Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system. The manifestation of MS is related to steroid changes during the menstrual cycle and pregnancy. As data focusing on the effect of anti-MS drug treatment on steroidome are scarce, we evaluated steroidomic changes (79 steroids) in 61 female MS patients of reproductive age 39 (29, 47) years (median with quartiles) after treatment with anti-MS drugs on the GC-MS/MS platform and immunoassays (cortisol and estradiol). The changes were assessed using steroid levels and steroid molar ratios (SMRs) that may reflect the activities of steroidogenic enzymes (SMRs). A repeated measures ANOVA, followed by multiple comparisons and OPLS models, were used for statistical analyses. The anti-MS treatment decreased steroid levels in the follicular phase. Anti-CD20 monoclonal antibodies (mAb), such as ofatumumab and ocrelizumab; inhibitors of the sphingosine-1-phosphate receptor (S1PRI); and IFNβ-1a decreased circulating 17-hydroxy-pregnanes and shifted the CYP17A1 functioning from the hydroxylase- toward the lyase step. Decreased conjugated/unconjugated steroid ratios were found after treatment with anti-MS drugs, especially for glatiramer acetate and anti-CD20 mAb. In the luteal phase, IFN-β1a treatment increased steroidogenesis; both IFN-β1a and ocrelizumab increased AKR1D1, and S1PRI increased SRD5A functioning. Anti-CD20 mAb reduced the functioning of enzymes catalyzing the synthesis of immunomodulatory 7α/β and 16α-hydroxy-androgens, which may affect the severity of MS. The above findings may be important concerning the alterations in bioactive steroids, such as cortisol; active androgens and estrogens; and neuroactive, neuroprotective, and immunomodulatory steroids in terms of optimization of anti-MS treatment.

Department of Neurology 1st Faculty of Medicine Charles University 128 21 Prague Czech Republic

Department of Neurology 3FM CU and UHKV 3rd Faculty of Medicine Charles University 100 34 Prague Czech Republic

Institute of Endocrinology 110 00 Prague Czech Republic

MS Center 2nd Faculty of Medicine Charles University 150 06 Prague Czech Republic

MS Center Jihlava Hospital 586 01 Jihlava Czech Republic

See more in PubMed

Ysrraelit M.C., Correale J. Impact of sex hormones on immune function and multiple sclerosis development. Immunology. 2019;156:9–22. doi: 10.1111/imm.13004. PubMed DOI PMC

Sparaco M., Bonavita S. The role of sex hormones in women with multiple sclerosis: From puberty to assisted reproductive techniques. Front. Neuroendocrinol. 2021;60:100889. doi: 10.1016/j.yfrne.2020.100889. PubMed DOI

Smith R., Studd J.W. A pilot study of the effect upon multiple sclerosis of the menopause, hormone replacement therapy and the menstrual cycle. J. R. Soc. Med. 1992;85:612–613. doi: 10.1177/014107689208501008. PubMed DOI PMC

Argyriou A.A., Makris N. Multiple sclerosis and reproductive risks in women. Reprod. Sci. 2008;15:755–764. doi: 10.1177/1933719108324138. PubMed DOI

Trombetta A.C., Meroni M., Cutolo M. Steroids and Autoimmunity. Front. Horm. Res. 2017;48:121–132. PubMed

Kamin H.S., Kertes D.A. Cortisol and DHEA in development and psychopathology. Horm. Behav. 2017;89:69–85. doi: 10.1016/j.yhbeh.2016.11.018. PubMed DOI

Mikulska J., Juszczyk G., Gawronska-Grzywacz M., Herbet M. HPA Axis in the Pathomechanism of Depression and Schizophrenia: New Therapeutic Strategies Based on Its Participation. Brain Sci. 2021;11:1298. doi: 10.3390/brainsci11101298. PubMed DOI PMC

Cherian K., Schatzberg A.F., Keller J. HPA axis in psychotic major depression and schizophrenia spectrum disorders: Cortisol, clinical symptomatology, and cognition. Schizophr. Res. 2019;213:72–79. doi: 10.1016/j.schres.2019.07.003. PubMed DOI

Misiak B., Piotrowski P., Chec M., Samochowiec J. Cortisol and dehydroepiandrosterone sulfate in patients with schizophrenia spectrum disorders with respect to cognitive performance. Compr. Psychoneuroendocrinol. 2021;6:100041. doi: 10.1016/j.cpnec.2021.100041. PubMed DOI PMC

