Epidemiological studies suggest an association between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). This study aimed to investigate the pathophysiological markers of AD vs. T2DM for each sex separately and propose models that would distinguish control, AD, T2DM, and AD-T2DM comorbidity groups. AD and T2DM differed in levels of some circulating steroids (measured mostly by GC-MS) and in other observed characteristics, such as markers of obesity, glucose metabolism, and liver function tests. Regarding steroid metabolism, AD patients (both sexes) had significantly higher sex hormone binding globulin (SHBG), cortisol, and 17-hydroxy progesterone, and lower estradiol and 5α-androstane-3α,17β-diol, compared to T2DM patients. However, compared to healthy controls, changes in the steroid spectrum (especially increases in levels of steroids from the C21 group, including their 5α/β-reduced forms, androstenedione, etc.) were similar in patients with AD and patients with T2DM, though more expressed in diabetics. It can be assumed that many of these steroids are involved in counter-regulatory protective mechanisms that mitigate the development and progression of AD and T2DM. In conclusion, our results demonstrated the ability to effectively differentiate AD, T2DM, and controls in both men and women, distinguish the two pathologies from each other, and differentiate patients with AD and T2DM comorbidities.

3rd Faculty of Medicine Charles University Ruská 2411 100 00 Prague Czech Republic

Department of Neurology 3rd Faculty of Medicine Charles University and Thomayer University Hospital Ruská 2411 100 00 Prague Czech Republic

Institute of Endocrinology Národní 8 110 00 Prague Czech Republic

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Nichols E., Szoeke C.E., Vollset S.E., Abbasi N., Abd-Allah F., Abdela J., Aichour M.T.E., Akinyemi R.O., Alahdab F., Asgedom S.W., et al. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18:88–106. PubMed PMC

Khan M.A.B., Hashim M.J., King J.K., Govender R.D., Mustafa H., Al Kaabi J. Epidemiology of Type 2 Diabetes—Global Burden of Disease and Forecasted Trends. J. Epidemiol. Glob. Health. 2020;10:107–111. doi: 10.2991/jegh.k.191028.001. PubMed DOI PMC

Adeghate E., Donath T., Adem A. Alzheimer disease and diabetes mellitus: Do they have anything in common? Curr. Alzheimer Res. 2013;10:609–617. doi: 10.2174/15672050113109990009. 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

Matos T.M., De Souza-Talarico J.N. How stress mediators can cumulatively contribute to Alzheimer’s disease. An allostatic load approach. Dement. Neuropsychol. 2019;13:11–21. doi: 10.1590/1980-57642018dn13-010002. PubMed DOI PMC

Corbo R.M., Gambina G., Broggio E., Scarabino D., Scacchi R. Association study of two steroid biosynthesis genes (COMT and CYP17) with Alzheimer’s disease in the Italian population. J. Neurol. Sci. 2014;344:149–153. doi: 10.1016/j.jns.2014.06.045. PubMed DOI

Lloyd-Evans E., Waller-Evans H. Biosynthesis and signalling functions of central and peripheral nervous system neurosteroids in health and disease. Essays Biochem. 2020;64:591–606. PubMed PMC

Hoyer S. Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J. Neural Transm. 1998;105:415–422. doi: 10.1007/s007020050067. PubMed DOI

Accardi G., Caruso C., Colonna-Romano G., Camarda C., Monastero R., Candore G. Can Alzheimer disease be a form of type 3 diabetes? Rejuvenation Res. 2012;15:217–221. doi: 10.1089/rej.2011.1289. PubMed DOI

Xu W.L., Pedersen N.L., Keller L., Kalpouzos G., Wang H.X., Graff C., Winblad B., Backman L., Fratiglioni L. HHEX_23 AA Genotype Exacerbates Effect of Diabetes on Dementia and Alzheimer Disease: A Population-Based Longitudinal Study. PLoS Med. 2015;12:e1001853. doi: 10.1371/journal.pmed.1001853. PubMed DOI PMC

De la Monte S.M., Wands J.R. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J. Diabetes Sci. Technol. 2008;2:1101–1113. doi: 10.1177/193229680800200619. PubMed DOI PMC

Norwitz N.G., Mota A.S., Norwitz S.G., Clarke K. Multi-Loop Model of Alzheimer Disease: An Integrated Perspective on the Wnt/GSK3beta, alpha-Synuclein, and Type 3 Diabetes Hypotheses. Front. Aging Neurosci. 2019;11:184. doi: 10.3389/fnagi.2019.00184. PubMed DOI PMC

