Lung cancer remains the leading cause of cancer-related mortality worldwide, accounting for significant morbidity and mortality among men and women alike.^{[1, 2]} Although smoking remains the primary risk factor, a considerable proportion of lung cancer cases occur in women who have never smoked, suggesting the presence of alternative contributing factors.^[3] The differential incidence of lung cancer between sexes, the predominance of adenocarcinoma in women, and emerging evidence of estrogen receptor expression in lung tissue raise the question of a hormonal influence in lung carcinogenesis.^[4] Reproductive and hormonal factors, such as pregnancy history, parity, age at menarche and menopause, and exposure to exogenous hormones, may play a role in modifying the risk of lung cancer, particularly in women.^[5]

Pregnancy-associated lung cancer (PALC) is defined as lung cancer diagnosed during pregnancy or within one year postpartum. It presents distinct clinical and epidemiological challenges. This systematic review highlights the intricate relationship between reproductive hormones and lung cancer susceptibility, underscoring estrogen’s multifaceted role in modulating risk.^[6] Although rare, PALC is associated with increasing maternal age at pregnancy and rising smoking prevalence among women of reproductive age. It poses complex diagnostic and treatment dilemmas due to overlapping symptoms with pregnancy and concerns about fetal safety during anticancer interventions.^[7] Recent studies highlight the molecular characteristics of PALC, such as the high prevalence of driver mutations like anaplastic lymphoma kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) mutations, which may influence treatment strategies and prognosis.^[8–10]

In addition to PALC, the role of reproductive factors in lung cancer risk has been extensively investigated.^[11] Parity has emerged as a potential protective factor, with higher parity associated with reduced lung cancer risk in several studies. Similarly, later age at menopause and a longer reproductive period have been linked to lower risk, particularly among lifetime nonsmokers.^[11] Conversely, conditions such as pre-eclampsia, a pregnancy-related hypertensive disorder, have shown inconsistent associations with lung cancer risk, with some studies reporting an elevated incidence of lung and other cancers in affected women.^[12]

Despite these findings, the relationship between pregnancy, reproductive hormones, and lung cancer risk remains poorly understood. The heterogeneity of study designs, limited sample sizes, and confounding factors, particularly smoking, contribute to the inconsistent results in literature. A systematic synthesis of available evidence is necessary to clarify these associations, identify potential biological mechanisms, and inform future research directions.

This systematic review aims to investigate the clinical features, molecular characteristics, and outcomes of PALC, with a focus on the association between reproductive and hormonal factors and lung cancer risk in women. It also examines the impact of pregnancy complications, such as pre-eclampsia, on lung cancer incidence. By consolidating current evidence, this review seeks to provide a comprehensive understanding of the interplay between pregnancy, reproductive hormones, and lung cancer, highlighting potential risk modifiers and clinical considerations for this unique population.

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure methodological rigor and transparency.^[13] This systematic review has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) with ID number CRD42024629181.

A total of 8 studies were included in this systematic review, evaluating the association between reproductive and hormonal factors and lung cancer risk in women.^{[5, 8, 15–20]}

The summary of the studies’ characteristics is displayed in Table 1.

Our review aligns with the findings of Yin et al.^[11] in emphasizing the significant role of reproductive and hormonal factors in influencing lung cancer risk in women. Both reviews highlight the protective effects of higher parity and prolonged reproductive periods, as well as the increased risk associated with abrupt hormonal changes, such as those following non-natural menopause. However, our review expands on this by focusing on PALC, its unique molecular features, and clinical challenges.

