{"paper_id":"28b9a9b2-38c6-42ec-9162-3ab0ff42ea48","body_text":"89\nChapter 5\nEndocrine Disruption in Women: A Cause \nof PCOS, Early Puberty, or Endometriosis\nJean Marie Wenger and Roberto Marci\n5.1  Introduction\nA growing number of scientific studies have shown, since the last decade, increas -\ning evidence suggesting that the human health and wildlife could be affected by a \nwide range of substances broadly disseminated in the environment and also found \nrecurrently in a wide array of everyday products. These products were identified as \ntoxicants with various effects on endocrine processes and functions as neoplasm \ndevelopment, reproductive dysfunctions, and immunological and thyroid disorders \n[1]. These endocrine-disrupting chemicals (EDCs), which are defined as “an \nexogenous chemical, or mixture of chemicals, that interferes with any aspect of \nhormone action” [2], are not rogue pharmaceuticals or rare contaminants.\nEDCs enter the human body via food, water, dust by inhalation, and the transder-\nmal route after contact and using cosmetics and creams. Transplacental transfer of \nthese substances to the developing fetus has also been demonstrated [ 3] and there-\nfore can be found in all body fluids (urine, serum, breast milk, and amniotic fluid). \nEDCs can accumulate and alter the adipose tissue, pancreas, liver, gastrointestinal \ntract, muscle, and brain homeostatic and hedonic pathways [ 4], and the effects of \ntheir metabolites can be functional at low doses and can persist for a long time [5].\nThe US Food and Drug Administration identified more than 1800 chemicals that \ndisrupt at least one of the three endocrine pathways (estrogen, androgen, and \nthyroid) [6], and 320 of 575 chemicals were screened during the instruction of the \nEuropean Commission, with either evidence or potential evidence for endocrine \ndisruption. Today, medical societies and governmental agencies such as the \nJ. M. Wenger (*) \nDepartment of gynecology, University of Geneva, Geneva, Switzerland\ne-mail: jean-marie.wenger@hcuge.ch \nR. Marci \nDepartment of Translational Medicine, University of Ferrara, Ferrara, Italy\ne-mail: mrcrrt@unife.it\n© The Author(s) 2023\nR. Marci (ed.), Environment Impact on Reproductive Health, \nhttps://doi.org/10.1007/978-3-031-36494-5_5\n\n90\nEndocrine Society [7], the International Federation of Gynecology and Obstetrics \n[8], the World Health Organization (WHO) and the United Nations Environment \nProgramme (UNEP) [9], and the American Academy of Pediatrics [ 10] document \nthe rapidly accelerating evidence and implications for human health. EDCs are \nusually used by the industries, as plastics (bisphenol A [BPA]), plasticizers \n(phthalates), solvents/lubricants (polybrominated biphenyls [PBBs], polychlorinated \nbiphenyls [PCBs], and dioxins), pesticides (chlorpyrifos, \ndichlorodiphenyltrichloroethane [DDT], and methoxychlor), fungicides \n(vinclozolin), and also as flame-retardant additives in manufactured materials and \npharmaceutical agents, for example, diethylstilbestrol (DES), a nonsteroidal \nsynthetic estrogen [ 11]. EDCs may also be made by nature; for example, \nphytoestrogens, which interfere with endogenous endocrine function, are produced \nby plants and act primarily through estrogen receptors [12].\nOne of the most widely discussed and abundant EDCs is bisphenol A (BPA). \nBisphenols are found in polycarbonates, epoxy resins, food, cosmetics packaging, \nand even dental composite materials [ 13]. BPA is able to interact with estrogen \nreceptors through its phenolic structure: This allows the modification of hormonal \nhomeostasis via a combination of agonist and/or antagonist actions depending on \nthe target tissue. BPA does act not only on estrogens but also on androgen, pregnane \nX, thyroid, and glucocorticoid receptors [ 14]. Although in the recent years the use \nof BPA has been limited, and replaced in some products by its structural analogs \nsuch as bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF), \ncomparable endocrine-disrupting effects have been observed with these alternative \nbisphenols, as the metabolism and mechanism of action are similar to BPA [ 15]. \nUnfortunately, BPS are not the only EDCs, and our body is subject to a “cocktail \neffect” as the addition and multiplication of each EDC occurs and can amplify the \nrisks. Many personal care products, foods, and pharmaceuticals contain mixtures of \nbisphenols, parabens, and other EDCs; esters of p-hydroxybenzoic acid are used as \nantimicrobial agents and preservatives. In addition to the estrogenic effect, several \nparabens also possess antiandrogenic activity as they can bind to androgen receptors \nand thereby inhibit testosterone-induced transcription [ 16]. Methylparaben (MP) \nand propylparaben (PP), along with ethylparaben (EP), butylparaben (BP), and \nbenzylparaben (benzylP), are among the most commonly used. In vivo studies \nindicate that parabens can disrupt reproduction, development, and homeostasis. In \nhumans, they have been detected in serum, urinary cord blood, meconium, milk, \namniotic fluid, and placental tissue [ 17, 18]. Relevant associations of MP and \nhormones affecting metabolic health and energy were observed, indicating \nobesogenic potential. Associations of methylparaben and hormones affecting \nenergy balance and metabolic health have been observed, indicating its obesogenic \npotential [19]. Moreover, their effect seems to be transgenerational, occurring over \nat least two or three generations. As the window of susceptibility, puberty is \nconsidered as the one of the hot spots in the lifetime when EDCs may exert their \neffects [20], and areas of concern appear to be conditions like polycystic ovaries \npathology [21, 22], precocious puberty issues [23], and endometriosis [24–27].