Endometriosis: Pathogenesis and Treatment 2014 Ed.

18. Prevention of Endometriosis

Ebru H. Biberoglu  and Kutay O. Biberoglu 

(1)

Dr. Zekai Tahir Burak Women Health Care, Education and Research Hospital Ankara, Ankara, Turkey

(2)

Gazi University Medical School, Professor of Obstetrics and Gynecology, Gynecological Endocrinology and Infertility Unit Besevler, Ankara, Turkey

Ebru H. Biberoglu (Corresponding author)

Email: ebru2513@gmail.com

Kutay O. Biberoglu

Email: kobiber@gmail.com

Abstract

There is an association between the presence of endometriosis and common autoimmune and atopic diseases and some of the cancers. There are also concerns about the risk for birth defects in the children of women with endometriosis. Prevention of endometriosis may also reduce the risk for these other health problems and their sequelae. To be able to prevent or delay the development of endometriosis and hopefully other associated comorbidities, risk factors for endometriosis should be defined. Exposure to environmental chemicals recently has been proposed to contribute to several gynecologic pathologies including endometriosis, especially when exposures occur during critical periods of development. Although potential role in the pathogenesis of endometriosis has not been established, exposure to certain endocrine-disrupting chemicals is shown to be higher in women affected by endometriosis compared to women without the disease. Although there is extensive scientific and clinical data applicable to endometriosis when it is regarded as a systemic inflammatory, endocrine, and immunological disease, the prevention of endometriosis per se, have not been addressed fully in the medical literature.

Keywords

ChemicalsEndometriosisEnvironmentLife styleNutritionPrevention

18.1 Risk Factors

Although science has not yet addressed directly, there are extensive scientific and clinical resources applicable to the prevention of endometriosis, especially when regarded as the systemic inflammatory, autoimmune and endocrine disease. Further, dioxin and endocrine-disrupting environmental toxicants that modify the inflammatory process have been strongly associated with endometriosis [1].

Endometriosis shares pathophysiological characteristics such as immune response alterations, increased inflammation, elevated levels of tissue-remodeling components, altered apoptosis, increased local and/or systemic levels of cytokines.

Growth factors including fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor-h (IGF-h) and granulocyte/macrophage-colony-stimulating factor (GM-CSF) and inflammatory mediators like IL-1, TNF-a, IL-2, IL-6, IL-8, IL-10, IL-11, MCP-1, and interferon-g (IFN-g) produced by peritoneal leukocytes are all elevated in the peritoneal fluid of women with endometriosis.

There is an association between the presence of endometriosis and common autoimmune and atopic diseases, such as systemic lupus erythematosus, Sjögren’s syndrome, rheumatoid arthritis, Crohn’s disease, psoriasis. chronic fatigue immune dysfunction syndrome, multiple sclerosis, hypothyroidism and fibromyalgia. Research has suggested that endometriosis may increase the risk of ovarian and breast cancer, non Hodgkin’s lymphoma, melanoma, thyroid, kidney and brain tumors. There are also concerns about the risk for birth defects in the children of women with endometriosis. Therefore, prevention of the disease processes involving endometriosis may also reduce the risk for these other health problems and their sequelae [13].

To be able to prevent or delay the development of endometriosis and hopefully other associated comorbidities, known risk factors for endometriosis should be defined at the first place. The plethora of risk factors for endometriosis may reflect varying methodologies such as study populations, definitions utilized for risk factors, and diagnostic accuracy. Infertility by itself is a significant risk factor for endometriosis. An infertility history increases the odds of an endometriosis diagnosis in both the operative (OR, 2.43; 95 % CI, 1.57–3.76) and population (OR, 7.91; 95 % CI, 1.69–37.2) cohorts [4]. Increasing age, alcohol use, early menarche, family history of endometriosis, infertility, intercourse during menses, low body weight, prolonged menstrual flow, and short cycle interval are known risk factors [58]. Endometriosis has been negatively associated with exercise and smoking [9]. Recently, red hair [10], blue or green eyes, and freckles have been reported to increase the odds of diagnosis [11]. It is possible that there may not be a classic set of risk factors generic to all women with endometriosis. Rather, risk factors may need tailoring to the subgroups of women by their behavioral and clinical characteristics.

18.1.1 Family History

First degree relatives of a woman with endometriosis carry 4–10 times higher risk of also having endometriosis when compared to the general population. Candidate genes such as ESR1, COMT, IL6, IL10, CYP17A1, CYP19A1, CYP1A1, MMP1, and MMP9 studied in genomic DNA showed no association with endometriosis [12].

In more than 1,000 families with two or more members with surgically documented endometriosis from Australia and the UK, significant linkage to 10q26 and 20p13 was demonstrated. However, no causative gene was identified [13]. It is likely that endometriosis is a common polygenic/multifactorial disease caused by an interaction between genes as well as the environment [1415].

18.1.2 Menstrual Cycle Characteristics

Early age at menarche (≤11 years old) might increase a woman’s exposure to menstruation during her reproductive lifetime and consequently increase the risk of endometriosis. The data, however, do not present strong evidence for the clinical utility of a history of early menarche in the evaluation of endometriosis [16]. The lowest risk was seen in those whose age at menarche was 15 years [17].

Increased exposure to menstruation in terms of short cycle length, long duration of flow, and low parity have frequently been identified as possible risk factors. The use of tampons does not seem to confer a risk for endometriosis.

Dysmenorrhea is likely to be a precursor to disease development, and shorter cycles may possibly suggest increased risk [1819].

In contrast to past studies, data of a recent study found no relationship between endometriosis and menstrual cycle history, including age at menarche, average cycle length, and number of menstrual cycles in the past 12 months. However, >80 % of the women in all groups in this study had a history of oral contraceptive use. This contraceptive use may have altered both recent menstrual cycle patterns or possibly the presence or absence of endometriosis [4].

Therefore, the potential role of menstrual cycle characteristics in the actual development of endometriosis remains an open question. At best they may be used to guide diagnostic and therapeutic strategies if other symptoms point to endometriosis as a possible diagnosis.

18.1.3 Lean Body Mass

Several studies have found that a lower body mass index (BMI) during adolescence and early adulthood is a risk factor for endometriosis. Taller women tend to have higher follicular-phase estradiol levels and thus may have an increased risk of endometriosis. This evidence was supported by a retrospective study that found that women with endometriosis have lower BMI and are less frequently obese than control subjects [20]. Indeed, for every unit increase in BMI, 12–14 % decrease in the likelihood of having endometriosis was claimed [21]. In a recent study, BMI (OR, 0.95; 95 % CI, 0.93–0.98) was found to decrease the odds of diagnosis of endometriosis [4]. The 20 years follow-up within the Nurses’ Health Study II prospective cohort revealed that BMI at age 18 and current BMI were each significantly inversely associated with endometriosis (P < 0.0001). Both associations were stronger among infertile women. Obese infertile women with current BMIs of 35–39.9 kg/m2 and ≥40 kg/m2 had a 55 % (95 % CI 0.30–0.67) and a 62 % (95 % CI 0.23–0.62) lower risk of endometriosis, respectively, compared with the low-normal BMI referent (18.5–22.4 kg/m2). Rates of endometriosis were nearly threefold higher in women with waist-to-hip ratios,0.60 (RR = 2.78, 95 % CI 1.38–5.60) compared with those with waist-to-hip ratios between 0.70 and 0.79 [22].

18.1.4 DES Exposure

The incidence rates of diagnosis of laparoscopically confirmed endometriosis was found to be 80 % greater among women exposed to diethylstilbestrol (DES) (RR = 1.8, CI = 1.2–2.8) [23]. Exposure to DES in utero has been associated with cervical stenosis, uterine smooth muscle abnormalities, and altered estrogen receptor expression in both mice and women [24]. In addition, it was reported that exposed women with vaginal epithelial changes had 50 % more autoimmune disease than exposed women without vaginal epithelial changes [25]. Therefore the relation between DES exposure and endometriosis may result from a combined effect of increased retrograde menstruation, immune dysfunction, and exogenous estrogen exposure.

18.1.5 Environmental Exposures

Endocrine-disrupting chemicals (EDC) directly through induction of gene expression or indirectly impair female reproduction by interfering with the production, release, transportation, metabolism, action, or elimination of natural hormones. Also the neuroendocrine (monitoring the environment and sending signals to the endocrine system) and the epigenetic (altering transcriptional capabilities without changing DNA sequence) routes could have been involved in the pathogenesis. In epigenetic disruption, the chemicals modify histones altering the DNA–nuclear protein interactions or promote DNA methylation. Most importantly, the resultant chromatin modifications can be passed on to future generations and increase the likelihood of a disease state later in life across several generations [2627].

Although potential role in the pathogenesis of endometriosis has not been established, exposure to certain EDCs is shown to be higher in women affected by endometriosis compared to women without the disease [2831].

A recent study demonstrated that infertile patients affected by endometriosis had higher percentage of serum sample with bisphenol A (BPA), perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), di-(2-ethylhexyl) phthalate (DEHP) and mono-ethylhexyl phthalate (MEHP) levels compared with infertile patients without endometriosis. The study group of infertile patients had also a significantly higher expression of several nuclear receptors that represent potential EDC targets, namely, estrogen receptor alpha (ERa) and beta (Erb), androgen receptor (AR), pregnane X receptor (PXR), aryl hydrocarbon receptor (AhR), and peroxisome proliferator-activated receptor gamma (PPARg) [32].

While some evidence from laboratory animal studies suggests that endometriosis can be promoted by many organochlorines, a class of xenobiotic chemicals including the dioxin TCDD, the pesticides methoxychlor and dichlorodiphenyltrichloroethane (DDT), and many polychlorinated biphenyls (PCBs) with dioxin-like effects, some others fail to find any significant relationship between the two. The hypothesis that EDC exposure during embryogenesis increases susceptibility for endometriosis, but subsequent adult hormone, immune, and/or EDC irregularities are required for disease onset was supported by the finding of larger implanted endometriotic lesions when exposure of the fetus to the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on gestational day 8 was combined with the adult exposure in the mouse model [3334].

It is possible that fetal exposure to TCDD promotes adult endometriosis through altered P action, because PR expression is reduced in the uterus of adult mice that were exposed to TCDD in utero [35]. It is also possible that TCDD which is an immunosuppressant promotes endometriosis through altered immune function enabling establishment and growth of peritoneal endometriosis under the influence of E2, proangiogenic, proliferative, and antiapoptotic factors [36]. Alternatively, TCDD could activate specific signaling pathways causing overexpression of K-ras thereby promoting peritoneal endometriosis [37].

Endometriotic lesions have increased expression of aromatase and 17β-HSD type 1 and decreased expression of 17β-HSD types 2 and 4, resulting in an increase in production of E2 [38]. If this expression pattern is established during fetal development via epigenetic mechanisms, then endometriosis could manifest during adulthood after estrogenic exposures [39].

Studies have found increased risk of endometriosis-associated infertility among workers exposed to formaldehyde, video display terminals, chemical dusts, or organic solvents, and among workers in agricultural industries and occupations, in particular farmworkers. Having ever worked as a flight attendant, service station attendant, or health worker, particularly as a nurse or health aide, is associated with increased risk of endometriosis (flight attendant: OR 9.80, 95 % CI 1.08–89.02; service station attendant: OR 5.77, 95 % CI 1.03–32.43; health worker: OR 1.49, 95 % CI 1.03–2.15) [40].

18.1.6 Cigarette Smoking, Alcohol, and Caffeine

Active cigarette smoking in adulthood or adolescence, with the known antiestrogenic effect of inhaled tobacco smoke, has generally been associated with decreased endometriosis risk in previous research [9]. Whereas, a deleterious effect on endometriosis risk through exposure to polycyclic aromatic hydrocarbons [41] or dioxins [42] in tobacco smoke may dominate. A negative effect of passive smoking during childhood on endometriosis risk has also been suggested but further research is needed to confirm this relationship [43]. In a recent study where smoking habits in endometriosis patients are studied, no correlation between smoking habits and the risk of any form of endometriosis (superficial peritoneal endometriosis, ovarian endometriomas, and deep infiltrating endometriosis) and with the revised American Fertility Society stages or scores have been demonstrated [44]. Alcohol and caffeine consumption have also been shown to increase the risk of endometriosis. It is known that alcohol increases estrogen levels in the body and may disrupt the immune response during the menstrual cycle. The effect of caffeine is likely related to its influence on the immune system as well [45].

18.1.7 History of Allergic, Inflammatory, and Autoimmune Diseases

Alterations in inflammatory response and in both cellular/humoral immunity ends up with overproduction of prostaglandins, metalloproteinases, cytokines, and chemokines, thus favoring an optimal environment for the survival and proliferation of endometriotic implants [46]. This might explain why women with endometriosis report symptoms of not only pain but also of nervousness, tension, anxiety, headaches, depression, fatigue, insomnia, indigestion, bloating, recurrent vaginitis, recurrent cystitis, autoimmune diseases, asthma, and allergies [4748].

