Anna Z. Pollack

Menstrual Bleeding Patterns Among Regularly Menstruating Women

Menstrual bleeding patterns are considered relevant indicators of reproductive health, though few studies have evaluated patterns among regularly menstruating premenopausal women. The authors evaluated self-reported bleeding patterns, incidence of spotting, and associations with reproductive hormones among 201 women in the BioCycle Study (2005-2007) with 2 consecutive cycles. Bleeding patterns were assessed by using daily questionnaires and pictograms. Marginal structural models were used to evaluate associations between endogenous hormone concentrations and subsequent total reported blood loss and bleeding length by weighted linear mixed-effects models and weighted parametric survival analysis models. Women bled for a median of 5 days (standard deviation: 1.5) during menstruation, with heavier bleeding during the first 3 days. Only 4.8% of women experienced midcycle bleeding. Increased levels of follicle-stimulating hormone (β = 0.20, 95% confidence interval: 0.13, 0.27) and progesterone (β = 0.06, 95% confidence interval: 0.03, 0.09) throughout the cycle were associated with heavier menstrual bleeding, and higher follicle-stimulating hormone levels were associated with longer menses. Bleeding duration and volume were reduced after anovulatory compared with ovulatory cycles (geometric mean blood loss: 29.6 vs. 47.2 mL; P = 0.07). Study findings suggest that detailed characterizations of bleeding patterns may provide more insight than previously thought as noninvasive markers for endocrine status in a given cycle.

The utility of menstrual cycle length as an indicator of cumulative hormonal exposure.

CONTEXT Associations between menstrual cycle length and chronic diseases are hypothesized to be due to differences in underlying hormonal patterns. OBJECTIVE The aim of the study was to evaluate the association between menstrual cycle length and the hormonal profile and anovulation. DESIGN AND SETTING We conducted a prospective cohort study at the University at Buffalo from 2005 to 2007. PARTICIPANTS We recruited 259 healthy, regularly menstruating women aged 18-44 yr. MAIN OUTCOME MEASURES Cycle length was observed for up to two cycles. Serum estradiol, progesterone, LH, and FSH were measured up to eight times per cycle for up to two cycles. RESULTS Women with short cycles (<26 d) had higher FSH concentrations during menses and in the late luteal phase, higher follicular estradiol concentrations, and lower LH concentrations across the cycle. Among women with longer cycles (>35 d), estradiol and LH peaks occurred on average about 3 d later, and FSH peaks about 1 d later compared to women with normal-length cycles. Both short and long cycles, compared with normal-length cycles, had an increased probability of anovulation. In general, per-cycle exposure to hormones was less in short cycles based on the area under the curve, although over time the cumulative exposure to estradiol would be greater for women with short cycles. CONCLUSIONS Short ovulatory cycles were associated with higher follicular phase estradiol, an earlier rise in FSH, and an increased risk of anovulation. These results suggest that menstrual cycle length may be a relevant indicator of estradiol exposure and risk of anovulation among regularly cycling women.

Kidney biomarkers associated with blood lead, mercury, and cadmium in premenopausal women: a prospective cohort study.

Certain metals are harmful to the kidney and liver at high levels, but associations with functional biomarkers at low exposure levels among premenopausal women apparently has not been evaluated. Healthy, regularly menstruating women (n = 259) were followed for up to 2 menstrual cycles with up to 16 visits. Renal and liver biomarkers were measured in serum at each clinic visit. Cadmium (Cd), lead (Pb), and mercury (Hg) were measured in whole blood at baseline. Linear mixed models were adjusted for age, body mass index (BMI), race, average calories, alcohol intake, smoking, and cycle day. Median levels of Cd, Pb, and Hg were 0.31 μg/L, 0.88 μg/dl, and 1.1 μg/L, respectively. One-third of women had diminished glomerular filtration rate (eGFR) (<90 ml/min/1.73 m2). Each twofold increase in Cd was associated with a negative 4.9% change in blood urea nitrogen (BUN) and bilirubin. Each twofold rise in Pb was associated with decreased eGFR and increased creatinine. A twofold elevation in Hg was associated with higher protein and reduced alkaline phosphatase. In healthy, predominantly nonsmoking women, low levels of Cd, Pb, and Hg were associated with changes in select biomarkers of kidney and liver function.

