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Activation profiles of monocyte-macrophages and HDL function in healthy women in relation to menstrual cycle and in polycystic ovary syndrome patients

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Abstract

Purpose

Hormonal status and menopause affect human macrophage function and cardiometabolic risk. In polycystic ovary syndrome (PCOS) patients the cardiometabolic risk increases through mechanisms that are largely unknown. We tested the hypotheses that macrophage activation is influenced by menstrual cycle and that ovarian dysfunction in PCOS patients is associated with altered macrophage inflammatory responses and cholesterol efflux capacity of serum HDL.

Methods

Blood samples were obtained in the follicular and luteal phases from cycling women (n = 10) and on a single visit from PCOS patients with ovarian dysfunction (n = 11). Monocyte-derived macrophage activation and monocyte subsets were characterized ex vivo using flow cytometry. The capacity of HDL to promote cell cholesterol efflux through the main efflux pathways, namely aqueous diffusion, ATP-binding cassette A1 and G1, was also evaluated.

Results

Hormone and metabolic profiles differed as expected in relation to menstrual cycle and ovulatory dysfunction. Overall, macrophage responses to activating stimuli in PCOS patients were blunted compared with cycling women. Macrophages in the follicular phase were endowed with enhanced responsiveness to LPS/interferon-γ compared with the luteal phase and PCOS. These changes were not related to baseline differences in monocytes. HDL cholesterol efflux capacity through multiple pathways was significantly impaired in PCOS patients compared to healthy women, at least in part independent from lower HDL-cholesterol levels.

Conclusions

Regular menstrual cycles entailed fluctuations in macrophage activation. Such dynamic pattern was attenuated in PCOS. Along with impaired HDL function, this may contribute to the increased cardiometabolic risk associated with PCOS.

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References

  1. E.J. Benjamin, S.S. Virani, C.W. Callaway, et al. American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation 137, e67–e492 (2018)

    Article  PubMed  Google Scholar 

  2. C.R. McCartney, J.C. Marshall Clinical practice—polycystic ovary syndrome. N. Engl. J. Med. 375(1), 54–64 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  3. A. Roe, J. Hillman, S. Butts, M. Smith, D. Rader, M. Playford, N.N. Mehta, A. Dokras Decreased cholesterol efflux capacity and atherogenic lipid profile in young women with PCOS. J. Clin. Endocrinol. Metab. 99(5), E841–847 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. R.A. Wild, E. Carmina, E. Diamanti-Kandarakis, A. Dokras, H.F. Escobar-Morreale, W. Futterweit, R. Lobo, R.J. Norman, E. Talbott, D.A. Dumesic Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J. Clin. Endocrinol. Metab. 95(5), 2038–2049 (2010)

    Article  CAS  PubMed  Google Scholar 

  5. R.S. Legro, S.A. Arslanian, D.A. Ehrmann, K.M. Hoeger, M.H. Murad, R. Pasquali, C.K. Welt; Endocrine Society Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 98(12), 4565–4592 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. T. Shirai, M. Hilhorst, D.G. Harrison, J.J. Goronzy, C.M. Weyand Macrophages in vascular inflammation—from atherosclerosis to vasculitis. Autoimmunity 48(3), 139–151 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. L. Honold, M. Nahrendorf Resident and monocyte-derived macrophages in cardiovascular disease. Circ. Res. 122, 113–127 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. I. Tabas, K.E. Bornfeldt Macrophage phenotype and function in different stages of atherosclerosis. Circ. Res. 118(4), 653–667 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. A. Toniolo, G.P. Fadini, S. Tedesco, R. Cappellari, E. Vegeto, A. Maggi, A. Avogaro, C. Bolego, A. Cignarella Alternative activation of human macrophages is rescued by estrogen treatment in vitro and impaired by menopausal status. J. Clin. Endocrinol. Metab. 100(1), E50–58 (2015)

    Article  CAS  PubMed  Google Scholar 

  10. C. Bolego, A. Cignarella, B. Staels, G. Chinetti-Gbaguidi, Macrophage function and polarization in cardiovascular disease: a role of estrogen signaling? Arterioscler. Thromb. Vasc. Biol. 33(6), 1127–1134 (2013)

