conventional IVF is difficult to predict in the absence of abnormal semen parameters; large-scale studies are lacking. The purpose of this study is to evaluate factors associated with low fertilization rates in conventional insemination IVF cycles. METHODS: A retrospective cohort study evaluating demographic, reproductive evaluation, and IVF cycle characteristics to identify predictors of low fertilization (defined as 2PN/MII ≤ 30% per cycle). Participants were included if they were undergoing their first IVF cycle utilizing fresh autologous oocytes and conventional insemination with male partner's sperm (with normal pretreatment semen analysis). They were randomly divided into a training set and a validation set; validation modeling with logistic regression and binary distribution was utilized to identify covariates associated with low fertilization. RESULTS: Postprocessing sperm concentration of less than 40 million/ml and postprocessing sperm motility < 50% on the day of retrieval were the strongest predictors of low fertilization in the training dataset. Next, in the validation set, cycles with either low postprocessing concentration (≤ 40 million/ml) or low postprocessing progressive motility (≤ 50%) were 2.9-times (95% CI 1.4, 6.2) more likely to have low fertilization than cycles without either risk factor. Furthermore, cycles with low postprocessing concentration and progressive motility were 13.4 times (95% CI 4.01, 45.06) more likely to have low fertilization than cycles without either risk factor. CONCLUSIONS: Postprocessing concentration and progressive motility on the day of oocyte retrieval are predictive of low fertilization in conventional IVF cycles with normal pretreatment diagnostic semen analysis parameters.

Fruit and vegetable consumption and risk of endometriosis.

STUDY QUESTION: Is there an association between intake of fruits and vegetables and risk of laparoscopically confirmed endometriosis? SUMMARY ANSWER: Higher intake of fruits, particularly citrus fruits, is associated with a lower risk of endometriosis. WHAT IS KNOWN ALREADY: Two case-control studies have examined the associations between fruit and vegetable intake and endometriosis risk with contrasting results. Diets rich in fruits and vegetables include higher levels of pro-vitamin A nutrients (alpha-carotene, beta-carotene, beta-cryptoxanthin) and women with endometriosis have been reported to have lower intake of vitamin A than women without endometriosis. STUDY DESIGN SIZE, DURATION: A prospective cohort study using data collected from 70 835 premenopausal women from 1991 to 2013 as part of the Nurses' Health Study II cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Diet was assessed with a validated food frequency questionnaire (FFQ) every 4 years. Cases were restricted to laparoscopically confirmed endometriosis. Cox proportional hazards models were used to calculate rate ratios (RR) and 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: During 840 012 person-years of follow-up, 2609 incident cases of laparoscopically confirmed endometriosis were reported (incidence rate = 311 per 100 000 person-years). We observed a non-linear inverse association between higher fruit consumption and risk of laparoscopically confirmed endometriosis (Psignificance of the curve = 0.005). This inverse association was particularly evident for citrus fruits. Women consuming ≥1 servings of citrus fruits/day had a 22% lower endometriosis risk (95% CI = 0.69-0.89; Ptrend = 0.004) compared to those consuming <1 serving/week. No association was observed between total vegetable intake and endometriosis risk. However, women consuming ≥1 servings/day cruciferous vegetables had a 13% higher risk of endometriosis (95% CI = 0.95-1.34; Ptrend = 0.03) compared to those consuming <1 serving/week. Of the nutrients examined, only beta-cryptoxanthin intake was significantly associated with lower endometriosis risk (RR fifth quintile = 0.88; 95% CI = 0.78-1.00; Ptrend = 0.02). LIMITATIONS REASONS FOR CAUTION: Some error in the self-reporting of dietary intake is expected, however, use of a validated FFQ and examining diet prospectively across multiple time points, make it unlikely that this non-differential misclassification strongly influenced the results. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that a higher intake of fruits, particularly citrus fruits, is associated with a lower risk of endometriosis, and beta-cryptoxanthin in these foods may partially explain this association. In contrast to what we hypothesized, consumption of some vegetables increased endometriosis risk which may indicate a role of gastrointestinal symptoms in both the presentation and exacerbation of endometriosis-related pain; however, it is not clear what components of these foods might underlie the observed associations. Future studies examining dietary patterns that consider different combinations of food intake may help clarify these associations. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by research grants HD4854, HD52473 and HD57210 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and grant P30 DK046200 from the National Institute of Diabetes and Digestive and Kidney Diseases. The Nurses' Health Study II is supported by the Public Health Service grant UM1 CA176726 from the National Cancer Institute, National Institutes of Health. HRH is supported by the National Cancer Institute, National Institutes of Health (K22 CA193860). No competing interests. TRIAL REGISTRATION NUMBER: n/a.

