Overview of tobacco and endometriosis

Several environmental factors, including reproductive, lifestyle and behavioral factors, have been linked to the etiology of endometriosis; however, the association with some of these factors remains inconclusive^9,12-14 . Many recent studies have reported and association between tobacco smoking and increased risk in endometriosis^15-17, whereas the authors of the latest meta-analysis published in 2014 concluded that there was no association between smoking and endometriosis ⁹. Nevertheless, the majority of the studies included in that meta-analysis were based on self-reports and provided crude estimates of association⁹. In contrast, a recent study, focused on more than 2 million women, has shown that women with both a family history of smoking and smoking themselves have higher risk of endometriosis than the general population (incidence rate ratio, IRR=4.28; 95% CI: 2.43–7.55)¹⁶. Among more than 500000 women, heavy tobacco users compared with never users presented a higher risk of endometriosis (summary relative risk=1.35; 95% CI: 1.15–1.59)¹⁸. Moreover, exposure to secondhand smoke during childhood due to maternal smoking was associated with increased odds of an endometriosis diagnosis (OR=2.70; 95% CI: 1.11–6.60)¹⁷.

Tobacco use encompasses smoking cigarettes, cigars, or pipes, as well as consuming smokeless tobacco products. The harmful effects of tobacco on human health are well documented, particularly its association with cardiovascular diseases¹⁹, respiratory conditions, and various cancers²⁰. However, the impact of tobacco on gynecological disorders like endometriosis is less widely known.

Molecular pathways involving tobacco smoking and leading to endometriosis

The association between tobacco smoking and endometriosis involves complex molecular pathways that contribute to the pathogenesis of the disease. Here, we provide detailed insights into the molecular pathways that connect tobacco smoking and endometriosis (Figure 1).

Figure 1

Molecular and cellular mechanisms involved in smoking-induced endometriosis

Inflammation

Tobacco smoke contains a wide array of toxic compounds that can initiate and sustain an inflammatory response in the body^21-23 (Table 1). These compounds include nicotine, carbon monoxide, polycyclic aromatic hydrocarbons (PAHs), and volatile organic compounds (VOCs)^24-26. When inhaled, these substances can directly activate immune cells and stimulate the release of pro-inflammatory cytokines, chemokines, and growth factors²¹.

Tobacco smoke components can activate immune cells in the pelvic cavity, including macrophages, neutrophils, and lymphocytes²⁷. Activation of these immune cells triggers the secretion of proinflammatory mediators, such as interleukin 1beta (IL-1β), IL-6, IL-8, and tumor necrosis factor alpha (TNF-α)^28,29. These cytokines play crucial roles in promoting inflammation, recruiting immune cells to the site of inflammation, and stimulating tissue remodeling processes³⁰.

The nuclear factor-kappa B (NF-κB) pathway is a central regulator of inflammation³¹. The components in tobacco can activate the NF-κB pathway³², leading to the transcriptional upregulation of various pro-inflammatory genes³³. NF-κB promotes the expression of cytokines, chemokines, adhesion molecules, and enzymes involved in the inflammatory response^34,35. This sustained activation of NF-κB perpetuates the inflammatory environment in endometriosis^36,37.

Tobacco smoke can stimulate the production of chemokines, such as IL-8 and monocyte chemoattractant protein-1 (MCP-1)^21,38. These chemokines attract leucocytes, including neutrophils and macrophages, to endometriotic lesions^39-41. The recruited immune cells contribute to the local inflammatory response and produce additional pro-inflammatory mediators, amplifying the inflammatory cascade⁴².

Tobacco can induce vascular permeability, leading to the leakage of plasma proteins and immune cells into the surrounding tissues⁴³. This increased vascular permeability facilitates the infiltration of inflammatory cells into endometriotic lesions, exacerbating the inflammatory response⁴⁴. Moreover, leakage of plasma proteins can further contribute to tissue inflammation and promote angiogenesis⁴⁵.

