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Background Experimental and epidemiological studies have linked metals with women's reproductive aging, but the mechanisms are not well understood. Disrupted ovarian folliculogenesis and diminished ovarian reserve could be a pathway through which metals impact reproductive hormones and outcomes. Objective The study aimed to evaluate the associations of heavy metals with anti-Müllerian hormone (AMH), a marker of ovarian reserve. Methods The study included 549 women from the Study of Women's Health Across the Nation with 2252 repeated AMH measurements from 10 to 0 years before the final menstrual period (FMP). Serum AMH concentrations were measured using picoAMH ELISA. Urinary concentrations of arsenic, cadmium, mercury, and lead were measured using high-resolution inductively coupled plasma mass spectrometry. Multivariable linear mixed regressions modeled AMH as a function of time before the FMP interaction terms between metals and time to the FMP were also included. Results Adjusting for confounders, compared with those in the lowest tertile, women in the highest tertile of urinary arsenic or mercury concentrations had lower AMH concentrations at the FMP (percent change: −32.1%; 95% CI, −52.9 to −2.2, P-trend = .03 for arsenic; percent change: −40.7%; 95% CI, −58.9 to −14.5, P-trend = .005 for mercury). Higher cadmium and mercury were also associated with accelerated rates of decline in AMH over time (percent change per year: −9.0%; 95% CI, −15.5 to −1.9, P-trend = .01 for cadmium; −7.3%; 95% CI, −14.0 to −0.1, P-trend = .04 for mercury). Conclusion Heavy metals including arsenic, cadmium, and mercury may act as ovarian toxicants by diminishing ovarian reserve in women approaching the FMP.

Optical frequency combs are increasingly being adopted in various measurement applications. However, the sensitivity of free-running optical frequency combs and the large size and complex connections required for locking equipment pose significant obstacles to their on-site application. To address these challenges, we present an integrated optical frequency comb repetition rate locking control system that greatly reduces the volume of the locking system.In this system, we firstly control the temperature of the resonator cavity to achieve a wide range of control over the effective length of the cavity. A temperature control box for the resonator cavity is designed, incorporating semiconductor cooling chips to regulate the temperature. Secondly, we employ piezoelectric ceramics to achieve small-scale stretching control of the resonator cavity length. These control methods work in synergy to achieve high-quality repetition rate locking. The use of a loop filter in the system establishes the dynamic performance of the repetition rate locking loop and effectively suppresses the high-frequency components of the phase discriminator output. Through testing of the research system, the temperature control system demonstrates a temperature control range of 20-40°C, with a temperature control accuracy of ±0.01°C. With the assistance of the temperature control system, the repetition rate locking system achieves a repetition rate locking duration of over 10 hours, with a fluctuation range of less than 5 mHz, an Allan deviation of 217 μHz@gate 1s, and a relative frequency stability of 3.89E-12.This system successfully achieves high-frequency stability and long-term locking of the optical frequency comb's repetition rate.

Phthalates, ubiquitous endocrine-disrupting chemicals, may affect ovarian folliculogenesis and steroidogenesis. We examined the associations of urinary phthalate metabolites with hormones including estradiol, testosterone, follicle-stimulating hormone (FSH), sex hormone–binding globulin (SHBG), and anti-Müllerian hormone (AMH), and timing of natural menopause in midlife women. Data were from 1189 multiracial/multiethnic women aged 45 to 56 years without hormone therapy from the Study of Women's Health Across the Nation (SWAN). Urinary concentrations of 12 phthalate metabolites and hormones were repeatedly measured in 1999 to 2000 and 2002 to 2003, resulting in a total of 2111 observations. Linear mixed-effect models were used to calculate percentage differences (%D) and 95% CIs in serum concentrations of estradiol, testosterone, FSH, SHBG, and AMH. Cox proportional-hazards models were used to calculate hazard ratios (HRs) and 95% CIs of natural menopause. We observed statistically significant associations of phthalate metabolites with lower testosterone concentrations: MCOP with testosterone (%D: −2.08%; 95% CI, −3.66 to −0.47) and MnBP with testosterone (%D: −1.99%; 95% CI, −3.82 to −0.13), after adjusting for multiple comparisons with false discovery rates less than 5%. Lower AMH concentrations were also found with higher MECPP (%D: −14.26%; 95% CI, −24.10 to −3.14), MEHHP (%D: −15.58%; 95% CI, −24.59 to −5.50), and MEOHP (%D: −13.50%; 95% CI, −22.93 to −2.90). No associations were observed for other hormones or timing of natural menopause. These results suggest that exposure to phthalates may affect circulating levels of testosterone and diminish the ovarian reserve in midlife women. Given the widespread exposure, reduced exposure to phthalates may be a key step to prevent reproductive effects of phthalates.