Serum omega-3 fatty acids and treatment outcomes among women undergoing assisted reproduction.

STUDY QUESTION: Are serum polyunsaturated fatty acids (PUFA) concentrations, including omega-3 (ω3-PUFA) and omega-6 (ω6-PUFA), related to ART outcomes? SUMMARY ANSWER: Serum levels of long-chain ω3-PUFA were positively associated with probability of live birth among women undergoing ART. WHAT IS KNOWN ALREADY: Intake of ω3-PUFA improves oocyte and embryo quality in animal and human studies. However, a recent cohort study found no relation between circulating ω3-PUFA levels and pregnancy rates after ART. STUDY DESIGN SIZE, AND DURATION: This analysis included a random sample of 100 women from a prospective cohort study (EARTH) at the Massachusetts General Hospital Fertility Center who underwent 136 ART cycles within one year of blood collection. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum fatty acids (expressed as percentage of total fatty acids) were measured by gas chromatography in samples taken between Days 3 and 9 of a stimulated cycle. Primary outcomes included the probability of implantation, clinical pregnancy and live birth per initiated cycle. Cluster-weighted generalized estimating equation (GEE) models were used to analyze the association of total and specific PUFAs with ART outcomes adjusting for age, body mass index, smoking status, physical activity, use of multivitamins and history of live birth. MAIN RESULTS AND ROLE OF CHANCE: The median [25th, 75th percentile] serum level of ω3-PUFA was 4.7% [3.8%, 5.8%] of total fatty acids. Higher levels of serum long-chain ω3-PUFA were associated with higher probability of clinical pregnancy and live birth. Specifically, after multivariable adjustment, the probability of clinical pregnancy and live birth increased by 8% (4%, 11%) and 8% (95% CI: 1%, 16%), respectively, for every 1% increase in serum long-chain ω3-PUFA levels. Intake of long-chain ω3-PUFA was also associated with a higher probability of life birth in these women, with RR of 2.37 (95% CI: 1.02, 5.51) when replacing 1% energy of long-chain ω3-PUFA for 1% energy of saturated fatty acids. Serum ω6-PUFA, ratios of ω6 and ω3-PUFA, and total PUFA were not associated with ART outcomes. LIMITATIONS REASONS FOR CAUTION: The generalizability of the findings to populations not undergoing infertility treatment may be limited. The use of a single measurement of serum fatty acids to characterize exposure may lead to potential misclassification during follow up. WIDER IMPLICATIONS OF THE FINDINGS: Serum ω3-PUFA are considered biomarkers of dietary intake. The association of higher serum long chain ω3-PUFA levels with improved ART outcomes suggests that increased intake of these fats be may be beneficial for women undergoing infertility treatment with ART. STUDY FUNDING/COMPETING INTERESTS: NIH grants R01-ES009718 from the National Institute of Environmental Health Sciences, P30-DK046200 and T32-DK007703-16 from the National Institute of Diabetes and Digestive and Kidney Diseases, and L50-HD085359 from the National Institute of Child Health and Human Development, and the Early Life Nutrition Fund from Danone Nutricia US. Dr Rueda is involved in a patent 9,295,662, methods for enhancing, improving, or increasing fertility or reproductive function (http://patents.com/us-9295662.html). This patent, however, does not lead to financial gain for Dr Rueda, or for Massachusetts General Hospital. Dr Rueda does not own any part of the company nor does he have any equity in any fertility related company. As Dr Rueda is not a physician, he does not evaluate patients or prescribe medications. All other coauthors have no conflicts of interest to declare.

Birth by cesarean section in relation to adult offspring overweight and biomarkers of cardiometabolic risk.