Various signaling pathways involved in inflammation can be induced by tobacco, including the mitogen-activated protein kinase (MAPK) pathway^46,47 and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway⁴⁸. These pathways regulate the expression of pro-inflammatory genes and modulate immune cell function⁴⁹. Activation of these pathways by tobacco smoke could contribute to the sustained inflammatory state in endometriosis⁵⁰.

Thus, the inflammatory response could be triggered by tobacco smoke can lead to a dysregulated cytokine network in endometriosis. Cytokines, such as IL-1β, TNF-α, and IL-6, can induce the production of other inflammatory mediators and promote the activation of immune cells²⁹. This cytokine crosstalk further amplifies the inflammatory cascade, perpetuating the chronic inflammatory environment in endometriotic lesions.

Oxidative stress

Tobacco contains a variety of toxic chemicals and free radicals that can generate reactive oxygen species (ROS) when inhaled^51,52 (Table 1). ROS, such as the superoxide anion (O2•^-), hydrogen peroxide (H₂O₂), and the hydroxyl radical (OH•), are highly reactive molecules that can cause oxidative damage to cellular components, including lipids, proteins, and DNA⁵³.

Oxidative stress induced by tobacco smoke overwhelms the body’s antioxidant defense mechanisms^52,54,55. Antioxidants, such as glutathione, superoxide dismutase (SOD), and catalase, neutralize ROS and protect cells from oxidative damage⁵⁶. However, tobacco smoke can deplete these antioxidants and impair their ability to counteract the excessive ROS production, leading to an imbalance between oxidative stress and the antioxidant capacity^57-59.

ROS generated by tobacco can initiate lipid peroxidation, a process that damages cell membranes and disrupts their integrity⁵². Lipid peroxidation products, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), can induce inflammation, impair cellular functions, and contribute to tissue damage⁶⁰. In endometriosis, lipid peroxidation can affect the viability and function of endometrial cells, exacerbating the disease^61,62.

Tobacco smoke-induced oxidative stress can impair mitochondrial function, including endometrial cells^63,64. Mitochondria are a major source of ROS production, and their dysfunction can lead to increased ROS generation^65,66. The compounds in tobacco can directly target mitochondria, disrupting their electron transport chain and impairing adenosine triphosphate (ATP) production^67,68. Mitochondrial dysfunction further exacerbates oxidative stress^69,70, perpetuating the cycle of oxidative damage and inflammation in endometriosis⁷¹.

ROS generated by tobacco can directly damage DNA in endometrial cells^72,73. This DNA damage includes DNA strand breaks, base modifications, and DNA adduct formation⁷⁴. Accumulated DNA damage can lead to genetic instability, mutations, and chromosomal aberrations in endometriotic lesions^75,76. The compromised DNA repair mechanisms in endometriosis may exacerbate the impact of tobacco smoke-induced DNA damage on disease progression⁷⁷.

Oxidative stress can activate various inflammatory signaling pathways in endometriosis^61,78,79. ROS can stimulate the NF-κB pathway, leading to the production of pro-inflammatory cytokines and chemokines⁸⁰. This activation of inflammatory pathways further amplifies the inflammatory response and contributes to the pathogenesis of endometriosis^81,82.

Tobacco smoke-induced oxidative stress can result in the oxidation and modification of proteins and enzymes involved in cellular functions^52,57. Oxidative modifications can disrupt protein structure and impair enzyme activity, changes that affect essential cellular processes⁸³. In endometriosis, oxidative stress can target proteins and enzymes involved in inflammation, hormone signaling, and tissue remodeling, further contributing to disease progression⁸⁴.

Hormonal dysregulation

Tobacco has been associated with alterations in estrogen levels, which play a crucial role in the development and maintenance of endometriosis^7,15,85 (Table 1). Smoking can decrease circulating estrogen levels by accelerating the metabolism and clearance of estrogen from the body⁸⁶. This estrogen imbalance can disrupt the normal endocrine environment, potentially promoting the growth and survival of endometrial tissue outside the uterus⁸⁷.