Riederer P., Bartl J., Laux G., Grunblatt E. Diabetes type II: A risk factor for depression-Parkinson-Alzheimer? Neurotox Res. 2011;19:253–265. doi: 10.1007/s12640-010-9203-1. PubMed DOI

Sanz C., Andrieu S., Sinclair A., Hanaire H., Vellas B., Group R.F.S. Diabetes is associated with a slower rate of cognitive decline in Alzheimer disease. Neurology. 2009;73:1359–1366. doi: 10.1212/WNL.0b013e3181bd80e9. PubMed DOI

Sergi G., De Rui M., Coin A., Inelmen E.M., Manzato E. Weight loss and Alzheimer’s disease: Temporal and aetiologic connections. Proc. Nutr. Soc. 2013;72:160–165. doi: 10.1017/S0029665112002753. PubMed DOI

Gillette Guyonnet S., Abellan Van Kan G., Alix E., Andrieu S., Belmin J., Berrut G., Bonnefoy M., Brocker P., Constans T., Ferry M., et al. IANA (International Academy on Nutrition and Aging) Expert Group: Weight loss and Alzheimer’s disease. J. Nutr. Health Aging. 2007;11:38–48. PubMed

Barrett-Connor E., Edelstein S.L., Corey-Bloom J., Wiederholt W.C. Weight loss precedes dementia in community-dwelling older adults. J. Am. Geriatr. Soc. 1996;44:1147–1152. doi: 10.1111/j.1532-5415.1996.tb01362.x. PubMed DOI

Qizilbash N., Gregson J., Johnson M.E., Pearce N., Douglas I., Wing K., Evans S.J.W., Pocock S.J. BMI and risk of dementia in two million people over two decades: A retrospective cohort study. Lancet Diabetes Endocrinol. 2015;3:431–436. doi: 10.1016/S2213-8587(15)00033-9. PubMed DOI

Hampl R., Bicikova M. Neuroimmunomodulatory steroids in Alzheimer dementia. J. Steroid Biochem. Mol. Biol. 2010;119:97–104. doi: 10.1016/j.jsbmb.2010.02.007. PubMed DOI

Qiao M., Chen C., Liang Y., Luo Y., Wu W. The Influence of Serum Uric Acid Level on Alzheimer’s Disease: A Narrative Review. BioMed Res. Int. 2021;2021:5525710. doi: 10.1155/2021/5525710. PubMed DOI PMC

Liu Q., Zhang J. Lipid metabolism in Alzheimer’s disease. Neurosci. Bull. 2014;30:331–345. doi: 10.1007/s12264-013-1410-3. PubMed DOI PMC

Saiz-Vazquez O., Puente-Martinez A., Ubillos-Landa S., Pacheco-Bonrostro J., Santabarbara J. Cholesterol and Alzheimer’s Disease Risk: A Meta-Meta-Analysis. Brain Sci. 2020;10:386. doi: 10.3390/brainsci10060386. PubMed DOI PMC

Zhou Z., Liang Y., Zhang X., Xu J., Lin J., Zhang R., Kang K., Liu C., Zhao C., Zhao M. Low-Density Lipoprotein Cholesterol and Alzheimer’s Disease: A Systematic Review and Meta-Analysis. Front. Aging Neurosci. 2020;12:5. doi: 10.3389/fnagi.2020.00005. PubMed DOI PMC

Akyol S., Ugur Z., Yilmaz A., Ustun I., Gorti S.K.K., Oh K., McGuinness B., Passmore P., Kehoe P.G., Maddens M.E., et al. Lipid Profiling of Alzheimer’s Disease Brain Highlights Enrichment in Glycerol(phospho)lipid, and Sphingolipid Metabolism. Cells. 2021;10:2591. doi: 10.3390/cells10102591. PubMed DOI PMC

Boden G., Laakso M. Lipids and glucose in type 2 diabetes: What is the cause and effect? Diabetes Care. 2004;27:2253–2259. doi: 10.2337/diacare.27.9.2253. PubMed DOI

Kuusisto J., Koivisto K., Mykkanen L., Helkala E.L., Vanhanen M., Hanninen T., Kervinen K., Kesaniemi Y.A., Riekkinen P.J., Laakso M. Association between features of the insulin resistance syndrome and Alzheimer’s disease independently of apolipoprotein E4 phenotype: Cross sectional population based study. BMJ. 1997;315:1045–1049. doi: 10.1136/bmj.315.7115.1045. PubMed DOI PMC

