Endocrine Disrupting Chemicals, Reproductive Aging, and Menopause: A Review

Abstract

Menopause marks the end of a woman’s reproductive lifetime and can have a significant effect on a woman’s quality of life. Menopause naturally occurs at 51 years of age on average, but recent literature suggests that endocrine disrupting chemicals (EDCs) in our environment can accelerate reproductive aging, causing women to reach menopause at earlier ages. This is concerning as menopause can significantly alter a woman’s quality of life and is associated with an increased risk of conditions such as depression, osteoporosis, and cardiovascular disease. EDC exposures have also been associated with more intense menopausal symptoms, making the menopausal transition more difficult for some women. This review highlights the associations between EDC exposure, early menopause, and reproductive aging, using both epidemiological and experimental studies.

In Brief:

This review article highlights the associations between endocrine disrupting chemicals, reproductive aging, and menopause. Collectively, the current literature indicates that phthalates, bisphenols, parabens, per- and polyfluoroalkyl substances, polychlorinated biphenyls, dioxins, and pesticides are associated with reproductive aging in women and animal models.

Introduction

The ovaries are unique as they age much sooner than other organs in the body (Duncan et al., 2018). The functional unit of the ovary is the follicle and it is responsible for hormone production along with releasing an egg for fertilization (Neff et al., 2022). At birth, the human ovary can contain approximately 1-2 million primordial (immature) follicles, with this number progressively dropping to 400,000 by puberty and to fewer than 1,000 at the onset of menopause (Duncan et al., 2018).

Markers of reproductive aging naturally begin to occur as a woman and her ovaries age. Markers of reproductive aging include, but are not limited to, changes in hormones and cyclicity, subfertility and infertility, loss of ovarian follicles, and the appearance of menopausal symptoms such as hot flashes and sleep disturbances. Reproductive aging can eventually lead to menopause, which can have profound effects on a woman’s wellbeing and can lead to increased risk for depression, osteoporosis, cardiovascular disease, and even early death (Okeke et al., 2013).

The age at which the menopausal transition occurs depends on many factors, such as socioeconomic status, personal health and lifestyle choices, and environmental factors (Ding et al., 2022). Recent literature suggests that endocrine disrupting chemicals (EDCs) in our environment can contribute to accelerated reproductive aging and early menopause in women (Levine and Hall, 2023, Ding et al., 2022). This is concerning as EDCs are ubiquitous in our environment and women can be exposed to them daily. EDCs are commonly present in food packaging, personal and feminine hygiene products, industrial products and building materials, pesticides, and other consumer products.

This review covers some of the most prominent EDCs in our environment and their effects on female reproductive aging. The EDCs chosen for review are among the most studied and include phthalates, bisphenols, parabens, per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), dioxins, and pesticides. The EDCs chosen for review have been linked to numerous markers of reproductive aging in women, such as changes in hormones and cyclicity, subfertility/infertility, loss of ovarian follicles, and early menopause. Experimental studies, primarily in mice and rats, support these findings for many of the selected EDCs.

Hormone Changes and Abnormal Cyclicity

In a normally cycling woman, gonadotropin releasing hormone (GnRH) from the hypothalamus stimulates the anterior pituitary to synthesize and release follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (Figure 1). FSH and LH from the pituitary act on the ovarian follicles to stimulate the production of estrogens and progesterone. Estrogens and progesterone work in the body to support many aspects of female reproductive health, and they act on the hypothalamus to regulate secretion of GnRH and on the pituitary to regulate the secretion of FSH and LH (Hannon and Flaws, 2015). This process is tightly controlled in reproductive age women, resulting in ovulation and menstruation approximately every 28 days.

Fig. 1:

Panel A shows the hypothalamic-pituitary-ovarian axis in a normally cycling woman of reproductive age. The hypothalamus synthesizes and secretes gonadotropin hormone (GnRH). GnRH then stimulates the anterior pituitary to synthesize and release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH bind to receptors in the ovary and stimulate follicle growth and production of sex steroids (estrogens and progesterone). Estrogen and progesterone can exert negative feedback at the hypothalamus and pituitary. Panel B shows the hypothalamic-pituitary-ovarian axis in a perimenopausal woman. At this point in life, follicles have been near-depleted and do not produce enough estrogen and progesterone to exert negative feedback on the hypothalamus and pituitary. This causes the hypothalamus and pituitary to secrete a continuous excess of LH and FSH, further accelerating follicular depletion and estrogen production until menopause. Inhibin B, a regulator of FSH, and AMH, an indicator of ovarian reserve, are also decreased at this time.

