In-utero exposure to polybrominated biphenyl (PBB) and menstrual cycle function in adulthood.

BACKGROUND: There is evidence that in-utero exposure to PBBs, and similar chemicals, are associated with several adverse reproductive health outcomes including altered pubertal timing. However, less is known about the effects of in-utero exposure to PBBs on menstrual cycle function and reproductive hormone levels in adulthood. METHODS: For this menstrual cycle study, we recruited reproductive-aged women in the Michigan PBB Registry who were not pregnant, lactating, or taking hormonal medications (2004-2014). A total of 41 women who were born after the PBB contamination incident (1973-1974) and were prenatally exposed to PBBs, were included in this analysis. We estimated in-utero PBB exposure using maternal serum PBB measurements taken after exposure and extrapolated to time of pregnancy using a PBB elimination model. Women were followed for up to 6 months during which they provided daily urine samples and completed daily diaries. The urine samples were assayed for estrone 3-glucuronide (E13G), pregnanediol 3-glucuronide (Pd3G), and follicle stimulating hormone (FSH). RESULTS: Women in our study were, on average, 27.5 (SD:5.3) years old and contributed 4.9 (SD:1.9) menstrual cycles of follow-up. Compared to women with low in-utero PBB exposure (≤1 ppb), women with medium (>1.0-3.0 ppb) and high (>3.0 ppb) exposure had higher maximum 3-day mean Pd3G levels during the luteal phase. Specifically, the age- and creatinine-adjusted maximum 3-day mean luteal phase Pd3G levels (95% CI) in increasing categories of in-utero PBB exposure were 9.2 (4.6,13.9), 14.8 (11.6,18.0), and 16.1 (12.9,19.3) µg/mg creatinine. There were no meaningful differences in average cycle length, follicular or luteal phase cycle length, bleed length, or creatinine-adjusted E13G or FSH levels by category of in-utero PBB exposure. CONCLUSION: Higher exposure to PBB in-utero was associated with increased progesterone levels across the luteal phase, however, most other menstrual cycle characteristics were largely unassociated with in-utero PBB exposure. Given our modest sample size, our results require cautious interpretation.

Characterization of inhalation exposures at a wildfire incident during the Wildland Firefighter Exposure and Health Effects (WFFEHE) Study.

Wildland firefighters (WFFs) are exposed to many inhalation hazards working in the wildland fire environment. To assess occupational exposures and acute and subacute health effects among WFFs, the wildland firefighter exposure and health effects study collected data for a 2-year repeated measures study. This manuscript describes the exposure assessment from one Interagency Hotshot Crew (N = 19) conducted at a wildfire incident. Exposures to benzene, toluene, ethylbenzene, xylene isomers, formaldehyde, acetaldehyde, and naphthalene were measured through personal air sampling each work shift. Biological monitoring was done for creatinine-adjusted levoglucosan in urine pre- and post-shift. For 3 days sampling at the wildfire incident, benzene, toluene, ethylbenzene, xylene isomers (m and p, and o) exposure was highest on day 1 (geometric mean [GM] = 0.015, 0.042, 0.10, 0.42, and 0.15 ppm, respectively) when WFFs were not exposed to smoke but used chainsaws to remove vegetation and prepare fire suppression breaks. Exposure to formaldehyde and acetaldehyde was highest on day 2 (GM = 0.03 and 0.036 ppm, respectively) when the WFFs conducted a firing operation and were directly exposed to wildfire smoke. The greatest difference of pre- and post-shift levoglucosan concentrations were observed on day 3 (pre-shift: 9.7 and post-shift: 47 µg/mg creatinine) after WFFs conducted mop up (returned to partially burned area to extinguish any smoldering vegetation). Overall, 65% of paired samples (across all sample days) showed a post-shift increase in urinary levoglucosan and 5 firefighters were exposed to benzene at concentrations at or above the National Institute for Occupational Safety and Health (NIOSH) recommended exposure limit. Our findings further demonstrate that exposure to inhalation hazards is one of many risks that wildland firefighters experience while suppressing wildfires.

Evaluating Exposure to VOCs and Naphthalene for Firefighters Wearing Different PPE Configurations through Measures in Air, Exhaled Breath, and Urine.