Women with endometriosis have a higher prevalence of allergies on medications, allergic rhinitis, asthma, and family history of allergic diseases compared to control subjects. In epidemiological studies, 48 % of women with endometriosis were reported to be allergic to at least one medication. Of these, 85 % had complaints of sinus and 14 % had suffered from asthma. Additionally, 80 % had a parent with allergic disease [49]. In another study, 61 % of the women with endometriosis reported allergies (compared with 18 % of the general female population), and 12 % had asthma (compared with 5 % of the general female population) [50]. In a recent study, a 4.6-fold increased frequency of allergic women with endometriosis compared with the control group was reported and the most prevalent allergen was found to be penicillin in this group [51].

Evidence available to date indicates that immune and inflammatory factors, whether they are released by immune or peritoneal, endometrial, and endometriotic cells, may play a critical role in the ectopic survival, implantation, and growth of endometrial tissue. Higher incidence of autoimmune diseases, abnormalities in T- and B-cell function, increased polyclonal B cell activity, high B-cell and T-cell counts, reduced natural killer (NK) cell activity, and the familial inheritance pattern and its recurring nature support an autoimmune aspect of endometriosis [47]. A recent genome-wide study suggests that endometriosis exhibits a gene expression signature in terms of increased presence and activation of plasma cells and macrophages and upregulation of complement system [52]. A macrophage product B lymphocyte stimulator (BLyS) which is a member of TNF superfamily is found to be elevated in the serum of women with in rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome [52] and with endometriosis in association with BLyS-817C⁄T polymorphism [53].

Recent studies support the contributing role of inflammation in endometriosis-related pain. The proinflammatory peptides facilitate endometriotic cell survival by stimulating cell proliferation and inhibiting apoptosis of endometriotic cells. The main cell processes that NF-κB regulates, contributing to endometriosis development, are inflammation, cell proliferation, and inhibition of apoptosis. Iron overload in the pelvic cavity of endometriosis patients is very probably an important facilitator or inductor of chronic NF-κB activation, enhancing the NF-κB-mediated inflammatory reaction and endometriotic cell survival and growth [54].

From the clinical perspective, patients with endometriosis have been shown to have a higher prevalence of several generalized autoimmune diseases, including systemic lupus, erythematosus, rheumatoid arthritis, and Sjogren’s syndrome, and also of irritable bowel syndrome, painful bladder syndrome, migraine head ache, and fibromyalgia [5557].

18.1.8 Fibromyalgia, Chronic Fatigue Syndrome, Irritable Bowel Syndrome, Painful Bladder Syndrome, and Migraine

In recent years, epidemiologic studies have identified an association between endometriosis and some other pain syndromes (such as fibromyalgia, chronic fatigue syndrome, interstitial cystitis, and irritable bowel syndrome) as well as various autoimmune and atopic conditions as already been discussed [50]. A recent study described a high prevalence of comorbid chronic pain syndromes (56 %) and mood disorders (48 %) in adolescents and young women with endometriosis [58]. Nevertheless, irritable bowel syndrome, painful bladder syndrome, and chronic headache were detected in 25 % versus 65 % [59]; in 16 % versus 65 % [60] and 19 % versus 38 % [61] in adolescent/young women compared to adult endometriosis patients, respectively. Fibromyalgia and chronic fatigue syndrome prevalences were found in 7 % and 4 % of young girls versus 6 % and 5 % of adult endometriosis women, respectively [50]. Women with endometriosis have a 30 % increased risk of migraines. There is also an increased prevalence of endometriosis in women with migraine. The subgroup of migraineurs with endometriosis is more likely to have other comorbid conditions affecting mood and pain [56]. Angiogenic cytokines are hypothesized to play a critical role in the pathogenesis of endometriosis and migraine, possibly by stimulating matrix metalloproteinases (MMPs) [62]. There may also be a neuro-immuno-endocrine link between endometriosis and migraine, fibromyalgia, irritable bowel syndrome, chronic fatigue syndrome, interstitial cystitis (painful bladder), and mood disorder through increased mast cell activation [63]. Mast cell activation without allergic degranulation has been documented to occur in response to stress and lead to painful sterile inflammatory states [64]. An increased prevalence of hypothyroidism, fibromyalgia and chronic fatigue syndrome, and autoimmune inflammatory diseases in women with endometriosis compared with the general female population was previously reported. The coexistence of all these conditions suggests an underlying role for the immune system in fibromyalgia and chronic fatigue syndrome [50].

18.1.9 Anatomical Obstruction of the Uterus and Surgical Scar Endometriosis

Sampson’s theory of retrograde menstruation and implantation is supported by evidence that obstructive Mullerian anomalies that enhance retrograde menstruation such as a narrowed or completely blocked cervix, a malformed or absent cervix, absence of the vagina, or a completely blocking hymen have been associated with endometriosis in adolescent women, and repair of these anomalies has been associated with resolution of endometriosis [6568].

Endometriosis has been reported at or near the site of surgical scars at the perineum, abdominal wall, even at the laparoscopic trocar port site, likely due to the mechanical transplantation of endometrial tissue during previous episiotomy, cesarean section, hysterectomy, hysteroscopy, tubal ligation, vulvar surgery, and accidental trauma [6973].

Timing of abdominal surgery was suggested to play role in the development of the disease. In women with endometriosis, the recurrence rate was higher in those who had surgery near the end of the menstrual cycle (days 22–28) than in those who had surgery earlier in their cycle [74].

18.1.10 Contraception

If nonsteroidal anti-inflammatory drugs fail in alleviating dysmenorrhea, oral contraceptive pills (OCP) are commonly offered to young women. The symptoms of dysmenorrhea usually disappear with the suppression of ovulation but recur once pill taking is discontinued [75]; therefore long-term use is recommended [76].

The risk of endometriosis appears to rise with greater lifetime number of ovulatory cycles. Besides suppressing ovulation, OCPs increase the low apoptotic activity of the endometrium of women with endometriosis [77]; progestins in OCPs prevent implantation of regurgitated endometrium, inhibit angiogenesis and also expression of matrix metalloproteinases, and reduce the inflammation of the endometriotic implants and the consequent immune response [78].

The findings of the reports studying the link between OCP and endometriosis are contradictory. Decreased [177980] or increased [8182] risk of endometriosis among OCP users have been published. On the other hand, some of the studies failed to find any association between the two [8384].

A cross-sectional study on a large series of patients revealed that past use of OCP if particularly given for treating severe dysmenorrhea was associated with all stages of endometriosis, especially deep infiltrative endometriosis (DIE) whereas no association was shown with endometriosis and current OCP use [85]. Meta-analysis are in agreement with decreased endometriosis prevalence in current but increased prevalence in past OCP users. Data from cohort studies (excluding case–control studies) demonstrate a protective effect of current OC use (relative reduction, 43 %; 95 % CI, 20–60 %), whereas previous use seems to increase the risk by 60 % (95 % CI from 40 to 82 %) [86]. The pill may reduce the risk of endometriosis by suppressing ovulation.

On the other hand, it was experimentally demonstrated that the regurgitated endometrial tissue into the peritoneum of castrated female monkeys survived only if estradiol was supplemented [87]. Therefore, it is quite possible that the estrogen in the pill may act as a rescue factor for regurgitated endometrial glands that would otherwise be resorped during hypo-estrogenic menstrual milieu.

The observed link might not be a causal one. It is well known that hormonal therapies are effective on pain symptoms [88], and women who receive OCP especially following failed NSAIDs for dysmenorrhea may already have developed endometriosis, but is still undiagnosed [89]. Since OCP use reduces pelvic pain symptoms, current users tend not to be investigated for endometriosis. On the other hand, women with endometriosis-induced dysmenorrhea might have been selectively excluded from the “never OC users” category, with a consequent increased risk for past users as a group.

In the end, it appears unlikely that OCs influence the risk of endometriosis to any great extent, because a consistent dose–response effect for lifetime duration of use has not been observed. Furthermore, also the pattern of risk with time since last use does not support a causal relationship [86].

If retrograde menstruation is involved in the etiology of endometriosis, exposure to nonhormonal intrauterine devices (IUD), by increasing the menstrual flow, may be a risk factor for endometriosis. The results of the studies are contradictory. Several studies have suggested that IUD use does not influence the development of endometriosis [819092]. Others have reported an increased prevalence of endometriosis among former IUD users [99394]. Even a weak protection has been observed in a subgroup for subjects who stopped using IUD more than 10 years ago [90].

There is no question that levonorgestrel-containing intrauterine systems (LNG IUS) which induce endometrial atrophy and decidual transformation of the stroma downregulate endometrial cell proliferation, increase apoptotic activity, which also has anti-inflammatory and immunomodulatory effects, and play a definite role in the treatment of endometriosis-associated symptoms [9596]. The LNG IUS also reduce the risk of recurrence of dysmenorrhea after conservative surgery for endometriosis [97].

Tubal ligation has been linked to development of endometriosis. Overall, no relationship between tubal ligation and prevalence of endometriosis was found in a group of women. On the other hand, tubal ligation was significantly associated with severity of disease [P = 0.036, crude OR (95 % CI) = 0.17 (0.02–0.85), adjusted OR (95 % CI) = 0.21 (0.04–1.08)]. In subgroups, moderate–severe endometriosis was found in 8.7 % and 36.4 % among patients with and without sterilization, respectively [98]. In another group of 3384 multiparous women who underwent tubal sterilization, endometriosis was detected in 126 patients (3.7 %), which was not different from the control group [92].

18.2 Boosting the Immune System and Reducing the Inflammation Stress

Activation of the hypothalamo–pituitary–adrenal (HPA) and sympathetic–adrenal–medullary axes in the presence of stress lead to abnormal corticotropin-releasing factor (CRF) secretion pattern, overexpression of glucocorticoid receptors, and chronic overreaction of the body’s stress system [99]. The release of cortisol also affects the immune system, in addition to its effects on the brain. Acute stressors are associated with an upregulation of the immune system, while prolonged increase in cortisol levels has been shown to depress immunologic function [100].

In women with chronic diseases such as gastrointestinal (GI) disorders causing chronic pelvic pain, chronic fatigue syndrome, dysmenorrhea, and mood disorders (e.g., anxiety, depression, posttraumatic stress syndrome), besides elevated levels of inflammatory cytokines, findings reflecting abnormal HPA responses and decreased cortisol levels have been reported. Chronic stress and hypocortisolism have been hypothesized to cause a deregulation in the neuroendocrine–immune axis leading to diseases including endometriosis. In fact, women with endometriosis have lower salivary and follicular fluid cortisol levels [101], but higher serum cortisol levels are detected in infertile women with advanced endometriosis [102]. It might be that other neuroendocrine factors, like CRF levels, could be more accurate and informative markers of HPA axis deregulation than systemic cortisol levels.

It is hypothesized that stressful life events can impact the immunological health of an individual. It is also known that endometriosis is associated with increased secretion of cytokines and impaired cell-mediated immunity, modulating the growth of ectopic endometrial implants [103]. The fibrosis and inflammation, particularly the mast cells in the infiltrate surrounding ectopic endometrial tissue, suggest that a hypersensitivity reaction, specifically, is strongly related to endometriosis [104105]. Increased activated and degranulating mast cells and its histological relationship with nerves in deeply infiltrating endometriosis lesions may be contributing to intense and typical deep pelvic pain [106107]

The increased frequency of having shorter cycle length which is a known risk factor for endometriosis in women with stressful jobs compared with those who did not consider their jobs stressful and twofold elevated dysmenorrhea prevalence in women reporting high levels of stress in the preceding menstrual cycle are indirect evidences supporting the link between stress and endometriosis [108109]. Although it is unknown whether stress is a causal or exacerbating factor in the development of endometriosis, establishment of psychological, behavioral, and stress-reduction interventions as part of multidisciplinary preventive management should be taken into consideration.

18.2.1 Vaccines

The use of bacillus Calmette–Guérin (BCG) and granulocyte–macrophage colony-stimulating factor (GM-CSF), among others, as boosters for the immune system in oncology cases, stimulated researchers to study their possible role in the prevention of endometriosis. In animal studies, systemic prophylaxis with BCG caused an inhibitory effect on endometrial transplantation [110].

The effects of mycobacteria in altering the ability of peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells to kill endometrial stromal cells have been assessed in in vitro model and endometrial stromal cell susceptibility to killer cells has been demonstrated [111].

Research on possible immunomodulatory role of pentoxifylline did not show any impact on future fertility in infertile women with asymptomatic minimal and mild endometriosis [112].

After vaccination with RESAN which is a complex of molecules extracted from xenogeneic tissues containing glycoproteins, peptides, and carbohydrate fragments of more than 40 different common tumor antigens, a reduction in endometriosis induction from 69.6 to 4.3 % was obtained in the rat model [113].

18.2.2 Retinoic Acid

Cytokines, chemokines, proteases, and angiogenic factors in the peritoneal cavity which are derived mainly from activated peritoneal macrophages promote the development and progression of endometriosis [114]. Defects in macrophage activation may lead to chronic immune activation with accompanying reduction in immune response contributing to the growth of endometriotic lesions [115]. Retinoic acid (RA) has been shown to modulate inflammation in autoimmune disease by enhancing regulatory T-cell (Treg) suppression of proinflammatory cells [116117]. In model systems involving activated monocytes/macrophages, RA decreases proinflammatory cytokines while increasing anti-inflammatory proteins such as interleukin-10 [118] also decrease the peritoneal fluid levels of interleukin-6 (IL-6) and macrophage chemotactic factor-1(MCP-1), which have been implicated in its pathogenesis of endometriosis [119]. These in vivo findings emphasize the potential use of retinoids to prevent and to treat women with endometriosis [120].

