Increased urinary cobalt and whole blood concentrations of cadmium and lead in women with uterine leiomyomata: Findings from the ENDO Study.

Multiple trace elements have estrogen receptor activity, but the association of these elements with uterine leiomyoma has not been defined. A cohort of 473 women aged 18-44 undergoing surgery for benign gynecologic indications provided whole blood and urine specimens for trace element analysis, which was performed by inductively coupled plasma mass spectrometry. Twenty elements were analyzed in blood and 3 in urine. The surgeon documented whether fibroids were present. Geometric mean concentrations were compared between women with and without fibroids, and logistic regression models were generated to assess the impact of the concentration of each trace element on the odds of fibroids. In multivariate regressions, odds of a fibroid diagnosis were higher with increased whole blood cadmium (AOR 1.44, 95% CI 1.02, 2.04) and lead (AOR 1.31 95% CI 1.02, 1.69), and urine cobalt (AOR 1.31, 95% CI 1.02, 1.70). Urinary cadmium and lead were not related to fibroid diagnosis. Increased exposure to trace elements may contribute to fibroid growth, and fibroids may serve as a reservoir for these elements. Differences between urinary and whole blood findings merit further investigation, as urinary cadmium has been considered a superior marker of exposure.

Luteal phase deficiency in regularly menstruating women: prevalence and overlap in identification based on clinical and biochemical diagnostic criteria.

CONTEXT: Although adequate luteal hormone production is essential for establishing pregnancy, luteal phase deficiency (LPD) is poorly characterized among eumenorrheic women. OBJECTIVE: We assessed the prevalence and overlap of two established LPD diagnostic criteria: short luteal phase duration less than10 days (clinical LPD) and suboptimal luteal progesterone of 5 ng/mL or less (biochemical LPD) and their relationship with reproductive hormone concentrations. DESIGN, SETTING, AND PARTICIPANTS: We conducted a prospective study in western New York (2005-2007) following 259 women, aged 18-44 years, for up to two menstrual cycles. RESULTS: Among ovulatory cycles with recorded cycle lengths (n = 463), there were 41 cycles (8.9%) with clinical LPD, 39 cycles (8.4%) with biochemical LPD, and 20 cycles (4.3%) meeting both criteria. Recurrent clinical and biochemical LPD was observed in eight (3.4%) and five (2.1%) women, respectively. Clinical and biochemical LPD were each associated with lower follicular estradiol (both P ≤ .001) and luteal estradiol (P = .03 and P = .02, respectively) after adjusting for age, race, and percentage body fat. Clinical, but not biochemical, LPD was associated with lower LH and FSH across all phases of the cycle (P ≤ .001). CONCLUSIONS: Clinical and biochemical LPD were evident among regularly menstruating women. Estradiol was lower in LPD cycles under either criterion, but LH and FSH were lower only in association with shortened luteal phase (ie, clinical LPD), indicating that clinical and biochemical LPD may reflect different underlying mechanisms. Identifying ovulation in combination with a well-timed luteal progesterone measurement may serve as a cost-effective and specific tool for LPD assessment by clinicians and researchers.

Increased androgen, anti-Müllerian hormone, and sporadic anovulation in healthy, eumenorrheic women: a mild PCOS-like phenotype?