BACKGROUND: Birth by Cesarean section (C-section) may increase the risk for non-communicable diseases. We aimed to examine the relation of birth by C-section with offspring overweight and markers of cardiometabolic risk in a prospective observational cohort with 20 years of follow-up. METHODS: The Danish Fetal Origins Cohort enrolled 965 pregnant women in 1988-1989. In 2008, a follow-up study of the offspring was completed. The offspring were invited to participate in a clinical examination with measurements of anthropometry and a fasting blood sample (n=443). In addition, 252 offspring completed a self-administered questionnaire with questions on height and weight, leaving us with a study sample of 695 offspring. Offspring overweight at 20 years was defined as body mass index (BMI)⩾25 kg m-2. We also analyzed blood pressure and fasting blood samples for cardiometabolic risk factors including insulin, leptin and adiponectin, and lipid concentrations. RESULTS: In the cohort, 7% were born by C-section, and at age 20 years, 18% of the offspring had a BMI ⩾25 kg m-2. Birth by C-section was associated with increased odds of overweight or obesity at 20 years (Odds ratio=2.17 (95% confidence interval (CI): 1.10, 4.27)) after adjustment for potential confounders. Birth by C-section was also associated with higher serum concentrations of total cholesterol (8.5%, 95% CI: 1.1-16.5), low-density lipoprotein cholesterol (12.6%, 95% CI: 1.0, 25.5), leptin (73.1%, 95% CI: 5.9, 183.1) and Apolipoprotein B (0.08 g l-1, 95% CI: 0.04, 0.15). In contrast, birth by C-section was not related to blood pressure or serum concentrations of insulin, adiponectin, triglycerides, high-density lipoprotein or Apolipoprotein A. CONCLUSION: Birth by C-section was associated with higher frequency of dysmetabolic traits in offspring independently of shared risk factors. Further research aimed at replicating these findings and elucidating the underlying biological mechanisms of this relation is needed.

The association between pre-treatment maternal alcohol and caffeine intake and outcomes of assisted reproduction in a prospectively followed cohort.

STUDY QUESTION: Is pre-treatment alcohol and caffeine intake associated with infertility treatment outcomes among women undergoing ART? SUMMARY ANSWER: Low to moderate alcohol and caffeine intakes in the year prior to infertility treatment were not related to ART outcomes. WHAT IS KNOWN ALREADY: Alcohol and caffeine intake have been found to be associated with infertility in some studies. Nevertheless, data on their relation with outcomes of infertility treatments are scarce and inconsistent. STUDY DESIGN, SIZE, DURATION: We included 300 women (493 ART cycles) from the Environment and Reproductive Health Study, an ongoing cohort study (2006-2016). PARTICIPANTS/MATERIALS, SETTING, METHODS: Pre-treatment intakes of alcohol and caffeine were assessed retrospectively using a validated food frequency questionnaire. Intermediate and clinical endpoints of ART were abstracted from electronic medical records. Generalized linear mixed models with random intercepts to account for multiple ART cycles per woman were used to evaluate the association with ART outcomes adjusting for age, BMI, smoking status, infertility diagnosis, protocol type, race, dietary patterns, and calories, vitamin B12 and folate intake. MAIN RESULTS AND THE ROLE OF CHANCE: Median (range) pre-treatment alcohol and caffeine intakes were 5.6 (0.0-85.8) g/day and 124.9 (0.3-642.2) mg/day, respectively. The adjusted percentage of initiated cycles resulting in live birth (95% CI) for women in increasing categories of pre-treatment alcohol intake was 34% (20, 52%) for non-consumers, 46% (36, 57%) for 0.1-6 g/day, 41% (29, 53%) for 6.1-12 g/day, 42% (31, 55%) for 12.1-24 g/day, and 41% (22, 63%) for >24 g/day (P, trend = 0.87). The adjusted percentage of cycles resulting in live birth (95% CI) for women in increasing categories of caffeine intake was 46% (36-57%) for <50 mg/day, 44% (29, 60%) for 50.1-100 mg/day, 42% (31, 53%) for 100.1-200 mg/day, 40% (28, 53%) for 200.1-300 mg/day and 40% (21, 63%) for >300 mg/day (P, trend = 0.34). When specific types of alcoholic and caffeinated beverages were evaluated, no relations with ART treatment outcomes were observed. LIMITATIONS, REASONS FOR CAUTION: Residual confounding by other diet and lifestyle factors cannot be ruled out owing to the observational nature of this study. It is also unclear how generalizable these results are to women who are conceiving without the assistance of ART. WIDER IMPLICATIONS OF THE FINDINGS: Our results provide reassurance that low to moderate intakes of alcohol (e.g. ≤12 g/day) and caffeine (e.g. <200 mg/day) in the year prior to infertility treatment initiation do not have an adverse effect on intermediate or clinical outcomes of ART. STUDY FUNDING/COMPETING INTEREST(S): The authors are supported by National Institutes of Health (NIH) grants ES022955, R01ES009718, R01ES000002, P30DK46200 and L50-HD085359. No conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NCT00011713.

The association of protein intake (amount and type) with ovarian antral follicle counts among infertile women: results from the EARTH prospective study cohort.