18.2.3 Melatonin as an Antioxidant

Proper regulation of matrix metalloproteinases (MMPs) is essential for physiological functioning of the endometrium, for invasion characteristics, and for remodeling of the extracellular matrix. Derangement of MMP regulation is critical in the development of endometriosis. Both MMP-2 and MMP-9 are activated by reactive oxygen species (ROS), and their expressions seem to be regulated by oxidant stress [121]. In the animal model, antioxidant enzymes like superoxide dismutase and catalase prevent intraperitoneal adhesions of endometriotic tissues in the peritoneal cavity [122].

Melatonin and its metabolites as antioxidants protect cellular components, stimulate secretion of progesterone, and have oncostatic, antiproliferative, and antiestrogenic effects [123124].

The role of melatonin in prevention and regression of endometriotic lesions is through upregulation of proMMP-9 and antiestrogenic activities. Also a new diagnostic marker, MMP-9/TIMP-1 (tissue inhibitors of matrix metalloproteinases) expression ratio in judging disease progression and severity have been demonstrated in animal model [125].

18.2.4 Anti-inflammatory Modulators

Endometriotic cells respond to TNF-α with increased secretion of MCP-1, which is a factor found to be elevated in peritoneal fluid of patients with endometriosis [126]. Experimental data emerging from treatments with anti-inflammatory modulators such as cyclooxygenase 2 inhibitors [127], peroxisome proliferator-activated receptor-γ agonist [128], and TNF-α inhibitors like TNFα-binding protein (TBP)-1, TNF-soluble high-affinity receptor complex, infliximab, and etanercept [129130] are promising and suggest potential for targeting the immune system to treat patients with endometriosis.

Macrophage migration inhibitory factor (MIF), an important regulator of the host immune system that promotes the proinflammatory functions of immune cells, plays a role in angiogenesis, tumorigenesis, as well as in many inflammatory and autoimmune diseases. Circulating and local peritoneal levels and expression of MIF which is a product of activated peritoneal macrophages are found to be elevated in the presence of early, vascularized, and most active endometriotic lesions. In in vivo model of endometriosis, ISO-1 [(S,R) 3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic methyl ester)], a highly specific inhibitor of MIF, has been shown to lead to regression of ectopic endometrial implants; downregulation of angiogenic, tissue remodeling, and survival factors such as integrins αv and β3, VEGF, IL8 and COX2; and the expressions of MMP2 and MMP9 and Bcl2 [131].

Several previous studies showed the benefit of targeting MIF and also of managing inflammatory diseases such as asthma, sepsis, and viral infection [132133].

18.2.5 25-Hydroxyvitamin D and Selective Vitamin D Receptor Agonist (VDR) as Immunoregulatory and Anti-inflammatory Agents

Endometriosis risk may be influenced by dietary vitamin D intake and plasma 25-hydroxyvitamin D concentration through immunomodulatory effects [134]. In a large prospective study, a significantly lower rate of laparoscopically confirmed endometriosis among women with greater predicted plasma 25(OH)D levels and among women with a higher intake of dairy foods has been demonstrated. Calcium, vitamin D, and magnesium intakes from foods were also inversely related to endometriosis [135]. Several other studies reported contradictory results [136138]. Moreover, data in humans suggest that high magnesium intake may be associated with lower levels of inflammatory markers, including interleukin-6 and tumor necrosis factor alpha receptor 2 [139]. Magnesium has also been shown to relax smooth muscles [140] and as a result may influence endometriosis through its effect on retrograde menstruation.

Several immunomodulatory effects could be mediated by the capacity of VDR agonists to inhibit the NF-κB [141142]. In addition, the inhibition of leucocyte infiltration into inflammatory sites by treatment with VDR agonists is associated with their capacity to inhibit chemokine production by cells in the target organ via the inhibition of NF-κB activation which results in interference with the growth of experimentally induced endometriosic lesions [142143].

It has been shown that the VDR agonist, elocalcitol, inhibits lesion development in a mouse model of endometriosis [144].

By administering elocalcitol during the perimenstrual and menstrual phase of the cycle, inhibition of inflammation, endometrial cell adhesion, and lesion organization could be exerted with the maximal efficacy; thereby prevention of the development of endometriotic implants could be feasible in subjects at high risk of disease recurrence.

18.2.6 Simvastatin

Statins reduce the rate of endometrial stromal growth and angiogenesis, interfere with the development and attachment of endometriotic implants, and also protect the subject from the development of endometriosis by virtue of their anti-inflammatory and antioxidant properties [145]. Considering its safety and minimal side effects, use of statins in treatment of endometriosis holds promise [146].

18.2.7 Pentoxifylline

A methylxanthine acting as a phosphodiesterase inhibitor, an anti-inflammatory agent, and also an immunomodulator which has been used for many years to modify blood viscosity and improve tissue oxygen delivery in the management of defective microcirculation reduces the production and action of cytokines such as TNF-α and interleukin-1 and thereby inhibits the inflammatory activation of polymorphonuclear neutrophils and also inhibits phagocytosis and the generation of toxic oxygen species and proteolytic enzymes by macrophages and granulocytes. Experimentally it has been shown that pentoxifylline can modulate rat endometriotic implant growth and production of implant-specific proteins [147]. Therefore, immunomodulation of peritoneal inflammatory cell hyperactivation with pentoxifylline may represent a new modality to specifically manage the pathophysiology of endometriosis. On the other hand, up until now, there still appears to be little evidence to support using pentoxifylline in the management of endometriosis [112148].

18.2.8 Sorafenib: An Antiangiogenic and Tyrosine Kinase Inhibitor

Various epigenetic aberrations have been described in endometriosis [149]. Mesenchymal stem cells (MSC), located in the microenvironment of the ectopic endometriotic lesion, may be modulated epigenetically and lead to the survival of the MSC cells with enhanced migratory, proliferative, and angiogenic properties. Since endometrial MSC do not express ER [150], the current use of antiestrogenic medications is likely to spare MSC and target only ER-positive cells which explains why symptom relief is just temporary and eradication of the disease is not possible.

Researchers just recently observed that sorafenib treatment inhibited the increased phosphorylation of ezrin which plays a major role in the regulation of cell morphology, migration, and attachment in ectopic MSC, and consequently limited the increased migration of ectopic MSC. Targeting the stem cell population may be relevant in achieving the complete eradication of endometriotic implants [151].

18.2.9 Curcumin as an Antioxidant, Anti-inflammatory, and Antiproliferative Agent

Curcumin is a naturally occurring polyphenolic yellow-/turmeric-colored compound derived from the rhizome of Curcuma longa which is widely used as a spice and coloring agent in several foods such as curry, mustard, and potato chips and also in cosmetics and drugs. The anti-inflammatory effects are mediated through interference with multiple key signaling molecules, including nuclear factor-kappaB (NF-κB). The increased MMP-9 activity and expression of tumor necrosis factor-alpha (TNF-α) in endometriotic tissues can be reversed by administration of curcumin in experimental models. Moreover, lipid peroxidation and protein oxidation in endometriotic tissues are prevented by curcumin [152]. Another study documents the Curcumin’s effect on regulation of matrix metalloproteinase (MMP-2) activity by tissue inhibitor of MMP (TIMP-2) during the early phase of endometriosis development [153]. It has also been demonstrated that curcumin can effectively suppress ICAM-1 and VCAM-1 gene and protein expression, as well as secretion of IL-6, IL-8, and MCP-1, by inhibiting the activation of NF-κB induced by TNF-α in human ectopic endometriotic stromal cells [154]. All these findings provide a novel rationale for the potential of curcumin in the prevention and treatment of endometriotic disease in humans.

18.2.10 Green Tea as a Potent Antiangiogenesis Agent

Endometriosis is an angiogenesis-dependent disorder. Since endometriotic lesions require new vessel formation to deliver the nutrient supply, dense vascularization is a typical pathological feature of endometriosis. Antiangiogenesis is one of the most well-characterized biological properties of green tea. The polyphenols, especially epigallocatechin-3-gallate (EGCG) in the leaves of the tea plant Camellia sinensis, have potent antioxidative, antimitotic, and antiangiogenic properties [155156].

In mice experimental endometriosis model, pro-EGCG, inhibits the development, growth, and angiogenesis of the implants [157158]. EGCG selectively suppresses vascular endothelial growth factor C (VEGFC) and tyrosine kinase receptor VEGF receptor 2 (VEGFR2) expressions in experimental endometriosis in vivo and endothelial cells in vitro [158].

Antiangiogenesis for the management of endometriosis has the potential advantage of lower recurrence rates and less endocrine side effects compared to conventional surgical and hormonal therapies.

18.2.11 Resveratrol: A Phytochemical Compound

Resveratrol (trans-3,5,4′-trihydroxystilbene) is a phytochemical compound of grapes, red wine, nuts, and different berries, affecting multiple cellular processes, including proliferation, apoptosis, and oxygen radical formation [159], and also suppressing the development of new blood vessels. Moreover, resveratrol dose-dependently suppresses the development of new blood vessels [160]. The most significant concentrations of resveratrol are found in the skin of grapes and therefore in red wines but not white wines. Resveratrol has been suggested as a promising therapeutic agent for the treatment of cancer [161] as well as several inflammatory, metabolic [162], and cardiovascular diseases [163]. A group of researchers just recently have shown in mice that resveratrol inhibits the establishment of endometriotic lesions by decreasing proliferative activity and by upregulating apoptotic cell death inside the lesions [164]. Another group have also demonstrated that resveratrol treatment suppresses the development of new microvessels and inhibits the proliferation of both stromal and glandular endometrial cells in peritoneal and mesenteric lesions [165]. Better understanding of the basic mechanisms of action of EGCG and resveratrol, as well as their bioavailability, is needed to determine the potential usefulness of these natural compounds as endometriosis-preventive agents [166].

18.2.12 Chinese Herbal Medicine: Puerarin as a Phytoestrogen

Puerarin, the main isoflavone glycoside derived from the Chinese medicinal herb Radix puerariae, exhibits antiestrogenic activity by suppressing P450arom and interferes with the invasion of endometrial stromal cells (ESC) and angiogenesis of ectopic tissues, in a model of endometriosis. This might be a good option for avoiding the relapse of endometriosis after the initial surgical and/or medical therapy, since it can be used for long periods without severe side effects, unlike the classical antiestrogenic medical treatment modalities [167].

According to several clinical studies in the medical literature, treatment with Chinese herbal medicine (CHM) involving formulae of between 10 and 20 separate herbal ingredients selected from a materia medica of several hundred commonly herbs that are administered as pills, enemas, and intramuscular injections prevents the recurrence of endometriosis after a conservative operation with fewer adverse reactions when compared with conventional “western medicine.” Better quality randomized controlled trials are needed to investigate a possible role for CHM in the prevention and management of endometriosis [168169].

18.3 Life Style

18.3.1 Pregnancy and Vaginal Parturition

It has been established that there is a higher prevalence of endometriosis in infertile women (48 %) than in fertile women (5 %) [170], and infertile women are 6–8 times more likely to have endometriosis than fertile women [171]. Gravidity (OR, 0.49; 95 % CI, 0.32–0.75) and parity (OR, 0.42; 95 % CI, 0.28–0.64) decrease the odds of diagnosis of endometriosis [4]. It is possible that pregnancy may indeed suppress the growth and inflammation of endometriotic lesions due to elevated progesterone levels.

Among parous women, parity and lifetime duration of lactation are associated with decreased risk. Among parous women, there is a linear decrease in risk with the number of liveborn children (rate ratio of 0.5 comparing >3 with 2 children; 95 % CI 0.4–0.7) and lifetime duration of lactation if time since last birth is less than 5 years (rate ratio of 0.2 comparing >23 months with never; 95 % CI 0.1–0.4) [17]. The recurrence rate of endometriosis has been found to be significantly lower in women who had vaginal parturition than in nulliparous women and those who delivered by cesarean section. Enlargement of the internal cervical ostium has been inversely related to the recurrence of endometriosis, confirming the role of retrograde bleeding in the occurrence and recurrence of the disease. Regardless of the presence of endometriosis, a relief in dysmenorrhea has been observed only in women who deliver vaginally [172].

