Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Endocrine-disrupting chemicals and female reproductive health: a growing concern

Nature Reviews Endocrinology volume 21, pages 593–607 (2025)Cite this article

Subjects

Abstract

Female fertility and reproductive health depend on a series of developmental steps from embryogenesis through puberty, in addition to the proper functioning of the reproductive system in adulthood. Two important steps are the establishment of the ovarian reserve and development of the hypothalamic–pituitary–ovarian axis. During reproductive years, maintaining an adequate ovarian reserve of follicles as well as balanced neuroendocrine control of reproductive organs is crucial for fertility. Dysregulation of either of these events, during development or in adulthood, can lead to reproductive disorders. Over the past five decades, human fertility rates have declined, whereas the incidence of female reproductive disorders has risen, trends partially linked to environmental factors such as exposure to endocrine-disrupting chemicals (EDCs). Here we outline epidemiological and mechanistic evidence for how EDCs affect the ovarian reserve during early development, its maintenance during adulthood and the establishment of the hypothalamic–pituitary control of puberty and ovulation. Our Review not only reveals strong support for the role of EDC exposure in the development of female reproductive disorders such as abnormal puberty, impaired fertility, premature menopause or polycystic ovarian syndrome, but also highlights knowledge gaps, including the difficulty to prove causality between exposure and human disease manifestation.

Key points

  • The prevalence of female reproductive disorders is increasing globally, and exposure to chemicals that disrupt the hormone system (endocrine-disrupting chemicals; EDCs) are considered a contributing factor.

  • There is evidence from epidemiological studies that links exposure to EDCs with reproductive disorders such as early puberty, early menopause and polycystic ovary syndrome.

  • Experimental studies with animals clearly show that exposure to EDCs during early life as well as in adulthood can negatively affect ovarian reserve, folliculogenesis and the hypothalamic control of puberty and ovulation.

  • Future studies are needed to better understand the effect of in utero exposure to EDCs on female reproductive health later in life and in future generations.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Female reproductive development and functions susceptible to perturbation by endocrine-disrupting chemicals.
Fig. 2: Secular trends in age at thelarche and menarche over past decades.
Fig. 3: Central versus peripheral disruption of puberty timing.

Similar content being viewed by others

References

  1. Eckert-Lind, C. et al. Worldwide secular trends in age at pubertal onset assessed by breast development among girls. JAMA Pediatr. 174, e195881 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Euling, S. Y. et al. Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings. Pediatrics 121, S172–S191 (2008).

    Article  PubMed  Google Scholar 

  3. Parent, A.-S. et al. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr. Rev. 24, 668–693 (2003).

    Article  PubMed  Google Scholar 

  4. Parent, A.-S., Franssen, D., Fudvoye, J., Gérard, A. & Bourguignon, J.-P. Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: revision of human observations and mechanistic insight from rodents. Front. Neuroendocrinol. 38, 12–36 (2015).

    Article  CAS  PubMed  Google Scholar 

  5. Bräuner, E. V. et al. Trends in the incidence of central precocious puberty and normal variant puberty among children in Denmark, 1998 to 2017. JAMA Netw. Open 3, e2015665 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Huttunen, H. et al. Central precocious puberty in boys: secular trend and clinical features. Eur. J. Endocrinol. 190, 211–219 (2024).

    Article  CAS  PubMed  Google Scholar 

  7. Chiaffarino, F. et al. Prevalence of polycystic ovary syndrome in European countries and USA: a systematic review and meta-analysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 279, 159–170 (2022).

    Article  PubMed  Google Scholar 

  8. Li, M. et al. The global prevalence of premature ovarian insufficiency: a systematic review and meta-analysis. Climacteric 26, 95–102 (2023).

    Article  CAS  PubMed  Google Scholar 

  9. Gliozheni, O. et al. ART in Europe, 2016: results generated from European registries by ESHRE. Hum. Reprod. Open. 2020, hoaa032 (2020).

    Article  Google Scholar 

  10. Bhattacharjee, N. V. et al. Global fertility in 204 countries and territories, 1950–2021, with forecasts to 2100: a comprehensive demographic analysis for the global burden of disease study 2021. Lancet 403, 2057–2099 (2024).

    Article  Google Scholar 

  11. Aitken, R. J. The changing tide of human fertility. Hum. Reprod. 37, 629–638 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Land, K. L., Miller, F. G., Fugate, A. C. & Hannon, P. R. The effects of endocrine‐disrupting chemicals on ovarian‐ and ovulation‐related fertility outcomes. Mol. Reprod. Dev. 89, 608–631 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Conforti, A. et al. Unravelling the link between phthalate exposure and endometriosis in humans: a systematic review and meta-analysis of the literature. J. Assist. Reprod. Genet. 38, 2543–2557 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kim, J. H. & Kim, S. H. Exposure to phthalate esters and the risk of endometriosis. Dev. Reprod. 24, 71–78 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Freire, C. et al. Association of prenatal exposure to phthalates and synthetic phenols with pubertal development in three European cohorts. Int. J. Hyg. Environ. Health 261, 114418 (2024).

    Article  CAS  PubMed  Google Scholar 

  16. Averina, M. et al. Early menarche and other endocrine disrupting effects of per- and polyfluoroalkyl substances (PFAS) in adolescents from Northern Norway. The Fit Futures study. Environ. Res. 242, 117703 (2024).

    Article  CAS  PubMed  Google Scholar 

  17. Pinney, S. M. et al. Exposure to perfluoroalkyl substances and associations with pubertal onset and serum reproductive hormones in a longitudinal study of young girls in greater Cincinnati and the San Francisco bay area. Environ. Health Perspect. 131, 97009 (2023).

    Article  CAS  PubMed  Google Scholar 

  18. Bellavia, A. et al. Association between chemical mixtures and female fertility in women undergoing assisted reproduction in Sweden and Estonia. Environ. Res. 216, 114447 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. World Health Organization. Global assessment on the state of the science of endocrine disruptors. WHO https://www.who.int/publications/i/item/WHO-PSC-EDC-02.2 (2002).

  20. Gore, A. C. et al. EDC-2: the Endocrine Society’s second scientific statement on endocrine-disrupting chemicals. Endocr. Rev. 36, E1–E150 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Endocrine disruptor list. The Danish Environmental Protection Agency https://edlists.org/ (2024).

  22. Lecante, L. L. et al. Acetaminophen (APAP, paracetamol) interferes with the first trimester human fetal ovary development in an ex vivo model. J. Clin. Endocrinol. Metab. 107, 1647–1661 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lin, C.-J. & Li, L.-A. Estrogenicity of major organic chemicals in cigarette sidestream smoke particulate matter. Atmosphere 14, 647 (2023).

    Article  CAS  Google Scholar 

  24. Johansson, H. K. L., Svingen, T., Fowler, P. A., Vinggaard, A. M. & Boberg, J. Environmental influences on ovarian dysgenesis — developmental windows sensitive to chemical exposures. Nat. Rev. Endocrinol. 13, 400–414 (2017).

    Article  PubMed  Google Scholar 

  25. van Duursen, M. B. M. et al. Safeguarding female reproductive health against endocrine disrupting chemicals — the FREIA project. Int. J. Mol. Sci. 21, 3215 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Vinnars, M.-T., Bixo, M. & Damdimopoulou, P. Pregnancy-related maternal physiological adaptations and fetal chemical exposure. Mol. Cell Endocrinol. 578, 112064 (2023).

