Environmental Pollution, Endocrine Disruptors, and Metabolic Status: Impact on Female Fertility—A Narrative Review

Abstract

Objectives: Female fertility is increasingly threatened by environmental pollutants such as fine particulate matter (PM_2.5 and NO₂), endocrine-disrupting chemicals (BPA, phthalates, PFAS, and PCBs), and microplastics. These exposures are associated with impaired ovarian reserve, reduced implantation rates, and lower assisted reproductive technology (ART) success. Given the rising prevalence of obesity and weight-loss interventions, particularly bariatric surgery, understanding the combined influence of metabolic and environmental factors on reproductive outcomes is of critical importance. This review aimed to synthesize recent evidence on how these exposures interact to affect female fertility. Methods: A narrative review was conducted of studies published between 2019 and 2025 using PubMed, Google Scholar, Web of Science, and Wiley Online Library. The PubMed Boolean search string was “female fertility”, “ovarian function”, “IVF” and “pollution”, “endocrine disruptors”, “air pollutants”, and “microplastics”. Searches were limited to English language publications, with the last search performed on 30 March 2025. Human, animal, and in vitro data were screened separately. Human evidence was prioritized, and confounding factors (age, BMI, and smoking) were considered during interpretation. Results: Environmental pollutants were consistently associated with diminished ovarian reserve, poor oocyte quality, and reduced live birth rates in ART. PFAS exposure correlated with lower fecundability, while PM_2.5 and NO₂ were linked to decreased AMH and AFC levels. Mechanistic animal and in vitro studies support these findings through pathways involving oxidative stress, endocrine disruption, and epigenetic alterations. Rapid metabolic changes, particularly post-bariatric surgery, may transiently increase circulating lipophilic toxicants and reduce antioxidant defenses, amplifying reproductive vulnerability. Conclusions: Environmental exposures, especially PM_2.5, NO₂, PFAS, and microplastics, adversely influence ovarian and embryonic competence. Rapid metabolic transitions may further modulate this susceptibility through pollutant mobilization and micronutrient imbalances. Future interdisciplinary prospective studies integrating exposure monitoring, metabolic profiling, and reproductive endpoints are essential to guide clinical recommendations and precision fertility counseling.

1. Introduction

Infertility, defined as the inability to achieve pregnancy after 12 months of regular and unprotected sexual intercourse, affects between 8 and 12% of couples of reproductive age globally. Environmental and metabolic determinants have emerged as two major, interrelated contributors to this burden. Obesity, regarded as a metabolic pandemic, is associated with an increased prevalence of infertility in women, through endocrine, inflammatory, and ovulatory mechanisms. In the obese female population, the risk of infertility is approximately 2–3 times higher compared to normal-weight women [1,2]. The main pathophysiologic mechanisms involved include insulin resistance, hyperandrogenism, ovulatory dysfunction, and chronic low-grade inflammation. These are associated with menstrual cycle disorders, decreased oocyte quality, and reduced chances of natural conception [3].

In the past decade, metabolic improvement strategies have emerged as effective approaches not only for sustained weight reduction but also for restoring reproductive function. By decreasing visceral adipose mass, normalizing the hormonal profile, and lowering insulin levels, such interventions can lead to the resumption of ovulation and increased spontaneous pregnancy rates, even in women with polycystic ovary syndrome [4]. These approaches may carry medium- and long-term risks such as nutritional deficiencies (iron, folate, vitamin B12, and vitamin D), which may affect fertility and pregnancy outcome [5].

In parallel, a rapidly expanding body of evidence underscores the significant role of environmental exposures—such as air pollutants, endocrine-disrupting chemicals (EDCs), heavy metals, and microplastics—in impairing female reproductive potential. These agents act through hormonal interference, oxidative stress, and direct effects on ovogenesis and endometrial receptivity [6]. While metabolic interventions target intrinsic physiological determinants of fertility, environmental toxicants represent external, modifiable stressors that can exacerbate or attenuate reproductive outcomes depending on metabolic context.

Despite the separate acknowledgment of both domains—metabolic health interventions and environmental exposures—in infertility research, their intersection remains poorly integrated in current reproductive medicine literature. Relevant data on the specific influence of pollutants in women undergoing major metabolic transitions (such as post-bariatric recovery or rapid weight loss) are still limited.

The primary aim of this narrative review is to synthesize recent human clinical evidence on how environmental exposures—including air pollutants (PM_2.5, NO₂, O₃), endocrine-disrupting chemicals (BPA, phthalates, PFAS, PCBs), heavy metals, and microplastics—are associated with ovarian reserve, assisted reproductive technology outcomes, and time-to-pregnancy. Each study is tagged at first mention as Human clinical, Human exposure, Animal, and In Vitro, ensuring consistent evidence tiering. Specifically, this review addresses the following question: “What is the human clinical evidence that environmental pollution and endocrine-disrupting chemicals influence female fertility outcomes and how might metabolic status (including obesity, rapid weight loss, or bariatric surgery) modify these effects?” The target population includes women of reproductive age seeking conception, and the outcomes of interest are ovarian reserve markers, ART outcomes, and time to pregnancy. Additionally, we examine how metabolic status may act as a potential effect modifier rather than a primary determinant of these environmental exposures.

2. Materials and Methods

We conducted a narrative literature review aimed at exploring the impact of reproductive disorders, including infertility, on women’s quality of life across different life stages. This review aimed to synthesize the available evidence rather than perform a systematic meta-analysis. A particular focus was placed on studies examining the intersection between environmental exposures and metabolic factors as modifiers of reproductive outcomes.

The objective of this synthesis was to raise awareness regarding the multifactorial burden of infertility in the context of modern stressors and environmental challenges. The primary review question guiding this synthesis was: “What is the human clinical evidence that ambient air pollution (PM_2.5, NO₂, and O₃), endocrine-disrupting chemicals (BPA, phthalates, PFAS, and PCBs), heavy metals, and microplastics affect ovarian reserve, assisted reproductive technology outcomes, and time-to-pregnancy, and how might metabolic status modify these effects in women of reproductive age?”

To inform our analysis, we performed a targeted search of the literature published between January 2019 and March 2025 in PubMed and other major academic databases (Web of Science, Wiley Online Library, and Google Scholar), using combinations of keywords such as “infertility”, “environmental exposure”, “endocrine disruption”, “female fertility”, “pollution”, and “ovarian function”. The Boolean search string used in PubMed was as follows: “female fertility”, “infertility”, “ovarian reserve”, “IVF” or “assisted reproduction” AND “pollution”, “PM_2.5”, “NO₂”, “air pollution”, “endocrine disruptors”, “phthalates”, “BPA”, “PFAS”, “PCBs”, and “microplastics”. The last search was conducted on 31st March 2025.

Only English language studies were included, with no restriction on publication type, provided that reproductive outcomes were reported. Titles and abstracts were screened for relevance, followed by a full-text review. A total of 1432 titles were screened and 213 full texts were reviewed. Screening was performed by a single reviewer, with discussion among co-authors for ambiguous cases. Studies were eligible if they included human participants of reproductive age, assessed exposure to environmental pollutants or endocrine-disrupting chemicals, and reported reproductive outcomes such as clinical pregnancy, live birth, or time-to-pregnancy. Studies focused exclusively on males; those with irrelevant outcomes or non-English language articles were excluded.

Each included study was categorized according to its evidence tier: human clinical, human exposure, animal, or in vitro, to distinguish mechanistic from clinical findings. Although all tiers were considered during the search, human data were prioritized and analyzed separately to maintain clinical relevance. Each human study was evaluated for methodological quality and risk of bias, including control for key confounders such as age, BMI, smoking status, and socioeconomic factors. Confounding control was verified qualitatively based on whether these variables were adjusted for in multivariate or regression analyses.