18.3.2 Diet

Over the past decade, many studies have provided evidence that higher intakes of fruit and vegetables, rich in antioxidants, among other micronutrients, improve the function of the immune system and fight free radical damage [173]. Manipulation of dietary polyunsaturated fatty acid (PUFA) composition demonstrably affects the proinflammatory activities of many cell types involved in the immune response, inflammatory reactions, and cytokine network and on the synthesis and biological activity of prostaglandins and cytokines such as IL-1, IL-2, IL-6, TNF, and interferon [174175]. In the presence of high n-6:n-3 PUFA ratios of dietary intake, biosynthesis of their metabolites steadies a prominent production of 2-series prostaglandins (PGE2, PGF2a), thromboxane A2, and 4-series leukotrienes, in contrast to high n-3:n-6 PUFA ratios. Moreover, a diet based on vitamin B, vegetables, fibers, and antioxidants decreases estrogenic state-related body fat excess implicated in the estrogen-dependent growth of endometriotic tissue [174]. Dietary supplementation induces enzymes of estradiol metabolism, and the subsequent defective formation and metabolism of steroid hormones are responsible for the promotion and development of endometriosis [176]. Although not well characterized, some observational studies have shown that plant-based and high in fiber diets decrease concentrations of bioavailable estrogen by increasing its excretion and thus lower endometriosis risk [177178]. Additionally, high-fat diets have been associated with increased estradiol levels in premenopausal women [177179], suggesting that diets low in fat and high in fiber may modify endometriosis risk by altering steroid hormone metabolism. The published reports on this issue are somewhat contradictory [34173]. A recent large cohort study using 12 years of prospectively collected data have failed to show any association between total dietary fat intake and endometriosis risk, but a decreased risk with increased long-chain n-3 fatty acid consumption and an increased risk with trans-fat intake have been demonstrated [180]. A recently published population-based case–control study [181] suggests a possible inverse risk of disease with dietary fat and dairy consumption and an increased risk of endometriosis with β-carotene and higher servings of fruit, but these findings have not been confirmed elsewhere and require further evaluation in a prospective investigation. Unfortunately, there are only few well-designed, randomized, controlled trials to evaluate the efficacy and safety of complementary dietary therapy to manage endometriosis. From the accumulated data, one can conclude that the effect of dietary fat on the risk and incidence of endometriosis, if any, is marginal and is not clinically relevant. There is no adequate scientific support to the suggestion that fish oil consumption is beneficial for the prevention of endometriosis. Keeping in mind that the diagnosis of endometriosis can be made by laparoscopy especially in women with pain and that women with a high fatty acid intake are less likely to undergo a laparoscopy since a high fatty acid intake can reduce menstrual pain, the association between the risk of undergoing a laparoscopy and fatty acid intake will therefore probably be as significant as the association between endometriosis and fatty acid intake. The impact of diet on endometriosis risk is urgently needed to be further studied before development of population-based strategies to prevent endometriosis can be suggested.

18.3.3 Physical Activity

Physical activity has been hypothesized to be protective since endometriosis is an estrogen-dependent disease, and physical activity may increase levels of sex hormone-binding globulin (SHBG), which would reduce estrogens. Regular exercise has been associated with a 40–80 % reduction in risk for endometriosis in several case–control studies. Four case–control studies have found inverse associations between physical activity and the risk of endometriosis, with relative risks ranging from 0.2 to 0.6 [934182]. 70 % decreased risk of developing an endometrioma with recent, frequent, and regular high intensity physical activity, as characterized by ≥3 times/week, ≥30 min/episode, ≥10 month/year for 2 years. Another study found a 40 % lower risk for women who reported “regular exercise” for 3–7 h/week and an 80 % risk reduction for those who exercised more than 7 h/week when compared with nonexercisers [183]. On the contrary to the others, in the Nurses’ Health Study II, activity reported 6 years prior to diagnosis and inactivity have not been found to be associated with endometriosis [184].

Although adult physical activity has been mostly associated with lower endometriosis risk [934182183185], little is known about the influence of childhood or adolescent physical activity on endometriosis.

One of the studies reported a 27 % increased risk of endometrioma for any physical activity at 12–21 years of age [182], and the other one, the Nurses’ Health Study II, also found a positive linear relationship between strenuous physical activity at 12–13 years of age and endometriosis risk [186], suggesting that the early adolescent period is a critical window of exposure for the implantation of endometriosis lesions, which physical activity might promote at that age.

18.4 The Timing of Exposure to Environmental Factors

Exposure to environmental chemicals recently has been proposed to contribute to several gynecologic pathologies including endometriosis, especially when exposures occur during critical periods of development. There are limited data on the prevalence of conditions that affect women’s reproductive health. Hormone-related diseases such as endometriosis and uterine fibroids, pubertal developmental abnormalities, and polycystic ovary syndrome are more common, although few data on population-based trends are available. The toxic chemicals altering reproductive health in females have been demonstrated by the consequences of diethylstilbestrol (DES) use by pregnant women. Other synthetic chemicals which are called endocrine-disrupting compounds (EDCs) used in commerce are known to mimic hormones and have been shown to contribute to disease onset [187].

The impact of the environment on reproductive physiology can be a direct inducer of gene expression, acting directly as hormones or disrupting the metabolism or synthesis of endogenous hormones, or through a neuroendocrine route, whereby the nervous system monitors the environment sending signals to the endocrine system, and an epigenetic route could have been chosen, whereby altering transcriptional capabilities without changing DNA sequence [188].

The data collected from the Nurses’ Health Study have revealed that DES daughters have an 80 % increased risk (relative risk [RR] 1.8, [CI] 1.2–2.8) of the development of endometriosis [23]. At the same time, in mice model, exposure to the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on gestational day 8 increases the size of implanted endometriotic lesions when combined with an adult exposure [33]. Based on these evidences, one can hypothesize that during embryogenesis, EDC exposure has an organizational effect that increases susceptibility for endometriosis, but subsequent adult hormone, immune, and/or EDC irregularities are required for disease onset.

Although estrogen is necessary for the progression of endometriosis, other factors also influence this progression. The most toxic dioxin, TCDD, induces endometriosis, not in ovariectomized mice but with an intact ovary [34]. Also, in women with peritoneal endometriosis, immune dysfunction by TCDD has been blamed since the immune system fails to prevent implantation of endometrial debris, despite high levels of activated macrophages and inflammatory cytokines in the peritoneal environment [189], suggesting that the progression of endometriosis is dependent on both hormonal and immune environments.

Increasing experimental evidence suggests an influence of environmental organochlorines, a class of xenobiotic chemicals on endometriosis development, including dioxin or dioxin-like compounds [190191] which are known to disrupt endocrine and immune functions [192].

Human endometrium is a known site for estrogen, and many environmental chemicals have been detected there [193] or may induce inflammation and the chronic stimulation of proinflammatory cytokines. At the same time, they have been associated with immunologic changes, downregulating natural killer cells or interleukin-1β and interleukin-12 [194].

Recently, organochlorine pesticides have also been shown to increase endometriosis risk in a laparoscopic cohort of US women [195] and other studies have reported increased risks with higher concentration of phthalates [196197], polychlorinated dibenzodioxins and polychlorinated dibenzofurans, and polychlorinated biphenyls [198199].

Experiments on rodents suggest that both adult and in utero exposure to dioxin can promote endometriosis during adulthood. Increased endometriotic lesion size was observed in mice exposed to TCDD during both perinatal and adult life stages [33].

Since in utero and lactational exposure to TCDD reduces circulating estradiol in vivo [200] and decreases ovarian estradiol production in cultures [201], and also causes degradation of ER-α [202], it is possible that fetal exposure to TCDD promotes adult endometriosis through altered P action, because PR expression is reduced in the uterus of adult mice that were exposed to TCDD in utero [35] and P insensitivity is characteristic of women with endometriosis [189203]. TCDD which is an immunosuppressant [36] might promote endometriosis by altering the immune function, thereby enabling establishment and growth of peritoneal endometriosis under the influence of E2, proangiogenic, proliferative, and antiapoptotic factors. Alternatively, TCDD could activate the expression of K-ras in the ovarian surface resulting in peritoneal endometriosis [37]. Endometriotic lesions have increased expression of aromatase and 17β-HSD type 1 and decreased expression of 17β-HSD types 2 and 4, resulting in an increase in production of estradiol [39]. If this expression pattern is established during fetal development via epigenetic mechanisms, then endometriosis could manifest during adulthood after estrogenic exposures. In ectopic endometrial tissue, ER-β is upregulated and acts as the mediator of endometrial proliferation [204205]. Therefore, adult exposures to high doses of ER-β agonists are hypothesized to promote ectopic endometrium growth after retrograde menstruation.

18.4.1 The “Developmental Origins of Adult Disease” Hypothesis

According to Barker hypothesis, adverse influences early in development, particularly during intrauterine life, can result in permanent changes in physiology and metabolism resulting in increased disease risk in adulthood, which is speculated to occur largely through epigenetic mechanisms [206]. As a typical example, low birth weight (LBW) is associated with a list of chronic diseases ranging from coronary artery disease (CAD), type II diabetes mellitus (T2DM), cancer, and osteoporosis to various psychiatric illnesses [207]. As stated by Dr. Ian Donald, The first 38 weeks of human life spent in the allegedly protected environment of the amniotic sac are medically more eventful and more fraught with danger than the next 38 years in the lifespan of most human individuals [208].

Regarding endometriosis, development of permanent increased estrogen sensitivity due to imprinting the regulatory gene HOXA10, in offspring exposed to bisphenol A (BPA) during pregnancy, has been reported [209].

Unfortunately, placenta instead of being a protective barrier for the fetus allows many toxic chemicals to pass to the fetus. BPA, for example, in animal model, passes to the fetus reaching to higher than maternal blood levels in less than 30 min after exposure [210211]. The embryo or fetus also cannot or partially detoxify the chemicals since the key enzyme, cytochrome P450 activity, is lacking or not fully developed in the fetus, even in young children [212].

Breastfed infants exposed to EDCs have much higher blood levels than formula-fed infants [213]. It has also been emphasized that breastfed infants receives about 50 times the daily PCB intake of adults and up to 18 % higher than those of formula-fed infants [214].

It is unknown whether breastfeeding can counteract or not, the detrimental effects of prenatal toxicant exposure. Given that toxic chemicals are being removed from the mother’s stores during lactation and that the longer the lactation, the more toxins removed, it might be expected that breastfeeding reduces breast cancer and endometriosis risk. In fact, among the benefits of breastfeeding to the mother are reduced risk of breast cancer and reduced risk of recurrence of endometriosis in women who have had children, not longer than 5 years ago [215216].

In addition to the recommendations to choose breastfeeding or not, mother to be should be as healthy as possible even before conception, lose weight if necessary, eat organically, be supplemented with antioxidants and other detoxifiers, and avoid all toxic exposures possible while breastfeeding [217218]. By losing weight in the postpartum period, whether there will be any remobilization or not of adipose tissue resulting in increased circulating levels of previously stored EDCs, thereby increasing the levels in breast milk, is unknown [219].

Parents should be advised to avoid plastic bottles and not to store foods including breast milk or formula for baby in plastics to avoid bisphenol A. There are also toxins including dioxin, xylene, ethylbenzene, and styrene in disposable diapers made of bleached paper and plastic [220]. Infants whose skin are exposed to lotion, powder, and shampoo reveal increased urinary concentrations of phthalates [221].

Since food is the primary exposure to EDCs, eating organic instead of genetically modified foods is very critical [222]. Another way to reduce exposure is to eat more vegetables, grains, fruits, and less animal products [223]. One might skip meat completely and go vegetarian. On the other hand, soy, corn, potatoes, squash, canola oil, cottonseed oil, papaya, and tomatoes are among the most commonly genetically engineered foods. Consuming lignin-containing vegetables like cabbage, cauliflower, broccoli, and Brussels sprouts, which helps in the removal of excess estrogen, is another way to reduce exposure [224]. In brief, contaminated fish, meats, dairy, eggs, processed oils and fast foods, fried foods, and refined processed foods should better be reduced or even avoided.

Avoiding pesticides and herbicides from other, non-food, sources is also important. Pesticides have been linked to some immune abnormalities seen in endometriosis, infections, asthma, and allergies. PVC, a source of phthalates, is prevalent worldwide in building materials, plumbing, shoes, rain gear, shower curtains, flooring, and toys. Dental sealants, used to protect teeth from decay-causing bacteria, typically contain bisphenol A [225]. Children who have been exposed to pesticides are 3–7 times more likely to develop non-Hodgkin’s lymphoma than children who have not been exposed to pesticides and this risk was similar for pesticide exposure to the mother during pregnancy and direct exposure after birth [226]. Since women with endometriosis have 40 % higher risk for developing hematopoietic malignancies, mainly non-Hodgkin lymphoma, this may be a problem which requires extra caution [227].

Menarche is correlated to percent body fat with about 17 % body fat required for menarche and 22 % body fat reported to be required to maintain or restore menstruation [228]. Since fat cells produce estrogen, heavier girls usually begin sexual development and periods earlier [229]. Fat cells also make cytokines, therefore keeping down fat should also avoid inflammation [230]. The fat consumed as a child may be even more an important risk than the fat consumed as an adult. Exercise is another way to keep body fat low and achieve the goal of delaying puberty and menarche [231].

The Nurses’ Health Study II (NHS II), in a well-characterized cohort, has reported that low birth weight, multiple gestation, and DES are associated with a diagnosis of endometriosis [23]. Another study demonstrated lower odds of the diagnosis with in utero exposure to cigarette smoking [232]. Women eventually diagnosed with endometriosis were leaner from childhood through diagnosis relative to women without endometriosis [21]. This finding was subsequently corroborated in the large Nurses Health III Cohort Study [233]. Despite some indirect evidence suggestive of an early origin for endometriosis, some recent studies failed to demonstrate an association between in utero exposures and increased odds of an endometriosis diagnosis [234235].