OBJECTIVE: To evaluate the association between protein intake (amount and type) and antral follicle count (AFC). DESIGN: Prospective cohort. SETTING: Academic fertility centre. POPULATION: Two hundred and sixty-five women undergoing fertility treatments at an academic fertility centre and participating in an ongoing study on environment and reproductive health. METHODS: We measured AFC in ultrasonographic evaluation among women undergoing infertility treatments. Women completed a previously validated semi-quantitative food frequency questionnaire. We used Poisson regression to evaluate the relation between protein intake and AFC while adjusting for age, body mass index, race, smoking status, and total energy intake. MAIN OUTCOME MEASURES: Antral follicle count. RESULTS: Among 265 women (mean age: 35.0 ± 3.9 years, 85% Caucasian), total protein intake (% energy) was unrelated to AFC. When protein from different food sources was considered separately, we found a negative association between dairy protein intake and AFC. The mean AFC was 14.4% (3.9-23.7%) lower for women in the highest quintile of dairy protein intake than for women in the bottom quintile after adjusting for potential confounders (P-trend = 0.04). This association was stronger among women who had never smoked (P-trend = 0.002) but was not observed among previous smokers (P-trend = 0.36). There were no associations between protein intake from either non-dairy animal or vegetable sources and AFC. CONCLUSION: Higher dairy protein intake (≥5.24% of energy) was associated with lower antral follicle counts among women presenting for infertility treatment. These findings should be further investigated in prospective studies also designed to clarify the biology underlying the observed associations. TWEETABLE ABSTRACT: Higher dairy protein intake was associated with lower antral follicle counts in an infertile population.

Male caffeine and alcohol intake in relation to semen parameters and in vitro fertilization outcomes among fertility patients.

Much of the literature on the impact of male caffeine and alcohol intake on reproductive outcomes has utilized semen quality as a proxy for male fertility, although semen parameters have a limited predictive value for spontaneous pregnancy. The objective of this study was to investigate whether male caffeine and alcohol intakes are associated with semen parameters and assisted reproductive technology outcome. The Environment and Reproductive Health Study, an ongoing prospective cohort study, enrolls subfertile couples presenting for treatment at an academic fertility center (2007-2012). A total of 171 men with 338 semen analyses and 205 assisted reproductive technology cycles were included in this analysis. Diet was assessed using a 131-item food frequency questionnaire. Mixed models adjusting for potential confounders were used to evaluate the relationships of male caffeine and alcohol intakes with semen parameters and assisted reproductive technology outcomes. There was no association between male caffeine and alcohol intake and semen quality. Male caffeine intake was negatively related to live birth after assisted reproductive technologies (p-trend < 0.01), and male alcohol intake was positively related to live birth after assisted reproductive technologies (p-trend = 0.04). Adjusted live birth rate among couples with a male partner in the highest quartile of caffeine intake (≥272 mg/day) compared to couples with a male partner in the lowest quartile of intake (<99 mg/day) was 19% vs. 55%, respectively, p < 0.01. In terms of alcohol intake, adjusted live birth rate among couples with a male partner in the highest quartile of alcohol intake (≥22 g/day) compared to couples with a male partner in the lowest quartile of intake (<3 g/day) was 61% vs. 28%, respectively, p = 0.05. In conclusion, male pre-treatment caffeine and alcohol intakes were associated with live birth after assisted reproductive technologies, but not with semen parameters, among fertility patients.

A prospective cohort study of endometriosis and subsequent risk of infertility.

