Endometriosis Pathogenesis, Clinical Impact and Management: Volume 9: Frontiers in Gynecological Endocrinology

By Andrea R. Genazzani and Robert N. Taylor

This volume focuses on endometriosis from its pathogenesis and the importance of the early diagnosis to treatment, throughout all aspects of femininity that this disease affects, impacting health and quality of life.

It also covers treatment strategies for the pain and for the disease management according to the age and needs of the patient, from adolescence to menopause, passing through the fertile age and the consequences that this disease can have on fertility and pregnancy.

This book  is a useful, clear and up-to-date tool for gynecologists, gynecological surgeons, reproductive medicine and general practitioners and  is an important source of information to face this more and more frequent and devastating disease.

• Language: English
• Publisher: Springer
• Release date: Dec 7, 2020
• ISBN: 9783030578664

Book preview

© International Society of Gynecological Endocrinology 2021

A. R. Genazzani et al. (eds.)Endometriosis Pathogenesis, Clinical Impact and ManagementISGE Serieshttps://doi.org/10.1007/978-3-030-57866-4_1

1. Endocrine Disruptors and Endometriosis Risk

Marco Palumbo¹   and Federica Di Guardo¹

(1)

Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania, Italy

Marco Palumbo

Email: [e-mail]

1.1 Introduction

Endometriosis is defined as the presence of endometrial-type mucosa outside the uterine cavity. Several theories have been proposed during the last 20 years to explain the disease pathogenesis; however, a unique consensus has not yet been established. Although the most recent pathogenic theory is based on inflammatory causes [1], hormonal influence is certainly involved not only in the endometriosis pathogenesis but also in its development and progression [2].

Ectopic endometrium seems, in fact, to be dependent on estrogens and to be resistant to progesterone. Estradiol, which represents the active form of estrogens, is hyper expressed in endometriosis tissue and acts as a transcription factor due to the capacity to link to nuclear receptors. In the same way, chemical environment substances can act as binding endogenous hormone receptors and are therefore called endocrine disruptors. These chemical compounds are able to bind the estrogen and progesterone receptor, as well as determining pro-inflammatory effects, and in this context, they may be potential risk factors for the development of endometriosis.

1.2 Endocrine Disruptors

In 2012, the United Nations Environment Programme (UNEP) and the World Health Organization (WHO) prepared a report entitled State of Science: Endocrine Distrupting Chemicals-2012. This document described about 800 chemicals suspected of being endocrine disrupters able of mimicking endogenous hormones or altering their regulation [3].

An endocrine disrupter is defined as an exogenous substance or mixture that can disturb the functions of the endocrine system and cause adverse health effects in the body or in the population [4].

Endocrine disruptors may act altering the production, secretion, metabolism, transport, or peripheral action of endogenous hormones binding to hormone receptors.

After binding the receptors, the results can manifest as an agonistic effect (mimicking the hormonal action) or antagonistic effect (contrasting the hormonal action by preventing the binding of the natural hormone). Endocrine disruptors may also be capable of binding allosteric sites, producing unexpected effects at very low concentrations.

In addition, these substances can also act by recruiting co-activators or co-expressers in various enzymatic pathways, modifying hormone synthesis, plasma clearance, or gene expression through epigenetic alterations.

Considering the response curve of these compounds, their adverse effects are not directly proportional to the exposure dose, meaning that very low quantity also could have significant effects on cell proliferation and development, creating problems for the human risk assessment [5].

Endocrine disrupters include a large and variegate group in terms of use, chemical structure, and mode of action (Table 1.1). Among them, there are persistent pollutants capable of bio-accumulation (dioxins, DDT, and cadmium), chemical substances used in plant or animal feed production (azole fungicides, etc.). Bisphenol A (BPA) and Di-(2-ethylhexyl) phthalate (DEHP) deserve a special mention, in order of their wide use in industry or consumer products (plastic bottles and other daily-life products) causing, therefore, continued exposure to humans. Phytoestrogens (hormonally active compounds of plant origin) are also included in the endocrine disrupters category.

Table 1.1

Endocrine disruptors interacting with female endocrine system receptors

As hormones may act on distant site target organs, in the same way the endocrine disruptors are supposed to affect several hormone pathways, making it difficult to understand their full mechanism of action [6].

However, the effects tend to be tissue-specific, in order of the fact that chemical substances are metabolized in specific sites. Resulting metabolites seem to interfere with hormone actions in the same tissues where they were generated. In addition, some tissues exhibit a higher receptor density or different receptor isoforms [7].

Endocrine disruptors have a broad spectrum of action on human health including effects on the development of reproductive and nervous systems, metabolism, and cancer.

They can act as determining indirect epigenetic molecular alterations at the germline level having a role in determining effects on subsequent generations. This phenomenon is called trans-generational inheritance [8, 9].

Moreover, several epidemiological studies have linked the direct individual exposure to endocrine disruptors with effects on the female endocrine system and reproductive tract (Table 1.1): early puberty, aneuploidy, polycystic ovary syndrome, early ovarian failure, and menstrual and fertility changes [8, 10].

