Endocrine Disruption in Women: A Cause of PCOS, Early Puberty, or Endometriosis

are conflicting, and further studies are needed to confirm or refute the effect of phthalate exposure on pubertal timing. 5.5 BPA (Bisphenol A) BPA is a precursor of plastics, polycarbonates, and epoxy resins coating the inside of beverage, found in plastics (e.g., bottles, Tupperware, food cans, etc.). It is the most commonly found estrogen-like endocrine disruptor that can also act as an antiandrogen in the environment. This chemical is almost ubiquitous, and even if the estrogen receptor agonist activity is weak, its potential should not be underestimated. In some experimental animals, it has been shown that BPA advances puberty [ 72], but no effect on pubertal timing [ 73]. Similar to the experimental animals, the results of BPA on human puberty are inconsistent. In a study of the US J. M. Wenger and R. Marci 95 girls, Wolff et al. reported that BPA had no influence on breast development [ 67]; however, in studies performed in Turkey and in Thailand, idiopathic central precocious puberty was associated with higher levels of BPA than in control girls [74, 75]. Watkins et al. studied the in utero and peripubertal exposure to phthalates and BPA in relation to sexual maturation and did not find any association between BPA and sexual maturation, although in utero phthalate exposure impacted on earlier timing of sexual maturation [ 76]. Other studies shown that EDCs are associated with premature thelarche, precocious puberty, and pubertal development [74, 77, 78]. On the other hand, in a recent review, of 19 studies, only seven showed a correlation between BPA and puberty with evidence of the possible disruptive role of BPA in people with central precocious puberty or isolated premature breast development aged from 2 months to 4 years, although the mechanism is not defined. Some studies have also found a close relationship between urinary BPA, body weight, and precocious puberty, which may be explained by the obesogenic effect of BPA itself [79]. 5.6 Pesticides They are classified into various classes, for example, insecticides, herbicides, and fungicides, and can enter the human body through water, air, and food and can pass from mother to fetus via the placenta and to the infant through mother’s milk. One of the well-known dichlorodiphenyltrichloroethane (DDT) is an organochlorine, originally developed as an insecticide for use in agriculture. Exposure to DDT is imperceptible, because it is odorless, tasteless, and colorless, and being exposed during fetal life and lactation can affect sexual development. Despite the fact that DDT is still widely used in some low-income countries and has been banned from our markets, it can persist in the environment as a persistent organic pollutant (POP). Dichlorodiphenyldichloroethane (DDE), a metabolite of DDT, has antiandrogenic, antiprogestin, and estrogenic effect and induces aromatase. Vasiliu et al. found an association between the exposure to these chemicals and precocious puberty and earlier age of menarche [80]. A study performed in Denmark, female offspring of mothers exposed to pesti - cide in a greenhouse showed a decreased age of breast development at 8.9 years, compared with 10.4 years in the unexposed population and 10.0 years in a Danish

population [81], but the significance of the association disappeared when weight at menarche was controlled for. Pesticide exposure to pesticides has also been suggested in adopted or immigrant girls in Belgium, with central precocious puberty (CPP), following the discovery of higher levels of plasma DDE [ 63]. Conversely, other studies did not found an association between DDE levels and early puberty [82], but unlike a puberty delay [83]. 5 Endocrine Disruption in Women: A Cause of PCOS, Early Puberty, or Endometriosis 96 Flame-retardant chemicals are added to the manufactured materials (plastics, textiles, surface finishes, and coatings) intended to prevent or slow the further development of ignition with their physical and chemical properties. Among them, organohalogen compounds such as polybrominated diphenyl ethers (PBDEs) are lipophilic persistent endocrine disruptors exhibiting estrogenic and androgenic properties. PBDEs might alter pubertal timing, resulting in later menarche in girls [84], but in girls with idiopathic central precocious puberty, particularly those with higher body mass index (BMI) have been found with higher serum concentrations of PBDEs [ 85]. Thus, the inconsistency of the results of the various studies examining the association of endocrine disruptor chemicals with the onset of puberty [86] makes it imperative that more studies on the subject are performed. Polychlorinated biphenyl (PCB) is a dioxin-like compound derived from biphe- nyl, used as a dielectric and coolant fluid in electrical apparatuses. Its mechanism of action is rather similar to that of dioxins, and there is evidence that exposure during the prenatal period leads to early onset of menarche and to delayed pubertal devel - opment [58]. The conclusion is that the onset of puberty occurs earlier in girls, and physiologi- cal variability and multiple other factors affect the onset of puberty. Exposure to a wide and growing range of known and unknown endocrine disruptors is ubiquitous, and changes in the onset of puberty may be influenced by exposures to endocrine disruptors at critical developmental windows. Endocrine disruptors are hormonally active substances that can act via several mechanisms to disrupt puberty