Estrada L.D., Ahumada P., Cabrera D., Arab J.P. Liver Dysfunction as a Novel Player in Alzheimer’s Progression: Looking Outside the Brain. Front. Aging Neurosci. 2019;11:174. doi: 10.3389/fnagi.2019.00174. PubMed DOI PMC

Nho K., Kueider-Paisley A., Ahmad S., MahmoudianDehkordi S., Arnold M., Risacher S.L., Louie G., Blach C., Baillie R., Han X., et al. Association of Altered Liver Enzymes with Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers. JAMA Netw. Open. 2019;2:e197978. doi: 10.1001/jamanetworkopen.2019.7978. PubMed DOI PMC

Li W., Yue L., Sun L., Xiao S. An Increased Aspartate to Alanine Aminotransferase Ratio Is Associated With a Higher Risk of Cognitive Impairment. Front. Med. 2022;9:780174. doi: 10.3389/fmed.2022.780174. PubMed DOI PMC

Mullur R., Liu Y.Y., Brent G.A. Thyroid hormone regulation of metabolism. Physiol. Rev. 2014;94:355–382. doi: 10.1152/physrev.00030.2013. PubMed DOI PMC

Choi H.J., Byun M.S., Yi D., Sohn B.K., Lee J.H., Lee J.Y., Kim Y.K., Lee D.Y., Group K.R. Associations of thyroid hormone serum levels with in-vivo Alzheimer’s disease pathologies. Alzheimer’s Res. Ther. 2017;9:64. doi: 10.1186/s13195-017-0291-5. PubMed DOI PMC

Quinlan P., Horvath A., Eckerstrom C., Wallin A., Svensson J. Altered thyroid hormone profile in patients with Alzheimer’s disease. Psychoneuroendocrinology. 2020;121:104844. doi: 10.1016/j.psyneuen.2020.104844. PubMed DOI

Kim J.W., Byun M.S., Yi D., Lee J.H., Jeon S.Y., Ko K., Jung G., Lee H.N., Lee J.Y., Sohn C.H., et al. Serum Uric Acid, Alzheimer-Related Brain Changes, and Cognitive Impairment. Front. Aging Neurosci. 2020;12:160. doi: 10.3389/fnagi.2020.00160. PubMed DOI PMC

Kim T.S., Pae C.U., Yoon S.J., Jang W.Y., Lee N.J., Kim J.J., Lee S.J., Lee C., Paik I.H., Lee C.U. Decreased plasma antioxidants in patients with Alzheimer’s disease. Int. J. Geriatr. Psychiatry. 2006;21:344–348. doi: 10.1002/gps.1469. PubMed DOI

Gonzalez-Dominguez R., Garcia-Barrera T., Gomez-Ariza J.L. Metabolite profiling for the identification of altered metabolic pathways in Alzheimer’s disease. J. Pharm. Biomed. Anal. 2015;107:75–81. doi: 10.1016/j.jpba.2014.10.010. PubMed DOI

Scheepers L., Jacobsson L.T.H., Kern S., Johansson L., Dehlin M., Skoog I. Urate and risk of Alzheimer’s disease and vascular dementia: A population-based study. Alzheimer’s Dement. J. Alzheimer’s Assoc. 2019;15:754–763. doi: 10.1016/j.jalz.2019.01.014. PubMed DOI

Boccardi V., Carino S., Marinelli E., Lapenna M., Caironi G., Bianco A.R., Cecchetti R., Ruggiero C., Mecocci P., Re G.S.G. Uric acid and late-onset Alzheimer’s disease: Results from the ReGAl 2.0 project. Aging Clin. Exp. Res. 2021;33:361–366. doi: 10.1007/s40520-020-01541-z. PubMed DOI

Hegazy S.H., Thomassen J.Q., Rasmussen I.J., Nordestgaard B.G., Tybjaerg-Hansen A., Frikke-Schmidt R. C-reactive protein levels and risk of dementia-Observational and genetic studies of 111,242 individuals from the general population. Alzheimer’s Dement. J. Alzheimer’s Assoc. 2022;18:2262–2271. doi: 10.1002/alz.12568. PubMed DOI PMC