Ritsner M., Maayan R., Gibel A., Strous R.D., Modai I., Weizman A. Elevation of the cortisol/dehydroepiandrosterone ratio in schizophrenia patients. Eur. Neuropsychopharmacol. 2004;14:267–273. doi: 10.1016/j.euroneuro.2003.09.003. PubMed DOI

Ritsner M., Gibel A., Maayan R., Ratner Y., Ram E., Modai I., Weizman A. State and trait related predictors of serum cortisol to DHEA(S) molar ratios and hormone concentrations in schizophrenia patients. Eur. Neuropsychopharmacol. 2007;17:257–264. doi: 10.1016/j.euroneuro.2006.09.001. PubMed DOI

Kancheva R., Hill M., Novak Z., Chrastina J., Kancheva L., Starka L. Neuroactive steroids in periphery and cerebrospinal fluid. Neuroscience. 2011;191:22–27. doi: 10.1016/j.neuroscience.2011.05.054. PubMed DOI

Begemann M.J., Dekker C.F., van Lunenburg M., Sommer I.E. Estrogen augmentation in schizophrenia: A quantitative review of current evidence. Schizophr. Res. 2012;141:179–184. doi: 10.1016/j.schres.2012.08.016. PubMed DOI

Qaiser M.Z., Dolman D.E.M., Begley D.J., Abbott N.J., Cazacu-Davidescu M., Corol D.I., Fry J.P. Uptake and metabolism of sulphated steroids by the blood-brain barrier in the adult male rat. J. Neurochem. 2017;142:672–685. doi: 10.1111/jnc.14117. PubMed DOI PMC

Cai H., Cao T., Zhou X., Yao J.K. Neurosteroids in Schizophrenia: Pathogenic and Therapeutic Implications. Front. Psychiatry. 2018;9:73. doi: 10.3389/fpsyt.2018.00073. PubMed DOI PMC

Powrie Y.S.L., Smith C. Central intracrine DHEA synthesis in ageing-related neuroinflammation and neurodegeneration: Therapeutic potential? J. Neuroinflammation. 2018;15:289. doi: 10.1186/s12974-018-1324-0. PubMed DOI PMC

Honcu P., Hill M., Bicikova M., Jandova D., Velikova M., Kajzar J., Kolatorova L., Bestak J., Macova L., Kancheva R., et al. Activation of Adrenal Steroidogenesis and an Improvement of Mood Balance in Postmenopausal Females after Spa Treatment Based on Physical Activity. Int. J. Mol. Sci. 2019;20:3687. doi: 10.3390/ijms20153687. PubMed DOI PMC

Noorbakhsh F., Ellestad K.K., Maingat F., Warren K.G., Han M.H., Steinman L., Baker G.B., Power C. Impaired neurosteroid synthesis in multiple sclerosis. Pt 9Brain. 2011;134:2703–2721. doi: 10.1093/brain/awr200. PubMed DOI PMC

Noorbakhsh F., Baker G.B., Power C. Allopregnanolone and neuroinflammation: A focus on multiple sclerosis. Front. Cell Neurosci. 2014;8:134. doi: 10.3389/fncel.2014.00134. PubMed DOI PMC

Cil A.P., Leventoglu A., Sonmezer M., Soylukoc R., Oktay K. Assessment of ovarian reserve and Doppler characteristics in patients with multiple sclerosis using immunomodulating drugs. J. Turk. Ger. Gynecol. Assoc. 2009;10:213–219. PubMed PMC

Griffiths W.J., Wang Y. Sterols, Oxysterols, and Accessible Cholesterol: Signalling for Homeostasis, in Immunity and During Development. Front. Physiol. 2021;12:723224. doi: 10.3389/fphys.2021.723224. PubMed DOI PMC

Sukocheva O., Wadham C., Gamble J., Xia P. Sphingosine-1-phosphate receptor 1 transmits estrogens’ effects in endothelial cells. Steroids. 2015;104:237–245. doi: 10.1016/j.steroids.2015.10.009. PubMed DOI

Lucki N.C., Li D., Sewer M.B. Sphingosine-1-phosphate rapidly increases cortisol biosynthesis and the expression of genes involved in cholesterol uptake and transport in H295R adrenocortical cells. Mol. Cell Endocrinol. 2012;348:165–175. doi: 10.1016/j.mce.2011.08.003. PubMed DOI PMC

