PROLACTIN AS AN IMMUNOMODULATOR IN RHEUMATIC DISEASES: THE POTENTIAL ROLE OF PHYSICAL EXERCISE IN THE PROLACTIN-IMMUNE AXIS
DOI:
https://doi.org/10.31435/ijitss.2(50).2026.5382Keywords:
Prolactin, Immunomodulator, Rheumatic Diseases, Physical Activity, Endocrinology, ImmunologyAbstract
Background and Objectives. Prolactin (PRL) is produced by pituitary and extra-pituitary tissues and signals via the prolactin receptor (PRLR), a class I cytokine receptor that activates pathways such as JAK2/STAT5, supporting a cytokine-like role in immune regulation [1-3]. Exercise and heat stress can transiently increase PRL and may confound interpretation in rheumatology [4-6]. We review PRL/PRLR evidence across systemic autoimmune rheumatic diseases and discuss implications for PRL testing around physical activity.
Materials and Methods. Narrative review of PubMed/MEDLINE and PubMed Central (inception–15 February 2026) using terms related to PRL/PRLR, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (pSS), exercise and heat stress. Evidence was synthesized qualitatively given heterogeneity in assays, sampling and outcomes. Macroprolactin and analytical interference were considered as key confounders [1, 7, 8].
Results. Associations between mildly elevated PRL and disease activity were most consistent in SLE, supported by observational studies and syntheses, while interventional data with dopamine agonists remain limited and heterogeneous [9-11]. Findings in RA and pSS were more variable, with stronger signals for local PRL/PRLR relevance than for serum PRL as a universal biomarker [12, 13]. Acute vigorous exercise and passive heat exposure can raise PRL, potentially mimicking disease-related hyperprolactinemia if sampling is not standardized [4, 5, 14, 15].
Conclusions. PRL is a plausible neuroendocrine-immune modulator in rheumatic disease, particularly SLE [11, 16, 17]. Exercise should not be restricted on PRL grounds, but PRL testing should be standardized relative to recent exertion and thermal stress [5, 14, 15, 18].
References
Chasseloup, F., Bernard, V., & Chanson, P. (2024). Prolactin: Structure, receptors, and functions. Reviews in Endocrine and Metabolic Disorders, 25(6), 953–966. https://doi.org/10.1007/s11154-024-09915-8
Borba, V. V., Zandman-Goddard, G., & Shoenfeld, Y. (2018). Prolactin and autoimmunity. Frontiers in Immunology, 9, 73. https://doi.org/10.3389/fimmu.2018.00073
Mousavi, M. J., Alizadeh, A., & Ghotloo, S. (2023). Interference of B lymphocyte tolerance by prolactin in rheumatic autoimmune diseases. Heliyon, 9(6), e16977. https://doi.org/10.1016/j.heliyon.2023.e16977
Mennitti, C., Farina, G., Imperatore, A., De Fonzo, G., Gentile, A., La Civita, E., et al. (2024). How does physical activity modulate hormone responses? Biomolecules, 14(11), 1418. https://doi.org/10.3390/biom14111418
Hannan, F. M., Leow, M. K. S., Lee, J. K. W., Kovats, S., Elajnaf, T., Kennedy, S. H., et al. (2024). Endocrine effects of heat exposure and relevance to climate change. Nature Reviews Endocrinology, 20(11), 673–684. https://doi.org/10.1038/s41574-024-01017-4
Burk, A., Timpmann, S., Kreegipuu, K., Tamm, M., Unt, E., & Oöpik, V. (2012). Effects of heat acclimation on endurance capacity and prolactin response to exercise in the heat. European Journal of Applied Physiology, 112(12), 4091–4101. https://doi.org/10.1007/s00421-012-2371-3
Coleman, K., & Saleem, M. (2024). Reference intervals for serum prolactin concentrations: Analytical and clinical considerations. Reviews in Endocrine and Metabolic Disorders, 25, 995–1002. https://doi.org/10.1007/s11154-024-09927-4
Fahie-Wilson, M. N. (2025). Macroprolactinaemia—Some progress but still an ongoing problem. Clinical Chemistry and Laboratory Medicine, 63(9), 1663–1666. https://doi.org/10.1515/cclm-2025-0586