Bisphenol A, benzophenone-type ultraviolet filters, and phthalates in relation to uterine leiomyoma

Bisphenol A, benzophenone-type UV filters, and phthalates are chemicals in high production and use including in a range of personal care products. Exposure of humans to these chemicals has been shown to affect endocrine function. Although short-lived, widespread exposure may lead to continual opportunity for these chemicals to elicit health effects in humans. The association of these chemicals with incident uterine leiomyoma, an estrogen sensitive disease, is not known. Urinary concentrations of bisphenol A (BPA), five benzophenone-type UV filters (2-hydroxy-4-methoxybenzophenone (2OH-4MeO-BP), 2,4-dihydroxybenzophenone (2,4OH-BP), 2,2׳-dihydroxybenzophenone (2,2׳OH-4MeO-BP), 2,2׳4,4׳-tetrahydroxybenzophenone (2,2׳4,4׳OH-BP), and 4-hydroxybenzophenone (4OH-BP), and 14 phthalate monoesters were quantified in 495 women who later underwent laparoscopy/laparotomy at 14 clinical sites for the diagnosis of fibroids. Significantly higher geometric mean creatinine-corrected concentrations of BPA, 2,4OH-BP, and 2OH-4MeO-BP were observed in women with than without fibroids [BPA: 2.09µg/g vs. 1.46µg/g p=0.004; 2,4OH-BP:11.10µg/g vs. 6.71µg/g p=0.01; 2OH-4MeO-BP: 11.31µg/g vs. 6.10µg/g p=0.01]. Mono-methyl phthalate levels were significantly lower in women with than without fibroids (1.78µg/g vs. 2.40µg/g). However, none of the exposures were associated with a significant odds ratio even when adjusting for relevant covariates. There was a lack of an association between select nonpersistent chemicals and the odds of a fibroid diagnosis.

Serum uric acid in relation to endogenous reproductive hormones during the menstrual cycle: findings from the BioCycle study

STUDY QUESTION Do uric acid levels across the menstrual cycle show associations with endogenous estradiol (E2) and reproductive hormone concentrations in regularly menstruating women? SUMMARY ANSWER Mean uric acid concentrations were highest during the follicular phase, and were inversely associated with E2 and progesterone, and positively associated with FSH. WHAT IS KNOWN ALREADY E2 may decrease serum levels of uric acid in post-menopausal women; however, the interplay between endogenous reproductive hormones and uric acid levels among regularly menstruating women has not been elucidated. STUDY DESIGN, SIZE, DURATION The BioCycle study was a prospective cohort study conducted at the University at Buffalo research centre from 2005 to 2007, which followed healthy women for one (n = 9) or 2 (n = 250) menstrual cycle(s). PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were healthy women aged 18-44 years. Hormones and uric acid were measured in serum eight times each cycle for up to two cycles. Marginal structural models with inverse probability of exposure weights were used to evaluate the associations between endogenous hormones and uric acid concentrations. MAIN RESULTS AND THE ROLE OF CHANCE Uric acid levels were observed to vary across the menstrual cycle, with the lowest levels observed during the luteal phase. Every log-unit increase in E2 was associated with a decrease in uric acid of 1.1% (β = -0.011; 95% confidence interval (CI): -0.019, -0.004; persistent-effects model), and for every log-unit increase in progesterone, uric acid decreased by ≈ 0.8% (β = -0.008; 95% CI: -0.012, -0.004; persistent-effects model). FSH was positively associated with uric acid concentrations, such that each log-unit increase was associated with a 1.6% increase in uric acid (β = 0.016; 95% CI: 0.005, 0.026; persistent-effects model). Progesterone and FSH were also associated with uric acid levels in acute-effects models. Of 509 cycles, 42 were anovulatory (8.3%). Higher uric acid levels were associated with increased odds of anovulation (odds ratio 2.39, 95% CI: 1.25, 4.56). LIMITATIONS, REASONS FOR CAUTION The change in uric acid levels among this cohort of healthy women was modest, and analysis was limited to two menstrual cycles. The women in this study were healthy and regularly menstruating, and as such there were few women with high uric acid levels and anovulatory cycles. WIDER IMPLICATIONS OF THE FINDINGS These findings demonstrate the importance of taking menstrual cycle phase into account when measuring uric acid in premenopausal women, and confirm the hypothesized beneficial lowering effects of endogenous E2 on uric acid levels. These findings suggest that there could be an underlying association affecting both sporadic anovulation and high uric acid levels among young, regularly menstruating women. Further studies are needed to confirm these findings and elucidate the connection between uric acid and reproductive and later cardiovascular health.

