{"paper_id":"88b6665b-791a-4a1e-901f-795bc280d3aa","body_text":"A growing number of scientific evidence has been collected over the past few years\nsuggesting that human reproductive capacity has been affected by a wide range of\nrecurrent substances present in a wide array of everyday products. Several\nindicators are showing increased incidence of cardiovascular disorders, obesity,\nhormone-dependent cancers, and chronic diseases, not to mention early puberty\ndevelopment, pregnancy length disorders, and other reproductive health\nabnormalities.\nAmong the acting agents are substances such as bisphenol A (BPA) and its byproducts\nbisphenol B, tetrabromobisphenol A, and bisphenols F and S. All of these and more\nhave been defined as endocrine disrupting chemicals (EDCs). Endocrine disruptors are\nchemicals that may interfere and cause adverse effects on the endocrine system at\nany life-stage on account of their resemblance with endogenous steroid hormones.\n Birnbaum (2013)  showed that the global\nproduction of these chemicals increased 23.5 fold between 1947 and 2007. In 2012\nalone, the US produced 9.5 trillion pounds - 2.09 trillion kilograms - of these\nchemicals embedded in products such as pesticides, plastics, chemical drugs, and\neven personal hygiene products.\nDeserving more attention are DDT (dichlorodiphenyltrichloroethane), DDE\n(dichlorodiphenyldichloroethylene), DDD (dichlorodiphenyldichloroethane) and their\nbyproducts such as atrazine and 2,4-dichlorophenoxyacetic acid found in toys, and\nothers containing lead and cadmium, materials used in the production of plastic\nbottles containing BPA, phthalates, and several other substances employed in the\ntextile and apparel industries ( Gore  et\nal ., 2015 ). Numerous studies examined the effects of EDCs\nand their adverse effects against different areas of the female reproductive\nsystem.\n\nBPA or 2,2-bis(4-hydroxyphenyl) propane was first synthesized by Dianin, in 1891, and\nits estrogenic properties were found by  Dodds &\nLawson (1936) . DES (diethylstilbestrol) was also found to have a powerful\nestrogenic effect ( Dodds  et al. ,\n1938 ). Later, in 1950, it was observed that BPA could be polymerized for\nthe manufacturing of plastics given its lightweight, moldability, and impact\nresistance. Diethylstilbestrol was defined as the first “endocrine disrupting\nchemical”, since abnormalities such as later development of vaginal adenosis, clear\ncell adenocarcinoma of the vagina, and/or uterine anomalies, were found in the\nexposed female offspring of pregnant women treated to prevent miscarriage.\n\nExamples of endocrine disruptors:\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.\nIts effects depend on dosage, targeted tissue, and tissue development on the\nsite where it acts. The occurrence of estrogenic or anti-estrogenic effects\ndepends on the tissue targeted and on their impact on receptors ( Rochester  et al. , 2015 ).\nGlobal production of BPA has steadily grown in recent years on account of its\nmultiple applications in the plastic and manufacturing industries, in food\npackaging and toys, causing a constant and permanent poisoning of food, water,\nand the environment. In 1950, it was found that bisphosphonates could be\npolymerized and, since then, they have been used to make polycarbonate plastics.\nThese plastics have convenient features such as lightweight, moldability, and\nimpact and heat resistance, and are not susceptible to changes over time. About\n20% of these plastics are used as a component of epoxy resin, serving as\ninternal coating for plastic containers and bottles. Therefore, it is a liquid\nand food contaminant present in abnormal levels in human serum analysis\naccording to the literature. BPA is rapidly metabolized to inactive forms with a\nmean life cycle of approximately 4-5 hours in adults, while in fetuses and\nchildren the metabolic rate is relatively low ( Gerona  et al ., 2013 ;  Sartain & Hunt, 2016 ). BPA can easily accumulate in\nadipose tissue for having lipophilic properties. Measurements of human serum\nhave determined varied and controversial toxicity rates. Currently, the United\nStates Environmental Protection Agency has established a safe level of\n50µg/kg/day and the European Food Safety Authority has established a\ntolerable daily intake below 4µg/kg/day. The list of products with\nbisphenols available in the market has grown steadily, with the most common\nbeing Bisphenol S,F,B, and AF.