Impact of lifestyle and diet on endometriosis: a fresh look to a busy corner

Endometriosis is a  chronic inflammatory disorder characterized by the presence of ectopic endometri- al-like glands and stroma, often involving the pelvic organs and frequently leading to anatomical distortion within the pelvis [1, 2]. The prevalence of this disease ranges between six and ten percent [3], while the in- cidence is believed to be above 33% for patients with acute pelvic pain [4]. Nevertheless, it is difficult to pre- cisely estimate the incidence and prevalence of super - ficial peritoneal endometriosis because of the absence of an accurate non-invasive biomarker [5]. The main symptoms for affected women include chronic pelvic pain, dysmenorrhea, infertility [6], and deep dyspareu- Impact of lifestyle and diet on endometriosis: a fresh look to a busy corner Nassir Habib1, Giovanni Buzzaccarini2, Gabriele Centini3, Gaby N. Moawad4, Pierre-Francois Ceccaldi5, Georgios Gitas6, Ibrahim Alkatout7, Giuseppe Gullo8, Sanja Terzic9, Zaki Sleiman10 1Obstetrics and Gynecology Department, Francois Quesnay Hospital, Mantes-La-Jolie, France 2Department of Women’s and Children’s Health, University of Padua, Padova, Italy 3Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy 4Gynecology Department, George Washington University, Washington, United States of America 5Obstetrics and Gynecology Department, Beaujon Teaching Hospital, Clichy and Paris Diderot University, Clichy, France 6Department of Obstetrics and Gynecology, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany 7Department of Obstetrics and Gynecology, University Hospital of Schleswig-Holstein, Kiel, Germany 8Azienda Ospedaliera Ospedali Riuniti (AOOR) Villa Sofia Cervello, IVF Public Center, University of Palermo, Palermo, Italy 9Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan 10Obstetrics and Gynecology Department, Lebanese American University, Beirut, Lebanon

Endometriosis is a chronic inflammatory disorder with a prevalence of six to ten percent in women of child- bearing age. As long as the aetiology of endometriosis is not fully understood and the disease has no definitive treatment, an examination of the environmental factors or interventions that could modify or cure endometriosis would greatly benefit women suffering from this chronic condition. This literature review utilized the electronic databases PubMed, EMBASE, and MEDLINE until February 2021. Studies indicate that fish oil may have a positive effect on reducing endometriosis-related pain due to the effects of pro-inflammatory prostaglandins derived from omega-3 fatty acids. The same effect was seen with the intro- duction of antioxidant vitamins C, D, and E. There is clinical viability of a low fermentable oligo-, di-, and mono- saccharides and polyols diet to successfully reduce the symptoms of patients who suffer from both endometriosis and irritable bowel syndrome. Despite the low level of evidence, there are frequent associations between endo- metriosis and gastrointestinal conditions in addition to the influence of various nutritional factors on the disease. The management of endometriosis requires a holistic approach focused on reducing overall inflammation, increasing detoxification, and attenuating troublesome symptoms. A dietician may provide great benefit in the management of these patients, especially at younger ages and in early stages. High-level evidence and well- designed randomized studies are lacking when it comes to studying the effect of lifestyle and dietary intake on endometriosis. Inarguably, further research with a more extensive focus is needed. Key words: endometriosis, nutrition, lifestyle, chronic pelvic pain, diet. nia [7]. However, the management of these symptoms is not standardized, and the disease can recur even after proper surgical [8] or pharmacological management [9]. In particular, we can consider surgery as a cytoreductive therapy, which removes the illness. However, endome- triosis can recur. On the other hand, medical therapy acts with a suppressive effect on endometriosis. Simi- larly but differently, in the case of medical therapy ces- sation, the illness may be reactivated. Different hypotheses explain the pathogenesis of en - dometriosis [10, 11]. The most widely accepted theo- ry involves retrograde menstruation [7], but the exact aetiology remains unknown. As long as the aetiology of endometriosis is not fully understood and the condi- tion has no definitive treatment [12], women suffering Corresponding author: Zaki Sleiman, Obstetrics and Gynecology Department, Lebanese American University, Beirut, Lebanon, e-mail: [email protected] Submitted: 03.01.2022 Accepted: 22.02.2022 Menopause Review/Przegląd Menopauzalny 21(2) 2022 125 from this chronic disease may greatly benefit from in- sights into environmental factors [13] or interventions that could prevent, modify, or cure endometriosis [14]. Endometriosis is a hormone-dependent chronic inflam- matory condition that depends on oestrogen for growth and maintenance. Oestrogen is produced by the ova- ries, skin and fatty tissue, and also could be produced locally by the endometriotic lesions themselves through a  positive feedback loop between PGE2, aromatase, oestrogen, and COX-2 [15, 16]. In this scenario, an asso- ciation has been found between diet and oestrogen-de- pendent diseases (similar to breast or endometrial can- cer). Many dietary and lifestyle modifications can play a considerable role in symptom minimization [17] and may influence disease severity or progression [18–20]. The purpose of this paper is to review the literature to evaluate the impact of environment, lifestyle, and diet on symptom expression and endometriosis pro- gression. We also aim to identify a potential diet to help women with endometriosis control their disease or at least find symptomatic relief.