Glezer, A., Elias, P. C. L., Nogueira, V., Garmes, H. M., Kasuki, L., Rollin, G., et al. (2025). Position statement on macroprolactinemia from the Department of Neuroendocrinology of the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society of Clinical Pathology/Laboratory Medicine (SBPC/ML). Archives of Endocrinology and Metabolism, 69(6), e250152. https://doi.org/10.20945/2359-4292-2025-0152
Alvarez-Nemegyei, J., Cobarrubias-Cobos, A., Escalante-Triay, F., Sosa-Muñoz, J., Miranda, J. M., & Jara, L. J. (1998). Bromocriptine in systemic lupus erythematosus: A double-blind, randomized, placebo-controlled study. Lupus, 7(6), 414–419. https://doi.org/10.1191/096120398678920334
Jakubaszek, M. P. (2023). The significance of prolactin in systemic connective tissue diseases. Reumatologia, 61(4), 264–270. https://doi.org/10.5114/reum/170319
Liu, F., Tian, Y., Qu, Z., Liu, Q., Xia, Y., & Hu, X. (2024). Adenohypophysis-inducible sex hormones correlate with interleukin-6, -8, and tumor necrosis factor-α in patients with systemic lupus erythematosus. Journal of Interferon & Cytokine Research, 44(12), 534–540. https://doi.org/10.1089/jir.2024.0160
Dohi, K., Kraemer, W. J., & Mastro, A. M. (2003). Exercise increases prolactin-receptor expression on human lymphocytes. Journal of Applied Physiology, 94(2), 518–524. https://doi.org/10.1152/japplphysiol.00004.2002
Langan, E. A. (2024). Prolactin: A mammalian stress hormone and its role in cutaneous pathophysiology. International Journal of Molecular Sciences, 25(13), 7100. https://doi.org/10.3390/ijms25137100
Spanoudaki, S., Maridaki, M., Chryssanthopoulos, C., & Philippou, A. (2025). Hormonal and glycemic responses during and after constant- and alternating-intensity exercise. Journal of Clinical Medicine, 14(2), 457. https://doi.org/10.3390/jcm14020457
Dos Santos, Á. A., de Castro, L. F., de Lima, C. L., da Motta, L. D. C., da Motta, L., & Amato, A. A. (2024). Circulating prolactin levels and the effect of dopaminergic agonists in systemic lupus erythematosus: A systematic review and meta-analysis. Scientific Reports, 14(1), 30143. https://doi.org/10.1038/s41598-024-74749-y
Patton, K. A., Siddique, F., & Lal, A. K. (2025). Systemic lupus and other autoimmune disorders during pregnancy. Obstetrics and Gynecology Clinics, 52(3), 581–597. https://doi.org/10.1016/j.ogc.2025.05.007
Blaess, J., Geneton, S., Goepfert, T., Appenzeller, S., Bordier, G., Davergne, T., et al. (2024). Recommendations for physical activity and exercise in persons living with systemic lupus erythematosus (SLE): Consensus by an international task force. RMD Open, 10(2). https://doi.org/10.1136/rmdopen-2024-004171
Ewerman, L., Landberg, E., Hellberg, S., Hovland, M., Sundin, A., Jenmalm, M. C., et al. (2020). Immunomodulating effects depend on prolactin levels in patients with hyperprolactinemia. Hormone and Metabolic Research, 52(4), 228–235. https://doi.org/10.1055/a-1126-4272
Borba, V., Carrera-Bastos, P., Zandman-Goddard, G., Lucia, A., & Shoenfeld, Y. (2024). Prolactin’s paradox: Friend, foe, or both in immune regulation? Autoimmunity Reviews, 23(11), 103643. https://doi.org/10.1016/j.autrev.2024.103643
Chasseloup, F., Bernard, V., & Chanson, P. (2024). Prolactin: Structure, receptors, and functions. Reviews in Endocrine and Metabolic Disorders, 25, 953–966. https://doi.org/10.1007/s11154-024-09915-8
Petersenn, S., Fleseriu, M., Casanueva, F. F., Giustina, A., Biermasz, N., Biller, B. M. K., et al. (2023). Diagnosis and management of prolactin-secreting pituitary adenomas: A Pituitary Society international consensus statement. Nature Reviews Endocrinology, 19(12), 722–740. https://doi.org/10.1038/s41574-023-00886-5
Jara, L. J., Gomez-Sanchez, C., Silveira, L. H., Martinez-Osuna, P., Vasey, F. B., & Espinoza, L. R. (1992). Hyperprolactinemia in systemic lupus erythematosus: Association with disease activity. American Journal of the Medical Sciences, 303(4), 222–226. https://doi.org/10.1097/00000441-199204000-00003