As a woman ages and naturally loses follicles, estrogen and progesterone production gradually decline, as do inhibin, a regulator of FSH secretion, and anti-Müllerian hormone (AMH), a regulator of follicular development (Overlie et al., 2005) (Moolhuijsen and Visser, 2020). The reduction of these hormones results in the loss of ovarian feedback to the pituitary, elevating LH and FSH levels. These changes in hormones are the primary contributors to menstrual fluctuations, and are often one of the first signs of reproductive aging in women.

Phthalates, which are chemicals used as solvents and plasticizers in consumer goods, are associated with changes in hormones in humans (Supplementary Table 1). The effects of individual phthalates on hormones differ, but Hlisnikova et al. demonstrated that phthalate exposure is consistently associated with elevated FSH, and lower estradiol, progesterone, and testosterone in adult women (Hlisnikova et al., 2020). However, these effects can vary by time of exposure. Chiang et al. demonstrated that in premenopausal and-perimenopausal women, exposure to ∑DEHP metabolites, ∑phthalate metabolites from plastics, and ∑anti-androgenic phthalate metabolites were associated with increased estradiol and progesterone levels, and exposure to mono-isobutyl phthalate (MiBP) and monobutyl phthalate (MBP) were associated with increased testosterone and anti-Müllerian hormone levels, respectively (Chiang et al., 2021). Bisphenol A (BPA), another prominent plasticizer, has also been shown to impair ovarian steroidogenesis in ways similar to phthalates (Shoorei et al., 2023). Many experimental studies in mice support these findings (Chiang et al., 2020a, Hannon et al., 2016, Chiang et al., 2020b).

PFAS are a group of synthetic chemicals found in many consumer products, such as protective coatings, building materials, and electric components (Gluge et al., 2020). According to the United States EPA, approximately 10,000-15,000 chemicals can be classified as PFAS (2024). This is concerning as PFAS do not break down easily in the environment and can accumulate in drinking water sources, exposing humans (Evich et al., 2022).

A few epidemiological studies associate perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) exposure with longer and irregular menstrual cycles (Supplementary Table 2). Women in the highest group of exposure to PFOA had significantly higher odds for longer cycles (>32 days) than women in the lowest group of exposure (Lyngso et al., 2014). Among Chinese women who were trying to get pregnant, high levels of PFOA, PFOS, PFNA, and PFHxS were significantly associated with irregular and longer menstrual cycles, along with decreased odds for severe, heavy periods (Zhou et al., 2017). Some studies suggest that PFOS exposure is associated with decreased estrogen and progesterone and increased FSH in adult women, but these same associations are not seen with exposure to PFOA and other PFAS chemicals (Ding et al., 2020). In vitro studies show that PFOA decreases estradiol and estrone levels as well as expression of steroidogenic genes (Star, Cyp11a1, and Hsd3b1) in mouse antral follicles compared to control (Yang et al., 2022). These same steroidogenic effects have been observed in mice dosed with perfluorododecanoic acid (PFDoA) (Shi et al., 2009). Collectively, these data suggest that PFAS are detrimental to normal hormone levels and cyclicity and could play a role in accelerating reproductive aging, but future studies should address this in detail.

Experimental studies show that parabens, chemicals used as preservatives in consumer products, are also capable of disrupting ovarian steroidogenesis in mice and rats (Yan et al., 2022, Li et al., 2021) (Supplementary Table 3). Limited epidemiological studies associate paraben exposure with altered hormones or cyclicity, but one study among Japanese university students found that women with higher urinary paraben concentrations had shorter menstrual cycles compared to women with the lowest urinary paraben concentrations (Nishihama et al., 2016)

PCBs are a group of chemicals that were used in many electric and industrial products from 1929 to 1977 until production was halted due to environmental and human health concerns (Erickson and Kaley, 2011). Despite this, PCBs are still a prominent persistent organic pollutant in our environment and are still present in soil samples (Di Guardo et al., 2017). Humans can be exposed to PCBs through contaminated foods such as fish and meat as well as through inhalation and dermal contact (Neff et al., 2022). A few epidemiological studies associate PCB exposure with longer cycling time, but limited evidence exists on the effects of PCBs on ovarian steroidogenesis (Buck Louis et al., 2011, Cooper et al., 2005) (Supplementary Table 3).