1.2.1 Focus on BPA and Phthalates

Bisphenol A (BPA) is an industrial chemical substance found in synthetic plastics: it is the main intermediate in the synthesis of polycarbonate polymers and epoxy resins, as well as a component of some polyvinyl chloride plastic. These materials are widely used in products such as feeding bottles, coating of food, beverage containers, and dental fillings. Human exposure to BPA migrates from plastic products to food or water during the heating process, capable of breaking the external bonds that allow the substance to be a polymer. This results in direct exposure to humans [11].

Phthalates are also widely used in consumer products, including food packaging, medical devices, and toys, mainly to improve the flexibility and durability of polyvinyl chloride plastics. Phthalates are not covalently bound to the plastic matrix, and therefore, they can be easily released into the environment. Recent epidemiological evidences suggest that women have an increased exposure to phthalates compared to men, as they are present in beauty products, including skin lotions, perfumes, and nail products. In particular, di-(2-ethylhexyl) phthalate (DEHP) represents the most used compound [12].

According to the lines above, the main route of exposure to the aforementioned compound is the oral route, followed by the inhalation and the dermal route [11].

BPA and phthalates are rapidly metabolized and excreted in urine without evidence of accumulation in the body; the elimination is considered complete within 24 h of exposure [13].

1.2.2 BPA and Phthalates Mechanisms of Action

The mechanism of action of BPA and phthalates is complex because they are not strictly specific in their binding to the hormone receptors.

BPA is a 2,2-bis(4-hydroxyphenyl)-propane, containing two functional phenolic groups that allow the substance to interact with the estrogen and androgen receptor, both as an agonist and as an antagonist [14].

Due to this interaction with the estrogen receptor (ER) α and ER β, the mechanism of action of the BPA is expressed through the ER-dependent signaling pathways. According to this, three well-characterized ER target genes were examined: GREB1 (estrogen regulation in breast cancer 1), PGR (progesterone receptor), and WISP-2/CNN5 (protein 2 of the WWT1-inducible signaling pathway). BPA has been shown to significantly induce these target genes mediating transcriptional activity via ER [15].

Bond assays for nuclear ER and transcriptional activation assays indicate that BPA has at least 10,000 times less affinity for the two nuclear estrogen receptors than Estradiol. This would suggest that BPA exposure is not significant if it occurs at environmental low levels. However, there is evidence that once tolerable exposure conditions have passed (below the threshold of 50 μg/kg body weight/day), BPA effects may be added to those of ovarian estrogens. According to some in vitro experiments, BPA can even act as Estradiol equivalent in some cellular endpoint systems. In accord with recent evidences acquired on the mimetic estrogens functioning in non-genomic signal pathways, BPA is capable of triggering signal cascades by binding to estrogens membrane receptors (in particular the GPR30 receptor). In this context, BPA behaves as SERM (selective modulators of the membrane estrogen receptor) capable of alternating with transcriptional co-modulators (histone acetyltransferase and histone deacetylase) to mediate different responses depending on the target tissue [16].

Other important BPA-related receptors are the aryl hydrocarbon receptors (AhR), peroxisome proliferator-activated receptors (PPAR), and Toll-like receptors (TLR) [17].

Phthalates are synthetic esters of phthalic anhydride. The chemical structure of each individual phthalate varies, mainly according to the expression of the lateral chains and molecular weight. They can be grouped into two broad categories: low-weight and high-weight phthalates.

Low molecular weight phthalates include dimethyl phthalate (DMP), diethyl phthalate (DEP), and dibutyl phthalate (DBP). High molecular weight phthalates include diethyl hexyl phthalate (DEHP), diisononyl phthalate (DINP), diisodecyl phthalate (DIDP), and benzyl butyl phthalate (BBzP) [18].

In contrast to BPA, phthalates do not appear to act by direct hormonal bounding; however, some of these including di(2-ethylhexyl) phthalate (DEHP) have been shown to have estrogenic activity in in vitro assays [19] as well as modulating androgen production. In this context, DEHP produces anti-androgenic effects through the reduction of testosterone production. It is also capable of binding and activating the receptors activated by the peroxisome proliferator (PPAR) [20] and the thyroid hormone receptor [9].

1.3 Endocrine Disruptors and Endometriosis: Literature Evidences

Endometriosis has been described as an estrogen-dependent pathology, in which onset and progression are involved alterations in endometrium steroidogenesis and peritoneal cavity balance, with excessive estrogen production from ectopic endometriosis lesions. It is therefore plausible that endocrine disruptors, who mimic or alter endogenous hormonal activity, may influence the risk of endometriosis and be involved in its development and progression.

In this scenario, positive associations have been found between persistent environmental exposure to organochlorine pesticides and endometriosis [21].

Several studies have also confirmed the role of the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), commonly known as dioxin, as a potential risk factor for the development of endometriosis [22, 23]. There is also a strong association between uterine exposure to diethylstilbestrol (DES) (prescribed from the 1940s to the 1970s for high-risk pregnancies to prevent miscarriage) and the development of endometriosis later in adult life, as well as other reproductive abnormalities such as cervical and vaginal hypoplasia, infertility, early menopause, and a rare case of clear-cell vaginal adenocarcinoma [24].

Considering the ability of BPA and phthalates to interact with ER, they may be involved in estrogen-dependent diseases such as endometriosis. In addition, BPA decreases PR progesterone receptor expression, as demonstrated by a primate model study in which PR expression decreased more after treatment with BPA and estradiol than after treatment with estradiol alone. In this way, the ability of progesterone to inhibit the action of estradiol on the endometrium is reduced, leading to increased endometrial proliferation [25]. Thus, BPA would also contribute to the progesterone-resistance phenomenon found in endometriosis.

On the other hand, recent studies have found pro-inflammatory responses induced by phthalates through the binding and activation of the receptor activated by the peroxisome proliferator (PPAR) and this can be related to endometriosis, a disease involving oxidative stress and inflammation [20]. Moreover, recent in vitro studies suggested that DEHP could increase the reactive oxygen species (ROS) generation and decrease the expression of superoxide dismutase (SOD). In this way, it seems to induce the ER α expression in a dose-dependent manner: the result can be the development of endocrine-related disease including endometriosis [26].

Laboratory tests have shown an endometriosis-like phenotype within the female offspring of mice exposed to BPA and phthalates in the perinatal phase [27].

This means that the disease has been induced by alterations during female embryological development through changes in genic and epigenetic modulation. This is in line with embryonic theory as a pathogenic hypothesis of endometriosis.

In contrast to laboratory studies, epidemiological studies have not given consistent results regarding the association between the levels of BPA and DEHP and endometriosis.

Literature evidences had shown a positive association between concentrations of the aforementioned substances in women with endometriosis and those without endometriosis [28–31].

A study conducted by Buck Louis [32] found a positive correlation between urinary levels of phthalate metabolites and diagnosis of endometriosis but found no such correlation with BPA. Even a cross-sectional Japanese study found no correlation between the urinary concentration of BPA and endometriosis compared to the daily expected concentration in the general population [33]. On the other hand, a case–control study of Upson showed an increase in urinary BPA levels in women with endometriosis compared to healthy women, but limited to cases of non-ovarian pelvic endometriosis; concentrations with ovarian endometriosis were not statistically significant [34]. Conversely, Rashidi found a positive correlation between higher BPA in the urine of women with ovarian endometriosis compared to healthy controls [35].

To the best of our knowledge, there is consistent evidence demonstrating that exposure to endocrine disruptors has a connection with the incidence of endometriosis.

Co-exposure to several endocrine disruptors (humans are most likely to be exposed to a mixture of chemicals rather than a single chemical) may exacerbate toxicological effects via different pathogenic mechanisms and targets tissues. Adequate sample size, occupational exposure, longitudinal investigation, and multi-center clinical studies need to be conducted trying to focus on pathogenic mechanism, on exposure dose, and exposure duration. Co-exposure to endocrine disruptors need to be further investigated in order to understand their interactions and make the existent evidence more credible.

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Okubo T, et al. Estimation of estrogenic and anti-estrogenic activities of some phthalate diesters and monoesters by MCF-7 cell proliferation assay in vitro. Biol Pharm Bull. 2003;26:1219–24.Crossref

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Upson K, et al. Organochlorine pesticides and risk of endometriosis: findings from a population-based case-control study. Environ Health Perspect. 2013;121(11–12):1319–24.Crossref

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© International Society of Gynecological Endocrinology 2021

A. R. Genazzani et al. (eds.)Endometriosis Pathogenesis, Clinical Impact and ManagementISGE Serieshttps://doi.org/10.1007/978-3-030-57866-4_2

2. Metabolomic Characteristics in Endometriosis Patients

Stefano Angioni¹  , Stefania Saponara¹, Antonio G. Succu¹, Marco Sigilli¹, Francesco Scicchitano¹ and Maurizio N. D’Alterio¹

(1)

Department of Surgical Sciences, University of Cagliari, Cagliari, Italy

Keywords

EndometriosisOmic sciencesMetabolomicsMetabolitesBiomarkers

2.1 Introduction

Endometriosis is an oestrogen-dependent disease, characterised by the presence of abnormal endometrial tissue (glands and stroma) outside the uterus, mainly localised within the pelvis (peritoneum, ovaries, recto-vaginal space, urinary tract) [1], as well as in extra-pelvic sites (lung, brain, umbilicus and surgical scars) [2]. Endometriosis is the most common benign gynaecological disease affecting women of reproductive age and is one of the most frequent causes of infertility [3]. Estimating the exact prevalence of endometriosis is still challenging, since many women with this pathology are asymptomatic and the diagnosis is often overlooked by many doctors; on average, its diagnosis is delayed for an average of 10 years [3]. The prevalence of the disease seems to be ~5%, with