Wright, H. E., McLellan, T. M., Friesen, B. J., Casa, D. J., & Kenny, G. P. (2012). Influence of circulating cytokines on prolactin during slow vs. fast exertional heat stress followed by active or passive recovery. Journal of Applied Physiology, 113(4), 574–583. https://doi.org/10.1152/japplphysiol.00523.2012
Soliman, H. M., Fahmy, B. S., Ali, M. G., & Shafie, E. S. (2023). Circulating prolactin level in juvenile systemic lupus erythematosus and its correlation with disease activity: A case control study. Pediatric Rheumatology Online Journal, 21(1), 128. https://doi.org/10.1186/s12969-023-00915-7
Mele, C., Zavattaro, M., Pitino, R., Romanisio, M., Ferrero, A., Sturnia, S., et al. (2025). Prolactin secreting pituitary neuroendocrine tumors treated by dopamine agonists: Predictors of response. Frontiers in Endocrinology, 16, 1664621. https://doi.org/10.3389/fendo.2025.1664621
Tang, M. W., Garcia, S., Malvar Fernandez, B., Gerlag, D. M., Tak, P. P., & Reedquist, K. A. (2017). Rheumatoid arthritis and psoriatic arthritis synovial fluids stimulate prolactin production by macrophages. Journal of Leukocyte Biology, 102(3), 897–904. https://doi.org/10.1189/jlb.2A0317-115RR
Cutolo, M., Soldano, S., Smith, V., Gotelli, E., & Hysa, E. (2025). Dynamic macrophage phenotypes in autoimmune and inflammatory rheumatic diseases. Nature Reviews Rheumatology, 21(9), 546–565. https://doi.org/10.1038/s41584-025-01279-w
Bandeira de Santana, L., de Souza Lima, T. A., Costa, A. R., Sandoval, L. A. M., de Souza, T. Y., da Mota, L. M. H., et al. (2024). Exploring the association of serum prolactin with serum glucose levels and clinical findings in a cohort of patients with early rheumatoid arthritis. Advances in Rheumatology, 64(1), 56. https://doi.org/10.1186/s42358-024-00394-8
Tang, M. W., Reedquist, K. A., Garcia, S., Fernandez, B. M., Codullo, V., Vieira-Sousa, E., et al. (2016). The prolactin receptor is expressed in rheumatoid arthritis and psoriatic arthritis synovial tissue and contributes to macrophage activation. Rheumatology, 55(12), 2248–2259. https://doi.org/10.1093/rheumatology/kew316
Rausch Osthoff, A. K., Niedermann, K., Braun, J., Adams, J., Brodin, N., Dagfinrud, H., et al. (2018). 2018 EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis. Annals of the Rheumatic Diseases, 77(9), 1251–1260. https://doi.org/10.1136/annrheumdis-2018-213585
Baraliakos, X., Kiltz, U., Kononenko, I., & Ciurea, A. (2023). Treatment overview of axial spondyloarthritis in 2023. Best Practice & Research Clinical Rheumatology, 37(3), 101858. https://doi.org/10.1016/j.berh.2023.101858
Cornwall, N., Swaithes, L., Woodcock, C., Healey, E. L., & Hider, S. L. (2023). Implementation of physical activity interventions for people with inflammatory arthritis: An overview and future recommendations. Rheumatology Advances in Practice, 7(1), rkac094. https://doi.org/10.1093/rap/rkac094
Mennitti, C., Farina, G., Imperatore, A., De Fonzo, G., Gentile, A., La Civita, E., et al. (2024). How does physical activity modulate hormone responses? Biomolecules, 14(11), 1418. https://doi.org/10.3390/biom14111418
Chaillou, T., Hogg, C., Treigyte, V., Juškevičiūtė, E., Eimantas, N., & Brazaitis, M. (2025). Exogenous heating induces a more pronounced rise in prolactin concentration than exertional heating in young men, despite a closely matched body core temperature increase. Journal of Thermal Biology, 133, 104290. https://doi.org/10.1016/j.jtherbio.2025.104290
Podstawski, R., Borysławski, K., Pomianowski, A., Krystkiewicz, W., & Żurek, P. (2021). Endocrine effects of repeated hot thermal stress and cold water immersion in young adult men. American Journal of Men’s Health, 15(2), 15579883211008339. https://doi.org/10.1177/15579883211008339
Kraemer, R. R., & Kraemer, B. R. (2023). The effects of peripheral hormone responses to exercise on adult hippocampal neurogenesis. Frontiers in Endocrinology, 14, 1202349. https://doi.org/10.3389/fendo.2023.1202349