A  literature review was conducted using the elec- tronic databases PubMed, EMBASE, and MEDLINE with the search terms ‘endometriosis’ (MeSH) and ‘nutrition’, ‘lifestyle’, ‘diet’, ‘irritable bowel disease’, ‘physical activity’, ‘weight’, or ‘body mass index’ (BMI). The review specifically evaluated articles published in the English language until February 2021. Multiple au- thors reviewed the papers and independently selected the articles included in this review. Risk factors and pathogenesis of endometriosis The incidence of dysmenorrhea has been quoted to be as high as 45–90% in developing countries, and it is a frequent complaint of women who suffer from endometriosis [21, 22], with a  robust potential nega- tive impact on the quality of life [23] and psychological wellbeing [24]. The combination of dysmenorrhoea and unexplained infertility [25] appears to be a significant predictor of endometriosis in women suffering from these two concomitant conditions [26, 27], which needs accurate differential diagnosis [28]. Early age at men- arche and shorter menstrual cycles have been consis- tently associated with a  higher risk of endometriosis [29–31], potentially as a result of an altered hormonal milieu and an increased duration of exposure to retro- grade menstruation. However, with less consistent evi- dence, researchers have found that endometriosis may be related to the monthly duration of menses, the reg- ularity of menstrual cycles, the heaviness of menstrual flow, and tampon use [30, 32, 33]. Along with its broad array of risk factors, endo- metriosis has a  multifactorial pathogenesis (Fig. 1). The retrograde menstruation theory can explain the pathogenesis of endometriosis to a  large extent, but not completely, as the theory notably lacks an expla- nation of how endometrial tissue grafts onto the peri- toneum. It is obvious that endometriosis is a complex Implantation and growht of pathological endometrial fragments Fig. 1. Pathogenesis and risk factors of endometriosis Structural endometrial abnormalities Impaired steroid biosynthesis over expression Neoangiogenesis, endometrial neurogenesis Proinflammatory profile in endometrial tissue Hormones, immune disorders Interaction of genetic and hereditary predisposition Epigenetic inflammatory and environmental factors Menopause Review/Przegląd Menopauzalny 21(2) 2022 126 phenomenon caused by the interaction of genetic and hereditary predispositions, epigenetic inflammatory and environmental factors, hormones, immune disor - ders, and certain structural endometrial abnormali- ties [1, 34–36]. Indeed, impaired steroid biosynthesis (e.g., hyperoestrogenism, progesterone resistance, or aromatase over-expression) increases the endometrial invasive potential associated with neoangiogenesis, en- dometrial neurogenesis, and a  pro-inflammatory pro- file in endometrial tissue compared with disease-free endometrium. These are examples of pre-existing en- dometrial abnormalities that could also promote the implantation and growth of pathological endometrial fragments outside the uterine cavity [37]. Meanwhile, it remains uncertain how these mechanisms partici- pate to create the different phenotypes of endometrio- sis, and the potential cross-talk of these elements with the immune system within the pelvic cavity [38]. Genetically, women with a first-degree relative suf- fering from endometriosis are six times more likely to be diagnosed with endometriosis compared to the gen- eral population [26]. Moreover, large studies of twins reveal a  heritability of approximately 50% [39, 40]. However, the identification of genetic factors causing this condition is incomplete, and the current evidence suggests that the likelihood of having a “major gene” involved in familial endometriosis is low [41–43]. No- tably, whole-genome association studies have reported a  dozen sensitive regions although these regions ac- count for just over four percent of heritability [36]. The involvement of endocrine-disrupting chemi- cals in endometriosis remains questionable [44–46]. At present, the evidence of a  direct relation between endometriosis and endocrine-disrupting chemicals is inconsistent [47]. New recent findings show that the glandular and stromal components of endometriosis originate from different sources. Moreover, the epithelial component of endometriosis harbours cancer-associated muta- tions, compared to the stromal component, which is mu- tation-free. These findings suggested that the stroma is regenerative, unlike the glands. Additionally, the en- dometriotic lesions were found to have epithelial pro- genitors and mesenchymal stem cells. All these insights show that endometriosis is derived from different sources and the pathogenetic mechanisms are more complex than expected [48].

Physical factors Birthweight Scientific advances in medicine have revealed how intrauterine exposures impact the embryo or fetus by continuously reprogramming its development for ex- trauterine life [49, 50]. The relationship between birth weight and the risk of developing endometriosis has been the subject of several studies [29, 51–53]. Extremes of birthweight, both low and high, have been found to be associated with a  higher risk of developing endo- metriosis over a  woman’s lifetime (RR = 1.3, 95% CI: 1.0–1.8) [29, 51]. However, conflicting data exist re- garding prematurity and endometriosis risk, with some studies reporting an increased risk [52–54] and others reporting no association [51, 55, 56]. For an accurate in- terpretation of the influence of birthweight on the risk of endometriosis, it is necessary to restrict analyses to term births, and for studies including preterm neonates to adjust for gestational age. Childhood, adolescent, and adult weight In the same sense as above, the relationship be- tween childhood and adolescent weights and the de- velopment of endometriosis is counterbalanced. Early studies described the current state of being thin and underweight as hallmarks of patients suffering from endometriosis, without insight into whether this is a cause or a consequence of their disease or its symp- toms [30, 33, 57–59]. Regardless of the patient’s age, current evidence suggests an inverse relationship be- tween BMI and the prevalence of endometriosis [56, 60–62]. However, the association between obesity and endometriosis remains debatable. Some researchers have discovered an elevated incidence of endometri- osis in obese women [63] with a correlation between the risk of developing endometriosis and prepubertal obesity [64]. Nagle et al. suggested that women who reported being overweight at 10 years of age had an increased risk of endometriosis (OR = 2.8; 95% CI: 1.1–7.5), whereas there was no clear evidence of an association between relative weight at 16 years of age and the risk of endometriosis [64]. Other researchers have reported an inverse relationship between obesity and the risk of endometriosis [32, 60, 65–69]. In a me- ta-analysis, Liu et al. found a significant inverse associ- ation; the overall analysis revealed a 33% reduction in the risk of endometriosis for each 5 kg/m 2 increase in BMI (RR = 0.67; 95% CI: 0.53–0.84), with statistically significant heterogeneity across the studies (p < 0.001, I = 86.9%) [67]. These contradictory results confirm the need for studies with larger numbers to elucidate the real association between being overweight or obese and endometriosis while taking into account metabolic and biochemical parameters. Physical activity In view of the inflammatory [70] and oestrogen-de- pendent profile of the disease [1], the role that physical activity can play in reducing the risk of endometriosis seems highly possible on an intuitive level. Current evidence suggests that