\nJ. M. Wenger and R. Marci\n\n91\n5.2  PCOS\nPolycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine dis-\norder in women of reproductive age [28]. Its prevalence is estimated to be between \n5% and 10% and even up to 21%, depending on the diagnostic criteria and the geo-\ngraphic location [ 29–31]. In 1990, the National Institute of Health proposed the \nfollowing diagnostic criteria: the presence of clinical and/or biochemical hyperan -\ndrogenism and oligomenorrhea/amenorrhea with anovulation [ 32]. In 2006, the \nAndrogen Excess Society proposed diagnostic criteria: an androgen in excess is a \ncritical element in the development and pathogenesis of PCOS that should be pres-\nent and accompanied by oligomenorrhea, polycystic ovarian morphology, or both \n[30]. According to the Rotterdam criteria, the PCOS diagnosis requires meeting two \nof the three criteria mentioned above [33]. Today, the Rotterdam criteria are used by \nthe medicals professional and researchers [34].\nHyperandrogenism seems to be the key feature of PCOS that contributes to clini-\ncal phenotypes and fertility dysregulation [ 35]. The most common sequelae of \nhyperandrogenism in the setting of the PCOS phenotype are hirsutism, acne, and \nalopecia [36]. The hormonal and metabolic alterations may result in reproductive \ndisruption, including menstrual cycle dysfunction, chronic anovulation, and \ninfertility [37], and the majority of women with PCOS have insulin resistance [ 38, \n39], which may lead to the development of obesity [40]. This obesity is characterized \nby metabolic disturbances similar to metabolic syndrome [ 41] such atherogenic \ndyslipidemia and decreased glucose tolerance, which can lead to type 2 diabetes \n[42], with higher blood pressure values, increased thrombotic activity and several \ncardiovascular markers [43], and hyperinsulinemia and peripheral insulin resistance, \nwhich can occur independently on body weight [ 44]. Obesity, which is not always \nfound in the ovaries with PCOS, where insulin resistance and compensatory \nhyperinsulinemia seem to play a vital role in the mechanisms of reproductive \ndisorders by directly affecting the insulin-resistant ovaries with PCOS, has a \ndetrimental impact on the ovulation process [ 21]. Conceiving difficulties may be \ndue to slightly enlarged ovaries with numerous antral follicles, by two- to three-fold \nthat of normal ovaries causing irregular ovulation and oligomenorrhea/amenorrhea. \nOther several features of PCOS are an excess of androgen [ 45], with a correlation \nwith of a two- to three-fold higher anti-Müllerian hormone (AMH) than in ovulatory \nwomen with normal ovaries [46].\nIn addition, a “vicious circle” of hyperandrogenemia is created [ 47], following \nan elevated luteinizing hormone (LH) levels that promote androgen production and \na reduction in estrogens. The underlying causes of PCOS are unclear, likely both \ngenetic and environmental/nutritional, and the variety of clinical manifestations \nraises the possibility that multiple etiological factors simultaneously promote the \nfinal PCOS phenotype [ 28]. While geographic location, ethnicity, lifestyle, and \nenvironmental factors [ 48] appear to play a role, the latter along with endocrine-  \ndisrupting chemicals (EDCs) in the pathogenetic mechanisms of PCOS has been \nevoked recently. EDCs are a heterogeneous group of molecules, of natural or \n5 Endocrine Disruption in Women: A Cause of PCOS, Early Puberty, or Endometriosis\n\n92\nsynthetic origin, capable of interacting with the endocrine system [28] by affecting \nhormonal biosynthesis, modifying their genomic and nongenomic effects, modifying \nthe mechanisms of control and regulation and their epigenetic manifestations [ 18]. \nEDCs can be found in many everyday products (e.g., plastic bottles, cosmetics, \nmetal cans, flame retardants, detergents, foods, toys, and pesticides) and penetrate \nin an organism through the ingestion of contaminated food and liquids, the breathing \nof contaminated air, and transdermal absorption [ 49]. Although in the recent years \nthe use of BPA has been limited, and replaced with some products by its structural \nanalogs such as bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF), \ncomparable endocrine-disrupting effects have been observed with these alternative \nbisphenols, as the metabolism and mechanism of action are similar to BPA [15, 50]. \nThe serum concentration of BPA is elevated in PCOS and correlates with androgen \nlevels [51, 52]. The data suggest that reproductive function is disturbed directly at \nthe ovary level by affecting ovarian steroid hormone production and the maturation \nof the follicle or indirectly by interfering with the hypothalamic–pituitary axis [21]. \nAs obesity is associated with PCOS, low-grade inflammation, and increased \ninflammatory cytokines, several groups have indicated elevated levels of specific \ncytokines in women with PCOS, pointing out that chronic low-grade inflammation \nmay affect the development of ovarian dysfunction and metabolic derangement [53, \n54] The question is if the principal role in low-grade inflammation is due to only \nobesity or also due to PCOS. It is known from the literature that the interaction \nbetween BPA and testosterone is complex. On the one hand, testosterone interacts \nwith BPA metabolism by decreasing uridine diphosphate glucuronosyl transferase \nactivity, which leads to increased levels of BPA. On the other hand, BPA interferes \nwith testosterone metabolism first by the inhibition of testosterone hydroxylases \n(2- and 6-hydroxylase), which are not that important in the degradation of \ntestosterone as much as oxidoreductases, but still can play a role in its metabolism, \nand secondary by displacing testosterone on sex hormone–binding globulin \n(SHBG), which leads to the increase of circulating free androgen concentration \n[21].These interactions, especially the influence on binding protein, could explain \nour findings of the correlation between BPA exposure and testosterone only in a \nhealthy control group, unlike in PCOS women, where the testosterone levels are \nhigh; thus, a “vicious circle” with BPA is formed.