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Hum. Reprod. Advance Access originally published online on October 23, 2007
Human Reproduction 2007 22(12):3232-3236; doi:10.1093/humrep/dem338
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© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Intrauterine exposures and risk of endometriosis

Germaine M. Buck Louis1,3, Mary L. Hediger1 and Josefa B. Peña2

1 Department of Health and Human Services, Epidemiology Branch, National Institute of Child Health & Human Development, 6100 Executive Blvd., Room 7B03, Rockville, Maryland 20852, USA 2 Department of Epidemiology and Biostatistics, School of Rural Public Health, Texas A & M University Health Science Center, College Station, Texas 77843, USA

3Correspondence address. Tel: +1-301-496-6155; Fax: +1-301-402-2084; E-mail: louisg{at}mail.nih.gov


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
BACKGROUND: Intrauterine environmental exposures have been adversely associated with male reproductive health in contrast to limited investigation of such exposures and female reproductive health.

METHODS: To address this research gap, a cohort comprising 84 women aged 18–40 years undergoing laparoscopy was recruited prior to surgery and followed through the post-operative period for endometriosis diagnosis. Women were interviewed about environmental exposures and those of their mothers while pregnant with them (use of alcohol, caffeinated beverages and cigarettes). Endometriosis was diagnosed in 32 women from the laparoscopy cohort; 52 women had no endometriosis visualized. Using unconditional logistic regression, odds ratios (OR) and 95% confidence intervals (CIs) were estimated for the intrauterine exposures adjusting for potential confounders.

RESULTS: No significant associations were seen between intrauterine exposure to alcohol or caffeine and a diagnosis of endometriosis. Adjusting for age, significant reductions in odds of an endometriosis diagnosis were observed for intrauterine cigarette exposure both in the absence (OR 0.22, 95% CI 0.06–0.82) or presence (OR 0.05, 95% CI 0.01–0.42) of women’s current smoking.

CONCLUSIONS: While speculative, in utero cigarette exposure may be associated with a lower risk of surgically diagnosed adult-onset endometriosis, possibly as a result of alterations in hormonal milieu or pathologic angiogensis.

Key words: angiogenesis/cigarette smoking/endometriosis/gynecologic health/intrauterine


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
A rapidly evolving body of evidence suggests that environmental exposures, particularly those occurring in utero, may adversely affect fetal growth and development and, thereby, permanently and irreversibly reprogram the developing organism for adult onset disease (Barker, 1992Go). The testicular dysgenesis hypothesis postulates that male fecundity may be adversely affected by in utero alterations in hormonal milieu following exposure to exogenous environmental agents (Skakkebaek et al., 2001Go) manifesting as secular increases in the rates of testicular cancer (Moller, 1998Go), hypospadias (Paulozzi et al., 1997Go), undescended testes (Chilvers et al., 1984Go) and declining semen quality (Carlsen et al., 1992Go). The causal ordering of these events in recent years is consistent with an in utero origin, given that men with fecundity impairments including those arising from genital-urinary malformations are at increased risk for testicular cancer (Berkowitz et al., 1995Go; Prener et al., 1996Go; Baker et al., 2005Go).

The extent to which in utero exposures may impact female fecundity as measured by gynecologic health endpoints are largely unknown, with noticeably few publications focusing on this question. While two recent reviews summarized the literature focusing on hormonally active environmental chemicals and female fecundity and fertility (Torf et al., 2005Go; Buck Louis et al., 2006Go), noticeably absent are studies focusing on the role of in utero exposures in the development and expression of endometriosis, other than two recent papers. Missmer et al. (2004)Go utilized data from the Nurses Health Study II to estimate the incidence of laparoscopically-confirmed endometriosis in relation to diethylstilbestrol (DES) exposure and reported an 80% increase in the rate of endometriosis among exposed women in comparison to unexposed women. In addition, incidence of endometriosis increased 30% for women with birth weights <5.5 pounds and 70% for women born as a part of a multiple birth in comparison to referent women. Hediger et al. (2005)Go reported that women diagnosed with laparoscopically-visualized endometriosis were found to have a lower body mass index (BMI, leaner body habitus) from adolescence through diagnosis suggesting an in utero or early childhood origin for endometriosis.