STUDY QUESTION: Is there a temporal relationship between endometriosis and infertility? SUMMARY ANSWER: Endometriosis is associated with a higher risk of subsequent infertility, but only among women age <35 years. WHAT IS KNOWN ALREADY: Endometriosis is the most commonly observed gynecologic pathology among infertile women undergoing laparoscopic examination. Whether endometriosis is a cause of infertility or an incidental discovery during the infertility examination is unknown. STUDY DESIGN, SIZE, DURATION: This study included data collected from 58 427 married premenopausal female nurses <40 years of age from 1989 to 2005, who are participants of the Nurses' Health Study II prospective cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Our exposure was laparoscopically confirmed endometriosis. Multivariate Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for infertility risk (defined as attempting to conceive for >12 months) among women with and without endometriosis. MAIN RESULTS AND THE ROLE OF CHANCE: We identified 4612 incident cases of infertility due to any cause over 362 219 person-years of follow-up. Compared with women without a history of endometriosis, women with endometriosis had an age-adjusted 2-fold increased risk of incident infertility (HR = 2.12, 95% CI = 1.76-2.56) that attenuated slightly after accounting for parity. The relationship with endometriosis was only observed among women <35 years of age (multivariate HR <35 years = 1.77, 95% CI = 1.46-2.14; multivariate HR 35-39 years = 1.20, 95% CI = 0.94-1.53; P-interaction = 0.008). Risk of primary versus secondary infertility was similar subsequent to endometriosis diagnosis. Among women with primary infertility, 50% became parous after the endometriosis diagnosis, and among all women with endometriosis, 83% were parous by age 40 years. LIMITATIONS, REASONS FOR CAUTION: We did not have information on participants' intentions to conceive, but by restricting the analytic population to married women we increased the likelihood that pregnancies were planned (and therefore infertility would be recognized). Women in our cohort with undiagnosed asymptomatic endometriosis will be misclassified as unexposed. However, the small proportion of these women are diluted among the >50 000 women accurately classified as endometriosis-free, minimizing the impact of exposure misclassification on the effect estimates. WIDER IMPLICATIONS OF THE FINDINGS: This study supports a temporal association between endometriosis and infertility risk. Our prospective analysis indicates a possible detection bias in previous studies, with our findings suggesting that the infertility risk posed by endometriosis is about half the estimates observed in cross-sectional analyses. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Institutes of Health (grant numbers: UM1 CA176726, HD52473, HD57210, T32DK007703, T32HD060454, K01DK103720). We have no competing interests to declare.

Adherence to the Mediterranean dietary pattern and BMI change among US adolescents.

BACKGROUND: Among adults, the Mediterranean dietary pattern (MDP) is inversely related to body mass index (BMI). Data are lacking on adherence to the MDP among youth in the United States and whether the MDP is related to weight change in that group. OBJECTIVE: To assess whether adherence to the MDP was associated with BMI change among adolescents. To examine temporality, we studied the association between baseline and 2-3-year changes in adherence to the MDP with concurrent changes in BMI, as well as subsequent changes in BMI over a 7-year period. METHODS: We prospectively followed 6002 females and 4916 males in the Growing Up Today Study II, aged 8-15 years in 2004, living across United States. Data were collected by questionnaire in 2004, 2006, 2008 and 2011. Dietary intake was assessed by the Youth/Adolescent Questionnaire. The KidMed Index was derived to measure the adherence to the MDP. We used generalized estimating equations with repeated measures within subjects to assess the association between MDP and BMI change. RESULTS: A two-point increment in the KidMed Index was independently associated with a lower gain in BMI (-0.04 kg m(-2); P=0.001). A greater increase in adherence to the KidMed Index was independently related to a lower gain in BMI in both the concurrent (P-for-trend<0.001) and the subsequent period (P-for-trend=0.002). CONCLUSIONS: Adherence to MDP was inversely associated with change in BMI among adolescents. Two-year improvement in adherence to MDP was independently associated with less steep gain in the BMI in both the concurrent and the subsequent period.

Dairy intake in relation to in vitro fertilization outcomes among women from a fertility clinic.

STUDY QUESTION: Is dairy food consumption associated with live birth among women undergoing infertility treatment? SUMMARY ANSWER: There was a positive association between total dairy food consumption and live birth among women ≥35 years of age. WHAT IS KNOWN ALREADY: Dairy food intake has been previously related to infertility risk and measures of fertility potential but its relation to infertility treatment outcomes are unknown. STUDY DESIGN, SIZE, DURATION: Our study population comprised a total of 232 women undergoing 353 in vitro fertilization (IVF) treatment cycles between February 2007 and May 2013, from the Environment and Reproductive Health study, an ongoing prospective cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Diet was assessed before assisted reproductive technology (ART) treatment using a validated food frequency questionnaire. Study outcomes included ovarian stimulation outcomes (endometrial thickness, estradiol levels and oocyte yield), fertilization rates, embryo quality measures and clinical outcomes (implantation, clinical pregnancy and live birth rates). We used generalized linear mixed models with random intercepts to account for multiple ART cycles per woman while simultaneously adjusting for age, caloric intake, BMI, race, smoking status, infertility diagnosis, protocol type, alcohol intake and dietary patterns. MAIN RESULTS AND THE ROLE OF CHANCE: The age- and calorie-adjusted difference in live birth between women in the highest (>3.0 servings/day) and lowest (<1.34 servings/day) quartile of dairy intake was 21% (P = 0.02). However, after adjusting for additional covariates, this association was observed only among women ≥35 years (P, interaction = 0.04). The multivariable-adjusted live birth (95% CI) in increasing quartiles of total dairy intake was 23% (11, 42%), 39% (24, 56%), 29% (17, 47%) and 55% (39, 69%) (P, trend = 0.02) among women ≥35 years old, and ranged from 46 to 54% among women <35 years old (P, trend = 0.69). There was no association between dairy intake and any of the intermediate outcomes. LIMITATIONS, REASONS FOR CAUTION: The lack of a known biological mechanism linking dairy intake to infertility treatment outcomes calls for caution when interpreting these results and for additional work to corroborate or refute them. WIDER IMPLICATIONS OF THE FINDINGS: Dairy intake does not appear to harm IVF outcomes and, if anything, is associated with higher chances of live birth. STUDY FUNDING/COMPETING INTERESTS: This work was supported by NIH grants R01-ES009718 and R01ES000002 from NIEHS, P30 DK046200 from NIDDK and T32HD060454 from NICHD. M.C.A. was supported by a Ruth L. Kirschstein National Research Service Award T32 DK 007703-16 from NIDDK. She is currently employed at the Nestlé Research Center, Switzerland and completed this work while at the Harvard School of Public Health. The other authors declare no conflicts of interest.