\nPhthalates and their esters consist of a large group of chemical compounds\nfrequently used in the plastic, coating, cosmetic, and toy industries, including\nthe manufacturing of medical equipment such as syringes and blood bags.\nPhthalates are byproducts of phthalic acid and are used in the plastics industry\nfor their excellent moldability. There are no regulations restricting the use of\nphthalates in the United States or in Brazil, but the European Community has\nbanned phthalates. In the roster of phthalates, three esters are considered\nendocrine disruptors with estrogenic effects: DHEP (diethyl-hexyl phthalate),\nBBP (benzyl-butyl phthalate), and DBP (dibutyl phthalate). Phthalates can be\nfound not only in serum and human urine, but also in milk samples. Tolerable\ndaily intake ranges between 3-30ug/kg/day ( Hines\n et al ., 2009 ;  Fromme  et al ., 2011 ;  Hannon & Flaws, 2015 ).\nAtrazine (2-chloro-4-ethylamino-6-isopropylamino-1,3,5-s-triazine), as\nchlorotriazine, is largely used in agriculture as a herbicide. It has been used\nto reduce the growth of leaves and weeds in wheat, soy, and sugar cane crops due\nto the inhibition of photosynthesis ( Gianessi,\n1998 ). Its metabolites remain active for long periods of time and, as\npesticides, they cause water contamination, including water sources for human\nconsumption ( Solomon  et al .,\n2013 ).\nPolychlorinated bisphenols (PCBs) are chemical substances with a phenolic ring\nand different degrees of chlorination. They were first manufactured in 1920, and\nwere used in the rubber, resin, adhesives, and paint industries ( Soto  et al ., 1995 ). These\nchemicals were extensively used around the world and contaminated schools and\nconstruction sites. They build up both in the environment and in adipose tissue,\nand are considered endocrine disruptors affecting the thyroid hormone with\nestrogenic and anti-androgenic activity. PCBs were banned in 1979 for their\npersistent pollutant effects. The polybrominated esters of bisphenols were first\nused as flame retardants and in mattresses and blankets ( ATSDR, 2004 ;  2017 ). Of\nall 209 synthesized products categorized as polybrominated aromatic compounds,\nfive esters top the list of toxicity: tetra BDE-47, penta BDE99 -100, -153 and\ndeca BDE-209 or PBDE= Polybrominated diphenyl ethers. ( Zota  et al ., 2011 ;  Costa & Giordano, 2007 ).\nThese are chemical compounds once widely used as insecticides with a long life\nand strong lipophilic properties. Evidenced as contaminants to the environment,\nexposure to these chemicals can lead to several endocrine diseases, although\nthey have been used to control insects that carry malaria ( National Toxicology Program, 2011 ;  McGlynn  et al ., 2008 ;  Hardell  et al ., 2004 ;\n Safe & Zacharewski, 1997 ). DDT\nwas banned in 1972 due to its high toxicity levels.\nIn addition to DDT, other pesticides deserve to be mentioned such as\nhexachlorocyclohexane, chlordane, and hexachlorobenzene. These products have\nbeen closely studied not only for persistently building up in nature but also\nfor being endocrine disrupting chemicals. However, there are new pesticides\nbeing launched in the market with shorter mean lives and similar effects, such\nas 2,4-dichlorophenol, 2,5-dichlorophenol, and 1-naphthol, present in 50% of\npregnant women in the Salinas Valley, California, USA.\nElements such as cadmium, lead, and mercury have been widely used in various\nscenarios leading to a great number of reproductive anomalies. Cadmium is used\nin batteries, metallic pigments, and plastics, but exposure to this chemical may\ncause harmful effects to the placental DNA and fetal umbilical cord, in addition\nto accumulating in the liver and kidneys. Lead was once extensively used in the\npaint, oil, and toy industries. Its adverse effects include genomic methylation\nand a number of different abnormalities in brain development. Mercury was once\nused in several industrial processes and emissions have been linked to burning\ncharcoal. Human exposure occurs mainly through the intake of contaminated fish\nfrom sites such as Minamata Bay, Japan, the Faroe Islands in the Northern\nAtlantic, and Nunavik in Canada.