A decrease in progesterone levels has been linked by tobacco^88,89. Progesterone is an important hormone that helps regulate the menstrual cycle and maintain the endometrium⁸⁷. A decrease in progesterone levels may disrupt the balance between estrogen and progesterone, promoting the growth and proliferation of endometriotic lesions^90.

Androgen hormone levels can be modulated by tobacco⁹¹. Smoking has been associated with increased androgen production and alterations in androgen metabolism⁹². These changes in androgen levels can affect the growth and survival of endometrial tissue outside the uterus^93,94. Androgens, such as testosterone, can stimulate the growth of endometriotic lesions and contribute to the pathogenesis of endometriosis⁹⁵.

Tobacco contains numerous chemicals that can interact with hormone receptors, including estrogen receptors (ERs) and progesterone receptors (PRs)⁹⁶. These interactions can disrupt the normal signaling pathways regulated by these receptors. Altered receptor activation and signaling can affect gene expression patterns, leading to dysregulation of key genes involved in inflammation, cell proliferation, and tissue remodeling in endometriosis⁹⁷.

The compounds in tobacco can interfere with hormone-related signaling pathways involved in endometriosis. For example, smoking has been shown to modulate the insulin-like growth factor (IGF) signaling pathway, which plays a role in cell growth and survival^98,99. Dysregulation of hormone-related signaling pathways can contribute to the aberrant growth and survival of endometrial tissue in endometriosis¹⁰⁰.

Tobacco can affect the hypothalamic-pituitary-gonadal axis by influencing the secretion and function of gonadotropin-releasing hormone (GnRH)^98,101. GnRH is a key hormone that regulates the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)¹⁰². Disruption of GnRH signaling by smoking can lead to imbalances in LH and FSH levels, which can impact ovarian function and the menstrual cycle, potentially contributing to endometriosis development and progression⁹⁸.

Epigenetic modifications were associated with tobacco, including DNA methylation and histone modifications^103,104. Epigenetic changes can alter gene expression patterns without altering the DNA sequence itself¹⁰⁵. Smoking-induced epigenetic modifications can affect the expression of genes involved in hormonal regulation and contribute to hormonal dysregulation in endometriosis¹⁰⁴.

DNA damage and epigenetic modifications

Tobacco contains numerous harmful chemicals that can directly damage DNA¹⁰⁶ (Table 1). These chemicals, such as PAHs, aromatic amines, and nitrosamines, can form DNA adducts and induce DNA strand breaks¹⁰⁷. The DNA damage caused by tobacco smoke can lead to genetic alterations and chromosomal abnormalities in endometrial cells, potentially promoting the development and progression of endometriosis^8,108.

The ROS generated by tobacco smoking can also cause oxidative damage to DNA⁵¹. ROS can react with DNA bases, leading to the formation of DNA adducts and base modifications¹⁰⁹. Additionally, ROS can induce DNA strand breaks and impair DNA repair mechanisms¹¹⁰. The accumulation of oxidative DNA damage in endometrial cells can contribute to genomic instability and the pathogenesis of endometriosis¹¹¹.

Tobacco smoking can interfere with DNA repair mechanisms in endometrial cells. The chemicals present in tobacco smoke can inhibit DNA repair enzymes, such as DNA polymerases and DNA repair proteins¹¹². This impaired DNA repair capacity can lead to the persistence of DNA damage and genomic instability in endometriotic lesions, promoting disease progression¹¹³.

Epigenetic modifications refer to heritable changes in gene expression patterns without altering the DNA sequence itself¹¹⁴. Tobacco smoking has been associated with epigenetic modifications, including DNA methylation and histone modifications^103,104. Smoking-induced epigenetic changes can alter the expression of genes involved in cellular processes such as inflammation, cell proliferation, and hormone signaling¹¹⁵. Thus, these modifications can contribute to the dysregulation of gene expression in endometrial cells and the pathogenesis of endometriosis.

