Marcella Warner

EPIDEMIOLOGY OF ENDOMETRIOSIS

This article summarizes present knowledge about the epidemiology of endometriosis. Surprisingly, little is known about the prevalence or risk factors of endometriosis, given the medical care and employment costs. Knowledge about the epidemiology of endometriosis is hampered by the inability to diagnose this disease in the general population. Based on a single cohort study, it is estimated that there is a 10% prevalence of endometriosis in the general population. Age is the only sociodemographic characteristic for which a consistent positive relationship has been observed. In general, the risk of endometriosis appears to increase for reproductive health factors that may relate to increased exposure to menstruation (i.e., shorter cycle length, longer duration of flow, or reduced parity). The risk appears to decrease for personal habits that may relate to decreased estrogen levels (i.e., smoking, exercise).

Validation study of nonsurgical diagnosis of endometriosis

OBJECTIVE To determine whether the surgical diagnosis of endometriosis can be predicted using symptoms, signs, and ultrasound findings. DESIGN Prospective study (study sample); retrospective record review (test sample). SETTING Hospital of Desio (study sample) and Mangiagalli Hospital (test sample), Italy. PATIENT(S) Ninety women scheduled to undergo laparoscopy or laparotomy (study sample); 120 women who underwent laparoscopy (test sample). INTERVENTION The study sample group was interviewed before surgery about infertility and dysmenorrhea, dyspareunia, and noncyclic pelvic pain and each member had a pelvic examination and a transvaginal ultrasound. At surgery, endometriosis was noted. For the test sample, the same information was abstracted from medical records after laparoscopy. MAIN OUTCOME MEASURE(S) The ability of symptoms, signs, and ultrasound to predict endometriosis at surgery. A classification tree was developed with the study sample and evaluated with the test sample. RESULT(S) Ovarian endometriosis, but not nonovarian endometriosis, could be reliably predicted with noninvasive tools. Ultrasound and examination best predicted ovarian endometriosis, correctly classifying 100% of cases with no false positive diagnoses in the study sample. Similar results were found in the test sample. CONCLUSION(S) Noninvasive tools may be used to identify women with ovarian, but not nonovarian endometriosis, with excellent agreement with surgical diagnosis.

Uterine fibroids and gynecologic pain symptoms in a population-based study.

OBJECTIVE To determine the association between dyspareunia, dysmenorrhea, and noncyclic pelvic pain and the presence and characteristics of uterine fibroids. DESIGN Population-based cross-sectional study. SETTING Desio, Italy. PATIENT(S) Six hundred thirty-five non-care-seeking participants of the Seveso Womens Health Study with an intact uterus who underwent transvaginal ultrasound. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Ultrasound-detected presence of uterine fibroids and fibroid characteristics including volume, number, location, and position. Current dyspareunia, dysmenorrhea, and noncyclic pelvic pain was measured by self-report on a visual analog scale. RESULT(S) Uterine fibroids were detected in 96 women (15%). Women with fibroids were more likely to report moderate or severe dyspareunia (adjusted odds ratio [OR] = 2.8, 95% confidence interval [CI] = 0.9-8.3, statistically significant trend) and moderate or severe noncyclic pelvic pain (adjusted OR = 2.6, 95% CI = 0.9-7.6, statistically significant trend) than women without fibroids. Moderate or severe dysmenorrhea was not associated with the presence of fibroids (adjusted OR = 1.1, 95% CI = 0.5-2.6). Number and total volume of fibroids were not related to pain. CONCLUSION(S) This is the first population-based study of gynecologic pain symptoms and fibroids. Dyspareunia and noncyclic pelvic pain, but not dysmenorrhea, increased in severity with the presence of uterine fibroids. Fibroid-associated pain symptomatology in a non-care-seeking population may be different from that of a clinic population.

Use of the fluorescent micronucleus assay to detect the genotoxic effects of radiation and arsenic exposure in exfoliated human epithelial cells