Firefighters are at an increased risk of cancer due to their occupational exposure to combustion byproducts, especially when those compounds penetrate the firefighter personal protective equipment (PPE) ensemble. This has led to questions about the impact of base layers (i.e., shorts vs. pants) under PPE ensembles. This study asked 23 firefighters to perform firefighting activities while wearing one of three different PPE ensembles with varying degrees of protection. Additionally, half of the firefighters unzipped their jackets after the scenario while the other half kept their jackets zipped for five additional minutes. Several volatile organic compound (VOC) and naphthalene air concentrations outside and inside of hoods, turnout jackets, and turnout pants were evaluated; biological (urinary and exhaled breath) samples were also collected. VOCs and naphthalene penetrated the three sampling areas (hoods, jackets, pants). Significant (p-value < 0.05) increases from pre- to post-fire for some metabolites of VOCs (e.g., benzene, toluene) and naphthalene were found. Firefighters wearing shorts and short sleeves absorbed higher amounts of certain compounds (p-value < 0.05), and the PPE designed with enhanced interface control features appeared to provide more protection from some compounds. These results suggest that firefighters can dermally absorb VOCs and naphthalene that penetrate the PPE ensemble.

Exposure assessment of polycyclic aromatic hydrocarbons in refined coal tar sealant applications.

BACKGROUND: Refined coal tar sealant (RCTS) emulsions are used to seal the surface of asphalt pavement. Nine of the 22 polycyclic aromatic hydrocarbons (PAHs) evaluated in this study are classified as known, probable, or possible human carcinogens. Exposure assessment research for RCTS workers has not been published previously. OBJECTIVES: The overall objective of this study was to develop a representative occupational exposure assessment of PAH exposure for RCTS workers based on worksite surveys. The specific aims were to: 1) quantify full-shift airborne occupational exposures to PAHs among RCTS workers; 2) quantify workers' dermal exposures to PAHs; 3) quantify biomarkers of PAH exposure in workers' urine; 4) identify specific job titles associated with RCTS exposure; and 5) apply these results to a biological exposure index to assess risk of potential genotoxicity from occupational exposures. METHODS: A total of twenty-one RCTS workers were recruited from three companies. Personal and area air samples were collected using a modification of NIOSH Method 5515. Dermal exposure was assessed by hand and neck wipes before and after shifts. Twenty-two PAHs were quantified via gas chromatography-mass spectrometry selected ion monitoring. Internal dose was estimated by quantifying select PAH metabolites in pre- and post-shift urine samples using on-line solid phase extraction-high performance liquid chromatography-tandem mass spectrometry. RESULTS: PAH levels in the worker breathing zones were highest for naphthalene, acenaphthene, and phenanthrene, with geometric means of 52.1, 11.4, and 9.8 µg/m3, respectively. Hand wipe levels of phenanthrene, fluoranthene and pyrene were the highest among the 22 PAHs with geometric means of 7.9, 7.7, and 5.5 µg/cm2, respectively. Urinary PAH biomarkers for naphthalene, fluorene, phenanthrene, and pyrene were detected in all workers and were higher for post-shift samples than those collected pre-shift. Urinary concentrations of the metabolite 1-hydroxypyrene were greater than the American Conference of Governmental Industrial Hygienists (ACGIH) Biological Exposure Index (BEI) for this metabolite in 89 percent of post-shift samples collected on the final day of the work week or field survey. Statistically significances were found between concentrations of fluorene, naphthalene, and phenanthrene in the breathing zone of workers and their corresponding urinary PAH biomarkers. Workers were placed in two work place exposure groups: applicators and non-applicators. Applicators had higher total PAH concentrations in personal breathing zone (PBZ) air samples than non-applicators and were more likely to have post-shift hand wipe concentrations significantly higher than pre-shift concentrations. Concentrations of post-shift urinary biomarkers were higher, albeit not significantly, for applicators than non-applicators. CONCLUSIONS: The exposure results from RCTS worker samples cannot be explained by proximal factors such as nearby restaurants or construction. Air and skin concentration levels were substantially higher for RCTS workers than previously published levels among asphalt workers for all PAHs. PAH profiles on skin wipes were more consistent with RCTS sealant product than air samples. Last day post-shift urinary concentrations of 1-hydroxypyrene greatly exceeded the ACGIH BEI benchmark of 2.5 µg/L in 25 of 26 samples, which suggests occupational exposure and risk of genotoxicity. When pyrene and benzo[a]pyrene were both detected, concentration ratios from personal exposure samples were used to calculate the adjusted BEI. Concentrations of 1-hydroxypyrene exceeded the adjusted BEIs for air, hand wipes, and neck wipes in most cases. These results indicate the need to increase safety controls and exposure mitigation for RCTS workers.

Evaluation of Test to Stay Strategy on Secondary and Tertiary Transmission of SARS-CoV-2 in K-12 Schools - Lake County, Illinois, August 9-October 29, 2021.