Mediterranean and western dietary patterns are related to markers of testicular function among healthy men.

STUDY QUESTION: Are there any associations of dietary patterns with semen quality, reproductive hormone levels, and testicular volume, as markers of testicular function? SUMMARY ANSWER: These results suggest that traditional Mediterranean diets may have a positive impact on male reproductive potential. WHAT IS KNOWN ALREADY: The Mediterranean diet has been related to lower risk of multiple chronic diseases, but its effects on reproduction potential are unclear. STUDY DESIGN, SIZE, DURATION: Cross-sectional sample of 215 male university students recruited from October 2010 to November 2011 in Murcia Region (Spain). PARTICIPANTS/MATERIALS, SETTING, METHODS: Two hundred and nine healthy men aged 18-23 years were finally included in this analysis. Diet was assessed using a validated food frequency questionnaire, and dietary patterns were identified by factor analysis. Linear regression was used to analyze the relation between diet patterns with semen quality parameters, reproductive hormone levels and testicular volume adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: We identified two dietary patterns: a Mediterranean (characterized by high intakes of vegetables, fruits and seafood) and a Western pattern (characterized by high intakes of processed meats, French fries and snacks). The Mediterranean pattern was positively associated with total sperm count (P, trend = 0.04). The Western pattern was positively related to the percentage of morphologically normal sperm (P, trend = 0.008). We found an inverse association between adherence to the Western pattern and sperm concentration among overweight or obese men (P, trend = 0.04). LIMITATIONS, REASONS FOR CAUTION: As with all cross-sectional studies, causal inference is limited. However, participants were blinded to the study outcomes thus reducing the potential influenced their report of diet. Although we adjusted for a large number of known and suspected confounders, we cannot exclude the possibility of residual confounding or chance findings. WIDER IMPLICATIONS OF THE FINDINGS: This study was carried out on healthy and young men, so it is difficult to predict whether and how the observed differences in semen quality translate into reproductive success for men in couples trying to conceive. These results suggest that traditional Mediterranean diets may have a positive impact on male reproductive potential.

Male soy food intake was not associated with in vitro fertilization outcomes among couples attending a fertility center.

Male factor etiology may be a contributing factor in up to 60% of infertility cases. Dietary intake of phytoestrogens has been related to abnormal semen quality and hormone levels. However, its effect on couple fecundity is still unclear. Intake of soy products was assessed in 184 men from couples undergoing infertility treatment with in vitro fertilization. Couples were recruited between February 2007 and May 2014 and prospectively followed to document treatment outcomes including fertilization, implantation, clinical pregnancy and live birth. Multivariate generalized linear mixed models with random intercepts, binomial distribution and logit link function were used to examine this relation while accounting for repeated treatment cycles and adjusting for potential confounders. Male partner's intake of soy foods and soy isoflavones was unrelated to fertilization rates, the proportions of poor quality embryos, accelerated or slow embryo cleavage rate, and implantation, clinical pregnancy and live birth. The adjusted live birth rates per initiated cycle (95% CI) for partners of men in increasing categories of soy food intake were 0.36 (0.28-0.45), 0.42 (0.29-0.56), 0.36 (0.24-0.51), and 0.37 (0.24-0.52), respectively. Soy food intake in men was not related to clinical outcomes among couples presenting at an infertility clinic. Data on the relation between phytoestrogens and male reproductive potential remain scarce and additional research is required to clarify its role in human reproduction.