18.5 Conclusion

In conclusion, medical literature have not yet addressed the prevention of endometriosis. However, there is extensive scientific and clinical data applicable to prevention of endometriosis when it is regarded as a systemic inflammatory, endocrine, and immunological disease. We hope this review will stimulate further basic and clinical research on this very critical health problem of women.

References

1.

Ballweg ML. Prevention of endometriosis: it might be possible. In: Matalliotakis I, Arici A, editors. New Developments in Endometriosis. CreateSpace; 2011. p. 1–44.

2.

Ballweg ML. Impact of endometriosis on women’s health: comparative historical data show that the earlier the onset, the more severe the disease. Best Pract Res Clin Obstet Gynaecol. 2004;18(2):201–18.PubMed

3.

Biberoglu K. Prevention of endometriosis: Is it possible? J Endometriosis. 2012;4(3):129–30.

4.

Peterson CM, Johnstone EB, Hammoud AO, Stanford JB, Varner MW, Kennedy A, et al. ENDO Study Working Group. Risk factors associated with endometriosis: importance of study population for characterizing disease in the ENDO study. Am J Obstet Gynecol. 2013;208:451. e1–11.PubMedCentralPubMed

5.

Matalliotakis IM, Cakmak H, Fragouli YG, Goumenou AG, Mahutte NG, Arici A. Epidemiological characteristics in women with and without endometriosis in the Yale series. Arch Gynecol Obstet. 2008;277:389–93.PubMed

6.

Vercellini P, De Giorgi O, Aimi G, Panazza S, Uglietti A, Crosignani PG. Menstrual characteristics in women with and without endometriosis. Obstet Gynecol. 1997;90:264–8.PubMed

7.

Nouri K, Ott J, Krupitz B, Huber JC, Wenzl R. Family incidence of endometriosis in first-, second-, and third-degree relatives: case–control study. Reprod Biol Endocrinol. 2010;8:85.PubMedCentralPubMed

8.

Filer RB, Wu CH. Coitus during menses: its effect on endometriosis and pelvic inflammatory disease. J Reprod Med. 1989;34:887–90.PubMed

9.

Cramer DW, Wilson E, Stillman RJ, Berger MJ, Belisle S, Schiff I, et al. The relation of endometriosis to menstrual characteristics, smoking, and exercise. JAMA. 1986;255:1904–8.PubMed

10.

Woodworth SH, Singh M, Yussman MA, Sanfilippo JS, Cook CL, Lincoln SR. A prospective study on the association between red hair color and endometriosis in infertile patients. Fertil Steril. 1995;64:651–2.PubMed

11.

Somigliana E, Vigano P, Abbiati A, Gentilini D, Parazzini F, Benaglia L, et al. ’Here comes the sun’: pigmentary traits and sun habits in women with endometriosis. Hum Reprod. 2010;25:728–33.PubMed

12.

Ewens KG, Stewart DR, Ankener W, Urbanek M, McAllister JM, Chen C, et al. Family-based analysis of candidate genes for polycystic ovary syndrome. J Clin Endocrinol Metab. 2010;95:2306–15.PubMedCentralPubMed

13.

Treloar SA, Wicks J, Nyholt DR, Montgomery GW, Bahlo M, Smith V, et al. Genomewide linkage study in 1176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26. Am J Hum Genet. 2005;77:365–76.PubMedCentralPubMed

14.

Matalliotakis IM, Arici A, Cakmak H, Goumenou AG, Koumantakis G, Mahutte NG. Familial aggregation of endometriosis in the Yale Series. Arch Gynecol Obstet. 2008;278(6):507–11.PubMed

15.

Layman LC. The genetic basis of female reproductive disorders: etiology and clinical testing. Mol Cell Endocrinol. 2013;370(1–2):138–48.PubMedCentralPubMed

16.

Nnoaham KE, Webster P, Kumbang J, Kennedy SH, Zondervan KT. Is early age at menarche a risk factor for endometriosis? A systematic review and meta-analysisof case–control studies. Fertil Steril. 2012;98(3):702–12.PubMedCentralPubMed

17.

Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Malspeis S, Willet WC, et al. Reproductive history and endometriosis among premenopausal women. Obstet Gynec. 2004;5(1):965–74.

18.

Treloar SA, Bell TA, Nagle CM, Purdie DM, Green AC. Early menstrual characteristics associated with subsequent diagnosis of endometriosis. Am J Obstet Gynecol. 2010;202:534. e1–6.PubMed

19.

Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 1997;24:235–58.PubMed

20.

Ferrero S, Anserini P, Remorgida V, Ragni N. Body mass index in endometriosis. Eur J Obstet Gynecol Reprod Biol. 2005;121:94–8.PubMed

21.

Hediger ML, Hartnett J, Buck Louis GM. Association of endometriosis with body size and figure. Fertil Steril. 2005;84(5):1366–74.PubMedCentralPubMed

22.

Shah DK, Correia KF, Vitonis AF, Missmer SA. Body size and endometriosis: results from 20 years of follow-up within the Nurses’ Health Study II prospective cohort. Hum Reprod. 2013;28:1783 [Epub ahead of print].PubMedCentralPubMed

23.

Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Michels KB, Hunter DJ. In utero exposures and the incidence of endometriosis. Fertil Steril. 2004;82(6):1501–8.PubMed

24.

Newbold R. Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmental estrogens. Environ Health Perspect. 1995;103:83–7.PubMedCentralPubMed

25.

Noller KL, Blair PB, O’Brien PC, Melton 3rd LJ, Offord JR, Kaufman RH, et al. Increased occurrence of autoimmune disease among women exposed in utero to diethylstilbestrol. Fertil Steril. 1988;49:1080–2.PubMed

26.

Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nat Rev Genet. 2007;8:253–62.PubMed

27.

Edwards TM, Myers JP. Environmental exposures and gene regulation in disease etiology. Environ Health Perspect. 2007;115:1264–70.PubMedCentralPubMed

28.

Anway MD, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors. Endocrinology. 2006;147:S43–9.PubMed

29.

Simsa P, Mihalyi A, Schoeters G, Koppen G, Kyama CM, Den Hond EM, et al. Increased exposure to dioxin-like compounds is associated with endometriosis in a case–control study in women. Reprod Biomed Online. 2010;20:681–8.PubMed

30.

Cobellis L, Colacurci N, Trabucco E, Carpentiero C, Grumetto L. Measurement of bisphenol A and bisphenol B levels in human blood sera from healthy and endoemtriotic women. Biomed Chromatogr. 2009;23:1186–90.PubMed

31.

Weuve J, Hauser R, Calafat AM, Missmer SA, Wise LA. Association of exposure to phthalates with endometriosis and uterine leiomyomata: findings from NHANES, 1999–2004. Environ Health Perspect. 2010;118:825–8.PubMedCentralPubMed

32.

Caserta D, Bordi G, Ciardo F, Marci R, La Rocca C, Tait S, et al. The influence of endocrine disruptors in a selected population of infertile women. Gynecol Endocrinol. 2013;29(5):444–7.PubMed

33.

Cummings AM, Hedge JM, Birnbaum LS. Effect of prenatal exposure to TCDD on the promotion of endometriotic lesion growth by TCDD in adult female rats and mice. Toxicol Sci. 1999;52:45–9.PubMed

34.

Cummings AM, Metcalf JL, Birnbaum L. Promotion of endometriosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats and mice: time-dose dependence and species comparison. Toxicol Appl Pharmacol. 1996;138:131–9.PubMed

35.

Nayyar T, Bruner-Tran KL, Piestrzeniewicz-Ulanska D, Osteen KG. Developmental exposure of mice to TCDD elicits a similar uterine phenotype in adult animals as observed in women with endometriosis. Reprod Toxicol. 2007;23:326–36.PubMedCentralPubMed

36.

Mueller MD, Vigne JL, Streich M, Tee MK, Raio L, Dreher E, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases glycodelin gene and protein expression in human endometrium. J Clin Endocrinol Metab. 2005;90:4809–15.PubMed

37.

Dinulescu DM, Ince TA, Quade BJ, Shafer SA, Crowley D, Jacks T. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med. 2005;11:63–70.PubMed

38.

Maia Jr H, Haddad C, Coelho G, Casoy J. Role of inflammation and aromatase expression in the eutopic endometrium and its relationship with the development of endometriosis. Womens Health (Lond Engl). 2012;8(6):647–58.

39.

Dassen H, Punyadeera C, Kamps R, Delvoux B, Van Langendonckt A, Donnez J, et al. Estrogen metabolizing enzymes in endometrium and endometriosis. Hum Reprod. 2007;22:3148–58.PubMed

40.

Marino JL, Holt VL, Chen C, Davis S. Lifetime occupational history and risk of endometriosis. Scand J Work Environ Health. 2009;35(3):233–40.PubMedCentralPubMed

41.

Zhong Y, Carmella SG, Upadhyaya P, Hochalter JB, Rauch D, Oliver A, et al. Immediate consequences of cigarette smoking: rapid formation of polycyclic aromatic hydrocarbon diol epoxides. Chem Res Toxicol. 2011;24:246–52.PubMedCentralPubMed

42.

Sadeu JC, Hughes CL, Agarwal S, Foster WG. Alcohol, drugs, caffeine, tobacco, and environmental contaminant exposure: reproductive health consequences and clinical implications. Crit Rev Toxicol. 2010;40:633–52.PubMed

43.

Kvaskoff M, Bijon A, Clavel-Chapelon F, Mesrine S, Boutron-Ruault MC. Childhood and adolescent exposures and the risk of endometriosis. Epidemiology. 2013;24(2):261–9.PubMed

44.

Chapron C, Souza C, de Ziegler D, Lafay-Pillet MC, Ngô C, Bijaoui G, et al. Smoking habits of 411 women with histologically proven endometriosis and 567 unaffected women. Fertil Steril. 2010;94(6):2353–5.PubMed

45.

McLeod BS, Retzloff MG. Epidemiology of endometriosis: an assessment of risk factors. Clin Obstet Gynecol. 2010;53(2):389–96.PubMed

46.

Olovsson M. Immunological aspects of endometriosis: an update. Am J Reprod Immunol. 2011;66:101–4.PubMed

47.

Matarese G, De Placido G, Nikas Y, Alviggi C. Pathogenesis of endometriosis: natural immunity dysfunction or autoimmune disease? Trends Mol Med. 2003;9:223–8.PubMed

48.

Kyama CM, Debrock S, Mwenda JM, D’ Hooghe TM. Potential involvement of the immune system in the development of endometriosis. Reprod Biol Endocrinol. 2003;1(123):1–9.

49.

Mabray CR, Burditt ML, Martin TL, Jaynes CR, Hayes JR. Treatment of common gynecologic-endocrinologic symptoms by allergy management procedures. Obstet Gynecol. 1982;59:560–4.PubMed

50.

Sinaii N, Cleary SD, Ballweg ML, Nieman LK, Stratton P. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis. Hum Reprod. 2002;17:2715–24.PubMed

51.

Matalliotakis I, Cakmak H, Matalliotakis M, Kappou D, Arıcı A. High rate of allergies among women with endometriosis. J Obstet Gynaecol. 2012;32(3):291–3.PubMed

52.

Hever A, Roth RB, Hevezi P, Marin ME, Acosta JA, Acosta H, et al. Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator. Proc Natl Acad Sci U S A. 2007;104:12451–6.PubMedCentralPubMed

53.

Christofolini DM, Cavalheiro CM, Teles JS, Lerner TG, Brandes A, Bianco B, et al. Promoter -817C>T variant of B lymphocyte stimulator gene (BLyS) and susceptibility to endometriosis-related infertility and idiopathic infertility in Brazilian population. Scand J Immunol. 2011;74(6):628–31.PubMed

54.

González-Ramos R, Defrère S, Devoto L. Nuclear factor-kappaB: a main regulator of inflammation and cell survival in endometriosis pathophysiology. Fertil Steril. 2012;98(3):520–8.PubMed

55.

Keller JJ, Liu SP, Lin HC. A case–control study on the association between rheumatoid arthritis and bladder pain syndrome/interstitial cystitis. Neurourol Urodyn. 2013;32(7):980–5.

56.

Tietjen GE, Bushnell CD, Herial NA, Utley C, White L, Hafeez F. Endometriosis is associated with prevalence of comorbid conditions in migraine. Headache. 2007;47(7):1069–78.PubMed

57.

Seaman SE, Ballard KD, Wright JT, de Vries CS. Endometriosis and its coexistence with irritable bowel syndrome and pelvic inflammatory disease: findings from a national case–control study- part 2. BJOG. 2008;115:1392–6.PubMed

58.

Smorgick N, Marsh CA, As-Sanie S, Smith YR, Quint EH. Prevalence of pain syndromes, mood conditions, and asthma in adolescents and young women with endometriosis. J Pediatr Adolesc Gynecol. 2013;26(3):171–5.PubMed

59.