either peripherally on the target organs (adipose tissue or adrenal glands) or centrally via the hypothalamic–pituitary–gonadal (HPG) axis. Nevertheless, the definitive evidence of associations between exposures to endocrine disruptors remains controversial [ 87, 88]. It seems obvious that some endocrine disruptors modify metabolic parameters: The increase in the latter [10] coincides with the increase in the prevalence of obesity with its risks over the last three decades and suggests that they are one of the major factors of the obesity epidemic [ 10]. The association between EDC and precocious puberty is subject to a bias that, as we have seen, is constituted by the improvement of health and nutritional conditions and the increase in the prevalence of obesity [ 89–91], which both can advance the age of puberty. However, current data are insufficient and conflicting to provide sufficient evidence for a causal relationship between exposure to endocrine disruptors and changes in the timing of puberty in humans. Definitive evidence for associations between exposures to endocrine disruptors remains controversial and still insufficient and contradictory to establish sufficient evidence for a causal relationship between exposure to endocrine disruptors and changes in the timing of puberty in humans. Further human epidemiological studies of a prospective and longitudinal nature are needed to determine the combined effect of EDC exposure on puberty and reproduction during critical periods. Furthermore, the underlying mechanisms by which early exposures to endocrine disruptors influence puberty, including epigenetic factors, need to be explored separately. J. M. Wenger and R. Marci 97 5.7 Endometriosis Endometriosis is a common benign condition with potentially significant morbidity such as pelvic pain, dysmenorrhea, dyspareunia, and infertility and is thought to affect 2–50% of women of reproductive age [ 92, 93]. It is present in 71–87% of women with chronic pelvic pain [94]. The incidence and the prevalence associated with this disease showed an increas- ing trend in countries with a high sociodemographic index between 1990 and 2017 [92, 93]. Biologically, endometriosis is an estrogen-dependent, inflammatory, potentially chronic gynecological condition characterized by the proliferation of cells resembling functional endometrial tissue and growing outside the uterine cavity [ 95]. Despite the proposal of many theories, the precise etiology of the disease remains unknown. The oldest and still recognized hypothesis is the theory of retrograde menstruation [ 96]. Although the attachment of ectopic glands emanating from menstrual debris from reflux remains a plausible mechanistic explanation for the development of endometriosis, it does not explain all the incidences and presentation of the disease. Other theories regarding the development of endometriosis include coelomic metaplasia, activation of remnant stem cells, and inherent epigenetic abnormalities [97–100]. An additional difficulty is associated with the fact that endometriosis may take several different forms (ovarian endometrioma, peritoneal endometriosis, deeply infiltrating endometriosis, and adenomyosis—or endometriosis of the uterine muscle), which not only differ in  location but also have different clinical presentations. In some cases, endometriosis remains asymptomatic, and a certain diagnosis can only be established by invasive evaluation (laparoscopy) and histopathological confirmation. Sometimes silent endometriosis is a condition in which the patient does not experience any discomfort resulting from the development of the disease, and symptoms may appear later in life or remain dormant. Today, it appears that the development of endometriosis is determined by com - plex interactions between the composite effects of genetic and environmental risk factors. Indeed, families of genes associated with the immune system and inflam - matory pathways, cell adhesion, and extracellular matrix remodeling have been described as being differentially expressed when comparing women with and with- out endometriosis [101, 102]. As a common environmental risk factor, endocrine- disrupting chemicals (EDCs) are ubiquitous in the environment and food chains and can affect the dynamic balance of sex hormones and mediate the innate dysregula - tion of immune cells, which may therefore play a role important in the pathogenesis of endometriosis [ 11, 103–106]. Nevertheless, there is a clear lack of well-estab - lished and modifiable risk factors for this disease; several existing publications have given conflicting results. There is therefore still no conclusive evidence for these potential risk factors regarding the combinations themselves or their management. Because of the potential association between exposure to EDCs and the develop- ment of endometriosis, many studies have been devoted to this topic. Such studies are difficult to design, as it is difficult to identify both the study group and the 5 Endocrine Disruption in Women: A Cause of PCOS, Early Puberty, or Endometriosis 98 control group and to measure the exposure to EDCs and the effects of other factors on the development of this condition. Of the many EDCs, compounds that are best understood in terms of potential involvement in the pathogenesis of endometriosis are bisphenols [107], dioxin and dioxin-like compounds [25, 104], phthalates [108], and others. 