Menstrual cycle-associated changes in blood levels of interleukin-6, α1 acid glycoprotein, and C-reactive protein
Abstract
Based on previous studies we hypothesized that interleukin-6 (IL-6) plasma levels would increase during the menstrual cycle, in analogy to the increase in IL-1 levels seen during the luteal phase. Thus we have investigated menstrual cycle-associated changes in IL-6, alpha1 acid glycoprotein (AGP), and C-reactive protein (CRP). The study design was cross-sectional and was conducted in 18 healthy premenopausal women with regular menstrual cycles and in 15 age-matched men. The women had blood drawings in the follicular phase, at midcycle, and in the luteal phase of the menstrual cycle. A single blood sample was obtained from men to compare IL-6 levels between sexes. The median IL-6 level was 0.68 pg/ml (95% confidence interval (CI): 0.60 to 1.05) in the follicular phase and did not change significantly during the menstrual cycle. IL-6 levels did not differ between women and men (0.79 pg/ml; CI: 0.66 to 1.05; p > 0.05). Median AGP levels decreased by 6% (CI: -14% to 1%) during the luteal phase (p = 0.005), and a significant correlation between mean AGP and IL-6 levels was found (r = 0.60; p = 0.01). Median CRP levels increased by 44% (CI: 27% to 59%; p < 0.001) at midcycle and by 31% (CI: 17% to 68%; p = 0.002) in the luteal phase, and there was a significant correlation between the relative increase in CRP at midcycle and the relative increase in progesterone levels during midcycle (r = 0.60; p = 0.01) and the luteal phase (r = 0.71; p = 0.001). In conclusion, we found no sustai…
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CRP levels in peripheral blood have been reported to be significantly higher during the midcycle and luteal phase when compared to the follicular phase.
“Thirdly, CRP levels in peripheral blood have been reported to be significantly higher during the midcycle and luteal phase when compared to the follicular phase [35].”
From A high sensitivity assay is more accurate than a classical assay for the measurement of plasma CRP levels in endometriosis (2011) · cites this paper as [35]
Inflammation levels fluctuate throughout female life according to hormonal changes owing to phase of menstrual cycle, use of hormonal contraceptives, menopause and use of estrogens.
“Inflammation levels fluctuate throughout female life according to hormonal changes owing to phase of menstrual cycle, use of hormonal contraceptives, menopause and use of estrogens,6, 7, 8”
From Association of depressive disorders, depression characteristics and antidepressant medication with inflammation (2012) · cites this paper as [8]
Hormonal changes throughout female life (menstrual cycle, hormonal contraceptives, menopause, estrogens) greatly impact inflammation levels.
“Hormonal changes throughout female life due to phase of menstrual cycle, use of hormonal contraceptives, menopause and use of estrogens greatly impact on inflammation levels,6, 7, 8”
From Association of depressive disorders, depression characteristics and antidepressant medication with inflammation (2012) · cites this paper as [8]
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Ritchie, R. F., Palomaki, G. E., Neveux, L. M., Navolotskaia, O., Ledue, T. B., & Craig, W. Y. (2002) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.10048 · Cited by 48 · see citing works
Links among inflammation, sexual activity and ovulation
Lorenz, T. K., Worthman, C. M., & Vitzthum, V. J. (2015) · Evolution Medicine and Public Health · doi:10.1093/emph/eov029 · Cited by 47 · see citing works
Notbohm, H. L., Moser, F., Goh, J., Feuerbacher, J. F., Bloch, W., & Schumann, M. (2023) · Acta Physiologica · doi:10.1111/apha.14013 · Cited by 45 · see citing works
“…et al. 2022 [99] Capobianco et al. 2010 [167] Chaireti et al. 2016 [101] Codner et al. 2016 [176] Dreon et al. 2002 [178] Gaskins et al. 2012 [181] Jilma et al. 1997 [102] Larsen et al. 2020 [91] Merino et al. 2015 [177] Puder et al. 2006 [119] Quinn et al. 2021 [180] Romero−Parra et al. 2020…”
Aziz, N., Detels, R., Quint, J. J., Gjertson, D. W., Ryner, T., & Butch, A. W. (2019) · BMC Immunology · doi:10.1186/s12865-019-0313-0 · Cited by 44 · see citing works
Folsom, A. R., Golden, S. H., Boland, L. L., & Szklo, M. (2005) · European Journal of Epidemiology · doi:10.1007/s10654-005-3657-0 · Cited by 44 · see citing works
“reported that CRP increased in parallel with progesterone increases during the menstrual cycle [30].”