Fertility Loss

In women, fertility naturally begins to decline at age 32 and decreases more rapidly around age 37 (American College of et al., 2014). Markers of infertility include trouble conceiving and maintaining pregnancy, as well as markers of reduced oocyte quality such as aneuploidy and mitotic defects (Moghadam et al., 2022). Recent literature suggests that EDC exposure can have a significant impact on women trying to become pregnant, and it can directly affect oocyte quality.

Data from the National Health and Nutrition Examination Surveys (NHANES), a prominent human health study in the United States, show that phthalates known as mono(3-carboxypropyl) phthalate (MCPP), di(2-ethylhexyl) phthalate (DEHP), mono-2-ethylhexyl phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) as well as BPA are all associated with infertility in adult women (Zhan et al., 2022). Exposure to BPA has also been linked to reduced fertility and fecundity in adult women. Another study comparing infertile and fertile women found that infertile women had significantly higher BPA serum concentrations compared to fertile women (Caserta et al., 2013).

PFASs have notably been associated with a variety of pregnancy complications in adult women, such as gestational diabetes, preeclampsia, and fetal growth restriction (Szilagyi et al., 2020). Some studies have linked PFAS exposure with significantly higher odds of infertility and time to pregnancy (Rickard et al., 2022), with one study showing that women in the highest group of exposure to PFOS and PFOA had 70-134% and 60-154% increased odds of infertility, respectively, compared to women in the lowest group of exposure (Fei et al., 2009). Some studies, however, report that PFAS exposure is not significantly associated with infertility in women (Green et al., 2021).

The impact of pesticides on fertility in women is not entirely clear. Although limited studies link pesticide exposure directly to fertilization rates, many studies link pesticide exposure to other markers of reproductive aging such as reduced ovarian reserve, longer time to pregnancy, and reduced implantation rates (Green et al., 2021, Bloom et al., 2017) prompting the need for more investigation into this potential relationship (Supplementary Table 4).

Telomere Length

While the exact mechanisms behind reproductive aging and infertility remain unclear, telomere length has been garnering interest as a potential cause of female reproductive aging and infertility in recent years. Telomeres are structures on the end of eukaryotic chromosomes comprised of repeating TTAGGG DNA sequences, responsible for protecting chromosomes from degradation and maintaining chromosomal stability (Vasilopoulos et al., 2019). Telomeres shorten naturally when a cell divides, until the telomere is too short and the cell dies. Telomere length in humans reflects biological age and is predictive of numerous age-related conditions such as cancer and cardiovascular disease (Kalmbach et al., 2013). Known factors that can affect telomere length include nutrition, exercise, and tobacco use (Vasilopoulos et al., 2019). A recent review found that a majority of female infertility factors were associated with shorter telomere lengths, with the exception of endometriosis, premature ovarian failure (POF), and clear cell carcinoma being associated with longer telomere length (Vasilopoulos et al., 2019). Estradiol has also been seen to protect telomere length and could play a role in the effects of telomere length on fertility (Barha et al., 2016).

Recent epidemiological studies suggest that exposure to EDCs in our environment can influence telomere length in humans. Data from the NHANES cohort show that participants in the third and fourth quartile of urinary MEHP exposure had statistically significantly longer leukocyte telomere lengths compared to participants in the lowest quartile of exposure (Scinicariello et al., 2016). Prenatal exposure to phthalates can also affect telomere length. Maternal exposure to monoethyl phthalate (MEP), MECPP, MEOHP, MEHHP, monobutyl phthalate (MBP), and DEHP during the first trimester were inversely related to cord blood telomere length, with MEP having a female-specific association (Song et al., 2019). Experimental studies on human cells show that ethyl-paraben and BPA can shorten telomere length as well, but more studies in humans and mice are warranted on this effect (Tran et al., 2020, Finot et al., 2017).