The COVID-19 pandemic has resulted in school closures and reduction of in-person learning (1). In August 2021, the Lake County Health Department (LCHD) in Illinois introduced a Test to Stay (TTS) strategy, whereby unvaccinated students, teachers, and staff members with certain school-related COVID-19 exposures could remain in school and participate in school-related extracurricular activities. Eligibility to participate in TTS required the following conditions to be met: 1) the exposure occurred while both the person with COVID-19 (index patient) and the close contact were masked; 2) the close contact remained asymptomatic, practiced consistent mask wearing, and maintained physical distancing; and 3) the close contact underwent testing for SARS-CoV-2 (the virus that causes COVID-19) on days 1, 3, 5, and 7 after exposure to the index patient. LCHD permitted kindergarten through grade 12 (K-12) schools in Lake County to implement TTS; 90 schools, representing 31 school districts in Lake County, implemented TTS during August 9-October 29, 2021. During the implementation period, 258 COVID-19 cases were reported. Among 1,035 students and staff members enrolled in TTS, the secondary attack risk (number of close contacts who received a positive SARS-CoV-2 test result within 14 days after exposure to an index patient, divided by total number of close contacts) was 1.5% (16 of 1,035). Among the 16 secondary cases identified, all were in students, and none appeared to transmit SARS-CoV-2 to other school-based contacts. However, nine tertiary cases were identified among household contacts of the 16 secondary cases, and four of the nine were fully vaccinated. Assuming a maximum of 8 missed school days for every 10-day quarantine period, up to 8,152 in-person learning days were saved among TTS participants. Implementation of TTS with other concurrent prevention strategies, including masking and physical distancing, limited further spread of SARS-CoV-2 within K-12 schools and allowed students to safely sustain in-person learning. Although vaccination remains the leading public health recommendation to protect against COVID-19 for those aged ≥5 years, schools might consider TTS as an option for allowing close contacts who are not fully vaccinated to remain in the classroom as an alternative to home quarantine.

Urinary and salivary endocrine measurements to complement Tanner staging in studies of pubertal development.

BACKGROUND: Many studies investigating pubertal development use Tanner staging to assess maturation. Endocrine markers in urine and saliva may provide an objective, sensitive, and non-invasive method for assessing development. OBJECTIVE: Our objective was to examine whether changes in endocrine levels can indicate the onset of pubertal development prior to changes in self-rated Tanner stage. METHODS: Thirty-five girls and 42 boys aged 7 to 15 years were enrolled in the Growth and Puberty (GAP) study, a longitudinal pilot study conducted from 2007-2009 involving children of women enrolled in the Agricultural Health Study (AHS) in Iowa. We collected saliva and urine samples and assessed pubertal development by self-rated Tanner staging (pubic hair, breast development (girls), genital development (boys)) at three visits over six months. We measured dehydroepiandrosterone (DHEA) in saliva and creatinine-adjusted luteinizing hormone (LH), testosterone, follicle stimulating hormone (FSH), estrone 3-glucuronide (E13G) and pregnanediol 3-glucuronide (Pd3G) concentrations in first morning urine. We evaluated the relationships over time between Tanner stage and each biomarker using repeated measures analysis. RESULTS: Among girls still reporting Tanner breast stage 1 at the final visit, FSH levels increased over the 6-month follow-up period and were no longer lower than higher stage girls at the end of follow-up. We observed a similar pattern for testosterone in boys. By visit 3, boys still reporting Tanner genital stage 1 or pubic hair stage 1 had attained DHEA levels that were comparable to those among boys reporting Tanner stages 2 or 3. CONCLUSIONS: Increasing concentrations of FSH in girls and DHEA and testosterone in boys over a 6-month period revealed the start of the pubertal process prior to changes in self-rated Tanner stage. Repeated, non-invasive endocrine measures may complement the more subjective assessment of physical markers in studies determining pubertal onset.

Hormonal Profiles of Menstrual Bleeding Patterns During the Luteal-Follicular Transition.

CONTEXT: Menstrual cycle function is determined by a complex endocrine axis that controls the ovaries and endometrium. While the late luteal phase is characterized by declining progesterone and estrogen, how these hormonal profiles relate to menstrual bleeding patterns is not well understood. OBJECTIVE: Characterize associations between luteal phase hormonal profiles and subsequent menstrual bleeding patterns, specifically spotting before bleeding. DESIGN, SETTING, AND PARTICIPANTS: We examined creatinine-adjusted urinary estrone 3-glucuronide (E13G) and pregnanediol 3-glucuronide (Pd3G) levels in relation to spotting in 116 premenopausal women (ages 20-47) who kept daily menstrual diaries and collected first morning urine samples for ≥ 2 consecutive cycles or 1 luteal-follicular transition (n = 283 transitions). We used linear mixed models to estimate associations between luteal phase hormone levels and spotting before bleeding. MAIN OUTCOME MEASURE(S) AND RESULTS: Transitions with ≥ 1 days of spotting before menstrual bleeding (n = 118) had greater luteal phase Pd3G levels vs nonspotting transitions (n = 165). Differences in Pd3G between spotting and nonspotting transitions were largest at menses onset (34.8%, 95% confidence interval, 18.9%, 52.7%). Pd3G levels for spotting transitions dropped to similar levels as nonspotting transitions an average of 1 day later, which aligned with the first day of bleeding for transitions with contiguous spotting. Spotting transitions were preceded by slower rates of Pd3G decline than nonspotting transitions, whereas E13G declines were similar. CONCLUSIONS: Self-reported bleeding patterns may provide insight into luteal phase Pd3G levels. First bleed appears to be the best choice for defining the end of the luteal phase and achieving hormonal consistency across transitions.