Guzman A., Rosales-Torres A.M., Medina-Moctezuma Z.B., Gonzalez-Aretia D., Hernandez-Coronado C.G. Effects and action mechanism of gonadotropins on ovarian follicular cells: A novel role of Sphingosine-1-Phosphate (S1P). A review. Gen. Comp. Endocrinol. 2024;357:114593. doi: 10.1016/j.ygcen.2024.114593. PubMed DOI

Siavoshi F., Ladakis D.C., Muller A., Nourbakhsh B., Bhargava P. Ocrelizumab alters the circulating metabolome in people with relapsing-remitting multiple sclerosis. Ann. Clin. Transl. Neurol. 2024;11:2485–2498. doi: 10.1002/acn3.52167. PubMed DOI PMC

Ito K., Ito N., Yadav S.K., Suresh S., Lin Y., Dhib-Jalbut S. Effect of switching glatiramer acetate formulation from 20 mg daily to 40 mg three times weekly on immune function in multiple sclerosis. Mult. Scler. J. Exp. Transl. Clin. 2021;7:20552173211032323. doi: 10.1177/20552173211032323. PubMed DOI PMC

Dargahi N., Katsara M., Tselios T., Androutsou M.E., de Courten M., Matsoukas J., Apostolopoulos V. Multiple Sclerosis: Immunopathology and Treatment Update. Brain Sci. 2017;7:78. doi: 10.3390/brainsci7070078. PubMed DOI PMC

Murdoch D., Lyseng-Williamson K.A. Spotlight on subcutaneous recombinant interferon-beta-1a (Rebif) in relapsing-remitting multiple sclerosis. BioDrugs. 2005;19:323–325. doi: 10.2165/00063030-200519050-00005. PubMed DOI

Giovannoni G., Munschauer F.E., 3rd, Deisenhammer F. Neutralising antibodies to interferon beta during the treatment of multiple sclerosis. J. Neurol. Neurosurg. Psychiatry. 2002;73:465–469. doi: 10.1136/jnnp.73.5.465. PubMed DOI PMC

Hauser S.L., Kappos L., Bar-Or A., Wiendl H., Paling D., Williams M., Gold R., Chan A., Milo R., Das Gupta A., et al. The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment. Neurol. Ther. 2023;12:1491–1515. doi: 10.1007/s40120-023-00518-0. PubMed DOI PMC

McGinley M.P., Moss B.P., Cohen J.A. Safety of monoclonal antibodies for the treatment of multiple sclerosis. Expert. Opin. Drug Saf. 2017;16:89–100. doi: 10.1080/14740338.2017.1250881. PubMed DOI

Lamb Y.N. Ocrelizumab: A Review in Multiple Sclerosis. Drugs. 2022;82:323–334. doi: 10.1007/s40265-022-01672-9. PubMed DOI PMC

Kancheva R., Hill M., Velikova M., Kancheva L., Vcelak J., Ampapa R., Zido M., Stetkarova I., Libertinova J., Vosatkova M., et al. Altered Steroidome in Women with Multiple Sclerosis. Int. J. Mol. Sci. 2024;25:12033. doi: 10.3390/ijms252212033. PubMed DOI PMC

Labrie F., Martel C., Belanger A., Pelletier G. Androgens in women are essentially made from DHEA in each peripheral tissue according to intracrinology. J. Steroid Biochem. Mol. Biol. 2017;168:9–18. doi: 10.1016/j.jsbmb.2016.12.007. PubMed DOI

Angeli A., Masera R.G., Sartori M.L., Fortunati N., Racca S., Dovio A., Staurenghi A., Frairia R. Modulation by cytokines of glucocorticoid action. Ann. N. Y. Acad. Sci. 1999;876:210–220. doi: 10.1111/j.1749-6632.1999.tb07641.x. PubMed DOI

de Kloet E.R., Joels M., Holsboer F. Stress and the brain: From adaptation to disease. Nat. Rev. Neurosci. 2005;6:463–475. doi: 10.1038/nrn1683. PubMed DOI

Hildebrandt H., Stachowiak R., Heber I., Schlake H.P., Eling P. Relation between cognitive fatigue and circadian or stress related cortisol levels in MS patients. Mult. Scler. Relat. Disord. 2020;45:102440. doi: 10.1016/j.msard.2020.102440. PubMed DOI