    Article  CAS  PubMed  Google Scholar 

  27. Wu, Y. et al. Maternal exposure to endocrine disrupting chemicals (EDCs) and preterm birth: a systematic review, meta-analysis, and meta-regression analysis. Environ. Pollut. 292, 118264 (2022).

    Article  CAS  PubMed  Google Scholar 

  28. Kek, T., Geršak, K. & Virant-Klun, I. Exposure to endocrine disrupting chemicals (bisphenols, parabens, and triclosan) and their associations with preterm birth in humans. Reprod. Toxicol. 125, 108580 (2024).

    Article  CAS  PubMed  Google Scholar 

  29. Poole, E. M. & Boland, M. R. A national study of the associations between hormonal modulators in hydraulic fracturing fluid chemicals and birth outcomes in the United States of America: a county-level analysis. Environ. Health Perspect. 132, 107001 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Haydardedeoglu, B. & Zeyneloglu, H. B. The impact of endometriosis on fertility. Womens Health 11, 619–623 (2015).

    CAS  Google Scholar 

  31. Chandrakanth, A., Firdous, S., Vasantharekha, R., Santosh, W. & Seetharaman, B. Exploring the effects of endocrine-disrupting chemicals and miRNA expression in the pathogenesis of endometriosis by unveiling the pathways: a systematic review. Reprod. Sci. 31, 932–941 (2024).

    Article  CAS  PubMed  Google Scholar 

  32. Kahn, L. G., Philippat, C., Nakayama, S. F., Slama, R. & Trasande, L. Endocrine-disrupting chemicals: implications for human health. Lancet Diabetes Endocrinol. 8, 703–718 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sharma, P., Tseng, H.-H., Lee, J.-Y. L., Tsai, E.-M. & Suen, J.-L. A prominent environmental endocrine disruptor, 4-nonylphenol, promotes endometriosis development via plasmacytoid dendritic cells. Mol. Hum. Reprod. 26, 601–614 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Wallace, W. H. B. & Kelsey, T. W. Human ovarian reserve from conception to the menopause. PLoS ONE 5, e8772 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gougeon, A. Dynamics of follicular growth in the human: a model from preliminary results. Hum. Reprod. 1, 81–87 (1986).

    Article  CAS  PubMed  Google Scholar 

  36. Gougeon, A. in Biology and Pathology of the Oocyte (eds Trounson, A., Gosden, R. & Eichenlaub-Ritter, U.) 50–61 (Cambridge Univ. Press, 2013).

  37. Monteleone, P., Mascagni, G., Giannini, A., Genazzani, A. R. & Simoncini, T. Symptoms of menopause — global prevalence, physiology and implications. Nat. Rev. Endocrinol. 14, 199–215 (2018).

    Article  PubMed  Google Scholar 

  38. Alberts, S. C. et al. Reproductive aging patterns in primates reveal that humans are distinct. Proc. Natl Acad. Sci. USA 110, 13440–13445 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ruth, K. S. et al. Genetic insights into biological mechanisms governing human ovarian ageing. Nature 596, 393–397 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Laisk, T. et al. Demographic and evolutionary trends in ovarian function and aging. Hum. Reprod. Update 25, 34–50 (2018).

    Google Scholar 

  41. Zhu, D. et al. Relationships between intensity, duration, cumulative dose, and timing of smoking with age at menopause: a pooled analysis of individual data from 17 observational studies. PLoS Med. 15, e1002704 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Schoenaker, D. A., Jackson, C. A., Rowlands, J. V. & Mishra, G. D. Socioeconomic position, lifestyle factors and age at natural menopause: a systematic review and meta-analyses of studies across six continents. Int. J. Epidemiol. 43, 1542–1562 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Laven, J. S. E. & Louwers, Y. V. Can we predict menopause and premature ovarian insufficiency? Fertil. Steril. 121, 737–741 (2024).

    Article  PubMed  Google Scholar 

  44. Green, D. M. et al. Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the childhood cancer survivor study. J. Clin. Oncol. 27, 2374–2381 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Jiang, C. et al. Birth weight and premature ovarian insufficiency: a systematic review and meta-analysis. J. Ovarian Res. 17, 74 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Langton, C. R. et al. Association of in utero exposures with risk of early natural menopause. Am. J. Epidemiol. 191, 775–786 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Ruth, K. S. et al. Events in early life are associated with female reproductive ageing: a UK biobank study. Sci. Rep. 6, 24710 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hatch, E. E. et al. Age at natural menopause in women exposed to diethylstilbestrol in utero. Am. J. Epidemiol. 164, 682–688 (2006).

    Article  PubMed  Google Scholar 

  49. Steiner, A. Z., D’Aloisio, A. A., DeRoo, L. A., Sandler, D. P. & Baird, D. D. Association of intrauterine and early-life exposures with age at menopause in the sister study. Am. J. Epidemiol. 172, 140–148 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Hoover, R. N. et al. Adverse health outcomes in women exposed in utero to diethylstilbestrol. N. Engl. J. Med. 365, 1304–1314 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Kaufman, R. Continued follow-up of pregnancy outcomes in diethylstilbestrol-exposed offspring. Obstet. Gynecol. 96, 483–489 (2000).

    CAS  PubMed  Google Scholar 

  52. Peycheva, D. et al. Risk factors for natural menopause before the age of 45: evidence from two British population-based birth cohort studies. BMC Womens Health 22, 438 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Hyland, A. et al. Associations between lifetime tobacco exposure with infertility and age at natural menopause: the Women’s Health Initiative Observational Study. Tob. Control. 25, 706–714 (2016).

    Article  PubMed  Google Scholar 

  54. Vabre, P. et al. Environmental pollutants, a possible etiology for premature ovarian insufficiency: a narrative review of animal and human data. Environ. Health 16, 37 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Grindler, N. M. et al. Persistent organic pollutants and early menopause in US women. PLoS ONE 10, e0116057 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Björvang, R. D. et al. Persistent organic pollutants and the size of ovarian reserve in reproductive-aged women. Environ. Int. 155, 106589 (2021).

    Article  PubMed  Google Scholar 

  57. Irie, N., Tang, W. W. C. & Azim Surani, M. Germ cell specification and pluripotency in mammals: a perspective from early embryogenesis. Reprod. Med. Biol. 13, 203–215 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Hartshorne, G. M., Lyrakou, S., Hamoda, H., Oloto, E. & Ghafari, F. Oogenesis and cell death in human prenatal ovaries: what are the criteria for oocyte selection? Mol. Hum. Reprod. 15, 805–819 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Aoki, T. & Takada, T. Bisphenol A modulates germ cell differentiation and retinoic acid signaling in mouse ES cells. Reprod. Toxicol. 34, 463–470 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Yu, M. et al. Effects of tamoxifen on the sex determination gene and the activation of sex reversal in the developing gonad of mice. Toxicology 321, 89–95 (2014).