Background: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are ubiquitous synthetic chemicals that may disrupt blood pressure controls; however, human evidence to support this hypothesis is scant. We examined the association between serum concentrations of PFAS and risks of developing hypertension. Methods: This study included 1058 midlife women initially free of hypertension from the multiracial and multiethnic SWAN (Study of Women’s Health Across the Nation) with annual follow-up visits between 1999 and 2017. Hypertension was defined as blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic or receiving antihypertensive treatment. Cox proportional hazards models were utilized to calculate hazard ratios and 95% CIs. Quantile g-computation was implemented to evaluate the joint effect of PFAS mixtures. Results: During 11 722 person-years of follow-up, 470 participants developed incident hypertension (40.1 cases per 1000 person-years). Compared with the lowest tertile, women in the highest tertile of baseline serum concentrations had adjusted hazard ratios of 1.42 (95% CI, 1.19–1.68) for perfluorooctane sulfonate ( P trend=0.01), 1.47 (95% CI, 1.24–1.75) for linear perfluorooctanoate ( P trend=0.01), and 1.42 (95% CI, 1.19–1.70) for 2-(N-ethyl-perfluorooctane sulfonamido) acetate ( P trend=0.01). No significant associations were observed for perfluorononanoate and perfluorohexane sulfonate. In the mixture analysis, women in the highest tertile of overall PFAS concentrations had a hazard ratio of 1.71 (95% CI, 1.15–2.54; P trend=0.008), compared with those in the lowest tertile. Conclusions: Several PFAS showed positive associations with incident hypertension. These findings suggest that PFAS might be an underappreciated contributing factor to women’s cardiovascular disease risk.

Aims/hypothesis Diabetogenic effects of per- and polyfluoroalkyl substances (PFAS) have been suggested. However, evidence based on prospective cohort studies is limited. We examined the association between serum PFAS concentrations and incident diabetes in the Study of Women’s Health Across the Nation Multi-Pollutant Study (SWAN-MPS). Methods We included 1237 diabetes-free women aged 45–56 years at baseline (1999–2000) who were followed up to 2017. At each follow-up visit, women with incident diabetes were identified by the presence of one or more of the following conditions: (1) use of a glucose-lowering medication at any visit; (2) fasting glucose ≥7 mmol/l on two consecutive visits while not on steroids; and (3) any two visits with self-reported diabetes and at least one visit with fasting blood glucose ≥7 mmol/l. Serum concentrations of 11 PFAS were quantified by online solid-phase extraction–HPLC–isotope dilution–tandem MS. Seven PFAS with high detection rates (>96%) (n-perfluorooctanoic acid [n-PFOA], perfluorononanoic acid [PFNA], perfluorohexane sulfonic acid [PFHxS], n-perfluorooctane sulfonic acid [n-PFOS], sum of perfluoromethylheptane sulfonic acid isomers [Sm-PFOS], 2-[N-methyl-perfluorooctane sulfonamido] acetic acid [MeFOSAA] and 2-[N-ethyl-perfluorooctane sulfonamido] acetic acid) were included in data analysis. Cox proportional hazards models were used to compute HRs and 95% CIs. Quantile-based g-computation was used to evaluate the joint effects of PFAS mixtures. Results After adjustment for race/ethnicity, site, education, smoking status, alcohol consumption, total energy intake, physical activity, menopausal status and BMI, the HR (95% CI) comparing the lowest with the highest tertile was 1.67 (1.21, 2.31) for n-PFOA (p_trend = 0.001), 1.58 (1.13, 2.21) for PFHxS (p_trend = 0.003), 1.36 (0.97, 1.90) for Sm-PFOS (p_trend = 0.05), 1.85 (1.28, 2.67) for MeFOSAA (p_trend = 0.0004) and 1.64 (1.17, 2.31) for the sum of four common PFAS (n-PFOA, PFNA, PFHxS and total PFOS) (p_trend = 0.002). Exposure to seven PFAS as mixtures was associated with an HR of 2.62 (95% CI 1.12, 6.20), comparing the top with the bottom tertiles for all seven PFAS. Conclusions/interpretation This study suggests that PFAS may increase diabetes risk in midlife women. Reduced exposure to these ‘forever and everywhere chemicals’ may be an important preventative approach to lowering population-wide diabetes risk. Graphical abstract