Mundell, A., Amarnani, R., Ainsworth, K., Chiwah, F., Hadjidemetriou, M., Katti, S., et al. (2025). The effects of exercise and physical activity in inflammatory rheumatic diseases: A narrative review. Journal of Science in Sport and Exercise, 7(2), 112–129. https://doi.org/10.1007/s42978-024-00303-x
Faron-Górecka, A., Latocha, K., Pabian, P., Kolasa, M., Sobczyk-Krupiarz, I., & Dziedzicka-Wasylewska, M. (2023). The involvement of prolactin in stress-related disorders. International Journal of Environmental Research and Public Health, 20(4), 3257. https://doi.org/10.3390/ijerph20043257
Zhang, Y., He, Z., Yin, Z., Wang, J., Gao, W., & Jie, L. (2025). Effect of exercise interventions for rheumatoid arthritis: A systematic review and network meta-analysis of randomised controlled trials. Journal of Pain Research, 18, 5109–5126. https://doi.org/10.2147/jpr.S537227
Sutherland, C., Gebrye, T., Ademoyegun, A., Fatoye, F., & Mbada, C. (2025). Effects of high-intensity interval training on patients with inflammatory arthritis: A systematic review. BMC Rheumatology, 9(1), 82. https://doi.org/10.1186/s41927-025-00540-9
Athanasiou, N., Bogdanis, G. C., & Mastorakos, G. (2023). Endocrine responses of the stress system to different types of exercise. Reviews in Endocrine and Metabolic Disorders, 24(2), 251–266. https://doi.org/10.1007/s11154-022-09758-1
Rufo, E., Martinez-Couselo, S., Jimenez-Anon, L., Fernandez-Prendes, C., Barallat, J., & Granada, M.-L. (2022). Marked geographical variation in the prevalence of macroprolactinemia. Clinical Chemistry and Laboratory Medicine, 60(3), 71–74. https://doi.org/10.1515/cclm-2021-1124
Thomsen, T., Aadahl, M., Hetland, M. L., & Esbensen, B. A. (2024). Physical activity guidance in the rheumatology clinic—What matters for patients with rheumatoid arthritis? A qualitative study. Rheumatology International, 44(1), 181–189. https://doi.org/10.1007/s00296-023-05466-4
Pedersen, B. K., & Hoffman-Goetz, L. (2000). Exercise and the immune system: Regulation, integration, and adaptation. Physiological Reviews, 80(3), 1055–1081. https://doi.org/10.1152/physrev.2000.80.3.1055
Jüngert, K., Paulsen, F., Jacobi, C., Horwath-Winter, J., & Garreis, F. (2022). Prolactin inducible protein, but not prolactin, is present in human tears, is involved in tear film quality, and influences evaporative dry eye disease. Frontiers in Medicine, 9, 892831. https://doi.org/10.3389/fmed.2022.892831
Kamounah, S., Sembler-Møller, M. L., Nielsen, C. H., & Pedersen, A. M. L. (2023). Sjögren’s syndrome: Novel insights from proteomics and miRNA expression analysis. Frontiers in Immunology, 14, 1183195. https://doi.org/10.3389/fimmu.2023.1183195
Oliveira, F. R., Valim, V., Pasoto, S. G., Fernandes, M. L. M. S., Lopes, M. L. L., de Magalhães Souza Fialho, S. C., et al. (2021). 2021 recommendations of the Brazilian Society of Rheumatology for the gynecological and obstetric care of patients with Sjogren’s syndrome. Advances in Rheumatology, 61(1), 54. https://doi.org/10.1186/s42358-021-00208-1
Jimenez-Anon, L., Barallat, J., Regidor, D., Urgell, E., Dolade, M., & Granada, M. L. (2020). Assessment of intraindividual agreement in prolactin results after post-polyethylene glycol precipitation test for the estimation of macroprolactin: Should the precipitation procedure be repeated in the same patient? Clinical Chemistry and Laboratory Medicine, 59(1), e27–e29. https://doi.org/10.1515/cclm-2020-0858
Ke, X., Wang, L., Duan, L., Yang, H., Yin, J., Qiu, L., et al. (2023). Comparison of PEG precipitation and ultrafiltration treatment for serum macroprolactin in Chinese patients with hyperprolactinemia. Clinica Chimica Acta, 544, 117358. https://doi.org/10.1016/j.cca.2023.117358
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Copyright (c) 2026 Monika Kuś, Grzegorz Słomkowski, Natalia Sara Kuśmierowska, Milena Polak, Dominika Karolak, Tymoteusz Białowąs, Konrad Wiśniewski, Magdalena Nowak, Kacper Cholewiński, Daria Valipur Kolti
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