A study investigating female firefighters and office workers found that PFOA and PFOS were associated with significantly longer telomere length, with these effects being pronounced in firefighters (Clarity et al., 2021). These effects can be multigenerational as well, as Eick et al. showed that cord blood PFAS levels were significantly associated with longer telomere lengths in newborns (Eick et al., 2021).

Studies investigating occupational exposure to pesticides often find that people working on farms have significantly shorter telomere lengths compared to those who do not work on farms (Passos et al., 2022). A study of Palestinian women showed that women living in proximity to agricultural fields had shorter telomere lengths compared to women who live further away, and women with higher levels of diethylphosphate (DE) derived pesticide metabolites (DEP, DETP, and DEDTP) had shorter telomeres compared to women in the lowest exposure groups (Ali et al., 2023). NHANES data showed similar results, with higher urinary 3,5,6-trichloro-2-pyridinol (TCPY) being associated with shorter telomere length and higher diethyl thiophosphate (DETP) being associated with longer telomere length in adults (Ock et al., 2020).

The exact effects of pesticide exposure on telomere length are still unclear because of a lack of published epidemiological and experimental studies published on the topic. As humans are exposed to many kinds of pesticides in the environment, more quality studies on this topic are warranted (Passos et al., 2022)

Loss of Ovarian Follicles

Primary ovarian insufficiency (POI) is a condition in which a woman’s ovaries have been depleted of follicles earlier than normal. This condition affects about 1% of women under the age of 40 (Jin et al., 2012). POI is marked by reduced ovarian function, which leads to reduced estradiol and increased FSH levels, and results in a premature loss of follicles, menstrual irregularities, and infertility (Laws et al., 2021). The exact mechanisms behind POI are unknown, but known contributing factors include genetic history, cancer and cancer treatment, and lifestyle choices such as smoking (De Vos et al., 2010).

Several studies suggest a link between phthalate metabolite levels and POI in adult women. A study of women in China shows that serum miBP was negatively associated with antral follicle counts, and serum mEHP and its metabolites were negatively associated with estradiol levels, a marker of POI (Li et al., 2022). Similar studies show that DEHP and MBP metabolite levels in women were also significantly associated with decreased antral follicle and odds for POI, respectively (Messerlian et al., 2016, Ozel et al., 2019). Animal studies have consistently shown that exposure to phthalates is significantly associated with decreased follicle counts, reduced fertility, and increased pregnancy loss (Hannon et al., 2016, Chiang et al., 2020a, Chiang and Flaws, 2019). BPA has also been linked to markers of reproductive aging and POI in humans and animals (Ozel et al., 2019, Rodriguez et al., 2010)

Studies of Chinese women show that higher exposures to pyrethroid pesticides and dioxin-like PCBs are significantly associated with an increased risk for POI, as well as hormone changes consistent with POI in women (Pan et al., 2019, Li et al., 2018). These same effects are seen in women exposed to PFAS (Zhang et al., 2018). Experimental studies in mice show that PFAS exposure can significantly alter follicle counts and follicular growth, as well as decrease hormones in a manner consistent with reproductive aging (Yang et al., 2022)

Studies investigating pesticides find that organochlorine pesticides are consistently associated with reduced ovarian weight, follicle growth, and oocyte viability in rodent studies (Borgeest et al., 2002, Rattan et al., 2017). Similar effects were seen in mice dosed with mancozeb (MCZ), endosulfan, and malathion (Bao et al., 2022, Koc et al., 2009). In female mice, lifelong exposure to environmentally relevant doses of cypermethrin, a pyrethroid, caused a significant decline in all types of follicle counts, increased apoptosis in ovarian follicles, and altered serum hormone levels (Ma et al., 2022). Collectively, these data suggest that pesticide exposure may accelerate reproductive aging in animal models.

Menopause

Menopause marks the end of a woman’s reproductive lifetime and can have a significant effect on a woman’s quality of life. In the United States, the median age at menopause is around 51 years old (Gold, 2011), but recent literature suggests that exposure to EDCs in our environment can accelerate reproductive aging and cause women to reach menopause at earlier ages. This is concerning as menopause significantly alters a woman’s quality of life and is associated with increased risk of conditions such as depression, osteoporosis, and cardiovascular disease (Santoro et al., 2021). EDC exposures have also been associated with more intense menopausal symptoms, making the menopausal transition difficult for some women. Additionally, EDC exposure has been linked with hormone changes consistent with the menopausal transition in women.