\nThis powerful synthetic non-steroidal estrogen was used in the USA from 1940 to\n1975 to prevent miscarriage and/or its complications. Initially, low doses of\n5mg/day were administered, but they were progressively increased to 125mg/day or\nmore, and eventually got to a mean dose of 3650-4000mg.  Dieckmann  et al . (1953)  proved this\ntreatment was ineffective.  Herbst  et\nal . (1971)  assessed young women and noticed a\ncorrelation between the use of DES and the appearance of clear cell vaginal\nadenocarcinoma. In 1976, the same author ( Herbst, 1976 ) described other abnormalities in the genital tract of\nyoung women whose mothers had been treated with DES.  Harris & Waring (2012)  and  Troisi  et al . (2013)  described increased\nnumbers of reproductive system disorders in the male and female children of\nmothers treated with DES. The disorders included cryptorchidism, uterine\nabnormalities such as T-shaped uterus, and some types of hormone-dependent\ncancers.\n\nThis review lists a number of reproductive abnormalities associated to endocrine\ndisruptors and their different effects:\nEndocrine glands secrete different hormones that regulate the development,\nphysiologic processes, and homeostasis of all organisms. These hormones interact\nwith various receptors on target cells, according to their affinity, and have\ndissociation constants ranging between 10-12 and 10-9, associated with their low\ncirculating concentrations. BPA is an endocrine disruptor that binds to estrogen\nreceptors alpha and beta with a binding affinity 1000 to 10000 times lower than\nthat of endogenous estradiol ( Kuiper  et\nal ., 1997 ;  Mlynarcíková  et al. , 2005 ). BPA\nfurther binds to the gamma and G-protein membrane receptors and to the pregnane\nX receptor, thus activating ion channels and inducing pro-inflammatory responses\nof cytokines and chemokines ( Chapin  et\nal ., 2008 ;  Huang &\nLeung, 2009 )\nCholesterol is the substrate needed for enzyme CYP450scc to complete its cleavage\nand catalyze the conversion from cholesterol to pregnenolone. Pregnenolone is\nthen converted into an androgenic precursor, DHEA (dehydroepiandrosterone),\nincluding the intermediary product, 17-Hydroxipregnenolone, involving two\nenzymes in this conversion: 17 alpha-hydroxylase and 17-20 desmolase.\nSubsequently, DHEA is converted into androstenedione, which, while in the theca\ncell compartments, is converted to testosterone, so that both can migrate\nthrough the basal lamina of the antral follicle to the granulosa cells. Since\nthere is aromatase CYP450 in the granulosa cells, both androgens are converted\ninto estrone and estradiol (E2) (Two cell theory by  Hillier  et al ., 1994 ).\nAn experimental study by  Peretz\n &  Flaws (2013)  evaluating female rat ovarian\nfollicles in the antral stage revealed that depending on the dose of BPA\nadministered and the time of action, there was a reduction in the synthesis of\nestradiol, estrone, testosterone, androstenedione, and DHEA sulfate after 120\nhours of exposure to 100µg/ml of BPA. This high level of BPA compromised\nfollicular growth, but no effect was observed following a dose reduction of\n1µg/ml ( Takayanagi  et\nal ., 2006 ). Other experimental studies ( Mlynarcíková  et\nal. , 2005 ;  Huang &\nLeung, 2009 ;  Watanabe  et\nal ., 2012 ) showed BPA inhibits the mechanism of\naromatase CYP450 in the granulosa cells, thus reducing the production of E2.\nOnly a few studies in humans associated BPA with ovarian follicle synthesis.\n Mok-Lin  et al. \n(2010) ,  Ehrlich  et\nal . (2012) , and  Manikkam\n et al . (2012a)  evaluated the relationship\nbetween BPA and hormone levels in the granulosa cells of patients submitted to\nin vitro fertilization, and found a low E2 peak prior to ovum pickup.  