Slominski R.M., Tuckey R.C., Manna P.R., Jetten A.M., Postlethwaite A., Raman C., Slominski A.T. Extra-adrenal glucocorticoid biosynthesis: Implications for autoimmune and inflammatory disorders. Genes. Immun. 2020;21:150–168. doi: 10.1038/s41435-020-0096-6. PubMed DOI PMC

Tucha L., Fuermaier A.B., Koerts J., Buggenthin R., Aschenbrenner S., Weisbrod M., Thome J., Lange K.W., Tucha O. Sustained attention in adult ADHD: Time-on-task effects of various measures of attention. J. Neural Transm. 2017;124((Suppl. 1)):39–53. doi: 10.1007/s00702-015-1426-0. PubMed DOI PMC

Vedhara K., Hyde J., Gilchrist I.D., Tytherleigh M., Plummer S. Acute stress, memory, attention and cortisol. Psychoneuroendocrinology. 2000;25:535–549. doi: 10.1016/S0306-4530(00)00008-1. PubMed DOI

Pereira G.M., Soares N.M., Souza A.R., Becker J., Finkelsztejn A., Almeida R.M.M. Basal cortisol levels and the relationship with clinical symptoms in multiple sclerosis: A systematic review. Arq. Neuropsiquiatr. 2018;76:622–634. doi: 10.1590/0004-282x20180091. PubMed DOI

Heidbrink C., Hausler S.F., Buttmann M., Ossadnik M., Strik H.M., Keller A., Buck D., Verbraak E., van Meurs M., Krockenberger M., et al. Reduced cortisol levels in cerebrospinal fluid and differential distribution of 11beta-hydroxysteroid dehydrogenases in multiple sclerosis: Implications for lesion pathogenesis. Brain Behav. Immun. 2010;24:975–984. doi: 10.1016/j.bbi.2010.04.003. PubMed DOI

Foroughipour A., Norbakhsh V., Najafabadi S.H., Meamar R. Evaluating sex hormone levels in reproductive age women with multiple sclerosis and their relationship with disease severity. J. Res. Med. Sci. 2012;17:882–885. PubMed PMC

Wei T., Lightman S.L. The neuroendocrine axis in patients with multiple sclerosis. Pt 6Brain. 1997;120:1067–1076. doi: 10.1093/brain/120.6.1067. PubMed DOI

Hamidovic A., Karapetyan K., Serdarevic F., Choi S.H., Eisenlohr-Moul T., Pinna G. Higher Circulating Cortisol in the Follicular vs. Luteal Phase of the Menstrual Cycle: A Meta-Analysis. Front. Endocrinol. 2020;11:311. doi: 10.3389/fendo.2020.00311. PubMed DOI PMC

Marx C.E., Keefe R.S., Buchanan R.W., Hamer R.M., Kilts J.D., Bradford D.W., Strauss J.L., Naylor J.C., Payne V.M., Lieberman J.A., et al. Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia. Neuropsychopharmacology. 2009;34:1885–1903. doi: 10.1038/npp.2009.26. PubMed DOI PMC

Matuszewska A., Kowalski K., Jawien P., Tomkalski T., Gawel-Dabrowska D., Merwid-Lad A., Szelag E., Blaszczak K., Wiatrak B., Danielewski M., et al. The Hypothalamic-Pituitary-Gonadal Axis in Men with Schizophrenia. Int. J. Mol. Sci. 2023;24:6492. doi: 10.3390/ijms24076492. PubMed DOI PMC

Tomassini V., Pozzilli C. Sex hormones, brain damage and clinical course of Multiple Sclerosis. J. Neurol. Sci. 2009;286:35–39. doi: 10.1016/j.jns.2009.04.014. PubMed DOI

Gubbels Bupp M.R., Jorgensen T.N. Androgen-Induced Immunosuppression. Front. Immunol. 2018;9:794. doi: 10.3389/fimmu.2018.00794. PubMed DOI PMC

Tomassini V., Onesti E., Mainero C., Giugni E., Paolillo A., Salvetti M., Nicoletti F., Pozzilli C. Sex hormones modulate brain damage in multiple sclerosis: MRI evidence. J. Neurol. Neurosurg. Psychiatry. 2005;76:272–275. doi: 10.1136/jnnp.2003.033324. PubMed DOI PMC