Pregnancy induces profound hormonal fluctuations, particularly in estrogen, progesterone, and human chorionic gonadotropin (hCG), which play critical roles in lung cancer susceptibility. Estrogen, through estrogen receptor (ER) signaling, can influence lung tissue by promoting cell proliferation, angiogenesis, and interaction with oncogenic pathways such as EGFR and phosphatidylinositol 3’-kinase (PI3K)/AKT. However, prolonged exposure to endogenous estrogen, as seen in women with higher parity and later menopause, appears to have a protective effect by maintaining hormonal stability and reducing oxidative stress. Progesterone, which rises during pregnancy, has been suggested to exert anti-inflammatory and immune-modulating effects, potentially counteracting estrogen-driven proliferation. Additionally, hCG, a pregnancy-specific hormone, has been linked to anti-tumor properties in other cancers and may influence lung cancer risk by modulating cell differentiation.^[21–24]

This review explores the complex link between reproductive hormones and lung cancer risk. It highlights estrogen’s role in influencing susceptibility. The protective effect of prolonged exposure to endogenous estrogen, indicated by a longer reproductive period, aligns with established theories about estrogen’s anti-inflammatory and antioxidative properties. These effects may mitigate oncogenic processes in lung tissue, providing a biologically plausible explanation for reduced cancer risk.^[20] Hormonal fluctuations during pregnancy and reproductive cycles may induce epigenetic changes, such as DNA methylation and histone modification, influencing the expression of oncogenes and tumor suppressor genes.^{[23, 24]}

The protective association of late menopause and the heightened risk linked to surgical menopause reflect the critical impact of hormonal fluctuations. The abrupt decline in estrogen levels observed in surgical menopause could disrupt cellular regulatory mechanisms, such as apoptosis and proliferation, emphasizing the importance of hormonal stability in pulmonary homeostasis.^[25] The findings regarding parity further suggest a robust protective effect, potentially driven by pregnancy-induced hormonal surges and immune modulation, which may recalibrate long-term endocrine and immune functions to inhibit lung tumorigenesis.^{[26, 27]} Postpartum immune reconstitution and hormonal resetting could enhance immune surveillance and stabilize hormonal cycles, potentially reducing lung cancer susceptibility.^[27]

The association between reproductive factors and adenocarcinoma prevalence strengthens the argument for hormonal involvement in lung carcinogenesis. This subtype-specific correlation is likely mediated by ER expression in lung tissue, implicating ER signaling pathways in tumor biology. ER signaling activates key pathways like mitogen-activated protein kinase (MAPK) and PI3K/Akt, promoting cell survival and proliferation.^[28] Concurrently, estrogen metabolism generates reactive oxygen species (ROS), contributing to DNA damage. While estrogen-mediated DNA repair mechanisms can mitigate these effects, they may inadvertently enhance the survival of damaged cells, promoting carcinogenesis.^[29]

Estrogen exerts a dual role in lung cancer progression, mediated through distinct functions of estrogen receptor subtypes and its influence on ROS metabolism. The two primary estrogen receptors, ERα (ESR1) and ERβ (ESR2), exhibit opposing effects in lung tissue. ERα activation is associated with increased cell proliferation, angiogenesis, and survival, largely through the activation of MAPK and PI3K/Akt/mTOR signaling. ERα also interacts with receptor tyrosine kinases, particularly the EGFR, amplifying mitogenic signaling and contributing to therapy resistance. In contrast, ERβ has tumor-suppressive properties, promoting apoptosis and inhibiting tumor growth, a function that is frequently lost in advanced lung cancers. The differential expression of these receptors in lung adenocarcinoma suggests that estrogen-mediated carcinogenesis is highly dependent on the ERα/ERβ balance.^[30]

Beyond receptor signaling, estrogen metabolism generates ROS, influencing DNA damage and repair mechanisms. Estrogen is metabolized into catechol estrogens, which undergo oxidation to form quinones, highly reactive compounds that promote DNA adduct formation. These estrogen-derived metabolites contribute to lung tumorigenesis by inducing oxidative stress and genetic instability. Additionally, estrogen upregulates CYP1A1, a cytochrome P450 enzyme involved in ROS metabolism, which further enhances oxidative DNA damage in lung epithelial cells. While estrogen has been shown to modulate DNA repair pathways such as base excision repair (BER) and nucleotide excision repair (NER), prolonged hormonal exposure may paradoxically promote the survival of damaged cells, facilitating tumor progression.^[31]