BackgroundAncelin, M., Farré, A., Carrière, I., Ritchie, K. A., Chaudieu, I., & Ryan, J. L. (2015) · Translational Psychiatry · doi:10.1038/tp.2014.145 · Cited by 42 · see citing works
Chiu, K. M., Arnaud, C. D., Ju, J., Mayes, D. M., Bacchetti, P., Weitz, S., & Keller, E. T. (2000) · Bone · doi:10.1016/s8756-3282(99)00243-4 · Cited by 42 · see citing works
Ho, P., Yeh, Y., Huang, S., & Liang, C. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.01.008 · Cited by 37 · see citing works
Jiang, W., & Gilkeson, G. S. (2014) · Journal of Immunotherapy Applications · doi:10.7243/2055-2394-1-1 · Cited by 37 · see citing works
“Results related to sex differences in IL-6 production in response to LPS in controls and patients with SLE are conflicting [102,105-109].”
BackgroundSaeidiFard, N., Djafarian, K., & Shab‐Bidar, S. (2020) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2019.10.010 · Cited by 36 · see citing works
Sasaki, Y., Itoh, F., Suzuki, H., Kobayashi, T., Kakiuchi, H., Hareyama, M., & Imai, K. (2000) · Journal of Clinical Laboratory Analysis · doi:10.1002/1098-2825(20001212)14:6 · Cited by 13 · see citing works
Effects of anticoagulation on thrombopoietin release during endotoxemia
Jilma‐Stohlawetz, P., Folman, C. C., Borne, A. E. G. K. V. D., Pernerstorfer, T., Hollenstein, U., Knechtelsdorfer, M., Eichler, H.-G., & Jilma, B. (2001) · Journal of Laboratory and Clinical Medicine · doi:10.1067/mlc.2001.111468 · Cited by 32 · see citing works
Self-citationMetabolic Syndrome, C-Reactive Protein and Increased Arterial Stiffness in Japanese Subjects
Saijo, Y., Yoshioka, E., FUKUI, T., Kawaharada, M., & Kishi, R. (2006) · Hypertension Research · doi:10.1291/hypres.29.589 · Cited by 32 · see citing works
“(42) reported observing menstrual cycle–associated changes in the blood levels of CRP.”
BackgroundModulation of Body Temperature, Interleukin-6 and Leptin by Oral Contraceptive Use
Salkeld, B. D., MacAulay, J. C., Ball, R. W., & Cannon, J. G. (2001) · NeuroImmunoModulation · doi:10.1159/000059389 · Cited by 31 · see citing works
Vodolazkaia, A., Bossuyt, X., Fassbender, A., Kyama, C. M., Meuleman, C., Peeraer, K., Tomassetti, C., & D'Hooghe, T. M. (2011) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-9-113 · Cited by 28 · see citing works
“Thirdly, CRP levels in peripheral blood have been reported to be significantly higher during the midcycle and luteal phase when compared to the follicular phase [35].”
BackgroundMajor depressive disorder increased risk of psoriasis: A propensity score matched cohort study
Chen, Y., Wang, W., Li, I., Kao, H., Yeh, C., & Kao, L. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.09.108 · Cited by 29 · see citing works
C-reactive protein and ART outcomes: a systematic review
Brouillet, S., Boursier, G., Anav, M., Boissière, B. D. B. D. L., Gala, A., Ferrières-Hoa, A., Touitou, I., & Hamamah, S. (2020) · Human Reproduction Update · doi:10.1093/humupd/dmaa012 · Cited by 28 · see citing works
Hollenstein, U., Pernerstorfer, T., Homoncik, M., Hansen, J. B., Finzen, H., Handler, S., & Jilma, B. (2002) · The Journal of Infectious Diseases · doi:10.1086/344646 · Cited by 27 · see citing works
Self-citationMarsik, C. L., Sunder‐Plaßmann, R., Jilma, B., Kovar, F. M., Mannhalter, C., Wagner, O. F., Rumpold, H., & Endler, G. (2006) · Clinical Chemistry · doi:10.1373/clinchem.2006.069823 · Cited by 27 · see citing works
“2 h after LPS TNF, ng/L 174 (32) 112 (28) 40 ( 12 ) 0.007b”
BackgroundSelf-citationQuinn, K., Cox, A. J., Roberts, L. A., Pennell, E. N., McKeating, D. R., Fisher, J. J., Perkins, A. V., & MINAHAN, C. L. (2021) · European Journal of Applied Physiology · doi:10.1007/s00421-021-04734-0 · Cited by 26 · see citing works
Early developmental exposures shape trade-offs between acquired and innate immunity in humans
Georgiev, A. V., Kuzawa, C. W., & McDade, T. W. (2016) · Evolution Medicine and Public Health · doi:10.1093/emph/eow022 · Cited by 25 · see citing works
Lorenz, T. K., Demas, G. E., & Heiman, J. R. (2016) · Fertility and Sterility · doi:10.1016/j.fertnstert.2016.11.010 · Cited by 24 · see citing works
Cho, S. H., Lim, J., Lee, J., Lee, J. S., Jeong, H., Lee, M., Ko, Y., Han, C., Ham, B., & Han, K. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.05.040 · Cited by 24 · see citing works
Nordskog, B. K., Brown, B. G., Marano, K. M., Campell, L. R., Jones, B. A., & Borgerding, M. F. (2015) · Inhalation Toxicology · doi:10.3109/08958378.2015.1013227 · Cited by 22 · see citing works
“Second, complications in data interpretation related to between-gender and within-gender differences (especially during menstrual cycle) in biomarkers of inflammation such as the ILs and C-reactive protein (Jilma et al., 1997).”
