Ebru H. Biberoglu1 and Kutay O. Biberoglu2
Dr. Zekai Tahir Burak Women Health Care, Education and Research Hospital Ankara, Ankara, Turkey
Gazi University Medical School, Professor of Obstetrics and Gynecology, Gynecological Endocrinology and Infertility Unit Besevler, Ankara, Turkey
Ebru H. Biberoglu (Corresponding author)
Kutay O. Biberoglu
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.
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 .
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 [1–3].
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 . 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 [5–8]. Endometriosis has been negatively associated with exercise and smoking . Recently, red hair , blue or green eyes, and freckles have been reported to increase the odds of diagnosis . 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 .
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 . It is likely that endometriosis is a common polygenic/multifactorial disease caused by an interaction between genes as well as the environment [14, 15].
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 . The lowest risk was seen in those whose age at menarche was 15 years .
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 [18, 19].
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 .
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 . Indeed, for every unit increase in BMI, 12–14 % decrease in the likelihood of having endometriosis was claimed . In a recent study, BMI (OR, 0.95; 95 % CI, 0.93–0.98) was found to decrease the odds of diagnosis of endometriosis . 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 .
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) . 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 . In addition, it was reported that exposed women with vaginal epithelial changes had 50 % more autoimmune disease than exposed women without vaginal epithelial changes . 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 [26, 27].
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 [28–31].
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) .
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 [33, 34].
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 . 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 . Alternatively, TCDD could activate specific signaling pathways causing overexpression of K-ras thereby promoting peritoneal endometriosis .
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 . If this expression pattern is established during fetal development via epigenetic mechanisms, then endometriosis could manifest during adulthood after estrogenic exposures .
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) .
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 . Whereas, a deleterious effect on endometriosis risk through exposure to polycyclic aromatic hydrocarbons  or dioxins  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 . 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 . 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 .
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 . 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 [47, 48].
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 . 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) . 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 .
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 . 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 . 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  and with endometriosis in association with BLyS-817C⁄T polymorphism .
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 .
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 [55–57].
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 . A recent study described a high prevalence of comorbid chronic pain syndromes (56 %) and mood disorders (48 %) in adolescents and young women with endometriosis . Nevertheless, irritable bowel syndrome, painful bladder syndrome, and chronic headache were detected in 25 % versus 65 % ; in 16 % versus 65 %  and 19 % versus 38 %  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 . 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 . Angiogenic cytokines are hypothesized to play a critical role in the pathogenesis of endometriosis and migraine, possibly by stimulating matrix metalloproteinases (MMPs) . 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 . Mast cell activation without allergic degranulation has been documented to occur in response to stress and lead to painful sterile inflammatory states . 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 .
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 [65–68].
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 [69–73].
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 .
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 ; therefore long-term use is recommended .
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 ; 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 .
The findings of the reports studying the link between OCP and endometriosis are contradictory. Decreased [17, 79, 80] or increased [81, 82] 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 [83, 84].
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 . 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 %) . 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 . 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 , and women who receive OCP especially following failed NSAIDs for dysmenorrhea may already have developed endometriosis, but is still undiagnosed . 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 .
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 [81, 90–92]. Others have reported an increased prevalence of endometriosis among former IUD users [9, 93, 94]. Even a weak protection has been observed in a subgroup for subjects who stopped using IUD more than 10 years ago .
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 [95, 96]. The LNG IUS also reduce the risk of recurrence of dysmenorrhea after conservative surgery for endometriosis .
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 . 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 .
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 . 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 .
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 , but higher serum cortisol levels are detected in infertile women with advanced endometriosis . 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 . 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 [104, 105]. 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 [106, 107]
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 [108, 109]. 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.
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 .
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 .
Research on possible immunomodulatory role of pentoxifylline did not show any impact on future fertility in infertile women with asymptomatic minimal and mild endometriosis .
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 .
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 . Defects in macrophage activation may lead to chronic immune activation with accompanying reduction in immune response contributing to the growth of endometriotic lesions . Retinoic acid (RA) has been shown to modulate inflammation in autoimmune disease by enhancing regulatory T-cell (Treg) suppression of proinflammatory cells [116, 117]. In model systems involving activated monocytes/macrophages, RA decreases proinflammatory cytokines while increasing anti-inflammatory proteins such as interleukin-10  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 . These in vivo findings emphasize the potential use of retinoids to prevent and to treat women with endometriosis .
