Hypothetical roadmap towards endometriosis: prenatal endocrine-disrupting chemical pollutant exposure, anogenital distance, gut-genital microbiota and subclinical infections

Abstract

BACKGROUND Endometriosis is a gynaecological hormone-dependent disorder that is defined by histological lesions generated by the growth of endometrial-like tissue out of the uterus cavity, most commonly engrafted within the peritoneal cavity, although these lesions can also be located in distant organs. Endometriosis affects ~10% of women of reproductive age, frequently producing severe and, sometimes, incapacitating symptoms, including chronic pelvic pain, dysmenorrhea and dyspareunia, among others. Furthermore, endometriosis causes infertility in ~30% of affected women. Despite intense research on the mechanisms involved in the initial development and later progression of endometriosis, many questions remain unanswered and its aetiology remains unknown. Recent studies have demonstrated the critical role played by the relationship between the microbiome and mucosal immunology in preventing sexually transmitted diseases (HIV), infertility and several gynaecologic diseases. OBJECTIVE AND RATIONALE In this review, we sought to respond to the main research question related to the aetiology of endometriosis. We provide a model pointing out several risk factors that could explain the development of endometriosis. The hypothesis arises from bringing together current findings from large distinct areas, linking high prenatal exposure to environmental endocrine-disrupting chemicals with a short anogenital distance, female genital tract contamination with the faecal microbiota and the active role of genital subclinical microbial infections in the development and clinical progression of endometriosis. SEARCH METHODS We performed a search of the scientific literature published until 2019 in the PubMed database. The search strategy included the following keywords in various combinations: endometriosis, anogenital distance, chemical pollutants, endocrine-disrupting chemicals, prenatal exposure to endocrine-disrupting chemicals, the microbiome of the female reproductive tract, microbiota and genital tract, bacterial vaginosis, endometritis, oestrogens and microbiota and microbiota–immune system interactions. OUTCOMES On searching the corresponding bibliography, we found frequent associations between environmental endocrine-disrupting chemicals and endometriosis risk. Likewise, recent evidence and hypotheses have suggested the active role of genital subclinical microbial infections in the development and clinical progression of endometriosis. Hence, we can envisage a direct relationship between higher prenatal exposure to oestrogens or estrogenic endocrine-disrupting compounds (phthalates, bisphenols, organochlorine pesticides and others) and a shorter anogenital distance, which could favour frequent postnatal episodes of faecal microbiota contamination of the vulva and vagina, producing cervicovaginal microbiota dysbiosis. This relationship would disrupt local antimicrobial defences, subverting the homeostasis state and inducing a subclinical inflammatory response that could evolve into a sustained immune dysregulation, closing the vicious cycle responsible for the development of endometriosis. WIDER IMPLICATIONS Determining the aetiology of endometriosis is a challenging issue. Posing a new hypothesis on this subject provides the initial tool necessary to design future experimental, clinical and epidemiological research that could allow for a better understanding of the origin of this disease. Furthermore, advances in the understanding of its aetiology would allow the identification of new therapeutics and preventive actions.

The impact of phthalate on reproductive function in women with endometriosis

“…Phthalates are common synthetic chemicals with ubiquitous exposures in our daily life. Till now, several epidemiologic evidences have reported that phthalates might be toxic to the male and female reproductive system 37 . Studies from laboratory examinations showed that phthalates interacted with the female reproductive system in animal models; these findings support the potential hazardous effects of phthalates in women.…”

“…Previous studies have demonstrated that sexually mature female rats exposed to di (2‐ethylhexyl) phthalate (DEHP) and its metabolite, mono (2‐ethylhexyl) phthalate (MEHP) showed a decrease in serum progesterone, delayed ovulation, and smaller preovulatory follicles with high levels of serum follicle‐stimulating hormone (FSH) 17,19,34,35 . Many studies demonstrated that phthalate exposure is significantly associated with endometriosis 10,36‐40 …”

Anogenital Distance and Gynaecological Diseases: A Narrative Review

“…The most widely accepted hypothesis is represented by the retrograde menstruation theory, characterised by the backward flux of menstrual debris that contains viable endometrial cells through the fallopian tubes into the pelvic cavity (20). However, some authors suggest an intrauterine origin of the disease (21,22), and the potential role of early-life influences, such as intrauterine hormonal environmental exposure to oestrogens or anti-androgens, are receiving growing consideration as a risk factor for endometriosis in adult life (23)(24)(25)(26)(27)(28)(29). In addition, accumulating evidence suggests that immune cells, adhesion molecules, extracellular matrix metalloproteinase and pro-inflammatory cytokines activate/alter peritoneal microenvironment, creating the conditions for differentiation, adhesion, proliferation, and survival of ectopic endometrial cells (30,31).…”

From Environmental to Possible Occupational Exposure to Risk Factors: What Role Do They Play in the Etiology of Endometriosis?

“…The exact etiology of endometriosis is unknown [3]. Several factors such as the genetic and immunological profile, the local inflammation, the hormonal activity and the metabolism of prostaglandins have been suggested to be involved in the onset and/or development of endometriosis [4]. From an epidemiological point of view, numerous hypotheses have been proposed and various investigations conducted to clarify the etiology of this disorder [5,6].…”