Polybrominated Biphenyl Exposure and Menstrual Cycle Function.

BACKGROUND: Brominated flame retardants, including polybrominated biphenyls (PBB), are persistent compounds reported to affect sex hormones in animals; less is known about potential effects in humans. An industrial accident in 1973-1974 exposed Michigan residents to PBB through contaminated food. We examined whether this exposure to PBB had long-term effects on menstrual cycle function. METHODS: In 2004-2006, we recruited reproductive-aged women in the Michigan PBB Registry who were not pregnant, lactating, or taking hormonal medications. Participants kept daily diaries and provided daily urine samples for up to 6 months. We assayed the urine samples for estrone 3-glucuronide (E13G), pregnanediol 3-glucuronide (Pd3G), and follicle stimulating hormone (FSH). We fit linear mixed models among women aged 35-42 years to describe the relation between serum PBB levels and log-transformed, creatinine-adjusted daily endocrine levels among women who were premenarchal during the exposure incident in 1973-1974 (n = 70). RESULTS: We observed that high (>3.0 parts per billion [ppb]) and medium (>1.0-3.0 ppb) PBB exposure were associated with lower E13G levels across the menstrual cycle and lower FSH levels during the follicular phase, compared with low PBB exposure (≤1.0 ppb). High PBB exposure was also associated with lower Pd3G levels across the cycle compared with low PBB exposure, whereas Pd3G levels were similar in women with medium and low PBB exposure. CONCLUSION: Our results are consistent with a hypothesized effect of exposure to an exogenous estrogen agonist but the modest sample size of the study requires cautious interpretation.

Thyroid hormones and menstrual cycle function in a longitudinal cohort of premenopausal women.

BACKGROUND: Previous studies have reported that hyperthyroid and hypothyroid women experience menstrual irregularities more often compared with euthyroid women, but reasons for this are not well-understood and studies on thyroid hormones among euthyroid women are lacking. In a prospective cohort study of euthyroid women, this study characterised the relationship between thyroid hormone concentrations and prospectively collected menstrual function outcomes. METHODS: Between 2004-2014, 86 euthyroid premenopausal women not lactating or taking hormonal medications participated in a study measuring menstrual function. Serum thyroid hormones were measured before the menstrual function study began. Women then collected first morning urine voids and completed daily bleeding diaries every day for three cycles. Urinary oestrogen and progesterone metabolites (estrone 3-glucuronide (E1 3G) and pregnanediol 3-glucuronide (Pd3G)) and follicle-stimulating hormone were measured and adjusted for creatinine (Cr). RESULTS: Total thyroxine (T4 ) concentrations were positively associated with Pd3G and E1 3G. Women with higher (vs lower) T4 had greater luteal phase maximum Pd3G (Pd3G = 11.7 µg/mg Cr for women with high T4 vs Pd3G = 9.5 and 8.1 µg/mg Cr for women with medium and low T4 , respectively) and greater follicular phase maximum E1 3G (E1 3G = 41.7 ng/mg Cr for women with high T4 vs E1 3G = 34.3 and 33.7 ng/mg Cr for women with medium and low T4 , respectively). CONCLUSIONS: Circulating thyroid hormone concentrations were associated with subtle differences in menstrual cycle function outcomes, particularly sex steroid hormone levels in healthy women. Results contribute to the understanding of the relationship between thyroid function and the menstrual cycle, and may have implications for fertility and chronic disease.

Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis.