    Article  CAS  PubMed  Google Scholar 

  11. M. Baum Letter: variations in leucocyte count during menstrual cycle. Br. Med. J. 3(5975), 102 (1975)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. N. Daikoku, K. Kitaya, T. Nakayama, S. Fushiki, H. Honjo Expression of macrophage inflammatory protein-3beta in human endometrium throughout the menstrual cycle. Fertil. Steril. 81(Suppl 1), 876–881 (2004)

    Article  CAS  PubMed  Google Scholar 

  13. D.L. Patton, S.S. Thwin, A. Meier, T.M. Hooton, A.E. Stapleton, D.A. Eschenbach Epithelial cell layer thickness and immune cell populations in the normal human vagina at different stages of the menstrual cycle. Am. J. Obstet. Gynecol. 183(4), 967–973 (2000)

    Article  CAS  PubMed  Google Scholar 

  14. P.M. Starkey, L.M. Clover, M.C. Rees Variation during the menstrual cycle of immune cell populations in human endometrium. Eur. J. Obstet. Gynecol. Reprod. Biol. 39(3), 203–207 (1991)

    Article  CAS  PubMed  Google Scholar 

  15. I. Zanotti, E. Favari, F. Bernini Cellular cholesterol efflux pathways: impact on intracellular lipid trafficking and methodological considerations. Curr. Pharm. Biotechnol. 13(2), 292–302 (2012)

    Article  CAS  PubMed  Google Scholar 

  16. N. Ronda, E. Favari, M.O. Borghi, F. Ingegnoli, M. Gerosa, C. Chighizola, F. Zimetti, M.P. Adorni, F. Bernini, P.L. Meroni Impaired serum cholesterol efflux capacity in rheumatoid arthritis and systemic lupus erythematosus. Ann. Rheum. Dis. 73(3), 609–615 (2014)

    Article  PubMed  Google Scholar 

  17. A.V. Khera, M. Cuchel, M. de la Llera-Moya, A. Rodrigues, M.F. Burke, K. Jafri, B.C. French, J.A. Phillips, M.L. Mucksavage, R.L. Wilensky, E.R. Mohler, G.H. Rothblat, D.J. Rader Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med. 364(2), 127–135 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. A.V. Khera, O.V. Demler, S.J. Adelman, H.L. Collins, R.J. Glynn, P.M. Ridker, D.J. Rader, S. Mora Cholesterol efflux capacity, high-density lipoprotein particle number, and incident cardiovascular events: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). Circulation 135(25), 2494–2504 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. K. Yakimchuk, M. Jondal, S. Okret Estrogen receptor α and β in the normal immune system and in lymphoid malignancies. Mol. Cell. Endocrinol. 375(1–2), 121–129 (2013)

    Article  CAS  PubMed  Google Scholar 

  20. S. Nadkarni, S. McArthur Oestrogen and immunomodulation: new mechanisms that impact on peripheral and central immunity. Curr. Opin. Pharmacol. 13(4), 576–581 (2013)

    Article  CAS  PubMed  Google Scholar 

  21. J.A. McCrohon, S. Nakhla, W. Jessup, K.K. Stanley, D.S. Celermajer Estrogen and progesterone reduce lipid accumulation in human monocyte-derived macrophages: a sex-specific effect. Circulation 100(23), 2319–2325 (1999)

    Article  CAS  PubMed  Google Scholar 

  22. X. Liang, M. He, T. Chen, Y. Wu, Y. Tian, Y. Zhao, Y. Shen, Y. Liu, Z. Yuan 17β-estradiol suppresses the macrophage foam cell formation associated with SOCS3. Horm. Metab. Res. 45(6), 423–429 (2013)

    Article  CAS  PubMed  Google Scholar 

  23. A. Dokras, M. Playford, P.M. Kris-Etherton, A.R. Kunselman, C.M. Stetter, N.I. Williams, C.L. Gnatuk, S.J. Estes, D.B. Sarwer, K.C. Allison, C. Coutifaris, N. Mehta, R.S. Legro Impact of hormonal contraception and weight loss on high-density lipoprotein cholesterol efflux and lipoprotein particles in women with polycystic ovary syndrome. Clin Endocrinol. 86, 739–746 (2017)

    Article  CAS  Google Scholar 

  24. W. Rosner, R.J. Auchus, R. Azziz, P.M. Sluss, H. Raff Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J. Clin. Endocrinol. Metab. 92(2), 405–413 (2007)