3. Results

3.1. Interplay of Metabolic and Environmental Factors in Female Reproductive Health

3.1.1. Infertility in Obese Women: Pathophysiologic Mechanisms

Obesity influences fertility through a series of complex endocrine-metabolic mechanisms that affect reproductive function at the hypothalamic–pituitary–ovarian level. At the central level, excess adipose tissue causes an increase in leptin and leptin resistance, leading to altered pulsatile GnRH secretion. In parallel, hyperinsulinemia associated with insulin resistance increases ovarian androgen production and inhibits SHBG synthesis, amplifying hyperandrogenism [7,8]. These hormonal imbalances contribute to chronic anovulation, PCOS-like manifestations, and altered follicular microenvironment. These findings were derived from human clinical and large-scale observational cohort studies.

Pro-inflammatory adipocytokines (IL-6, TNF-α) secreted by visceral adipose tissue promoted chronic low-grade inflammation, which impaired ovulatory function and endometrial receptivity [9]. This inflammatory background also disrupts granulosa cell function and endometrial vascularization, both essential for implantation. Studies demonstrated an inverse correlation between BMI and AMH levels, suggesting impaired ovarian reserve in obesity [10]. These results are derived from human clinical cohorts assessing ovarian reserve markers.

Obesity is characterized by a deficiency in adiponectin, an adipokine that plays a crucial role in regulating ovarian function. Low adiponectin levels observed in obese women are associated with diminished AMH and kisspeptin expression, both vital for follicular development and the maintenance of ovarian reserve. This deficit contributed to impaired oocyte maturation and ovulatory dysfunction, further exacerbating infertility risks in this population [11]. Evidence originates primarily from human serum and follicular fluid analyses, indicating that local ovarian signaling pathways are significantly affected by metabolic dysregulation.

Oxidative stress caused by elevated free fatty acids and chronic inflammation in obesity leads to mitochondrial dysfunction in oocytes, impairing their quality and reducing fertilization potential. High levels of reactive oxygen species induced apoptosis in granulosa cells and disrupted follicular development, as shown in clinical studies [12]. Mechanistic insights are supported by both human clinical and in vitro investigations, highlighting the crucial role of oxidative imbalance in ovarian aging and poor reproductive performance.

Obesity significantly contributed to subfertility and infertility in women, often worsening reproductive outcomes regardless of conception method. Polycystic ovary syndrome (PCOS), a leading cause of infertility, is frequently associated with overweight and obesity. Weight loss remained the most effective approach to improve fertility and pregnancy outcomes. Emerging evidence highlighted a pathophysiological link between obesity, altered glucagon-like peptide-1 (GLP-1) activity, and PCOS development. GLP-1 receptor agonists have shown promising results in promoting weight loss and reducing androgen levels in obese women with PCOS [13,14] (human clinical intervention studies).

An important study identified significant links between specific metabolites and female reproductive endocrine disorders such as PCOS, endometriosis, and female infertility. Some metabolites were associated with increased risk, while others appeared protective, underscoring the complex metabolic influences on these conditions [15]. These findings were derived from human plasma and follicular metabolomic analyses.

Obesity negatively impacts female fertility through multiple mechanisms, including hormonal imbalances, disruption of the hypothalamus–pituitary–ovarian axis, and altered menstrual cycles, leading to higher rates of oligo or anovulation. Elevated leptin levels in obese women may reduce fecundity, while obesity also impairs endometrial development and implantation. Women with obesity and PCOS tended to exhibit more severe symptoms and greater fertility challenges. Additionally, obesity reduced the effectiveness of assisted reproductive technologies, as shown in human IVF cohort studies [16].

A non-linear association was found between bedtime and infertility, with increased infertility risk observed in women who go to bed after 22:45. This relationship was stronger among women with higher BMI. These findings suggested that a late bedtime may contribute to infertility risk, highlighting the importance of sleep timing in reproductive health for women of childbearing age (human observational study); sleep and circadian rhythm disruption may amplify insulin resistance and reproductive hormonal imbalance, providing a novel behavioral target for fertility optimization [17].

Obesity increased the risk of infertility, though many obese individuals remained fertile. In women, obesity was linked to ovulatory dysfunction, reduced ovarian response, impaired oocyte and endometrial function, and lower IVF success rates. It also raises risks for maternal and fetal complications during pregnancy. Weight loss through lifestyle changes, medical treatments, or bariatric surgery can improve fertility, especially in anovulatory women, though improvements in live birth rates are less certain (human clinical cohorts) [18]. Overall, evidence supports that metabolic health restoration enhances reproductive potential, yet environmental exposures may modulate these outcomes.

3.1.2. Bariatric Surgery, Rapid Weight Loss and Fertility (Text About Bariatric Surgery Only to Illustrate Metabolic Status as a Potential Modifier of Environmental Exposure)

Bariatric interventions were consistently associated with restoration of ovulatory function. Significant postoperative weight loss resulted in decreased insulinemia, increased SHBG, normalization of FSH and LH values, and resumption of regular ovulatory cycles (human clinical and observational evidence) [19].

Studies suggest an increase in conception rates following bariatric surgery compared with standard medical management (human observational and meta-analytic evidence). However, causality cannot be inferred, as most studies are observational and subject to confounding by age and baseline metabolic severity [20].

The immediate postoperative period was associated with important nutritional risks (iron, vitamin B12, folate, zinc, and vitamin D deficiency), which may negatively influence oocyte quality and embryo development [21]. Societies such as ASRM and ASMBS recommended postponing pregnancy for at least 12–18 months post-bariatric to allow metabolic stabilization and correction of deficiencies. Similar caution is advisable following rapid weight loss from restrictive diets or other intensive interventions, as the associated metabolic changes and potential nutrient deficiencies may also impact fertility and pregnancy outcomes [22]. From an environmental health perspective, these metabolic shifts may also alter the distribution and mobilization of lipophilic pollutants, temporarily increasing circulation levels after rapid adipose reduction. This reinforces the need to interpret fertility improvements after bariatric surgery in light of possible transient increases in systemic toxicants burden.

In addition to the restoration of spontaneous ovulation, recent data suggested that bariatric surgery or rapid weight loss may also enhance the outcomes of assisted reproductive technologies (ART), including in vitro fertilization (IVF). A multicenter retrospective study showed that women with a history of bariatric surgery achieved comparable cumulative live birth rates to non-surgical controls when matched for age and BMI [23]. This improvement was thought to stem not only from normalization of the hypothalamic–pituitary–ovarian axis, but also from reductions in systemic inflammation and endocrine dysregulation associated with obesity [24]. These associations remain correlative; mechanistic confirmation from controlled prospective cohorts is still lacking.

Beyond hormonal rebalancing, bariatric surgery or rapid weight loss through very low-calorie or restrictive diets have been associated with modulation of adipokines, such as leptin and adiponectin, which are closely linked to reproductive dysfunction. This leads to decreased leptin levels, which may restore gonadotropin-releasing hormone pulsatility and downstream luteinizing hormone secretion, thereby promoting folliculogenesis and ovulation [25]. The surgery-induced decline in inflammatory cytokines, particularly interleukin-6 and tumor necrosis factor-alpha, has been correlated with improvements in endometrial receptivity and embryo implantation potential [26]. The anatomical and absorptive changes introduced by these procedures warrant careful preconceptional counseling.

The risk of persistent deficiencies, particularly in iron, folic acid, and vitamin B12, remained substantial, even with adherence to supplementation protocols. These micronutrient deficiencies have been implicated in impaired DNA synthesis, abnormal oocyte maturation, and neural tube defects [27]. For this reason, international guidelines emphasize the importance of thorough nutritional assessment and individualized care prior to conception in women with a history of bariatric surgery or rapid weight loss through very low-calorie or restrictive diets [28].

Early conception may increase the risk of small-for-gestational-age infants, which can be mitigated by delaying pregnancy and ensuring proper nutrition. Bariatric surgery or rapid weight loss through very low-calorie or restrictive diets were also linked to lower risks of gestational diabetes, preeclampsia, and cesarean delivery. Breast milk composition appeared unaffected, though further research is needed. Optimal outcomes required specialized prenatal care and consistent micronutrient supplementation [29].