Objectives The safety and efficacy of the 3C-like protease inhibitor GC376 was tested on a cohort of client-owned cats with various forms of feline infectious peritonitis (FIP). Methods Twenty cats from 3.3-82 months of age (mean 10.4 months) with various forms of FIP were accepted into a field trial. Fourteen cats presented with wet or dry-to-wet FIP and six cats presented with dry FIP. GC376 was administered subcutaneously every 12 h at a dose of 15 mg/kg. Cats with neurologic signs were excluded from the study. Results Nineteen of 20 cats treated with GC376 regained outward health within 2 weeks of initial treatment. However, disease signs recurred 1-7 weeks after primary treatment and relapses and new cases were ultimately treated for a minimum of 12 weeks. Relapses no longer responsive to treatment occurred in 13 of these 19 cats within 1-7 weeks of initial or repeat treatment(s). Severe neurologic disease occurred in 8/13 cats that failed treatment and five cats had recurrences of abdominal lesions. At the time of writing, seven cats were in disease remission. Five kittens aged 3.3-4.4 months with wet FIP were treated for 12 weeks and have been in disease remission after stopping treatment and at the time of writing for 5-14 months (mean 11.2 months). A sixth kitten was in remission for 10 weeks after 12 weeks of treatment, relapsed and is responding to a second round of GC376. The seventh was a 6.8-year-old cat with only mesenteric lymph node involvement that went into remission after three relapses that required progressively longer repeat treatments over a 10 month period. Side effects of treatment included transient stinging upon injection and occasional foci of subcutaneous fibrosis and hair loss. There was retarded development and abnormal eruption of permanent teeth in cats treated before 16-18 weeks of age. Conclusions and relevance GC376 showed promise in treating cats with certain presentations of FIP and has opened the door to targeted antiviral drug therapy.

Association Between Biomarkers of Ovarian Reserve and Infertility Among Older Women of Reproductive Age.

Importance: Despite lack of evidence of their utility, biomarkers of ovarian reserve are being promoted as potential markers of reproductive potential. Objective: To determine the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age. Design, Setting, and Participants: Prospective time-to-pregnancy cohort study (2008 to date of last follow-up in March 2016) of women (N = 981) aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, recruited from the community in the Raleigh-Durham, North Carolina, area. Exposures: Early-follicular-phase serum level of antimüllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and urinary level of FSH. Main Outcomes and Measures: The primary outcomes were the cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability (probability of conception in a given menstrual cycle). Conception was defined as a positive pregnancy test result. Results: A total of 750 women (mean age, 33.3 [SD, 3.2] years; 77% white; 36% overweight or obese) provided a blood and urine sample and were included in the analysis. After adjusting for age, body mass index, race, current smoking status, and recent hormonal contraceptive use, women with low AMH values (<0.7 ng/mL [n = 84]) did not have a significantly different predicted probability of conceiving by 6 cycles of attempt (65%; 95% CI, 50%-75%) compared with women (n = 579) with normal values (62%; 95% CI, 57%-66%) or by 12 cycles of attempt (84% [95% CI, 70%-91%] vs 75% [95% CI, 70%-79%], respectively). Women with high serum FSH values (>10 mIU/mL [n = 83]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (63%; 95% CI, 50%-73%) compared with women (n = 654) with normal values (62%; 95% CI, 57%-66%) or after 12 cycles of attempt (82% [95% CI, 70%-89%] vs 75% [95% CI, 70%-78%], respectively). Women with high urinary FSH values (>11.5 mIU/mg creatinine [n = 69]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (61%; 95% CI, 46%-74%) compared with women (n = 660) with normal values (62%; 95% CI, 58%-66%) or after 12 cycles of attempt (70% [95% CI, 54%-80%] vs 76% [95% CI, 72%-80%], respectively). Inhibin B levels (n = 737) were not associated with the probability of conceiving in a given cycle (hazard ratio per 1-pg/mL increase, 0.999; 95% CI, 0.997-1.001). Conclusions and Relevance: Among women aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility. These findings do not support the use of urinary or blood follicle-stimulating hormone tests or antimüllerian hormone levels to assess natural fertility for women with these characteristics.

Urinary Bisphenol A (BPA) Concentrations among Workers in Industries that Manufacture and Use BPA in the USA.

Background: Bisphenol A (BPA) toxicity and exposure risk to humans has been the subject of considerable scientific debate; however, published occupational exposure data for BPA are limited. Methods: In 2013-2014, 77 workers at six US companies making BPA, BPA-based resins, or BPA-filled wax provided seven urine samples over two consecutive work days (151 worker-days, 525 samples). Participant information included industry, job, tasks, personal protective equipment used, hygiene behaviors, and canned food/beverage consumption. Total (free plus conjugated) BPA, quantified in urine by mass spectrometry, was detected in all samples. Results: The geometric mean (GM) creatinine-adjusted total BPA (total BPACR) concentration was 88.0 µg g-1 (range 0.78-18900 µg g-1), ~70 times higher than in US adults in 2013-2014 (1.27 µg g-1). GM total BPACR increased during Day 1 (26.6-127 µg g-1), decreased by pre-shift Day 2 (84.4 µg g-1) then increased during Day 2 to 178 µg g-1. By industry, baseline and post-baseline total BPACR was highest in BPA-filled wax manufacturing/reclaim (GM = 111 µg g-1) and lowest in phenolic resin manufacturing (GM = 6.56 µg g-1). By job, total BPACR was highest at baseline in maintenance workers (GM = 157 µg g-1) and post-baseline in those working with molten BPA-filled wax (GM = 441 µg g-1). Workers in the job of flaking a BPA-based resin had the lowest concentrations at baseline (GM = 4.81 µg g-1) and post-baseline (GM = 23.2 µg g-1). In multiple regression models, at baseline, industry significantly predicted increased total BPACR (P = 0.0248); post-baseline, handling BPA containers (P = 0.0035), taking ≥3 process/bulk samples with BPA (P = 0.0002) and wearing a Tyvek® coverall (P = 0.0042) significantly predicted increased total BPACR (after adjusting for total BPACR at baseline, time point, and body mass index). Conclusion: Several work-related factors, including industry, job, and certain tasks performed, were associated with increased urinary total BPACR concentrations in this group of manufacturing workers. The potential for BPA-related health effects among these workers is unknown.