Estrogen’s interaction with oncogenic driver mutations, particularly EGFR and ALK alterations, further underscores its role in lung carcinogenesis. EGFR mutations, commonly found in never-smoking women with lung adenocarcinoma, drive tumor growth through constitutive activation of the MAPK and PI3K/Akt pathways. Estrogen amplifies EGFR signaling by inducing EGFR phosphorylation and upregulating its expression through ERα-mediated transcriptional regulation. This estrogen-driven EGFR activation has been implicated in resistance to EGFR inhibitors such as osimertinib, highlighting the potential need for combination strategies targeting both pathways. Similarly, ALK rearrangements, particularly EML4-ALK fusions, activate downstream oncogenic cascades that are further enhanced by estrogen signaling. Estrogen has been shown to increase ALK expression and induce crosstalk between ALK and ER pathways, leading to resistance against ALK inhibitors such as crizotinib. This suggests that hormonal modulation may play a crucial role in the therapeutic response of lung cancer patients harboring ALK rearrangements.^{[32, 33]}

Given these interactions, estrogen-targeted therapies have been proposed as potential adjuncts to standard lung cancer treatments. Aromatase inhibitors such as letrozole and anastrozole reduce estrogen synthesis, potentially limiting estrogen-driven oncogenic signaling. Selective estrogen receptor modulators (SERMs) like fulvestrant and tamoxifen may be beneficial in ERα-positive lung cancers, particularly in combination with EGFR or ALK inhibitors. Moreover, ROS scavengers such as N-acetylcysteine and vitamin C could mitigate estrogen-induced oxidative stress, offering an additional therapeutic avenue.^{[34, 35]} The unique pathophysiological features of PALC, including its association with driver mutations like ALK rearrangements and EGFR mutations, suggest a complex interplay between hormonal factors and genetic predispositions. The predominance of these mutations in non-smoking women further reinforces the hypothesis of hormonal modulation as a distinct etiological pathway.

PALC’s frequent presentation at advanced stages reflects diagnostic challenges compounded by overlapping symptoms of pregnancy and lung cancer. This highlights the necessity for heightened clinical vigilance in pregnant patients presenting with respiratory symptoms. The promising survival outcomes associated with targeted therapies, such as ALK inhibitors, emphasize the need for genetic profiling in this demographic.^[36] However, their use necessitates a balance between therapeutic efficacy and fetal safety, necessitating individualized treatment protocols.

The inconsistent association between pregnancy complications, such as pre-eclampsia, and lung cancer risk underscores the complexity of these interactions. Mechanistic pathways involving systemic inflammation and vascular dysfunction are plausible contributors but remain inadequately substantiated. The elevated levels of inflammatory cytokines and dysregulated angiogenesis observed in pre-eclampsia suggest potential carcinogenic pathways.^{[12, 37]}

The independent protective effects of reproductive factors, irrespective of smoking status, challenge the conventional dominance of smoking in lung cancer etiology. While smoking remains a critical risk factor, its interplay with hormonal influences may amplify carcinogenesis, particularly through metabolic pathways like cytochrome P450 family 1 subfamily A member 1 (CYP1A1) induction. This enzyme’s role in estrogen metabolism introduces a dual-hit mechanism, combining oxidative stress with hormonal modulation, necessitating further exploration of these interactions.^{[38, 39]}

The association between reproductive factors and lung cancer risk involves various hormonal and molecular mechanisms. Estrogen, a key female sex hormone, has been implicated in lung carcinogenesis through ER activation, particularly ERα and ERβ, which promote cell proliferation and inhibit apoptosis in lung tissue.^[5] Estrogen also interacts with growth factor signaling pathways, such as the EGFR pathway, enhancing mitogenic activity and contributing to malignant transformation.^[5] Additionally, estrogen metabolites can induce DNA damage, leading to mutations if not properly repaired, while also influencing gene expression related to DNA repair mechanisms, thereby affecting genomic stability.^[5] A large-scale epidemiological study suggested that earlier menarche and later menopause, which extend estrogen exposure, are associated with an increased risk of lung cancer, while a shorter reproductive span may be protective.^[40] Higher parity and later age at first birth have been linked to reduced lung cancer risk, potentially due to the hormonal changes during pregnancy that exert protective effects on lung tissue.^[5] The role of HRT remains controversial, with some studies indicating an increased risk of lung cancer, while others report no significant association, suggesting that the effects may depend on the type and duration of hormone exposure.^[5]