Gong C., Wei D., Wang Y., Ma J., Yuan C., Zhang W., Yu G., Zhao Y. A Meta-Analysis of C-Reactive Protein in Patients With Alzheimer’s Disease. Am. J. Alzheimer’s Dis. Other Dement. 2016;31:194–200. doi: 10.1177/1533317515602087. PubMed DOI PMC

Somboonporn W., Davis S.R., National H., Medical Research C. Testosterone effects on the breast: Implications for testosterone therapy for women. Endocr. Rev. 2004;25:374–388. doi: 10.1210/er.2003-0016. PubMed DOI

Caldwell J.D., Jirikowski G.F. Sex hormone binding globulin and aging. Horm. Metab. Res. 2009;41:173–182. doi: 10.1055/s-0028-1093351. PubMed DOI

Hammond G.L. Endocrinology of the life span. In: Winters S.J., Huhtaniemi I.T., editors. Male Hypogonadism. Humana Press; Cham, Switzerland: 2017. pp. 305–324.

Kim C., Halter J.B. Endogenous sex hormones, metabolic syndrome, and diabetes in men and women. Curr. Cardiol. Rep. 2014;16:467. doi: 10.1007/s11886-014-0467-6. PubMed DOI PMC

Hoskin E.K., Tang M.X., Manly J.J., Mayeux R. Elevated sex-hormone binding globulin in elderly women with Alzheimer’s disease. Neurobiol. Aging. 2004;25:141–147. doi: 10.1016/S0197-4580(03)00046-0. PubMed DOI

Paoletti A.M., Congia S., Lello S., Tedde D., Orru M., Pistis M., Pilloni M., Zedda P., Loddo A., Melis G.B. Low androgenization index in elderly women and elderly men with Alzheimer’s disease. Neurology. 2004;62:301–303. doi: 10.1212/01.WNL.0000094199.60829.F5. PubMed DOI

Xu J., Xia L.L., Song N., Chen S.D., Wang G. Testosterone, Estradiol, and Sex Hormone-Binding Globulin in Alzheimer’s Disease: A Meta-Analysis. Curr. Alzheimer Res. 2016;13:215–222. doi: 10.2174/1567205013666151218145752. PubMed DOI

Xu W., Su B.J., Shen X.N., Bi Y.L., Tan C.C., Li J.Q., Cao X.P., Dong Q., Tan L., Alzheimer’s Disease Neuroimaging Initiative et al. Plasma sex hormone-binding globulin predicts neurodegeneration and clinical progression in prodromal Alzheimer’s disease. Aging. 2020;12:14528–14541. doi: 10.18632/aging.103497. PubMed DOI PMC

Marriott R.J., Murray K., Flicker L., Hankey G.J., Matsumoto A.M., Dwivedi G., Antonio L., Almeida O.P., Bhasin S., Dobs A.S., et al. Lower serum testosterone concentrations are associated with a higher incidence of dementia in men: The UK Biobank prospective cohort study. Alzheimer’s Dement. J. Alzheimer’s Assoc. 2022;18:1907–1918. doi: 10.1002/alz.12529. PubMed DOI

Perry J.R., Weedon M.N., Langenberg C., Jackson A.U., Lyssenko V., Sparso T., Thorleifsson G., Grallert H., Ferrucci L., Maggio M., et al. Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. Hum. Mol. Genet. 2010;19:535–544. doi: 10.1093/hmg/ddp522. PubMed DOI PMC

Muller M., Schupf N., Manly J.J., Mayeux R., Luchsinger J.A. Sex hormone binding globulin and incident Alzheimer’s disease in elderly men and women. Neurobiol. Aging. 2010;31:1758–1765. doi: 10.1016/j.neurobiolaging.2008.10.001. PubMed DOI PMC

Brand J.S., Wareham N.J., Dowsett M., Folkerd E., van der Schouw Y.T., Luben R.N., Khaw K.T. Associations of endogenous testosterone and SHBG with glycated haemoglobin in middle-aged and older men. Clin. Endocrinol. 2011;74:572–578. doi: 10.1111/j.1365-2265.2010.03951.x. PubMed DOI

Fenske B., Kische H., Gross S., Wallaschofski H., Volzke H., Dorr M., Nauck M., Keevil B.G., Brabant G., Haring R. Endogenous Androgens and Sex Hormone-Binding Globulin in Women and Risk of Metabolic Syndrome and Type 2 Diabetes. J. Clin. Endocrinol. Metab. 2015;100:4595–4603. doi: 10.1210/jc.2015-2546. PubMed DOI

