Variations in Serum Steroid Hormones and Complement Levels throughout Different Stages of Lung Cancer
DOI:
https://doi.org/10.14500/aro.12827Keywords:
Biomarker, Complement system proteins, Glucocorticoids, Lung cancer, Steroid hormonesAbstract
Lung cancer is a leading cause of cancer mortality worldwide. Steroid hormones and complement proteins may contribute to lung cancer progression and immune regulation. This case-control study enrolled 111 individuals, including 66 newly diagnosed patients with lung cancer and 45 healthy controls. Blood samples were collected from all participants between 7:00 and 9:00 AM following an overnight fast of at least 8 h before the initiation of any treatment in the lung cancer patient group. Serum steroid hormones were statistically higher in the lung cancer group than in the control group (p = 0.0001). In addition, the levels of serum complement C3 (p = 0.006) and C4 (p < 0.0001) in the lung cancer group were higher than those in the control group. Levels increased with disease progression. Elevated serum concentrations of pregnenolone (odds ratio [OR] = 5.12, p = 0.036) and progesterone (OR = 7.20, p = 0.023) were significantly associated with an increased risk of lung cancer. The discriminatory power for serum cortisol (area under the curve [AUC] = 0.927), progesterone (AUC = 0.948), dehydroepiandrosterone (AUC = 0.935), and complement C4 was excellent (AUC = 0.962). Increased expression of several steroid hormones and complement proteins is linked to lung cancer and continuously increases with the development of the disease. Most of the steroid hormones and complement C4 showed a favorable capacity for early diagnosis and risk prediction of lung cancer. Nevertheless, pregnenolone and progesterone are now identified as the most relevant independent biomarkers.
Downloads
References
Adhya, D., Annuario, E., Lancaster, M.A., Price, J., Baron‐Cohen, S., and Srivastava, D.P., 2018. Understanding the role of steroids in typical and atypical brain development: Advantages of using a “brain in a dish” approach. Journal of Neuroendocrinology, 30(2), p.e12547. DOI: https://doi.org/10.1111/jne.12547
Ajona, D., Okrój, M., and Pajares, M., 2017. Complement C4d-specific antibodies for the diagnosis of lung cancer. Oncotarget, 9, pp.6346-6355. DOI: https://doi.org/10.18632/oncotarget.23690
Ajona, D., Remirez, A., Sainz, C., Bertolo, C., Gonzalez, A., Varo, N., Lozano, M.D., Zulueta, J.J., Mesa-Guzman, M., and Martin, A.C., 2021. A model based on the quantification of complement C4c, CYFRA 21-1 and CRP exhibits high specificity for the early diagnosis of lung cancer. Translational Research, 233, pp.77-91. DOI: https://doi.org/10.1016/j.trsl.2021.02.009
Anderson, A.C., and Acharya, N., 2022. Steroid hormone regulation of immune responses in cancer. Immunometabolism, 4(4), p.e00012. DOI: https://doi.org/10.1097/IN9.0000000000000012
Bai, Y., Shen, W., Zhu, M., Zhang, L., Wei, Y., Tang, H., and Zhao, J., 2019. Combined detection of estrogen and tumor markers is an important reference factor in the diagnosis and prognosis of lung cancer. Journal of Cellular Biochemistry, 120(1), pp.105-114. DOI: https://doi.org/10.1002/jcb.27130
Bandovkina, V.A., Kit, O.I., Frantsiyants, E.M., Ayrapetova, T.G., Legostaev, V.M., Babenkov, O.M., Chubaryan, A.V., Ilchenko, M.G., and Agarkova, E.I., 2019. Can Steroid Imbalance in Intracrine Synthesis of Sex Hormones in the Lung be a Pathognomonic Factor of Lung Cancer-American Society of Clinical Oncology, United States. DOI: https://doi.org/10.1200/JCO.2019.37.15_suppl.e20020