This review offers a comprehensive synthesis of evidence regarding the intersection of pregnancy, reproductive hormones, and lung cancer risk, filling a critical gap in understanding the role of hormonal factors in lung carcinogenesis. A systematic approach was employed following PRISMA guidelines, ensuring methodological rigor in study selection and data extraction. The inclusion of studies spanning diverse populations and geographic regions enhances the generalizability of findings. Furthermore, the review uniquely integrates evidence on PALC and its molecular characteristics, such as ALK and EGFR mutations, providing valuable insights into targeted treatment strategies. The integration of hormonal mechanisms and their plausible biological pathways strengthens the theoretical foundation of the findings.

This systematic review has significant clinical and translational implications by highlighting the role of reproductive hormones and pregnancy-associated factors in lung cancer risk, particularly among female never-smokers. The findings support integrating reproductive history into lung cancer risk models to improve early detection and risk stratification. Additionally, the identification of hormone-driven molecular pathways and actionable mutations (ALK, EGFR) in PALC underscores the need for personalized treatment approaches, optimizing targeted therapies while ensuring fetal safety. Beyond clinical applications, this review lays the foundation for future research on hormonal biomarkers and the development of hormone-based prevention strategies, ultimately advancing precision medicine in lung cancer management. Despite its strengths, this review has several limitations. The reliance on observational studies, which are prone to residual confounding and bias, constrains causal inferences. Smoking, a critical confounder in lung cancer research, was variably controlled across the included studies, potentially influencing the observed associations. The heterogeneity in study designs, exposure definitions, and outcome measures limits the comparability and pooling of results. Many studies had small sample sizes or focused on specific subpopulations, reducing statistical power and external validity. Additionally, the data on PALC remains sparse, necessitating cautious interpretation of findings in this subgroup. Finally, publication bias, inherent to systematic reviews, may have skewed the results towards studies reporting significant associations, while grey literature was not fully exhaustively explored.

The integration of reproductive and hormonal history into risk stratification models offers an opportunity to refine early detection strategies for lung cancer. For PALC, the application of molecular-targeted therapies holds significant promise but requires tailored approaches that consider the unique needs of pregnant patients. Investigating the interaction between reproductive factors and genetic mutations may unveil novel therapeutic targets, while prospective cohort studies are essential to address confounding variables and strengthen causal inferences.

Integrating reproductive history into lung cancer screening guidelines requires a multi-faceted approach that enhances risk prediction models, refines screening eligibility criteria, and incorporates hormonal and genetic factors into clinical assessments. Existing lung cancer risk models, such as PLCOm2012 and USPSTF guidelines, could be modified to include reproductive factors such as parity, age at menarche and menopause, reproductive period duration, and pregnancy complications. A reproductive lung cancer risk index (RLC-RI) could be developed to quantify risk, assigning weighted values based on epidemiological evidence showing that later menopause and higher parity reduce risk, whereas surgical menopause and early menopause increase susceptibility. This index could be integrated into electronic medical records to generate automated screening recommendations. Stratification of high-risk subgroups, particularly never-smoking women, would allow targeted screening for those with early menopause, low parity, a history of surgical menopause, or pregnancy complications such as pre-eclampsia. In addition to clinical risk factors, biomarker analysis, including estrogen receptor expression and hormonal metabolites, could refine risk assessment, particularly in women with genetic predispositions such as EGFR and ALK mutations. Personalized screening recommendations should prioritize annual low-dose CT scans for high-risk women, even those without a smoking history, while those with moderate reproductive risk factors may benefit from enhanced risk counseling. A crucial aspect of this strategy is providing education, ensuring that reproductive history is systematically evaluated in lung cancer risk assessments. Collaboration between oncologists and gynecologists could further enhance early detection, particularly in women undergoing hormonal transitions such as menopause or pregnancy. Future research should focus on large-scale cohort studies and machine learning-based predictive models to validate these associations and refine individualized screening strategies, ultimately improving early lung cancer detection and prevention in women.