Importantly, given the lipophilic nature of many endocrine-disrupting chemicals, rapid weight loss may transiently elevate circulating pollutant concentrations, potentially modifying ovarian and endometrial responses to toxic exposure. This concept supports interpreting post-surgical fertility improvements within a broader environmental health framework. While bariatric surgery showed strong potential in fertility care, consistent research methods and thorough multidisciplinary follow-up are essential to ensure safe and effective outcomes [30].

Obesity negatively affects reproductive health, but bariatric surgery or rapid weight loss through very low-calorie diets has proven effective in promoting long-term weight loss and improving fertility outcomes. In women, this intervention enhances hormonal balance and increases both spontaneous conception and ART success rates. In men, weight loss improves sexual function and hormone levels, though its impact on sperm quality remains unclear [31] (

Table 1. (a) Pathophysiological mechanisms linking obesity to female infertility. (b) Restorative effects after bariatric surgery or rapid weight loss.

(a)
Pathophysiological Mechanism	Impact in Obese Women	Reference
Hypothalamic–Pituitary–Ovarian Axis	Disrupted GnRH pulsatility, altered LH/FSH secretion	Practice Committee of the American Society for Reproductive Medicine. Electronic address: asrm@asrm.org; Practice Committee of the American Society for Reproductive Medicine. Obesity and reproduction: a committee opinion. Fertil Steril. 2021 Nov;116(5):1266–1285. doi: 10.1016/j.fertnstert.2021.08.018. Epub 2021 Sep 25. PMID: 34583840 [18].
Hyperinsulinemia and Insulin Resistance	Increased ovarian androgens, decreased SHBG, hyperandrogenism	Cena H, Chiovato L, Nappi RE. Obesity, Polycystic Ovary Syndrome, and Infertility: A New Avenue for GLP-1 Receptor Agonists. J Clin Endocrinol Metab. 2020 Aug 1;105(8):e2695–709. doi: 10.1210/clinem/dgaa285. PMID: 32442310; PMCID: PMC7457958 [13].
Adipokine imbalance	Elevated leptin resistance, low adiponectin → impaired folliculogenesis and oocyte quality	Merhi Z, Bazzi AA, Bonney EA, Buyuk E. Role of adiponectin in ovarian follicular development and ovarian reserve. 1(1):1–5. doi: 10.3892/br.2019.1213. PMID: 31258901; PMCID: PMC6566571 [11].
Oxidative stress and inflammation	Mitochondrial dysfunction, ROS accumulation → granulosa cell apoptosis, poor oocyte quality	Sasaki H, Hamatani T, Kamijo S, Iwai M, Kobanawa M, Ogawa S, Miyado K, Tanaka M. Impact of Oxidative Stress on Age-Associated Decline in Oocyte Developmental Competence. Front Endocrinol (Lausanne). doi: 10.3389/fendo.2019.00811. PMID: 31824426; PMCID: PMC6882737 [12].
Anovulation and menstrual irregularity	Chronic anovulation, PCOS-like symptoms	Cena H, Chiovato L, Nappi RE. Obesity, Polycystic Ovary Syndrome, and Infertility: A New Avenue for GLP-1 Receptor Agonists. J Clin Endocrinol Metab. 2020 Aug 1;105(8):e2695–709. doi: 10.1210/clinem/dgaa285. PMID: 32442310; PMCID: PMC7457958 [13].
Altered hormone profiles	Lower AMH, altered kisspeptin, estrogen/progesterone imbalance	Lu FF, Wang Z, Yang QQ, Yan FS, Xu C, Wang MT, Xu ZJ, Cai SY, Guan R. Investigating the metabolomic pathways in female reproductive endocrine disorders: a Mendelian randomization study. Front Endocrinol (Lausanne). 2024 Oct 31;15:1438079. doi: 10.3389/fendo.2024.1438079. PMID: 39544240; PMCID: PMC11560792 [15].
Impaired ART outcomes	Lower oocyte yield, poor embryo quality, reduced implantation and live birth rates	Nilsson-Condori E, Mattsson K, Thurin-Kjellberg A, Hedenbro JL, Friberg B. Outcomes of in vitro fertilization after bariatric surgery: a national register-based case–control study. Hum Reprod. 2022 Sep 30;37(10):2474–2481. doi: 10.1093/humrep/deac164. PMID: 35904469; PMCID: PMC9527453 [2].
Endometrial dysfunction	Impaired receptivity due to inflammation and leptin signaling	BLu FF, Wang Z et al. Front Endocrinol (Lausanne). 2024;15:1438079. PMID: 39544240ellver J et al., Fertil Steril. 2021;115(6):1453–1463. doi:10.1016/j.fertnstert.2021.03.003 [15]
Pregnancy outcomes	Increased risk of infertility, miscarriage, preeclampsia, cesarean delivery	Almutairi H, Aldhalea MS, Almaaz MA, Aljuhani SA, Aloraini RI, Alamoudi AA, Alkhalifah WF, Alrushaid LA, Alanzy HW, Alzuwayyid M, Alrumaih FA, Al-Harbi MM, Al-Aboudi AA, Alqadi FS, Alshammari RS. The Effectiveness of Bariatric Surgery on Treating Infertility in Women-A Systematic Review and Meta-Analysis. J Clin Med. 2024 Sep 19;13(18):5569. doi: 10.3390/jcm13185569. PMID: 39337056; PMCID: PMC11433424 [1].
(b)
Pathophysiological Mechanism	Effect After Bariatric Surgery or Rapid Weight Loss	Reference
Hypothalamic–Pituitary–Ovarian axis	Restoration of GnRH pulsatility and hormonal balance; resumption of ovulatory cycles	Samarasinghe SNS, Leca B, Alabdulkader S, Dimitriadis GK, Davasgaium A, Thadani P, Parry K, Luli M, O’Donnell K, Johnson B, Abbara A, Seyfried F, Morman R, Ahmed AR, Hakky S, Tsironis C, Purkayastha S, le Roux CW, Franks S, Menon V, Randeva H, Miras AD. Bariatric surgery for spontaneous ovulation in women living with polycystic ovary syndrome: the BAMBINI multicentre, open-label, randomized controlled trial. Lancet. 2024 Jun 8;403(10443):2489–2503. doi: 10.1016/S0140-6736(24)00538-5. Epub 2024 May 20. PMID: 38782004 [4].
Hyperinsulinemia and insulin resistance	Improved insulin sensitivity, decreased androgen excess, normalized SHBG	Cena H, Chiovato L, Nappi RE. Obesity, Polycystic Ovary Syndrome, and Infertility: A New Avenue for GLP-1 Receptor Agonists. J Clin Endocrinol Metab. 2020 Aug 1;105(8):e2695–709. doi: 10.1210/clinem/dgaa285. PMID: 32442310; PMCID: PMC7457958 [13].
Adipokine imbalance	Decreased leptin levels, increased adiponectin → improved folliculogenesis	Merhi Z, Bazzi AA, Bonney EA, Buyuk E. Role of adiponectin in ovarian follicular development and ovarian reserve. Biomed Rep. 1(1):1–5. PMID: 31258901 [11]
Oxidative stress and inflammation	Reduced systemic inflammation and oxidative stress → improved oocyte quality and endometrial receptivity	Choromańska B, Myśliwiec P, Łuba M, Wojskowicz P, Dadan J, Myśliwiec H, Choromańska K, Zalewska A, Maciejczyk M. A Longitudinal Study of the Antioxidant Barrier and Oxidative Stress in Morbidly Obese Patients after Bariatric Surgery. Does the Metabolic Syndrome Affect the Redox Homeostasis of Obese People? J Clin Med. 2020 Apr 1;9(4):976. doi: 10.3390/jcm9040976. PMID: 32244612; PMCID: PMC7230760 [32].
Anovulation and menstrual irregularity	Regularized menstrual cycles and restored spontaneous ovulation	Samarasinghe SNS et al. Lancet. 2024;403(10443):2489–2503. PMID: 38782004 [4]
Altered hormone profiles	Improved AMH levels and hormonal regulation	Lu FF, Wang Z, Yang QQ, Yan FS, Xu C, Wang MT, Xu ZJ, Cai SY, Guan R. Investigating the metabolomic pathways in female reproductive endocrine disorders: a Mendelian randomization study. Front Endocrinol (Lausanne). 2024 Oct 31;15:1438079. doi: 10.3389/fendo.2024.1438079. PMID: 39544240; PMCID: PMC11560792 [15].
ART outcomes	Enhanced ART success rates comparable to BMI-matched controls	Nilsson-Condori E, Mattsson K, Thurin-Kjellberg A, Hedenbro JL, Friberg B. Outcomes of in vitro fertilization after bariatric surgery: a national register-based case–control study. Hum Reprod. 2022 Sep 30;37(10):2474–2481. doi: 10.1093/humrep/deac164. PMID: 35904469; PMCID: PMC9527453 [2].
Endometrial function	Improved receptivity; enhanced embryo implantation	Lu FF, Wang Z et al. Front Endocrinol (Lausanne). 2024;15:1438079. PMID: 39544240 [15]
Micronutrient status	Risk of iron, B12, folate, zinc, vitamin D deficiencies → requires close follow-up	Berardi G, Vitiello A, Abu-Abeid A, Schiavone V, Franzese A, Velotti N, Musella M. Micronutrients Deficiencies in Candidates of Bariatric Surgery: Results from a Single Institution over a 1-Year Period. Obes Surg. 2023 Jan;33(1):212–218. doi: 10.1007/s11695-022-06355-8. Epub 2022 Nov 4. PMID: 36331725; PMCID: PMC9834098 [33].
Pregnancy outcomes	Lower preeclampsia rates post-surgery; small-for-gestational-age risk if conception occurs too early	Almutairi H et al. The Effectiveness of Bariatric Surgery on Treating Infertility in Women. J Clin Med. 2024;13(18):5569. PMID: 39337056 [1]

