Bisphenol A: an emerging threat to female fertility

Claudia Pivonello, Pivonello C, Giovanna Muscogiuri, Antonio Nardone, Nardone A, Francesco Garifalos, Provvisiero DP, Donatella Paola Provvisiero, Nunzia Verde, Verde N, De Angelis C, Cristina de Angelis, Alessandro Conforti, Mariangela Piscopo, Piscopo M, Auriemma RS, Renata S. Auriemma, Renata Simona Auriemma, Annamaria Colao, Colao A, Rosario Pivonello, Pivonello R
Reproductive biology and endocrinology : RB&E · 2020 · vol. 18(1) , pp. 22 · doi:10.1186/s12958-019-0558-8 · PMID:32171313 · PMC7071611 · W2924162063
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This manuscript reviews clinical and preclinical studies linking bisphenol A exposure to impaired female fertility, particularly through disruption of the hypothalamic-pituitary-ovarian axis and ovarian development.

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This review evaluates evidence linking bisphenol A (BPA), an endocrine-disrupting chemical primarily encountered through diet from leaching out of food-contact materials, to female infertility. It synthesizes human epidemiological studies of serum/urinary BPA and infertility (including natural conception, medical assisted reproduction outcomes, and infertility-related disorders such as endometriosis and polycystic ovary syndrome) alongside in vitro, ex vivo, and in vivo animal studies assessing effects on the hypothalamus–pituitary–ovary axis and reproductive organ morphology and functions, while explicitly noting complexities such as the ongoing debate over “low” versus “high” BPA dose definitions and variation in exposure timing and model systems. Key mechanistic themes include BPA’s estrogen- and androgen-receptor activity, its influence on ovarian and uterine processes like steroidogenesis, folliculogenesis, uterine receptivity, and embryo implantation, and the potential for prenatal exposure via placental deconjugation of BPA metabolites. Relevance to endometriosis: the review states it will critically review infertility–related disorders “particularly endometriosis,” situating BPA exposure as a candidate factor in endometriosis-associated infertility, though the paper’s main focus is a broad overview of BPA and female infertility.

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Abstract

Bisphenol-A (BPA) has been reported to be associated to female infertility. Indeed, BPA has been found to be more frequently detected in infertile women thus leading to hypothesize a possible effect of BPA on natural conception and spontaneous fecundity. In addition, in procedures of medically assisted reproduction BPA exposure has been found to be negatively associated with peak serum estradiol levels during gonadotropin stimulation, number of retrieved oocytes, number of normally fertilized oocytes and implantation. BPA deleterious effects are more critical during perinatal exposure, causing dysregulation of hypothalamic-pituitary-ovarian axis in pups and adults, with a precocious maturation of the axis through a damage of GnRH pulsatility, gonadotropin signaling and sex steroid hormone production. Further, BPA exposure during early lifestage may have a transgenerational effect predisposing the subsequent generations to the risk of developing BPA related disease. Experimental studies suggested that prenatal, perinatal and postnatal exposure to BPA can impair several steps of ovarian development, induce ovarian morphology rearrangement and impair ovarian function, particularly folliculogenesis, as well as can impair uterus morphology and function, in female adult animal and offspring. Finally, studies carried out in animal models have been reported the occurrence of endometriosis-like lesions after BPA exposure. Moreover, BPA exposure has been described to encourage the genesis of PCOS-like abnormalities through the impairment of the secretion of sex hormones affecting ovarian morphology and functions, particularly folliculogenesis. The current manuscript summarizes the evidence regarding the association between BPA exposure and female infertility, reviewing both clinical and preclinical studies.
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Search

Articles were individually retrieved by each author up until February 2018, by search in PubMed (MEDLINE) using the following search terms: ‘bisphenol- A’, ‘ovary’, ‘uterus’, ‘HPO axis’, ‘oviduct’, ‘vagina’, ‘PCOS’, ‘endometriosis’, ‘endocrine disruptor’, ‘female fertility’, ‘female infertility’, ‘time to pregnancy’, ‘environment’, ‘endocrine disruptors’. The reference lists of relevant articles and reviews were also searched manually.