Garcia-Estrada J., Del Rio J.A., Luquin S., Soriano E., Garcia-Segura L.M. Gonadal hormones down-regulate reactive gliosis and astrocyte proliferation after a penetrating brain injury. Brain Res. 1993;628:271–278. doi: 10.1016/0006-8993(93)90964-O. PubMed DOI

Bovolenta P., Wandosell F., Nieto-Sampedro M. CNS glial scar tissue: A source of molecules which inhibit central neurite outgrowth. Prog. Brain Res. 1992;94:367–379. PubMed

Burda J.E., Sofroniew M.V. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron. 2014;81:229–248. doi: 10.1016/j.neuron.2013.12.034. PubMed DOI PMC

Dalal M., Kim S., Voskuhl R.R. Testosterone therapy ameliorates experimental autoimmune encephalomyelitis and induces a T helper 2 bias in the autoantigen-specific T lymphocyte response. J. Immunol. 1997;159:3–6. doi: 10.4049/jimmunol.159.1.3. PubMed DOI

Caruso A., Di Giorgi Gerevini V., Castiglione M., Marinelli F., Tomassini V., Pozzilli C., Caricasole A., Bruno V., Caciagli F., Moretti A., et al. Testosterone amplifies excitotoxic damage of cultured oligodendrocytes. J. Neurochem. 2004;88:1179–1185. doi: 10.1046/j.1471-4159.2004.02284.x. PubMed DOI

Ghoumari A.M., Ibanez C., El-Etr M., Leclerc P., Eychenne B., O’Malley B.W., Baulieu E.E., Schumacher M. Progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum. J. Neurochem. 2003;86:848–859. doi: 10.1046/j.1471-4159.2003.01881.x. PubMed DOI

Bodhankar S., Wang C., Vandenbark A.A., Offner H. Estrogen-induced protection against experimental autoimmune encephalomyelitis is abrogated in the absence of B cells. Eur. J. Immunol. 2011;41:1165–1175. doi: 10.1002/eji.201040992. PubMed DOI PMC

Gupta M.K., Guryev O.L., Auchus R.J. 5alpha-reduced C21 steroids are substrates for human cytochrome P450c17. Arch. Biochem. Biophys. 2003;418:151–160. doi: 10.1016/j.abb.2003.07.003. PubMed DOI

Rege J., Nakamura Y., Wang T., Merchen T.D., Sasano H., Rainey W.E. Transcriptome profiling reveals differentially expressed transcripts between the human adrenal zona fasciculata and zona reticularis. J. Clin. Endocrinol. Metab. 2014;99:E518–E527. doi: 10.1210/jc.2013-3198. PubMed DOI PMC

Park-Chung M., Wu F.S., Purdy R.H., Malayev A.A., Gibbs T.T., Farb D.H. Distinct sites for inverse modulation of N-methyl-D-aspartate receptors by sulfated steroids. Mol. Pharmacol. 1997;52:1113–1123. doi: 10.1124/mol.52.6.1113. PubMed DOI

Park-Chung M., Malayev A., Purdy R.H., Gibbs T.T., Farb D.H. Sulfated and unsulfated steroids modulate gamma-aminobutyric acidA receptor function through distinct sites. Brain Res. 1999;830:72–87. doi: 10.1016/S0006-8993(99)01381-5. PubMed DOI

Smejkalova T., Korinek M., Krusek J., Hrcka Krausova B., Candelas Serra M., Hajdukovic D., Kudova E., Chodounska H., Vyklicky L. Endogenous neurosteroids pregnanolone and pregnanolone sulfate potentiate presynaptic glutamate release through distinct mechanisms. Br. J. Pharmacol. 2021;178:3888–3904. doi: 10.1111/bph.15529. PubMed DOI PMC

Labrie F. Adrenal androgens and intracrinology. Semin. Reprod. Med. 2004;22:299–309. doi: 10.1055/s-2004-861547. PubMed DOI

Majewska M.D. Steroid regulation of the GABAA receptor: Ligand binding, chloride transport and behaviour. Ciba Found. Symp. 1990;153:83–97; discussion 97–106. PubMed

Petrovic M., Sedlacek M., Horak M., Chodounska H., Vyklicky L., Jr. 20-oxo-5beta-pregnan-3alpha-yl sulfate is a use-dependent NMDA receptor inhibitor. J. Neurosci. 2005;25:8439–8450. doi: 10.1523/JNEUROSCI.1407-05.2005. PubMed DOI PMC