Hu J., Zhang A., Yang S., Wang Y., Goswami R., Zhou H., Zhang Y., Wang Z., Li R., Cheng Q., et al. Combined effects of sex hormone-binding globulin and sex hormones on risk of incident type 2 diabetes. J. Diabetes. 2016;8:508–515. doi: 10.1111/1753-0407.12322. PubMed DOI

Muka T., Nano J., Jaspers L., Meun C., Bramer W.M., Hofman A., Dehghan A., Kavousi M., Laven J.S., Franco O.H. Associations of Steroid Sex Hormones and Sex Hormone-Binding Globulin With the Risk of Type 2 Diabetes in Women: A Population-Based Cohort Study and Meta-analysis. Diabetes. 2017;66:577–586. doi: 10.2337/db16-0473. PubMed DOI

Labrie F. Intracrinology and menopause: The science describing the cell-specific intracellular formation of estrogens and androgens from DHEA and their strictly local action and inactivation in peripheral tissues. Menopause. 2019;26:220–224. doi: 10.1097/GME.0000000000001177. PubMed DOI

Hill M., Triskala Z., Honcu P., Krejci M., Kajzar J., Bicikova M., Ondrejikova L., Jandova D., Sterzl I. Aging, hormones and receptors. Physiol. Res. 2020;69((Suppl. S2)):S255–S272. doi: 10.33549/physiolres.934523. PubMed DOI PMC

Tagawa N., Ohta M., Nakamura N., Nakano K., Obayashi H., Kobayashi Y. Serum concentrations of delta 5-3 beta-hydroxysteroids in type 2 diabetes mellitus. Biol. Pharm. Bull. 2002;25:1634–1638. doi: 10.1248/bpb.25.1634. PubMed DOI

Diboun I., Al-Mansoori L., Al-Jaber H., Albagha O., Elrayess M.A. Metabolomics of Lean/Overweight Insulin-Resistant Females Reveals Alterations in Steroids and Fatty Acids. J. Clin. Endocrinol. Metab. 2021;106:e638–e649. doi: 10.1210/clinem/dgaa732. PubMed DOI

Jiang J., Liu X., Liu X., Tian Z., Zhang H., Qian X., Luo Z., Wei D., Jin S., Wang C., et al. The effect of progesterone and pregnenolone on diabetes status in Chinese rural population: A dose-response analysis from Henan Rural Cohort. Eur. J. Endocrinol. 2019;181:603–614. doi: 10.1530/EJE-19-0352. PubMed DOI

Liu W., Yuan D., Han M., Huang J., Xie Y. Development and validation of a sensitive LC-MS/MS method for simultaneous quantification of thirteen steroid hormones in human serum and its application to the study of type 2 diabetes mellitus. J. Pharm. Biomed. Anal. 2021;199:114059. doi: 10.1016/j.jpba.2021.114059. PubMed DOI

Mayo W., Le Moal M., Abrous D.N. Pregnenolone sulfate and aging of cognitive functions: Behavioral, neurochemical, and morphological investigations. Horm. Behav. 2001;40:215–217. doi: 10.1006/hbeh.2001.1677. PubMed DOI

Naylor J.C., Hulette C.M., Steffens D.C., Shampine L.J., Ervin J.F., Payne V.M., Massing M.W., Kilts J.D., Strauss J.L., Calhoun P.S., et al. Cerebrospinal fluid dehydroepiandrosterone levels are correlated with brain dehydroepiandrosterone levels, elevated in Alzheimer’s disease, and related to neuropathological disease stage. J. Clin. Endocrinol. Metab. 2008;93:3173–3178. doi: 10.1210/jc.2007-1229. PubMed DOI PMC

Vankova M., Hill M., Velikova M., Vcelak J., Vacinova G., Dvorakova K., Lukasova P., Vejrazkova D., Rusina R., Holmerova I., et al. Preliminary evidence of altered steroidogenesis in women with Alzheimer’s disease: Have the patients “OLDER” adrenal zona reticularis? J. Steroid Biochem. Mol. Biol. 2016;158:157–177. doi: 10.1016/j.jsbmb.2015.12.011. PubMed DOI

Kim S.B., Hill M., Kwak Y.T., Hampl R., Jo D.H., Morfin R. Neurosteroids: Cerebrospinal fluid levels for Alzheimer’s disease and vascular dementia diagnostics. J. Clin. Endocrinol. Metab. 2003;88:5199–5206. doi: 10.1210/jc.2003-030646. PubMed DOI