Age at menopause

Many different classes of EDCs have been linked to altered menopausal timing in women, but pesticides are some of the most studied EDCs in relation to menopausal timing. Data from the Hispanic Health and Nutrition examination Survey (HHANES) show that women with the highest serum levels of p,p'-DDT, trans-nonachlor, beta-HCH, and p,p’-DDE reached menopause 5.7, 5.2, 3.4, and 1.7 years earlier on average, respectively, compared to women with the lowest serum levels (Akkina et al., 2004). Among women in North Carolina, women with the highest serum levels of DDE had a 1 year earlier median age at menopause compared to women with the lowest serum DDE levels (Cooper et al., 2002). In contrast, not all studies have shown an association between pesticide exposure and early menopause (Farr et al., 2006). A study of women living and working on farms in Iowa and North Carolina found that women who handled pesticides reached menopause approximately three months later compared to women who did not handle pesticides. Women who specifically handled hormonally active pesticides reached menopause approximately five months later compared to women who did not handle pesticides (Farr et al., 2006). The reasons why some pesticides are associated with a later age at menopause and some pesticides are associated with an early age at menopause are unclear. The reasons could stem from differences in chemical toxicity, routes of exposure, lengths of exposure, or study populations.

Another EDC of significance is PFAS. Data from NHANES associated several measures of PFAS chemicals (PFOS, PFOA ,PFNA, PFHxS) with a significantly increased risk for earlier menopause (Taylor et al., 2014). Similar data from the Study of Women’s Health Across the Nation (SWAN) cohort show that women in the top quarter of PFAS exposure have a two year earlier median time to menopause compared to women in the lowest quarter of PFAS exposure (Ding et al., 2020).

The C8 Health Project (C8HP) was created as part of a settlement agreement reached in the case of Jack W. Leach, et al. v. E.I. du Pont de Nemours & Company (no. 01-C-608 W.Va., Wood County Circuit Court, filed 10 April 2002), where people residing in six unique water districts near the DuPont Washington Works facility in Parkersburg, West Virginia were exposed to large amounts of PFOA via contaminated drinking water (Frisbee et al., 2009). The C8HP was created to monitor and document the health effects of PFOA on residents in the affected water districts. Participants from this cohort were seen to have PFOA levels up to 500% higher than participants in the NHANES cohort, but PFOS levels were comparable between cohorts (Knox et al., 2011). In both the perimenopausal and menopausal age groups, the odds of having experienced menopause were significantly increased in women in the highest quintile of PFOA and PFOS exposure compared to women in the lowest quintile.

Phthalates have also been associated with early menopause. In NHANES, women with the top 10% of phthalate metabolites in their urine experienced menopause 3.17-3.8 years earlier on average than women with the lowest urinary phthalate metabolite levels (Grindler et al., 2015)

Limited research has been conducted on PCB exposure and age at menopause. Data from NHANES show that women with high levels of PCB congeners −70, −99, −105, −118, −138, −153, −156, −170, and −183 had mean ages at menopause 1.9 to 3.8 years earlier on average than women with low levels of PCB exposure (Grindler et al., 2015). Other studies, however, did not find a significant association between PCB exposure and age at menopause (Blanck et al., 2004, Yu et al., 2000, Cooper et al., 2002)

Dioxins, which are unwanted chemicals created through combustion processes and share many traits with PCBs, have also been shown to affect age at menopause. The Seveso Women’s Health Study (SWHS) was created to monitor the health of women living near a chemical plant that exploded in Seveso, Italy. The explosion exposed nearby residents to the highest recorded human exposure levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Eskenazi et al., 2021). Data from the SWHS show that women with the highest serum TCDD levels had a nonsignificant increased risk of menopause compared to women in the lowest quintile, but women in the second, third, and fourth quintiles had a significantly increased risk for earlier menopause compared to women in the lowest quintile, indicating that TCDD may have non-monotonic dose effects (Eskenazi et al., 2005).