endometriosis symptoms may be reduced by physical activity [62, 71]. However, this Menopause Review/Przegląd Menopauzalny 21(2) 2022 127 association is inconsistent [72]. Case-control studies have inconclusively found that patients who exercised regularly had fewer symptoms compared to individu- als without self-reported regular exercise [58, 73, 74]. When comparing women with the highest physical activity levels to the lowest, researchers discovered a non-significant decrease in the reporting of endome- triosis-related symptoms (RR = 0.89, 95% CI: 0.77–1.03) [75]. Nevertheless, physical activity may influence en- dometriosis symptomatology and progression due to its known influence on hormonal levels, such as de- creasing luteal oestrogens [76] and increasing sex hor - mone binding globulin levels [77]. Breastfeeding In a  prospective cohort study of 72,394 women, Farland et al. found that breastfeeding was a  protec- tive factor for endometriosis-related symptoms among the 3,296 (4.6%) women who had laparoscopically con- firmed endometriosis [78]. Additionally, the rate of en- dometriosis-related symptoms was decreased among women with at least six months of postpartum breast- feeding. Although the causation behind this correla- tion is not fully understood, the present belief is that the symptomatic relief is due to amenorrhoea [78, 79]. Dietary factors Alcohol consumption Data are mixed regarding alcohol consumption and the development of endometriosis [68, 71, 80]. Several studies have identified an association between alcohol consumption and symptoms related to endometrio- sis, whereas others have not [30, 62, 71, 74, 81–83]. Still, the available evidence is not without limitations. In the studies where researchers found an association between endometriosis and alcohol consumption, it is difficult to ascertain whether the consumption is due to the disease or vice versa. At this time, it also remains unknown whether different types of alcohol affect this disease differently. Diet Inflammation, oestrogen activity, menstrual regular- ity, and prostaglandin physiology are important patho- physiologic processes to consider when diagnosing and treating endometriosis [80]. Diet is an integral compo- nent of these factors and, as such, consumption likely has a role in the development and progression of this disease. In fact, a recent case-control study found that women who consume diets with high inflammatory potential are significantly more likely to have endome- triosis in comparison to those with less inflammatory diets [84]. A  prospective cohort study of the Nurses’ Health Study II population found that women who consume more than two servings a day of red meat have a 56% higher risk of endometriosis diagnosis compared to those who consume less than one serving per week (95% CI: 1.22–1.99), with the association being high- est for those who consume non-processed red meats [85]. In contrast, a  case-control study comparing the frequency and consumption per week of selected items in the Iranian diet found the intake of red meat to be associated with a  lower risk of endometriosis (OR = 0.61, 95% CI: 0.41–0.91) [86]. Jurkiewicz-Przondzi- ono et al. highlighted dietary factors that potentially in- crease the risk of developing endometriosis, including the high intake of ham, red meat, and trans-unsatu- rated fatty acids [80]. The authors surmised that the pro-inflammatory profiles of these foods account for their associations with the disease [80]. Omega-6 fatty [87] acids derived from the diet are the precursors of the pro-inflammatory prostaglandins PGE2 and PGF2α, which likely increase uterine cramps and cause the painful symptoms of endometriosis [88]. In the same review, it was also suggested that antiox- idant vitamins (D, E, and B-group vitamins) [89, 90], as well as foods rich in calcium and omega-3 fatty acids, may protect against the development of endometrio- sis [80]. In the cohort study by Darling et al. including 70,617 women (n = 1,383 for the experimental group with confirmed endometriosis and n = 69,234 for the control group), the consumption of products rich in vita- mins such as folic acid (p = 0.003), vitamin C (p = 0.02), and vitamin E (p < 0.0001) was inversely proportional to the risk of developing endometriosis [91]. The au- thors did not find that endometriosis symptoms were mitigated by providing these same vitamins through dietary supplements [91]. A  recent double-blind ran- domized placebo-controlled trial examining treatment with vitamin D [92], omega-3 fatty acids, or placebo in women with surgically confirmed endometriosis and pelvic pain found that women in both the vitamin D and placebo arms had similarly significant improvements in pain scores, while those in the omega-3 arm demon- strated lesser improvements [93]. Thus, while pro-in- flammatory omega-6 fatty acids may increase endome- triosis-related pain, antioxidant vitamins and omega-3 fatty acids may be protective against these symptoms. Methylation changes [94], which are a  hallmark of cancers and endometriosis [95], are influenced by di- etary factors such as folate consumption, calorie intake, and polyphenol content. Such compounds tend to bio- accumulate in lipids contained particularly in meat, liv- er, and dairy products and can also be counted among the risk factors for endometriosis. However, nowhere in the literature is this association reported. In a study of curcumin and its impact on endome- triosis, the authors found that this spice might have potential benefits for the prevention and treatment of endometriosis. The benefits from curcumin are believed Menopause Review/Przegląd Menopauzalny 21(2) 2022 128 to be due to its anti-inflammatory, antioxidant, anti-tu- mour, and anti-angiogenic profile [96]. However, because of the limited studies on this topic and inconsistent data, further studies are needed to improve the knowledge of the true impact of curcumin on endometriosis. Fasting Fasting can help preserve energy levels [97], there- by providing the body time to regenerate and heal. In- creased hormonal modulation, reduced inflammation [98], and increased stress resistance are ways in which fasting may help reduce chronic pain severity. In clinical practice, we have found that strategic fasting can help reduce symptomatic flares among patients suffering from symptoms related to endometriosis. We some- times advise outpatients to eat lightly or to fast prior to their menstrual cycles in order to lessen the activity of the gastrointestinal (GI) tract, thereby reducing the uncomfortable and painful GI symptoms associated with endometriosis. Currently, there are no studies on the role of fasting in the management of endometriosis. FODMAPs and irritable bowel syndrome Irritable bowel syndrome (IBS) impacts 11.2% of the population worldwide and significantly affects quality of life for many women. The role of diet is very import- ant in IBS, both in worsening and improving symp- toms for patients suffering from this disorder. The fer - mentable oligo-, di-, and mono-saccharides and polyols (FODMAPs) comprise a group of carbohydrates resistant to digestion that are found in a broad range of foods. FODMAPs play a substantial role in initiating the symp- toms of IBS [96, 99, 100]. Diets low in FODMAPs have a proven efficacy with a high level of evidence in alleviat- ing symptoms related to IBS, and as such were adopted in the IBS treatment guidelines of the National Institute for Health and Care Excellence and the British Dietetic Association. Initiating a diet low in FODMAPs requires the expertise of a dietitian or a clinician with the proper training and experience in this approach [100]. Patients who suffer from IBS are often found to have concurrent