Menstrual cycle perturbation by organohalogens and elements in the Cree of James Bay, Canada.

Persistent organohalogens (POHs) and metals have been linked to alterations in menstrual cycle function and fertility in humans. The Cree First Nations people living near James Bay in Ontario and Quebec, Canada, have elevated levels of POHs, mercury and lead compared to other Canadians. The present study examines the interrelationships between selected POHs and elements on menstrual cycle function in these Cree women. Menstrual cycle characteristics were derived from structured daily diaries and endocrine measurements from daily urine samples collected during one cycle for 42 women age 19-42. We measured 31 POHs in blood plasma and 18 elements in whole blood, for 31 of the participants. POHs and elements detected in ≥ 70% of the participants were transformed by principal component (PC) analysis to reduce the contaminant exposure data to fewer, uncorrelated PCA variables. Multiple regression analysis revealed that, after adjusting for confounders, PC-3 values showed significant negative association with cycle length, after adjusting for confounders (p = 0.002). PC-3 accounted for 9.2% of the variance and shows positive loadings for cadmium, selenium, and PBDE congeners 47 and 153, and a negative loading for copper. Sensitivity analysis of the model to quantify likely effect sizes showed a range of menstrual cycle length from 25.3 to 28.3 days using the lower and upper 95% confidence limits of mean measured contaminant concentrations to predict cycle length. Our observations support the hypothesis that the menstrual cycle function of these women may be altered by exposure to POHs and elements from their environment.

Time-related increase in urinary testosterone levels and stable semen analysis parameters after bariatric surgery in men.

The aim of this prospective cohort study was to determine the time-course in androgen and semen parameters in men after weight loss associated with bariatric surgery. Six men aged 18-40 years, meeting National Institutes of Health bariatric surgery guidelines, were followed between 2005 and 2008. Study visits took place at baseline, then 1, 3, 6 and 12 months after surgery. All men underwent Roux-en-y gastric bypass (RYGB). At each visit, biometric, questionnaire, serum, and urinary specimens and seman analysis were collected. Urinary integrated total testosterone levels increased significantly (P < 0.0001) by 3 months after surgery, and remained elevated throughout the study. Circulating testosterone levels were also higher at 1 and 6 months after surgery, compared with baseline. Serum sex hormone-binding globulin levels were significantly elevated at all time points after surgery (P < 0.01 to P = 0.02). After RYGB surgery, no significant changes occurred in urinary oestrogen metabolites (oestrone 3-glucuronide), serum oestradiol levels, serial semen parameters or male sexual function by questionnaire. A threshold of weight loss is necessary to improve male reproductive function by reversing male hypogonadism, manifested as increased testosterone levels. Further serial semen analyses showed normal ranges for most parameters despite massive weight loss.

Urinary follicle-stimulating hormone as a measure of natural fertility in a community cohort.

High serum follicle-stimulating hormone (FSH) levels have been associated with diminished ovarian reserve; however, the association between high urinary FSH and reduced natural fertility has yet to be established. We sought to characterize the relationship between a single or multiple measurements of early follicular phase urinary FSH and fertility. Women (n = 209), 30 to 44 years old with no history of infertility, who had been trying to conceive for less than 3 months, provided early follicular phase urine. Participants subsequently kept a diary to record bleeding and intercourse and conducted standardized pregnancy testing for up to 6 months. A subset of women (N = 95) collected urine on cycle day 3 for up to 6 cycles. Urine was analyzed for FSH and creatinine (cr) corrected. Proportional hazard models were used to calculate fecundability ratios (FRs). Urinary FSH levels across cycles from the same woman were highly correlated (adjusted intraclass correlation = .77); within-woman variance was 3-fold lower than variance among women. Women with an initial urinary FSH level <7 mIU/mg cr exhibited a nonsignificant reduction in the probability of pregnancy (adjusted FR 0.71, 95% confidence interval [CI]: 0.45-1.13), as did women with elevated urinary FSH (≥12 mIU/mg cr; adjusted FR 0.78, 95% CI: 0.46-1.32). Using the most recent or maximum urinary FSH value did not strengthen the association. In the general population, urinary FSH levels appear to be nonlinearly associated with fertility; however, broad CIs indicate a lack of statistical significance. Repetitive testing appears to be of little benefit.