    Article  CAS  PubMed  Google Scholar 

  25. S. Tedesco, M. Zusso, L. Facci, A. Trenti, C. Boscaro, F. Belluti, G.P. Fadini, S.D. Skaper, P. Giusti, C. Bolego, A. Cignarella Bisdemethoxycurcumin and its cyclized pyrazole analogue differentially disrupt lipopolysaccharide signalling in human monocyte-derived macrophages. Mediators. Inflamm. 2018, 2868702 (2018)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. S. Tedesco, F. De Majo, J. Kim, A. Trenti, L. Trevisi, G.P. Fadini, C. Bolego, P.W. Zandstra, A. Cignarella, L. Vitiello Convenience versus biological significance: are PMA-differentiated THP-1 cells a reliable substitute for blood-derived macrophages when studying in vitro polarization? Front. Pharmacol. 9, 71 (2018)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. G.P. Fadini, S.V. de Kreutzenberg, E. Boscaro, M. Albiero, R. Cappellari, N. Kränkel, U. Landmesser, A. Toniolo, C. Bolego, A. Cignarella, F. Seeger, S. Dimmeler, A. Zeiher, C. Agostini, A. Avogaro An unbalanced monocyte polarisation in peripheral blood and bone marrow of patients with type 2 diabetes has an impact on microangiopathy. Diabetologia 56(8), 1856–1866 (2013)

    Article  CAS  PubMed  Google Scholar 

  28. M.P. Adorni, N. Ferri, S. Marchianò, V. Trimarco, F. Rozza, R. Izzo, F. Bernini, F. Zimetti Effect of a novel nutraceutical combination on serum lipoprotein functional profile and circulating PCSK9. Ther. Clin. Risk. Manag. 13, 1555–1562 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. P. Mody, P.H. Joshi, A. Khera, C.R. Ayers, A. Rohatgi Beyond coronary calcification, family history, and C-reactive protein: cholesterol efflux capacity and cardiovascular risk prediction. J. Am. Coll. Cardiol. 67(21), 2480–2487 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. N. Ronda, D. Greco, M.P. Adorni, F. Zimetti, E. Favari, G. Hjeltnes, K. Mikkelsen, M.O. Borghi, E.G. Favalli, R. Gatti, I. Hollan, P.L. Meroni, F. Bernini Newly identified antiatherosclerotic activity of methotrexate and adalimumab: complementary effects on lipoprotein function and macrophage cholesterol metabolism. Arthritis Rheumatol. 67(5), 1155–1164 (2015)

    Article  CAS  PubMed  Google Scholar 

  31. L. Pisciotta, E. Favari, L. Magnolo, S. Simonelli, M.P. Adorni, R. Sallo, T. Fancello, I. Zavaroni, D. Ardigò, F. Bernini, L. Calabresi, G. Franceschini, P. Tarugi, S. Calandra, S. Bertolini Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3. Circ Cardiovasc Genet. 5(1), 42–50 (2012)

    Article  CAS  PubMed  Google Scholar 

  32. R. Cappellari, M. D’Anna, B.M. Bonora, M. Rigato, A. Cignarella, A. Avogaro, G.P. Fadini Shift of monocyte subsets along their continuum predicts cardiovascular outcomes. Atherosclerosis. 266, 95–102 (2017)

    Article  CAS  PubMed  Google Scholar 

  33. B.W. Whitcomb, S.L. Mumford, N.J. Perkins, J. Wactawski-Wende, E.R. Bertone-Johnson, K.E. Lynch, E.F. Schisterman Urinary cytokine and chemokine profiles across the menstrual cycle in healthy reproductive-aged women. Fertil. Steril. 101(5), 1383–1391 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. S. Gidwani, N. Phelan, J. McGill, A. McGowan, A. O’Connor, I.S. Young, J. Gibney, J. McEneny Polycystic ovary syndrome influences the level of serum amyloid A and activity of phospholipid transfer protein in HDL2 and HDL3. Hum. Reprod. 29, 1518–1525 (2014)

    Article  CAS  PubMed  Google Scholar 

  35. M. Miilunpohja, A. Uphoff, P. Somerharju, A. Tiitinen, K. Wähälä, M.J. Tikkanen Fatty acid esterification of lipoprotein-associated estrone in human plasma and follicular fluid. J. Steroid. Biochem. Mol. Biol. 100(1–3), 59–66 (2006)