To address the critical data gap regarding a possible in utero origin of endometriosis, we sought to assess such exposures in relation to odds of endometriosis diagnosis in a cohort of women undergoing laparoscopy for diagnostic or therapeutic indications.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Funding
 Acknowledgements
 References
 
Study cohort
The referent cohort comprised 100 women aged 18–40 years undergoing incident laparoscopy for any gynecologic indication including sterilization between April 1999 and January 2000. The distribution of preoperative diagnoses for the 84 women comprising the study cohort included: suspected endometriosis (n = 28); infertility or pelvic pain (n = 26); tubal ligation (n = 23); pelvic inflammatory disease (n = 4) and polycystic ovaries or fibroids (n = 3). Participating surgeons introduced the study to eligible women and ascertained their approval for release of contact information to study personnel. Subsequently, a research assistant, who was blinded to women’s preoperative diagnosis, contacted participants to further inform them about the study and to elicit their participation. All participating women provided informed consent consistent with the human subjects’ approval protocol given for the conduct of this study. A more complete description of the study cohort has previously been published (Buck Louis et al., 2005).

Data collection
Women participated in standardized interviews, conducted prior to surgery, designed to elicit information on sociodemographic and lifestyle characteristics and on reproductive and medical history. Particular attention was paid to in utero exposures, defined as behaviors of their mothers while pregnant with the study participant. Specifically, women were queried on four intrauterine exposures using the following question format:

To the best of your knowledge, did your mother: (i) smoke cigarettes; (ii) drink alcoholic beverages; (iii) drink caffeinated beverages or (iv) use diethylstilbestrol (DES) while pregnant with you?

Response options for each exposure were ‘yes’, ‘no’ or ‘unsure’. ‘Yes’ denoted in utero exposure, while ‘no’ indicated no exposure; there were no ‘unsure’ responses given to these questions. In an attempt to delineate intrauterine exposure from current exposure, women were queried about their own current usage of cigarettes (number smoked per day); average number of monthly alcoholic beverages consumed during the past year and the daily average number of cups of coffee or tea and/or glasses of caffeinated soft drinks. Information on ever smoked (at least 100 cigarettes lifetime) and whether or not the women had smoked in the past year was also elicited. Other study covariates included gravidity (number of pregnancies), parity (number of live births) and self-reported BMI (weight in kilograms/height in meters2), given their reported association with endometriosis (McCann et al., 1993Go; Batt et al., 1997Go). BMI was subsequently categorized as: <25 kg/m2 (normal weight); 25.0–29.9 25 kg/m2 (overweight) and >30.0 25 kg/m2 (obese) (National Institutes of Health, 1998Go).

Operative procedures
Participating laparoscopic surgeons (n = 3) inspected the pelvis for endometriosis regardless of preoperative diagnosis and staged it according to the revised American Fertility’s Society classification (American Society for Reproductive Medicine, 1997Go): stage I (minimal), stage II (mild), stage III (moderate) and stage IV (severe). Surgeons were blinded, to the extent possible, with regard to the information (including smoking) reported by women during the baseline interview. Laparoscopic-confirmed endometriosis was observed in 32 women of which 15 women had minimal, 5 had mild, 6 had moderate and 6 had severe disease. No endometriosis was observed in 52 women, including 30 women with other gynecologic pathology (e.g. fibroids, polycystic ovaries, pelvic inflammatory disease and idiopathic infertility) and 22 women without any pathology observed (undergoing tubal sterilization procedures).

Statistics
Descriptive analyses included inspecting the data for completeness and valid ranges for all covariates. Women with and without gynecologic pathology other than endometriosis were compared in relation to the exposures and other relevant covariates to assess comparability and the eventual merging of group. No significant differences were observed so the two groups were merged.

Using unconditional logistic regression, we estimated the odds of an endometriosis diagnosis in relation to each of the four in utero exposures, current exposures and other covariates, such as age and parity. Odds ratios (OR) and 95% confidence intervals (95% CIs) were estimated separately for each of the four in utero exposures. For cigarette smoking, joint effects were estimated using women who were both unexposed in utero and current non-smokers as the referent. The inclusion of age as a covariate significantly affected the OR and was retained in the model. No evidence of confounding was observed for parity; hence, it was not considered further in the analysis. CIs exclusive of unity were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Funding
 Acknowledgements
 References
 
The study cohort comprised mostly non-Hispanic white women (89%) who were largely married or living as married (78%) with a mean (±SD) age of 32 (±5) years. As Table I reflects, women with endometriosis were significantly different from women without disease in that they were more likely to have college educations, to have lower mean BMI, and to have diminished fecundity (later age at menarche and first intercourse) and fertility (lower gravidity and parity).