CONTEXT: Hyperandrogenism is a hallmark of polycystic ovary syndrome (PCOS) in women with irregular menses, yet the relationship between androgens and ovarian dysfunction remains poorly understood in eumenorrheic women. OBJECTIVE: The objective of the study was to evaluate whether sporadic anovulation was associated with higher T and anti-müllerian hormone (AMH; marker of ovarian follicle count) concentrations in eumenorrheic women. DESIGN: This was a prospective cohort study from 2005 to 2007. SETTING: The study was conducted at the University of Buffalo in western New York state. PARTICIPANTS: A total of 259 eumenorrheic women without a self-reported history of infertility, PCOS, or other endocrine disorder participated in the study. MAIN OUTCOME MEASURES: Total T and AMH were measured five to eight times per cycle for one (n = 9) or two (n = 250) cycles per woman (n = 509 cycles) with timing of menstrual cycle phase assisted by fertility monitors. Anovulatory cycles were defined biochemically by progesterone and LH concentrations. Repeated-measures ANOVA was conducted on log-transformed data with adjustment for age. RESULTS: Compared with ovulatory cycles (n = 467), sporadic anovulatory cycles (n = 42) had marginally higher total and significantly higher free T [mean 23.7 ng/dL (95% confidence interval [CI] 21.4-26.3) vs 21.6 ng/dL (95% CI 20.9-22.3), P = .08, and 0.36 ng/dL (95% CI 0.33-0.40) vs 0.32 ng/dL (95% CI 0.31-0.33), P = .02, respectively] during menses and also throughout the luteal phase (P < .01 for all). Women with higher T had elevated AMH concentrations, increased reporting of a history of acne requiring medical treatment, but not increased hirsutism. CONCLUSIONS: Mechanisms of androgen-related ovulatory dysfunction that characterize PCOS in women with menstrual disturbances may occur across a continuum of T concentrations, including in eumenorrheic women without clinical hyperandrogenism.

Risk factors associated with endometriosis: importance of study population for characterizing disease in the ENDO Study.

OBJECTIVE: We sought to identify risk factors for endometriosis and their consistency across study populations in the Endometriosis: Natural History, Diagnosis, and Outcomes (ENDO) Study. STUDY DESIGN: In this prospective matched, exposure cohort design, 495 women aged 18-44 years undergoing pelvic surgery (exposed to surgery, operative cohort) were compared to an age- and residence-matched population cohort of 131 women (unexposed to surgery, population cohort). Endometriosis was diagnosed visually at laparoscopy/laparotomy or by pelvic magnetic resonance imaging in the operative and population cohorts, respectively. Logistic regression estimated the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for each cohort. RESULTS: The incidence of visualized endometriosis was 40% in the operative cohort (11.8% stage 3-4 by revised criteria from the American Society for Reproductive Medicine), and 11% stage 3-4 in the population cohort by magnetic resonance imaging. An infertility history increased the odds of an endometriosis diagnosis in both the operative (AOR, 2.43; 95% CI, 1.57-3.76) and population (AOR, 7.91; 95% CI, 1.69-37.2) cohorts. In the operative cohort only, dysmenorrhea (AOR, 2.46; 95% CI, 1.28-4.72) and pelvic pain (AOR, 3.67; 95% CI, 2.44-5.50) increased the odds of diagnosis, while gravidity (AOR, 0.49; 95% CI, 0.32-0.75), parity (AOR, 0.42; 95% CI, 0.28-0.64), and body mass index (AOR, 0.95; 95% CI, 0.93-0.98) decreased the odds of diagnosis. In all sensitivity analyses for different diagnostic subgroups, infertility history remained a strong risk factor. CONCLUSION: An infertility history was a consistent risk factor for endometriosis in both the operative and population cohorts of the ENDO Study. Additionally, identified risk factors for endometriosis vary based upon cohort selection and diagnostic accuracy. Finally, endometriosis in the population may be more common than recognized.

Comparative analysis of human CYP3A4 and rat CYP3A1 induction and relevant gene expression by bisphenol A and diethylstilbestrol: implications for toxicity testing paradigms.

Bisphenol A (BPA) and diethylstilbestrol (DES) are endocrine-disrupting chemicals that interact with the human pregnane X receptor (PXR). CYP3A4 enzyme is essential in the hydroxylation of steroid hormones and is regulated by PXR. In the present study, human and rat hepatoma cell lines were exposed to BPA and DES. Both BPA and DES (10-50µM) caused a significant activation of the CYP3A4 promoter via the PXR in the DPX2 human hepatoma cell line. No activation of rat PXR was seen. BPA and DES treated DPX2 cells demonstrated increased expression of CYP3A4 mRNA, and increased enzyme activity. In summary, BPA, in concentrations relevant to current safety levels of human exposure, activates the human PXR and demonstrates an increase in CYP3A4 mRNA expression and enzyme activity. BPA actions in this model system occur to a greater extent than DES. This study raises concerns regarding our current toxicity testing paradigms and species utilization.