) (human clinical and observational studies). Overall, metabolic recovery represents a key modifier of environmental susceptibility, warranting integrated assessment of both pollutant exposure and metabolic state in reproductive medicine.

3.1.3. Environmental Factors Relevant to Fertility (Table 2)

Female fertility is influenced by a variety of endogenous and exogenous factors, among which environmental exposures play an increasingly documented role. In recent years, research has focused on how air pollutants, endocrine disruptors, heavy metals, tobacco, and emerging contaminants (such as microplastics) interfere with reproductive physiology, with direct effects on oocytes, hormonal axis, embryonic development, and implantation success. These associations are supported by evidence from human observational cohorts and mechanistic in vitro studies [34].

Air pollution, in particular exposure to fine particulate matter (PM_2.5), nitrogen dioxide (NO₂), and ozone (O₃), has been associated with decreased fecundability and poorer outcomes in assisted reproductive technology. Epidemiological cohort studies have demonstrated that higher levels of PM_2.5 and NO₂ were inversely correlated with live birth rates, even after adjusting for confounders such as age and BMI. Proposed mechanisms include systemic inflammation, endothelial dysfunction, and epigenetic alterations in ovarian and endometrial tissue, supported by human mechanistic and in vitro studies [35].

Endocrine-disrupting chemicals, including bisphenol A (BPA), phthalates, and perfluoroalkyl substances (PFAS) are ubiquitous in plastic packaging, cosmetics, food containers, or textiles. These substances may exhibit estrogenic or antiandrogenic activity and can disrupt the hypothalamic–pituitary–ovarian axis. Several clinical studies reported that elevated urinary concentrations of endocrine-disrupting chemicals metabolites and lower antral follicle count lead to reduced anti-Müllerian hormone levels and impaired oocyte quality in IVF patients [36,37].

Heavy metals such as cadmium, lead, and mercury accumulate in ovarian tissue and induce oxidative stress, DNA damage, and mitochondrial dysfunction. A case–control study among infertile women revealed significantly higher cadmium concentrations in women with diminished ovarian reserve, correlating with decreased fertilization rates [38]. Cadmium and lead interfere with follicular development by inhibiting aromatase expression and disturbing oestradiol synthesis, potentially leading to anovulation, a mechanism supported by human in vitro and cohort studies [3].

Emerging contaminants, particularly microplastics, represent a novel threat to reproductive health. Recent human cohort data have confirmed the presence of microplastic fragments in human follicular fluid. Their presence raises concerns regarding direct physical and biochemical interactions with maturing oocytes. These particles may serve as carriers for endocrine-disrupting chemical and heavy metals, amplifying their local toxic potential. Experimental models demonstrated that exposure to polystyrene particles disrupts spindle formation and meiotic progression in mammalian oocytes [39] (animal and in vitro models, with preliminary human clinical detection).

Lifestyle-related environmental factors such as active and passive tobacco smoke exposure, also exerted significant negative effects on female fertility. Cigarette smoke contains over 7000 chemicals, including known reproductive toxicants. These can lead to impaired ovarian vascularization, accelerated follicular atresia, and increased aneuploidy rates in oocytes, as shown in human epidemiological and mechanistic in vitro studies [40].

While current smoking status (active or passive) was not universally linked to reduced ovarian reserve, a dose-dependence has been observed. Each additional cigarette smoked daily, and greater cumulative exposure (pack-years), increases the odds of diminished ovarian reserve, particularly among non-PCOS women and long-term smokers. Smoking thus remains a major risk factor for impaired fertility and earlier menopause, as well as for adverse maternal-fetal outcomes. Smoking cessation before conception is strongly recommended [41,42,43]

Although e-cigarettes are marketed as safer alternatives, they also contain harmful substances including nicotine and toxic compounds from flavorings that may negatively impact fertility. Animal studies raised concerns about their reproductive effects, but human data were limited. Given the increasing use of e-cigarettes, more research is needed, and caution is advised regarding their impact on reproductive health (animal studies and limited human observational reports) [44].

Taken together, the cumulative burden of environmental exposures may be particularly deleterious in women with pre-existing metabolic or endocrine vulnerability such as those with a history of bariatric surgery or rapid weight loss. These conditions may modify susceptibility to environmental toxicants by altering metabolic clearance, hormonal balance, or micronutrient availability, a hypothesis supported by human cohort observations and mechanistic reasoning.

3.1.4. Presence of Microplastics in Follicular Fluid

A recent study revealed for the first time the presence of microplastics (MP < 10 µm) in follicular fluid of women undergoing in vitro fertilization (n = 18), with a mean concentration of ~2 191 particles/mL found in 14 of 18 samples [3] (human clinical cohort). Complementary in vitro studies demonstrated that comparable concentrations of microplastics impair bovine oocyte maturation and alter proteomic profiles related to oxidative stress and DNA integrity (animal and in vitro studies). These findings introduced a new dimension to female reproductive toxicology. While these findings in bovine models provide mechanistic insights, their direct translation to human reproductive outcomes remains to be confirmed. Given that follicular fluid mediates oocyte development, the intrusion of microplastics and their potential to carry endocrine-disrupting chemicals into the ovarian microenvironment raised concerns regarding possible effects on oocyte competency and subsequent fertilization rates, a hypothesis based on human clinical detection and animal mechanistic data [45].

Micro and nanoplastics (MNPs) are emerging environmental pollutants that may severely impair female fertility. Animal studies show that MNP exposure is associated with damaged ovarian function, reduced follicle count, disrupted hormonal balance, and may influence fetal development. MNPs have been detected in human placenta, breast milk, and infant tissues (human observational data), raising concerns about reproductive and generational health. Further research is needed to understand their full impact on human fertility (animal and limited human observational data) [46].

A recent animal study detected microplastics in the placenta and fetuses of pregnant cats at early gestational stages. The findings suggested that microplastics can cross the placental barrier and accumulate in fetal tissues, highlighting potential early exposure risks during pregnancy [47].

3.1.5. Microplastics, Endocrine Disruptors and Oocyte Quality

Microplastics can act as vectors for toxicants, potentially carrying endocrine-disrupting chemicals into ovarian tissue (human and mechanistic studies tagged consistently). Studies show that high affinity exists between polystyrene particles and EDCs, suggesting a “Trojan horse” mechanism whereby microplastics may introduce pollutants directly into ovarian tissue. In vitro exposure to polyethylene microplastics has been associated with elevated expression of inflammation related genes and increased reactive oxygen species in follicular cells, which may impair oocyte quality (animal and in vitro studies, evidence tagged consistently) [48].