Establishing an international registry for PALC would be a crucial step in addressing the significant data gaps surrounding its epidemiology, molecular characteristics, and clinical management. Given the rarity of PALC, current evidence is limited to small-scale studies and case reports, making it difficult to draw definitive conclusions about risk factors, optimal diagnostic approaches, and treatment outcomes. A global registry would facilitate the collection of standardized, high-quality data from multiple institutions and geographic regions, enabling a more comprehensive understanding of this condition. The registry should include demographic, reproductive, and hormonal history, clinical presentation, tumor histology, molecular profiling (including actionable mutations such as ALK and EGFR), treatment regimens, pregnancy outcomes, and long-term maternal and fetal health data. By pooling data from diverse populations, the registry could help identify high-risk subgroups, evaluate the impact of pregnancy-related hormonal fluctuations on lung cancer progression, and refine clinical management strategies. Additionally, it would serve as a valuable resource for prospective research, allowing investigators to explore genetic predispositions, hormonal biomarkers, and novel therapeutic approaches. Collaboration among oncology, obstetrics, and epidemiology experts would be essential to ensure comprehensive data collection and to develop evidence-based guidelines for diagnosing and managing PALC. Furthermore, integrating the registry with existing cancer databases and leveraging artificial intelligence for predictive modeling could enhance risk stratification and treatment personalization. Ultimately, an international PALC registry would not only advance scientific knowledge but also improve clinical outcomes by enabling earlier detection, optimizing treatment decisions, and ensuring better maternal-fetal care in affected patients.

Fig. 2 illustrates the interplay of reproductive factors, hormonal modulation, and molecular pathways in PALC.

This systematic review underscores the complex interplay between pregnancy, reproductive hormones, and lung cancer risk in women. The findings highlight the protective role of reproductive factors such as parity, later menopause, and prolonged reproductive periods, likely mediated by hormonal stabilization and immune modulation. Additionally, the distinct clinical and molecular characteristics of PALC, including high rates of actionable mutations such as ALK and EGFR, suggest unique etiological pathways and emphasize the potential for targeted therapeutic strategies. However, challenges such as diagnostic delays during pregnancy and balancing treatment efficacy with fetal safety remain significant hurdles.

This study provides key insights but has limitations. It relies on observational data, which limits causal inference. Additionally, factors such as smoking and environmental exposures may affect the observed associations. Second, the heterogeneity of study designs and sample sizes reduces the comparability of findings. Many included studies had small sample sizes, limiting statistical power and generalizability. Third, while PALC presents distinct molecular and clinical features, data on PALC remain sparse, necessitating cautious interpretation of its associations with reproductive factors. Lastly, publication bias may have influenced the synthesis of available data, as studies reporting significant associations are more likely to be published.

Future research should prioritize large-scale prospective cohort studies and mechanistic investigations to better elucidate the hormonal and genetic interactions in lung carcinogenesis. Clinically, integrating reproductive history into lung cancer risk models could improve early detection and risk stratification, particularly in high-risk subgroups. Addressing these limitations will enhance the accuracy and applicability of findings, ultimately improving prevention and management strategies for lung cancer in women.

Eleni-Maria Sotiropoulou: conceptualization, methodology, writing–original draft, data collection, writing–review and editing; Antigoni Sarantaki: data interpretation, data collection, literature review; Giannoula Kyrkou: data interpretation, data collection, literature review; Vasiliki Epameinondas Georgakopoulou: data collection, writing–review and editing, project administration, supervision; Athina Diamanti: data collection, writing–review and editing, project administration, supervision. The Corresponding author confirms that all authors meet the criteria for authorship as outlined by the International Committee of Medical Journal Editors (ICMJE) criteria, have read the manuscript and agreed for publication.

Not applicable

Not applicable.

The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

None

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.