Becerra-Diaz, M., Song, M., and Heller, N., 2020. Androgen and androgen receptors as regulators of monocyte and macrophage biology in the healthy and diseased lung. Frontiers in Immunology, 11, p.1698. DOI: https://doi.org/10.3389/fimmu.2020.01698
Brown, A.M., and Gervais, N.J., 2020. Role of ovarian hormones in the modulation of sleep in females across the adult lifespan. Endocrinology, 161(9), p.bqaa128. DOI: https://doi.org/10.1210/endocr/bqaa128
Buendía-González, F.O., and Legorreta-Herrera, M., 2022. The similarities and differences between the effects of testosterone and DHEA on the innate and adaptive immune response. Biomolecules, 12(12), p.1768. DOI: https://doi.org/10.3390/biom12121768
Cernera, G., Di Donato, M., Higgins, P.J., and Schlaepfer, I.R., 2022. The Role of Steroid Hormones and Growth Factors in Cancer. Vol. 10. Frontiers Media SA, Lausanne, pp.887529. DOI: https://doi.org/10.3389/fcell.2022.887529
Chakraborty, S., Ganti, A.K., Marr, A., and Batra, S.K., 2010. Lung cancer in women: Role of estrogens. Expert Review of Respiratory Medicine, 4(4), pp.509-518. DOI: https://doi.org/10.1586/ers.10.50
Chen, X.Q., Zheng, L.X., Li, Z.Y., and Lin, T.Y., 2017. Clinicopathological significance of oestrogen receptor expression in non-small cell lung cancer. Journal of International Medical Research, 45(1), pp.51-58. DOI: https://doi.org/10.1177/0300060516666229
Deng, S., Ramos-Castaneda, M., Velasco, W.V., Clowers, M.J., Gutierrez, B.A., Noble, O., Dong, Y., Zarghooni, M., Alvarado, L., and Caetano, M.S., 2020. Interplay between estrogen and Stat3/NF-κB-driven immunomodulation in lung cancer. Carcinogenesis, 41(11), pp.1529-1542. DOI: https://doi.org/10.1093/carcin/bgaa064
Drzewiecka, H., Gałęcki, B., Jarmołowska-Jurczyszyn, D., Kluk, A., Dyszkiewicz, W., and Jagodziński, P.P., 2015. Increased expression of 17-beta-hydroxysteroid dehydrogenase type 1 in non-small cell lung cancer. Lung Cancer, 87(2), pp.107-116. DOI: https://doi.org/10.1016/j.lungcan.2014.12.012
Durovski, D., Jankovic, M., and Prekovic, S., 2023. Insights into androgen receptor action in lung cancer. Endocrines, 4(2), pp.269-280. DOI: https://doi.org/10.3390/endocrines4020022
Feng, Z., Fu, J., Wang, K., Yang, J., Jiang, X., and Wu, Q., 2025. Causal relationship between hormone levels and lung cancer: A Mendelian randomization study. Frontiers in Endocrinology, 16, p.1462531. DOI: https://doi.org/10.3389/fendo.2025.1462531
Fuentes, N., Silva Rodriguez, M., and Silveyra, P., 2021. Role of sex hormones in lung cancer. Experimental Biology and Medicine, 246(19), pp.2098-2110. DOI: https://doi.org/10.1177/15353702211019697
Hsu, L.H., Chu, N.M., and Kao, S.H., 2017. Estrogen, estrogen receptor and lung cancer. International Journal of Molecular Sciences, 18(8), p.1713. DOI: https://doi.org/10.3390/ijms18081713
Ishibashi, H., Suzuki, T., Suzuki, S., Niikawa, H., Lu, L., Miki, Y., Moriya, T., Hayashi, S.I., Handa, M., and Kondo, T., 2005. Progesterone receptor in non small cell lung cancer-a potent prognostic factor and possible target for endocrine therapy. Cancer Research, 65(14), pp.6450-6458. DOI: https://doi.org/10.1158/0008-5472.CAN-04-3087
Kanter, N.G., Cohen‐Woods, S., Balfour, D., Burt, M.G., Waterman, A.L., and Koczwara, B., 2024. Hypothalamic–pituitary–adrenal axis dysfunction in people with cancer: A systematic review. Cancer Medicine, 13(22), p.e70366. DOI: https://doi.org/10.1002/cam4.70366
King, P.T., 2015. Inflammation in chronic obstructive pulmonary disease and its role in cardiovascular disease and lung cancer. Clinical and Translational Medicine, 4(1), p26. DOI: https://doi.org/10.1186/s40169-015-0068-z