    Article  CAS  PubMed  Google Scholar 

  36. A. Cignarella, S. Tedesco, R. Cappellari, G.P. Fadini The continuum of monocytes phenotypes: experimental evidence and prognostic utility in assessing cardiovascular risk. J. Leukoc. Biol. 103, 1021–1028 (2018)

    Article  CAS  Google Scholar 

  37. L. Ibáñez, S.E. Oberfield, S. Witchel, R.J. Auchus, R.J. Chang, E. Codner, P. Dabadghao, F. Darendeliler, N.S. Elbarbary, A. Gambineri, C. Garcia Rudaz, K.M. Hoeger, A. López-Bermejo, K. Ong, A.S. Peña, T. Reinehr, N. Santoro, M. Tena-Sempere, R. Tao, B.O. Yildiz, H. Alkhayyat, A. Deeb, D. Joel, R. Horikawa, F. de Zegher, P.A. Lee An International Consortium update: pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Horm. Res. Paediatr. 88(6), 371–395 (2017)

    Article  PubMed  CAS  Google Scholar 

  38. P.D. Lima, A.L. Nivet, Q. Wang, Y.A. Chen, A. Leader, A. Cheung, C.R. Tzeng, B.K. Tsang Polycystic ovary syndrome: possible involvement of androgen-induced, chemerin-mediated ovarian recruitment of monocytes/macrophages. Biol. Reprod. 99(4), 838–852 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  39. M. Karadeniz, M. Erdoğan, Z. Ayhan, M. Yalcin, M. Olukman, S. Cetinkalp, G.E. Alper, Z. Eroglu, A. Tetik, V. Cetintas, A.G. Ozgen, F. Saygili, C. Yilmaz Effect of G2706A and G1051A polymorphisms of the ABCA1 gene on the lipid, oxidative stress and homocystein levels in Turkish patients with polycystic ovary syndrome. Lipids. Health Dis. 10, 193 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. R. Frikke-Schmidt, B.G. Nordestgaard, G.B. Jensen, A. Tybjaerg-Hansen Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population. J. Clin. Invest. 114, 1343–1353 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. A.E. Stanhewicz, M.M. Wenner, N.S. Stachenfeld Sex differences in endothelial function important to vascular health and overall cardiovascular disease risk across the lifespan. Am. J. Physiol. Heart Circ. Physiol. 315(6), H1569–H1588 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We wish to thank Dr. Fabrizio Veglia for his valuable help in statistical analyses of HDL CEC data.

Author Contributions

G.P.F., C.B., and A.C. conceived the idea and planned the experiments. R.M., M.B., S.P., C.S., and G.P.F. conducted the clinical part of the study, S.T. and R.C performed cell culture and flow cytometry analyses, S.T. and G.P.F. carried out statistical analysis, M.P.A., N.R., and F.B performed CEC and intracellular cholesterol assays and refined statistical analyses, M.P. was responsible for laboratory medicine data. A.C. wrote the draft and all authors made substantial contributions to the final manuscript.

Funding

This study was funded by institutional funding to M.P., C.B., C.S., F.B., G.P.F., and A.C.

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Author notes

  1. These authors contributed equally: Serena Tedesco, Maria Pia Adorni

Authors and Affiliations

  1. Venetian Institute of Molecular Medicine, Padova, Italy

    Serena Tedesco, Roberta Cappellari & Gian Paolo Fadini

  2. Department of Food and Drug, University of Parma, Parma, Italy

    Maria Pia Adorni, Nicoletta Ronda & Franco Bernini

  3. Clinica Medica 3, University Hospital, Padova, Italy

    Roberto Mioni

  4. Endocrinology Unit, University Hospital, Padova, Italy

    Mattia Barbot, Silvia Pinelli & Carla Scaroni

  5. Department of Medicine, University of Padova, Padova, Italy

    Mario Plebani, Carla Scaroni, Gian Paolo Fadini & Andrea Cignarella

  6. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy

    Chiara Bolego

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  1. Serena Tedesco
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  2. Maria Pia Adorni
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Correspondence to Andrea Cignarella.

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Tedesco, S., Adorni, M.P., Ronda, N. et al. Activation profiles of monocyte-macrophages and HDL function in healthy women in relation to menstrual cycle and in polycystic ovary syndrome patients. Endocrine 66, 360–369 (2019). https://doi.org/10.1007/s12020-019-01911-2

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