Aberrant DNA methylation patterns in endometrial cells have been induced by tobacco smoking ¹¹⁶. DNA methylation is a common epigenetic modification that involves the addition of a methyl group to DNA molecules, typically leading to gene silencing¹¹⁶. Smoking-induced DNA methylation changes can affect the expression of genes involved in hormone metabolism, inflammation, and tissue remodeling, potentially promoting the development and progression of endometriosis^104,117.

Tobacco smoking can also influence histone modifications, which regulate the accessibility of DNA to transcription factors and other proteins involved in gene expression¹¹⁸. Smoking-induced histone modifications can alter the structure of chromatin and affect the expression of genes implicated in endometriosis^104,119. These modifications can lead to dysregulated gene expression patterns and contribute to the molecular and cellular changes associated with the disease.

Tobacco smoking-induced DNA damage and epigenetic modifications can potentially have transgenerational effects on offspring¹²⁰. Smoking-related alterations in sperm and egg cells can lead to inherited epigenetic changes that may influence the susceptibility to endometriosis in future generations^121,122. These transgenerational effects highlight the long-lasting impact of tobacco smoking on the molecular pathways involved in endometriosis.

Immune dysfunction

Tobacco can modulate the immune system, leading to dysregulation of immune cells and molecules involved in the pathogenesis of endometriosis²⁷ (Table 1). Smoking can suppress the activity of immune cells, such as natural killer (NK) cells, macrophages, and T cells, reducing their ability to eliminate endometrial cells outside the uterus^8,123. This impaired immune response allows the survival and proliferation of ectopic endometrial tissue, contributing to the development of endometriosis.

Tobacco may disrupt the production and balance of cytokines, which are important immune signaling molecules²¹. Smoking has been associated with increased production of pro-inflammatory cytokines, such as IL-6 and TNF-α, and decreased production of anti-inflammatory cytokines, such as IL-10¹²⁴. This imbalance in cytokine production can contribute to chronic inflammation and tissue damage in endometriosis¹²⁵.

A chronic inflammatory state in the body is induced by tobacco smoking, characterized by elevated levels of inflammatory markers and immune cells¹²⁴. Smoking-related inflammation can promote the recruitment of immune cells to endometriotic lesions and exacerbate tissue inflammation²². This persistent inflammatory response can contribute to the growth, invasion, and persistence of endometriotic lesions¹²⁶.

Tobacco smoking can affect the function of immune cells involved in endometriosis. For example, smoking can impair the cytotoxic activity of NK cells, which play a crucial role in eliminating abnormal cells, including endometrial cells^127,128. Smoking-related alterations in immune cell function can compromise the surveillance and clearance of endometrial cells outside the uterus, contributing to the establishment and progression of endometriosis¹²⁹.

Immune tolerance refers to the ability of the immune system to recognize and tolerate selft-issues¹³⁰. In endometriosis, there is a breakdown in immune tolerance, allowing ectopic endometrial tissue to survive and evade immune surveillance^126,131. Tobacco smoking can further disrupt immune tolerance mechanisms, leading to an aberrant immune response against endometrial cells and perpetuating the immune dysregulation observed in endometriosis21,27,104.

The compounds found in tobacco smoke can modulate the expression and function of cellular adhesion molecules involved in immune cell trafficking and tissue inflammation. Smoking-induced alterations in adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), can recruit immune cells to endometriotic lesions and contribute to the inflammatory process^132,133.

Tobacco smoking can impair wound healing and tissue repair processes, which are essential for the resolution of inflammation and the restoration of tissue integrity¹³⁴. Smoking-related factors can interfere with the production and activity of growth factors, such as transforming growth factor beta (TGF-β), which play a critical role in tissue repair¹³⁵. Impaired wound healing can perpetuate the inflammatory response and contribute to the persistence and progression of endometriotic lesions¹³⁶.