Several studies have found an association between active cigarette smoking and early menopause (Supplementary Table 5). The Women’s Health Initiative Observational Study (WHI OS) found that women who were smokers at least once in their lives had an elevated odds ratio of 1.26 (95% CI 1.16 to 1.35) for early menopause compared to non-smokers. On average, active-ever smokers reached menopause 21.7 months earlier than non-smokers not exposed to secondhand smoke (Hyland et al., 2016). These effects were more pronounced with increased cigarettes smoking. In the Nurses Health Study II (NHSII) cohort, women who smoked for 11-15 pack years (1 pack/day/year) had an elevated hazard ratio of 1.72 (95% CI: 1.36, 2.18) for early menopause compared to non-smokers (Whitcomb et al., 2018). Women who smoked for 16-20 pack years had an elevated hazard ratio of 1.72 (95% CI: 1.38, 2.14) compared to non-smokers and women who smoked for more than 20 pack years had an elevated odds ratio of 2.42 (95% CI: 2.11, 2.77) compared to non-smokers (Whitcomb et al., 2018).

Cessation of smoking has been shown to partially reverse the associations between cigarette smoking and early menopause. In the NHSII cohort, women who were light smokers (<10 per day) before age 25, but quit by age 25, had no increased risk of early menopause compared to never smokers. Women who smoked heavily (>10 per day), but quit by age 35, had a hazard ratio of 1.27 (95% CI: 1.05, 1.53) for early menopause, significantly lower than currently smoking women (Whitcomb et al., 2018).

Menopause Symptoms

Clinically, the menopausal transition is marked by changes in the menstrual cycle (± 7 days) and/or by the onset of menopausal symptoms (Voedisch et al., 2021). Up to 80% of women experience some kind of adverse menopausal symptom, with the most prevalent being vasomotor symptoms (hot flashes) (Gracia and Freeman, 2018). Hot flashes are sudden periods of intense heat in the upper body and face, followed by profuse sweating and flushing of the skin. Other symptoms of menopause that often accompany hot flashes are changes in mood, problems with sleeping, and sexual disfunction (Santoro et al., 2021).

Limited studies have been conducted on EDC exposure and their relation to menopausal symptoms. The Midlife Women’s Health Study (MWHS) is one study that examined EDC exposure and the incidence of hot flashes in pre-and-perimenopausal women in the United States (Ziv-Gal et al., 2016). Data from the MWHS cohort show that urinary phthalate metabolites are associated with more frequent hot flashes, altered hormones, and sleep disruptions (Ziv-Gal et al., 2016, Warner et al., 2021, Hatcher et al., 2020). Data from this same cohort also show that paraben exposure is associated with higher odds for recent and monthly hot flashes, as well as higher odds for hot flashes of mild severity (Pacyga et al., 2022).

Cigarette smoke is also known to contribute to hot flashes in peri- and post-menopausal women. Data from the MWHS have shown associations between cigarette smoking and an increased risk for severe hot flashes and daily hot flashes, as well as an overall increased risk of having hot flashes compared to non-smokers (Whiteman et al., 2003, Gallicchio et al., 2006, Cochran et al., 2008). Cessation of smoking partially reverses these effects; in the MWHS, women who quit smoking for longer than 5 years had decreased odds, severity, and frequency of hot flashes compared to current smokers (Smith et al., 2015).

Conclusion

A wide body of work indicates that EDCs in our environment can adversely affect human and animal health. Of particular concern are the associations between EDC exposure, reproductive aging, and the menopausal transition in women. Many EDCs have been associated with markers of reproductive aging and early menopause, but the mechanisms behind these relationships remain unclear. Thus, future studies should focus on the mechanisms by which EDCs are associated with reproductive aging and early menopause. Perhaps future studies can make use of information identified in a novel study identifying transcriptomic changes in the aging mouse ovary to provide some insight into potential mechanisms of ovarian aging. Isola et al. found that 9-month-old mice, when compared to 3-month-old mice, had over double the number of immune cells present in the ovary, which was confirmed with flow cytology (Isola et al., 2024). The ovaries of 9-month-old mice also presented an age-related downregulation of collagenase pathways in stromal fibroblasts, which corresponds to increased ovarian fibrosis. Finally, follicular cells presented stress-response, immunogenic, and fibrotic signaling pathway inductions as they aged (Isola et al., 2024). Future studies could focus on the interactions between EDC exposure and these markers of unique markers of ovarian aging. Uncovering the mechanisms behind such markers could set the foundation for identifying interventions or protections against EDC-accelerated reproductive aging, allowing women to have a longer and healthier reproductive lifespan.