A recent study demonstrated the presence of microplastics in human follicular fluid—human observational study (first evidence of direct human detection) and investigated their effects on oocyte maturation. Functional tests in mice showed that smaller particles can enter the oocytes, while larger particles remained attached to the outside (animal mechanistic study). While these findings are based on in vitro and animal models, they provide mechanistic insights; their direct translation to human reproductive outcomes remains uncertain. All types of microplastics tested were associated with significantly affected oocyte maturation. These findings suggest that microplastic contamination in human follicular fluid may negatively impact female fertility by disrupting oocyte development [49].

Endocrine-disrupting chemicals were increasingly recognized as threats to human reproduction because they interfere with the hormone signaling essential for conception and maintenance of pregnancy. These chemicals are thought to act by disrupting hormone receptors, signaling pathways, epigenetics, and hormone metabolism. Persistent chemicals continue to be detected in ovarian follicular fluid, indicating ongoing exposure of oocytes. Associations between their presence and poorer outcomes in assisted reproductive technologies have been reported. These observations highlight an urgent need for further research to confirm causal links and to inform evidence-based regulatory policies to reduce exposure and protect reproductive health (human clinical and observational studies) [50].

3.1.6. Rapid Weight Loss Improves Fertility but Introduces Oxidative and Toxicant Vulnerability

Multiple systematic reviews and meta-analyses confirmed that rapid weight loss, through intensive interventions such as very low-calorie diets or medically supervised programs, is associated with significant enhancement of fertility in obese women (human clinical and meta-analytic studies). A comprehensive meta-analysis (n = 231) reported improved conception rates following substantial weight reduction (human clinical cohort) [20]. A 2024 PMC study (n = 444) corroborated improvements in hormonal profiles, menstrual regularity, and spontaneous pregnancies within 12 months after rapid weight loss (human observational study). These findings position controlled, significant weight reduction as an effective intervention for obesity-related reproductive dysfunction, with evidence primarily from human studies [1].

Rapid adipose tissue catabolism may mobilize stored lipophilic toxicants, including EDCs and PFAS, potentially leading to transient elevations in circulation and exposure to ovarian fluid (mechanistic reasoning based on human and animal data). No measurements of serum or follicular toxicant levels post weight loss exist, highlighting a knowledge gap. Such interventions may also predispose to deficiencies in key micronutrients (iron, folate, B12, vitamin D, and zinc) that are essential for antioxidant enzyme function. These deficiencies may heighten oxidative damage in ovarian tissues if toxic exposures occur concomitantly [33,51].

A systematic review and meta-analysis examined how rapid weight loss affects maternal health in the periconceptional period and its implications for reproduction. Analyzing 51 studies, the authors found that substantial weight reduction is associated with improved fertility by restoring hormonal balance and menstrual regularity (human clinical studies). It also increased the risk of vitamin deficiencies due to rapid weight loss, which can affect maternal and fetal health. The review highlighted the need for tailored preconception care following rapid weight reduction, including delaying pregnancy until weight stabilizes and vitamin levels are corrected. Regular monitoring and supplementation are recommended, and long-term follow-up is essential to optimize reproductive outcomes after rapid weight loss [52].

A prospective study investigated the effects of rapid weight loss on hormonal and clinical parameters in 67 obese women evaluated before and at 3 and 6 months after intensive weight reduction. Significant weight loss was observed, especially in the first 3 months, along with marked hormonal changes. Androstenedione and total testosterone levels decreased, while SHBG, AMH, and DHEA-S increased. No significant changes in FSH and LH were observed. Clinically, the prevalence of hirsutism and polycystic ovarian morphology decreased, and dysmenorrhea improved. These findings indicate that rapid weight reduction is associated with improvements in hormonal balance and reproductive health in women with obesity (human clinical cohort) [53].

3.1.7. PFAS Compounds: Links to Reduced Fecundability and Time to Pregnancy

Perfluoroalkyl substances (PFOA, PFOS, and PFNA) accumulated in adipose tissue and persist in circulation. A prospective cohort study reported that increasing PFAS quartiles were associated with lower fecundability, although exact effect sizes depend on study design and sample size (human clinical cohort). PFDA and PFOS were associated with reduced clinical pregnancy and live birth odds (human observational study) [54]. Earlier research in European populations confirmed associations between PFAS exposure and prolonged time to pregnancy. Mechanistic studies implicated PFAS in disrupting steroidogenesis and endometrial function (animal and in vitro mechanistic studies) [55].

It is plausible that PFAS sequestered in adipose tissue may be mobilized during rapid fat loss, transiently increasing serum PFAS exposure and potentially affecting ovarian function or early embryonic development (hypothesis supported by mechanistic reasoning).

In women, PFAS have been associated with a disrupted hypothalamic–pituitary axis, decreased FSH and LH levels, affected folliculogenesis, and reduced oocyte quality (human observational and mechanistic studies). In men, PFAS exposure has been associated with adverse effects on sperm motility and morphology, testosterone production, and essential processes such as capacitation and acrosome response. PFAS also compromised post fertilization embryonic development. The published studies strengthen the evidence that PFAS exposure is associated with impaired gamete function and fertilization potential, highlighting their significant threat to human reproductive health (human observational and mechanistic studies) [56].

A cross-sectional study examined the impact of serum PFAS exposure on pregnancy and live birth rates in US women aged 20–50 years. Six PFAS compounds were analyzed, adjusting for demographic and reproductive factors. All models showed negative associations between PFAS levels and the number of pregnancies and live births, with Perfluorononanoic acid (PFNA) showing the strongest effect (human clinical cohort). These findings highlight that PFAS exposure is associated with reduced reproductive outcomes in women of reproductive age (human observational data) [57].

3.1.8. Ambient Air Pollution Impairs Ovarian Reserve and ART Outcomes

Fine particulate matter (PM_2.5) and nitrogen oxides (NO₂/NOₓ) were repeatedly associated with reduced ovarian reserve. A large human cohort (n = 2212) reported that PM_2.5 exposure during critical follicle development stages was associated with lower AMH and antral follicle count (human clinical cohort) [58]. Independent retrospective analysis of frozen embryo transfers indicated that women in the highest quartile of PM_2.5 exposure before oocyte retrieval had a 34% reduction in live birth odds, while PM₁₀ exposure 2 weeks pre retrieval was associated with a 38% reduction (human IVF cohort) [59]. In adolescent patients experiencing rapid weight loss, elevated air pollution may attenuate some metabolic benefits. Similar suppressive effects on reproductive recovery in adults undergoing rapid weight reduction remain unknown and unstudied [6].

The impact of air pollution on ovarian reserve, as measured by anti-Müllerian hormone (AMH) levels, was assessed. Exposure to PM₁, PM_2.5, PM₁₀, and NO₂ during early follicular development windows was associated with AMH reductions of up to 8.8% for each 10 μg/m³ increase (human observational cohort). Women from inland areas and those with low education appeared more vulnerable (human observational cohort). These results suggested that fine particulate matter and NO₂ negatively affect ovarian reserve, especially during early folliculogenesis [60].

Increased exposure to PM_2.5 and its specific chemical components, particularly ammonium (NH₄⁺), nitrate (NO₃⁻), and sulfate (SO₄²⁻), was associated with decreased anti-Müllerian hormone levels, indicating a diminished ovarian reserve (human observational study, confounders adjusted for age and BMI). The associations were more pronounced in women under 35 years of age, those living in urban areas, and during the cold season. These findings suggest that PM_2.5 and its constituents negatively affected female reproductive potential (human observational evidence) [61].