Johansson T., Le Greves P. The effect of dehydroepiandrosterone sulfate and allopregnanolone sulfate on the binding of [(3)H]ifenprodil to the N-methyl-d-aspartate receptor in rat frontal cortex membrane. J. Steroid Biochem. Mol. Biol. 2005;94:263–266. doi: 10.1016/j.jsbmb.2005.01.020. PubMed DOI

Barnard L., Gent R., van Rooyen D., Swart A.C. Adrenal C11-oxy C(21) steroids contribute to the C11-oxy C(19) steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone. J. Steroid Biochem. Mol. Biol. 2017;174:86–95. doi: 10.1016/j.jsbmb.2017.07.034. PubMed DOI

do Nascimento F.V., Piccoli V., Beer M.A., von Frankenberg A.D., Crispim D., Gerchman F. Association of HSD11B1 polymorphic variants and adipose tissue gene expression with metabolic syndrome, obesity and type 2 diabetes mellitus: A systematic review. Diabetol. Metab. Syndr. 2015;7:38. doi: 10.1186/s13098-015-0036-1. PubMed DOI PMC

Bottasso O., Bay M.L., Besedovsky H., del Rey A. The immuno-endocrine component in the pathogenesis of tuberculosis. Scand. J. Immunol. 2007;66:166–175. doi: 10.1111/j.1365-3083.2007.01962.x. PubMed DOI

Du C., Khalil M.W., Sriram S. Administration of dehydroepiandrosterone suppresses experimental allergic encephalomyelitis in SJL/J mice. J. Immunol. 2001;167:7094–7101. doi: 10.4049/jimmunol.167.12.7094. PubMed DOI

Rontzsch A., Thoss K., Petrow P.K., Henzgen S., Brauer R. Amelioration of murine antigen-induced arthritis by dehydroepiandrosterone (DHEA) Inflamm. Res. 2004;53:189–198. PubMed

Tan X.D., Dou Y.C., Shi C.W., Duan R.S., Sun R.P. Administration of dehydroepiandrosterone ameliorates experimental autoimmune neuritis in Lewis rats. J. Neuroimmunol. 2009;207:39–44. doi: 10.1016/j.jneuroim.2008.11.011. PubMed DOI

Choi I.S., Cui Y., Koh Y.A., Lee H.C., Cho Y.B., Won Y.H. Effects of dehydroepiandrosterone on Th2 cytokine production in peripheral blood mononuclear cells from asthmatics. Korean J. Intern. Med. 2008;23:176–181. doi: 10.3904/kjim.2008.23.4.176. PubMed DOI PMC

Sudo N., Yu X.N., Kubo C. Dehydroepiandrosterone attenuates the spontaneous elevation of serum IgE level in NC/Nga mice. Immunol. Lett. 2001;79:177–179. doi: 10.1016/S0165-2478(01)00285-1. PubMed DOI

Kasperska-Zajac A., Brzoza Z., Rogala B. Dehydroepiandrosterone and dehydroepiandrosterone sulphate in atopic allergy and chronic urticaria. Inflammation. 2008;31:141–145. doi: 10.1007/s10753-008-9059-1. PubMed DOI

Romagnani S., Kapsenberg M., Radbruch A., Adorini L. Th1 and Th2 cells. Res. Immunol. 1998;149:871–873. doi: 10.1016/S0923-2494(99)80016-9. PubMed DOI

Pratschke S., von Dossow-Hanfstingl V., Dietz J., Schneider C.P., Tufman A., Albertsmeier M., Winter H., Angele M.K. Dehydroepiandrosterone modulates T-cell response after major abdominal surgery. J. Surg. Res. 2014;189:117–125. doi: 10.1016/j.jss.2014.02.002. PubMed DOI

Sterzl I., Hampl R., Sterzl J., Votruba J., Starka L. 7Beta-OH-DHEA counteracts dexamethasone induced suppression of primary immune response in murine spleenocytes. J. Steroid Biochem. Mol. Biol. 1999;71:133–137. doi: 10.1016/S0960-0760(99)00134-X. PubMed DOI

Hennebert O., Chalbot S., Alran S., Morfin R. Dehydroepiandrosterone 7alpha-hydroxylation in human tissues: Possible interference with type 1 11beta-hydroxysteroid dehydrogenase-mediated processes. J. Steroid Biochem. Mol. Biol. 2007;104:326–333. doi: 10.1016/j.jsbmb.2007.03.026. PubMed DOI