5.8 Bisphenols Bisphenol A (BPA) was the first to be synthesized, but evidences gathered in 1936 showed a low estrogen effect with affinity for the nuclear estrogen receptor. Its effects depend on dosage, targeted tissue, and tissue development on the site where it acts. The occurrence of estrogenic or antiestrogenic effects depends on the tissue targeted and on their impact on receptors [ 50]. Global production of BPA has steadily grown in the recent years on account of its multiple applications in the plastic and manufacturing industries, in food packaging, and in toys, causing a constant and permanent poisoning of food, water, and the environment. In 1950, it was found that bisphosphonates could be polymerized, and since then, they have been used to make polycarbonate plastics. These plastics have convenient features such as lightweight, moldability, and impact and heat resistance and are not susceptible to changes over time. About 20% of these plastics are used as a component of epoxy resin, serving as internal coating for plastic containers, bottles, and dental sealants. Therefore, it is a liquid and food contaminant present in abnormal levels in human serum analysis according to the literature. BPA is rapidly metabolized to inactive forms with a mean life cycle of approximately 4–5  h in adults, while in fetuses and children the metabolic rate is relatively low [109]. BPA can easily accumulate in adipose tissue for having lipophilic properties. Measurements of human serum have determined varied and controversial toxicity rates. Currently, the United States Environmental Protection Agency has established a safe level of 50 μg/kg/day, and the European Food Safety Authority has established a tolerable daily intake of less than 4  μg/kg/day. The list of products containing bisphenols available on the market has continued to grow, the most common being bisphenols BPS, BPF, BPB, and BPAF, which nevertheless seem to have the same properties. Bisphenols are therefore estrogen-mimicking EDCs that are capable of maintain- ing low levels of progesterone receptors that can lead to disruptions in uterine cyclicity, a potential mechanism for the development of endometriosis [ 107]. The first, bisphenol A (BPA), previously used in the manufacturing of food cans and dental sealants, is one of the most well-studied and widespread EDCs. Several previous experimental studies reported that the exposure of prenatal mice to bisphenol A (BPA) can cause endometriosis-like symptoms in offspring [110]. In human, it was abundantly present in sera of women with endometriosis compared with women without disease [111, 112]. A population-based case–control study to determine whether BPA exposure was linked to an increased risk of J. M. Wenger and R. Marci 99 endometriosis, after measuring total urinary BPA concentrations in 143 cases (women with surgically diagnosed endometriosis) and 287 controls (women without a known endometriosis diagnosis), revealed a statistically significant, positive correlation between urinary BPA concentrations and peritoneal endometriosis, but not ovarian disease [ 113]. In contrast, in other studies, patients with ovarian endometriomas were found to have significantly higher urinary BPA concentrations than controls [112]. Other studies found no association between urinary [114, 115]. Inconsistencies among human studies likely reflect differences in populations, experimental design variations, and the rigorousness of the control groups [115]. 5.9 Dioxins and Dioxin-Like Compounds Dioxins and dioxin-like compounds are extremely resistant by-products of various industrial processes (e.g., waste incineration and iron/steel industries) or natural, and they represent ubiquitous environmental pollutants, chemically stable and lipophilic [116], and are polycyclic aromatic agents with chloral substituents. Dioxins and dioxin-like compounds include the following: (a) Polychlorinated dibenzo-p-dioxins (PCDDs or dioxins): There are 75 PCDDs. (b) Seven of them are highly toxic polychlorinated dibenzofurans (PCDFs): There are 135 PCDFs. They are not dioxins, but ten of them have dioxin-like properties, the polychlorinated biphenyls (PCBs): There are 209 PCBs, and 12 of them have dioxin-like properties (the so-called coplanar PCBs because of the absence of chlorine substitution in ortho positions that gives the molecule a planar configuration). They have been widely used as dielectric and coolant fluids until they were banned worldwide in the 1980s [104]. PCDDs, PCDFs, and PCBs together form the group of polyhalogenated hydro - carbons and were found, by some authors, to be significantly associated with endo- metriosis [117, 118]. Dioxin generally enters the environment after accidents like the one in Seveso, Italy, in 1976. Dioxins then get into soil sediments, being carried by weather patterns, and become incorporated into the food chain [119]. They mainly enter the human body through food and, due to their lipophilic nature, accumulate in tissues with high-fat content [ 116]. Because of this property, it does not surprise to find high levels of dioxin and dioxin-like compounds in older people and reduced levels after delivery or breastfeeding [120]. Ten PCDFs, 12 PCBs (those with dioxin-like properties), and seven PCDDs bind to the aryl hydrocarbon receptor (AhR), an activated ligand transcription factor. AhR could be mostly found in the cytosol (sometimes in the nucleus) and represents the key component of the dioxin pathways [121]. In order to quantify their biological potency, all dioxin-like compounds have received a toxic equivalency factor (TEF) in terms of the most toxic dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]), which has a TEF of 1. However, the toxicity of a mixture of these compounds is often expressed in pg TEQ (toxic 5 Endocrine Disruption in Women: A Cause of PCOS, Early Puberty, or Endometriosis 100 equivalent units)/g lipids, which represents the sum of the product of the concentra- tion of each compound multiplied by its TEF [104]. The concentration is expressed per g lipids because they are mainly stored in adipose tissue [122]. The most toxic dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), due to its lipophilic nature, has the particularity of being very resistant to degradation and is able to modulate signaling processes mediated by estrogen and progesterone, steroid hormones necessary for the maintenance of normal uterine physiology. Exposure to TCDD has been experimentally linked to the development of reproductive disorders in mammals, most notably in a publication first reported by Rier in 1993, which found a positive correlation between exposure to TCDD and the incidence of endometriosis in a colony of rhesus monkeys [123]. Several studies have since been followed to examine the potential link between exposure to TCDD and the development of endometriosis [117, 124–126]. Concerning PCBs, within the reproductive tract, coplanar PCBs are particularly suited to act in concert with TCDD to disrupt key elements of communication between the immune and endocrine systems ([ 127, 128], potentially promoting reproductive disorders such as endometriosis. Rier, who had previously linked TCDD and endometriosis [ 123], subsequently reported a probable coexposure of these animals to significant levels of dioxin-like PCBs following food contaminated with toxic substances [129]. It therefore appears that, even within the framework of a controlled experimental study, it may be difficult to completely exclude additional occult sources of exposure to environmental toxicants via food or water [126, 129]. As with TCDD, although systematic review and meta-analysis results have shown that total PCBs are significantly associated with the risk of endometriosis, epidemiological data remain weak [130], or mixed [131], as for TCDD [126], with a number of studies failing to identify a clear association between TCDD exposure and endometriosis [115], even if certain authors concluded that a bad classification of the disease could have led to underestimating the risk [125]. 5.10 Phthalates Phthalates and their esters consist of a large group of chemical compounds with antiandrogenic and estrogenic activity frequently used in the plastic, coating, cosmetic, and toy industries and medical devices such as syringes and blood bags, and women are generally more at risk than men due to their employment in feminine care products and cosmetics [ 132]. Phthalates are the by-products of phthalic acid and are used in the plastics industry for their excellent moldability. In the roster of phthalates, three esters are considered endocrine disruptors with estrogenic effects: diethyl-hexyl phthalate (DHEP), benzyl-butyl phthalate (BBP), and dibutyl phthalate (DBP). Phthalates can be found not only in serum and human urine, but J. M. Wenger and R. Marci 101 also in milk samples. Nevertheless, the mechanisms triggering the development of endometriosis by phthalates remain unclear. Tolerable daily intake ranges between 3 and 30 μg/kg/day [133–135]. In women with advanced endometriosis, significantly higher levels of mono-ethylhexyl phthalate (MEHP) and di-(2-ethylhexyl) phthalate (DEHP) were found in their plasma compared with disease-free women [136, 137]. The results of other studies, the National Health and Nutrition Examination Survey (NHANES), and the Endometriosis, Natural History, Diagnosis, and Outcomes study also revealed a significant association between urinary phthalates and endometriosis [115, 138]. Studies on the association between phthalate exposure and the presence of disease in Taiwanese women revealed a significant increase (p < 0.05) in urinary mono-n-butyl phthalate (MBP) and MEHP in patients with endometriosis [ 139, 140]. Nevertheless, other epidemiological studies failed to validate these findings. Upson [141], in a study including women from the northeast of the United States of America, showed an inverse association between the risk of developing endometriosis and levels of MEHP. These data were confirmed by Itoh [142] in a study of infertile women, although the authors only included 57 cases with endometriosis and 80 controls without endometriosis. Despite suspicions of causation between phthalates and endometriosis, there are no regulations limiting their use in the United States or Brazil, although the European Community has banned them. 5.11 Medications as Endocrine Disruptors 5.11.1 Diethylstilbestrol Historically, one of the most well-known pharmaceutical exposures to EDCs was the consequence of the consumption of diethylstilbestrol (DES) by pregnant women, which was originally prescribed with the aim of mitigating the risk of miscarriage, premature delivery, and other pregnancy-related complications [ 26]. DES is a synthetic, highly potent estrogen that was initially prescribed to women with high- risk pregnancies. Soon after, it was recommended to all pregnant women from the 1940s through the 1970s. In 1971, DES was banned in the United States because, in addition to being completely ineffective in preventing miscarriage, it was shown to increase the risk of serious illness in mothers and their children [143, 144]. Relevant to the current discussion, additional studies revealed an increased inci- dence of endometriosis in women whose mothers were prescribed DES compared with the daughters of women that were not given DES during pregnancy [145, 146]. 