Energy-containing beverages: reproductive hormones and ovarian function in the BioCycle Study.

BACKGROUND: Energy-containing beverages are widely consumed among premenopausal women, but their association with reproductive hormones is not well understood. OBJECTIVE: The objective was to assess the association of energy-containing beverages, added sugars, and total fructose intake with reproductive hormones among ovulatory cycles and sporadic anovulation in healthy premenopausal women. DESIGN: Women (n = 259) in the BioCycle Study were followed for up to 2 menstrual cycles; they provided fasting blood specimens during up to 8 visits/cycle and four 24-h dietary recalls/cycle. RESULTS: Women who consumed ≥1 cup (1 cup = 237 mL) sweetened soda/d had 16.3% higher estradiol concentrations compared with women who consumed less sweetened soda (86.5 pg/mL compared with 74.4 pg/mL, P = 0.01) after adjustment for age, BMI, race, dietary factors, and physical activity. Similarly elevated estradiol concentrations were found for ≥1 cup cola/d and noncola soda intake. Neither artificially sweetened soda nor fruit juice intake ≥1 cup/d was significantly associated with reproductive hormones. Added sugar above the average US woman's intake (≥73.2 g/d) or above the 66th percentile in total fructose intake (≥41.5 g/d) was associated with significantly elevated estradiol but not consistently across all models. No associations were found between beverages, added sugars, or total fructose intake and anovulation after multivariate adjustment. CONCLUSIONS: Even at moderate consumption amounts, sweetened soda is associated with elevated follicular estradiol concentrations among premenopausal women but does not appear to affect ovulatory function. Further research into the mechanism driving the association between energy-containing beverages and reproductive hormones, and its potential implications for women's health, is warranted.

Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters.

Vitamin D levels have been linked to various health outcomes including reproductive disorders. The purpose of this study was to explore the association between serum vitamin D level (25-hydroxy-vitamin D, or 25OHD) and semen and hormonal parameters. This is a cross-sectional study that included 170 healthy men recruited for the study of spermatogenesis from the general population. Men completed general and reproductive health questionnaires, and donated blood and semen samples. The main measures were hormonal (total and free testosterone, sex hormone-binding globulin, estradiol, follicle-stimulating hormone and luteinizing hormone) and semen parameters, adjusted (n=147) for age, body mass index (BMI), season, alcohol intake and smoking, in relation to categories of vitamin D levels, determined a priori. The mean age of the study population was 29.0±8.5 years and mean BMI was 24.3±3.2 kg m(-2). The mean 25OHD was 34.1±15.06 ng ml(-1). BMI showed a negative association with 25OHD. Sperm concentration, sperm progressive motility, sperm morphology, and total progressively motile sperm count were lower in men with '25OHD≥50 ng ml(-1)' when compared to men with '20 ng ml(-1)≤25OHD<50 ng ml(-1)'. Total sperm count and total progressive motile sperm count were lower in men with '25OHD<20 ng ml(-1)' when compared to men with '20 ng ml(-1)≤25OHD<50 ng ml(-1)'. The adjusted means of various hormonal parameters did not show statistical difference in the different categories of 25OHD. In conclusion, serum vitamin D levels at high and low levels can be negatively associated with semen parameters.

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 (ß = -0.15; 95% CI: -0.26, -0.05) and positively associated among Asian women (ß = 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: ß = 0.14 (95% CI: 0.06, 0.22) and ß = 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.

Sleep apnea, reproductive hormones and quality of sexual life in severely obese men.