Lee  et al . (2014) \ndescribed found that young people on early puberty exposed to BPA had\nsignificant increases in testosterone, estradiol, and pregnenolone levels. On\nthe other hand,  Mínguez-Alarcón\n et al . (2015)  found no statistical significance\nbetween BPA levels found in urine, serum E2 levels, and endometrial thickness\nmeasured by ultrasound examination after adjusting the findings for age, body\nmass index, race, smoking habit, and diagnosis of infertility.\nOnly a few studies evaluating the harmful effects of exposure to phthalates and\nthe negative effects on steroidogenesis where performed, with insufficient data\ncollection and inadequate statistical methods. On a study called \"The Western\nAustralian Pregnancy Cohort Study\",  Hart\n et al . (2014)  described the negative effects of\nphthalate metabolites on maternal serum SHBG levels, while the association\nbetween those same metabolites with the maternal androgen levels was\ninconsistent. Other animal and in vitro studies described the impact of\nphthalates on normal steroidogenesis.  Xu\n et al . (2010)  showed that in rats, aromatase\ninhibition in the granulosa cells led to decreased E2 levels.  Svechnikova  et al . (2007) \nand  Liu  et al . (2014) \nreported decreased progesterone levels in rats exposed to DEHP (diethylhexyl\nphthalate) and decreased E2 levels in female rats at 20 days of age, but also\ndecreased sexual hormone levels in adult rats even though the results are still\ncontroversial.\nClaims that exposure to pesticides may change steroidogenesis in women also have\ntheir limitations. A previous study by  Luderer\n et al . (2013)  including 457 Hawaiian\nparticipants exposed to heptachlor epoxide, observed a shorter luteal phase and\ndecreased serum levels of progesterone and estradiol metabolites. Atrazine\neffects in steroidogenesis seem to differ according to age, dose, and\nexperimental model. In vitro studies by  Fa\n et al . (2013)  showed that Atrazine might alter\nenzyme expression in steroidogenesis and E2 levels with immature granulosa cells\nof female rats. In vivo studies with adult animals by  Taketa  et al . (2011) ,  Quignot  et al . (2012) ,\n Tinfo  et al .\n(2011) , and  Buck Louis  et\nal . (2014)  showed that repeated doses of Atrazine\nincreased enzyme expression in steroidogenesis and sexual hormone levels. An\ninsufficient number of studies have been performed with female patients. Further\nresearch is needed to verify whether these pesticides are harmful to\nsteroidogenesis and fecundity. To this day, only Buck  Louis  et al . (2014)  with the LIFE Study\nshowed some evidence on the adverse effects of different DEC to female\nfecundity.\nEnvironmental Toxicants:  Su  et\nal . (2012)  conducted studies in humans showing that high\nconcentrations of dioxins and polychlorinated biphenyl byproducts decreased\nplasma estradiol levels. Experimental trials with different animals demonstrated\nthat exposure to dioxins adversely affected ovarian steroidogenesis. Further\neffects included decreases in estradiol production and synthesis in the antral\nfollicles of female rats, and loss of enzyme synthesis ( Karman  et al ., 2012a ;  2012b ). However, there are clear\nlimitations in these trials and further research in humans is required.\nPolycystic ovary syndrome (PCOS) is an endocrine disorder that includes multiple\nclinical conditions such as anovulatory cycles, hyperandrogenism, obesity, and\nregular insulin resistance associated with hypercholesterolemia, dyslipidemia\nand other metabolic alterations. Today, more than 800 chemical products\ncategorized as endocrine disruptors may strongly affect hormone receptors, act\nas agonists or antagonists, and lead to anovulation. An evaluation of different\nphenotypes of patients with PCOS revealed a wide ethnical, geographical, and\nfamilial diversity even among twin siblings. Recent studies showed many women\nexposed to chemical compounds have a genetic susceptibility to developing PCOS\nand several related metabolic disorders. Time of exposure to these endocrine\ndisruptors is crucial to determine their effect, especially during fetal\ndevelopment, given their potential harmful effects to pregnancy hormones and\nfetal cellular programming ( Palioura &\nDiamanti-Kandarakis, 2015 ;  Diamanti-Kandarakis  et al ., 2007 ).