Bisphenol

PCOS is a multifactorial metabolic-endocrine disorder characterized by the existence of different phenotypes, affecting women of reproductive age [ 123 ]. The diagnosis of PCOS is formulated with the presence of at least two of the three criteria: (1) clinical hyperandrogenism (with hirsutism, acne, seborrhea and alopecia) and/or increased circulating androgens levels; (2) presence of ovarian cysts assessed by ultrasound examination and (3) oligo-amenorrhea with oligo-anovulation, according with the Rotterdam criteria [ 113 ]. Growing evidence suggests that BPA exposure may play a role in the pathogenesis of PCOS. The experimental in vitro, ex vivo and in vivo studies reporting the association of BPA with PCOS are summarized in Table  6 . Table 6 Bisphenol A and PCOS Source Strain Age Exposure route Time of exposure Doses Time of observation Outcome Outcome observed in Reference n° Experimental studies in vitro and ex vivo Human Granulosa-lutein cells 33.8 ± 4.5 years In vitro administration 72 h 1; 100; 1000; 10,000 ng/mL 72 h Increase of MMP9 levels at 100 and 1000 ng/mL concentrations. Decrease of MMP9 levels at 10000 ng/mL concentration. Decrease of cell viability at 1000 and 10,000 ng/mL concentrations. Dominguez 2008 [ 124 ] Experimental studies in vivo Rats Sprague-Dawley Female pups Subcutaneous injection From PND1 to PND10 5, 50 and 500 μg/kg bw/day 4–5 months of age Increase of Testosterone and Estradiol levels and decrease of Progesterone levels in adulthood. Altered GnRH secretion in adulthood. Altered ovarian morphology, increase in cysts number and infertility at 500 μg/kg bw/day. Reduced fertility at 50 μg/kg bw/day. Infertility at 500 μg/kg bw/day. Adult female Fernandez 2010 [ 80 ] Rats Wistar Female pups Drinking water From GD6 to PND40 1 mg/L PND40 Induction of PCOS hallmarks. Pubertal female Patisaul 2014 [ 125 ] Bisphenol A and PCOS Only one experimental ex vivo study has investigated the relationship between BPA exposure and the occurrence of PCOS. The wealth of research on PCOS has been provided evidence that genetic, hormonal, metabolic and environmental factors may play a role in the development and clinical manifestations of this complex syndrome. A role of BPA in the pathogenesis of PCOS has been suggested by an experimental ex vivo study in which low BPA doses induced a reduction of cell viability of granulosa-lutein cells isolated from follicular fluid of PCOS women undergoing ART [ 124 ]. In the same study, it has been demonstrated that low BPA doses increase the secretion of MMP9 as well as the activity of MMP9 in primary culture of granulosa-lutein cells derived by women with PCOS [ 124 ]. Few experimental in vivo studies have investigated the relationship between BPA exposure and the occurrence of PCOS. BPA exposure has been described to influence the secretion of sex hormones affecting ovarian morphology and functions, particularly folliculogenesis with the genesis of PCOS-like abnormalities [ 80 , 125 ]. Moreover, even perinatal exposure to low BPA doses could promote the development of PCOS-like abnormalities at adulthood [ 80 , 125 ]. An in vivo study in rats evaluated the differential effects of exposure to phytoestrogens or low BPA doses from prenatal to pubertal phase, on the induction of PCOS hallmarks, including cystic follicles, irregular estrus, elevated body weight and baseline serum glucose, at adulthood. The results of the study showed that either BPA, phytoestrogens, or combined treatments postnatally increased body weight. In adulthood body weight in animal exposed to low BPA doses was higher compared to animal exposed to combined BPA plus phytoestrogens. These results suggest that phytoestrogens mitigated the BPA-induced weight gain [ 125 ]. Moreover, BPA treatment induced premature vaginal opening, a sign of puberty, which was hypothesized to be mediated by BPA related weight gain [ 125 ]. Rats exposed to phytoestrogens had a higher number of corpus luteum and multiple follicles compared to rats exposed to low BPA doses, which is suggestive of an early ovulation, despite longer estrous cycles [ 125 ]; it is unclear whether these changes in ovarian morphology could be translated to a potential younger age at first pregnancy, or to premature follicular depletion [ 125 ]. Moreover, rats exposed to phytoestrogens had more cysts at adulthood compared to rats exposed to low BPA doses, confirming a major effect exerted by phytoestrogens comparing with BPA exposure on ovarian morphology [ 125 ]. Lastly, phytoestrogens, but not BPA, exposure affected baseline glucose levels [ 125 ]. It is noteworthy that circulating androgens levels at adulthood was not changed by exposure of BPA or phytoestrogens [ 125 ]. These data are insufficient to discriminate whether BPA might specifically enhance adiposity or overall growth and development [ 125 ]. In summary this study highlights the role of BPA in inducing obesity that could be considered as a PCOS related metabolic comorbidity. A hypothetical relationship between PCOS and BPA has drawn attention in recent years and has been suggested by observational studies, although the underlying mechanisms are poorly understood [ 126 – 129 , 132 – 135 ]. BPA has been reported to have a steroid potential thus it can blunt HPO axis functions by disrupting the steroid feedbacks at the hypothalamus and pituitary level and steroid action at the level of the ovary [ 126 ]. In addition, BPA seems to contribute to derange metabolic profile in PCOS as reported by a recent metanalysis including 11 case-control studies (seven studies were conducted in Asia and four studies recruited Caucasian participants) and involving 493 PCOS patients and 440 controls in which serum BPA levels were higher in Caucasian PCOS patients, in non-PCOS obese patients and in non-PCOS insulin-resistant patients, therefore leading to hypothesize that BPA might be involved in the insulin resistance of PCOS [ 127 ]. In fact, BPA promotes an inflammatory milieu through the development of obesity having a direct action on adipocytes and macrophages infiltrating the adipose tissue [ 128 ]. As well-known and showed in Fig.  2 , chronic inflammation contributes to the pathogenesis of insulin resistance and compensatory hyperinsulinemia that in turn plays a role in the development of the typical increased amplitude and frequency of GnRH and LH pulse secretion seen in PCOS [ 129 – 131 ]. The fact that BPA was associated with a decrease of antral follicle count in infertile women with PCOS suggests that BPA may impair ovarian reserve [ 132 ]. Furthermore, BPA appears to lead to androgen excess, also in lean phenotype, as reported by a prospective observational case control study performed in 112 adolescents with PCOS and 61 controls that had higher serum BPA levels, independently of obesity [ 134 ]. This finding has been also found in a prospective observational cross-sectional study carried out in healthy women, where a positive correlation between increased serum T and serum BPA levels has been found [ 133 ]. This could be due to the effect of BPA in displacing sex steroid hormones from SHBG therefore increasing the amount of free T. At the same time, it appears that metabolism and excretion of BPA may be impaired in PCOS [ 135 ]. This impairment might depend on the effect of androgen excess in blocking the activity and transcription of the liver enzyme uridine diphosphate-glucuronosyl transferase, which clears BPA from circulation under normal conditions; this might partly explain why BPA levels are typically higher in women with PCOS [ 135 ]. Taken together these results suggest that BPA levels are higher in women with PCOS than in reproductively healthy women, but the direction of causality has not been established. BPA seems to act disrupting hormonal patterns but also disrupting normal metabolic activity, contributing the to development of PCOS. Fig. 2 The effect of BPA in the pathogenesis of PCOS. BPA may play a part in the development of PCOS through its steroid potential that can blunt hypothalamic-pituitary-ovarian axis functions by disrupting the steroidal feedbacks at the hypothalamus and pituitary level and steroid action at the level of the ovary. Further, BPA promotes an inflammatory milieu through adipose tissue having a direct action on adipocytes and macrophages infiltrating the adipose tissue and thus contributing to the onset of insulin resistance and compensatory hyperinsulinemia. In turn insulin worsens amplitude and frequency of GnRH and LH pulse secretion seen in PCOS The effect of BPA in the pathogenesis of PCOS. BPA may play a part in the development of PCOS through its steroid potential that can blunt hypothalamic-pituitary-ovarian axis functions by disrupting the steroidal feedbacks at the hypothalamus and pituitary level and steroid action at the level of the ovary. Further, BPA promotes an inflammatory milieu through adipose tissue having a direct action on adipocytes and macrophages infiltrating the adipose tissue and thus contributing to the onset of insulin resistance and compensatory hyperinsulinemia. In turn insulin worsens amplitude and frequency of GnRH and LH pulse secretion seen in PCOS

