Stacey A. Missmer

The Epidemiology of Endometriosis

Abstract: Advances in understanding the epidemiology of endometriosis have lagged behind other diseases because of methodologic problems related to disease definition and control selection. Nevertheless, a better picture of the epidemiology of endometriosis has emerged over the past few decades. Prevalence estimates of the disease in clinic populations vary from about a 4% occurrence of largely asymptomatic endometriosis found in women undergoing tubal ligation to 50% of teenagers with intractable dysmenorrhea. General population incidence during the 1970s in this country has been suggested to be 1.6 per 1000 white females aged 15‐49, while a more current study based upon hospital discharges finds endometriosis as a first listed diagnosis in 1.3 per 1000 discharges in women aged 15‐44. There is a clinical impression that blacks have lower rates of endometriosis and Orientals have higher rates than whites. A variety of personal risk factors for endometriosis have also been described. Women with endometriosis may be taller and thinner. Menstrual factors reported to increase risk include dysmenorrhea, early menarche, and shorter cycle lengths. There is support for the idea that lifestyle exposures that might raise or lower estrogen levels could affect risk, including a decreased risk associated with smoking and exercise and an increased risk associated with caffeine or alcohol use. These risk factors appear to be compatible with the central importance of retrograde menstruation influenced by outflow obstruction that might affect its amount, immune factors that might affect its ability to be cleared, or hormonal stimuli that might affect its growth. In this model, dysmenorrhea could be either a disease symptom or a manifestation of outflow obstruction. Nulliparity could be either a consequence of disease or a cause since nulliparous women would not have the benefit of cervical dilation associated with labor and delivery. Since there is evidence that family history is a risk factor for disease, a challenge is how to integrate genetic factors into the model. The genetics of endometriosis might be advanced if we could identify an “endometriosis phenotype”. We propose that this may consist of early menarche, short cycles, painful periods, subfertility, and possibly tall stature that could be explained by genetic factors that predispose to poor endowment of germ cells and canalization defects of the cervix. The value of establishing an “endometriosis phenotype” is that, as candidates for genetic markers are identified, particular genotypes can be correlated with these factors even if a formal diagnosis of endometriosis has not been made. Additional well‐designed case‐control and cohort studies will be necessary to test theories related to pathogenesis, establish the precise relationship between reproductive morbidity and endometriosis, identify specific genetic factors, and establish long‐term risks.

Exposure to Fumonisins and the Occurrence of Neural Tube Defects Along the Texas–Mexico Border

Along the Texas–Mexico border, the prevalence of neural tube defects (NTDs) among Mexican-American women doubled during 1990–1991. The human outbreak began during the same crop year as epizootics attributed to exposure to fumonisin, a mycotoxin that often contaminates corn. Because Mexican Americans in Texas consume large quantities of corn, primarily in the form of tortillas, they may be exposed to high levels of fumonisins. We examined whether or not maternal exposure to fumonisins increases the risk of NTDs in offspring using a population-based case–control study. We estimated fumonisin exposure from a postpartum sphinganine:sphingosine (sa:so) ratio, a biomarker for fumonisin exposure measured in maternal serum, and from maternal recall of periconceptional corn tortilla intake. After adjusting for confounders, moderate (301–400) compared with low (≤ 100) consumption of tortillas during the first trimester was associated with increased odds ratios (ORs) of having an NTD-affected pregnancy (OR = 2.4; 95% confidence interval, 1.1–5.3). No increased risks were observed at intakes higher than 400 tortillas (OR = 0.8 for 401–800, OR = 1.0 for > 800). Based on the postpartum sa:so ratio, increasing levels of fumonisin exposure were associated with increasing ORs for NTD occurrences, except for the highest exposure category (sa:so > 0.35). Our findings suggest that fumonisin exposure increases the risk of NTD, proportionate to dose, up to a threshold level, at which point fetal death may be more likely to occur. These results also call for population studies that can more directly measure individual fumonisin intakes and assess effects on the developing embryo.