Issa B, Onon TS, Agrawal A, Shekhar C, Morris J, Hamdy S, et al. Visceral hypersensitivity in endometriosis:a new target for treatment? Gut. 2012;61:367–72.PubMed

60.

Butrick CW. Patients with chronic pelvic pain: endometriosis or interstitial cystitis/painful bladder syndrome? JSLS. 2007;11:182–9.PubMedCentralPubMed

61.

Ferrero S, Pretta S, Bertoldi S, Anserini P, Remorgida V, Del Sette M, et al. Increased frequency of migraine among women with endometriosis. Hum Reprod. 2004;19:2927–32.PubMed

62.

Tamburro S, Canis M, Albuisson E, Dechelotte P, Darcha C, Mage G. Expression of transforming growth factor β1 in nerve fibers is related to dysmenorrhea and laparoscopic appearance of endometriotic implants. Fertil Steril. 2003;80:1131–6.PubMed

63.

Kempuraj D, Papadopoulou N, Stanford EJ, Christodoulou S, Madhappan B, Sant GR, et al. Increased numbers of activated mast cells in endometriosis lesions positive for corticotropin releasing hormone and urocortin. Am J Reprod Immunol. 2004;52:267–75.PubMed

64.

Theoharides TC. Mast cells and stress—a psychoneuroimmunological perspective. J Clin Psychopharmacol. 2002;22:103–8.PubMed

65.

Laufer MR, Sanfilippo J, Rose G. Adolescent endometriosis: diagnosis and treatment approaches. J Pediatr Adolesc Gynecol. 2003;16:S3.PubMed

66.

Bricou A, Batt RE, Chapron C. Peritoneal fluid flow influences anatomical distribution of endometriotic lesions: Why Sampson seems to be right. Eur J Obstet Gynecol Reprod Biol. 2008;138:127.PubMed

67.

Mok-Lin EY, Wolfberg A, Hollinquist H, Laufer MR. Endometriosis in a patient with Mayer–Rokitansky–Küster–Hauser syndrome and complete uterine agenesis: evidence to support the theory of coelomic metaplasia. J Pediatr Adolesc Gynecol. 2010;23(1):e35–7.PubMed

68.

Uğur M, Turan C, Mungan T, Kuşçu E, Senöz S, Ağiş HT, et al. Endometriosis in association with müllerian anomalies. Gynecol Obstet Invest. 1995;40(4):261–4.PubMed

69.

Nasu K, Okamoto M, Nishida M, Narahara H. Endometriosis of the perineum. J Obstet Gynaecol Res. 2013;39(5):1095–7.PubMed

70.

Emre A, Akbulut S, Yilmaz M, Bozdag Z. Laparoscopic trocar port site endometriosis: a case report and brief literature review. Int Surg. 2012;97(2):135–9.PubMedCentralPubMed

71.

Horton JD, Dezee KJ, Ahnfeldt EP, Wagner M. Abdominal wall endometriosis: a surgeon’s perspective and review of 445 cases. Am J Surg. 2008;196(2):207–12.PubMed

72.

Odobasic A, Pasic A, Iljazovic-Latifagic E, Arnautalic L, Odobasic A, Idrizovic E, et al. Perineal endometriosis: a case report and review of the literature. Tech Coloproctol. 2010;14 Suppl 1:S25–7.PubMed

73.

Nominato NS, Prates LF, Lauar I, Morais J, Maia L, Geber S. Caesarean section greatly increases risk of scar endometriosis. Eur J Obstet Gynecol Reprod Biol. 2010;152(1):83–5.PubMed

74.

Schweppe KW, Ring D. Peritoneal defects and the development of endometriosis in relation to the timing of endoscopic surgery during the menstrual cycle. Fertil Steril. 2002;78(4):763–6.PubMed

75.

Harada T, Momoeda M, Taketani Y, Hoshiai H, Terakawa N. Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebo-controlled, double-blind, randomized trial. Fertil Steril. 2008;90:1583–8.PubMed

76.

ACOG Committee Opinion. Number 310, April 2005. Endometriosis in adolescents. Obstet Gynecol. 2005;105:921–7.

77.

Meresman GF, Auge L, Baranao RI, Lombardi E, Tesone M, Sueldo C. Oral contraceptive suppress cell proliferation and enhance apoptosis of eutopic endometrial tissue from patients with endometriosis. Fertil Steril. 2002;77:1141–7.PubMed

78.

Vercellini P, Fedele L, Pietropaolo G, Frontino G, Somigliana E, Crosignani PG. Progestogens for endometriosis: forward to the past. Hum Reprod Update. 2003;9:387–96.PubMed

79.

Vessey MP, Villard-Mackintosh L, Painter R. Epidemiology of endometriosis in women attending family planning clinics. BMJ. 1993;306:182–4.PubMedCentralPubMed

80.

Fraser IS, Kovacs GT. The efficacy of non-contraceptive uses for hormonal contraceptives. Med J Aust. 2003;178:621–3.PubMed

81.

Parazzini F, Ferraroni M, Bocciolone L, Tozzi L, Rubessa S, La Vecchia C. Contraceptive methods and risk of pelvic endometriosis. Contraception. 1994;49:47–55.PubMed

82.

Italian Endometriosis Study Group. Oral contraceptive use and risk of endometriosis. BJOG. 1999;106:695–9.

83.

Darrow SL, Vena JE, Batt RE, Zielezny MA, Michalek AM, Selman S. Menstrual cycle characteristics and the risk of endometriosis. Epidemiology. 1993;4:135–42.PubMed

84.

Heilier JF, Donnez J, Nackers F, Rousseau R, Verougstraete V, Rosenkranz K, et al. Environmental and host-associated risk factors in endometriosis and deep endometriotic nodules: a matched case–control study. Environ Res. 2007;103:121–9.PubMed

85.

Chapron C, Souza C, Borghese B, Lafay-Pillet MC, Santulli P, Bijaoui G, et al. Oral contraceptives and endometriosis: the past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis. Hum Reprod. 2011;26(8):2028–35.PubMed

86.

Vercellini P, Eskenazi B, Consonni D, Somigliana E, Parazzini F, Abbiati A, et al. Oral contraceptives and risk of endometriosis: a systematic review and meta-analysis. Hum Reprod Update. 2011;17:159–70.PubMed

87.

Di Zerega GB, Barber DL, Hodgen GD. Endometriosis: role of ovarian steroids in initiation, maintenance and suppression. Fertil Steril. 1980;33:649–53.

88.

Seracchioli R, Mabrouk M, Frasca C, Manuzzi L, Savelli L, Venturoli S. Long-term oral contraceptive pills and postoperative pain management after laparoscopic excision of ovarian endometrioma: a randomized controlled trial. Fertil Steril. 2010;94:464–71.PubMed

89.

Somigliana E, Vercellini P, Vigano P, Abbiati A, Benaglia L, Fedele L. Endometriosis and estroprogestins: the chicken or the egg causality dilemma. Fertil Steril. 2011;95:431–3.PubMed

90.

Hemmings R, Rivard M, Olive DL, Poliquin-Fleury J, Gagné D, Hugo P, et al. Evaluation of risk factors associated with endometriosis. Fertil Steril. 2004;81(6):1513–21.PubMed

91.

Moen MH. Endometriosis in women at interval sterilization. Acta Obstet Gynecol Scand. 1987;66:451–4.PubMed

92.

Sangi-Haghpeykar H, Poindexter AN. Epidemiology of endometriosis among parous women. Obstet Gynecol. 1995;85(6):983–92.PubMed

93.

Mahmood TA, Templeton A. Prevalence and genesis of endometriosis. Hum Reprod. 1991;6:544–9.PubMed

94.

Kirshon B, Poindexter AN. Contraception: a risk factor for endometriosis. Obstet Gynecol. 1988;71:829–31.PubMed

95.

Lan S, Ling L, Jianhong Z, Xijing J, Lihui W. Analysis of the levonorgestrel-releasing intrauterine system in women with endometriosis. J Int Med Res. 2013;41(3):548–58.PubMed

96.

ESHRE Capri Workshop Group. Intrauterine devices and intrauterine systems. Hum Reprod Update. 2008;14(3):197–208.

97.

Vercellini P, Frontino G, De Giorgi O, Aimi G, Zaina B, Crosignani PG. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril. 2003;80:305–9.PubMed

98.

Cheewadhanaraks S. Effect of tubal ligation on pelvic endometriosis externa in multiparous women with chronic pelvic pain. J Med Assoc Thai. 2004;87(7):735–9.PubMed

99.

Kudielka BM, Kirschbaum C. Sex differences in HPA axis responses to stress: a review. Biol Psychol. 2005;69(1):113–32.PubMed

100.

De Longis A, Folkman S, Lazarus RS. The impact of daily stress on health and mood: psychological and social resources as mediators. J Pers Soc Psychol. 1988;54(3):486–95.

101.

Petrelluzzi KF, Garcia MC, Petta CA, Grassi-Kassisse DM, Spadari-Bratfisch RC. Salivary cortisol concentrations, stress and quality of life in women with endometriosis and chronic pelvic pain. Stress. 2008;11(5):390–7.PubMed

102.

Lima AP, Moura MD, Rosa e Silva AAM. Prolactin and cortisol levels in women with endometriosis. Braz J Med Biol Res. 2006;39(8):1121–7.PubMed

103.

Christodoulakos G, Augoulea A, Lambrinoudaki I, Sioulas V, Creatsas G. Pathogenesis of endometriosis: the role of defective ‘immunosurveillance’. Eur J Contracept Reprod Health Care. 2007;12(3):194–202.PubMed

104.

Tariverdian N, Theoharides TC, Siedentopf F, Gutiérrez G, Jeschke U, Rabinovich GA, et al. Neuroendocrine-immune disequilibrium and endometriosis: an interdisciplinary approach. Semin Immunopathol. 2007;29(2):193–210.PubMedCentralPubMed

105.

Cuevas M, Flores I, Thompson KJ, Ramos-Ortolaza DL, Torres-Reveron A, Appleyard CB. Stress exacerbates endometriosis manifestations and inflammatory parameters in an animal model. Reprod Sci. 2012;19(8):851–62.PubMedCentralPubMed

106.

Sugamata M, Ihara T, Uchiide I. Increase of activated mast cells in human endometriosis. Am J Reprod Immunol. 2005;53(3):120–5.PubMed

107.

Anaf V, Chapron C, Nakadi IE, De Moor V, Simonart T, Noel JC. Pain, mast cells, and nerves in peritoneal, ovarian and deep infiltrating endometriosis. Fertil Steril. 2006;86(5):1336–43.PubMed

108.

Fenster L, Waller K, Chen J, Hubbard AE, Windham GC, Elkin E, et al. Psychological stress in the workplace and menstrual function. Am J Epidemiol. 1999;149(2):127–34.PubMed

109.

Wang L, Wang X, Wang W, Chen C, Ronnennberg AG, Guang W, et al. Stress and dysmenorrhoea: a population based prospective study. Occup Environ Med. 2004;61(12):1021–6.PubMedCentralPubMed

110.

Gul A, Yaspar T, Ugras S. BCG vaccination to prevent implantation of endometriosis: an experimental study in rats. Eur J Obstet Gynecol Reprod Biol. 2001;98:209–12.PubMed

111.

Clayton RD, Duffy SR, Wilkinson N, Garry R, Jackson AM. Increase in peripheral blood mononuclear cell (PBMC)- and CD56+ cell-mediated killing of endometrial stromal cells by mycobacteria; a possible role in endometriosis immunotherapy? Hum Reprod. 2004;19(8):1886–93.PubMed

112.

Balasch J, Creus M, Fabregas F, Carmona F, Martínez-Román S, Manau D, et al. Pentoxifylline versus placebo in the treatment of infertility associated with minimal or mild endometriosis: a pilot randomized clinical trial. Hum Reprod. 1997;12:2046–50.PubMed

113.

Szymanowski K, Chmaj-Wierzchowska K, Yantczenko A, Niepsuj-Biniaś J, Florek E, Opala T, et al. Endometriosis prophylaxis and treatment with the newly developed xenogenic immunomodulator RESAN in an animal model. Eur J Obstet Gynecol Reprod Biol. 2009;142(2):145–8.PubMed

114.

Chuang PC, Wu MH, Shoji Y, Tsai SJ. Downregulation of CD36 results in reduced phagocytic ability of peritoneal macrophages of women with endometriosis. J Pathol. 2009;219:232–41.PubMed

115.

Sidell N, Han SW, Parthasarathy S. Regulation and modulation of abnormal immune responses in endometriosis. Ann N Y Acad Sci. 2002;955:159–73. 99–200, 396–406.PubMed

116.

Jadidi-Niaragh F, Mirshafiey A. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol. 2011;74:1–13.PubMed

117.

Elias KM, Laurence A, Davidson TS, Stephens G, Kano Y, Shevach EM, et al. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood. 2008;111:1013–20.PubMedCentralPubMed

118.

Wang X, Allen C, Ballow M. Retinoic acid enhances the production of IL-10 while reducing the synthesis of IL-12 and TNF-alpha from LPS-stimulated monocytes/macrophages. J Clin Immunol. 2007;27:193–200.PubMed

119.