Job strain and changes in the body mass index among working women: a prospective study.

OBJECTIVE: The relationship between job strain and weight gain has been unclear, especially for women. Using data from over 52,000 working women, we compare the association between change in job strain and change in body mass index (BMI) across different levels of baseline BMI. SUBJECTS/METHODS: We used data from participants in the Nurses' Health Study II (n=52,656, mean age=38.4 years), an ongoing prospective cohort study. Using linear regression, we modeled the change in BMI over 4 years as a function of the change in job strain, baseline BMI and the interaction between the two. Change in job strain was characterized in four categories combining baseline and follow-up levels as follows: consistently low strain (low at both points), decreased strain (high strain at baseline only), increased strain (high strain at follow-up only) and consistently high strain (high at both points). Age, race/ethnicity, pregnancy history, job types and health behaviors at baseline were controlled for in the model. RESULTS: In adjusted models, women who reported high job strain at least once during the 4-year period had a greater increase in BMI (ΔBMI=0.06-0.12, P<0.05) compared with those who never reported high job strain. The association between the change in job strain exposure and the change in BMI depended on the baseline BMI level (P=0.015 for the interaction): the greater the baseline BMI, the greater the BMI gain associated with consistently high job strain. The BMI gain associated with increased or decreased job strain was uniform across the range of baseline BMI. CONCLUSIONS: Women with higher BMI may be more vulnerable to BMI gain when exposed to constant work stress. Future research focusing on mediating mechanisms between job strain and BMI change should explore the possibility of differential responses to job strain by initial BMI.

Fruit and vegetable intake and their pesticide residues in relation to semen quality among men from a fertility clinic.

STUDY QUESTION: Is consumption of fruits and vegetables with high levels of pesticide residues associated with lower semen quality? SUMMARY ANSWER: Consumption of fruits and vegetables with high levels of pesticide residues was associated with a lower total sperm count and a lower percentage of morphologically normal sperm among men presenting to a fertility clinic. WHAT IS KNOWN ALREADY: Occupational and environmental exposure to pesticides is associated with lower semen quality. Whether the same is true for exposure through diet is unknown. STUDY DESIGN, SIZE, DURATION: Men enrolled in the Environment and Reproductive Health (EARTH) Study, an ongoing prospective cohort at an academic medical fertility center. Male partners (n = 155) in subfertile couples provided 338 semen samples during 2007-2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Semen samples were collected over an 18-month period following diet assessment. Sperm concentration and motility were evaluated by computer-aided semen analysis (CASA). Fruits and vegetables were categorized as containing high or low-to-moderate pesticide residues based on data from the annual United States Department of Agriculture Pesticide Data Program. Linear mixed models were used to analyze the association of fruit and vegetable intake with sperm parameters accounting for within-person correlations across repeat samples while adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Total fruit and vegetable intake was unrelated to semen quality parameters. High pesticide residue fruit and vegetable intake, however, was associated with poorer semen quality. On average, men in highest quartile of high pesticide residue fruit and vegetable intake (≥1.5 servings/day) had 49% (95% confidence interval (CI): 31%, 63%) lower total sperm count and 32% (95% CI: 7%, 58%) lower percentage of morphologically normal sperm than men in the lowest quartile of intake (<0.5 servings/day) (P, trend = 0.003 and 0.02, respectively). Low-to-moderate pesticide residue fruit and vegetable intake was associated with a higher percentage of morphologically normal sperm (P, trend = 0.04). LIMITATIONS, REASONS FOR CAUTION: Surveillance data, rather than individual pesticide assessment, was used to assess the pesticide residue status of fruits and vegetables. CASA is a useful method for clinical evaluation but may be considered less favorable for accurate semen analysis in the research setting. Owing to the observational nature of the study, confirmation is required by interventional studies as well. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first report on the consumption of fruits and vegetables with high levels of pesticide residue in relation to semen quality. Further confirmation of these findings is warranted. STUDY FUNDING/COMPETING INTERESTS: Supported by National Institutes of Health grants ES009718, ES022955, ES000002, P30 DK046200 and Ruth L. Kirschstein National Research Service Award T32 DK007703-16. None of the authors has any conflicts of interest to declare.

Paternal physical and sedentary activities in relation to semen quality and reproductive outcomes among couples from a fertility center.