    Article  CAS  PubMed  Google Scholar 

  61. Britt, K. L. et al. The ovarian phenotype of the aromatase knockout (ArKO) mouse. J. Steroid Biochem. Mol. Biol. 79, 181–185 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Stewart, M. K., Mattiske, D. M. & Pask, A. J. Exogenous oestrogen impacts cell fate decision in the developing gonads: a potential cause of declining human reproductive health. Int. J. Mol. Sci. 21, 8377 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Pepling, M. E. & Spradling, C. A. female mouse germ cells form synchronously dividing cysts. Development 125, 3323–3328 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Nagaoka, S. I., Hassold, T. J. & Hunt, P. A. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat. Rev. Genet. 13, 493–504 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Susiarjo, M., Hassold, T. J., Freeman, E. & Hunt, P. A. Bisphenol A exposure in utero disrupts early oogenesis in the mouse. PLoS Genet. 3, e5 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Peters, A. E. et al. Impact of bisphenol A and its alternatives on oocyte health: a scoping review. Hum. Reprod. Update 30, 653–691 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hunt, P. A. et al. Bisphenol A alters early oogenesis and follicle formation in the fetal ovary of the rhesus monkey. Proc. Natl Acad. Sci. USA 109, 17525–17530 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Loup, B. et al. BPA disrupts meiosis I in oogonia by acting on pathways including cell cycle regulation, meiosis initiation and spindle assembly. Reprod. Toxicol. 111, 166–177 (2022).

    Article  CAS  PubMed  Google Scholar 

  69. Brieño-Enríquez, M. A. et al. Human meiotic progression and recombination are affected by bisphenol A exposure during in vitro human oocyte development. Hum. Reprod. 26, 2807–2818 (2011).

    Article  PubMed  Google Scholar 

  70. Peretz, J. et al. Bisphenol A and reproductive health: update of experimental and human evidence, 2007–2013. Environ. Health Perspect. 122, 775–786 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Acconcia, F., Pallottini, V. & Marino, M. Molecular mechanisms of action of BPA. Dose Response 13, 155932581561058 (2015).

    Article  Google Scholar 

  72. Watanabe, M., Ohno, S. & Nakajin, S. Effects of bisphenol A on the expression of cytochrome P450 aromatase (CYP19) in human fetal osteoblastic and granulosa cell-like cell lines. Toxicol. Lett. 210, 95–99 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Shoorei, H. et al. Different types of bisphenols alter ovarian steroidogenesis: special attention to BPA. Heliyon 9, e16848 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Zhang, X.-F. et al. Transgenerational inheritance of ovarian development deficiency induced by maternal diethylhexyl phthalate exposure. Reprod. Fertil. Dev. 27, 1213 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. Tu, Z. et al. Dibutyl phthalate exposure disrupts the progression of meiotic prophase I by interfering with homologous recombination in fetal mouse oocytes. Environ. Pollut. 252, 388–398 (2019).

    Article  CAS  PubMed  Google Scholar 

  76. Yun, Y. et al. Oocyte development and quality in young and old mice following exposure to atrazine. Environ. Health Perspect. 130, 117007 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Can, A., Semiz, O. & Cinar, O. Bisphenol-A induces cell cycle delay and alters centrosome and spindle microtubular organization in oocytes during meiosis. Mol. Hum. Reprod. 11, 389–396 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Machtinger, R. et al. Bisphenol-A and human oocyte maturation in vitro. Hum. Reprod. 28, 2735–2745 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Yang, L., Baumann, C., De La Fuente, R. & Viveiros, M. M. Mechanisms underlying disruption of oocyte spindle stability by bisphenol compounds. Reproduction 159, 383–396 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Tarumi, W., Itoh, M. T. & Suzuki, N. Effects of 5α-dihydrotestosterone and 17β-estradiol on the mouse ovarian follicle development and oocyte maturation. PLoS ONE 9, e99423 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Solak, K. A. et al. Naringenin (NAR) and 8-prenylnaringenin (8-PN) reduce the developmental competence of porcine oocytes in vitro. Reprod. Toxicol. 49, 1–11 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Overland, M. R. et al. Development of the human ovary: fetal through pubertal ovarian morphology, folliculogenesis and expression of cellular differentiation markers. Differentiation 129, 37–59 (2023).

    Article  CAS  PubMed  Google Scholar 

  83. Fowler, P. A. et al. Development of steroid signaling pathways during primordial follicle formation in the human fetal ovary. J. Clin. Endocrinol. Metab. 96, 1754–1762 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. George, F. W. & Wilson, J. D. Conversion of androgen to estrogen by the human fetal ovary. J. Clin. Endocrinol. Metab. 47, 550–555 (1978).

    Article  CAS  PubMed  Google Scholar 

  85. Greco, T. L. & Payne, A. H. Ontogeny of expression of the genes for steroidogenic enzymes P450 side-chain cleavage, 3 beta-hydroxysteroid dehydrogenase, P450 17 alpha-hydroxylase/C17-20 lyase, and P450 aromatase in fetal mouse gonads. Endocrinology 135, 262–268 (1994).

    Article  CAS  PubMed  Google Scholar 

  86. Jolivet, G. et al. Fetal estrogens are not involved in sex determination but critical for early ovarian differentiation in rabbits. Endocrinology 163, bqab210 (2022).

    Article  PubMed  Google Scholar 

  87. Vazakidou, P. et al. The profile of steroid hormones in human fetal and adult ovaries. Reprod. Biol. Endocrinol. 22, 60 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Morel, Y. et al. Evolution of steroids during pregnancy: maternal, placental and fetal synthesis. Ann. Endocrinol. 77, 82–89 (2016).

    Article  Google Scholar 

  89. Spiller, C. & Bowles, J. Sex determination in mammalian germ cells. Asian J. Androl. 17, 427 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Nilsson, C. Retinoids in mammalian reproduction, with an initial scoping effort to identify regulatory methods. Nordic Co-operation https://www.norden.org/en/publication/retinoids-mammalian-reproduction-initial-scoping-effort-identify-regulatory-methods.Nordic.Co-operation (2020).

  91. Dean, A. et al. Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences. Sci. Rep. 6, 19789 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Meli, R., Monnolo, A., Annunziata, C., Pirozzi, C. & Ferrante, M. C. Oxidative stress and BPA toxicity: an antioxidant approach for male and female reproductive dysfunction. Antioxidants 9, 405 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Abdallah, S. et al. Foetal exposure to the bisphenols BADGE and BPAF impairs meiosis through DNA oxidation in mouse ovaries. Environ. Pollut. 317, 120791 (2023).

    Article  CAS  PubMed  Google Scholar 

  94. Handel, M. A. & Schimenti, J. C. Genetics of mammalian meiosis: regulation, dynamics and impact on fertility. Nat. Rev. Genet. 11, 124–136 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Richardson, M. C., Guo, M., Fauser, B. C. J. M. & Macklon, N. S. Environmental and developmental origins of ovarian reserve. Hum. Reprod. Update 20, 353–369 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Baltus, A. E. et al. In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic DNA replication. Nat. Genet. 38, 1430–1434 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Choi, Y., Ballow, D. J., Xin, Y. & Rajkovic, A. Lim homeobox gene, Lhx8, is essential for mouse oocyte differentiation and survival. Biol. Reprod. 79, 442–449 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Holt, J. E. et al. The APC/C activator FZR1 is essential for meiotic prophase I in mice. Development 141, 1354–1365 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Wong, J. C. Y. et al. Targeted disruption of exons 1 to 6 of the fanconi anemia group a gene leads to growth retardation, strain-specific microphthalmia, meiotic defects and primordial germ cell hypoplasia. Hum. Mol. Genet. 12, 2063–2076 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Hussein, M. R. Apoptosis in the ovary: molecular mechanisms. Hum. Reprod. Update 11, 162–178 (2005).