symptoms of endometriosis. Women diagnosed with endometriosis are two to three times more likely to receive a  concomitant diagnosis of IBS compared to women without endometriosis [96, 101]. Schink et al. found a nearly four-fold increase in food intolerances in patients with endometriosis compared to controls [102]. In addition, Schomacker et al. found a  higher prevalence of IBS in women diagnosed with endometriosis compared to women with no endome- triosis, regardless of whether or not there was endo- metriosis infiltrating the bowel [103]. Interestingly, a prospective cohort study found that although 52% of women with confirmed endometriosis had IBS, more severe IBS symptoms were found in patients with low- er-stage endometriosis [104]. It seems plausible that the association between IBS and endometriosis is not only epidemiological but that there are also shared pathophysiological pathways. Both disorders cause similar symptoms for patients and are defined by their chronic low-grade inflamma- tory state. An awareness of the association between IBS and endometriosis is extremely important for the management of patients with endometriosis-associat- ed pelvic pain. While observing a series of 160 women with IBS, Moore et al. reported a  significant improve- ment in symptoms with the effect of the low-FODMAP diet for patients with IBS and endometriosis compared to patients with IBS alone (72% vs. 40%, respectively, p = 0.001) [99]. The authors concluded that a low-FOD- MAP diet may be beneficial for women suffering from symptoms related to both IBS and endometriosis [99]. Evidence suggests using a multidisciplinary approach to the care of patients with GI symptoms related to either IBS or endometriosis in order to reach an appropriate diagnosis followed by the correct therapy [105]. Soy and phytoestrogens The weak oestrogenic effect of phytoestrogens pres- ent in soy has been found to be associated with an in- creased risk of oestrogen-dependent diseases [106, 107]. In Japan, soy is commonly consumed and the high phytoestrogen intake there has been associated with an elevated risk of endometriosis. Liu et al. compared the change of endometrial thickness before and after isoflavone supplementation [107]. The authors found that a  daily isoflavone dose of more than 54  mg per day may decrease endometrial thickness in post-meno- pausal women and produce different effects on popu- lations [107]. Nevertheless, it seems that not all phytoestrogens have the same impact on endometriosis. Some animal models have indicated that puerarin and genistein, two phytoestrogens with antineoplastic properties, re- duce the burden of endometriotic lesions via inhibiting aromatase and oestrogen receptor-a  expression and reducing oestrogen concentrations [107]. In a  small case series, Chandrareddy et al. found that dietary phy- toestrogens were associated with abnormal uterine bleeding in women [108]. Although these women had a variety of symptoms and pathologies discovered, they all had symptomatic improvement when phytoestro- gens were withdrawn from their diet [108]. Gluten-free diet and coeliac disease Oxidative stress, chronic inflammation, and immu- nological disorders are features shared between coeli- ac disease and endometriosis. The literature is scarce regarding the association between these two diseases. Santoro et al. investigated this hypothetical associa- tion and detected a  higher prevalence of coeliac dis- ease among women diagnosed with endometriosis, but Menopause Review/Przegląd Menopauzalny 21(2) 2022 129 the results were not statistically significant [109]. Caser- ta et al. reported a case of a woman suffering from en- dometriosis with concomitant coeliac disease, where a gluten-free diet improved her fertility [110]. Marziali et al. tested the gluten-free diet in 207 symptomatic women suffering from endometriosis and reported a  statistically significant improvement in symptoms in 75% of the women [111]. Women exposed to a glu- ten-free diet had a significantly better quality of life in addition to improved physical and social functioning (p < 0.005) [110]. Both endometriosis and coeliac disease are associated with chronic inflammation, and both present with significant elevations of inter - feron-gamma (IFN-γ) and interleukin-6 (IL-6). Thus, the authors concluded that a gluten-free diet is efficient in improving endometriosis symptoms after 12 months of treatment and plays an antagonist role by decreasing IFN-γ and IL-6 [111]. High-fat diet High fat consumption is associated with oxidative stress and inflammation – two key features of endome- triosis. Some inflammatory markers, such as IL-6, are found in higher concentrations in women with endo- metriosis, and are increased by specific fatty acid expo- sure [112]. In contrast, decreasing oxidative stress us- ing diets rich in antioxidants may be protective against the progression or development of endometriosis [113]. Heard et al. reported an increase in endometriosis le- sion development in mouse models after exposure to a high-fat diet independent of overt obesity and weight gain [114]. This association was believed to be due to promoted oxidative stress and inflammatory pathways provoked by high-fat diets. Maintaining a healthy diet has considerable health benefits and may also decrease the risk of endometriosis [114, 115]. The missing link: new insights into fertility outcomes Recent discoveries in micronutrients have made prog- ress thanks to the pharmaceutical field. In particular, a great effort has been spent on inositol research. Ino- sitols, in the form of myo-inositol and D-inositol, have been proposed as pharmaceutical agents with a positive effect on insulin sensitivity and PCOS women. For this reason, their administration is widely accepted and pro- posed as adjuvant therapy in women affected by PCOS with difficulty in conceiving [115–120]. Similarly, vitamin D has also been proposed as a possible adjuvant for fer- tility. However, unlike the inositols, vitamin D excessive levels may play a detrimental role in infertility [121–123].

This paper reviewed the impact of different lifestyle and dietary factors on the development and severity of endometriosis as reported in the literature, empha- sizing that this disease is multifactorial with a  con- comitant inflammatory pattern. High-level evidence and well-designed randomized studies are lacking when it comes to studying the effect of these modi- fiable risk factors on endometriosis. However, certain studies indicate that fish oil may have a positive effect on reducing pain due to the effects of the anti-inflam- matory prostaglandins PGE3 and PGE3α derived from omega-3 fatty acids. The same effects were seen with the introduction of the antioxidant vitamins C, D, and E. Current literature demonstrates that there is clinical viability of a  low-FODMAP diet to successfully reduce the symptoms of patients who suffer from both endo- metriosis and IBS. Despite the low level of evidence, there are frequent associations between endometriosis and GI conditions in addition to the influence of dif- ferent nutritional factors on the disease. There is also evidence that the adaptation of individualized dietary changes yields statistically significant improvements in endometriosis-related symptoms [124]. Thus, there may be great benefit to including a  dietician in the management of these patients, especially at younger ages and in early stages. The management of endome- triosis requires a  holistic approach focused on reduc- ing overall inflammation, increasing detoxification, and attenuating troublesome symptoms. Inarguably, further research with a more extensive focus is needed. Disclosure The authors report no conflict of interest.