Le Mee S., Hennebert O., Ferrec C., Wulfert E., Morfin R. 7beta-Hydroxy-epiandrosterone-mediated regulation of the prostaglandin synthesis pathway in human peripheral blood monocytes. Steroids. 2008;73:1148–1159. doi: 10.1016/j.steroids.2008.05.001. PubMed DOI

Pettersson H., Lundqvist J., Norlin M. Effects of CYP7B1-mediated catalysis on estrogen receptor activation. Biochim. Biophys. Acta. 2010;1801:1090–1097. doi: 10.1016/j.bbalip.2010.05.011. PubMed DOI

Tang W., Eggertsen G., Chiang J.Y., Norlin M. Estrogen-mediated regulation of CYP7B1: A possible role for controlling DHEA levels in human tissues. J. Steroid Biochem. Mol. Biol. 2006;100:42–51. doi: 10.1016/j.jsbmb.2006.02.005. PubMed DOI

Ahlem C.N., Page T.M., Auci D.L., Kennedy M.R., Mangano K., Nicoletti F., Ge Y., Huang Y., White S.K., Villegas S., et al. Novel components of the human metabolome: The identification, characterization and anti-inflammatory activity of two 5-androstene tetrols. Steroids. 2011;76:145–155. doi: 10.1016/j.steroids.2010.10.005. PubMed DOI

Reading C.L., Frincke J.M., White S.K. Molecular targets for 17alpha-ethynyl-5-androstene-3beta,7beta,17beta-triol, an anti-inflammatory agent derived from the human metabolome. PLoS ONE. 2012;7:e32147. doi: 10.1371/journal.pone.0032147. PubMed DOI PMC

Reddy D.S. Neurosteroids: Endogenous role in the human brain and therapeutic potentials. Prog. Brain Res. 2010;186:113–137. PubMed PMC

Balan I., Beattie M.C., O’Buckley T.K., Aurelian L., Morrow A.L. Endogenous Neurosteroid (3alpha,5alpha)3-Hydroxypregnan-20-one Inhibits Toll-like-4 Receptor Activation and Pro-inflammatory Signaling in Macrophages and Brain. Sci. Rep. 2019;9:1220. doi: 10.1038/s41598-018-37409-6. PubMed DOI PMC

Lapchak P.A. The neuroactive steroid 3-alpha-ol-5-beta-pregnan-20-one hemisuccinate, a selective NMDA receptor antagonist improves behavioral performance following spinal cord ischemia. Brain Res. 2004;997:152–158. doi: 10.1016/j.brainres.2003.10.047. PubMed DOI

Kudova E., Mares P., Hill M., Vondrakova K., Tsenov G., Chodounska H., Kubova H., Vales K. The Neuroactive Steroid Pregnanolone Glutamate: Anticonvulsant Effect, Metabolites and Its Effect on Neurosteroid Levels in Developing Rat Brains. Pharmaceuticals. 2021;15:49. doi: 10.3390/ph15010049. PubMed DOI PMC

Abramova V., Leal Alvarado V., Hill M., Smejkalova T., Maly M., Vales K., Dittert I., Bozikova P., Kysilov B., Hrcka Krausova B., et al. Effects of Pregnanolone Glutamate and Its Metabolites on GABA(A) and NMDA Receptors and Zebrafish Behavior. ACS Chem. Neurosci. 2023;14:1870–1883. doi: 10.1021/acschemneuro.3c00131. PubMed DOI PMC

Munawar Cheema M., Macakova Kotrbova Z., Hrcka Krausova B., Adla S.K., Slavikova B., Chodounska H., Kratochvil M., Vondrasek J., Sedlak D., Balastik M., et al. 5beta-reduced neuroactive steroids as modulators of growth and viability of postnatal neurons and glia. J. Steroid Biochem. Mol. Biol. 2024;239:106464. doi: 10.1016/j.jsbmb.2024.106464. PubMed DOI

Akwa Y. Steroids and Alzheimer’s Disease: Changes Associated with Pathology and Therapeutic Potential. Int. J. Mol. Sci. 2020;21:4812. doi: 10.3390/ijms21134812. PubMed DOI PMC