5 Endocrine Disruption in Women: A Cause of PCOS, Early Puberty, or Endometriosis 102 5.12 Conclusion The various studies concerning these three pathologies cited above, which show not only sometimes strong but also weak or contradictory relationships with endocrine disruptors, their involvement in complex metabolic disorders, and the new harmful effects on health of endocrine disruptors frequently used, highlight the full complexity of the problem. Taking this complexity into account in the assessment, management, and attempts to resolve it requires an approach from several points of view: environmental, ethical, scientific, epidemiological, economic, political, strategic, and preventive. Compounds potentially incriminated as endocrine disruptors are ubiquitous, present in our daily life (diet and lifestyle), increasing exponentially, persistent but also sporadic, and capable of producing potentially active metabolites. The scientific challenges are numerous due to the difficulties in dosing the compounds, the confusions, the complex mixtures of exposures and their interrelationships [147], the variability of the distributions of exposure from one study to another that can explain the differences in results, the design of numerous studies, and the imprecision of the exposure assessment methods (dosage, the number of patients, the duration of exposure, statistical bias, and difficulty in assaying the substances in question in the target organs), in particular for the chemicals with short half-life. In addition, biostatistical developments have not yet resulted in an ideal method to manage associated exposures that might exist in the human body [ 148]. Sometimes the limit values that can be considered toxic are unclear, and the relevance of animal models transferred to humans is questionable. Moreover, with the exception of evidence from accidentally exposed populations, experimental evidence demonstrates that developmental exposure to endocrine disruptors can lead to transgenerational adverse effects with health consequences: Such a concept is difficult to prove in humans because randomized designs of interventions to increase or decrease exposure are generally not applicable due to obvious ethical and logistical considerations. A recurring theme in the studies reviewed is the appearance on the market of a colossal quantity of new substances, but also of their substitutes, little tested, wrongly assumed to be less toxic [ 15], and on the contrary revealing new signs of toxicity [ 26]. What about the recommended doses for BPA by the American Environmental Protection Agency for a safety level of 50  μg/kg/day, while the European Food Safety Authority has established a tolerable daily intake of less than 4  μg/kg/day? or concerning restrictions on phthalates, totally absent in the United States or Brazil, but banned by the European Community [ 149]? Are there diver- gences between financial interests and public health? The otherwise justified terms “possible” or “probable” found in the literature for the risky should not obscure the precautionary principle, in light of reality: It is increasingly clear that endocrine disruptors are involved in diseases that are not transferable. Nevertheless, these synthetic compounds are ignored or at least underestimated as sustainable development goals (SDGs) of 2030, and decreasing exposure to synthetic chemicals with endocrine-disrupting or other harmful J. M. Wenger and R. Marci 103 properties is not identified as one of the SDGs, although these rightly highlight that air pollution and climate change as global priorities [ 150] and despite the fact that intervention studies have produced rapid decreases in exposure to organophosphate pesticides, bisphenols, phthalates, parabens, and triclosans [ 151]. However, the decisions must come not only from the decision-makers, but also from the consumers. Since the majority of exposure to endocrine disruptors occurs through diet, choosing organic foods, lean meats, or a vegetarian lifestyle can help everyone minimize exposure. In addition, reducing the use of canned foods containing a BPA liner, using BPA-/BPS-free products, and avoiding long-term storage or heating of foods in plastic containers will also reduce the accidental exposure to the endocrine disruptors [26]. Therefore, in light of the above, clear-cut strategies and recommendations should be targeted to reduce human exposure to protect future generations from ever- increasing adverse health effects, and regulators should strengthen premarketing toxicological testing [152]. The need for additional further research is evident to further elaborate the effects of endocrine disruptors and other products on human health looking, of course, at causation and actions to reduce exposure to endocrine disruptors, taking into account the evidence and issues involved in decisions [153] and finding alternative manufacturing practices that can be applied to mitigate exposure to endocrine disruptors [24]. The additional costs to society can be weighed against the economic benefits of reduced disease and disability and other societal effects (e.g., ecosystem effects) [24], by always bearing in mind, however, that human health must take precedence over any other interest.

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