1. Vercellini P , Viganò P , Somigliana E, et al. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 2014; 10: 261-275. 2. Djokovic D, Pinto P , van Herendael BJ, Laganà AS, Thomas V , Keckstein J. Structured report for dynamic ultrasonography in patients with sus- pected or known endometriosis: recommendations of the Interna- tional Society for Gynecologic Endoscopy (ISGE). Eur J Obstet Gynecol Reprod Biol 2021; 263: 252-260. 3. Giudice LC, Kao LC. Endometriosis. Lancet Lond Engl 2004; 364: 1789-1799. 4. Guo S-W, Wang Y. The prevalence of endometriosis in women with chronic pelvic pain. Gynecol Obstet Invest 2006; 62: 121-130. 5. Králíčková M, Vetvicka V , Fiala L, Laganà AS, Garzon S. The search for biomarkers in endometriosis: a long and windy road. Reprod Sci 2021. 6. Terzic M, Aimagambetova G, Garzon S, et al. Ovulation induction in in- fertile women with endometriotic ovarian cysts: current evidence and potential pitfalls. Minerva Med 2020; 111: 50-61. 7. Missmer SA, Cramer DW. The epidemiology of endometriosis. Obstet Gynecol Clin North Am 2003; 30: 1-19 vii. 8. D’Alterio MN, Saponara S, D’Ancona G, et al. Role of surgical treatment in endometriosis. Minerva Obstet Gynecol 2021; 73: 317-332. 9. Laganà AS, La Rosa VL. Multidisciplinary management of endome- triosis: current strategies and future challenges. Minerva Med 2020; 111: 18-20. 10. Laganà AS, Vitale SG, Salmeri FM, et al. Unus pro omnibus, omnes pro uno: a  novel, evidence-based, unifying theory for the pathogenesis of endometriosis. Med Hypotheses 2017; 103: 10-20. 11. Laganà AS, Garzon S, Götte M, et al. The pathogenesis of endometrio- sis: molecular and cell biology insights. Int J Mol Sci 2019; 20: 5615. Menopause Review/Przegląd Menopauzalny 21(2) 2022 130 12. Missmer SA, Chavarro JE, Malspeis S, et al. A prospective study of di- etary fat consumption and endometriosis risk. Hum Reprod Oxf Engl 2010; 25: 1528-1535. 13. Sofo V , Götte M, Laganà AS, et alS. Correlation between dioxin and endometriosis: an epigenetic route to unravel the pathogenesis of the disease. Arch Gynecol Obstet 2015; 292: 973-986. 14. Dababou S, Garzon S, Laganà AS, et al. Linzagolix: a  new GnRH-an- tagonist under investigation for the treatment of endometriosis and uterine myomas. Expert Opin Investig Drugs 2021; 30: 903-911. 15. Attar E, Bulun SE. Aromatase and other steroidogenic genes in endo- metriosis: translational aspects. Hum Reprod Update 2006; 12:49-56. 16. Naem A, Shamandi A, Al-Shiekh A, Alsaid B. Free large sized intra-ab- dominal endometrioma in a postmenopausal woman: a case report. BMC Womens Health 2020; 20: 190. 17. D’Alterio MN, Giuliani C, Scicchitano F , et al. Possible role of microbi- ome in the pathogenesis of endometriosis. Minerva Obstet Gynecol 2021; 73: 193-214. 18. Kitawaki J, Kado N, Ishihara H, et al. Endometriosis: the pathophysi- ology as an estrogen-dependent disease. J Steroid Biochem Mol Biol 2002; 83: 149-155. 19. Tsubura A, Uehara N, Kiyozuka Y, et al. Dietary factors modifying breast cancer risk and relation to time of intake. J Mammary Gland Biol Neo- plasia 2005; 10: 87-100. 20. Burns KA, Korach KS. Estrogen receptors and human disease: an up- date. Arch Toxicol 2012; 86: 1491-1504. 21. Ozerdogan N, Sayiner D, Ayranci U, et al. Prevalence and predictors of dysmenorrhea among students at a university in Turkey. Int J Gynaecol Obstet Off Organ Int Fed Gynaecol Obstet 2009; 107: 39-43. 22. Chang SF , Chuang M. Factors that affect self-care behaviour of female high school students with dysmenorrhoea: a cluster sampling study. Int J Nurs Pract 2012; 18: 117-124. 23. Laganà AS, Condemi I, Retto G, et al. Analysis of psychopathological co- morbidity behind the common symptoms and signs of endometriosis. Eur J Obstet Gynecol Reprod Biol 2015; 194: 30-33. 24. Laganà AS, La Rosa V , Petrosino B, Vitale SG. Comment on “Risk of de- veloping major depression and anxiety disorders among women with endometriosis: a  longitudinal follow-up study”. J Affect Disord 2017; 208: 672-673. 25. Bianco B, Loureiro FA, Trevisan CM, et al. Effects of FSHR and  FSHB Vari- ants on hormonal profile and reproductive outcomes of infertile wom- en with endometriosis. Front Endocrinol (Lausanne) 2021; 12: 760616. 26. Stefansson H, Geirsson RT, Steinthorsdottir V , et al. Genetic factors contribute to the risk of developing endometriosis. Hum Reprod Oxf Engl 2002; 17: 555-559. 27. Whitehill K, Yong PJ, Williams C. Clinical predictors of endometriosis in the infertility population: is there a better way to determine who needs a laparoscopy? J Obstet Gynaecol Can JOGC J Obstet Gynecol Can JOGC 2012; 34: 552-557. 28. Barra F , Biscaldi E, Scala C, et al. A prospective study comparing three- dimensional rectal water contrast transvaginal ultrasonography and computed tomographic colonography in the diagnosis of rectosigmoid endometriosis. Diagnostics (Basel) 2020; 10: 252. 29. Missmer S, Hankinson S, Spiegelman D, et al. Reproductive history and endometriosis among premenopausal women. Obstet Gynecol 2004; 104: 965-974. 30. Matalliotakis IM, Cakmak H, Fragouli YG, et al. Epidemiological charac- teristics in women with and without endometriosis in the Yale series. Arch Gynecol Obstet 2008; 277: 389-393. 31. Nnoaham KE, Webster P , Kumbang J, et al. Is early age at menarche a risk factor for endometriosis? A systematic review and meta-analysis of case-control studies. Fertil Steril 2012; 98: 702-712.e6. 