A retrospective study analyzed 16,290 IVF cycles and found that ambient air pollutants were associated with lower live birth rates in frozen embryo transfer cycles, but not in fresh transfers (human clinical cohort). Women at the highest level of SO₂ and O₃ exposure had significantly reduced chances of live birth. These findings suggested that embryos in frozen embryo transfer cycles may be more sensitive to ambient air quality, and seasonal or regional fluctuations in success rates may be partly driven by variations in ambient pollution levels (human clinical evidence) [62].

In the 5354 women undergoing ART treatment in one study, exposure to PM₁, PM_2.5, PM₁₀, SO₂, and NO₂ was associated with a lower number of antral follicles and a reduced likelihood of live birth (human clinical cohort, confounders considered). The analysis showed that the decrease in antral follicles partially explained the negative effect of pollutants, particularly NO₂ and SO₂. The results also suggested that air pollution may affect the success of fertility treatment by reducing ovarian reserve (human clinical cohort) [63].

In another study involving 194 women who underwent 486 embryo transfers, exposure to particulate matter showed trends toward higher miscarriage and lower clinical pregnancy rates, with significant risks particularly for PM exposure three days prior to transfer (human IVF clinical study). Subacute exposure may exacerbate these effects. Overall, particulate matter negatively affected IVF reproductive outcomes (human IVF clinical study) [35].

3.1.9. Synergy of Oxidative Stress and Micronutrient Deficiency

Rapid weight loss and associated nutrient deficiencies can compromise cellular antioxidant systems, including glutathione, catalase, superoxide dismutase, and glutathione peroxidase, leading to impaired DNA repair and increased oxidative vulnerability. Studies in individuals with obesity experiencing rapid adipose tissue reduction showed pre-existing low levels of superoxide dismutase and glutathione, along with elevated markers of lipid (8-isoprostanes) and protein oxidation (advanced oxidation protein products, AOPP); partial recovery may occur over time, but antioxidant capacity can remain attenuated, especially in those with prior metabolic dysfunction (human clinical observational studies, confounders considered) [32].

Environmental pollutants such as PFAS, PM_2.5, and microplastics are associated with increased reactive oxygen species production. Mouse oocytes exposed in vitro to PFOS, PFOA, PFHxS, and PFNA exhibited significant increases in ROS levels, mitochondrial dysfunction, and chromosomal or spindle abnormalities (animal and in vitro mechanistic studies) [64]. Similarly, studies showed PM_2.5 exposure prior to pregnancy leads to increased ROS production in oocytes and reduced litter size (in vitro animal studies) [65].

Collectively, these findings confirm that pollutant-induced oxidative stress is associated with disruption of oocyte structure and reproductive success. The potential synergy whereby oxidative insult from environmental pollutants overlays on a backdrop of reduced micronutrient-mediated antioxidant defense remains a hypothesis requiring prospective validation (mechanistic reasoning, human relevance implied) [66].

3.1.10. Postoperative PFAS Redistribution into Circulation

Longitudinal observations of plasma PFAS (including PFHxS and PFOS) during periods of rapid weight loss showed a transient increase or plateau in circulating levels during the first few months, followed by a gradual decline over subsequent months (human clinical cohort, metabolic intervention) [67].

These kinetics suggest a potential window during active adipose tissue catabolism when ovarian follicular fluid could be exposed to elevated PFAS concentrations, although no studies have yet directly measured follicular PFAS levels in women undergoing rapid weight loss.

3.1.11. Microplastics Induce Ovarian Oxidative Injury In Vivo

In a 2021 rat model, oral polystyrene microplastics caused granulosa cell apoptosis, ovarian fibrosis, and reduced AMH, mediated by oxidative stress activation, as evidenced through flow cytometry and histology—animal in vivo mechanistic study [68]. These findings demonstrate that environmental microplastics alone are associated with damage to ovarian structures; in humans, such effects remain speculative and require dedicated clinical confirmation.

Exposure to polystyrene microplastics in female rats for 90 days reduced growing ovarian follicles and antioxidant enzyme activities, while increasing oxidative stress markers. Elevated inflammation and cell death in ovarian granulosa cells occurred. These findings suggest that microplastics are associated with ovarian cell apoptosis, posing a potential risk for female infertility (animal in vivo mechanistic study) [69].

It was found that polystyrene microplastics accumulated in the ovaries of mice after 35 days of exposure, causing an increase in follicular atresia and granulosa cell apoptosis. Mitochondrial abnormalities, disrupted spindle integrity, increased ROS, and a lower number of oocytes per ovulatory cycle were observed. Exposed females showed reduced fertility. An in vitro follicular culture system was developed to assess reproductive toxicity. This study demonstrated that microplastics are associated with impaired ovarian function and highlights the mechanisms underlying female reproductive toxicity (animal in vivo and in vitro mechanistic studies) [70]. Although these in vivo rodent studies demonstrate potential ovarian toxicity, translation to human fertility should be interpreted cautiously (knowledge gap, human extrapolation), and further clinical studies are warranted.

Polystyrene microplastics negatively affected the female reproductive system, causing enlarged ovaries with fewer follicles, reduced follicle production, embryo retrieval, and decreased pregnancy rates in mice. They disrupted the balance of sex hormones and induced oxidative stress, affecting fertility. In addition, they affected ovarian reserve, oocyte maturation, and oocyte quality. In marine animals, they disrupted the hypothalamic–pituitary–gonadal axis, reducing hatching rates and offspring size, causing transgenerational reproductive effects. This evidence highlighted the key mechanisms by which PS-MPs affect female reproduction, with clear distinctions between animal and marine species mechanistic studies (animal and marine mechanistic evidence) [71] (Figure 1).

Table 2. Evidence-map of environmental and metabolic factors affecting female fertility.