Kalu E, Sumar N, Giannopoulos T, Patel P, Croucher C, Sherriff E, et al. Cytokine profiles in serum and peritoneal fluid from infertile women with and without endometriosis. J Obstet Gynaecol Res. 2007;33:490–5.PubMed

120.

Wieser F, Wu J, Shen Z, Taylor RN, Sidell N. Retinoic acid suppresses growth of lesions, inhibits peritoneal cytokine secretion, and promotes macrophage differentiation in an immunocompetent Mouse model of endometriosis. Fertil Steril. 2012;97(6):1430–7.PubMedCentralPubMed

121.

Alpay Z, Saed GM, Diamond MP. Female infertility and free radicals: potential role in adhesions and endometriosis. J Soc Gynecol Invest. 2006;13:390–8.

122.

Portz DM, Elkins TE, White R, Warren J, Adadevoh S, Randolph J. Oxygen free radicals and pelvic adhesion formation: I. Blocking oxygen free radical toxicity to prevent adhesion formation in an endometriosis model. Int J Fertil. 1991;36:39–42.PubMed

123.

Del Río B, García Pedrero JM, Martínez-Campa C, Zuazua P, Lazo PS, Ramos S. Melatonin, an endogenous-specific inhibitor of estrogen receptor alpha via calmodulin. J Biol Chem. 2004;279:38294–302.PubMed

124.

Rato AG, Pedrero JG, Martinez MA, del Rio B, Lazo PS, Ramos S. Melatonin blocks the activation of estrogen receptor for DNA binding. FASEB J. 1999;13:857–68.PubMed

125.

Paul S, Sharma AV, Mahapatra PD, Bhattacharya P, Reiter RJ, Swarnakar S. Role of melatonin in regulating matrix metalloproteinase-9 via tissue inhibitors of metalloproteinase-1 during protection against endometriosis. J Pineal Res. 2008;44(4):439–49.PubMed

126.

Akoum A, Lemay A, McColl S, Turcot-Lemay L, Maheux R. Elevated concentration and biologic activity of monocyte chemotactic protein-1 in the peritoneal fluid of patients with endometriosis. Fertil Steril. 1996;66:17–23.PubMed

127.

Matsuzaki S, Canis M, Darcha C, Dallel R, Okamura K, Mage G. Cyclooxygenase-2 selective inhibitor prevents implantation of eutopic endometrium to ectopic sites in rats. Fertil Steril. 2004;82:1609–15.PubMed

128.

Lebovic DI, Mwenda JM, Chai DC, Mueller MD, Santi A, Fisseha S, et al. PPAR-gamma receptor ligand induces regression of endometrial explants in baboons: a prospective, randomized, placebo- and drug-controlled study. Fertil Steril. 2007;88:1108–19.PubMedCentralPubMed

129.

Barrier BF, Bates GW, Leland MM, Leach DA, Robinson RD, Propst AM. Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous endometriosis in baboons. Fertil Steril. 2004;81 Suppl 1:775–9.PubMed

130.

Altan ZM, Denis D, Kagan D, Grund EM, Palmer SS, Nataraja SG. A long-acting tumor necrosis factor alpha-binding protein demonstrates activity in both in vitro and in vivo models of endometriosis. J Pharmacol Exp Ther. 2010;334(2):460–6.PubMed

131.

Khoufache K, Bazin S, Girard K, Guillemette J, Roy MC, Verreault JP, et al. Macrophage migration inhibitory factor antagonist blocks the development of endometriosis in vivo. PLoS One. 2012;7(5):e37264.PubMedCentralPubMed

132.

Chen PF, Luo YL, Wang W, Wang JX, Lai WY, Hu SM, et al. ISO-1, a macrophage migration inhibitory factor antagonist, inhibits airway remodeling in a murine model of chronic asthma. Mol Med. 2010;16:400–8.PubMedCentralPubMed

133.

Hou XQ, Gao YW, Yang ST, Wang CY, Ma ZY, Xia XZ. Role of macrophage migration inhibitory factor in influenza H5N1 virus pneumonia. Acta Virol. 2009;53:225–31.PubMed

134.

Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis. 2007;66(9):1137–42.PubMedCentralPubMed

135.

Harris HR, Chavarro JE, Malspeis S, Willett WC, Missmer SA. Dairy-food, calcium, magnesium, and vitamin D intake and endometriosis: a prospective cohort study. Am J Epidemiol. 2013;177(5):420–30.PubMedCentralPubMed

136.

Hartwell D, Rodbro P, Jensen SB, Thomsen K, Christiansen C. Vitamin D metabolites—relation to age, menopause and endometriosis. Scand J Clin Lab Invest. 1990;50(2):115–21.PubMed

137.

Somigliana E, Panina-Bordignon P, Murone S, Di Lucia P, Vercellini P, Vigano P. Vitamin D reserve is higher in women with endometriosis. Hum Reprod. 2007;22(8):2273–8.PubMed

138.

Agic A, Xu H, Altgassen C, Noack F, Wolfler MM, Diedrich K, et al. Relative expression of 1,25-dihydroxyvitamin D3 receptor, vitamin D 1α-hydroxylase, vitamin D 24-hydroxylase, and vitamin D 25-hydroxylase in endometriosis and gynecologic cancers. Reprod Sci. 2007;14(5):486–97.PubMed

139.

Chacko SA, Song Y, Nathan L, Tinker L, de Boer IH, Tylavsky F, et al. Relations of dietary magnesium intake to biomarkers of inflammation and endothelial dysfunction in an ethnically diverse cohort of postmenopausal women. Diabetes Care. 2010;33(2):304–10.PubMedCentralPubMed

140.

D’Angelo EK, Singer HA, Rembold CM. Magnesium relaxes arterial smooth muscle by decreasing intracellular Ca2+ without changing intracellular Mg2+. J Clin Invest. 1992;89(6):1988–94.PubMedCentralPubMed

141.

Shand AW, Nassar N, Von Dadelszen P, Innis SM, Green TJ. Maternal vitamin D status in pregnancy and adverse pregnancy outcomes in a group at high risk for pre-eclampsia. BJOG. 2010;13:1593–8.

142.

Gonzalez-Ramos R, Van Langendonckt A, Defrere S, Lousse JC, Mettlen M, Guillet A, et al. Agents blocking the nuclear factor-kappa B pathway are effective inhibitors of endometriosis in an in vivo experimental model. Gynecol Obstet Invest. 2008;3:174–86.

143.

Griffin MD, Xing N, Kumar R. Vitamin D and its analogs as regulators of immune activation and antigen presentation. Annu Rev Nutr. 2003;23:117–45.PubMed

144.

Mariani M, Viganò P, Gentilini D, Camisa B, Caporizzo E, Di Lucia P, et al. The selective vitamin D receptor agonist, elocalcitol, reduces endometriosis development in a mouse model by inhibiting peritoneal inflammation. Hum Reprod. 2012;27(7):2010–9.PubMed

145.

Bruner-Tran KL, Osteen KG, Duleba AJ. Simvastatin protects against the development of endometriosis in a nude mouse model. J Clin Endocrinol Metab. 2009;94(7):2489–94.PubMedCentralPubMed

146.

Sokalska A, Cress A, Bruner-Tran KL, Osteen KG, Taylor HS, Ortega I, et al. Simvastatin decreases invasiveness of human endometrial stromal cells. Biol Reprod. 2012;87(1):2. 1–6.PubMedCentralPubMed

147.

Nothnick WB, Curry TE, Vernon MW. Immunomodulation of rat endometriotic implant growth and protein production. Am J Reprod Immun. 1994;31:151–62.

148.

Lu D, Song H, Li Y, Clarke J, Shi G. Pentoxifylline for endometriosis. CochrDatabase Syst Rev. 2012; (1): CD007677.

149.

Guo SW. Epigenetics of endometriosis. Mol Hum Reprod. 2009;15:587–607.PubMed

150.

Olive DL. Medical therapy of endometriosis. Semin Reprod Med. 2003;21:209–22.PubMed

151.

Moggio A, Pittatore G, Cassoni P, Marchino GL, Revelli A, Bussolati B. Sorafenib inhibits growth, migration, and angiogenic potential of ectopic endometrial mesenchymal stem cells derived from patients with endometriosis. Fertil Steril. 2012;98(6):1521–30. e2.PubMed

152.

Swarnakar S, Paul S. Curcumin arrests endometriosis by downregulation of matrix metalloproteinase-9 activity. Indian J Biochem Biophys. 2009;46(1):59–65.PubMed

153.

Jana S, Rudra DS, Paul S, Snehasikta S. Curcumin delays endometriosis development by inhibiting MMP-2 activity. Indian J Biochem Biophys. 2012;49(5):342–8.PubMed

154.

Kim KH, Lee EN, Park JK, Lee JR, Kim JH, Choi HJ, et al. Curcumin attenuates TNF-α-induced expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and proinflammatory cytokines in human endometriotic stromal cells. Phytother Res. 2012;26(7):1037–47.PubMed

155.

Xu H, Lui WT, Chu CY, Ng PS, Wang CC, Rogers MS. Anti-angiogenic effects of green tea catechin on an experimental endometriosis mouse model. Hum Reprod. 2009;24:608–18.PubMed

156.

Hull ML, Charnock-Jones DS, Chan CL, Bruner-Tran KL, Osteen KG, Tom BD, et al. Antiangiogenic agents are effective inhibitors of endometriosis. J Clin Endocrinol Metab. 2003;88:2889–99.PubMed

157.

Wang CC, Xu H, Man GC, Zhang T, Chu KO, Chu CY, et al. Prodrug of green tea epigallocatechin-3-gallate (Pro-EGCG) as a potent anti-angiogenesis agent for endometriosis in mice. Angiogenesis. 2013;16(1):59–69.PubMed

158.

Xu H, Becker CM, Lui WT, Chu CY, Davis TN, Kung AL, et al. Green tea epigallocatechin-3-gallate inhibits angiogenesis and suppresses vascular endothelial growth factor C/vascular endothelial growth factor receptor 2 expression and signaling in experimental endometriosis in vivo. Fertil Steril. 2011;96:1021–8.PubMed

159.

Athar M, Back JH, Kopelovich L, Bickers DR, Kim AL. Multiple molecular targets of resveratrol: anti-carcinogenic mechanisms. Arch Biochem Biophys. 2009;486:95–102.PubMedCentralPubMed

160.

Chen Y, Tseng SH. Review. Pro- and anti-angiogenesis effects of resveratrol. In Vivo. 2007;21:365–70.PubMed

161.

Aluyen JK, Ton QN, Tran T, Yang AE, Gottlieb HB, Bellanger RA. Resveratrol: potential as anticancer agent. J Diet Suppl. 2012;9:45–56.PubMed

162.

Beaudeux JL, Nivet-Antoine V, Giral P. Resveratrol: a relevant pharmacological approach for the treatment of metabolic syndrome? Curr Opin Clin Nutr Metab Care. 2010;13:729–36.PubMed

163.

Petrovski G, Gurusamy N, Das DK. Resveratrol in cardiovascular health and disease. Ann N Y Acad Sci. 2011;1215:22–33.PubMed

164.

Bruner-Tran KL, Osteen KG, Taylor HS, Sokalska A, Haines K, Duleba AJ. Resveratrol inhibits development of experimental endometriosis in vivo and reduces endometrial stromal cell invasiveness in vitro. Biol Reprod. 2011;84:106–12.PubMedCentralPubMed

165.

Rudzitis-Auth J, Menger MDM, Laschke MW. Resveratrol is a potent inhibitor of vascularization and cell proliferation in experimental endometriosis. Hum Reprod. 2013;28(5):1339–47.PubMed

166.

Ricci AG, Olivares CN, Bilotas MA, Bastón JI, Singla JJ, Meresman GF, et al. Natural therapies assessment for the treatment of endometriosis. Hum Reprod. 2013;28(1):178–88.PubMed

167.

Wang D, Liu Y, Han J, Zai D, Ji M, Cheng W, et al. Puerarin suppresses invasion and vascularization of endometriosis tissue stimulated by 17β-estradiol. PLoS One. 2011;6(9):e25011.PubMedCentralPubMed

168.

Flower A, Liu JP, Lewith G, Little P, Li Q. Chinese herbal medicine for endometriosis. Cochrane Database of Systematic Reviews. 2012;(5):CD006568.

169.

Zhao RH, Hao ZP, Zhang Y, Lian FM, Sun WW, Liu Y, Wang R, Long L, Cheng L, Ding YF, Song DR, Meng QW, Wang AM. Controlling the recurrence of pelvic endometriosis after a conservative operation: comparison between Chinese herbal medicine and western medicine. Chin J Integr Med. 2013;19(11):820–5.

170.

Strathy JH, Molgaard CA, Coulam CB, Melton 3rd LJ. Endometriosis and infertility: a laparoscopic study of endometriosis among fertile and infertile women. Fertil Steril. 1982;38:667–72.PubMed

171.

Verkauf BS. The incidence, symptoms, and signs of endometriosis in fertile and infertile women. J Fla Med Assoc. 1987;74:671–5.PubMed

172.