\nPrenatal androgenization leads to epigenetic changes and future development of\nPCOS phenotypes ( Xu  et al .,\n2011 ). Plastic substances caused DNA methylation in animals, and\nexposure to biphenyl and phthalates in the F0-generation Zero led to\ntrans-generational changes up to the third generation (F3) ( Nilsson  et al ., 2012 ;\n Manikkam  et al .,\n2012b ;  2014 ). An observational\nstudy with female rats given high doses of EDCs such as BPA in the neonatal\nstage resulted in adult PCOS phenotypes with increased plasma testosterone and\nestradiol levels, decreased progesterone levels, and development of ovarian\ncysts ( Fernández  et al .,\n2010 ).  Fernández  et\nal . (2009)  also described alterations in the pulsatile\nsecretion of GNRH and LH secretion from the pituitary gland.\nAlthough there is a large number of findings in animal studies, translating their\nconclusions to humans is rather difficult, once the cystic aspect and the\ndifferent phenotypes found in animals differ from the findings in humans of PCOS\nantral follicles. Exposure to testosterone in the beginning of gestation in\nrhesus monkeys provokes metabolic disorders similar to many women with PCOS.\nLate exposure to dihydrotestosterone and EDCs causes hyperandrogenism and\nirregular menstrual cycles, similarly to women with PCOS ( Abbott  et al ., 2013 ).\nCoexistence of insulin resistance is found in 50-80% of women with PCOS, leading\nto decreased insulin sensitivity and hyperglycemia and hyperinsulinemia,\nfollowed by hyperandrogenism and chronic anovulation. The mechanisms linked to\ninsulin resistance are still unclear. However,  Polyzos  et al . (2012)  suggested the involvement of\nEDCs in the etiology of insulin resistance. BPA is considered a causal factor of\nchild obesity linked to decreased adiponectin levels, onset of inflammation, and\ngreater risk of developing diabetes type 2 and cardiovascular disorders ( Menale  et al ., 2017 ).\nOther mechanisms have been connected to BPA-related hyperglycemia and\nhyperinsulinemia with direct effect on pancreatic cells, although no alterations\non the pancreas islets have been documented ( Alonso-Magdalena  et al. , 2005 ;  2006 ).\nAn enigmatic condition, endometriosis is an estrogen-dependent disease with\nnumerous endocrine disruptors affecting the ectopic endometrial tissue and a\nwide array of etiological factors. EDCs such as TCDD\n(2,3,7,8-tetrachlorodibenzo-p-dioxin) and PCBs (dioxin-like polychlorinated\nbiphenyl) may induce the development of peritoneal endometriosis in female\nRhesus monkeys, and the magnitude of the effect depends on the level of\ncontamination ( Rier  et al .,\n2001 ).  Bredhult  et\nal . (2007)  evidenced by the proliferation of endometrial\ncells triggered by the angiogenic effect of TCCD’s estrogenization action.\nAttention should be paid to The studies with humans performed by  Pauwels  et al . (2001) ,\n Eskenazi  et al .\n(2002) ,  Fierens  et\nal . (2003) ,  Heilier\n et al . (2005) , and  Simsa  et al . (2010)  deserve attention for\nthe correlations drawn between the effects of dioxin-like products and the\ngenesis of pelvic endometriosis. However, other authors were unable to verify\ntheir findings or describe a correlation between PCB and endometriosis ( Porpora  et al. , 2009 ;\n Buck Louis  et al .,\n2012 ).\nPhthalates may also have a proliferative effect on endometrial tissue. A\nprospective case-control study by  Kim  et\nal . (2011)  showed that women with advanced pelvic\nendometriosis had increased plasma levels of DEHP (di-(2-ethylhexyl) phthalate)\nand MEHP (mono-(2-ethylhexyl) phthalate) compared to endometriosis-free\ncontrols. An additional case-control study found that women with endometriosis\nhad significantly higher concentrations of mono-n-butyl-phthalates in urine than\ncontrols ( Huang  et al .,\n2010 ).  Buck Louis  et\nal . (2013)  reported levels twice as high of six\nphthalate metabolites in women with pelvic endometriosis.\nNevertheless, other epidemiological studies failed to validate these findings.\n Upson  et al .\n(2013) , in a study including women from the Northeast of the USA, showed\nan inverse association between the risk of developing endometriosis and levels\nof MEHP.  