\nThe higher levels of BPA in PCOS patients were found compared with healthy \ncontrols [51, 52] without differences between those with normal-weight and obese \nones and higher cytokines levels in obese ones with PCOS [13], which, in complexity, \nreflect activation and proinflammatory state. Findings in obese women with PCOS \n(insulin resistance, lousy lipid profile, risk of fatty liver disease, and proinflammatory \nstate) compared with normal-weight PCOS women, which have very similar \nmetabolic profile as healthy control, are confirmation of how obesity could obscure \nthe searching of PCOS etiopathogenesis. The combination of genetic predispositions \nassociated with environmental factors favored PCOS. In this context, being able to \ninteract with the metabolism of testosterone, EDCs constitute one of the causes \nof PCOS.\nJ. M. Wenger and R. Marci\n\n93\nWe can conclude that these findings confirm that BPA could be one of the essen-\ntial elements in the PCOS etiopathogenesis [13].\nIt is important to emphasize that other studies will have to be done because the \nnumber of endocrine disruptors continues to increase. For women with PCOS, it is \nessential that they maintain their body weight within normal range as this may \nprotect them from the metabolic complications associated with this condition.\n5.3  Early Puberty and EDCs\nEarly puberty is defined by the presence of clinical and auxological signs of puber-\ntal development between the age of 8 and 10 years [55], between the age of 7.5 and \n8.5 years [ 56], or between the age of 8 and 9 years [57]. Some authors consider that, \nwhen pubertal onset occurs before the age of 8 years, it is considered precocious, \nand when it occurs after 8 years but before 9 years of age, it is considered early. The \nmechanism of early pubertal development has not been clarified yet [ 58]. Puberty \nbegins with the release of the hypothalamic gonadotropin-releasing hormone \n(GnRH) pulse generator from central nervous system inhibition after a quiescent \nperiod during childhood [ 59]. The age of menarche has definitely decreased from \n16 years in the 1800s to 13 years in the 1960s, after which this downward trend \nseems to have slowed or even stopped [ 60]. Although genetic factors remain the \nmain determinant of the timing of puberty [ 61], the trend toward earlier onset of \npuberty has coincided with improvements in public health and nutrition [62]. At the \nsame time, endocrine-disrupting chemicals (EDCs) have been suggested as affecting \nthe age of pubertal onset, especially in girls. Hence, researchers were led to \nhypothesize that increasing exposure to EDC had a role in the trend for earlier \nsexual maturation. Moreover, it was suggested that early puberty manifesting in \nimmigrants from the developing countries was the result of previous exposure to \norganochlorine pesticides [63]. Constitutional advancement of growth (CAG) is the \ngrowth pattern of early growth acceleration, which is present in the majority of girls \nwith idiopathic precocious puberty and in girls with early puberty [ 64]. While \nendocrine disruptors are commonly used by the industries, such as plastics \n(bisphenol A [BPA]), solvents/lubricants (polybrominated biphenyls [PBBs], \npolychlorinated biphenyls [PCBs]), dioxins, plasticizers (phthalates), pesticides \n(chlorpyrifos, dichlorodiphenyltrichloroethane [DDT], and methoxychlor), \nfungicides (vinclozolin), flame-retardant additives in manufactured materials and \npharmaceutical agents, for example, diethylstilbestrol (DES), a nonsteroidal \nsynthetic estrogen [ 11], they can also be natural, for example, phytoestrogens, \nproduced by plants and that act mainly through estrogen receptors [ 12]. The large \nquantity of endocrine disruptors and their ability to interact with the endocrine \nsystem combined with the tendency toward the early onset of puberty have led many \nresearchers to associate them with precocious puberty, especially since they have \n5 Endocrine Disruption in Women: A Cause of PCOS, Early Puberty, or Endometriosis\n\n94\nestrogenic activity. Several EDCs have been studied, and we will cite the main ones \nsuch as phthalates, bisphenol A (BPA), pesticides, flame-retardant chemicals, \nand PCBs.\n5.4  Phthalates\nPhthalates are esters of phthalic anhydride, used as liquid plasticizers in plastics, \nflooring, personal care products, medical devices, and tubing because they increase \nthe flexibility, transparency, durability, and longevity of materials. Their most \ncommon use is to soften polyvinyl chloride (PVC). Phthalates can be classified as \nlow- or high-molecular-weight phthalates, and depending on the class and the \ntiming of exposure, different outcomes have been observed.\nTheir endocrine-disrupting mechanism is not fully clarified, but they act either as \nestrogen receptor agonists and antagonists or as androgen receptor antagonists and \ncan also disrupt androgen synthesis. Different studies have demonstrated a \nsignificant association with premature thelarche and precocious or early puberty \n[65, 66]. High-molecular-weight phthalate levels several years before puberty are \nassociated with later pubic hair development and younger age of menarche. Low-  \nmolecular- weight phthalate levels are related to advanced breast or pubic hair \ndevelopment [67]. In a study of the Danish schoolgirls, high phthalate excretion in \nurine was associated with delayed pubarche, but not thelarche, which suggests \nantiandrogenic actions of phthalate [68]. Similar results were obtained in a study of \nthe US girls [69]. In contrast, in another study on the US girls with central precocious \npuberty (CPP), such an association was not found [ 70], and furthermore, a recent \nKorean study showed that phthalate metabolites in girls with central precocious \npuberty were significantly lower than the prepubertal control girls [ 71]. Many \nresults are conflicting, and further studies are needed to confirm or refute the effect \nof phthalate exposure on pubertal timing.