    Article  PubMed  Google Scholar 

  101. Zhou, J., Peng, X. & Mei, S. Autophagy in ovarian follicular development and atresia. Int. J. Biol. Sci. 15, 726–737 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hu, J. et al. Ovarian aging‐associated downregulation of GPX4 expression regulates ovarian follicular development by affecting granulosa cell functions and oocyte quality. FASEB J. 39, e70469 (2025).

    Article  CAS  PubMed  Google Scholar 

  103. Jurisicova, A. et al. Maternal exposure to polycyclic aromatic hydrocarbons diminishes murine ovarian reserve via induction of harakiri. J. Clin. Investig. 117, 3971–3978 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Matikainen, T. et al. Aromatic hydrocarbon receptor-driven bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat. Genet. 28, 355–360 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Matikainen, T. M. et al. Ligand activation of the aromatic hydrocarbon receptor transcription factor drives bax-dependent apoptosis in developing fetal ovarian germ cells. Endocrinology 143, 615–620 (2002).

    Article  CAS  PubMed  Google Scholar 

  106. Panagiotou, E. M., Ojasalo, V. & Damdimopoulou, P. Phthalates, ovarian function and fertility in adulthood. Best Pract. Res. Clin. Endocrinol. Metab. 35, 101552 (2021).

    Article  CAS  PubMed  Google Scholar 

  107. Li, T. et al. Persistent organic pollutants dysregulate energy homeostasis in human ovaries in vitro. Environ. Int. 187, 108710 (2024).

    Article  CAS  PubMed  Google Scholar 

  108. Panagiotou, E. M. et al. Exposure to the phthalate metabolite MEHP impacts survival and growth of human ovarian follicles in vitro. Toxicology 505, 153815 (2024).

    Article  CAS  PubMed  Google Scholar 

  109. Davis, B. J., Maronpot, R. R. & Heindel, J. J. Di-(2-ethylhexyl) Phthalate suppresses estradiol and ovulation in cycling rats. Toxicol. Appl. Pharmacol. 128, 216–223 (1994).

    Article  CAS  PubMed  Google Scholar 

  110. Li, N., Zhou, L., Zhu, J., Liu, T. & Ye, L. Role of the 17β-hydroxysteroid dehydrogenase signalling pathway in di-(2-ethylhexyl) phthalate-induced ovarian dysfunction: an in vivo study. Sci. Total. Environ. 712, 134406 (2020).

    Article  CAS  PubMed  Google Scholar 

  111. Lee, S. G. et al. Bisphenol A exposure during adulthood causes augmentation of follicular atresia and luteal regression by decreasing 17β-estradiol synthesis via downregulation of aromatase in rat ovary. Environ. Health Perspect. 121, 663–669 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Hallberg, I. et al. Suspect and non-target screening of ovarian follicular fluid and serum — identification of anthropogenic chemicals and investigation of their association to fertility. Environ. Sci. Process. Impacts 23, 1578–1588 (2021).

    Article  CAS  PubMed  Google Scholar 

  113. Björvang, R. D. & Damdimopoulou, P. Persistent environmental endocrine-disrupting chemicals in ovarian follicular fluid and in vitro fertilization treatment outcome in women. Ups. J. Med. Sci. 125, 85–94 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Varik, I. et al. Reduced ovarian cholesterol and steroid biosynthesis along with increased inflammation are associated with high DEHP metabolite levels in human ovarian follicular fluids. Environ. Int. 191, 108960 (2024).

    Article  CAS  PubMed  Google Scholar 

  115. Björvang, R. D. et al. Follicular fluid and blood levels of persistent organic pollutants and reproductive outcomes among women undergoing assisted reproductive technologies. Environ. Res. 208, 112626 (2022).

    Article  PubMed  Google Scholar 

  116. Karwacka, A., Zamkowska, D., Radwan, M. & Jurewicz, J. Exposure to modern, widespread environmental endocrine disrupting chemicals and their effect on the reproductive potential of women: an overview of current epidemiological evidence. Hum. Fertil. 22, 2–25 (2019).

    Article  CAS  Google Scholar 

  117. Ijaz, S., Ullah, A., Shaheen, G. & Jahan, S. Exposure of BPA and its alternatives like BPB, BPF, and BPS impair subsequent reproductive potentials in adult female sprague dawley rats. Toxicol. Mech. Methods 30, 60–72 (2020).

    Article  CAS  PubMed  Google Scholar 

  118. Viguié, C. et al. Evidence-based adverse outcome pathway approach for the identification of BPA as en endocrine disruptor in relation to its effect on the estrous cycle. Mol. Cell Endocrinol. 475, 10–28 (2018).

    Article  PubMed  Google Scholar 

  119. Hannon, P. R. & Flaws, J. A. The effects of phthalates on the ovary. Front. Endocrinol. 6, 8 (2015).

    Article  Google Scholar 

  120. Chiang, C. & Flaws, J. A. Subchronic exposure to di(2-ethylhexyl) phthalate and diisononyl phthalate during adulthood has immediate and long-term reproductive consequences in female mice. Toxicol. Sci. 168, 620–631 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Fletcher, E. et al. Effects of phthalate mixtures on ovarian folliculogenesis and steroidogenesis. Toxics 10, 251 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Tarvainen, I. et al. Identification of phthalate mixture exposure targets in the human and mouse ovary in vitro. Reprod. Toxicol. 119, 108393 (2023).

    Article  CAS  PubMed  Google Scholar 

  123. Panagiotou, E. M. et al. AOP key event relationship report: linking decreased androgen receptor activation with decreased granulosa cell proliferation of gonadotropin-independent follicles. Reprod. Toxicol. 112, 136–147 (2022).

    Article  CAS  PubMed  Google Scholar 

  124. Gervásio, C. G., Bernuci, M. P., Silva-de-Sá, M. F. & Rosa-e-Silva, A. C. J. de S. The role of androgen hormones in early follicular development. ISRN Obstet. Gynecol. 2014, 1–11 (2014).

    Article  Google Scholar 

  125. Neuvonen, R., Huovinen, M., Dorman, D. C., Laitinen, H. & Sahlman, H. Phthalates and polycystic ovary syndrome — systematic literature review. Reprod. Toxicol. 121, 108473 (2023).

    Article  CAS  PubMed  Google Scholar 

  126. Wehkalampi, K. et al. Genetic and environmental influences on pubertal timing assessed by height growth. Am. J. Hum. Biol. 20, 417–423 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Sorensen, K. et al. Birth size and age at menarche: a twin perspective. Hum. Reprod. 28, 2865–2871 (2013).

    Article  PubMed  Google Scholar 

  128. Arcari, A. J. et al. Prevalence of polycystic ovarian syndrome in girls with a history of idiopathic central precocious puberty. Horm. Res. Paediatr. 97, 134–139 (2024).

    Article  CAS  PubMed  Google Scholar 

  129. Guaraldi, F., Beccuti, G., Gori, D. & Ghizzoni, L. Management of endocrine disease: long-term outcomes of the treatment of central precocious puberty. Eur. J. Endocrinol. 174, R79–R87 (2016).