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  		Table I. Sociodemographic and reproductive characteristics of women visually diagnosed with (n = 32) or without (n = 52) endometriosis at laparoscopy.

 
In utero exposure to cigarette smoke, alcohol and caffeine were associated with reductions in the odds of an endometriosis diagnosis, though only the CI for smoking excluded unity (Table II). Only two women without endometriosis reported in utero DES exposure resulting in no further analysis. With regard to current usage of cigarettes or alcoholic or caffeinated beverages, only cigarette smoking significantly reduced the odds of an endometriosis diagnosis by ~70% (OR 0.3, 95% CI 0.1–0.8).


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  		Table II. Comparison of in utero and current environmental exposures by disease status.

 
Table III presents the adjusted OR (AOR) for combined in utero and current exposure to cigarette smoking controlling for age (in years) and using women without either exposure as the referent group. As anticipated, current cigarette smoking in the absence of in utero exposure was associated with a decreased odds of an endometriosis diagnosis (AOR 0.21, 95% CI 0.05–0.87). Moreover, in utero exposure in the absence of current smoking was equally associated with a reduced odds of an endometriosis diagnosis by ~78% (AOR 0.22, 95% CI 0.06–0.82), and by 95% (AOR 0.05, 95% CI 0.01–0.42) for combined in utero and current cigarette smoking.


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  		Table III. Risk of endometriosis diagnosis by intrauterine and current cigarette smoking exposure.

 
To further explore the association between smoking and severity of endometriosis, we estimated odds of endometriosis diagnosis controlling for age among women with stages III and IV in comparison to women without a diagnosis. Both in utero and current smoking conferred reductions in the odds of an endometriosis diagnosis (0.20 and 0.39, respectively). This reduction in the OR remained when women with stages III and IV were compared with all other women (0.29 and 0.61, respectively). All CIs were wide and included one, reflecting the limited sample size, which precluded our ability to assess the joint effects of in utero and current smoking by severity of disease.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Funding
 Acknowledgements
 References
 
The results of this study affirm previous findings that current cigarette smoking is associated with a reduced likelihood of an endometriosis diagnosis (Cramer et al., 1986Go; Missmer and Cramer, 2003Go) while providing new evidence that this protective effect may arise independently in utero with exposure through one’s mother. To our knowledge, this is the first paper to report a relation between intrauterine cigarette exposure and laparoscopy-confirmed endometriosis. However, caution is needed in the full interpretation of these findings, given the use of retrospectively reported data on cigarette smoking and other study covariates, the absence of biomarker-confirmed exposure status and the potential for residual confounding.

The absence of previous findings focusing on in utero smoking exposures limits our ability to fully interpret the results, especially given the dynamic and complex nature of endometriosis whose etiology and pattern of expression remain unknown despite numerous hypothesized etiologies and an inconsistent epidemiology. The magnitude (80–95%) of our observed protective smoking effect is intriguing yet concerning, given the well established health risks associated with smoking. However, similar protective effects have been reported for smoking and gravid health conditions such as gestational hypertension and preeclampsia (England et al., 2002Go; Hammoud et al., 2005Go). More intriguing is a recent study reporting a lower incidence of preeclampsia and pregnancy-induced hypertension among women with endometriosis-associated infertility (0.8 and 3.5%, respectively) undergoing IVF in comparison to women with male-factor infertility, i.e. 5.8 and 8.7%, respectively (Brosens et al., 2007Go).

Since endometriosis is typically characterized as an estrogen-dependent disease, one possible explanation for the protective role of cigarette smoking may be attributed to the hypoestrogenic state it can induce in some women. Lower urinary concentrations of estrone, estradiol and estriol have been observed in premenopausal women who smoke in comparison with non-smokers (MacMahon et al., 1982Go). Two components of cigarette smoke—nicotine and cotinine—have been reported to interfere with steroid synthesis and, thereby, impair the conversion of androgens into estrogens (Barbieri et al., 1986Go). These mechanisms may underlie the observed irregularities in menses associated with cigarette smoking including those consistent with the retrograde menstruation hypothesis (Sampson, 1927Go). The relatively low prevalence of menstruating women diagnosed with endometriosis challenge a more complete interpretation regarding menstrual cycle characteristics and risk of endometriosis.