The exfoliated cell micronucleus (MN) assay using fluorescent in situ hybridization (FISH) with a centromeric probe is a rapid method for determining the mechanism of MN formation in epithelial tissues exposed to carcinogenic agents. Here, we describe the use of this assay to detect the presence or absence of centromeric DNA in MN induced in vivo by radiation therapy and chronic arsenic (As) ingestion. We examined the buccal cells of an individual receiving 6,500 rads of photon radiation to the head and neck. Exfoliated cells were collected before, during, and after treatment. After radiation exposure a 16.6‐fold increase in buccal cell MN frequency was seen. All induced MN were centromere negative (MN −) resulting from chromosome breakage. This finding is consistent with the clastogenic action of radiation and confirmed the reliability of the method. Three weeks post‐therapy, MN frequencies returned to baseline. We also applied the assay to exfoliated bladder cells of 18 people chronically exposed to high levels of inorganic arsenic (In‐As) in drinking water (average level, 1,312 μg As/L) and 18 matched controls (average level, 16 μg As/L). The combined increase in MN frequency was 1.8‐fold (P = 0.001, Fishers exact test). Frequencies of micronuclei containing acentric fragments (MN −) and those containing whole chromosomes (MN+) both increased (1.65‐fold, P = 0.07, and 1.37‐fold, P = 0.15, respectively), suggesting that arsenic may have both clastogenic and weak aneuploidogenic properties in vivo. After stratification on sex, the effect was stronger in male than in female bladder cells. In males the MN‐frequency increased 2.06‐fold (P = 0.07) while the frequency of MN+ increased 1.86‐fold (P = 0.08). In addition, the frequencies of MN − and MN+ were positively associated with urinary arsenic and its metabolites. However, the association was stronger for micronuclei containing acentric fragments. By using FISH with centromeric probes, the mechanism of chemically induced genotoxicity can now be determined in epithelial tissues.

Dioxin Exposure and Cancer Risk in the Seveso Women’s Health Study

Background: 2,3,7,8-Tetrachlorodibenzo-para-dioxin (TCDD), a widespread environmental contaminant, disrupts multiple endocrine pathways. The International Agency for Research on Cancer classified TCDD as a known human carcinogen, based on predominantly male occupational studies of increased mortality from all cancers combined. Objectives: After a chemical explosion on 10 July 1976 in Seveso, Italy, residents experienced some of the highest levels of TCDD exposure in a human population. In 1996, we initiated the Seveso Women’s Health Study (SWHS), a retrospective cohort study of the reproductive health of the women. We previously reported a significant increased risk for breast cancer and a nonsignificant increased risk for all cancers combined with individual serum TCDD, but the cohort averaged only 40 years of age in 1996. Herein we report results for risk of cancer from a subsequent follow-up of the cohort in 2008. Methods: In 1996, we enrolled 981 women who were 0–40 years of age in 1976, lived in the most contaminated areas, and had archived sera collected near the explosion. Individual TCDD concentration was measured in archived serum by high-resolution mass spectrometry. A total of 833 women participated in the 2008 follow-up study. We examined the relation of serum TCDD with cancer incidence using Cox proportional hazards models. Results: In total, 66 (6.7%) women had been diagnosed with cancer. The adjusted hazard ratio (HR) associated with a 10-fold increase in serum TCDD for all cancers combined was significantly increased [adjusted HR = 1.80; 95% confidence interval (CI): 1.29, 2.52]. For breast cancer, the HR was increased, but not significantly (adjusted HR = 1.44; 95% CI: 0.89, 2.33). Conclusions: Individual serum TCDD is significantly positively related with all cancer incidence in the SWHS cohort, more than 30 years later. This all-female study adds to the epidemiologic evidence that TCDD is a multisite carcinogen.

Seveso Women's Health Study : a study of the effects of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin on reproductive health

Although reproductive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure have been reported in numerous investigations of animals, studies of this association in humans are limited. In 1976, an explosion in Seveso, Italy exposed the surrounding population to among the highest levels of TCDD recorded in humans. The relatively pure exposure to TCDD and the ability to quantify individual level TCDD exposure from sera collected in 1976 for the Seveso cohort affords a unique opportunity to evaluate the potential dose-response relationship between TCDD exposure and a spectrum of reproductive endpoints. The Seveso Womens Health Study (SWHS) is the first comprehensive study of the reproductive health of a human population exposed to TCDD. The primary objectives of the study are to investigate the relationship of TCDD and the following endpoints: (1) endometriosis; (2) menstrual cycle characteristics; (3) age at menarche; (4) birth outcomes of pregnancies conceived after 1976; (5) time to conception and clinical infertility; and (6) age at menopause. Included in the SWHS cohort are women who were 0-40 yr old in 1976, who have adequate stored sera collected between 1976 and 1980, and who resided in Zones A or B at the time of the accident. All women were interviewed extensively about their reproductive and pregnancy history and had a blood draw. For an eligible subset of women, a pelvic exam and transvaginal ultrasound were conducted and a menstrual diary was completed. More than 95% of the women were located 20 yr after the accident and roughly 80% of the cohort agreed to participate. Data collection was completed in July 1998, serum TCDD analysis of samples for analysis of endometriosis as a nested case-control study was completed in October 1998, and statistical analysis of these data should be completed in early 1999. Serum samples are now being analyzed in order to relate TCDD levels with the remaining reproductive outcomes.