The epidemiology of endometriosis

The epidemiologic study of endometriosis presents researchers with unique challenges. As a result, few well-designed studies have been published. The authors briefly describe the primary pathogenic hypotheses, discuss methodologic issues specific to endometriosis, and review the small body of literature addressing risk factors. Finally, they offer a brief interpretation of these findings and suggest hypotheses for future research.

Female obesity adversely affects assisted reproductive technology (ART) pregnancy and live birth rates

BACKGROUND Obesity has risen among women in the USA, including those seeking infertility treatments. In 2007, height and weight were added to the Society for Assisted Reproductive Technology Clinic Online Reporting System (SART CORS), permitting calculation of BMI (weight/height(2)) for the first time using this national dataset. METHODS The SART CORS was used to evaluate the odds of failure to achieve a clinical intrauterine pregnancy and failure to achieve a live birth by the womans age, BMI and oocyte source (autologous versus donor), controlling for race and ethnicity, day of embryo transfer, number of embryos transferred and infertility diagnoses. The reference population was women with normal BMI. RESULTS There were 45 163 ART embryo transfers where maternal height and weight were recorded. Increasing obesity was associated with a significant rise in failure to achieve a clinical pregnancy with the use of autologous oocytes (P< 0.0001), but no difference with the use of donor oocytes. Among women using autologous oocytes who did conceive, failure to achieve a live birth increased with increasing obesity, to a greater extent among women <35 years of age. CONCLUSIONS Higher BMI is associated with an increased failure to achieve a clinical intrauterine gestation; this risk was overcome with the use of donor oocytes. Failure to achieve a live birth increases with higher BMI, significantly with the use of autologous oocytes (P< 0.0001), and to a greater extent among women <35 years of age (P< 0.0001).

Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF

STUDY QUESTION In women undergoing IVF, are urinary bisphenol A (BPA) concentrations associated with ovarian response and early reproductive outcomes, including oocyte maturation and fertilization, Day 3 embryo quality and blastocyst formation? SUMMARY ANSWER Higher urinary BPA concentrations were found to be associated with decreased ovarian response, number of fertilized oocytes and decreased blastocyst formation. WHAT IS KNOWN ALREADY Experimental animal and in vitro studies have reported associations between BPA exposure and adverse reproductive outcomes. We previously reported an association between urinary BPA and decreased ovarian response [peak serum estradiol (E(2)) and oocyte count at the time of retrieval] in women undergoing IVF; however, there are limited human data on reproductive health outcomes, such as fertilization and embryo development. STUDY DESIGN, SIZE AND DURATION Prospective preconception cohort study. One hundred and seventy-four women aged 18-45 years and undergoing 237 IVF cycles were recruited at the Massachusetts General Hospital Fertility Center, Boston, MA, USA, between November 2004 and August 2010. These women were followed until they either had a live birth or discontinued treatment. Cryothaw and donor egg cycles were not included in the analysis. PARTICIPANTS/MATERIALS, SETTING AND METHODS Urinary BPA concentrations were measured by online solid-phase extraction-high-performance liquid chromatography-isotope dilution-tandem mass spectrometry. Mixed effect models, poisson regression and multivariate logistic regression models were used wherever appropriate to evaluate the association between cycle-specific urinary BPA concentrations and measures of ovarian response, oocyte maturation (metaphase II), fertilization, embryo quality and cleavage rate. We accounted for correlation among multiple IVF cycles in the same woman using generalized estimating equations. MAIN RESULTS AND THE ROLE OF CHANCE The geometric mean (SD) for urinary BPA concentrations was 1.50 (2.22) µg/l. After adjustment for age and other potential confounders (Day 3 serum FSH, smoking, BMI), there was a significant linear dose-response association between increased urinary BPA concentrations and decreased number of oocytes (overall and mature), decreased number of normally fertilized oocytes and decreased E(2) levels (mean decreases of 40, 253 and 471 pg/ml for urinary BPA quartiles 2, 3 and 4, when compared with the lowest quartile, respectively; P-value for trend = 0.001). The mean number of oocytes and normally fertilized oocytes decreased by 24 and 27%, respectively, for the highest versus the lowest quartile of urinary BPA (trend test P < 0.001 and 0.002, respectively). Women with urinary BPA above the lowest quartile had decreased blastocyst formation (trend test P-value = 0.08). LIMITATIONS AND REASONS FOR CAUTION Potential limitations include exposure misclassification due to the very short half-life of BPA and its high variability over time; uncertainty about the generalizability of the results to the general population of women conceiving naturally and limited sample. WIDER IMPLICATIONS OF THE FINDINGS The results from this extended study, using IVF as a model to study early reproductive health outcomes in humans, indicate a negative dose-response association between urinary BPA concentrations and serum peak E(2) and oocyte yield, confirming our previous findings. In addition, we found significantly decreased metaphase II oocyte count and number of normally fertilizing oocytes and a suggestive association between BPA urinary concentrations and decreased blastocyst formation, thus indicating that BPA may alter reproductive function in susceptible women undergoing IVF. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants ES009718 and ES000002 from the National Institute of Environmental Health Sciences and grant OH008578 from the National Institute for Occupational Safety and Health. None of the authors has actual or potential competing financial interests. DISCLAIMER The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