32. Cramer DW, Wilson E, Stillman RJ, et al. The relation of endometriosis to menstrual characteristics, smoking, and exercise. JAMA 1986; 255: 1904-1908. 33. Darrow S, Vena J, Batt R, et al. Menstrual cycle characteristics and the risk of endometriosis. Epidemiology 1993; 4: 135-142. 34. Bianconi L, Hummelshoj L, Coccia ME, et al. Recognizing endometriosis as a social disease: the European Union encouraged Italian Senate ap- proach. Fertil Steril 2007; 88: 1285-1287. 35. Bulletti C, Coccia ME, Battistoni S, et al. Endometriosis and infertility. J Assist Reprod Genet 2010; 27: 441-447. 36. Borghese B, Zondervan KT, Abrao MS, et al. Recent insights on the ge- netics and epigenetics of endometriosis. Clin Genet 2017; 91: 254-264. 37. Bulun SE. Endometriosis. N Engl J Med 2009; 360: 268-279. 38. Barra F , Laganà AS, Casarin J, et al. Molecular targets for endometriosis therapy: where we are and where we are going? Int J Fertil Steril 2019; 13: 89-92. 39. Treloar SA, O’Connor DT, O’Connor VM, et al. Genetic influences on endometriosis in an Australian twin sample. Fertil Steril 1999; 71: 701- 710. 40. Saha R, Pettersson HJ, Svedberg P , et al. Heritability of endometriosis. Fertil Steril 2015; 104: 947-952. 41. Treloar S, Hadfield R, Montgomery G, et al. The International Endogene Study: a collection of families for genetic research in endometriosis. Fertil Steril 2002; 78: 679-685. 42. Treloar SA, Wicks J, Nyholt DR, et al. Genomewide linkage study in 1,176 affected sister pair families identifies a  significant susceptibil- ity locus for endometriosis on chromosome 10q26. Am J Hum Genet 2005; 77: 365-376. 43. Zondervan KT, Treloar SA, Lin J, et al. Significant evidence of one or more susceptibility loci for endometriosis with near- Mendelian inheritance on chromosome 7p13-15. Hum Reprod Oxf Engl 2007; 22: 717-728. 44. Buck Louis GM, Peterson CM, Chen Z, et al. Bisphenol A and phthalates and endometriosis: the Endometriosis: Natural History, Diagnosis and Outcomes Study. Fertil Steril 2013; 100: 162-9.e1-2. 45. Upson K, Sathyanarayana S, De Roos AJ, et al. Phthalates and risk of endometriosis. Environ Res 2013; 126: 91-97. 46. Martínez-Zamora MA, Mattioli L, Parera J, et al. Increased levels of di- oxin-like substances in adipose tissue in patients with deep infiltrating endometriosis. Hum Reprod Oxf Engl 2015; 30: 1059-1068. 47. Smarr MM, Kannan K, Buck Louis GM. Endocrine disrupting chemicals and endometriosis. Fertil Steril 2016; 106: 959-966. 48. Laganà A.S., Naem A. The pathogenesis of endometriosis: are endo- metrial stem/progenitor cells involved? In: Virant-Klun I, ed. Stem cells in reproductive tissues and organs. stem cell biology and regenerative medicine, vol 70. Humana, Cham. https://doi.org/10.1007/978-3-030- 90111-0_9. 49. Barker DJ. In utero programming of chronic disease. Clin Sci (Lond) 1998; 95: 115-128. 50. Chiofalo B, Laganà AS, Vaiarelli A, et al. Do miRNAs play a role in fetal growth restriction? A fresh look to a busy corner. Biomed Res Int 2017; 2017: 6073167. 51. Wolff EF , Sun L, Hediger ML, et al. In utero exposures and endome- triosis: the Endometriosis, Natural History, Disease, Outcome (ENDO) Study. Fertil Steril 2013; 99: 790-795. 52. Upson K, Sathyanarayana S, Scholes D, et al. Early-life factors and en- dometriosis risk. Fertil Steril 2015; 104: 964-71.e5. 53. Vannuccini S, Lazzeri L, Orlandini C, et al. Potential influence of in utero and early neonatal exposures on the later development of endometrio- sis. Fertil Steril 2016; 105: 997-1002. 54. Gao M, Allebeck P , Mishra GD, et al. Developmental origins of endome- triosis: a Swedish cohort study. J Epidemiol Community Health 2019; 73: 353-359. 55. Missmer SA, Hankinson SE, Spiegelman D, et al. In utero exposures and the incidence of endometriosis. Fertil Steril 2004; 82: 1501-1508. 56. Aarestrup J, Jensen BW, Ulrich LG, et al. Birth weight, childhood body mass index and height and risks of endometriosis and adenomyosis. Ann Hum Biol 2020; 47: 173-180. 57. McCann SE, Freudenheim JL, Darrow SL, et al. Endometriosis and body fat distribution. Obstet Gynecol 1993; 82: 545-549. 58. Signorello LB, Harlow BL, Cramer DW, et al. Epidemiologic determi- nants of endometriosis: a hospital-based case-control study. Ann Epi- demiol 1997; 7: 267-741. 59. Hemmings R, Rivard M, Olive DL, et al. Evaluation of risk factors associ- ated with endometriosis. Fertil Steril 2004; 81: 1513-1521. 60. Viganò P , Somigliana E, Panina P , et al. Principles of phenomics in endo- metriosis. Hum Reprod Update 2012; 18: 248-259. 61. Shah DK, Correia KF , Vitonis AF , et al. Body size and endometriosis:

from 20 years of follow-up within the Nurses’ Health Study II prospective cohort. Hum Reprod 2013; 28: 1783-1792. 62. Ek M, Roth B, Nilsson PM, et al. Characteristics of endometriosis: a case-cohort study showing elevated IgG titers against the TSH recep- Menopause Review/Przegląd Menopauzalny 21(2) 2022 131 tor (TRAb) and mental comorbidity. Eur J Obstet Gynecol Reprod Biol 2018; 231: 8-14. 63. Nava-González EJ, de la Garza-Casas YE, Salazar-Montalvo RG, et al. Relationship among anthropometric and gluco-metabolic parameters, bone mineral density and endometriosis. Rev Medica Inst Mex Seguro Soc 2013; 51: 522-531. 64. Nagle CM, Bell TA, Purdie DM, et al. Relative weight at ages 10 and 16 years and risk of endometriosis: a case-control analysis. Hum Reprod Oxf Engl 2009; 24: 1501-1506. 