Li, N., Hu, H., Wu, G., and Sun, B., 2019. Value of immune factors for monitoring risk of lung cancer in patients with interstitial lung disease. Journal of International Medical Research, 47(7), pp.3344-3353. DOI: https://doi.org/10.1177/0300060519847403
Mariotto, A.B., Enewold, L., Zhao, J., Zeruto, C.A., and Yabroff, K.R., 2020. Medical care costs associated with cancer survivorship in the United States. Cancer Epidemiology, Biomarkers and Prevention, 29(7), pp.1304-1312. DOI: https://doi.org/10.1158/1055-9965.EPI-19-1534
Miki, Y., Suzuki, T., Abe, K., Suzuki, S., Niikawa, H., Iida, S., Hata, S., Akahira, J.I., Mori, K., and Evans, D.B., 2010. Intratumoral localization of aromatase and interaction between stromal and parenchymal cells in the non-small cell lung carcinoma microenvironment. Cancer Research, 70(16), pp.6659-6669. DOI: https://doi.org/10.1158/0008-5472.CAN-09-4653
Musial, C., Zaucha, R., Kuban-Jankowska, A., Konieczna, L., Belka, M., Marino Gammazza, A., Baczek, T., Cappello, F., Wozniak, M., and Gorska-Ponikowska, M., 2021. Plausible role of estrogens in pathogenesis, progression and therapy of lung cancer. International Journal of Environmental Research and Public Health, 18(2), p.648. DOI: https://doi.org/10.3390/ijerph18020648
Nuvoli, B., Sacconi, A., Bottillo, G., Sciarra, F., Libener, R., Maconi, A., Carosi, M., Piperno, G., Mastropasqua, E., and Papale, M., 2024. DHEA-S, Androstenedione, 17-β-estradiol signature as novel biomarkers for early prediction of risk of malignant pleural mesothelioma linked to asbestos-exposure: A preliminary investigation. Biomedicine and Pharmacotherapy, 175, p.116662. DOI: https://doi.org/10.1016/j.biopha.2024.116662
Ørsted, D., Nordestgaard, B., and Bojesen, S., 2014. Plasma testosterone in the general population, cancer prognosis and cancer risk: A prospective cohort study. Annals of Oncology, 25(3), pp.712-718. DOI: https://doi.org/10.1093/annonc/mdt590
Pelizzo, G., Calcaterra, V., Baldassarre, P., Marinaro, M., Taranto, S., Ceresola, M., Capelo, G., Gazzola, C., and Zuccotti, G., 2024. The impact of hormones on lung development and function: An overlooked aspect to consider from early childhood. Frontiers in Endocrinology, 15, p.1425149. DOI: https://doi.org/10.3389/fendo.2024.1425149
Pio, R., Ajona, D., and Lambris, J.D., 2013. Complement inhibition in cancer therapy. Seminars in Immunology, 25, pp.54-64. DOI: https://doi.org/10.1016/j.smim.2013.04.001
Rodriguez-Lara, V., Cortés-Ramírez, G., Angeles-Torres, I.A., Rodriguez-Cid, J., Pedraza-Reyes, S.M.L., Avila-Costa, M.R., Ordoñez-Librado, J.L., and Cerbón, M., 2025. Expression patterns of estrogen and androgen receptors in NSCLC patients according to the PD-L1 profile. Frontiers in Immunology, 16, p.1602579. DOI: https://doi.org/10.3389/fimmu.2025.1602579
Rodriguez-Lara, V., Hernandez-Martinez, J.M., and Arrieta, O., 2018. Influence of estrogen in non-small cell lung cancer and its clinical implications. Journal of Thoracic Disease, 10(1), p.482. DOI: https://doi.org/10.21037/jtd.2017.12.61
Rutkowski, M.J., Sughrue, M.E., Kane, A.J., Ahn, B.J., Fang, S., and Parsa, A.T., 2010. The complement cascade as a mediator of tissue growth and regeneration. Inflammation Research, 59(11), pp.897-905. DOI: https://doi.org/10.1007/s00011-010-0220-6
Schwarzlmueller, P., Triebig, A., Assié, G., Jouinot, A., Theurich, S., Maier, T., Beuschlein, F., Kobold, S., and Kroiss, M., 2025. Steroid hormones as modulators of anti-tumoural immunity. Nature Reviews Endocrinology, 21, pp.1-13. DOI: https://doi.org/10.1038/s41574-025-01102-2
Sharma, P., Mathur, K., Sharma, R., and Sankhla, M., 2014. Serum cortisol level in lung cancer patients at various stages of diagnosis. International Journal of Basic and Applied Physiology, 3, pp.67-69.