Hill M., Parizek A., Simjak P., Koucky M., Anderlova K., Krejci H., Vejrazkova D., Ondrejikova L., Cerny A., Kancheva R. Steroids, steroid associated substances and gestational diabetes mellitus. Physiol. Res. 2021;70((Suppl. 4)):S617–S634. doi: 10.33549/physiolres.934794. PubMed DOI PMC

Burczynski M.E., Sridhar G.R., Palackal N.T., Penning T.M. The reactive oxygen species--and Michael acceptor-inducible human aldo-keto reductase AKR1C1 reduces the alpha,beta-unsaturated aldehyde 4-hydroxy-2-nonenal to 1,4-dihydroxy-2-nonene. J. Biol. Chem. 2001;276:2890–2897. doi: 10.1074/jbc.M006655200. PubMed DOI

Murgia F., Giagnoni F., Lorefice L., Caria P., Dettori T., D’Alterio M.N., Angioni S., Hendren A.J., Caboni P., Pibiri M., et al. Sex Hormones as Key Modulators of the Immune Response in Multiple Sclerosis: A Review. Biomedicines. 2022;10:3107. doi: 10.3390/biomedicines10123107. PubMed DOI PMC

Xu C., Liu W., You X., Leimert K., Popowycz K., Fang X., Wood S.L., Slater D.M., Sun Q., Gu H., et al. PGF2alpha modulates the output of chemokines and pro-inflammatory cytokines in myometrial cells from term pregnant women through divergent signaling pathways. Mol. Hum. Reprod. 2015;21:603–614. doi: 10.1093/molehr/gav018. PubMed DOI PMC

Zheng L., Fei J., Feng C.M., Xu Z., Fu L., Zhao H. Serum 8-iso-PGF2alpha Predicts the Severity and Prognosis in Patients With Community-Acquired Pneumonia: A Retrospective Cohort Study. Front. Med. 2021;8:633442. doi: 10.3389/fmed.2021.633442. PubMed DOI PMC

Sharma I., Dhaliwal L.K., Saha S.C., Sangwan S., Dhawan V. Role of 8-iso-prostaglandin F2alpha and 25-hydroxycholesterol in the pathophysiology of endometriosis. Fertil. Steril. 2010;94:63–70. doi: 10.1016/j.fertnstert.2009.01.141. PubMed DOI

Tchernof A., Mansour M.F., Pelletier M., Boulet M.M., Nadeau M., Luu-The V. Updated survey of the steroid-converting enzymes in human adipose tissues. J. Steroid Biochem. Mol. Biol. 2015;147:56–69. doi: 10.1016/j.jsbmb.2014.11.011. PubMed DOI

Nakamura Y., Hornsby P.J., Casson P., Morimoto R., Satoh F., Xing Y., Kennedy M.R., Sasano H., Rainey W.E. Type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) contributes to testosterone production in the adrenal reticularis. J. Clin. Endocrinol. Metab. 2009;94:2192–2198. doi: 10.1210/jc.2008-2374. PubMed DOI PMC

Ostinelli G., Vijay J., Vohl M.C., Grundberg E., Tchernof A. AKR1C2 and AKR1C3 expression in adipose tissue: Association with body fat distribution and regulatory variants. Mol. Cell Endocrinol. 2021;527:111220. doi: 10.1016/j.mce.2021.111220. PubMed DOI PMC

Rizner T.L., Penning T.M. Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism. Steroids. 2014;79:49–63. doi: 10.1016/j.steroids.2013.10.012. PubMed DOI PMC

Luu-The V. Assessment of steroidogenesis and steroidogenic enzyme functions. J. Steroid Biochem. Mol. Biol. 2013;137:176–182. doi: 10.1016/j.jsbmb.2013.05.017. PubMed DOI

Miller W.L., Auchus R.J. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr. Rev. 2011;32:81–151. doi: 10.1210/er.2010-0013. PubMed DOI PMC

Thompson A.J., Banwell B.L., Barkhof F., Carroll W.M., Coetzee T., Comi G., Correale J., Fazekas F., Filippi M., Freedman M.S., et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17:162–173. doi: 10.1016/S1474-4422(17)30470-2. PubMed DOI

Hill M., Hana V., Jr., Velikova M., Parizek A., Kolatorova L., Vitku J., Skodova T., Simkova M., Simjak P., Kancheva R., et al. A method for determination of one hundred endogenous steroids in human serum by gas chromatography-tandem mass spectrometry. Physiol. Res. 2019;68:179–207. doi: 10.33549/physiolres.934124. PubMed DOI