Angiogenesis may be another explanation, building upon earlier work supportive of a relation with preeclampsia (Levine et al., 2006Go), menorrhagia and endometriosis (McLaren et al., 1996Go; Healy et al., 1998Go). The uterus and ovaries undergo cyclic angiogenesis (Strowitzki et al., 2006Go) regulated by the ratio of pro- and anti-angiogenic molecules [e.g. vascular endothelial growth factor (VEGF) and its receptors, angiopoietins (Ang), cytokines, chemokines, enzymes and coagulation factors] whose primary target is the endothelial cells. Disturbances in this ratio may result in pathologic angiogenesis manifesting in a number of ways including, but not limited to, endometriosis or preeclampsia. Consistent with the angiogenesis hypothesis is recognition that ectopic endometrial explants require neovascularization for their establishment, proliferation and invasion into the peritoneal cavity. Women with endometriosis are reported to have enhanced expression of angiogenic factors (e.g. Ang, cytokines and VEGF) in comparison with unaffected women (Taylor et al., 2002Go).

Gonadotropins and nicotine also have angiogenic properties. Gonadotropins, long known for their role in steroidogenesis, are reported to play a role in the regulation of vascular growth possibly by influencing the expression of VEGF and its receptors and modulating Ang (Reisinger et al., 2007Go). The mechanisms underlying the relation between gonadotropins and endometrial angiogenesis remain unknown. Nicotine is reported to have pro-angiogenic properties (Heeschen et al., 2001Go), but may impact development of endometriosis through altered immune function evident by a reduction in the number and cytotoxic activity of natural killer cells (Zeidel et al., 2002Go) or decreased T-cell mitogen response (Sopori, 2002Go). Among women undergoing IVF, smokers were reported to have higher concentrations of VEGF’s soluble fms-like tyrosine receptor in their follicular fluid than non-smokers. The anti-angiogenic action of this molecule may decrease ovarian vascularization and oocyte maturation (Motejlek et al., 2006Go). Nicotine, a major component of cigarette smoke, has recently been identified as a potent angiogenic agent capable of promoting pathologic angiogenesis, by accelerating tumor growth and atherosclerotic plaque progression (Cooke and Bitterman, 2004Go).

The relation between cigarette smoking and other xenobiotics agents such as environmental chemicals requires further study, given that women in this cohort with serum polychlorinated biphenyl (PCB) concentrations in the highest tertile were approximately three times more likely to have endometriosis in comparison to women in the lowest tertile (Buck Louis et al., 2005Go). While beyond the scope of this paper, further study of cytochrome P450 (CYP) enzymes appears warranted, given their role in metabolizing xenobiotics agents and a host of cellular functions including steroid synthesis and metabolism (Nebert and Dalton, 2006Go). Cigarette smoke and select congeners of PCBs have both been shown to be potent inducers of CYP1 enzymes (Boden et al., 1995Go; Safe and Krishnan, 1995Go) and may account for the many adverse reproductive and developmental effects associated with exposure.

In sum, our findings allow us to speculate that the in utero environment may be important for the development of endometriosis, but fall short of identifying the relevant mechanisms. The strong statistically protective effects observed for both in utero and current cigarette smoking and risk of endometriosis diagnosis require corroboration and further consideration with regard to disturbances in both angiogenesis and hormonal milieu during sensitive windows of human development. Ideally, a life course approach (Ben-Shlomo and Kuh, 2002Go) suitable for the collection of data and biospecimens across a continuum of sensitive windows is needed. Absent this, consideration of gynecologic diseases that share a similar etiology or that may be in the causal pathway of pregnancy related disorders is warranted, and may lead to new clues about the etiology of a spectrum of diseases affecting women of reproductive age and the parturient woman.


   Funding
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Funding
Acknowledgements
 References
 
National Institute of Environmental Health Sciences (1R01ES09 044-01) and the Intramural Research Program (HD008730) of the National Institute of Child Health and Human Development.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Funding
 Acknowledgements
References
 
The authors thank Dr Richard Levine for his helpful comments on an earlier version of the paper.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
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Submitted on August 21, 2007; resubmitted on September 19, 2007; accepted on September 27, 2007.


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