    Article  CAS  PubMed  Google Scholar 

  130. Gajbhiye, R., Fung, J. N. & Montgomery, G. W. Complex genetics of female fertility. npj Genom. Med. 3, 29 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  131. McGrath, I. M., Mortlock, S. & Montgomery, G. W. Genetic regulation of physiological reproductive lifespan and female fertility. Int. J. Mol. Sci. 22, 2556 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Elks, C. E. et al. Age at menarche and type 2 diabetes risk. Diabetes Care 36, 3526–3534 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Prentice, P. & Viner, R. M. Pubertal timing and adult obesity and cardiometabolic risk in women and men: a systematic review and meta-analysis. Int. J. Obes. 37, 1036–1043 (2013).

    Article  CAS  Google Scholar 

  134. Herman-Giddens, M. E. et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the pediatric research in office settings network. Pediatrics 99, 505–512 (1997).

    Article  CAS  PubMed  Google Scholar 

  135. Shu, W., Zong, X. & Li, H. Secular trends in age at pubertal onset assessed by breast development among Chinese girls: a systematic review. Front. Endocrinol. 13, 1042122 (2022).

    Article  Google Scholar 

  136. Jaruratanasirikul, S. & Sriplung, H. Secular trends of growth and pubertal maturation of school children in southern Thailand. Ann. Hum. Biol. 42, 447–454 (2015).

    Article  PubMed  Google Scholar 

  137. Ferrari, V., Stefanucci, S., Ciofi, D. & Stagi, S. Analysis of the timing of puberty in a recent cohort of Italian girls: evidence for earlier onset compared to previous studies. J. Pediatr. Adolesc. Gynecol. 35, 23–29 (2022).

    Article  PubMed  Google Scholar 

  138. Cabrera, S. M., Bright, G. M., Frane, J. W., Blethen, S. L. & Lee, P. A. Age of thelarche and menarche in contemporary US females: a cross-sectional analysis. J. Pediatr. Endocrinol. Metab. 27, 47–51 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Wohlfahrt-Veje, C. et al. Pubertal onset in boys and girls is influenced by pubertal timing of both parents. J. Clin. Endocrinol. Metab. 101, 2667–2674 (2016).

    Article  CAS  PubMed  Google Scholar 

  140. Lohiya, N., Jahagirdar, R., Deshpande, R. & Goyal, A. Sexual maturity assessment in Indian children — a study from western India. J. Pediatr. Endocrinol. Metab. 34, 567–572 (2021).

    Article  PubMed  Google Scholar 

  141. Jaruratanasirikul, S., Chanpong, A., Tassanakijpanich, N. & Sriplung, H. Declining age of puberty of school girls in southern Thailand. World J. Pediatrics 10, 256–261 (2014).

    Article  Google Scholar 

  142. Reinehr, T. & Roth, C. L. Is there a causal relationship between obesity and puberty? Lancet Child. Adolesc. Health 3, 44–54 (2019).

    Article  PubMed  Google Scholar 

  143. Sørensen, K. et al. Recent secular trends in pubertal timing: implications for evaluation and diagnosis of precocious puberty. Horm. Res. Paediatr. 77, 137–145 (2012).

    Article  PubMed  Google Scholar 

  144. Mouritsen, A. et al. Hypothesis: exposure to endocrine‐disrupting chemicals may interfere with timing of puberty. Int. J. Androl. 33, 346–359 (2010).

    Article  CAS  PubMed  Google Scholar 

  145. Lopez-Rodriguez, D., Franssen, D., Heger, S. & Parent, A.-S. Endocrine-disrupting chemicals and their effects on puberty. Best Pract. Res. Clin. Endocrinol. Metab. 35, 101579 (2021).

    Article  CAS  PubMed  Google Scholar 

  146. Liu, W. et al. A secular trend in age at menarche in Yunnan Province, China: a multiethnic population study of 1,275,000 women. BMC Public Health 21, 1890 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Garenne, M. Age at menarche in Nigerian demographic surveys. J. Biosoc. Sci. 53, 745–757 (2021).

    Article  PubMed  Google Scholar 

  148. Marván, M. L., Castillo‐López, R. L., del‐Callejo‐Canal, D. D., Canal‐Martínez, M. E. & Núñez‐de la Mora, A. Secular trends in age at menarche in 20th century Mexico: differences by ethnicity, area of residency, and socioeconomic status. Am. J. Hum. Biol. 32, e23404 (2020).

    Article  PubMed  Google Scholar 

  149. Lin, Y.-C., Yen, H.-R., Wang, C.-H., Liao, Y.-C. & Lin, R.-T. Trends in age at menarche from 1943 through 1989 in Taiwan: a retrospective population-based analysis. Pediatr. Neonatol. 65, 64–70 (2024).

    Article  PubMed  Google Scholar 

  150. Ulubay, M., Fidan, U. & Ozturk, M. The decreasing age of menarche in Turkey: global warming, socioeconomic development, and environmental factors. Eur. Rev. Med. Pharmacol. Sci. 27, 6780–6784 (2023).

    CAS  PubMed  Google Scholar 

  151. Iwase, M. et al. A century of change: unraveling the impact of socioeconomic/historical milestones on age at menarche and other female reproductive factors in Japan. J. Epidemiol. 34, JE20230155 (2024).

    Article  Google Scholar 

  152. Wu, X. et al. Secular trends of age at menarche and the effect of famine exposure on age at menarche in rural Chinese women. Ann. Hum. Biol. 49, 35–40 (2022).

    Article  CAS  PubMed  Google Scholar 

  153. Asrullah, M., L’Hoir, M., Feskens, E. J. M. & Melse-Boonstra, A. Trend in age at menarche and its association with body weight, body mass index and non-communicable disease prevalence in Indonesia: evidence from the Indonesian Family Life Survey (IFLS). BMC Public Health 22, 628 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Queiroga, A. C., Silva, R. S., Santos, A. C., Maia, I. & Barros, H. Secular trend in age at menarche in women in Portugal born between 1920 and 1992: results from three population‐based studies. Am. J. Hum. Biol. 32, e23392 (2020).

    Article  PubMed  Google Scholar 

  155. Tey, N.-P., Lai, S.-L. & Ng, S.-T. Age at menarche and sexual debut among young Filipino women. J. Biosoc. Sci. 51, 77–94 (2019).

    Article  PubMed  Google Scholar 

  156. Hrabovszky, E. & Liposits, Z. Afferent neuronal control of type-I gonadotropin releasing hormone neurons in the human. Front. Endocrinol. 4, 130 (2013).

    Article  Google Scholar 

  157. Campbell, R. E., Coolen, L. M., Hoffman, G. E. & Hrabovszky, E. Highlights of neuroanatomical discoveries of the mammalian gonadotropin‐releasing hormone system. J. Neuroendocrinol. 34, e13115 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Herbison, A. E. The gonadotropin-releasing hormone pulse generator. Endocrinology 159, 3723–3736 (2018).

    Article  CAS  PubMed  Google Scholar 

  159. Terasawa, E. Mechanism of pulsatile GnRH release in primates: unresolved questions. Mol. Cell Endocrinol. 498, 110578 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Goodman, R. L., Herbison, A. E., Lehman, M. N. & Navarro, V. M. Neuroendocrine control of gonadotropin‐releasing hormone: pulsatile and surge modes of secretion. J. Neuroendocrinol. 34, e13094 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Argente, J. et al. Molecular basis of normal and pathological puberty: from basic mechanisms to clinical implications. Lancet Diabetes Endocrinol. 11, 203–216 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Anderson, G. M. et al. Metabolic control of puberty: 60 years in the footsteps of Kennedy and Mitra’s seminal work. Nat. Rev. Endocrinol. 20, 111–123 (2024).