Itoh  et al .\n(2009)  confirmed these findings in a study enrolling infertile women,\nalthough the authors included only 57 cases of endometriosis and 80\nendometriosis-free controls. The mechanism triggering the development of\nendometriosis by phthalates remains unclear. Only  Kim  et al . (2010)  in an in vitro study\nshowed that DEHP (di-(2-ethylhexyl) phthalate) stimulated the stroma of\nendometrial cells and increased the viability of Ishikawa cells.\nIn recent years, a number of animal and in vitro studies looked into\nabnormalities in the development of the ovaries linked to endocrine disruptors.\nThe impact of BPA in the development of human ovaries remains unclear. Previous\nstudies by  Rivera  et al. \n(2011)  and  Veiga-Lopez  et\nal . (2013)  demonstrated that low doses of BPA in sheep\nmight lead to increased ovarian follicles with multiple oocytes and altered\novarian steroidogenesis.  Hunt  et\nal . (2012)  described the impact of BPA in the fetal\ndevelopment of female monkey ovaries affecting early meiosis, causing synaptic\nalterations, and interfering with the recombination between homologous\nchromosomes.\nInsufficient data is available on the impact of phthalates, pesticides, and other\nenvironmental toxicants in human prenatal ovarian development. Studies on human\npostnatal ovarian development are also limited. Sheep and rats exposed to BPA\nduring pregnancy had ovarian anomalies. Low doses of BPA decreased the number of\nfollicles and increased follicular atresia in female rats. On the other hand,\nhigh doses of BPA might lead to increased follicular cystification, corpus\nluteum depletion, and decreased antral follicle counts ( Rodríguez  et al ., 2010 ;  Delclos  et al ., 2014 ).\nAccording to  Chen  et al. \n(2012) , human ovaries exposed after birth to phthalates such as\nbenzyl butyl phthalate have greater chances of developing granulosa cell\napoptosis.\nNumerous pesticides such as endosulfan, malathion chlorpyriphos, and cypermethrin\ncause postnatal ovary anomalies, inducing decreased follicle counts and\nincreased follicular atresia as described by  Koç  et al . (2009)  and  Nandi  et al . (2011) . While looking into\nanother noteworthy environmental toxicant,  Petro\n et al . (2012)  linked increased levels of\nchlorinated bisphenols in humans and in ovarian follicular liquid to decreased\nfertilization rates and poor conditions for oocyte development.\nThe uterus is a muscle organ consisting of two main elements: the body, which\nincludes the endometrium, and the caudal end, or cervix, both exposed to\nsignificant hormonal influence from their early stages of development. After\npuberty, the uterus has periodical cycles of hormonal variation and greatly\nexpands during pregnancy, while after menopause the uterus involutes and\ndecreases in size.\nThe prospective effects of BPA and pesticides in uterine structure and function\nremain unknown, but abnormalities have been reported in animal studies. Exposure\nto BPA in the gestational and neonatal periods causes the development of\nendometrial glands and stroma, as seen in the adipose tissue next to the genital\ntract of type Balb-c-adult female rats ( Signorile  et al. , 2010 ;  2012 ). A single Australian study found that human exposure\nto mono (carboxy-isooctyl) phthalate changed the uterine volume ( Hart  et al ., 2014 ). As\npreviously demonstrated ( Dieckmann  et\nal. , 1953 ;  Herbst\n et al. , 1971 ;  Herbst, 1976 ;  Harris & Waring,\n2012 ;  Troisi  et\nal. , 2013 ), diethylstilbestrol caused a great number of\nuterine abnormalities in the exposed daughters of pregnant women treated to\nprevent miscarriage during gestation. Along the same lines, other recent studies\nshowed that exposure to DES induced endometrial hyperplasia/dysplasia and\nincreased the chances of endometrial adenocarcinoma and uterine anomalies in\nfemale rats and hamsters ( Alwis  et\nal ., 2011 ;  Yoshida\n et al ., 2011 ).\nOther environmental toxicants have been tested in animals and in humans.  Su  et al . (2012)  found\nthat dioxin and polychlorinated aromatic byproducts of biphenyls caused\nanomalies in the uterine structure, function, and fundus of 33 young girls.