\n5.5  BPA (Bisphenol A)\nBPA is a precursor of plastics, polycarbonates, and epoxy resins coating the inside \nof beverage, found in plastics (e.g., bottles, Tupperware, food cans, etc.). It is the \nmost commonly found estrogen-like endocrine disruptor that can also act as an \nantiandrogen in the environment. This chemical is almost ubiquitous, and even if \nthe estrogen receptor agonist activity is weak, its potential should not be \nunderestimated. In some experimental animals, it has been shown that BPA advances \npuberty [ 72], but no effect on pubertal timing [ 73]. Similar to the experimental \nanimals, the results of BPA on human puberty are inconsistent. In a study of the US \nJ. M. Wenger and R. Marci\n\n95\ngirls, Wolff et al. reported that BPA had no influence on breast development [ 67]; \nhowever, in studies performed in Turkey and in Thailand, idiopathic central \nprecocious puberty was associated with higher levels of BPA than in control girls \n[74, 75]. Watkins et al. studied the in utero and peripubertal exposure to phthalates \nand BPA in relation to sexual maturation and did not find any association between \nBPA and sexual maturation, although in utero phthalate exposure impacted on \nearlier timing of sexual maturation [ 76]. Other studies shown that EDCs are \nassociated with premature thelarche, precocious puberty, and pubertal development \n[74, 77, 78]. On the other hand, in a recent review, of 19 studies, only seven showed \na correlation between BPA and puberty with evidence of the possible disruptive role \nof BPA in people with central precocious puberty or isolated premature breast \ndevelopment aged from 2 months to 4 years, although the mechanism is not defined. \nSome studies have also found a close relationship between urinary BPA, body \nweight, and precocious puberty, which may be explained by the obesogenic effect \nof BPA itself [79].\n5.6  Pesticides\nThey are classified into various classes, for example, insecticides, herbicides, and \nfungicides, and can enter the human body through water, air, and food and can pass \nfrom mother to fetus via the placenta and to the infant through mother’s milk. One \nof the well-known dichlorodiphenyltrichloroethane (DDT) is an organochlorine, \noriginally developed as an insecticide for use in agriculture. Exposure to DDT is \nimperceptible, because it is odorless, tasteless, and colorless, and being exposed \nduring fetal life and lactation can affect sexual development. Despite the fact that \nDDT is still widely used in some low-income countries and has been banned from \nour markets, it can persist in the environment as a persistent organic pollutant (POP). \nDichlorodiphenyldichloroethane (DDE), a metabolite of DDT, has antiandrogenic, \nantiprogestin, and estrogenic effect and induces aromatase. Vasiliu et al. found an \nassociation between the exposure to these chemicals and precocious puberty and \nearlier age of menarche [80].\nA study performed in Denmark, female offspring of mothers exposed to pesti -\ncide in a greenhouse showed a decreased age of breast development at 8.9 years, \ncompared with 10.4 years in the unexposed population and 10.0 years in a Danish \nreference population [81], but the significance of the association disappeared when \nweight at menarche was controlled for. Pesticide exposure to pesticides has also \nbeen suggested in adopted or immigrant girls in Belgium, with central precocious \npuberty (CPP), following the discovery of higher levels of plasma DDE [ 63]. \nConversely, other studies did not found an association between DDE levels and \nearly puberty [82], but unlike a puberty delay [83].\n5 Endocrine Disruption in Women: A Cause of PCOS, Early Puberty, or Endometriosis\n\n96\nFlame-retardant chemicals are added to the manufactured materials (plastics, \ntextiles, surface finishes, and coatings) intended to prevent or slow the further \ndevelopment of ignition with their physical and chemical properties. Among them, \norganohalogen compounds such as polybrominated diphenyl ethers (PBDEs) are \nlipophilic persistent endocrine disruptors exhibiting estrogenic and androgenic \nproperties. PBDEs might alter pubertal timing, resulting in later menarche in girls \n[84], but in girls with idiopathic central precocious puberty, particularly those with \nhigher body mass index (BMI) have been found with higher serum concentrations \nof PBDEs [ 85]. Thus, the inconsistency of the results of the various studies \nexamining the association of endocrine disruptor chemicals with the onset of \npuberty [86] makes it imperative that more studies on the subject are performed.\nPolychlorinated biphenyl (PCB) is a dioxin-like compound derived from biphe-\nnyl, used as a dielectric and coolant fluid in electrical apparatuses. Its mechanism of \naction is rather similar to that of dioxins, and there is evidence that exposure during \nthe prenatal period leads to early onset of menarche and to delayed pubertal devel -\nopment [58].