The effect of sleep apnea on the reproductive function of obese men is not entirely elucidated. The objective of this study was to define the effect of sleep apnea on the reproductive hormones and sexual function in obese men. This study included 89 severely obese men with BMI ≥35 kg/m2 considering gastric bypass surgery. Anthropometrics (weight, and BMI), reproductive hormones, and sleep studies were measured. The sexual quality of life was assessed using the Impact of Weight on Quality of Life-Lite questionnaire (IWQOL-Lite). The mean age of our patients was 46.9 ± 11.0 years, the mean BMI was 47.8 ± 8.7 kg/m2 and the mean weight was 337.7 ± 62.4 lb. After correction for age and BMI, means of free testosterone per severity group of sleep apnea were as follows: no or mild sleep apnea 74.4 ± 3.8 pg/ml, moderate sleep apnea 68.6 ± 4.2 pg/ml, and severe sleep apnea 60.2 ± 2.92 pg/ml, P = 0.014. All other parameters of sleep apnea including hypopnea index, percent time below a SpO2 of 90%, and percent time below a SpO2 of 80% were also negatively correlated with testosterone levels after correction for age and BMI. BMI and presence of coronary artery disease decreased the sexual quality of life. Sleep apnea was associated with reduced sexual quality of life. In summary, sleep apnea negatively affects testosterone levels independent of BMI. Severely obese men had decreased sexual quality of life.

Association of aromatase (TTTAn) repeat polymorphism length and the relationship between obesity and decreased sperm concentration.

BACKGROUND: Obesity in men is associated with low sperm count, however, this finding is inconsistent. Here, we describe length of the short tandem repeat aromatase (CYP19A1) polymorphism and its relationship to increased weight and sperm count. METHODS: A cohort of 215 men was recruited from the community and BMI, hormone levels and sperm parameters were determined at enrollment. Men (196) were genotyped for length of the tetranucleotide TTTA repeats polymorphism (TTTA(n)), defined as short (S ≤ 7 repeats) or long (L > 7 repeats). Genotypes were categorized using allele combinations as 'low repeats' = S-S, or 'high repeats' = S-L/L-L. Weight and sperm parameters were examined in relation to size of TTTA(n) repeat. RESULTS: Mean (±SD) age was 29.8 ± 8.6 years and mean BMI was 25.6 ± 4.6 kg/m(2). Men with high repeats had higher estradiol (E(2)) levels (98.0 ± 33.36 pmol/l) than men with low repeats (85.9 ± 26.61 pmol/l; P= 0.026). Lower FSH levels tended to be present in men with high repeats versus men with low repeats (P= 0.052). After stratification by genotype, a negative correlation between BMI and sperm count (Pearson's coefficient = 0.406) was seen only among men with high repeats (P= 0.019). Only men with high repeats exhibited increased E(2) with increased weight. A decrease in testosterone: E(2) ratio with increasing BMI was more pronounced in men with high versus low, repeats (R(2) = 0.436 versus 0.281). CONCLUSIONS: Higher TTTA repeat numbers (>7 repeats) in the aromatase gene are associated with a negative relationship between obesity and sperm count. The effect of obesity on E(2) and sperm count appears to be absent in men with low (≤7) repeats.

Volume change of uterine myomas during pregnancy: do myomas really grow?