BackgroundAcute Effect of a Single Dose of Tomato Sofrito on Plasmatic Inflammatory Biomarkers in Healthy Men
Hurtado‐Barroso, S., Martínez‐Huélamo, M., de Alvarenga, J. F. R., Quifer‐Rada, P., Vallverdú‐Queralt, A., Pérez-Fernández, S., & Lamuela-Raventós, R. M. (2019) · Nutrients · doi:10.3390/nu11040851 · Cited by 22 · see citing works
Gürsoy, A. Y., Çağlar, G. S., Kiseli, M., Pabuçcu, E., Çandar, T., & Demırtaş, S. (2015) · Interventional Medicine and Applied Science · doi:10.1556/1646.7.2015.4.2 · Cited by 21 · see citing works
“Supporting this data, 44% increase in CRP levels in midcycle was documented previously [19].”
MethodResultStudy of cardiovascular disease biomarkers among tobacco consumers, part 1: biomarkers of exposure
Campbell, L. R., Brown, B. G., Jones, B. A., Marano, K. M., & Borgerding, M. F. (2015) · Inhalation Toxicology · doi:10.3109/08958378.2015.1013228 · Cited by 21 · see citing works
“…low potential recruitment pool for the MSC group, and because of the complications in data interpretation related to between-gender and within-gender differences (especially during menstrual cycles) in biomarkers of inflammation such as the interleukins and C-reactive protein (Jilma et al., 1997).”
BackgroundInflammation, Reproduction, and the Goldilocks Principle
Clancy, K. B. H. (2012) · Springer eBooks · doi:10.1007/978-1-4614-4060-4_1 · Cited by 17 · see citing works
Abrahamsen, B., Stilgren, L. S., Rettmer, E., Bonnevie‐Nielsen, V., & Beck‐Nielsen, H. (2003) · Calcified Tissue International · doi:10.1007/s00223-002-2037-y · Cited by 17 · see citing works
“increased in the luteal phase, not the circulating amounts [11, 12, 21].”
BackgroundOkimura, H., Tanaka, Y., Fujii, M., Shimura, K., Maeda, E., Ito, F., Khan, K. N., Nakamura, Y., Mori, T., & Kitawaki, J. (2022) · American Journal of Reproductive Immunology · doi:10.1111/aji.13636 · Cited by 16 · see citing works
Sim, M., DAWSON, B. T., Landers, G. J., Swinkels, D. W., Wiegerinck, E. T. G., Yeap, B. B., Trinder, D., & Peeling, P. (2017) · Annals of Nutrition and Metabolism · doi:10.1159/000465530 · Cited by 16 · see citing works
Trzonkowski, P., Myśliwska, J. M., Łukaszuk, K., Szmit, E., Bryl, E., & Myśliwski, A. (2001) · Hormone and Metabolic Research · doi:10.1055/s-2001-15420 · Cited by 16 · see citing works
Inflammation Through a Psychoneuroimmunological Lens
Bennett, J. M., Gillie, B. L., Lindgren, M. E., Fagundes, C. P., & Kiecolt-Glaser, J. K. (2013) · Handbook of Systems and Complexity in Health · doi:10.1007/978-1-4614-4998-0_19 · Cited by 15 · see citing works
Souter, I. C., Janzen, C., Martı́nez-Maza, O., Breen, E. C., Stanczyk, F. Z., Chaudhuri, G., & Nathan, L. (2005) · Fertility and Sterility · doi:10.1016/j.fertnstert.2004.11.048 · Cited by 14 · see citing works
Souter, I. C., Huang, A., Martı́nez-Maza, O., Breen, E. C., DeCherney, A. H., Chaudhuri, G., & Nathan, L. (2008) · Fertility and Sterility · doi:10.1016/j.fertnstert.2008.04.039 · Cited by 14 · see citing works
C-reactive protein level in late-onset depression: A case–control study
Mishra, D., Sardesai, U., & Razdan, R. (2018) · Indian Journal of Psychiatry · doi:10.4103/psychiatry.indianjpsychiatry_127_17 · Cited by 13 · see citing works
“[22] Hormonal changes throughout female life due to phase of menstrual cycle, use of hormonal contraceptives, menopause, and use of estrogens greatly impact on inflammation levels,[23-25] which could confound a clear association between depression and inflammation.”