    Article  CAS  PubMed  Google Scholar 

  163. Pinilla, L., Aguilar, E., Dieguez, C., Millar, R. P. & Tena-Sempere, M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol. Rev. 92, 1235–1316 (2012).

    Article  CAS  PubMed  Google Scholar 

  164. Ratra, D. V. & Elias, C. F. Chemical identity of hypothalamic neurons engaged by leptin in reproductive control. J. Chem. Neuroanat. 61–62, 233–238 (2014).

    Article  PubMed  Google Scholar 

  165. Starrett, J. R. & Moenter, S. M. Hypothalamic kisspeptin neurons as potential mediators of estradiol negative and positive feedback. Peptides 163, 170963 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Watkins, D. J. et al. In utero and peripubertal exposure to phthalates and BPA in relation to female sexual maturation. Env. Res. 134, 233–241 (2014).

    Article  CAS  Google Scholar 

  167. Watkins, D. J. et al. Phthalate and bisphenol A exposure during in utero windows of susceptibility in relation to reproductive hormones and pubertal development in girls. Environ. Res. 159, 143–151 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Berger, K. et al. Association of prenatal urinary concentrations of phthalates and bisphenol A and pubertal timing in boys and girls. Environ. Health Perspect. 126, 97004 (2018).

    Article  CAS  PubMed  Google Scholar 

  169. Franssen, D. et al. Pubertal timing after neonatal diethylstilbestrol exposure in female rats: neuroendocrine vs peripheral effects and additive role of prenatal food restriction. Reprod. Toxicol. 44, 63–72 (2014).

    Article  CAS  PubMed  Google Scholar 

  170. Franssen, D. et al. Delayed neuroendocrine sexual maturation in female rats after a very low dose of bisphenol A through altered GABAergic neurotransmission and opposing effects of a high dose. Endocrinology 157, 1740–1750 (2016).

    Article  CAS  PubMed  Google Scholar 

  171. Burdea, L. & Sharma, L. in StatPearls (ed. Mendez, M.) (StatPearls Publishing, 2023).

  172. Goto, M. In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development. J. Clin. Investig. 116, 953–960 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Pignatti, E., du Toit, T. & Flück, C. E. Development and function of the fetal adrenal. Rev. Endocr. Metab. Disord. 24, 5–21 (2023).

    Article  PubMed  Google Scholar 

  174. Uldbjerg, C. S. et al. Prenatal and postnatal exposures to endocrine disrupting chemicals and timing of pubertal onset in girls and boys: a systematic review and meta-analysis. Hum. Reprod. Update 28, 687–716 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Soriano-Guillén, L. et al. Central precocious puberty in children living in Spain: incidence, prevalence, and influence of adoption and immigration. J. Clin. Endocrinol. Metab. 95, 4305–4313 (2010).

    Article  PubMed  Google Scholar 

  176. Le Moal, J. et al. Marked geographic patterns in the incidence of idiopathic central precocious puberty: a nationwide study in France. Eur. J. Endocrinol. 178, 33–41 (2018).

    Article  PubMed  Google Scholar 

  177. Kim, Y. J. et al. Incidence and prevalence of central precocious puberty in Korea: an epidemiologic study based on a national database. J. Pediatr. 208, 221–228 (2019).

    Article  PubMed  Google Scholar 

  178. Almstrup, K., Frederiksen, H., Andersson, A.-M. & Juul, A. Levels of endocrine-disrupting chemicals are associated with changes in the peri-pubertal epigenome. Endocr. Connect. 9, 845–857 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Almstrup, K. et al. Pubertal development in healthy children is mirrored by DNA methylation patterns in peripheral blood. Sci. Rep. 6, 28657 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Binder, A. M. et al. Childhood and adolescent phenol and phthalate exposure and the age of menarche in Latina girls. Environ. Health 17, 32 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Su, P.-H. et al. Prenatal exposure to phthalate ester and pubertal development in a birth cohort in central Taiwan: a 12-year follow-up study. Environ. Res. 136, 324–330 (2015).

    Article  CAS  PubMed  Google Scholar 

  182. Xie, C. et al. Elevated phthalates’ exposure in children with constitutional delay of growth and puberty. Mol. Cell Endocrinol. 407, 67–73 (2015).

    Article  CAS  PubMed  Google Scholar 

  183. Franssen, D. et al. Perinatal exposure to the fungicide ketoconazole alters hypothalamic control of puberty in female rats. Front. Endocrinol. 14, 1140886 (2023).

    Article  Google Scholar 

  184. López-Rodríguez, D. et al. Persistent vs transient alteration of folliculogenesis and estrous cycle after neonatal vs adult exposure to bisphenol A. Endocrinology 160, 2558–2572 (2019).

    PubMed  Google Scholar 

  185. Tang, C. et al. Chronic exposure to low dose of bisphenol A causes follicular atresia by inhibiting kisspeptin neurons in anteroventral periventricular nucleus in female mice. Neurotoxicology 79, 164–176 (2020).

    Article  CAS  PubMed  Google Scholar 

  186. Ruiz-Pino, F. et al. Environmentally relevant perinatal exposures to bisphenol a disrupt postnatal Kiss1/NKB neuronal maturation and puberty onset in female mice. Environ. Health Perspect. 127, 107011 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Martini, M. et al. Perinatal exposure to methoxychlor affects reproductive function and sexual behavior in mice. Front. Endocrinol. 11, 639 (2020).

    Article  Google Scholar 

  188. Guarnieri, G. et al. Effects of benzo[a]pyrene on the reproductive axis: impairment of kisspeptin signaling in human gonadotropin-releasing hormone primary neurons. Environ. Pollut. 317, 120766 (2023).

    Article  CAS  PubMed  Google Scholar 

  189. Marty, M. Evaluation of the EDSTAC female pubertal assay in CD rats using 17beta-estradiol, steroid biosynthesis inhibitors, and a thyroid inhibitor. Toxicol. Sci. 52, 269–277 (1999).

    Article  CAS  PubMed  Google Scholar 

  190. Ma, M. et al. Exposure of prepubertal female rats to inhaled di(2-ethylhexyl)phthalate affects the onset of puberty and postpubertal reproductive functions. Toxicol. Sci. 93, 164–171 (2006).

    Article  CAS  PubMed  Google Scholar 

  191. Patiño-García, D., Cruz-Fernandes, L., Buñay, J., Palomino, J. & Moreno, R. D. Reproductive alterations in chronically exposed female mice to environmentally relevant doses of a mixture of phthalates and alkylphenols. Endocrinology 159, 1050–1061 (2018).

    Article  PubMed  Google Scholar 

  192. López-Rodríguez, D. et al. Multi- and transgenerational outcomes of an exposure to a mixture of endocrine-disrupting chemicals (EDCs) on puberty and maternal behavior in the female rat. Environ. Health Perspect. 129, 87003 (2021).

    Article  PubMed  Google Scholar 

  193. Rogers, R. E., Chai, S., Pask, A. J. & Mattiske, D. M. Prenatal exposure to diethylstilbestrol has long-lasting, transgenerational impacts on fertility and reproductive development. Toxicol. Sci. 195, 53–60 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Shi, M., Whorton, A. E., Sekulovski, N., MacLean, J. A. & Hayashi, K. Prenatal exposure to bisphenol A, E, and S induces transgenerational effects on female reproductive functions in mice. Toxicol. Sci. 170, 320–329 (2019).

