Impact of endocrine disruptors on female fertility: an update

Endocrine disruptors (EDs) refer to a broad group of chemicals capable of interfering with the normal functioning of the endocrine system [ 1 , 2 ] . These compounds, whether naturally occurring or synthetic, can alter the production, release, transport, metabolism, or elimination of hormones, hence altering the physiological processes they regulate. Among the most studied PEs are bisphenol A (BPA), phthalates, certain pesticides such as dichlorodiphenyltrichloroethane (DDT), parabens, and dioxins. They are present in many everyday consumer products: plastics, cosmetics, household products, food packaging, and even agricultural residues, leading to widespread exposure of the population. BPA, phthalates, some pesticides such as DDT, parabens, and dioxins are some of the most investigated PEs. The potential effects of these substances on female fertility, ranging from ovulation disorders to decreased ovarian reserve, are increasingly documented. This article is in accordance with the TITAN guidelines [ 1 – 3 ] . This article aims to review the mechanisms of action of EDs and to explore current data concerning their impact on female fertility. EDs act through several complex mechanisms, which can interfere at different levels of hormonal regulation and reproductive development. Many Endocrine-Disrupting Chemicals (EDC)s act as hormone agonists or antagonists. By binding to estrogen, androgen, or progestin receptors, they can either mimic the action of natural hormones or block their effects [ 2 , 4 ] . For example, BPA can bind to estrogen receptors, inducing inappropriate signals or interfering with those of endogenous estrogens. This mechanism can lead to alterations in the menstrual cycle, ovulation, or follicular development [ 1 ] . EDs can also act by modulating the expression of genes involved in epigenetic mechanisms [ 3 ] . Changes in DNA methylation or histone structure can be induced, lastingly affecting genetic regulation. These effects can occur as early as intrauterine life and persist throughout life. Some studies even suggest intergenerational transmission of these alterations, raising the question of epigenetic inheritance of the effects of EDs [ 2 , 5 , 6 ] . Additionally, EDs can alter how steroid hormones are produced, especially in the ovaries. Their disruption of estrogen, progesterone, or testosterone production may affect follicle maturation and oocyte quality [ 4 ] . Furthermore, several EDs influence the secretion of gonadotropins (Follicle-Stimulating Hormone (FSH), Luteinizing Hormone (LH)), which are essential for regulating the menstrual cycle, by acting on the hypothalamic-pituitary-gonadal axis [ 4 , 7 ] . Data from experimental studies reinforce suspicions about the impact of PE on female fertility. Animal studies have shown that exposure to EDCs can lead to a significant decrease in the number of ovarian follicles, reflecting a reduction in ovarian reserve [ 1 , 5 ] . Impairments in ovulation and embryo implantation have also been observed, compromising the chances of conception. Furthermore, several studies have reported abnormalities in oocyte maturation, which affects the quality of the eggs and, consequently, their ability to be fertilized [ 6 , 8 , 9 ] . These alterations are particularly pronounced when exposure occurs during sensitive periods of development, notably during fetal life, early childhood, and puberty, key moments for the establishment of reproductive functions. Epidemiological data in humans partly confirm experimental observations, although they are limited by methodological difficulties [ 7 ] . Several studies have demonstrated an association between urinary or blood levels of certain EDCs, including phthalates and BPA, and various female fertility disorders, particularly cases of infertility with no apparent cause [ 8 , 9 ] . These substances may impair ovarian function or disrupt the menstrual cycle. However, these studies remain essentially observational, and establishing a direct causal link remains complex [ 1 , 5 ] . Research also suggests a link between chronic exposure to EDCs and an increased risk of developing polycystic ovary syndrome and endometriosis, two gynecological conditions frequently associated with infertility. Some EDCs may contribute to the hyperandrogenism or inflammatory dysregulation observed in these conditions [ 6 – 10 ] . The exact mechanisms, however, have not yet been determined. The impact of PE on ART outcomes is also documented. Several studies have reported a decrease in oocyte quality, a decrease in in vitro fertilization rates, and a reduction in embryo implantation rates in women exposed to high concentrations of PE [ 9 , 11 ] . These data suggest that environmental exposure could negatively influence the chances of success of assisted reproductive techniques. The majority of human research is observational, which hinders explicitly demonstrating a causative link between exposure and infertility. This is one of the methodological constraints that affect the interpretation of PE studies, despite concerning results [ 12 ] . There is a great variability in doses and routes of exposure (inhalation, ingestion, and skin contact), as well as difficulty in identifying critical periods of sensitivity. The cocktail effect, that is, the synergistic interactions between several chemical substances, is rarely taken into account, although it is probably decisive. Finally, the exposure biomarkers used in studies are not always standardized, which limits the comparability of results and the reproducibility of conclusions [ 13 – 15 ] (Table 1 ). Table 1 Key studies on the impact of endocrine disruptors (EDCs) on female fertility Author(s) Year EDCs studied Main findings Tian et al [ 1 ] 2024 Phthalates Reduced fertilization rates and lower oocyte quality Gore et al [ 2 ] 2015 BPA, dioxins, others Hormonal disruption at multiple regulatory levels Peretz et al [ 4 ] 2014 BPA Reduced fertilization rates and lower oocyte quality Land et al [ 5 ] 2022 Various EDCs Decreased ovarian reserve and menstrual cycle disturbances Cai et al [ 11 ] 2019 Phthalates Impaired ovulation and follicular maturation Yi et al [ 12 ] 2023 Phthalates Ovarian dysfunction in women with endometriosis Values were presented n (%) or mean ± AR, autologous tissue reconstruction; IBR, implant-based reconstruction; SD; SD, standard deviation; SMD, standard mean difference. Key studies on the impact of endocrine disruptors (EDCs) on female fertility Values were presented n (%) or mean ± AR, autologous tissue reconstruction; IBR, implant-based reconstruction; SD; SD, standard deviation; SMD, standard mean difference. Faced with potential risks, several avenues of prevention can be considered: On an individual level, reducing exposure involves simple actions, such as limiting the use of plastics, particularly in microwaves, favoring paraben-free cosmetics, consuming unprocessed foods, and avoiding pesticides in food. At the collective level, regulatory initiatives such as the REACH regulation in Europe or the actions of the WHO aim to limit the marketing and use of substances suspected of being EDs. It is essential to inform health professionals and women of childbearing age about environmental risks related to fertility for better prevention. Investigating genetic or epigenetic susceptibility biomarkers would enhance the identification of women most at risk from exposure and inform public health recommendations. On an individual level, reducing exposure involves simple actions, such as limiting the use of plastics, particularly in microwaves, favoring paraben-free cosmetics, consuming unprocessed foods, and avoiding pesticides in food. At the collective level, regulatory initiatives such as the REACH regulation in Europe or the actions of the WHO aim to limit the marketing and use of substances suspected of being EDs. It is essential to inform health professionals and women of childbearing age about environmental risks related to fertility for better prevention. Investigating genetic or epigenetic susceptibility biomarkers would enhance the identification of women most at risk from exposure and inform public health recommendations.

EDs represent a significant threat to female reproductivity health. Several studies have highlighted their deleterious effects, especially those from chronic or early exposure. However, current human studies present significant methodological bias, limiting the establishment of definitive conclusions. Hence, to preserve future generations’ fertility, it’s essential to strengthen scientific research, provide adequate regulations on harmful chemical substances, and develop targeted strategies on preventive methods both at the individual and the community level. Proactive management to tackle this alarming situation will be essential for preserving female reproductive health.