Definition

The proper definition of BPA low-doses or high-doses range has been extensively discussed. In the current review, in accordance with the Chapel Hill BPA expert panel consensus statement [ 43 ], “low BPA doses” have been considered as follow: 1) in human epidemiological studies, doses below the reference dose of Tolerable Daily Intake (TDI), corresponding to 0.05 mg/kg (50 μg/kg) body weight/day (bw/day) that, as established by the United States Environmental Protection Agency (EPA), is based, on grounds of prudence, on a 1000-fold reduction of lowest observed adverse effect level (LOAEL), defined by US National Toxicology Program (NTP) and corresponding to 50 mg/kg/day for oral exposure in laboratory animals in traditional toxicological studies conducted for risk assessment [ 43 , 44 ]; 2) in animal models, doses below the LOAEL (50 mg/kg bw/day) [ 43 , 44 ] and 3) in in vitro models, doses below 1 × 10 −7 M for cell culture experiments, corresponding circulating BPA levels in animals after administration of BPA at LOAEL concentration [ 44 ]. BPA levels higher than that previously specified have been considered “high BPA doses”. In experimental in vivo studies, BPA exposure is finalized to observe BPA effects in female adult animals or in both female adult pregnant animals and in female offspring. Most of the studies have been performed on laboratory mouse and rat models with variation regarding to the exact timing of exposure during development. BPA exposure of female offspring have been considered “prenatal” when female adult pregnant animals have been treated and consequently female fetuses have been exposed from the embryonic day 1 (E1) to E17; “perinatal” when female adult pregnant animals have been treated and female fetuses have been exposed from E18 until the day of birth; and “postnatal” when female pups have been exposed after birth from PND1 to approximately 3 weeks of age (PND21-PND24). BPA exposure have been also evaluated on female pups in pre-pubertal and pubertal phases till the animals reach sexual maturity (from PND25 to PND47,) and on female adult animals (starting from PND48) [ 45 ].

Regulation

Female reproduction in humans and in rodents is closely related to a proper function of HPO axis. Indeed, after sexual maturation, HPO axis coordinates ovarian function and particularly ovarian steroidogenesis and folliculogenesis with the final ovulation and prepares reproductive organs to support a potential pregnancy [ 3 ]. Humans and rodents, share the same regulation of reproductive system by the HPO axis, including the regulatory hypothalamic system that releases gonadotropin releasing hormone (GnRH) in rhythmic pulses, the pituitary gland that secretes follicle stimulating hormone (FSH) and luteinizing hormone (LH), and the ovary itself that releases sex hormones, including estrogens, particularly E2, and progesterone (P), which control the function of reproductive system, particularly ovarian and uterine function in the classical cycles [ 71 , 72 ]. However, species vary significantly in the detailed functioning of ovarian and uterine cycles. Some female primates, including human females, are characterized by a menstrual cycle, in which menstruation occurs in the absence of pregnancy and the females may be sexually receptive at any time during the cycle. Menstrual cycle can be described by the ovarian and uterine cycles. The ovarian cycle refers to a series of changes in ovary during folliculogenesis by which a recruited primordial follicle grows and develops into a specialized Graafian follicle with the potential to be fertilized or to die by atresia. The ovarian cycle consists of the follicular phase, ovulation, and the luteal phase [ 71 , 72 ]. The uterine cycle refers to a series of changes in the endometrial lining of the uterus and consists in menstruation phase, proliferative phase, and secretory phase. Follicles, located in the cortex of ovary, represent the basic functional unit of reproductive system in females. For humans, follicle development starts during fetal life when primordial follicles are formed. Follicle consists of theca cells that are endocrine cells surrounding the follicle, and of granulosa cells that are somatic cells surrounding the oocyte within the follicle [ 71 ]. At the endocrine level the hypothalamus secrets the GnRH to the anterior pituitary in rhythmic pulses by the electrical GnRH neuronal activity. The GnRH pulse generator is the hypothalamic structure that releases GnRH synthesized in specialized neurons [ 73 ]. In humans, most GnRH neurons are localized in the mediobasal hypothalamus. GnRH neurons do not express ER and receive E2 signaling from ER-expressing neurons elsewhere within the hypothalamus, such as the kisspeptin (Kiss1) neurons. In humans two major populations of Kiss1 neurons have been identified: one located in the arcuate nucleus (ARC) and another in the preoptic area (POA). Kiss1 neurons send projections to the POA in close proximity to GnRH neurons, stimulating these latter to release GnRH [ 74 ]. Secreted pulses of GnRH into the portal blood vessels causes a pulsatile release of FSH and LH, which act on ovary and uterus to control ovarian and uterine cycles [ 73 ]. Concentrations of LH and FSH vary throughout the menstrual cycle. In the early follicular and luteal phases FSH is predominant over LH, whereas LH is dominant over FSH in the late follicular phase [ 73 ]. During follicular phase of ovarian cycle and proliferative phase of uterine cycle, the activated primordial follicles with a single layer of granulosa cells surrounding the primordial oocytes develop into primary, secondary, and eventually antral follicles under FSH stimulation. A few of antral follicles reach the preovulatory stage, whereas most antral follicles undergo atretic degeneration. In antral follicle LH stimulates the conversion of cholesterol into androgens in the theca cells, thereby increasing endogenous intra-ovarian androgen production, in particular T. At the same time, FSH stimulates the expression and activity of aromatase in granulosa cells, inducing the conversion of androgens into estrogens, mainly E2. The E2 released by antral follicle reaches the maximum circulating level in the preovulatory stage to further regulate follicular maturation, increasing growth and differentiation of granulosa cells, and to regulate the HPO with a negative feedback mechanism [ 75 , 76 ]. Increased E2 production induces the thickening of endometrium, the uterine inner epithelial layer, along with its mucous membrane, and activates Kiss-1 neurons with a consequent increased of GnRH pulse frequency and amplitude. Fast GnRH pulse frequencies induce LH synthesis leading to the LH surge [ 73 ]. The spike in LH causes ovulation during which the dominant preovulatory follicle ovulates to release the mature oocyte for fertilization. Following ovulation, in the luteal phase, the remaining theca and granulosa cells undergo transformation to become the corpus luteum that produces P as well as E2 [ 71 ]. Luteinization of the granulosa cells increases P production, acting to stabilize the endometrium at the optimal thickness to support implantation, to become receptive to the fertilized egg and to prepare the endometrium for the potential the egg implantation, and to thrive for the duration of the pregnancy and slowing GnRH pulse frequency that in turn decreases LH production and increases FSH production to stimulate the next round of ovulation. If fertilization does not occur, the corpus luteum will start to break down resulting in a drop in E2 and P levels, which induce menstrual discharges, due to the shedding and collapse of the endometrium. Under the FSH-dependent estrogens stimuli uterine lining thickens and the cycle begins again [ 71 , 73 ]. Non-primate females, including rodent females, instead, are characterized by an estrus cycle, in which the endometrium is reabsorbed if conception does not occur during the cycle and in which there are recurring periods when the females are fertile and sexually receptive (estrus) interrupted by periods in which the females are not fertile and not sexually receptive (anestrus) [ 77 ]. Estrous cycles start after puberty in sexually mature females and typically continue until death; rodents undergo estrus cycles throughout the whole year [ 77 ]. In rodents, follicle development starts during neonatal life when primordial follicles are formed. In rodents, GnRH cell bodies reside in the POA and rostral hypothalamus and Kiss1 neurons in the rostral periventricular area of the third ventricle (RP3V). RP3V in rodents consists of Kiss1 cells clustered in the anteroventral periventricular nucleus (AVPV) that extend caudally into the adjacent periventricular preoptic zone (PeN) [ 74 ]. Kiss1 neurons send projections to the RP3V in close proximity to GnRH neurons, stimulating these latter to release GnRH. Many evidences indicate that Kiss1 neurons in RP3V-AVPV regulate GnRH/LH-surge generation, while ARC Kiss1 neuronal population regulates GnRH pulse generation [ 74 , 78 ]. Hypothalamic regulation of rodent reproductive cycle is the same described for humans. Differently from humans, in female of rodents, reproductive processes, are characterized by cyclic morphological changes in female reproductive system and cyclic sexual receptivity [ 77 ]. The recurrent period of receptivity, or “heat” is called estrus. The entire estrus cycle, that occurs over 4–5 days, is formed by four stages: 1) diestrus, during which in ovary small follicles are present with large corpora lutea from the previous ovulation, the uterus is atrophic and with low motility. During this stage E2 levels start to increase whereas FSH and LH levels are low; 2) proestrus, during which ovarian follicles grow rapidly and the uterus is hypertrophic and with a pronounced contractility. This stage corresponds to pre-ovulatory day characterized by increased E2 and P levels and the occurrence of the ovulation after LH and FSH surges; 3) estrus, during which ovulation of more than 15 eggs occur and the uterus reach the maximum development of endometrium. E2 levels remains elevated during the morning and fall down in the afternoon; and 4) metestrus, during which many corpora lutea secrete P only for a short time and the uterus decrease in size and in vascularity with the degeneration and replacement of endometrium. E2, LH and FSH levels are low [ 77 ].

Conclusions

The evidence summarized in the current review suggest that BPA might have a role in the pathogenesis of female infertility. BPA has been often detected in infertile women, thus leading to hypothesize that BPA could interfere with natural conception. BPA exposure has been also associated with negative outcomes of ART and in particular to a decreased E2 production during gonadotropin stimulation, to a decreased number of oocytes retrieved at the end of ovarian stimulation and implantation failure. Findings of studies conducted on animal models pointed out that the deleterious effect of BPA could vary depending on doses, administration route, window of exposure and animal models. In particular, studies on rodent models have demonstrated that the exposure to low BPA doses, but also the high BPA doses, during prenatal and perinatal period, therefore during embryo development, cause dysregulation in HPO axis function and morphological damages to HPO axis organs. Moreover, the BPA exposure in adulthood induces reversible damage in HPO axis function whereas prenatal and perinatal BPA exposure induces irreversible effects in female offsprings. Higher BPA levels have been detected in women with endometriosis and a hypothetical role of BPA in the pathogenesis of endometriosis has been confirmed by experimental animal studies reporting the occurrence of endometriosis-like lesions after BPA exposure. The onset of PCOS-like abnormalities has been found after BPA exposure and this might be induced through the BPA related impairment of the secretion of sex hormones affecting ovarian morphology and functions, particularly folliculogenesis. The several limits of the reported studies prevent to draw final conclusions. This could be due to the fact that most of the studies were retrospective and were not designed aiming to specifically investigate the association between BPA and female fertility. Further, they provide a proxy evaluation of BPA that could not be a parameter to assess the chronic exposure. Therefore, it will be mandatory to perform further studies to investigate the link between BPA and female fertility in order to make the population aware about the health risks related to BPA exposure.

Introduction

In the last decades the environmental pollution caused by urbanization and industrialization has been reported to affect human health [ 1 , 2 ]. Endocrine disrupting chemicals (EDCs), which can be found in agriculture, industry, drugs or food chain, comprise a wide variety of exogenous chemicals including synthetic compounds able to affect hormones synthesis, metabolism, and function [ 3 ]. The EDCs exposure can occur via ingestion of water, food and dust, via inhalation of gases and air particles and via dermal absorption of cosmetics and/or substances deriving from thermal paper. Moreover, a transmission from the pregnant woman to the developing fetus or child, during gestation and lactation, through the placenta and breast milk, was also demonstrated [ 4 , 5 ]. After absorption, EDCs can accumulate in fat tissue for a long time and their metabolites can be detrimental to the human organism but it may not become evident until later in life [ 6 ]. Despite this evidence, the long-term effects of EDCs exposure were not deeply investigated. EDCs exert their actions triggering mainly genomic mechanisms but also promoting non-genomic actions [ 7 – 9 ], through the binding to several hormone receptors, including thyroid and, especially, steroid receptors, mainly estrogen (ER) or androgen (AR) receptors, compromising reproductive system and negatively affect the fetal and neonatal development and physiology [ 10 ]. Despite several evidences in literature on the potential effects of EDCs on human reproduction, the molecular mechanisms underlying these effects are not completely understood. Bisphenol-A [2,2-bis(4-hydroxyphenyl) propane (BPA), CAS No. 80–05-7] is one of the most investigated EDCs. BPA is largely found in polycarbonate resin mainly used for plastic bags, bottles and packaging, particularly water and milk bottles, coated tins, particularly food and drink cans, and microwave ovenware [ 11 – 13 ]. The primary source of exposure to BPA is diet; indeed, BPA, being a constituent of food containers and packaging, can leach into food products, especially after heating [ 14 , 15 ]. In humans, BPA is adsorbed by gastrointestinal tract, metabolized in the liver and finally excreted by urine [ 16 ]. Several studies have highlighted the negative effects of BPA on reproductive system [ 17 ]. Particularly, it has been shown that BPA displays a high affinity for ER, having an estrogen-mimicking behavior and consequently stimulating estrogen function [ 11 – 13 ]; therefore, BPA has been hypothesized to be involved in several diseases of female reproductive system [ 3 , 18 – 22 ], due to its property to stimulate ER-dependent gene expression involved in the pathophysiology of female reproductive system [ 23 – 26 ]. Moreover, BPA is also able to inhibit androgen function by binding AR [ 27 ]. Particularly, BPA is able to influence ovarian morphology [ 6 ] and function, especially steroidogenesis [ 28 – 34 ] and folliculogenesis [ 32 , 34 – 36 ], and, as well as uterine morphology [ 37 ] and function, especially uterine receptivity, consisting of the uterine ability to accommodate embryo attachment [ 38 – 40 ], and embryo implantation [ 37 – 40 ]. The impairment of endocrine function, and the consequent impairment of ovarian and uterine morphology and function, may lead to the development of several diseases involving reproductive system, especially ovary and uterus [ 19 , 41 , 42 ]. The ultimate consequence of the impairment of endocrine function and the morphology and function of the female reproductive system may be represented by female infertility. The current review aims to give an overview of the link between BPA exposure and female infertility by reporting the few epidemiological studies available in humans and by providing, in particular, in vitro, ex vivo and in vivo animal-based evidences of BPA implication in the pathogenesis and progression of female infertility. In particular, studies describing the BPA effect observed on regulation of hypothalamus-pituitary-ovary (HPO) axis and on female reproductive organs (ovary, oviduct, uterus and vagina) morphology and functions (estrous cyclicity, steroidogenesis, folliculogenesis, uterine receptivity, embryo implantation and vaginal opening) will be focused. Moreover, the current manuscript will critically review the observational studies in humans evaluating the association of serum and/or urinary BPA levels and female infertility mostly focusing on natural conception, in medical assisted reproduction (MAR) outcome and on infertility–related reproductive disorders, particularly endometriosis and polycystic ovary syndrome (PCOS).

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endometriosisinfertility

MeSH descriptors

Benzhydryl Compounds Fertility Infertility, Female Phenols Prenatal Exposure Delayed Effects Reproduction Animals Benzhydryl Compounds Bisphenol A Compounds Endocrine Disruptors Endocrine Disruptors Female Fertility Fertility Humans Infertility, Female Infertility, Female Infertility, Female Phenols Pregnancy

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