Exposure	Outcome	Direction of Effect	Design/N	Key Confounders	Certainty
Obesity	Infertility, ovulatory dysfunction, ↓ ovarian reserve	Negative	Human cohorts (n > 500)	Age, PCOS, lifestyle	High	Practice Committee of the American Society for Reproductive Medicine. Electronic address: asrm@asrm.org; Practice Committee of the American Society for Reproductive Medicine. Obesity and reproduction: a committee opinion. Fertil Steril. 2021 Nov;116(5):1266–1285. doi: 10.1016/j.fertnstert.2021.08.018. Epub 2021 Sep 25. PMID: 34583840 [18].
Bariatric surgery or Rapid weight loss	↑ Ovulation, ↑ spontaneous conception, ↑ ART outcomes; transient toxicant exposure	Positive	Human clinical meta-analysis (n = 231–444)	Age, BMI, nutrition	High (fertility), Moderate (toxicant)	Choromańska B, Myśliwiec P, Łuba M, Wojskowicz P, Dadan J, Myśliwiec H, Choromańska K, Zalewska A, Maciejczyk M. A Longitudinal Study of the Antioxidant Barrier and Oxidative Stress in Morbidly Obese Patients after Bariatric Surgery. Does the Metabolic Syndrome Affect the Redox Homeostasis of Obese People? J Clin Med. 2020 Apr 1;9(4):976. doi: 10.3390/jcm9040976. PMID: 32244612; PMCID: PMC7230760 [32].
PFAS (PFOA, PFOS, PFNA, PFDA)	↓ Fecundability, ↓ live birth, impaired oocyte quality	Negative	Prospective and cross-sectional human cohorts	Age, BMI, parity, lifestyle, metabolic status	Moderate–High	Rickard BP, Rizvi I, Fenton SE. Per- and poly-fluoroalkyl substances (PFAS) and female reproductive outcomes: PFAS elimination, endocrine-mediated effects, and disease. Toxicology. 2022 Jan 15;465:153031. doi: 10.1016/j.tox.2021.153031. Epub 2021 Nov 10. PMID: 34774661; PMCID: PMC8743032 [55].
Air pollutants (PM1, PM2.5, PM10, NO2, SO2, O3)	↓ AMH, ↓ AFC, ↓ ART success	Negative	Human IVF studies (n = 194–16,290)	Age, BMI, geography	High	Huang K, Hu M, Zhang Z, Li Z, Hu C, Bai S, Li R, Wu LM, Zhang XJ, Xu B. Associations of ambient air pollutants with pregnancy outcomes in women undergoing assisted reproductive technology and the mediating role of ovarian reserve: A longitudinal study in eastern China. Sci Total Environ. 2025 Jan 1;958:177919. doi: 10.1016/j.scitotenv.2024.177919. Epub 2024 Dec 9. PMID: 39657336 [63].
Endocrine-disrupting chemicals (BPA, phthalates, PFAS)	↓ AMH, ↓ AFC, impaired oocyte quality	Negative	Human clinical cohorts	Age, BMI, lifestyle	Moderate–High	Björvang RD, Damdimopoulou P. Persistent environmental endocrine-disrupting chemicals in ovarian follicular fluid and in vitro fertilization treatment outcome in women. Ups J Med Sci. 2020 May;125(2):85–94. doi: 10.1080/03009734.2020.1727073. Epub 2020 Feb 25. PMID: 32093529; PMCID: PMC7721012 [50].
Heavy metals (Cd, Pb, Hg)	↓ Ovarian reserve, ↓ fertilization	Negative	Human case–control and cohorts	Age, BMI, occupation, smoking	Moderate	Génard-Walton M, Warembourg C, Duros S, Ropert-Bouchet M, Lefebvre T, Guivarc’h-Levêque A, Le Martelot MT, Jacquemin B, Cordier S, Costet N, Multigner L, Garlantézec R. Heavy metals and diminished ovarian reserve: single-exposure and mixture analyses amongst women consulting in French fertility centers. Reprod Biomed Online. 2023 Sep;47(3):103241. doi: 10.1016/j.rbmo.2023.05.013. Epub 2023 Jun 2. PMID: 37451971 [38].
Microplastics	Detected in follicular fluid, impaired oocyte maturation	Negative	Human (n = 18), animal, in vitro	Age, BMI, exposures	Low–Moderate (human), High (mechanistic)	Jeong J, Thi Quynh Mai N, Moon BS, Choi JK. Impact of polystyrene microplastics (PS-MPs) on the entire female mouse reproductive cycle: Assessing reproductive toxicity of microplastics through in vitro follicle culture. Ecotoxicol Environ Saf. 2025 Jun 1;297:118228. doi: 10.1016/j.ecoenv.2025.118228. Epub 2025 May 1. PMID: 40315747 [70].
Tobacco smoke	↓ Ovarian reserve, ↑ miscarriage, impaired fertility	Negative	Human, in vitro studies	Age, BMI, lifestyle, comorbidities	High	Lyngsø J, Kesmodel US, Bay B, Ingerslev HJ, Pisinger CH, Ramlau-Hansen CH. Female cigarette smoking and successful fertility treatment: A Danish cohort study. Acta Obstet Gynecol Scand. 2021 Jan;100(1):58–66. doi: 10.1111/aogs.13979. Epub 2020 Sep 18. PMID: 32865819 [43].
Rapid weight loss, micronutrient deficiencies	↑ Oxidative stress in ovaries, mobilization of stored toxicants	Negative	Human clinical and prospective (n = 51–67)	Baseline BMI, micronutrients, lifestyle	Moderate	Brown RH, Ng DK, Steele K, Schweitzer M, Groopman JD. Mobilization of Environmental Toxicants Following Bariatric Surgery. Obesity (Silver Spring).27(11):1865–1873. doi: 10.1002/oby.22618. PMID: 31689012 [51].

Table 2. Evidence-map of environmental and metabolic factors affecting female fertility.

Exposure	Outcome	Direction of Effect	Design/N	Key Confounders	Certainty
Obesity	Infertility, ovulatory dysfunction, ↓ ovarian reserve	Negative	Human cohorts (n > 500)	Age, PCOS, lifestyle	High	Practice Committee of the American Society for Reproductive Medicine. Electronic address: asrm@asrm.org; Practice Committee of the American Society for Reproductive Medicine. Obesity and reproduction: a committee opinion. Fertil Steril. 2021 Nov;116(5):1266–1285. doi: 10.1016/j.fertnstert.2021.08.018. Epub 2021 Sep 25. PMID: 34583840 [18].
Bariatric surgery or Rapid weight loss	↑ Ovulation, ↑ spontaneous conception, ↑ ART outcomes; transient toxicant exposure	Positive	Human clinical meta-analysis (n = 231–444)	Age, BMI, nutrition	High (fertility), Moderate (toxicant)	Choromańska B, Myśliwiec P, Łuba M, Wojskowicz P, Dadan J, Myśliwiec H, Choromańska K, Zalewska A, Maciejczyk M. A Longitudinal Study of the Antioxidant Barrier and Oxidative Stress in Morbidly Obese Patients after Bariatric Surgery. Does the Metabolic Syndrome Affect the Redox Homeostasis of Obese People? J Clin Med. 2020 Apr 1;9(4):976. doi: 10.3390/jcm9040976. PMID: 32244612; PMCID: PMC7230760 [32].
PFAS (PFOA, PFOS, PFNA, PFDA)	↓ Fecundability, ↓ live birth, impaired oocyte quality	Negative	Prospective and cross-sectional human cohorts	Age, BMI, parity, lifestyle, metabolic status	Moderate–High	Rickard BP, Rizvi I, Fenton SE. Per- and poly-fluoroalkyl substances (PFAS) and female reproductive outcomes: PFAS elimination, endocrine-mediated effects, and disease. Toxicology. 2022 Jan 15;465:153031. doi: 10.1016/j.tox.2021.153031. Epub 2021 Nov 10. PMID: 34774661; PMCID: PMC8743032 [55].
Air pollutants (PM1, PM2.5, PM10, NO2, SO2, O3)	↓ AMH, ↓ AFC, ↓ ART success	Negative	Human IVF studies (n = 194–16,290)	Age, BMI, geography	High	Huang K, Hu M, Zhang Z, Li Z, Hu C, Bai S, Li R, Wu LM, Zhang XJ, Xu B. Associations of ambient air pollutants with pregnancy outcomes in women undergoing assisted reproductive technology and the mediating role of ovarian reserve: A longitudinal study in eastern China. Sci Total Environ. 2025 Jan 1;958:177919. doi: 10.1016/j.scitotenv.2024.177919. Epub 2024 Dec 9. PMID: 39657336 [63].
Endocrine-disrupting chemicals (BPA, phthalates, PFAS)	↓ AMH, ↓ AFC, impaired oocyte quality	Negative	Human clinical cohorts	Age, BMI, lifestyle	Moderate–High	Björvang RD, Damdimopoulou P. Persistent environmental endocrine-disrupting chemicals in ovarian follicular fluid and in vitro fertilization treatment outcome in women. Ups J Med Sci. 2020 May;125(2):85–94. doi: 10.1080/03009734.2020.1727073. Epub 2020 Feb 25. PMID: 32093529; PMCID: PMC7721012 [50].
Heavy metals (Cd, Pb, Hg)	↓ Ovarian reserve, ↓ fertilization	Negative	Human case–control and cohorts	Age, BMI, occupation, smoking	Moderate	Génard-Walton M, Warembourg C, Duros S, Ropert-Bouchet M, Lefebvre T, Guivarc’h-Levêque A, Le Martelot MT, Jacquemin B, Cordier S, Costet N, Multigner L, Garlantézec R. Heavy metals and diminished ovarian reserve: single-exposure and mixture analyses amongst women consulting in French fertility centers. Reprod Biomed Online. 2023 Sep;47(3):103241. doi: 10.1016/j.rbmo.2023.05.013. Epub 2023 Jun 2. PMID: 37451971 [38].
Microplastics	Detected in follicular fluid, impaired oocyte maturation	Negative	Human (n = 18), animal, in vitro	Age, BMI, exposures	Low–Moderate (human), High (mechanistic)	Jeong J, Thi Quynh Mai N, Moon BS, Choi JK. Impact of polystyrene microplastics (PS-MPs) on the entire female mouse reproductive cycle: Assessing reproductive toxicity of microplastics through in vitro follicle culture. Ecotoxicol Environ Saf. 2025 Jun 1;297:118228. doi: 10.1016/j.ecoenv.2025.118228. Epub 2025 May 1. PMID: 40315747 [70].
Tobacco smoke	↓ Ovarian reserve, ↑ miscarriage, impaired fertility	Negative	Human, in vitro studies	Age, BMI, lifestyle, comorbidities	High	Lyngsø J, Kesmodel US, Bay B, Ingerslev HJ, Pisinger CH, Ramlau-Hansen CH. Female cigarette smoking and successful fertility treatment: A Danish cohort study. Acta Obstet Gynecol Scand. 2021 Jan;100(1):58–66. doi: 10.1111/aogs.13979. Epub 2020 Sep 18. PMID: 32865819 [43].
Rapid weight loss, micronutrient deficiencies	↑ Oxidative stress in ovaries, mobilization of stored toxicants	Negative	Human clinical and prospective (n = 51–67)	Baseline BMI, micronutrients, lifestyle	Moderate	Brown RH, Ng DK, Steele K, Schweitzer M, Groopman JD. Mobilization of Environmental Toxicants Following Bariatric Surgery. Obesity (Silver Spring).27(11):1865–1873. doi: 10.1002/oby.22618. PMID: 31689012 [51].