Caffeinated beverage intake and reproductive hormones among premenopausal women in the BioCycle Study.

BACKGROUND Caffeinated beverages are widely consumed among women of reproductive age, but their association with reproductive hormones, and whether race modifies any such associations, is not well understood. OBJECTIVE We assessed the relation between caffeine and caffeinated beverage intake and reproductive hormones in healthy premenopausal women and evaluated the potential effect modification by race. DESIGN Participants (n = 259) were followed for up to 2 menstrual cycles and provided fasting blood specimens for hormonal assessment at up to 8 visits per cycle and four 24-h dietary recalls per cycle. Weighted linear mixed models and nonlinear mixed models with harmonic terms were used to estimate associations between caffeine and hormone concentrations, adjusted for age, adiposity, physical activity, energy and alcohol intakes, and perceived stress. On the basis of a priori assumptions, an interaction between race and caffeine was tested, and stratified results are presented. RESULTS Caffeine intake ≥200 mg/d was inversely associated with free estradiol concentrations among white women (β = -0.15; 95% CI: -0.26, -0.05) and positively associated among Asian women (β = 0.61; 95% CI: 0.31, 0.92). Caffeinated soda intake and green tea intake ≥1 cup/d (1 cup = 240 mL) were positively associated with free estradiol concentrations among all races: β = 0.14 (95% CI: 0.06, 0.22) and β = 0.26 (95% CI: 0.07, 0.45), respectively. CONCLUSIONS Moderate consumption of caffeine was associated with reduced estradiol concentrations among white women, whereas caffeinated soda and green tea intakes were associated with increased estradiol concentrations among all races. Further research is warranted on the association between caffeine and caffeinated beverages and reproductive hormones and whether these relations differ by race.

Assessment of anovulation in eumenorrheic women: comparison of ovulation detection algorithms

OBJECTIVE To compare previously used algorithms to identify anovulatory menstrual cycles in women self-reporting regular menses. DESIGN Prospective cohort study. SETTING Western New York. PATIENT(S) Two hundred fifty-nine healthy, regularly menstruating women followed for one (n=9) or two (n=250) menstrual cycles (2005-2007). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Prevalence of sporadic anovulatory cycles identified using 11 previously defined algorithms that use E2, P, and LH concentrations. RESULT(S) Algorithms based on serum LH, E2, and P levels detected a prevalence of anovulation across the study period of 5.5%-12.8% (concordant classification for 91.7%-97.4% of cycles). The prevalence of anovulatory cycles varied from 3.4% to 18.6% using algorithms based on urinary LH alone or with the primary E2 metabolite, estrone-3-glucuronide, levels. CONCLUSION(S) The prevalence of anovulatory cycles among healthy women varied by algorithm. Mid-cycle LH surge urine-based algorithms used in over-the-counter fertility monitors tended to classify a higher proportion of anovulatory cycles compared with luteal-phase P serum-based algorithms. Our study demonstrates that algorithms based on the LH surge, or in conjunction with estrone-3-glucuronide, potentially estimate a higher percentage of anovulatory episodes. Addition of measurements of postovulatory serum P or urine pregnanediol may aid in detecting ovulation.