Angiogenesis

Angiogenesis refers to the formation of new blood vessels from pre-existing ones¹³⁷ (Table 1). In endometriosis, angiogenesis plays a crucial role in the establishment and growth of ectopic endometrial tissue¹³⁸. Tobacco smoking has been linked to increased angiogenesis^139-141, which can contribute to the progression and persistence of endometriotic lesions.

Tobacco smoke contains various chemicals that can promote angiogenesis. For example, nicotine, a key component of tobacco, has been shown to stimulate the release of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF)¹⁴² and basic fibroblast growth factor (bFGF)¹⁴³. These factors can enhance the formation of new blood vessels, providing a blood supply to endometriotic lesions and supporting their growth^144,145.

In addition to promoting angiogenesis, tobacco smoking can disrupt the balance of angiogenesis inhibitors ¹⁴¹. Endostatin, thrombospondin-1 (TSP-1), and angiostatin are examples of naturally occurring substances that inhibit blood vessel formation^146,147. Smoking-related factors could interfere with the production and function of these angiogenesis inhibitors, thus allowing angiogenesis to proceed unchecked in endometriosis.

Inflammatory cells and cytokines present in the endometriotic micro-environment can promote the production of pro-angiogenic factors, which contribute to neovascularization^137,148. These newly formed blood vessels provide nutrients and oxygen to endometriotic lesions, facilitating their survival and growth.

Tobacco can induce hypoxic conditions in tissues due to decreased oxygen availability^149,150. Hypoxia is a potent stimulator of angiogenesis, as it triggers the release of hypoxia-inducible factors (HIFs)¹³⁷. These proteins promote the expression of VEGF and other pro-angiogenic factors, facilitating the formation of new blood vessels in the hypoxic environment of endometriotic lesions^151,152.

Tobacco smoking can disrupt the remodeling of the extracellular matrix (ECM), which is essential for angiogenesis¹⁵³. The ECM provides structural support for blood vessels and influences their formation and stability¹⁵⁴. Smoking-related factors can affect the production and degradation of ECM components¹⁵⁵, leading to an imbalance in ECM remodeling and promoting angiogenesis in endometriosis.

Angiogenesis supports the growth of endometriotic lesions and facilitates their invasion into surrounding tissues. The newly formed blood vessels provide a pathway for the migration of endometrial cells, enabling them to establish new lesions and to expand the disease. Therefore, smoking-induced angiogenesis can contribute to the invasive and metastatic behavior of endometriosis.

Limitations

While this narrative review provides a synthesis of existing literature on the relationship between tobacco smoking and endometriosis, several limitations must be acknowledged. First, most of the included studies rely on observational data, which inherently limits causal inference (Table 2). Although emerging evidence suggests a potential link between smoking and endometriosis, confounding factors such as genetic predisposition, environmental exposures, and lifestyle factors may influence the observed associations. Second, self-reported smoking status, a common data collection method in epidemiological studies, may introduce recall bias and misclassification. Individuals may underreport or overestimate their smoking behavior, leading to potential misinterpretation of results. Additionally, differences in study designs, population characteristics, and exposure definitions contribute to heterogeneity across studies, making direct comparisons challenging.

The biological mechanisms linking tobacco smoking to endometriosis remain complex and incompletely understood. While this narrative review highlights several molecular pathways, such as inflammation, oxidative stress, hormonal dysregulation, and epigenetic modifications, causality cannot be definitively established. Further experimental and longitudinal studies are needed to clarify these mechanisms. Finally, while this narrative review provides an overview of the evidence, a systematic review with a comprehensive search strategy, critical appraisal of included studies, and synthesis of findings, would have provided a more conclusive evidence base and hence would be warranted.