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 . In the animal model, antioxidant enzymes like superoxide dismutase and catalase prevent intraperitoneal adhesions of endometriotic tissues in the peritoneal cavity .
Melatonin and its metabolites as antioxidants protect cellular components, stimulate secretion of progesterone, and have oncostatic, antiproliferative, and antiestrogenic effects [123, 124].
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 .
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 . Experimental data emerging from treatments with anti-inflammatory modulators such as cyclooxygenase 2 inhibitors , peroxisome proliferator-activated receptor-γ agonist , and TNF-α inhibitors like TNFα-binding protein (TBP)-1, TNF-soluble high-affinity receptor complex, infliximab, and etanercept [129, 130] 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 .
Several previous studies showed the benefit of targeting MIF and also of managing inflammatory diseases such as asthma, sepsis, and viral infection [132, 133].
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 . 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 . Several other studies reported contradictory results [136–138]. 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 . Magnesium has also been shown to relax smooth muscles  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 [141, 142]. 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 [142, 143].
It has been shown that the VDR agonist, elocalcitol, inhibits lesion development in a mouse model of endometriosis .
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.
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 . Considering its safety and minimal side effects, use of statins in treatment of endometriosis holds promise .
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 . 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 [112, 148].
18.2.8 Sorafenib: An Antiangiogenic and Tyrosine Kinase Inhibitor
Various epigenetic aberrations have been described in endometriosis . 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 , 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 .
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 . 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 . 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 . 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 [155, 156].
In mice experimental endometriosis model, pro-EGCG, inhibits the development, growth, and angiogenesis of the implants [157, 158]. 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 .
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 , and also suppressing the development of new blood vessels. Moreover, resveratrol dose-dependently suppresses the development of new blood vessels . 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  as well as several inflammatory, metabolic , and cardiovascular diseases . 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 . 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 . 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 .
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 .
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 [168, 169].
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 %) , and infertile women are 6–8 times more likely to have endometriosis than fertile women . 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 . 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) . 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 .
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 . 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 [174, 175]. 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 . 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 . 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 [177, 178]. Additionally, high-fat diets have been associated with increased estradiol levels in premenopausal women [177, 179], 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 [34, 173]. 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 . A recently published population-based case–control study  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 [9, 34, 182]. 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 . 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 .
Although adult physical activity has been mostly associated with lower endometriosis risk [9, 34, 182, 183, 185], 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 , 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 , 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 .
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 .
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 . 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 . 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 . 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 , 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 [190, 191] which are known to disrupt endocrine and immune functions .
Human endometrium is a known site for estrogen, and many environmental chemicals have been detected there  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 .
Recently, organochlorine pesticides have also been shown to increase endometriosis risk in a laparoscopic cohort of US women  and other studies have reported increased risks with higher concentration of phthalates [196, 197], polychlorinated dibenzodioxins and polychlorinated dibenzofurans, and polychlorinated biphenyls [198, 199].
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 .
Since in utero and lactational exposure to TCDD reduces circulating estradiol in vivo  and decreases ovarian estradiol production in cultures , and also causes degradation of ER-α , 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  and P insensitivity is characteristic of women with endometriosis [189, 203]. TCDD which is an immunosuppressant  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 . 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 . 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 [204, 205]. 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 . 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 . 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” .
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 .
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 [210, 211]. 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 .
Breastfed infants exposed to EDCs have much higher blood levels than formula-fed infants . 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 .
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 [215, 216].
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 [217, 218]. 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 .
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 . Infants whose skin are exposed to lotion, powder, and shampoo reveal increased urinary concentrations of phthalates .
Since food is the primary exposure to EDCs, eating organic instead of genetically modified foods is very critical . Another way to reduce exposure is to eat more vegetables, grains, fruits, and less animal products . 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 . 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 . 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 . 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 .
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 . Since fat cells produce estrogen, heavier girls usually begin sexual development and periods earlier . Fat cells also make cytokines, therefore keeping down fat should also avoid inflammation . 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 .
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 . Another study demonstrated lower odds of the diagnosis with in utero exposure to cigarette smoking . Women eventually diagnosed with endometriosis were leaner from childhood through diagnosis relative to women without endometriosis . This finding was subsequently corroborated in the large Nurses Health III Cohort Study . 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 [234, 235].
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.
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