Bulletti C, Montini A, Setti PL, Palagiano A, Ubaldi F, Borini A. Vaginal parturition decreases recurrence of endometriosis. Fertil Steril. 2010;94(3):850–5.PubMed

173.

Parazzini F, Chiaffarino F, Surace M, Chatenoud L, Cipriani S, Chiantera V, et al. Selected food intake and risk of endometriosis. Hum Reprod. 2004;19:1755–9.PubMed

174.

Kidd PM. Omega-3 DHA and EPA for cognition, behavior, and mood: clinical findings and structural-functional synergies with cell membrane phospholipids. Altern Med Rev. 2007;12:207–27.PubMed

175.

Halliwell B, Gutteridge JM. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol. 1990;186:1–85.PubMed

176.

Harel Z, Biro FM, Kottenhahn RK, Rosenthal SL. Supplementation with omega-3 polyunsaturated fatty acids in the management of dysmenorrhea in adolescents. Am J Obstet Gynecol. 1996;174:1335–8.PubMed

177.

Kaneda N, Nagata C, Kabuto M, Shimizu H. Fat and fiber intakes in relation to serum estrogen concentration in premenopausal Japanese women. Nutr Cancer. 1997;27:279–83.PubMed

178.

Armstrong BK, Brown JB, Clarke HT, Crooke DK, Hähnel R, Masarei JR, et al. Diet and reproductive hormones: a study of vegetarian and nonvegetarian postmenopausal women. J Natl Cancer Inst. 1981;67:761–7.PubMed

179.

Longcope C, Gorbach S, Goldin B, et al. The effect of a low fat diet on estrogen metabolism. J Clin Endocrinol Metab. 1987;64:1246–50.PubMed

180.

Missmer SA, Chavarro JE, Malspeis S, Bertone-Johnson ER, Hornstein MD, Spiegelman D, et al. A prospective study of dietary fat consumption and endometriosis risk. Hum Reprod. 2010;25:1528–35.PubMedCentralPubMed

181.

Trabert B, Peters U, De Roos AJ, Scholes D, Holt VL. Diet and risk of endometriosis in a population-based case–control study. Br J Nutr. 2011;105(3):459–67.PubMedCentralPubMed

182.

Dhillon PK, Holt VL. Recreational physical activity and endometrioma risk. Am J Epidemiol. 2003;158:156–64.PubMed

183.

Missmer SA, Cramer DW. The epidemiology of endometriosis. Obstet Gynecol Clin North Am. 2003;30:1–19.PubMed

184.

Vitonis AF, Hankinson SE, Hornstein MD, Missmer SA. Adult physical activity and endometriosis risk. Epidemiology. 2010;21(1):16–23.PubMedCentralPubMed

185.

Signorello LB, Harlow BL, Cramer DW, Spiegelman D, Hill JA. Epidemiologic determinants of endometriosis: a hospital-based case–control study. Ann Epidemiol. 1997;7:267–741.PubMed

186.

Vitonis AF, Maruti SS, Se H, Hornstein MD, Missmer SA. Adolescent physical activity and endometriosis risk. J Endometriosis. 2009;1:157–63.

187.

Crain DA, Janssen SJ, Edwards TM, Heindel J, Ho SM, Hunt P, et al. Female reproductive disorders: the roles of endocrine- disrupting compounds and developmental timing. Fertil Steril. 2008;90(4):911–40.PubMedCentralPubMed

188.

Gilbert SF. Mechanisms for the environmental regulation of gene expression: ecological aspects of animal development. J Biosci. 2005;30:65–74.PubMed

189.

Bumey RO, Giudice LC. The pathogenesis of endometriosis. In: Nezhat’s operative gynecologic laparoscopy and hysteroscopy. 3rd ed. New York: Cambridge University Press; 2008. p. 251–7.

190.

Dl A, Foster WG. The link between environmental toxicant exposure and endometriosis. Front Biosci. 2008;13:1578–93.

191.

Kl B-T, Yeaman GR, Crispens MA, Igarashi TM, Osteen KG. Dioxin may promote inflammation-related development of endometriosis. Fertil Steril. 2008;89(5 suppl):1287–98.

192.

Herington JL, Bruner-Tran KL, Lucas JA, Osteen KG. Immune interactions in endometriosis. Expert Rev Clin Immunol. 2011;7:611–26.PubMedCentralPubMed

193.

Schaefer WR, Hermann T, Meinhold-Heerlein I, Deppert WR, Zahradnik HP. Exposure of human endometrium to environmental estrogens, antiandrogens, and organochlorine compounds. Fertil Steril. 2000;74:558–63.PubMed

194.

Quaranta MG, Porpora MG, Mattioli B, Giordani L, Libri I, Ingelido AM, et al. Impaired NK-cell-mediated cytotoxic activity and cytokine production in patients with endometriosis: a possible role for PCBs and DDE. Life Sci. 2006;79:491–8.PubMed

195.

Cooney MA, Buck Louis GM, Hediger ML, Vexler A, Kostyniak PJ. Organochlorine pesticides and endometriosis. Reprod Toxicol. 2010;30:365–9.PubMed

196.

Cobellis L, Latini G, De Felice C, Razzi S, Paris I, Ruggieri F, et al. High plasma concentrations of di-(2-ethylhexyl)-phthalate in women with endometriosis. Hum Reprod. 2003;18:1512–5.PubMed

197.

Reddy BS, Rozati R, Reddy S, Kodampur S, Reddy P, Reddy R. High plasma concentrations of polychlorinated biphenyls and phthalate esters in women with endometriosis: a prospective case control study. Fertil Steril. 2006;85:775–9.PubMed

198.

Buck Louis GM, Weiner JM, Whitcomb BW, Sperrazza R, Schisterman EF, Lobdell DT, et al. Environmental PCB exposure and risk of endometriosis. Hum Reprod. 2005;20:279–85.

199.

Buck Louis GM, Chen Z, Peterson CM, Hediger ML, Croughan MS, Sundaram R, et al. Persistent lipophilic environmental chemicals and endometriosis : the ENDO Study. Environ Health Perspect. 2012;120(6):811–6.PubMed

200.

Myllymaki SA, Haavisto TE, Brokken LJ, Viluksela M, Toppari J, Paranko J. In utero and lactational exposure to TCDD; steroidogenic outcomes differ in male and female rat pups. Toxicol Sci. 2005;88:534–44.PubMed

201.

Pesonen SA, Haavisto TE, Viluksela M, Toppari J, Paranko J. Effects of in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on rat follicular steroidogenesis. Reprod Toxicol. 2006;22:521–8.PubMed

202.

Wormke M, Stoner M, Saville B, Safe S. Crosstalk between estrogen receptor alpha and the aryl hydrocarbon receptor in breast cancer cells involves unidirectional activation of proteasomes. FEBS Lett. 2000;478:109–12.PubMed

203.

Osteen KG, Bruner-Tran KL, Eisenberg E. Reduced progesterone action during endometrial maturation: a potential risk factor for the development of endometriosis. Fertil Steril. 2005;83:529–37.PubMed

204.

Fazleabas AT, Brudney A, Chai D, Langoi D, Bulun SE. Steroid receptor and aromatase expression in baboon endometriotic lesions. Fertil Steril. 2003;80 Suppl 2:820–7.PubMed

205.

Hudelist G, Keckstein J, Czerwenka K, Lass H, Walter I, Auer M, et al. Estrogen receptor beta and matrix metalloproteinase 1 are coexpressed in uterine endometrium and endometriotic lesions of patients with endometriosis. Fertil Steril. 2005;84 Suppl 2:1249–56.PubMed

206.

Daxinger L, Whitelaw E. Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat Rev Genet. 2012;13:153–62.PubMed

207.

Calkins K, Devaskar SU. Fetal origins of adult disease. Curr Probl Pediatr Adolesc Health Care. 2011;41(6):158–76.PubMed

208.

Genuis SJ. The chemical erosion of human health: adverse environmental exposure and in-utero pollution- determinants of congenital disorders and chronic disease. J Perinat Med. 2006;34:185–95.PubMed

209.

Taylor HS M.D. Endocrine disruptors affect developmental programming of HOX gene expression. Fertil Steril. 2008;89(1):e57–8.PubMedCentralPubMed

210.

Takahashi O, Oishi S. Disposition of orally administered 2,2-Bis (4-hydroxyphenyl) propane (Bisphenol A) in pregnant rats and the placental transfer to fetuses. Environ Health Perspect. 2000;108:931–5.PubMedCentralPubMed

211.

Zalko D, Soto AM, Dolo L, Dorio C, Rathahao E, Debrauwer L, et al. Biotransformations of bisphenol A in a mammalian model: answers and new questions raised by low-dose metabolic fate studies in pregnant CDI mice. Environ Health Perspect. 2003;111:309–19.PubMedCentralPubMed

212.

Oesterheld J. A review of developmental aspects of cytochrome P450. J Child Adolesc Psychopharm. 1998;8:161–74.

213.

Kreuzer PE, Csanady GA, Baur C, Kessler W, Papke O, Greim H, et al. 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition. Arch Toxicol. 1997;71:383–400.PubMed

214.

Jorissen J. Literature review: outcomes associated with postnatal exposure to polychlorinated biphenyls (PCBs) via breast milk. Adv Neonatal Care. 2007;7(5):230–7.PubMed

215.

Boersema ER, Lanting CI. Environmental exposure to polychlorinated biphenyls (PCBs) and dioxins. Consequences for longterm neurological and cognitive development of the child lactation. Adv Exp Med Biol. 2000;478:271–87.

216.

Lee SY, Kim MT, Kim SW, Song MS, Yoon SJ. Effect of lifetime lactation on breast cancer risk: a Korean women’s cohort study. Int J Canc. 2003;105:390–3.

217.

Daniels JL, Jen-Pan I, Jones R, Anderson S, Patterson DG, Needham LL, et al. Individual characteristics associated with PBDE levels in U.S. human milk samples. Environ Health Perspect. 2010;118(1):155–60.PubMedCentralPubMed

218.

Miyata H, Takenaka T, Nakao T, Aozasa O, Ohta S, Fujimine Y, et al. Investigation of the main source of halogenated environmental pollutants in human breast milk (The Third Report)- Influence by fasting. Organohalogen Comp. 2006;68:145–8.

219.

LaKind JS. Recent global trends and physiologic origins of dioxins and furans in human milk. J Expo Sci Environ Epidemiol. 2007;17(6):510–24.PubMed

220.

Anderson RC, Anderson JH. Acute respiratory effects if diaper emissions. Arch Environ Health. 1999;54(5):353.PubMed

221.

Sathyanarayana S, Karr CJ, Lozano P, Brown E, Calafat AM, Liu F, et al. Baby care products: possible sources of infant phthalate exposure. Pediatrics. 2008;121(2):e260–8.PubMed

222.

Curl C, Fenske RA, Elgethun K. Organophosphorus pesticide exposure of urban and suburban preschool children with organic and conventional diets. Environ Health Perspect. 2003;111(3):377–82.PubMedCentralPubMed

223.

Kimbrell A. Fatal harvest: the tragedy of industrial agriculture. Washington: Foundation for Deep Ecology and Island Press; 2002. p. 211.

224.

Zeligs MA. Diet and estrogen status: the cruciferous connection. J Med Food. 1998;1(2):67–82.

225.

Estrogenic agents leach from dental sealant. Science News April 11, 1996;49:214.

226.

Buckley JD, Meadows AT, Kadin ME, Le Beau MM, Siegel S. Pesticide exposures in children with non Hodgkin’s Lymphoma. Cancer. 2000;89(11):2315–21.PubMed

227.

Kokcu A. Relationship between endometriosis and cancer from current perspective. Arch Gynecol Obstet. 2011;284(6):1473–9.PubMed

228.

Frisch RE. Body fat, menarche and fertility. Hum Reprod. 1987;2(6):521–33.PubMed

229.

Stark O, Peckham CS, Moynihan C. Weight and age at menarche. Arch Dis Child. 1989;64:383–7.PubMedCentralPubMed

230.

Diamond F. The function of adipose tissue. Growth Genet Horm. 2002;18(2):17–22.

231.

Chavarro JE, Peterson KE, Sobol AM, Wiecha JL, Gortmaker SL. Effect of a school-based obesity-prevention on menarche. Cancer Causes Control. 2005;16:1245–52.PubMed

232.

Buck Louis GM, Hediger ML, Peńa JB. Intrauterine exposures and risk of endometriosis. Hum Reprod. 2007;22:3232–6.PubMed

233.

Vitonis AF, Baer HJ, Hankinson SE, Laufer MR, Missmer SA. A prospective study of body size during childhood and early adulthood and the incidence of endometriosis. Hum Reprod. 2010;25:1325–34.PubMedCentralPubMed

234.

Somigliana E, Vigano P, Abbiati A, Paffoni A, Benaglia L, Vercellini P, et al. Perinatal environment and endometriosis. Gynecol Obstet Invest. 2011;72:135–40.PubMed

235.

Wolff EF, Sun L, Hediger ML, Sundaram R, Peterson CM, Chen Z, et al. In utero exposures and endometriosis: the Endometriosis, Natural History, Disease, Outcome(ENDO) Study. Fertil Steril. 2013;99(3):790–5.PubMedCentralPubMed