BackgroundKaraoulanis, S. E., Rizouli, K. A., Rizoulis, A. A., & Angelopoulos, N. V. (2014) · BMC Psychiatry · doi:10.1186/1471-244x-14-164 · Cited by 14 · see citing works
Lovastatin raises serum osteoprotegerin level in people with type 2 diabetic nephropathy
Nezami, N., Safa, J., Eftekharsadat, A., Salari, B., Ghorashi, S., Sakhaee, K., & Khosraviani, K. (2010) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2010.08.012 · Cited by 13 · see citing works
Park, S. W., Park, S., Kim, E., Sung, W.-S., Ha, I., & Jung, B. (2020) · Health and Quality of Life Outcomes · doi:10.1186/s12955-020-01597-5 · Cited by 12 · see citing works
Meisinger, C., Goßlau, Y., Warm, T. D., Leone, V., Hyhlik-Dürr, A., Linseisen, J., & Kirchberger, I. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.902140 · Cited by 11 · see citing works
“serum levels could be affected by hormonal/menstrual cycle (28).”
BackgroundGugapriya, T. S. (2014) · JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH · doi:10.7860/jcdr/2014/8118.4240 · Cited by 11 · see citing works
“The finding was consistent with conclusion of many previous studies [13, 26, 28, 29, 30], except the study by few authors who found no variability in measures of insulin sensitivity and glucose mediated metabolism within and between menstrual phases [24, 25, 27].”
BackgroundResultC-reactive protein level following treatment and withdrawal of lovastatin in diabetic nephropathy.
Rashtchizadeh, N., Argani, H., Ghorbanihaghjo, A., Nezami, N., Safa, J., & Montazersaheb, S. (2009) · Iranian Journal of Kidney Diseases · Cited by 11 · see citing works
Zhai, S., Li, T., Zhang, D., Qu, Y., Xie, Y., Wu, X., Zou, L., Yang, Y., Tao, F., & Tao, S. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1036739 · Cited by 9 · see citing works
“Besides, because of the potentially confounding effects of the menstrual cycle and estrogen on inflammatory biomarkers, systematic studies targeting women are highly warranted (52, 53).”
BackgroundNezami, N., Safa, J., Salari, B., Ghorashi, S., Khosraviani, K., Davari-Farid, S., Aghdam, Y. H., Nargabad, O. N., & Tabrizi, J. S. (2012) · Nucleosides Nucleotides & Nucleic Acids · doi:10.1080/15257770.2012.657763 · Cited by 9 · see citing works
“Female patients were not enrolled because periodic changes in their sexual hormones affect biochemical and inflammatory factors.[9] All participants were given an informed written consent, and the study protocol was approved by the Ethics Committee of TUMS which was in compliance with the Helsinki declaration.”
MethodLovastatin for reduction of leptin in nondialysis patients with type 2 diabetic nephropathy.
Gholamin, S., Razavi, S., Taghavi-Garmestani, S.-M., Ghorbanihaghjo, A., Rashtchizadeh, N., Safa, J., Vatankhah, A. M., Azizi, T., & Argani, H. (2014) · Iranian Journal of Kidney Diseases · Cited by 9 · see citing works
Evaluation of menstrual cycle-related changes in 85 clinical laboratory analytes
Masuda, S., Ichihara, K., Yamanishi, H., Hirano, Y., Tanaka, Y., & Kamisako, T. (2015) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/0004563215617212 · Cited by 9 · see citing works
Chen, B., Dong, J., Guo, W., & Li, T. (2024) · BMC Psychiatry · doi:10.1186/s12888-024-06123-1 · Cited by 8 · see citing works
“Variations in sex hormones, especially cyclical variations in ovarian hormones, are known to affect levels of C-reactive protein [30, 31].”
BackgroundOxygen saturation during sleep as a predictor of inflammation in anovulatory women
Araujo, P., Polesel, D. N., Hachul, H., Bittencourt, L., Tufik, S., & Andersen, M. L. (2020) · Sleep And Breathing · doi:10.1007/s11325-020-02233-8 · Cited by 8 · see citing works
Effects of insulin-lowering drugs in PCOS: endocrine, metabolic and inflammatory aspects
Rautio, K. (2006) · Cited by 7 · see citing works
Inflammation and Ovarian Function in Reproductive‐Aged Women
Long, A. M., Steiner, A. Z., Thompson, A. L., Jahnke, H. R., Harris, B. S., & Jukic, A. M. Z. (2024) · American Journal of Human Biology · doi:10.1002/ajhb.24196 · Cited by 6 · see citing works
“Elevated CRP may represent tissue repair caused by the process of follicle development and ovulation, however, the boundaries of the normative inflammatory response during the ovarian cycle are not yet well-understood (Jilma et al. 1997).”
Malan, L., Mashele, N., Malan, N. T., Harvey, B. H., Potgieter, J. C., & van Rooyen, J. M. (2016) · The Journal of Cardiovascular Nursing · doi:10.1097/jcn.0000000000000358 · Cited by 6 · see citing works
“Interleukin-6 plays a role in the induction of C-reactive protein secretion and also has effects on fibrinogen production.(39,40) Findings from this study suggest that fibrinogen in this ethnic group may be more a marker of the hemostatic/ coagulation cascade than inflammation, as seen by the unaltered fibrinogen leve…”
BackgroundGiuliani, A., Mitterhammer, H., Burda, A., Egger, G., & Glasner, A. (2004) · Fertility and Sterility · doi:10.1016/j.fertnstert.2004.05.091 · Cited by 6 · see citing works
Golabi, S., Robahat, T., Madjdinasab, N., Kamyari, N., & Naghashpour, M. (2025) · Food Science & Nutrition · doi:10.1002/fsn3.70884 · Cited by 5 · see citing works
“Consequently, it is important to standardize CRP measurements based on the menstrual cycle phase in women of reproductive age (Blum et al. 2005; Capobianco et al. 2010; Gaskins et al. 2012; Jilma et al. 1997; Wander et al. 2008; Wunder et al. 2006).”
Blood and Imaging Biomarkers in the Long-term Follow-up of Bicuspid Aortic Valve Patients
Keuning, Z. A., Hendriks, P. M., Duijnhouwer, A. L., Meccanici, F., Siebelink, H. J., van den Hoven, A. T., Geenen, L. W., Eindhoven, J. A., Baggen, V. J. M., Cuypers, J. A. A. E., et al. (2023) · CJC Open · doi:10.1016/j.cjco.2023.09.012 · Cited by 5 · see citing works
“It is 21,22 We believe that the signi fi cant sex-related differences in blood biomarker levels found in our study are similar to fi ndings in a healthy population and that these are not speci fi c to BAV.”
ResultBlood inflammatory and endothelial markers in women with von Willebrand disease
Govorov, I., Bremme, K. A., Larsson, A. O., Holmström, M., Komlichenko, E. V., Chaireti, R., & Mints, M. (2019) · PLoS ONE · doi:10.1371/journal.pone.0210544 · Cited by 5 · see citing works
Proceedings of an expert workshop on the induction and stabilisation of patients onto methadone
Humenuik, R., Ali, R. L., White, J. M., Hall, W., & Farrell, M. (2000) · Cited by 5 · see citing works
- Authors
- Jilma, B., Dirnberger, E., Löscher, I., Rumplmayr, A., Hildebrandt, J., Eichler, H.-G., Kapiotis, S., & Wagner, O. F.
- Affiliations
- Medical University of Vienna (AT)
- Corresponding author
- Jilma, Bernd
- ORCID
- Jilma, Bernd
- Venue
- Journal of Laboratory and Clinical Medicine
- Publisher
- Elsevier BV
- Published
- 1997-07
- Volume
- 130
- Issue
- 1
- Pages
- 69-75
- ISSN
- 0022-2143 (ISSN-L)
- OpenAlex
- W1969728728
- Cited by
- 117
- References
- 39
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 3 · 2016: 3 · 2015: 7 · 2014: 8 · 2013: 4 · 2012: 8
- FWCI
- 4.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Laboratory and Clinical Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Menstrual Health and Disorders
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Keywords
- menstrual cycle, interleukin-6, alpha-1-acid glycoprotein, C-reactive protein, luteal phase, follicular phase, progesterone, sex differences, premenopausal women, acute phase proteins, inflammatory markers, plasma cytokines
- MeSH terms
- Adult, C-Reactive Protein, Female, Humans, Male, Menstrual Cycle, Orosomucoid, Sex Characteristics, Cohort Studies, Interleukin-6
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