\nThe conclusion is that the onset of puberty occurs earlier in girls, and physiologi-\ncal variability and multiple other factors affect the onset of puberty. Exposure to a \nwide and growing range of known and unknown endocrine disruptors is ubiquitous, \nand changes in the onset of puberty may be influenced by exposures to endocrine \ndisruptors at critical developmental windows. Endocrine disruptors are hormonally \nactive substances that can act via several mechanisms to disrupt puberty either \nperipherally on the target organs (adipose tissue or adrenal glands) or centrally via \nthe hypothalamic–pituitary–gonadal (HPG) axis. Nevertheless, the definitive \nevidence of associations between exposures to endocrine disruptors remains \ncontroversial [ 87, 88]. It seems obvious that some endocrine disruptors modify \nmetabolic parameters: The increase in the latter [10] coincides with the increase in \nthe prevalence of obesity with its risks over the last three decades and suggests that \nthey are one of the major factors of the obesity epidemic [ 10]. The association \nbetween EDC and precocious puberty is subject to a bias that, as we have seen, is \nconstituted by the improvement of health and nutritional conditions and the increase \nin the prevalence of obesity [ 89–91], which both can advance the age of puberty. \nHowever, current data are insufficient and conflicting to provide sufficient evidence \nfor a causal relationship between exposure to endocrine disruptors and changes in \nthe timing of puberty in humans. Definitive evidence for associations between \nexposures to endocrine disruptors remains controversial and still insufficient and \ncontradictory to establish sufficient evidence for a causal relationship between \nexposure to endocrine disruptors and changes in the timing of puberty in humans. \nFurther human epidemiological studies of a prospective and longitudinal nature are \nneeded to determine the combined effect of EDC exposure on puberty and \nreproduction during critical periods. Furthermore, the underlying mechanisms by \nwhich early exposures to endocrine disruptors influence puberty, including \nepigenetic factors, need to be explored separately.\nJ. M. Wenger and R. Marci\n\n97\n5.7  Endometriosis\nEndometriosis is a common benign condition with potentially significant morbidity \nsuch as pelvic pain, dysmenorrhea, dyspareunia, and infertility and is thought to \naffect 2–50% of women of reproductive age [ 92, 93]. It is present in 71–87% of \nwomen with chronic pelvic pain [94].\nThe incidence and the prevalence associated with this disease showed an increas-\ning trend in countries with a high sociodemographic index between 1990 and 2017 \n[92, 93]. Biologically, endometriosis is an estrogen-dependent, inflammatory, \npotentially chronic gynecological condition characterized by the proliferation of \ncells resembling functional endometrial tissue and growing outside the uterine \ncavity [ 95]. Despite the proposal of many theories, the precise etiology of the \ndisease remains unknown. The oldest and still recognized hypothesis is the theory \nof retrograde menstruation [ 96]. Although the attachment of ectopic glands \nemanating from menstrual debris from reflux remains a plausible mechanistic \nexplanation for the development of endometriosis, it does not explain all the \nincidences and presentation of the disease. Other theories regarding the development \nof endometriosis include coelomic metaplasia, activation of remnant stem cells, and \ninherent epigenetic abnormalities [97–100].\nAn additional difficulty is associated with the fact that endometriosis may take \nseveral different forms (ovarian endometrioma, peritoneal endometriosis, deeply \ninfiltrating endometriosis, and adenomyosis—or endometriosis of the uterine \nmuscle), which not only differ in  location but also have different clinical \npresentations. In some cases, endometriosis remains asymptomatic, and a certain \ndiagnosis can only be established by invasive evaluation (laparoscopy) and \nhistopathological confirmation. Sometimes silent endometriosis is a condition in \nwhich the patient does not experience any discomfort resulting from the development \nof the disease, and symptoms may appear later in life or remain dormant.\nToday, it appears that the development of endometriosis is determined by com -\nplex interactions between the composite effects of genetic and environmental risk \nfactors. Indeed, families of genes associated with the immune system and inflam -\nmatory pathways, cell adhesion, and extracellular matrix remodeling have been \ndescribed as being differentially expressed when comparing women with and with-\nout endometriosis [101, 102]. As a common environmental risk factor, endocrine-\ndisrupting chemicals (EDCs) are ubiquitous in the environment and food chains and \ncan affect the dynamic balance of sex hormones and mediate the innate dysregula -\ntion of immune cells, which may therefore play a role important in the pathogenesis \nof endometriosis [ 11, 103–106]. Nevertheless, there is a clear lack of well-estab -\nlished and modifiable risk factors for this disease; several existing publications have \ngiven conflicting results. There is therefore still no conclusive evidence for these \npotential risk factors regarding the combinations themselves or their management.\nBecause of the potential association between exposure to EDCs and the develop-\nment of endometriosis, many studies have been devoted to this topic. Such studies \nare difficult to design, as it is difficult to identify both the study group and the \n5 Endocrine Disruption in Women: A Cause of PCOS, Early Puberty, or Endometriosis\n\n98\ncontrol group and to measure the exposure to EDCs and the effects of other factors \non the development of this condition.\nOf the many EDCs, compounds that are best understood in terms of potential \ninvolvement in the pathogenesis of endometriosis are bisphenols [107], dioxin and \ndioxin-like compounds [25, 104], phthalates [108], and others.