65. Missmer SA, Hankinson SE, Spiegelman D, et al. Incidence of laparo- scopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am J Epidemiol 2004; 160: 784-796. 66. Farland LV , Missmer SA, Bijon A, et al. Associations among body size across the life course, adult height and endometriosis. Hum Reprod Oxf Engl 2017; 32: 1732-1742. 67. Liu Y, Zhang W. Association between body mass index and endome- triosis risk: a meta-analysis. Oncotarget 2017; 8: 46928-46936. 68. Hemmert R, Schliep KC, Willis S, et al. Modifiable lifestyle factors and risk for incident endometriosis. Paediatr Perinat Epidemiol 2019; 33: 19-25. 69. Holdsworth-Carson SJ, Dior UP , Colgrave EM, et al. The association of body mass index with endometriosis and disease severity in women with pain. J Endometr Pelvic Pain Disord 2018; 10: 79-87. 70. Laganà AS, Garzon S, Casarin J, et al. Know your enemy: potential role of cabergoline to target neoangiogenesis in endometriosis. J Invest Surg 2021; 34: 902-903. 71. Parazzini F , Esposito G, Tozzi L, et al. Epidemiology of endometriosis and its comorbidities. Eur J Obstet Gynecol Reprod Biol 2017; 209: 3-7. 72. Ricci E, Viganò P , Cipriani S, et al. Physical activity and endometriosis risk in women with infertility or pain: Systematic review and meta- analysis. Medicine (Baltimore) 2016; 95: e4957. 73. Dhillon PK, Holt VL. Recreational physical activity and endometrioma risk. Am J Epidemiol 2003; 158: 156-164. 74. Heilier JF , Donnez J, Nackers F , et al. Environmental and host-associ- ated risk factors in endometriosis and deep endometriotic nodules: a matched case-control study. Environ Res 2007; 103: 121-129. 75. Vitonis AF , Hankinson SE, Hornstein MD, et al. Adult physical activity and endometriosis risk. Epidemiol Camb Mass 2010; 21: 16-23. 76. Tworoger SS, Missmer SA, Eliassen AH, et al. Physical activity and inac- tivity in relation to sex hormone, prolactin, and insulin-like growth fac- tor concentrations in premenopausal women. Cancer Causes Control 2007; 18: 743-752. 77. An P , Rice T, Gagnon J, et al. A genetic study of sex hormone--binding globulin measured before and after a  20-week endurance exercise training program: the HERITAGE Family Study. Metabolism 2000; 49: 1014-1020. 78. Farland LV , Eliassen AH, Tamimi RM, et al. History of breast feeding and risk of incident endometriosis: prospective cohort study. BMJ 2017; 358: j3778. 79. Burgio MA, Laganà AS, Sicilia A, et al. Breastfeeding education: where are we going? A systematic review article. Iran J Public Health 2016; 45: 970-977. 80. Jurkiewicz-Przondziono J, Lemm M, Kwiatkowska-Pamuła A, et al. Influ- ence of diet on the risk of developing endometriosis. Ginekol Pol 2017; 88: 96-102. 81. Britton JA, Westhoff C, Howe G, et al. Diet and benign ovarian tumors (United States). Cancer Causes Control CCC 2000; 11: 389-401. 82. Savaris AL, do Amaral VF. Nutrient intake, anthropometric data and cor- relations with the systemic antioxidant capacity of women with pelvic endometriosis. Eur J Obstet Gynecol Reprod Biol 2011; 158: 314-318. 83. Trabert B, Peters U, De Roos AJ, et al. Diet and risk of endometriosis in a population-based case-control study. Br J Nutr 2011; 105: 459-467. 84. Demézio da Silva CV , Felipe VL, Shivappa N, et al. Dietary Inflammatory Index score and risk of developing endometriosis: a case-control study. J Endometr Pelvic Pain Disord 2021; 13: 32-39. 85. Yamamoto A, Harris HR, Vitonis AF , et al. A prospective cohort study of meat and fish consumption and endometriosis risk. Am J Obstet Gynecol. 2018; 219: 178.e1-178.e10. 86. Ashrafi M, Jahangiri N, Sadatmahalleh SJ, et al. Diet and the risk of endometriosis in Iranian women: a case-control study. Int J Fertil Steril 2020; 14: 193-200. 87. Rizzo G, Laganà AS. The Link between homocysteine and omega-3 polyunsaturated fatty acid: critical appraisal and future directions. Bio- molecules 2020; 10: 219. 88. Butticè S, Laganà AS, Barresi V , et al. Lumbar ureteral stenosis due to endometriosis: our experience and review of the literature. Case Rep Urol 2013; 2013: 812475. 89. Rizzo G, Laganà AS, Rapisarda AM, et al. Vitamin B 12 among vegetar - ians: status, assessment and supplementation. Nutrients 2016; 8: 767. 90. Giampaolino P , Della Corte L, Foreste V , Bifulco G. Is there a relationship between vitamin d and endometriosis? An overview of the literature. Curr Pharm Des 2019; 25: 2421-2427. 91. Darling AM, Chavarro JE, Malspeis S, et al. A prospective cohort study of vitamins B, C, E, and multivitamin intake and endometriosis. J Endo- metr 2013; 5: 17-26. 92. Colonese F , Laganà AS, Colonese E, et al. The pleiotropic effects of vita- min D in gynaecological and obstetric diseases: an overview on a hot topic. Biomed Res Int 2015; 2015: 986281. 93. Nodler JL, Divasta AD, Vitonis AF , et al. Supplementation with vitamin D or ω-3 fatty acids in adolescent girls and young women with endo- metriosis (SAGE): a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 2020; 112: 229-236. 94. Maniglio P , Ricciardi E, Laganà AS, Triolo O, Caserta D. Epigenetic modi- fications of primordial reproductive tract: a common etiologic pathway for Mayer-Rokitansky-Kuster-Hauser Syndrome and endometriosis? Med Hypotheses 2016; 90: 4-5. 95. Terzic M, Aimagambetova G, Kunz J, et al. Molecular basis of endome- triosis and endometrial cancer: current knowledge and future perspec- tives. Int J Mol Sci 2021; 22: 9274. 