Effect of obesity on oocyte and embryo quality in women undergoing in vitro fertilization.

OBJECTIVE: To estimate the effect of body mass index (BMI) on oocyte and embryo parameters and cycle outcomes in women undergoing in vitro fertilization (IVF). METHODS: We evaluated a retrospective cohort of 1,721 women undergoing a first IVF cycle with fresh, autologous embryos between 2007 and 2010 in an academic infertility practice. Main outcome measures included number of mature and normally fertilized oocytes, embryo morphology, estradiol on the day of human chorionic gonadotropin administration, clinical pregnancy, spontaneous abortion, and live birth. We performed multivariable analyses, adjusting for potential confounders, including age at cycle start, infertility diagnosis, type of stimulation, total gonadotropin dose, use of intracytoplasmic sperm injection, and number of embryos transferred. RESULTS: Compared with women of normal BMI, women with class II (BMI 35–39.9) and III (BMI 40 or higher) obesity had fewer normally fertilized oocytes (9.3 compared with 7.6 and 7.7, P<.03) and lower estradiol levels (2,047 pg/mL compared with 1,498 and 1,361, P<.001) adjusting for age and despite similar numbers of mature oocytes. Odds of clinical pregnancy (odds ratio [OR] 0.50, 95% confidence interval [CI] 0.31–0.82) and live birth (OR 0.51, 95% CI 0.29–0.87) were 50% lower in women with class III obesity as compared with women of normal BMI. CONCLUSION: Obesity was associated with fewer normally fertilized oocytes, lower estradiol levels, and lower pregnancy and live birth rates. Infertile women requiring IVF should be encouraged to maintain a normal weight during treatment. LEVEL OF EVIDENCE: II

Urinary Bisphenol A Concentrations and Implantation Failure among Women Undergoing in Vitro Fertilization

Background: Bisphenol A (BPA) is a synthetic chemical widely used in the production of polycarbonate plastic and epoxy resins found in numerous consumer products. In experimental animals, BPA increases embryo implantation failure and reduces litter size. Objective: We evaluated the association of urinary BPA concentrations with implantation failure among women undergoing in vitro fertilization (IVF). Methods: We used online solid phase extraction–high performance liquid chromatography–isotope dilution tandem mass spectrometry to measure urinary BPA concentrations in 137 women in a prospective cohort study among women undergoing IVF at the Massachusetts General Hospital Fertility Center in Boston, Massachusetts. We used logistic regression to evaluate the association of cycle-specific urinary BPA concentrations with implantation failure, accounting for correlation among multiple IVF cycles in the same woman using generalized estimating equations. Implantation failure was defined as a negative serum β-human chorionic gonadotropin test (β-hCG < 6 IU/L) 17 days after egg retrieval. Results: Among 137 women undergoing 180 IVF cycles, urinary BPA concentrations had a geometric mean (SD) of 1.53 (2.22) µg/L. Overall, 42% (n = 75) of the IVF cycles resulted in implantation failure. In adjusted models, there was an increased odds of implantation failure with higher quartiles of urinary BPA concentrations {odds ratio (OR) 1.02 [95% confidence interval (CI): 0.35, 2.95}, 1.60 (95% CI: 0.70, 3.78), and 2.11 (95% CI: 0.84, 5.31) for quartiles 2, 3, and 4, respectively, compared with the lowest quartile (p-trend = 0.06). Conclusion: There was a positive linear dose–response association between BPA urinary concentrations and implantation failure.