    Article  CAS  PubMed  Google Scholar 

  195. Rattan, S., Brehm, E., Gao, L. & Flaws, J. A. Di(2-ethylhexyl) phthalate exposure during prenatal development causes adverse transgenerational effects on female fertility in mice. Toxicol. Sci. 163, 420–429 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Azziz, R. et al. Polycystic ovary syndrome. Nat. Rev. Dis. Prim. 2, 16057 (2016).

    Article  PubMed  Google Scholar 

  197. Diamanti-Kandarakis, E. Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications. Expert Rev. Mol. Med. 10, e3 (2008).

    Article  PubMed  Google Scholar 

  198. Joham, A. E. et al. Polycystic ovary syndrome. Lancet Diabetes Endocrinol. 10, 668–680 (2022).

    Article  CAS  PubMed  Google Scholar 

  199. Christ, J. P. & Cedars, M. I. Current guidelines for diagnosing PCOS. Diagnostics 13, 1113 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Kiconco, S., Teede, H. J., Azziz, R., Norman, R. J. & Joham, A. E. The need to reassess the diagnosis of polycystic ovary syndrome (PCOS): a review of diagnostic recommendations from the international evidence-based guideline for the assessment and management of PCOS. Semin. Reprod. Med. 39, 071–077 (2021).

    Article  Google Scholar 

  201. Miazgowski, T., Martopullo, I., Widecka, J., Miazgowski, B. & Brodowska, A. National and regional trends in the prevalence of polycystic ovary syndrome since 1990 within Europe: the modeled estimates from the Global Burden of Disease Study 2016. Arch. Med. Sci. 17, 343–351 (2021).

    Article  PubMed  Google Scholar 

  202. Liu, J. et al. Measuring the global disease burden of polycystic ovary syndrome in 194 countries: Global Burden of Disease Study 2017. Hum. Reprod. 36, 1108–1119 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  203. Yang, R. et al. Changes in the prevalence of polycystic ovary syndrome in China over the past decade. Lancet Reg. Health West. Pac. 25, 100494 (2022).

    PubMed  PubMed Central  Google Scholar 

  204. Risal, S. et al. Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome. Nat. Med. 25, 1894–1904 (2019).

    Article  CAS  PubMed  Google Scholar 

  205. Takeuchi, T., Tsutsumi, O., Ikezuki, Y., Takai, Y. & Taketani, Y. Positive relationship between androgen and the endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction. Endocr. J. 51, 165–169 (2004).

    Article  CAS  PubMed  Google Scholar 

  206. Kandaraki, E. et al. Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS. J. Clin. Endocrinol. Metab. 96, E480–E484 (2011).

    Article  CAS  PubMed  Google Scholar 

  207. Hossein, R. B. et al. The association between bisphenol A and polycystic ovarian syndrome: a case–control study. Acta Med. Iran 55, 759–764 (2017).

    Google Scholar 

  208. Akın, L. et al. The endocrine disruptor bisphenol A may play a role in the aetiopathogenesis of polycystic ovary syndrome in adolescent girls. Acta Paediatr. 104, e171–e177 (2015).

    Article  PubMed  Google Scholar 

  209. Guo, Z. et al. Association of serum organochlorine pesticides concentrations with reproductive hormone levels and polycystic ovary syndrome in a Chinese population. Chemosphere 171, 595–600 (2017).

    Article  CAS  PubMed  Google Scholar 

  210. Yang, Q. et al. Association of serum levels of typical organic pollutants with polycystic ovary syndrome (PCOS): a case–control study. Hum. Reprod. 30, 1964–1973 (2015).

    Article  CAS  PubMed  Google Scholar 

  211. Hammarstrand, S. et al. Perfluoroalkyl substances (PFAS) in drinking water and risk for polycystic ovarian syndrome, uterine leiomyoma, and endometriosis: a Swedish cohort study. Environ. Int. 157, 106819 (2021).

    Article  CAS  PubMed  Google Scholar 

  212. Zhang, Y. et al. Per- and polyfluoroalkyl substances exposure is associated with polycystic ovary syndrome risk among women attending a fertility clinic. Sci. Total. Environ. 950, 175313 (2024).

    Article  CAS  PubMed  Google Scholar 

  213. Zhan, W. et al. Environmental exposure to emerging alternatives of per- and polyfluoroalkyl substances and polycystic ovarian syndrome in women diagnosed with infertility: a mixture analysis. Environ. Health Perspect. 131, 57001 (2023).

    Article  CAS  PubMed  Google Scholar 

  214. Hart, R. et al. The influence of antenatal exposure to phthalates on subsequent female reproductive development in adolescence: a pilot study. Reproduction 147, 379–390 (2014).

    Article  CAS  PubMed  Google Scholar 

  215. Moolhuijsen, L. M. E. & Visser, J. A. Anti-Müllerian hormone and ovarian reserve: update on assessing ovarian function. J. Clin. Endocrinol. Metab. 105, 3361–3373 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Stener-Victorin, E. et al. Animal models to understand the etiology and pathophysiology of polycystic ovary syndrome. Endocr. Rev. 41, bnaa010 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Mimouni, N. E. H. & Giacobini, P. Polycystic ovary syndrome mouse model by prenatal exposure to high anti-Müllerian hormone. Star Protoc. 2, 100684 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Landers, R. S. M., Padmanabhan, V. & Cardoso, R. C. Developmental programming: gestational testosterone excess disrupts LH secretion in the female sheep fetus. Reprod. Biol. Endocrinol. 18, 106 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Padmanabhan, V. & Veiga-Lopez, A. Sheep models of polycystic ovary syndrome phenotype. Mol. Cell Endocrinol. 373, 8–20 (2013).

    Article  CAS  PubMed  Google Scholar 

  220. Yang, Z. et al. A pilot study on polycystic ovarian syndrome caused by neonatal exposure to tributyltin and bisphenol A in rats. Chemosphere 231, 151–160 (2019).

    Article  CAS  PubMed  Google Scholar 

  221. Fernández, M., Bianchi, M., Lux-Lantos, V. & Libertun, C. Neonatal exposure to bisphenol A alters reproductive parameters and gonadotropin releasing hormone signaling in female rats. Environ. Health Perspect. 117, 757–762 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  222. Newbold, R. R., Jefferson, W. N. & Padilla-Banks, E. Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract. Reprod. Toxicol. 24, 253–258 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Eroschenko, V. P., Abuel-Atta, A. A. & Grober, M. S. Neonatal exposures to technical methoxychlor alters ovaries in adult mice. Reprod. Toxicol. 9, 379–387 (1995).

    Article  CAS  PubMed  Google Scholar 

  224. Feng, Y. et al. Effects of bisphenol analogues on steroidogenic gene expression and hormone synthesis in H295R cells. Chemosphere 147, 9–19 (2016).

    Article  CAS  PubMed  Google Scholar 

  225. Zhou, W., Liu, J., Liao, L., Han, S. & Liu, J. Effect of bisphenol A on steroid hormone production in rat ovarian theca-interstitial and granulosa cells. Mol. Cell Endocrinol. 283, 12–18 (2008).