\n5.8  Bisphenols\nBisphenol A (BPA) was the first to be synthesized, but evidences gathered in 1936 \nshowed a low estrogen effect with affinity for the nuclear estrogen receptor. Its \neffects depend on dosage, targeted tissue, and tissue development on the site where \nit acts. The occurrence of estrogenic or antiestrogenic effects depends on the tissue \ntargeted and on their impact on receptors [ 50]. Global production of BPA has \nsteadily grown in the recent years on account of its multiple applications in the \nplastic and manufacturing industries, in food packaging, and in toys, causing a \nconstant and permanent poisoning of food, water, and the environment. In 1950, it \nwas found that bisphosphonates could be polymerized, and since then, they have \nbeen used to make polycarbonate plastics. These plastics have convenient features \nsuch as lightweight, moldability, and impact and heat resistance and are not \nsusceptible to changes over time. About 20% of these plastics are used as a \ncomponent of epoxy resin, serving as internal coating for plastic containers, bottles, \nand dental sealants. Therefore, it is a liquid and food contaminant present in \nabnormal levels in human serum analysis according to the literature. BPA is rapidly \nmetabolized to inactive forms with a mean life cycle of approximately 4–5  h in \nadults, while in fetuses and children the metabolic rate is relatively low [109]. BPA \ncan easily accumulate in adipose tissue for having lipophilic properties. \nMeasurements of human serum have determined varied and controversial toxicity \nrates. Currently, the United States Environmental Protection Agency has established \na safe level of 50 μg/kg/day, and the European Food Safety Authority has established \na tolerable daily intake of less than 4  μg/kg/day. The list of products containing \nbisphenols available on the market has continued to grow, the most common being \nbisphenols BPS, BPF, BPB, and BPAF, which nevertheless seem to have the same \nproperties.\nBisphenols are therefore estrogen-mimicking EDCs that are capable of maintain-\ning low levels of progesterone receptors that can lead to disruptions in uterine \ncyclicity, a potential mechanism for the development of endometriosis [ 107]. The \nfirst, bisphenol A (BPA), previously used in the manufacturing of food cans and \ndental sealants, is one of the most well-studied and widespread EDCs.\nSeveral previous experimental studies reported that the exposure of prenatal \nmice to bisphenol A (BPA) can cause endometriosis-like symptoms in offspring \n[110]. In human, it was abundantly present in sera of women with endometriosis \ncompared with women without disease [111, 112]. A population-based case–control \nstudy to determine whether BPA exposure was linked to an increased risk of \nJ. M. Wenger and R. Marci\n\n99\nendometriosis, after measuring total urinary BPA concentrations in 143 cases \n(women with surgically diagnosed endometriosis) and 287 controls (women without \na known endometriosis diagnosis), revealed a statistically significant, positive \ncorrelation between urinary BPA concentrations and peritoneal endometriosis, but \nnot ovarian disease [ 113]. In contrast, in other studies, patients with ovarian \nendometriomas were found to have significantly higher urinary BPA concentrations \nthan controls [112]. Other studies found no association between urinary [114, 115]. \nInconsistencies among human studies likely reflect differences in populations, \nexperimental design variations, and the rigorousness of the control groups [115].\n5.9  Dioxins and Dioxin-Like Compounds\nDioxins and dioxin-like compounds are extremely resistant by-products of various \nindustrial processes (e.g., waste incineration and iron/steel industries) or natural, \nand they represent ubiquitous environmental pollutants, chemically stable and \nlipophilic [116], and are polycyclic aromatic agents with chloral substituents.\nDioxins and dioxin-like compounds include the following:\n (a) Polychlorinated dibenzo-p-dioxins (PCDDs or dioxins): There are 75 PCDDs.\n (b) Seven of them are highly toxic polychlorinated dibenzofurans (PCDFs): There \nare 135 PCDFs. They are not dioxins, but ten of them have dioxin-like properties, \nthe polychlorinated biphenyls (PCBs): There are 209 PCBs, and 12 of them \nhave dioxin-like properties (the so-called coplanar PCBs because of the absence \nof chlorine substitution in ortho positions that gives the molecule a planar \nconfiguration). They have been widely used as dielectric and coolant fluids until \nthey were banned worldwide in the 1980s [104].\nPCDDs, PCDFs, and PCBs together form the group of polyhalogenated hydro -\ncarbons and were found, by some authors, to be significantly associated with endo-\nmetriosis [117, 118].\nDioxin generally enters the environment after accidents like the one in Seveso, \nItaly, in 1976. Dioxins then get into soil sediments, being carried by weather \npatterns, and become incorporated into the food chain [119]. They mainly enter the \nhuman body through food and, due to their lipophilic nature, accumulate in tissues \nwith high-fat content [ 116]. Because of this property, it does not surprise to find \nhigh levels of dioxin and dioxin-like compounds in older people and reduced levels \nafter delivery or breastfeeding [120]. Ten PCDFs, 12 PCBs (those with dioxin-like \nproperties), and seven PCDDs bind to the aryl hydrocarbon receptor (AhR), an \nactivated ligand transcription factor. AhR could be mostly found in the cytosol \n(sometimes in the nucleus) and represents the key component of the dioxin pathways \n[121]. In order to quantify their biological potency, all dioxin-like compounds have \nreceived a toxic equivalency factor (TEF) in terms of the most toxic dioxin \n(2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]), which has a TEF of 1. However, the \ntoxicity of a mixture of these compounds is often expressed in pg TEQ (toxic \n5 Endocrine Disruption in Women: A Cause of PCOS, Early Puberty, or Endometriosis\n\n100\nequivalent units)/g lipids, which represents the sum of the product of the concentra-\ntion of each compound multiplied by its TEF [104]. The concentration is expressed \nper g lipids because they are mainly stored in adipose tissue [122].\nThe most toxic dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), due to its \nlipophilic nature, has the particularity of being very resistant to degradation and is \nable to modulate signaling processes mediated by estrogen and progesterone, steroid \nhormones necessary for the maintenance of normal uterine physiology. Exposure to \nTCDD has been experimentally linked to the development of reproductive disorders \nin mammals, most notably in a publication first reported by Rier in 1993, which \nfound a positive correlation between exposure to TCDD and the incidence of \nendometriosis in a colony of rhesus monkeys [123]. Several studies have since been \nfollowed to examine the potential link between exposure to TCDD and the \ndevelopment of endometriosis [117, 124–126].\nConcerning PCBs, within the reproductive tract, coplanar PCBs are particularly \nsuited to act in concert with TCDD to disrupt key elements of communication \nbetween the immune and endocrine systems ([ 127, 128], potentially promoting \nreproductive disorders such as endometriosis. Rier, who had previously linked \nTCDD and endometriosis [ 123], subsequently reported a probable coexposure of \nthese animals to significant levels of dioxin-like PCBs following food contaminated \nwith toxic substances [129]. It therefore appears that, even within the framework of \na controlled experimental study, it may be difficult to completely exclude additional \noccult sources of exposure to environmental toxicants via food or water [126, 129].\nAs with TCDD, although systematic review and meta-analysis results have \nshown that total PCBs are significantly associated with the risk of endometriosis, \nepidemiological data remain weak [130], or mixed [131], as for TCDD [126], with \na number of studies failing to identify a clear association between TCDD exposure \nand endometriosis [115], even if certain authors concluded that a bad classification \nof the disease could have led to underestimating the risk [125].\n5.10  Phthalates\nPhthalates and their esters consist of a large group of chemical compounds with \nantiandrogenic and estrogenic activity frequently used in the plastic, coating, \ncosmetic, and toy industries and medical devices such as syringes and blood bags, \nand women are generally more at risk than men due to their employment in feminine \ncare products and cosmetics [ 132]. Phthalates are the by-products of phthalic acid \nand are used in the plastics industry for their excellent moldability. In the roster of \nphthalates, three esters are considered endocrine disruptors with estrogenic effects: \ndiethyl-hexyl phthalate (DHEP), benzyl-butyl phthalate (BBP), and dibutyl \nphthalate (DBP). Phthalates can be found not only in serum and human urine, but \nJ. M. Wenger and R. Marci\n\n101\nalso in milk samples. Nevertheless, the mechanisms triggering the development of \nendometriosis by phthalates remain unclear. Tolerable daily intake ranges between \n3 and 30 μg/kg/day [133–135]. In women with advanced endometriosis, significantly \nhigher levels of mono-ethylhexyl phthalate (MEHP) and di-(2-ethylhexyl) phthalate \n(DEHP) were found in their plasma compared with disease-free women [136, 137]. \nThe results of other studies, the National Health and Nutrition Examination Survey \n(NHANES), and the Endometriosis, Natural History, Diagnosis, and Outcomes \nstudy also revealed a significant association between urinary phthalates and \nendometriosis [115, 138]. Studies on the association between phthalate exposure \nand the presence of disease in Taiwanese women revealed a significant increase \n(p < 0.05) in urinary mono-n-butyl phthalate (MBP) and MEHP in patients with \nendometriosis [ 139, 140]. Nevertheless, other epidemiological studies failed to \nvalidate these findings. Upson [141], in a study including women from the northeast \nof the United States of America, showed an inverse association between the risk of \ndeveloping endometriosis and levels of MEHP. These data were confirmed by Itoh \n[142] in a study of infertile women, although the authors only included 57 cases \nwith endometriosis and 80 controls without endometriosis.\nDespite suspicions of causation between phthalates and endometriosis, there are \nno regulations limiting their use in the United States or Brazil, although the European \nCommunity has banned them.\n5.11  Medications as Endocrine Disruptors\n5.11.1  Diethylstilbestrol\nHistorically, one of the most well-known pharmaceutical exposures to EDCs was \nthe consequence of the consumption of diethylstilbestrol (DES) by pregnant women, \nwhich was originally prescribed with the aim of mitigating the risk of miscarriage, \npremature delivery, and other pregnancy-related complications [ 26]. DES is a \nsynthetic, highly potent estrogen that was initially prescribed to women with high-  \nrisk pregnancies. Soon after, it was recommended to all pregnant women from the \n1940s through the 1970s. In 1971, DES was banned in the United States because, in \naddition to being completely ineffective in preventing miscarriage, it was shown to \nincrease the risk of serious illness in mothers and their children [143, 144].\nRelevant to the current discussion, additional studies revealed an increased inci-\ndence of endometriosis in women whose mothers were prescribed DES compared \nwith the daughters of women that were not given DES during pregnancy [145, 146].