4. Discussion

Female infertility in the context of severe obesity is associated with a multifactorial interplay of hormonal dysregulation, chronic low-grade inflammation, and oxidative stress. Interventions that promote weight reduction and metabolic improvement may contribute to reversing obesity-associated reproductive dysfunction. By enhancing insulin sensitivity, normalizing gonadotropin secretion, and reducing systemic inflammation, such interventions are associated with improvements in spontaneous ovulation and conception rates. However, the physiological changes accompanying rapid metabolic improvement may create new vulnerabilities that remain insufficiently studied.

Rapid adipose tissue catabolism associated with significant weight loss may mobilize lipophilic environmental pollutants, potentially affecting ovarian physiology. High rates of micronutrient deficiencies, specifically in iron, folate, vitamin B12, zinc, and vitamin D, can compromise antioxidant defenses and DNA integrity, rendering ovarian tissue more susceptible to environmental oxidative insults.

Current evidence indicates that exposure to air pollution, endocrine-disrupting chemicals, and microplastics is associated with diminished ovarian reserve, poor oocyte quality, impaired embryo development, and reduced success rates in assisted reproductive technologies. While these associations are consistently reported in human clinical cohorts, most mechanistic data come from animal or in vitro models and their direct translation to human reproductive outcomes should be interpreted cautiously. Although these effects are well documented in the general population, there remains a lack of clinical data specifically addressing how environmental exposures impact fertility outcomes in women undergoing rapid metabolic or nutritional changes.

In clinical practice, actionable recommendations based on human evidence include minimizing exposure to airborne pollutants through indoor air filtration and avoidance of high-pollution environments, reducing contact with plastic containers and packaging known to contain endocrine-disrupting chemicals (BPA, phthalates, and PFAS), encouraging cessation of active and passive tobacco exposure, ensuring adequate intake of micronutrients (iron, folate, vitamin B12, zinc, and vitamin D) through diet or supplementation, particularly in women undergoing rapid metabolic changes or post-bariatric surgery.

Future research could address this critical knowledge gap through dedicated prospective studies that integrate environmental exposure assessment, oxidative stress biomarker monitoring, and comprehensive reproductive evaluation in women undergoing significant metabolic or nutritional changes. Understanding these interactions is essential to developing preventive strategies, guiding preconception counseling, and optimizing fertility outcomes.

A rigorously designed prospective cohort study could enroll women experiencing rapid weight loss, with serial sampling at baseline, 6, 12, and 24 months for plasma and follicular PFAS levels, oxidative biomarkers, micronutrient panels, and reproductive markers. This longitudinal design would allow for dynamic monitoring of pollutant redistribution following rapid adipose tissue loss, capturing critical windows during which elevated circulating toxicants may influence ovarian reserve, oocyte quality, and subsequent fertility outcomes. By correlating environmental pollutant burdens with oxidative stress markers and micronutrient deficiencies, this study would address a current evidence gap regarding mechanistic pathways linking rapid weight loss to altered reproductive function.

Moreover, integrating comprehensive reproductive markers such as antral follicle count, anti-Müllerian hormone levels and clinical pregnancy outcomes would provide robust endpoints to evaluate the clinical relevance of biochemical changes. This framework also offers an opportunity to validate whether findings from experimental models are reproducible in human populations, guiding personalized fertility counseling and interventions.

Nutritional assessments and supplementation strategies embedded within the cohort could further clarify how micronutrient status modulates vulnerability to pollutant toxicity, potentially identifying modifiable factors to improve reproductive prognosis. This approach aligns with precision medicine principles, enabling tailored management plans that address the combined impact of environmental exposures and metabolic changes post-bariatric surgery.

Beyond individual patient care, the data generated could inform broader public health targeting environmental pollutant regulation, especially concerning reproductive-age women and vulnerable populations. Ultimately, this comprehensive clinical framework aims to inform evidence-based guidelines and preventive strategies, mitigate the reproductive risks associated with pollutant exposure in the context of rapid adipose tissue loss.

In clinical practice, assessing environmental exposures can be integrated into fertility counseling by evaluating patients’ occupational and residential histories, lifestyle factors, and potential contact with endocrine-disrupting chemicals or air pollutants. This information, combined with standard reproductive evaluations, can guide personalized recommendations for minimizing risks, optimizing timing of conception, and planning targeted nutritional or antioxidant interventions.

Nutritional assessment and appropriate supplementation remain key components of mitigating environmental risks. Ensuring adequate intake of micronutrients such as iron, folate, vitamin B12, zinc, and vitamin D supports antioxidant defenses and oocyte quality, particularly in women undergoing rapid metabolic changes or post-bariatric surgery. Incorporating these strategies into preconception care may enhance resilience against pollutant-induced oxidative stress.

Taken together, these considerations highlight the importance of a precision medicine approach, where reproductive counseling is tailored to the individual’s metabolic status, environmental exposures, and nutritional profile. Such an approach enables clinicians to provide actionable, evidence-informed guidance that addresses both the physiological and environmental determinants of fertility outcomes.

5. Conclusions

Air pollution (PM_2.5, NO₂, and O₃): Human epidemiological studies consistently associate higher exposure with lower ovarian reserve (AMH and AFC) and reduced live birth rates in ART (human observational studies). Mechanistic evidence from in vitro and animal models supports oxidative stress and endothelial dysfunction as potential underlying pathways (animal, in vitro mechanistic studies).

Endocrine-disrupting chemicals (BPA, phthalates, PFAS, and PCBs): Human cohort and IVF studies show associations with diminished ovarian reserve, impaired oocyte quality, and reduced fecundability (human observational IVF studies). Animal and in vitro studies provide mechanistic plausibility through steroidogenesis disruption and hormonal interference (animal/in vitro mechanistic studies).

Heavy metals (cadmium, lead, and mercury): Human observational studies report negative impacts on follicular development and fertilization outcomes, while in vitro and animal studies highlight oxidative stress and endocrine disruption as mechanisms.

Microplastics: Emerging human data detect microplastics in follicular fluid, suggesting potential reproductive risks (human observational study). Animal and in vitro studies indicate impaired oocyte maturation and oxidative injury, providing mechanistic support. Further human studies are needed to confirm clinical relevance.

Metabolic status and rapid weight loss: Rapid weight reduction and bariatric surgery are associated with improved ovulatory function and fertility outcomes (human clinical studies) but may transiently increase susceptibility to environmental toxicants due to mobilization of lipophilic compounds and micronutrient deficiencies (hypothesis based on mechanistic reasoning and observational data). Nutritional optimization is crucial to support antioxidant defenses and mitigate potential oxidative damage (human clinical guidance).

Overall, environmental exposures and metabolic status interact to influence female fertility, with the strongest human evidence for air pollution and PFAS, as well as emerging but biologically plausible concerns for microplastics. Clinical strategies should consider both reducing exposure and optimizing metabolic and nutritional status to support reproductive outcomes (evidence-informed recommendation).