    Article  CAS  PubMed  Google Scholar 

  226. Neff, A. M. & Flaws, J. A. The effects of plasticizers on the ovary. Curr. Opin. Endocr. Metab. Res. 18, 35–47 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Berga, S. L., Guzick, D. S. & Winters, S. J. Increased luteinizing hormone and alpha-subunit secretion in women with hyperandrogenic anovulation. J. Clin. Endocrinol. Metab. 77, 895–901 (1993).

    CAS  PubMed  Google Scholar 

  228. Silva, M. S. B. et al. Overactivation of GnRH neurons is sufficient to trigger polycystic ovary syndrome-like traits in female mice. EBioMedicine 97, 104850 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Tata, B. et al. Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood. Nat. Med. 24, 834–846 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Mimouni, N. E. H. et al. Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process. Cell Metab. 33, 513–530.e8 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Cimino, I. et al. Novel role for anti-Müllerian hormone in the regulation of GnRH neuron excitability and hormone secretion. Nat. Commun. 7, 10055 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Barbotin, A.-L. et al. Hypothalamic neuroglial plasticity is regulated by anti-Müllerian hormone and disrupted in polycystic ovary syndrome. EBioMedicine 90, 104535 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Hakim, C., Padmanabhan, V. & Vyas, A. K. Gestational hyperandrogenism in developmental programming. Endocrinology 158, 199–212 (2017).

    Article  CAS  PubMed  Google Scholar 

  234. Messerlian, C., Martinez, R. M., Hauser, R. & Baccarelli, A. A. Omics’ and endocrine-disrupting chemicals — new paths forward. Nat. Rev. Endocrinol. 13, 740–748 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Nugent, B. M. & Bale, T. L. The omniscient placenta: metabolic and epigenetic regulation of fetal programming. Front. Neuroendocrinol. 39, 28–37 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Mao, J. et al. Bisphenol A and bisphenol S disruptions of the mouse placenta and potential effects on the placenta–brain axis. Proc. Natl Acad. Sci. USA 117, 4642–4652 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Marinello, W. P. et al. Gestational exposure to firemaster 550 (FM 550) disrupts the placenta–brain axis in a socially monogamous rodent species, the prairie vole (Microtus ochrogaster). Mol. Cell Endocrinol. 576, 112041 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Wang, Y. et al. Gut microbiota–metabolite interactions meditate the effect of dietary patterns on precocious puberty. iScience 27, 109887 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Lin, C. et al. Aspartame intake delayed puberty onset in female offspring rats and girls. Mol. Nutr. Food Res. 68, e2300270 (2024).

    Article  PubMed  Google Scholar 

  240. Nguyen, N. N. et al. Natural sweetener glycyrrhizin protects against precocious puberty by modulating the gut microbiome. Life Sci. 350, 122789 (2024).

    Article  CAS  PubMed  Google Scholar 

  241. Liang, Y. et al. Gut microbiota dysbiosis in polycystic ovary syndrome: association with obesity — a preliminary report. Can. J. Physiol. Pharmacol. 98, 803–809 (2020).

    Article  CAS  PubMed  Google Scholar 

  242. Calero-Medina, L. et al. Dietary exposure to endocrine disruptors in gut microbiota: a systematic review. Sci. Total. Environ. 886, 163991 (2023).

    Article  CAS  PubMed  Google Scholar 

  243. Vitale, S. G. et al. The role of genital tract microbiome in fertility: a systematic review. Int. J. Mol. Sci. 23, 180 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  244. Ono, Y. et al. Uterine endometrium microbiome in women with repeated implantation failure complicated by endometriosis. J. Clin. Med. 13, 4605 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Tamburini, S., Shen, N., Wu, H. C. & Clemente, J. C. The microbiome in early life: implications for health outcomes. Nat. Med. 22, 713–722 (2016).

    Article  CAS  PubMed  Google Scholar 

  246. Fan, Y. & Pedersen, O. Gut microbiota in human metabolic health and disease. Nat. Rev. Microbiol. 19, 55–71 (2021).

    Article  CAS  PubMed  Google Scholar 

  247. Ceasrine, A. M. et al. Maternal diet disrupts the placenta–brain axis in a sex-specific manner. Nat. Metab. 4, 1732–1745 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Svingen, T. et al. Enhanced identification of endocrine disruptors through integration of science-based regulatory practices and innovative methodologies: the MERLON Project. Open. Res. Eur. 4, 68 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  249. La Merrill, M. A. et al. Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification. Nat. Rev. Endocrinol. 16, 45–57 (2020).

    Article  PubMed  Google Scholar 

  250. Pask, A. J. A role for estrogen in somatic cell fate of the mammalian gonad. Chromosome Res. 20, 239–245 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the support of Horizon Europe (EU Horizon 2020 project FREIA25, grant agreement no. 825100, and EU Horizon Health project MERLON248, grant agreement no. 101137411) and the European Research Council (ERC project SAFER, grant agreement no. 101124440) as well as the Belgian National Foundation for Research (FNRS). Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union or the Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for them.

Author information

Authors and Affiliations

  1. Neuroendocrinology Unit, GIGA Neurosciences, University of Liege, Liege, Belgium

    Anne-Simone Parent, Delphine Franssen & Julie Fudvoye

  2. Department of Paediatrics, University Hospital Liege, Liege, Belgium

    Anne-Simone Parent & Julie Fudvoye

  3. Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Huddinge, Sweden

    Pauliina Damdimopoulou

  4. Department of Women’s and Children’s Health, Karolinska Institutet, Solna, Sweden

    Pauliina Damdimopoulou

  5. National Food Institute, Technical University of Denmark, Lyngby, Denmark

    Hanna K. L. Johansson, Monica K. Draskau & Terje Svingen

  6. Environmental Health and Toxicology, Amsterdam Institute for Life and Environment, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    Nora Bouftas & Majorie van Duursen

Authors
  1. Anne-Simone Parent
    View author publications

    Search author on:PubMed Google Scholar

  2. Pauliina Damdimopoulou
    View author publications

    Search author on:PubMed Google Scholar

  3. Hanna K. L. Johansson
    View author publications

    Search author on:PubMed Google Scholar

  4. Nora Bouftas
    View author publications

    Search author on:PubMed Google Scholar

  5. Monica K. Draskau
    View author publications

    Search author on:PubMed Google Scholar

  6. Delphine Franssen
    View author publications

    Search author on:PubMed Google Scholar

  7. Julie Fudvoye
    View author publications

    Search author on:PubMed Google Scholar

  8. Majorie van Duursen
    View author publications

    Search author on:PubMed Google Scholar

  9. Terje Svingen
    View author publications

    Search author on:PubMed Google Scholar

Contributions

All authors researched data for the article and reviewed and/or edited the manuscript before submission. A.S.P., P.D., H.K.L.J., N.B., M.K.D., D.F., M.v.D. and T.S. contributed substantially to discussion of the content and wrote the article.

Corresponding author

Correspondence to Anne-Simone Parent.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Endocrinology thanks Patricia Hunt and the other, anonymous, reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Parent, AS., Damdimopoulou, P., Johansson, H.K.L. et al. Endocrine-disrupting chemicals and female reproductive health: a growing concern. Nat Rev Endocrinol 21, 593–607 (2025). https://doi.org/10.1038/s41574-025-01131-x

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41574-025-01131-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing