Bisphenol A: an emerging threat to female fertility

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).

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.

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 × 10⁻⁷M 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].

BPA is a chemical mainly used as a monomer in the manufacturing of polymers, in particular polycarbonate resins, but also epoxy polyester, polysulfone and polyacrylate resins, and flame retardants [11‐13]. Since the polycarbonate is used for the production of plastic bags, bottles and packaging, particularly water and milk bottles and including infant feeding bottles, coated tins, particularly food and drink cans, and microwave ovenware, BPA exposure is essentially conveyed via diet, contributing to more than 90% of the overall exposure [15]. BPA may leach into food depending on temperature (high temperature) and pH (alkaline conditions) [15]. BPA may reach the body by ingestion and or absorption of materials derived from leaching of resin-based dental filling products [15]. BPA is also used to print surface of thermal paper like airlines and train tickets as a heat-activated developer; therefore, the handling of thermal paper represent a different way to BPA exposure, which occur via dermal absorption, similarly to the exposure induced by the cosmetics [46]. The exposure to BPA occurring through the dermal absorption by the handling of thermal paper or by the application of cosmetics, together with air inhalation and dust and dental material ingestion, represents only the 5% of alternative and less common exposure [15].

BPA daily human exposure, assessed by measuring the urinary excretion of BPA, may vary widely worldwide, as well as the daily dietary intake, assessed by measuring BPA levels in food [13]. According to the World Health Organization (WHO) and to the Food and Agriculture Organization (FAO) of the United Nations, in Europe it has been estimated that BPA daily intake is around 0.2 μg/kg bw/day for breast-fed babies and around 11 μg/kg bw/day in formula-fed babies for which feeding polycarbonate bottles were used. The estimated daily intake for adults is around 1.5 μg/kg bw/day. Moreover, WHO, Food and Drug Administration (FDA) and European Food Safety Authority (EFSA), based on rodent studies, have also determined the no adverse effect level (NOAEL) for the systemic toxicity of BPA in animals, corresponding, for dietary exposure, to 5 mg/kg bw/day [13, 47]. In consideration of the differences in toxicokinetics among the species, EFSA, on grounds of prudence, applied a default uncertainty factor of 100 to the overall NOAEL and of 1000 to the overall LOAEL, establishing a TDI of 0.05 mg/kg bw (50 μg/kg bw/day) for humans over the life-time [13].

BPA is a lipophilic synthetic organic compound that, following oral administration, is absorbed through the gastrointestinal tract and transported to the liver where it is metabolized acquiring characteristics of hydrophilicity [48, 49]. BPA is metabolized and inactivated through glucuronidation by uridine diphosphate glucuronosyltransferases and sulfation, by phenol-sulfotransferases in hepatocytes microsomes. The conjugated, glucuronidated and sulfated, inactive forms of BPA acquire hydrophilic characteristics and are excreted into the bile and urine, with a half-life corresponding to around 6 hours [47‐49]. Nevertheless, the expression of β-glucuronidase enzyme, a member of the glycosidase family of enzymes which cleave the glucuronide group from the metabolite via hydrolysis, in several tissues, like lungs, liver, kidneys and placenta of animals and humans, ensures deconjugation of BPA and therefore the release of its active form into the blood and again its distribution into the body [50]. This mechanism is of a great impact considering that, in mammals, including humans, during pregnancy, conjugated form of BPA cross the placenta, undergo deconjugation, and definitively induce prenatal exposure [51].

BPA active form exerts its primary endocrine disrupting activity mimicking estrogens, but also different hormones, including androgens, such as testosterone (T) and dihydrotestosterone (DHT), and thyroid hormones. Indeed, BPA has a conformational structure that confers the ability to bind both ER alpha (ERα) and beta (ERβ), although, according to in vivo models, the affinity of BPA for ER is 1000-fold to 10,000-fold less than the affinity of 17β-estradiol (E2) [49]. BPA generally induce slow actions through genomic pathways, by directly interacting with nuclear ER and inducing regulation of several genes, generally triggered by direct ER-DNA interactions, or, alternatively, by interacting with gene expression co-regulators; however, BPA can also induce rapid actions through non-genomic pathways, by the activation of kinase signaling cascades via membrane receptors or by the modulation of cell calcium influx variation [52]. Genomic and non-genomic mechanisms can be triggered by BPA low- and high-dose exposure [53].

Approximately 1 to 2.5 ng/mL of active BPA, evaluated by different detection methods (ELISA, HPLC and LC/MS), were absorbed mainly through the primary route (diet) and different sources of exposure (dermal absorption, air inhalation, dust and dental material ingestion), and circulates in human blood [54]. The presence of circulating active BPA has been associated with several human diseases, including metabolic disease (obesity, insulin resistance, diabetes) [47, 55, 56] but has been also associated with female infertility and diseases impairing female fertility [57].

The review will be divided in several sections focused on the following topics: 1) the main epidemiological studies evaluating the association between BPA levels and overall female fertility, in both conditions natural conception and MAR, and 2) the main in vitro, ex vivo and in vivo studies concerning: a) BPA effects on HPO axis; b) BPA effects on female reproductive organs morphology and functions; and 3) the main in vitro, ex vivo, and in vivo studies on BPA role in the development of reproductive disorders, mainly endometriosis and PCOS, including epidemiological studies in humans.

Increasing evidences have been suggested that BPA might affect female fertility and could contribute to the pathogenesis of female infertility. In general, infertility affects 25% of couples in developing countries and is defined as the inability to become pregnant after 12 months of regular unprotected sexual intercourse [58]. Couple infertility depends on female factor for around 37%, male factor for around 29% and on combined male and female infertility around 18% of cases, with the remaining 16% due to genetic factors (1%) or due to unknown factors (15%) and therefore indicated as idiopathic infertility (http://​old.​iss.​it/​rpma/​). The increase in the prevalence of couple, including female infertility, worldwide has been also related to the increased environmental contaminants registered worldwide [59].

The current section describes the present evidence in epidemiological studies concerning the impact of BPA in female infertility, including both natural conception and MAR [60, 61].

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].

The HPO axis plays a critical role in the development and regulation of reproductive system. Fluctuations in this axis cause changes in the hormones produced by each gland and triggering various local and systemic effects. GnRH is secreted from the hypothalamus by GnRH-expressing neurons and activates the anterior portion of the pituitary gland to produce LH and FSH. Both gonadotropins stimulate the ovary to produce E2 and T. The following section describes the available data on the putative effects, and underlying mechanisms, of BPA on HPO axis, obtained in experimental in vitro, ex vivo and in vivo studies. The studies will be described dividing the target of HPO axis, such as hypothalamus, pituitary and ovary. The studies reporting the effects of BPA on HPO axis, with impact on reproductive function, particularly ovarian steroidogenesis, and, therefore, on female fertility are summarized in Tables 1, 2 and 3.

The female reproductive system includes the paired ovaries, the oviducts, the uterus, and the vagina. These organs are finely tuned and coordinated to perform the primary functions reproductive system, including folliculogenesis, fertilization, and support of the development of embryo, and to allow the birth of fetus. Morphological and functional changes of reproductive system, particularly the alterations of ovary and uterus, can impair female fertility. In human and rodents, the ovaries are composed by a central highly vascular medulla surrounded by a cortex in which ovarian follicles can be found at different stages of development. The morphological alterations of ovaries can take place during ovarian development or after puberty in fertile-aged females, such as in specific reproductive diseases, like polycystic ovary syndrome (PCOS). In humans and rodents, ovarian development is a dynamic process consisting in the growth of the ovary and establishment of the finite pool of primordial follicles, occurring predominantly during the embryonic period [91]. In particular, in humans, ovarian development is sustained for years while in rodents it can occurs in mere weeks, beginning on E5 and finishes on PND2 [92]. During embryonic development, in humans and rodents, primordial germ cells, precursors of oocytes, undergo extensive mitotic proliferation, maintain pluripotency and form clusters termed germ cell nests, surrounded by a single layer of granulosa cells, and then enter meiosis to form oocytes. Approximately 70% of the oocytes in the germ cell nests die, a process that leads to germ cell nest breakdown and allows the formation of individual primordial follicles. Primordial follicles represent a finite pool of resting oocytes, namely the entire ovarian reserve, available during their entire reproductive lifespan [91, 92]. In humans and rodents, the functional alterations of ovary, which can be cause or consequence of alterations of ovarian morphology, include mainly the impairment of folliculogenesis, beyond the impairment of steroidogenesis and sex hormones production. Humans have a pear-shaped uterus with a single triangular-shaped cavity. Rodents have a bicornuate uterus consisting of two lateral horns (cornua) that join distally into a single body (corpus). Hystological examination revealed that in both human and rodents the uterus is composed of three tissue layers: 1) the endometrium, the inner and functional layer responding to reproductive hormones; 2) the myometrium, the intermediate layer composed of smooth muscle cells; and 3) the perimetrium, the thin outer layer composed of epithelial cells [93]. In humans and rodents, the functional alterations of uterus, which can be consequence of morphological uterine alterations, include mainly the uterine receptivity [94].

The following section describes the available data on the putative effects, and underlying mechanisms, of BPA on the morphology and function of female reproductive organs, in particular on ovary and ovarian folliculogenesis and on uterus and embryo implantation, obtained in experimental in vitro, ex vivo and in vivo studies. The studies reporting the effects of BPA on morphology and functions of reproductive system organs and, therefore, on female fertility are summarized in Table 4.

A growing body of evidence have been reported that exposure to BPA may contribute to the pathogenesis of female reproductive disorders, due to its ability to disturb endocrine activity in animals and humans. In particular, most of the evidence have been reported a role of BPA in the pathogenesis of endometriosis, a chronic inflammatory disease where cells similar to endometrial cells are found outside the uterine cavity, most commonly in the pelvis [112]. Furthermore, the female gonad appears to be a particularly sensitive target of BPA, as indicated by evidence of interference with ovarian morphology and ovarian functions, such as steroidogenesis, and particularly folliculogenesis. All these mechanisms might contribute to the pathogenesis of PCOS, a complex condition characterized by increased androgen levels, menstrual irregularities, and/or small cysts on one or both ovaries [113]. The following paragraphs describe the available data on the role of BPA in the pathogenesis of endometriosis and PCOS, obtained in experimental in vitro, ex vivo and in vivo studies.

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.

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.