Soda consumption and overweight status of 2-year-old mexican-american children in California

Objective: The prevalence of overweight in United States children, 2 to 5 years old, has increased 2‐fold since 1975, with the highest prevalence in Mexican Americans. The objective of this study was to determine the association between current soda consumption and overweight in 2‐year‐old Mexican‐American children.

Serum dioxin concentrations and age at menarche.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant, is associated with delays in pubertal development in animal studies. On 10 July 1976, as a result of a chemical explosion, residents of Seveso, Italy, experienced the highest levels of TCDD exposure experienced by a human population. Twenty years later, we initiated the Seveso Women’s Health Study (SWHS), a retrospective cohort study of female residents of the most contaminated areas, to determine whether the women were at higher risk for reproductive disease. We examined the association of TCDD serum levels, based on measurements in serum collected soon after the explosion, with reported age at menarche among the 282 SWHS women who were premenarcheal at the time of the explosion. We found no change in risk of onset of menarche with a 10-fold increase in TCDD (e.g., 10–100 ppt; hazard ratio = 0.95; 95% confidence interval, 0.83–1.09; p-value for trend = 0.46). When TCDD levels were categorized, there was also no evidence of a dose–response trend (p = 0.65). In summary, we found that individual serum TCDD measurements are not significantly related to age at menarche among women in the SWHS cohort. The women in this study experienced substantial TCDD exposure during the postnatal but prepubertal developmental period. Given that animal evidence suggests in utero exposure has the most significant effect on onset of puberty, continued follow-up of the offspring of the SWHS cohort is important.

Serum Dioxin Concentrations and Age at Menopause

2,3,7,8-Tetrachlorobenzo-p-dioxin (TCDD), a halogenated compound that binds the aryl hydrocarbon receptor, is a by-product of numerous industrial processes including waste incineration. Studies in rats and monkeys suggest that TCDD may affect ovarian function. We examined the relationship of TCDD and age at menopause in a population of women residing near Seveso, Italy, in 1976, at the time of a chemical plant explosion. We included 616 of the women who participated 20 years later in the Seveso Women’s Health Study. All women were premenopausal at the time of the explosion, had TCDD levels measured in serum collected soon after the explosion, and were ≥ 35 years of age at interview. Using proportional hazards modeling, we found a 6% nonsignificant increase in risk of early menopause with a 10-fold increase in serum TCDD. When TCDD levels were categorized, compared with women in the lowest quintile (< 20.4 ppt), women in quintile 2 (20.4–34.2 ppt) had a hazard ratio (HR) of 1.1 (p = 0.77), quintile 3 (34.3–54.1 ppt) had an HR of 1.4 (p = 0.14), quintile 4 (54.2–118 ppt) had an HR of 1.6 (p = 0.10), and quintile 5 (> 118 ppt) had an HR of 1.1 (p = 0.82) for risk of earlier menopause. The trend toward earlier menopause across the first four quintiles is statistically significant (p = 0.04). These results suggest a nonmonotonic dose-related association with increasing risk of earlier menopause up to about 100 ppt TCDD, but not above.

Diabetes, Metabolic Syndrome, and Obesity in Relation to Serum Dioxin Concentrations: The Seveso Women’s Health Study

Background: In animal studies, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters glucose transport and increases serum lipid levels and blood pressure. Epidemiologic evidence suggests an association between TCDD and metabolic disease. Objectives: On 10 July 1976, a chemical explosion in Seveso, Italy, resulted in the highest known residential exposure to TCDD. Using data from the Seveso Women’s Health Study (SWHS), a cohort study of the health of the women, we examined the relation of serum TCDD to diabetes, metabolic syndrome, and obesity > 30 years later. Methods: In 1996, we enrolled 981 women who were newborn to 40 years of age in 1976 and resided in the most contaminated areas. Individual TCDD concentration was measured in archived serum that had been collected soon after the explosion. In 2008, 833 women participated in a follow-up study. Diabetes was classified based on self-report or fasting serum glucose and glycated hemoglobin levels. Metabolic syndrome was defined by International Diabetes Federation criteria. Obesity was defined as body mass index ≥ 30 kg/m2. Results: A 10-fold increase in serum TCDD (log10TCDD) was not associated with diabetes (adjusted hazard ratio = 0.76; 95% CI: 0.45, 1.28) or obesity [adjusted odds ratio (OR) = 0.80; 95% CI: 0.58, 1.10]. Log10TCDD was associated with metabolic syndrome, but only among women who were ≤ 12 years of age at the time of the explosion (adjusted OR = 2.03; 95% CI: 1.25, 3.29; pinteraction = 0.01). Conclusions: We found an increased prevalence of metabolic syndrome associated with TCDD, but only among women who were the youngest at the time of the explosion. Continued follow-up of the SWHS cohort will be informative.