Siegfried, J.M., 2014. Smoking out reproductive hormone actions in lung cancer. Molecular Cancer Research, 12(1), pp.24-31. Siegfried, J.M., and Stabile, L.P., 2014. Estrogenic steroid hormones in lung cancer. Seminars in Oncology, 41, pp.5-16. DOI: https://doi.org/10.1053/j.seminoncol.2013.12.009
Smith, L.C., Ramar, M., Riley, G., Mathias, C., and Lee, J.Y., 2025. Steroid hormone regulation of immunometabolism and inflammation. Frontiers in Immunology, 16, 1654034. DOI: https://doi.org/10.3389/fimmu.2025.1654034
Stabile, L.P., Dacic, S., Land, S.R., Lenzner, D.E., Dhir, R., Acquafondata, M., Landreneau, R.J., Grandis, J.R., and Siegfried, J.M., 2011. Combined analysis of estrogen receptor β-1 and progesterone receptor expression identifies lung cancer patients with poor outcome. Clinical Cancer Research, 17(1), pp.154-164. DOI: https://doi.org/10.1158/1078-0432.CCR-10-0992
Suliman, L.A.E.M., Moawad, A.A., Elshahawy, H., and Abdalla, D.A., 2021. Role of complement activation product C4d as a predictor biomarker in lung cancer diagnosis: A case–control study. The Egyptian Journal of Chest Diseases and Tuberculosis, 70(2), pp.231-235. DOI: https://doi.org/10.4103/ejcdt.ejcdt_92_20
Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., and Bray, F., 2021. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71(3), pp.209-249. DOI: https://doi.org/10.3322/caac.21660
Team, N.L.S.T.R., 2011. Reduced lung-cancer mortality with low-dose computed tomographic screening. New England Journal of Medicine, 365(5), pp.395-409. DOI: https://doi.org/10.1056/NEJMoa1102873
Verma, M.K., Miki, Y., and Sasano, H., 2011. Aromatase in human lung carcinoma. Steroids, 76(8), pp.759-764. DOI: https://doi.org/10.1016/j.steroids.2011.02.020
Wang, Y., Zhou, Y., Yao, Y., and Zheng, C., 2025. The mechanism of steroid hormones in non-small cell lung cancer: From molecular signaling to clinical application. Biomedicines, 13(8), p.1992. DOI: https://doi.org/10.3390/biomedicines13081992
Wu, J.R., Chen, V.C.H., Fang, Y.H., Hsieh, C.C., and Wu, S.I., 2024. The associates of anxiety among lung cancer patients: Dehydroepiandrosterone (DHEA) as a potential biomarker. BMC cancer, 24(1), p.476. DOI: https://doi.org/10.1186/s12885-024-12195-9
Wu, Y.Q., Lin, X.J., Zhong, G.C., Fu, Y.Y., Wu, J.J., and Lian, X., 2019. Serum testosterone and estradiol levels correlate with disease severity and prognosis in male patients with liver failure. MOJ Public Health, 8(5), pp.189-196. DOI: https://doi.org/10.15406/mojph.2019.08.00306
Zhang, Y., Darville, L., Hogue, S., Hallanger Johnson, J.E., Rose, T., Kim, Y., Bailey, A., Gray, J.E., and Robinson, L.A., 2024. High pretreatment DHEA is associated with inferior immunotherapy response in metastatic non-small cell lung cancer. Cancers, 16(6), p.1152 DOI: https://doi.org/10.3390/cancers16061152
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Van A. Ahmed, Hazhar M. Balaky, Namama S. Hamad, Parween A. Ismail
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Authors who choose to publish their work with Aro agree to the following terms:
-
Authors retain the copyright to their work and grant the journal the right of first publication. The work is simultaneously licensed under a Creative Commons Attribution License [CC BY-NC-SA 4.0]. This license allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
-
Authors have the freedom to enter into separate agreements for the non-exclusive distribution of the journal's published version of the work. This includes options such as posting it to an institutional repository or publishing it in a book, as long as proper acknowledgement is given to its initial publication in this journal.
-
Authors are encouraged to share and post their work online, including in institutional repositories or on their personal websites, both prior to and during the submission process. This practice can lead to productive exchanges and increase the visibility and citation of the published work.
By agreeing to these terms, authors acknowledge the importance of open access and the benefits it brings to the scholarly community.
Accepted 2026-03-24
Published 2026-06-20
ARO Journal is a scientific, peer-reviewed, periodical, and diamond OAJ that has no APC or ASC.