The influence of sporadic anovulation on hormone levels in ovulatory cycles

STUDY QUESTION Do ovulatory hormone profiles among healthy premenopausal women differ between women with and without sporadic anovulation? SUMMARY ANSWER Women with one anovulatory cycle tended to have lower estradiol, progesterone and LH peak levels during their ovulatory cycle. WHAT IS KNOWN ALREADY Anovulation occurs sporadically in healthy premenopausal women, but the influence of hormones in a preceding cycle and the impact on a subsequent cycles hormone levels is unknown. STUDY DESIGN, SIZE, DURATION The BioCycle Study was a prospective cohort including 250 healthy regularly menstruating women, 18-44 years of age, from Western New York with no history of menstrual or ovulation disorders. The women were followed with up to eight study visits per cycle for two cycles, most of which were consecutive. PARTICIPANTS/MATERIALS, SETTING AND METHODS All study visits were timed to menstrual cycle phase using fertility monitors and located at the University at Buffalo womens health research center from 2005 to 2007. The main outcomes measured were estradiol, progesterone, LH and follicle-stimulating hormone levels in serum at up to 16 visits over two cycles. Anovulation was defined as peak serum progesterone concentrations ≤5 ng/ml and no serum LH peak detected during the mid- or late-luteal phase visit. MAIN RESULTS AND THE ROLE OF CHANCE Reproductive hormone concentrations were lower during anovulatory cycles, but significant reductions were also observed in estradiol (-25%, P = 0.003) and progesterone (-22%, P = 0.001) during the ovulatory cycles of women with one anovulatory cycle compared with women with two ovulatory cycles. LH peak concentrations were decreased in the ovulatory cycle of women with an anovulatory cycle (significant amplitude effect, P = 0.004; geometric mean levels 38% lower, P < 0.05). LIMITATIONS, REASONS FOR CAUTION Follow-up was limited to two menstrual cycles, and no ultrasound assessment of ovulation was available. Data were missing for a total of 168 of a possible 4072 cycle visits (4.1%), though all women had at least five visits per cycle (94% had seven or more per cycle). WIDER IMPLICATIONS OF THE FINDINGS These results suggest a possible underlying cause of anovulation, such as a longer-term subclinical follicular, ovarian or hypothalamic/pituitary dysfunction, even among healthy, regularly menstruating women.

Realignment and multiple imputation of longitudinal data: an application to menstrual cycle data

Reproductive hormone levels are highly variable among premenopausal women during the menstrual cycle. Accurate timing of hormone measurement is essential, especially when investigating day- or phase-specific effects. The BioCycle Study used daily urine home fertility monitors to help detect the luteinising hormone (LH) surge in order to schedule visits with biologically relevant windows of hormonal variability. However, as the LH surge is brief and cycles vary in length, relevant hormonal changes may not align with scheduled visits even when fertility monitors are used. Using monitor data, measurements were reclassified according to biological phase of the menstrual cycle to more accurate cycle phase categories. Longitudinal multiple imputation methods were applied after reclassification if no visit occurred during a given menstrual cycle phase. Reclassified cycles had more clearly defined hormonal profiles, with higher mean peak hormones (up to 141%) and reduced variability (up to 71%). We demonstrate the importance of realigning visits to biologically relevant windows when assessing phase- or day-specific effects and the feasibility of applying longitudinal multiple imputation methods. Our method has applications in settings where missing data may occur over time, where daily blood sampling for hormonal measurements is not feasible, and in other areas where timing is essential.

Caffeine consumption and miscarriage: a prospective cohort study

Caffeine consumption has been equivocally associated with miscarriage, despite an absence of prospective longitudinal measurement of caffeine intake during sensitive windows of human development. In response to this critical data gap, we analyzed daily caffeine consumption while attempting pregnancy through 12 menstrual cycles at risk for pregnancy and found that caffeine consumption did not increase the risk or hazard of miscarriage, even after adjusting for relevant covariates.