\nUterine myomas or fibromyomas are mostly benign tumors, affecting approximately\n70-80% of the female population throughout their lives. The growth of nodular\ntumors and multiple myomas is hormone-dependent and connected to the estradiol\nand progesterone receptors in the myometrium. The estradiol produced in the\ngranulosa cells of the ovarian follicles regulates the endometrium and\nmyometrium cells by activating their alpha and beta cellular receptors. The\nbinding affinity between estradiol and its receptor can trigger a number of\nevents, mostly in the cell nucleus, by recruiting important proteins to cellular\nreproduction.\nFollowing ovulation, the corpus luteum produces progesterone, an essential\nhormone to female reproduction, binding to the A and B progesterone receptors.\nThese receptors promote and regulate the expression of several genes, leading to\ndifferent cellular responses. No significant correlation has been found between\nBPA activity and its capacity to promote the development of fibromas. Two\nChinese case-control studies by  Shen  et\nal . (2013)  and  Zhou\n et al . (2013)  showed an association between\nhigher levels of BPA, nonylphenol and octylphenol in women with uterine\nmyomas.\nOther authors found positive correlations between disease and phthalates. In\n2010, the NHANES study showed that mono-benzyl phthalate increased the risk of\nmyoma in 1227 women. However, other phthalates such as MEHP (mono-(2-ethylhexyl)\nphthalate), MEHHP (mono-(2-ethyl-5-hydrohexyl) phthalate), and EOP (mono-\n(2-ethyl-oxohexyl) phthalate) were inversely correlated ( Weuve  et al ., 2010 ) with the onset of\ndisease.\nMeanwhile, few studies reported that prenatal exposure to DES\n(diethylstilbestrol) increased the number of fibromas. The NURSES study included\n11831 and followed them for over 20 years. DES exposure during gestation\nincreased the risk of fibroma by 13%, while DES exposure during the first\ntrimester of pregnancy increased the risk of fibroma by 21% in comparison to\nnon-exposed women ( Baird & Newbold,\n2005 ;  Mahalingaiah  et\nal ., 2014 ). Another NIEHS Uterine Fibroid Study\ncompleted in Washington-DC including 1364 exposed women aged 35-49 reported an\nodds ratio of 2.4 for Caucasian women (Baird & Newbold, 2005). Subsequently,\nthe NIEHS Sister Study evaluated a group of 3534 African-American women and\nshowed increased risk of developing fibromas after exposure to DES in women with\nmaternal and gestational diabetes and women pregnant with monozygotic twins,\nwith respective odds ratios of 2.02, 1.54, and 1.94 according to  D'Aloisio  et al . (2012) .\nThis study included 19972 Caucasian women and documented five significant risk\nfactors: prenatal exposure to DES; gestational diabetes; getting pregnant while\nhaving a history of diabetes; use of soy protein-based formula; and advanced\nmaternal age. All these factors represented an increase of more than 20% in the\nrisk of having fibromas.\nAs described in 1953, chemical disruptors such as DES (diethylstilbestrol) induce\nthe development of neoplasms such as vaginal adenosis and clear cell\nadenocarcinoma on the vaginal walls ( Dieckmann\n et al ., 1953 ;  Herbst  et al ., 1971 ;  Herbst, 1976 ;  Harris &\nWaring, 2012 ;  Troisi  et\nal ., 2013 ). DES (Diethylstilbestrol) inhibits the\nvaginal stroma causing a persistent down-regulation of the transcription factors\n( Laronda  et al .,\n2013 ;  Katoh  et al .,\n2013 ;  Nakamura  et\nal ., 2012a ;  2012b ).\nOnly a handful of human studies have looked into the correlation between\nbisphenols, phthalates, and pesticides and harmful effects on the anterior\npituitary gland compartment. On the other hand,  Xi  et al . (2011)  and  Brannick  et al . (2012)  showed that\nprenatal and immediate postnatal exposure to BPA stimulated the\nhypothalamic-pituitary axis and increased the number and replication of\npituitary gonadotropins in female rats. A recent study by  Souter  et al.  (2013)  found no correlation\nbetween exposure to BPA and FSH levels in women on the third day of IVF cycles.