Effects of gestational and lactational exposure to heptachlor epoxide on age at puberty and reproductive function in men and women.

BACKGROUND: For 15 months in 1981-1982, the commercial milk supply on the Hawaiian island of Oahu was contaminated with heptachlor epoxide, a metabolite of the insecticide heptachlor, resulting in gestational and/or lactational exposure to offspring of women who drank cow milk during that period. OBJECTIVE: To determine whether gestational and lactational exposure to heptachlor epoxide alters reproductive function and age at puberty in men or women. METHODS: 457 participants were recruited from a prior high school enrollment sampling frame of 20,000 adults born during 1981-1982 who lived on Oahu since at least first grade. Number of glasses of cow milk consumed weekly by the mother during the participant's gestation was used as a surrogate measure of heptachlor epoxide exposure. Reproductive function measures included semen analyses; reproductive hormones or their metabolites in daily urine specimens for one menstrual cycle; serum reproductive hormone levels in both sexes; and reported ages of onset for pubertal milestones. RESULTS: We observed no strong associations of heptachlor epoxide exposure during gestation and lactation with reproductive endpoints. In females, heptachlor epoxide exposure was associated with longer luteal phase length and slower drop in the ratio of estradiol to progesterone metabolites after ovulation. In males, heptachlor epoxide exposure was weakly associated with higher serum follicle stimulating hormone and luteinizing hormone concentrations, but no dose-response relationship was apparent. CONCLUSIONS: The results provide limited evidence that gestational and lactational exposure to heptachlor epoxide, due to milk contamination on Oahu in 1981-1982, resulted in clinically significant disturbances of reproductive function in men or women.

Effects of gastric bypass surgery on female reproductive function.

CONTEXT: Reproductive function may improve after bariatric surgery, although the mechanisms and time-related changes are unclear. OBJECTIVE: The objective of the study was to determine whether ovulation frequency/quality as well as associated reproductive parameters improve after Roux en Y gastric bypass surgery. DESIGN: This was a prospective cohort study that enrolled female subjects from 2005 to 2008 with study visits at baseline and then 1, 3, 6, 12, and up to 24 months after surgery. SETTING: The study was conducted at an academic health center. PATIENTS: Twenty-nine obese, reproductive-aged women not using confounding medications participated in the study. MAIN OUTCOME MEASURES: The primary outcome was integrated levels of urinary progestin (pregnanediol 3-glururonide) from daily urinary collections at 12 months postoperatively. Secondary outcomes were changes in vaginal bleeding, other biometric, hormonal, ultrasound, dual-energy x-ray absorptiometry measures, and Female Sexual Function Index. RESULTS: Ninety percent of patients with morbid obesity had ovulatory cycles at baseline, and the ovulatory frequency and luteal phase quality (based on integrated pregnanediol 3-glururonide levels) were not modified by bariatric surgery. The follicular phase was shorter postoperatively [6.5 d shorter at 3 months and 7.9-8.9 d shorter at 6-24 months (P < 0.01)]. Biochemical hyperandrogenism improved, largely due to an immediate postoperative increase in serum SHBG levels (P < 0.01), with no change in clinical hyperandrogenism (sebum production, acne, hirsutism). Bone density was preserved, contrasting with a significant loss of lean muscle mass and fat (P < 0.001), reflecting preferential abdominal fat loss (P < 0.001). Female sexual function improved 28% (P = 0.02) by 12 months. CONCLUSIONS: Ovulation persists despite morbid obesity and the changes from bypass surgery. Reproductive function after surgery is characterized by a shortened follicular phase and improved female sexual function.

Menstrual cycle characteristics and reproductive hormone levels in women exposed to atrazine in drinking water.