STUDY OBJECTIVE: To estimate changes in uterine myoma volume during pregnancy. DESIGN: Review of departmental electronic perinatal database and medical records. Canadian Task Force Classification II-3. SETTING: Obstetrical ultrasound unit in an academic tertiary care center. PATIENTS: One hundred-seven patients diagnosed with uterine myomas during pregnancy and who had two or more obstetrical ultrasounds in different periods of pregnancy. INTERVENTIONS: We analyzed the change in volume of uterine myomas between the first half of pregnancy (up until 19 weeks), third quarter (20-30 weeks), and last quarter (31 weeks to term). The volume of largest uterine myoma was calculated using the formula Volume (mm3)=Pi/6x(length mm)x(width mm)x(height mm). MEASUREMENTS AND MAIN RESULTS: The mean age of the population was 31+/-6 years. Between the first and the second study periods, the percentage of uterine myomas that decreased in size was 55.1% (95% CI: 43-66), with a mean decrease in volume of 35%+/-4%; while the percentage of uterine myomas that enlarged was 44.9% (95% CI: 34-56), with a mean increase in volume of 69%+/-11%. Between the second and the third study periods, 75% (95% CI: 56-87) became smaller, with a mean decrease in volume of 30%+/-3%; while 25% (95% CI: 13-43) enlarged, with a mean increase in volume of 102%+/-62%. CONCLUSION: Contrary to common belief, we found that uterine myomas commonly decrease in volume over the course of pregnancy.

Ultrasonography-guided transvaginal endometrial biopsy: a useful technique in patients with cervical stenosis.

BACKGROUND: In patients with failed dilatation and curettage due to stenotic cervix, options for endometrial sampling are limited. We propose the ultrasonography-guided transvaginal endometrial biopsy. CASES: Two postmenopausal women presented with bleeding and failed dilatation and curettage due to a stenotic cervix. Under direct transvaginal ultrasound guidance, a 20-gauge needle was inserted through the vaginal vault and anterior uterine wall into the endometrium. The endometrium was aspirated, and specimen was submitted to cytology. One patient had endometrial adenocarcinoma and underwent a staging procedure. The other patient had a benign cytology and was followed up clinically. CONCLUSION: The ultrasonography-guided endometrial biopsy is a viable option for endometrial sampling in the presence of stenotic cervix.

Smoking in pregnancy revisited: findings from a large population-based study.

OBJECTIVE: The purpose of this study was to characterize the effect of smoking on the incidence of various pregnancy complications. STUDY DESIGN: A population-based retrospective analysis with a perinatal database of 170,254 singleton pregnancies was performed. The rate of pregnancy complications was calculated in 4 strata of smokers: Nonsmokers, 1 to 5 cigarettes per day, 6 to 10 cigarettes per day, and >10 cigarettes per day. Logistic regression was used to calculate odds ratios as measures of an association of smoking with various pregnancy complications after correction for confounding factors. RESULTS: The mean age of the study population was 29 +/- 4.8 years. The odds ratio for preeclampsia was 0.64 (95 % CI, 0.59-0.70), for intrauterine growth restriction was 2.4 (95% CI, 2.34-2.53), and for preterm delivery was 1.2 (95% CI, 1.13-1.28). CONCLUSION: Smoking decreased the incidence of preeclampsia in a dose-effect manner and was shown to increase the rate of intrauterine growth restriction and preterm delivery.

The role of sonographic endometrial patterns and endometrial thickness in the differential diagnosis of ectopic pregnancy.

OBJECTIVE: The purpose of this study was to examine the usefulness of the endometrial trilaminar pattern and thickness in the diagnosis of ectopic pregnancy. STUDY DESIGN: We reviewed patient records for clinical and ultrasonographic data for patients with the suspicion of ectopic pregnancy. The trilaminar pattern and endometrial thickness were tested as predictors for the diagnosis of ectopic pregnancy. RESULTS: The trilaminar pattern had a specificity of 94% and sensitivity of 38% (n = 403 women). The mean endometrial thickness was thinner in patients with ectopic, compared with normal pregnancy (9.5 +/- 5.7 mm vs 12.4 +/- 5.9 mm; P = .035). Patients with normal pregnancy or first-trimester losses had comparable thicknesses (12.4 +/- 5.9 mm vs 12.5 +/- 8.0 mm). The receiver operator curve showed that there was no thickness value useful for the diagnosis of ectopic pregnancy. CONCLUSION: The trilaminar pattern is specific for the diagnosis of ectopic pregnancy, but it is associated with low sensitivity. The endometrial thickness tends to be thinner in patients with an ectopic pregnancy.