Association of Exposure to Phthalates with Endometriosis and Uterine Leiomyomata: Findings from NHANES, 1999–2004

Background Phthalates are ubiquitous chemicals used in consumer products. Some phthalates are reproductive toxicants in experimental animals, but human data are limited. Objective We conducted a cross-sectional study of urinary phthalate metabolite concentrations in relation to self-reported history of endometriosis and uterine leiomyomata among 1,227 women 20–54 years of age from three cycles of the National Health and Nutrition Examination Survey (NHANES), 1999–2004. Methods We examined four phthalate metabolites: mono(2-ethylhexyl) phthalate (MEHP), monobutyl phthalate (MBP), monoethyl phthalate (MEP), and monobenzyl phthalate (MBzP). From the last two NHANES cycles, we also examined mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP). We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for potential confounders. Results Eighty-seven (7%) and 151 (12%) women reported diagnoses of endometriosis and leiomyomata, respectively. The ORs comparing the highest versus lowest three quartiles of urinary MBP were 1.36 (95% CI, 0.77–2.41) for endometriosis, 1.56 (95% CI, 0.93–2.61) for leiomyomata, and 1.71 (95% CI, 1.07–2.75) for both conditions combined. The corresponding ORs for MEHP were 0.44 (95% CI, 0.19–1.02) for endometriosis, 0.63 (95% CI, 0.35–1.12) for leiomyomata, and 0.59 (95% CI, 0.37–0.95) for both conditions combined. Findings for MEHHP and MEOHP agreed with findings for MEHP with respect to endometriosis only. We observed null associations for MEP and MBzP. Associations were similar when we excluded women diagnosed > 7 years before their NHANES evaluation. Conclusion The positive associations for MBP and inverse associations for MEHP in relation to endometriosis and leiomyomata warrant investigation in prospective studies.

Hormone replacement therapy, cancer, controversies, and women’s health: historical, epidemiological, biological, clinical, and advocacy perspectives

Routine acceptance of use of hormone replacement therapy (HRT) was shattered in 2002 when results of the largest HRT randomised clinical trial, the women’s health initiative, indicated that long term use of oestrogen plus progestin HRT not only was associated with increased risk of cancer but, contrary to expectations, did not decrease, and may have increased, risk of cardiovascular disease. In June 2004 a group of historians, epidemiologists, biologists, clinicians, and women’s health advocates met to discuss the scientific and social context of and response to these findings. It was found that understanding the evolving and contending knowledge on hormones and health requires: (1) considering its societal context, including the impact of the pharmaceutical industry, the biomedical emphasis on individualised risk and preventive medicine, and the gendering of hormones; and (2) asking why, for four decades, since the mid-1960s, were millions of women prescribed powerful pharmacological agents already demonstrated, three decades earlier, to be carcinogenic? Answering this question requires engaging with core issues of accountability, complexity, fear of mortality, and the conduct of socially responsible science.

Relationship between caffeine intake and plasma sex hormone concentrations in premenopausal and postmenopausal women.

Circulating estrogens and androgens are important factors in the development of various female cancers. Caffeine intake may decrease risk of breast and ovarian cancer, although the data are not entirely consistent. Whether or not caffeine affects cancer risk by altering sex hormone levels is currently unknown.