\n Miao  et al . (2015) \ndescribed a positive correlation between exposure to BPA and urinary levels of\nprolactin, although a negative correlation was established with FSH levels.\nAnimal studies have occasionally described harmful effects of other toxicants\nsuch as DES and dioxins ( Yoshida  et\nal ., 2011 ;  Ishikawa\n et al ., 2014 ) as having rather controversial\neffects on the pituitary gland and human gonadotropins. Insufficient human\nstudies were made in the last five years with regard to the effects of toxicants\non fertility and menstrual cycles. According to  Buck Louis  et al . (2011) , organochlorine pollutants\nled to an increase of three additional days on the interval between the periods\nof women willing to conceive. Few studies demonstrated abnormalities in the\nmenstrual cycles due to exposure to phthalates. Exposure to BPA induced\nabnormalities in the estrous cycle of rats according to  Fernández  et al . (2009) , and  Nah  et al . (2011) .  Vélez  et al .\n(2015) , in the MIREC Study the Maternal-Infant Research on\nEnvironmental Chemicals, included 2001 women in the first trimester of pregnancy\nexposed to bisphenols and phthalates and the time of conception. Higher\nconcentrations of Triclosan (>72ng/ml), a bactericide with phenolic\ncompounds, decreased fertility, but no correlation was found with bisphenols and\nphthalates.\nIn Brazil, for many years several authors have shown their concern and have\nlooked into the effects of environmental EDCs on the population and as a factor\nin occupational health ( Branco, 1984 ;\n Nogueira  et al .,\n1987 ;  Della Rosa & Gomes,\n1988 ;  Assunção &\nPesquero, 1999 ;  Sanseverino\n et al ., 2001 ).  Studies by Peres  et al . (2001) ,  Lara  et al . (2011) , and\n Cremonese  et al .\n(2012)  also evaluated EDC potential harmful effects in the field of\nreproductive health.\n\nGrowing outspread exposure to a number of different chemicals has caused multiple\nabnormalities in the reproductive system of women and different animal species. Tens\nof millions of these chemicals are available in the global market, and even when\nadministered in minimal doses, they have been described as endocrine disrupting\nchemicals or potential conditioners. Exposure to EDCs is extremely toxic and harmful\nto the reproductive system. Despite the occasional absence of a match between\nexperimental and epidemiological data, it is clear that EDCs can produce adverse\neffects on the genital tract. The reproductive effects may be dose-dependent and\nassociated to extended exposure and the level of activity of the compound at hand.\nUnfortunately, a significant number of these compounds are already a part of the\nenvironmental chain, making it difficult to assess their potential harmful\neffects.\nDi Renzo  et al.  (2015)  in the\nFIGO (International Federation of Gynecology and Obstetrics) drafted the following\nguidelines that must be observed by gynecologists, obstetricians, nurses, and other\nhealthcare workers in this field:\nExtensive guidance and education to ensure preventive measures are in\nplace with respect to exposure to toxicants; Appropriate measures to ensure healthy food is provided in the entire\nfood chain; make sure pesticides are banned from farms so as not to\ncontaminate vegetables, fresh fruits, or whole wheat grains; reduce the\nintake of animal fat or fish contaminated by heavy metals; Educational and participatory guidance involving the entire society to\nensure they are aware of the risks related to the intake of these\ntoxicants.\nExtensive guidance and education to ensure preventive measures are in\nplace with respect to exposure to toxicants;\nAppropriate measures to ensure healthy food is provided in the entire\nfood chain; make sure pesticides are banned from farms so as not to\ncontaminate vegetables, fresh fruits, or whole wheat grains; reduce the\nintake of animal fat or fish contaminated by heavy metals;\nEducational and participatory guidance involving the entire society to\nensure they are aware of the risks related to the intake of these\ntoxicants.\nFurther prospective studies are needed to better elucidate the possible abnormalities\naffecting women by millions of EDCs.","source_license":"CC-BY-4.0","license_restricted":false}