Background: Volatile organic compounds (VOCs) have been detected in feminine hygiene products (FHPs), especially in tampons and sanitary pads. However, little is known about whether menstrual products can contribute to VOC exposure in women. Our objectives were to: (1) examine the variations of urinary VOC concentrations during menstrual cycles; (2) evaluate the relationships between the use of menstrual products and urinary VOC concentrations; and (3) link urinary VOC concentrations to those measured in menstrual products. Methods: We measured urinary concentrations of 98 target VOCs in 25 reproductive-aged women with 100 repeated measures collected between October 2018 and February 2019. First-morning-void urine samples were collected four times for each woman during one menstrual cycle. Urinary VOC concentrations were measured using gas chromatography–mass spectroscopy. Results: Of 98 target VOCs measured in the urine samples, 36 VOCs were detected. We did not see statistically significant variations in VOC concentrations across the menstrual cycle. After multivariable adjustment, tampon users had significantly higher concentrations of 2-butanone ( β = 1.58 log ng/g, 95% confidence interval [CI]: 0.16–3.00, p = 0.03) and methyl isobutyl ketone ( β = 0.63 log ng/g, 95% CI: 0.03–1.22, p = 0.04), compared with pad users. Higher n-nonane, benzene, and toluene estimated from menstrual products were associated with higher urinary concentrations in women. Conclusion: The use of FHPs during menses might be a potential source of VOCs. A larger cohort study is warranted to confirm our results and evaluate clinical implications.

Context Per- and polyfluoroalkyl substances (PFAS) are widespread chemicals that may affect sex hormones and accelerate reproductive aging in midlife women. Objective To examine associations between serum PFAS concentrations at baseline (1999-2000) and longitudinal serum concentrations of follicle-stimulating hormone (FSH), estradiol, testosterone, and sex hormone-binding globulin (SHBG) at baseline and through 2015-2016. Design Prospective cohort. Setting General community. Participants 1371 midlife women 45 to 56 years of age at baseline in the Study of Women’s Health Across the Nation (SWAN). Main Outcome Measure(s) FSH, estradiol, testosterone, SHBG. Results In linear mixed models fitted with log-transformed hormones and log-transformed PFAS adjusting for age, site, race/ethnicity, smoking status, menopausal status, parity, and body mass index, FSH was positively associated with linear perfluorooctanoate [n-PFOA; 3.12% (95% CI 0.37%, 5.95%) increase for a doubling in serum concentration), linear perfluorooctane sulfonate [PFOS; 2.88% (0.21%, 5.63%)], branched perfluorooctane sulfonate [2.25% (0.02%, 4.54%)], total PFOS (3.03% (0.37%, 5.76%)), and 2-(N-ethyl-perfluorooctane sulfonamido) acetate [EtFOSAA; 1.70% (0.01%, 3.42%)]. Estradiol was inversely associated with perfluorononanoate [PFNA; −2.47% (−4.82%, −0.05%)) and n-PFOA (−2.43% (−4.97%, 0.18%)]. Significant linear trends were observed in the associations between PFOS and EtFOSAA with SHBG across parity (Ps trend ≤ 0.01), with generally inverse associations among nulliparous women but positive associations among women with 3+ births. No significant associations were observed between PFAS and testosterone. Conclusions This study observed positive associations of PFOA and PFOS with FSH and inverse associations of PFNA and PFOA with estradiol in midlife women during the menopausal transition, consistent with findings that PFAS affect reproductive aging.