96. Wu CY, Chang WP , Chang YH, et al. The risk of irritable bowel syndrome in patients with endometriosis during a 5-year follow-up: a nationwide population-based cohort study. Int J Colorectal Dis 2015; 30: 907-912. 97. Chiofalo B, Laganà AS, Palmara V , et al. Fasting as possible comple- mentary approach for polycystic ovary syndrome: hope or hype? Med Hypotheses 2017; 105: 1-3. 98. Sturlese E, Salmeri FM, Retto G, et al. Dysregulation of the Fas/FasL system in mononuclear cells recovered from peritoneal fluid of women with endometriosis. J Reprod Immunol 2011; 92: 74-81. 99. Moore JS, Gibson PR, Perry RE, et al. Endometriosis in patients with irritable bowel syndrome: Specific symptomatic and demographic pro- file, and response to the low FODMAP diet. Aust N Z J Obstet Gynaecol 2017; 57: 201-205. 100. Trott N, Aziz I, Rej A, et al. How Patients with IBS use low FODMAP dietary information provided by general practitioners and gastroenter- ologists: a qualitative study. Nutrients 2019; 11. 101. Chiaffarino F , Cipriani S, Ricci E, et al. Endometriosis and irritable bowel syndrome: a systematic review and meta-analysis. Arch Gynecol Ob- stet 2021; 303: 17-25. 102. Schink M, Konturek PC, Herbert SL et al. Different nutrient intake and prevalence of gastrointestinal comorbidities in women with endome- triosis. J Physiol Pharmacol. 2019 Apr;70(2). 103. Schomacker ML, Hansen KE, Ramlau-Hansen CH, et al. Is endometrio- sis associated with irritable bowel syndrome? A cross-sectional study. Eur J Obstet Gynecol Reprod Biol 2018; 231: 65-69. 104. Lee CE, Yong PJ, Williams C, et al. Factors associated with severity of irritable bowel syndrome symptoms in patients with endometriosis. J Obstet Gynaecol Can 2018; 40: 158-164. 105. Parazzini F , Viganò P , Candiani M, Fedele L. Diet and endometriosis risk: a literature review. Reprod Biomed Online 2013; 26: 323-336. 106. Della Corte L, Noventa M, Ciebiera M, et al. Phytotherapy in endome- triosis: an up-to-date review. J Complement Integr Med 2020; 17. 107. Liu J, Yuan F , Gao J, et al. Oral isoflavone supplementation on endo- metrial thickness: a meta-analysis of randomized placebo- controlled trials. Oncotarget 2016; 7: 17369-17379. 108. Chandrareddy A, Muneyyirci-Delale O, McFarlane SI, et al. Adverse ef- fects of phytoestrogens on reproductive health: a report of three cases. Complement Ther Clin Pract 2008; 14: 132-135. 109. Santoro L, Campo S, D’Onofrio F , et al. Looking for celiac disease in Ital- ian women with endometriosis: a case control study. BioMed Res Int 2014; 2014: 236821. Menopause Review/Przegląd Menopauzalny 21(2) 2022 132 110. Caserta D, Matteucci E, Ralli E, et al. Celiac disease and endometriosis: an insidious and worrisome association hard to diagnose: a case re- port. Clin Exp Obstet Gynecol 2014; 41: 346-348. 111. Marziali M, Venza M, Lazzaro S, et al. Gluten-free diet: a new strategy for management of painful endometriosis related symptoms? Minerva Chir 2012; 67: 499-504. 112. Bedaiwy MA, Falcone T, Sharma RK, et al. Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod Oxf Engl 2002; 17: 426-431. 113. Mier-Cabrera J, Aburto-Soto T, Burrola-Méndez S, et al. Women with endometriosis improved their peripheral antioxidant markers after the application of a high antioxidant diet. Reprod Biol Endocrinol RBE 2009; 7: 54. 114. Heard ME, Melnyk SB, Simmen FA, et al. High-Fat diet promotion of en- dometriosis in an immunocompetent mouse model is associated with altered peripheral and ectopic lesion redox and inflammatory status. Endocrinology 2016; 157: 2870-2882. 115. Della Corte L, Di Filippo C, Gabrielli O, et al. The burden of endometrio- sis on women’s lifespan: a narrative overview on quality of life and psychosocial wellbeing. Int J Environ Res Public Health 2020; 17: 4683. 116. Vitale SG, La Rosa VL, Petrosino B, Rodolico A, Mineo L, Laganà AS. The impact of lifestyle, diet, and psychological stress on female fertil- ity. Oman Med J 2017; 32: 443-444. 117. Garzon S, Laganà AS, Monastra G. Risk of reduced intestinal absorp- tion of myo-inositol caused by D-chiro-inositol or by glucose trans- porter inhibitors. Expert Opin Drug Metab Toxicol 2019; 15: 697-703. 118. Muscogiuri G, Palomba S, Laganà AS, Orio F. Current insights into inositol isoforms, mediterranean and ketogenic diets for polycystic ovary syndrome: from bench to bedside. Curr Pharm Des 2016; 22: 5554-5557. 119. Iervolino M, Lepore E, Forte G, Laganà AS, Buzzaccarini G, Unfer V . Natural molecules in the management of polycystic ovary syndrome (PCOS): an analytical review. Nutrients 2021; 13: 1677. 120. Gambioli R, Forte G, Buzzaccarini G, Unfer V , Laganà AS. Myo-inositol as a key supporter of fertility and physiological gestation. Pharmaceu- ticals (Basel) 2021; 14: 504. 121. Laganà AS, Vitale SG, Ban Frangež H, Vrtačnik-Bokal E, D’Anna R. Vi- tamin D in human reproduction: the more, the better? An evidence- based critical appraisal. Eur Rev Med Pharmacol Sci 2017; 21: 4243-4251. 122. Bezerra Espinola MS, Bertelli M, Bizzarri M, et al. Inositol and vitamin D may naturally protect human reproduction and women undergoing as- sisted reproduction from COVID-19 risk. J Reprod Immunol 2021; 144: 103271. 123. Colonese F , La Rosa VL, Laganà AS, Vitale SG, Cortinovis D, Bidoli P. Comment on: “Is there a role for vitamin D in human reproduction?” Horm Mol Biol Clin Investig 2017; 29: 37-38. 124. Karlsson JV , Patel H, Premberg A. Experiences of health after dietary changes in endometriosis: a qualitative review study. BMJ Open 2020; 10: e032321.