Atrazine is the most commonly used herbicide in the U.S. and a wide-spread groundwater contaminant. Epidemiologic and laboratory evidence exists that atrazine disrupts reproductive health and hormone secretion. We examined the relationship between exposure to atrazine in drinking water and menstrual cycle function including reproductive hormone levels. Women 18-40 years old residing in agricultural communities where atrazine is used extensively (Illinois) and sparingly (Vermont) answered a questionnaire (n=102), maintained menstrual cycle diaries (n=67), and provided daily urine samples for analyses of luteinizing hormone (LH), and estradiol and progesterone metabolites (n=35). Markers of exposures included state of residence, atrazine and chlorotriazine concentrations in tap water, municipal water and urine, and estimated dose from water consumption. Women who lived in Illinois were more likely to report menstrual cycle length irregularity (odds ratio (OR)=4.69; 95% confidence interval (CI): 1.58-13.95) and more than 6 weeks between periods (OR=6.16; 95% CI: 1.29-29.38) than those who lived in Vermont. Consumption of >2 cups of unfiltered Illinois water daily was associated with increased risk of irregular periods (OR=5.73; 95% CI: 1.58-20.77). Estimated "dose" of atrazine and chlorotriazine from tap water was inversely related to mean mid-luteal estradiol metabolite. Atrazine "dose" from municipal concentrations was directly related to follicular phase length and inversely related to mean mid-luteal progesterone metabolite levels. We present preliminary evidence that atrazine exposure, at levels below the US EPA MCL, is associated with increased menstrual cycle irregularity, longer follicular phases, and decreased levels of menstrual cycle endocrine biomarkers of infertile ovulatory cycles.

Antimüllerian hormone as a predictor of natural fecundability in women aged 30-42 years.

OBJECTIVE: To generate estimates of the association between markers of ovarian aging and natural fertility in a community sample at risk for ovarian aging. METHODS: Women aged 30-44 years with no history of infertility who had been trying to conceive for less than 3 months provided early-follicular phase serum and urine (N=100). Subsequently, these women kept a diary to record menstrual bleeding and intercourse and conducted standardized pregnancy testing for up to 6 months. Serum was analyzed for estradiol, follicle-stimulating hormone (FSH), antimüllerian hormone, and inhibin B. Urine was analyzed for FSH and estrone 3-glucuronide. Diary data on menstrual cycle day and patterns of intercourse were used to calculate day-specific fecundability ratios. RESULTS: Sixty-three percent of participants conceived within 6 months. After adjusting for age, 18 women (18%) with serum antimüllerian hormone levels of 0.7 ng/mL or less had significantly reduced fecundability given intercourse on a fertile day compared with women with higher antimüllerian hormone levels (fecundability ratio 0.38; 95% confidence interval [CI] 0.08-0.91). The day-specific fecundability for women with early-follicular phase serum FSH values greater than 10 milli-international units/mL compared with women with lower FSH levels was also reduced, although nonsignificantly (11% of women affected; fecundability ratio 0.44; 95% CI 0.08-1.10). The association with urinary FSH was weaker (27% women affected; fecundability ratio 0.61; 95% CI 0.26-1.26), and the associations for the other markers were weaker still. CONCLUSION: Early-follicular phase antimüllerian hormone appears to be associated with natural fertility in the general population. LEVEL OF EVIDENCE: II.

Effects of continuous versus cyclical oral contraception: a randomized controlled trial.

CONTEXT: Continuous oral contraception may better suppress the ovary and endometrium, lending itself to the treatment of other medical conditions. OBJECTIVE: Our objective was to determine the effects of continuous vs. cyclical oral contraception. DESIGN: This was a randomized double-blind trial. SETTING: This trial was performed at an academic medical center in Pennsylvania. PATIENTS: A total of 62 healthy women with regular menses were included in the study. INTERVENTION: Cyclical oral contraception (21-d active/7-d placebo given for six consecutive 28-d cycles) vs. continuous (168-d active pill) therapy using a monophasic pill (20 microg ethinyl estradiol and 1 mg norethindrone acetate) was examined. MAIN OUTCOME MEASURES: The primary outcome was vaginal bleeding, and secondary outcomes included hormonal, pelvic ultrasound, quality of life, and safety measures. RESULTS: There was no statistically significant difference in the number of total bleeding days between groups, but moderate/heavy bleeding was significantly greater with the cyclical regimen [mean 11.0 d (sd 8.5) vs. continuous 5.2 d (sd 6.8); P = 0.005], with both groups decreasing over time. Endogenous serum and urinary estrogens measured over six cycles were significantly lower (P = 0.02 and 0.04, respectively) in the continuous group than the cyclical group. Women in the continuous group also had a smaller ovarian volume and lead follicle size over the course of the trial by serial ultrasound examinations. The Moos Menstrual Distress Questionnaire showed that women on continuous therapy had less associated menstrual pain (P = 0.01) and favorable improvements in behavior (P = 0.04) during the premenstrual period. CONCLUSIONS: Continuous oral contraception does not result in a reduction of bleeding days over a 168-d period of observation but provides greater suppression of the ovary and endometrium. These effects are associated with improved patient symptomatology.