\n5 Endocrine Disruption in Women: A Cause of PCOS, Early Puberty, or Endometriosis\n\n102\n5.12  Conclusion\nThe various studies concerning these three pathologies cited above, which show not \nonly sometimes strong but also weak or contradictory relationships with endocrine \ndisruptors, their involvement in complex metabolic disorders, and the new harmful \neffects on health of endocrine disruptors frequently used, highlight the full \ncomplexity of the problem. Taking this complexity into account in the assessment, \nmanagement, and attempts to resolve it requires an approach from several points of \nview: environmental, ethical, scientific, epidemiological, economic, political, \nstrategic, and preventive. Compounds potentially incriminated as endocrine \ndisruptors are ubiquitous, present in our daily life (diet and lifestyle), increasing \nexponentially, persistent but also sporadic, and capable of producing potentially \nactive metabolites. The scientific challenges are numerous due to the difficulties in \ndosing the compounds, the confusions, the complex mixtures of exposures and their \ninterrelationships [147], the variability of the distributions of exposure from one \nstudy to another that can explain the differences in results, the design of numerous \nstudies, and the imprecision of the exposure assessment methods (dosage, the \nnumber of patients, the duration of exposure, statistical bias, and difficulty in \nassaying the substances in question in the target organs), in particular for the \nchemicals with short half-life. In addition, biostatistical developments have not yet \nresulted in an ideal method to manage associated exposures that might exist in the \nhuman body [ 148]. Sometimes the limit values that can be considered toxic are \nunclear, and the relevance of animal models transferred to humans is questionable. \nMoreover, with the exception of evidence from accidentally exposed populations, \nexperimental evidence demonstrates that developmental exposure to endocrine \ndisruptors can lead to transgenerational adverse effects with health consequences: \nSuch a concept is difficult to prove in humans because randomized designs of \ninterventions to increase or decrease exposure are generally not applicable due to \nobvious ethical and logistical considerations.\nA recurring theme in the studies reviewed is the appearance on the market of a \ncolossal quantity of new substances, but also of their substitutes, little tested, \nwrongly assumed to be less toxic [ 15], and on the contrary revealing new signs of \ntoxicity [ 26]. What about the recommended doses for BPA by the American \nEnvironmental Protection Agency for a safety level of 50  μg/kg/day, while the \nEuropean Food Safety Authority has established a tolerable daily intake of less than \n4  μg/kg/day? or concerning restrictions on phthalates, totally absent in the United \nStates or Brazil, but banned by the European Community [ 149]? Are there diver-\ngences between financial interests and public health?\nThe otherwise justified terms “possible” or “probable” found in the literature for \nthe risky should not obscure the precautionary principle, in light of reality: It is \nincreasingly clear that endocrine disruptors are involved in diseases that are not \ntransferable. Nevertheless, these synthetic compounds are ignored or at least \nunderestimated as sustainable development goals (SDGs) of 2030, and decreasing \nexposure to synthetic chemicals with endocrine-disrupting or other harmful \nJ. M. Wenger and R. Marci\n\n103\nproperties is not identified as one of the SDGs, although these rightly highlight that \nair pollution and climate change as global priorities [ 150] and despite the fact that \nintervention studies have produced rapid decreases in exposure to organophosphate \npesticides, bisphenols, phthalates, parabens, and triclosans [ 151]. However, the \ndecisions must come not only from the decision-makers, but also from the \nconsumers. Since the majority of exposure to endocrine disruptors occurs through \ndiet, choosing organic foods, lean meats, or a vegetarian lifestyle can help everyone \nminimize exposure. In addition, reducing the use of canned foods containing a BPA \nliner, using BPA-/BPS-free products, and avoiding long-term storage or heating of \nfoods in plastic containers will also reduce the accidental exposure to the endocrine \ndisruptors [26].\nTherefore, in light of the above, clear-cut strategies and recommendations should \nbe targeted to reduce human exposure to protect future generations from ever-  \nincreasing adverse health effects, and regulators should strengthen premarketing \ntoxicological testing [152].\nThe need for additional further research is evident to further elaborate the effects \nof endocrine disruptors and other products on human health looking, of course, at \ncausation and actions to reduce exposure to endocrine disruptors, taking into \naccount the evidence and issues involved in decisions [153] and finding alternative \nmanufacturing practices that can be applied to mitigate exposure to endocrine \ndisruptors [24]. 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Proc R Soc Med. \n1965;58:295–300.\nOpen Access  This chapter is licensed under the terms of the Creative Commons Attribution 4.0 \nInternational License ( http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, \nadaptation, distribution and reproduction in any medium or format, as long as you give appropriate \ncredit to the original author(s) and the source, provide a link to the Creative Commons license and \nindicate if changes were made.\nThe images or other third party material in this chapter are included in the chapter's Creative \nCommons license, unless indicated otherwise in a credit line to the material. 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