STUDY QUESTION: Is paternal physical activity associated with semen quality parameters and with outcomes of infertility treatment? SUMMARY ANSWER: Among men presenting for infertility treatment, weightlifting and outdoor activities were associated with higher sperm concentrations but not with greater reproductive success. WHAT IS ALREADY KNOWN: Higher physical activity is related to better semen quality but no studies to date have investigated whether it predicts greater reproductive success. STUDY DESIGN, SIZE, DURATION: The Environment and Reproductive Health (EARTH) Study is an on-going prospective cohort study which enrolls subfertile couples presenting at Massachusetts General Hospital (2005-2013). In total, 231 men provided 433 semen samples and 163 couples underwent 421 IVF or intrauterine insemination cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Leisure time spent in physical and sedentary activities over the past year was self-reported using a validated questionnaire. We used mixed models to analyze the association of physical and sedentary activities with semen quality and with clinical pregnancy and live birth rates. MAIN RESULTS AND THE ROLE OF CHANCE: Men in this cohort engaged in a median of 3.2 h/week of moderate-to-vigorous activities. Men in the highest quartile of moderate-to-vigorous activity had 43% (95% confidence interval (CI) 9, 87%) higher sperm concentrations than men in the lowest quartile (P-trend = 0.04). Men in the highest category of outdoor activity (≥1.5 h/week) and weightlifting (≥2 h/week) had 42% (95% CI 10, 84%) and 25% (95% CI -10, 74%) higher sperm concentrations, respectively, compared with men in the lowest category (0 h/week) (P-trend = 0.04 and 0.02). Conversely, men who reported bicycling ≥1.5 h/week had 34% (95% CI 4, 55%) lower sperm concentrations compared with men who reported no bicycling (P-trend = 0.05). Paternal physical and sedentary activities were not related to clinical pregnancy or live birth rates following infertility treatment. LIMITATIONS, REASONS FOR CAUTION: The generalizability of the findings on live birth rates to populations not undergoing infertility treatment is limited. WIDER IMPLICATIONS OF THE FINDINGS: Certain types of physical activity, specifically weightlifting and outdoor activities, may improve semen quality but may not lead to improved success of infertility treatments. Further research is needed in other non-clinical populations. STUDY FUNDING/COMPETING INTERESTS: The authors are supported by NIH grants R01-ES009718, ES000002, P30-DK046200, T32-DK007703-16 and ES022955 T32-HD060454. None of the authors has any conflicts of interest to declare.

Sugar-sweetened beverage intake in relation to semen quality and reproductive hormone levels in young men.

STUDY QUESTION: Is consumption of sugar-sweetened beverages (SSB) associated with semen quality? SUMMARY ANSWER: Higher consumption of SSB was associated with lower sperm motility among healthy, young men. WHAT IS KNOWN ALREADY: The existing literature on the potential role of SSBs on male reproductive function is scarce and primarily focused on the relation between caffeinated beverages and semen quality. However, a rodent model suggests that SSBs may hamper male fertility. STUDY DESIGN, SIZE, DURATION: The Rochester Young Men's Study; a cross-sectional study of 189 healthy young men carried out at the University of Rochester during 2009-2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men aged 18-22 years provided semen and blood samples, underwent a physical examination and completed a previously validated food frequency questionnaire (FFQ). Linear regression was used to analyze the association of SSBs with sperm parameters and reproductive hormone levels while adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: SSB intake was inversely related to progressive sperm motility. Men in the highest quartile of SSB intake (≥1.3 serving/day) had 9.8 (95% CI: 1.9,17.8) percentage units lower progressive sperm motility than men in the lowest quartile of intake (<0.2 serving/day) (P, trend = 0.03). This association was stronger among lean men (P, trend = 0.005) but absent among overweight or obese men (P, trend = 0.98). SSB intake was unrelated to other semen quality parameters or reproductive hormones levels. LIMITATIONS, REASONS FOR CAUTION: As in all cross-sectional studies, causal inference is limited. An additional problem is that only single semen sample was obtained from each subject. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first report on the relation between SSB intake and low semen quality beyond the contribution of caffeinated beverages. While our findings are in agreement with recent experimental data in rodents, more studies are required to draw conclusions on the relation of SSB with semen quality or male infertility. STUDY FUNDING/COMPETING INTEREST(S): Supported by the European Union Seventh Framework Program (Environment), 'Developmental Effects of Environment on Reproductive Health' (DEER) grant 212844. Grant P30 DK046200 and Ruth L. Kirschstein National Research Service Award T32 DK007703-16 and T32HD060454 from the National Institutes of Health. None of the authors has any conflicts of interest to declare.