Oeckl P., Otto M. A Review on MS-Based Blood Biomarkers for Alzheimer’s Disease. Neurol. Ther. 2019;8((Suppl. S2)):113–127. doi: 10.1007/s40120-019-00165-4. PubMed DOI PMC

Weill-Engerer S., David J.P., Sazdovitch V., Liere P., Eychenne B., Pianos A., Schumacher M., Delacourte A., Baulieu E.E., Akwa Y. Neurosteroid quantification in human brain regions: Comparison between Alzheimer’s and nondemented patients. J. Clin. Endocrinol. Metab. 2002;87:5138–5143. doi: 10.1210/jc.2002-020878. PubMed DOI

Schumacher M., Weill-Engerer S., Liere P., Robert F., Franklin R.J., Garcia-Segura L.M., Lambert J.J., Mayo W., Melcangi R.C., Parducz A., et al. Steroid hormones and neurosteroids in normal and pathological aging of the nervous system. Prog. Neurobiol. 2003;71:3–29. doi: 10.1016/j.pneurobio.2003.09.004. PubMed DOI

Pan X., Wu X., Kaminga A.C., Wen S.W., Liu A. Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate in Alzheimer’s Disease: A Systematic Review and Meta-Analysis. Front. Aging Neurosci. 2019;11:61. doi: 10.3389/fnagi.2019.00061. PubMed DOI PMC

Cho S.H., Jung B.H., Lee W.Y., Chung B.C. Rapid column-switching liquid chromatography/mass spectrometric assay for DHEA-sulfate in the plasma of patients with Alzheimer’s disease. Biomed. Chromatogr. BMC. 2006;20:1093–1097. doi: 10.1002/bmc.647. PubMed DOI

Nasman B., Olsson T., Backstrom T., Eriksson S., Grankvist K., Viitanen M., Bucht G. Serum dehydroepiandrosterone sulfate in Alzheimer’s disease and in multi-infarct dementia. Biol. Psychiatry. 1991;30:684–690. doi: 10.1016/0006-3223(91)90013-C. PubMed DOI

Ray L., Khemka V.K., Behera P., Bandyopadhyay K., Pal S., Pal K., Basu D., Chakrabarti S. Serum Homocysteine, Dehydroepiandrosterone Sulphate and Lipoprotein (a) in Alzheimer’s Disease and Vascular Dementia. Aging Dis. 2013;4:57–64. PubMed PMC

Hayashi K., Gonzales T.K., Kapoor A., Ziegler T.E., Meethal S.V., Atwood C.S. Development of Classification Models for the Prediction of Alzheimer’s Disease Utilizing Circulating Sex Hormone Ratios. J. Alzheimer’s Dis. JAD. 2020;76:1029–1046. doi: 10.3233/JAD-200418. PubMed DOI

Ponholzer A., Madersbacher S., Rauchenwald M., Jungwirth S., Fischer P., Tragl K.H. Serum androgen levels and their association to depression and Alzheimer dementia in a cohort of 75-year-old men over 5 years: Results of the VITA study. Int. J. Impot. Res. 2009;21:187–191. doi: 10.1038/ijir.2009.10. PubMed DOI

Bernardi F., Lanzone A., Cento R.M., Spada R.S., Pezzani I., Genazzani A.D., Luisi S., Luisi M., Petraglia F., Genazzani A.R. Allopregnanolone and dehydroepiandrosterone response to corticotropin-releasing factor in patients suffering from Alzheimer’s disease and vascular dementia. Eur. J. Endocrinol. 2000;142:466–471. doi: 10.1530/eje.0.1420466. PubMed DOI

Kalakh S., Mouihate A. Androstenediol Reduces Demyelination-Induced Axonopathy in the Rat Corpus Callosum: Impact on Microglial Polarization. Front. Cell Neurosci. 2017;11:49. doi: 10.3389/fncel.2017.00049. PubMed DOI PMC

Vecchione M.B., Eiras J., Suarez G.V., Angerami M.T., Marquez C., Sued O., Ben G., Perez H.M., Gonzalez D., Maidana P., et al. Determination of dehydroepiandrosterone and its biologically active oxygenated metabolites in human plasma evinces a hormonal imbalance during HIV-TB coinfection. Sci. Rep. 2018;8:6692. doi: 10.1038/s41598-018-24771-8. PubMed DOI PMC

Sterzl I., Hill M., Starka L., Velikova M., Kanceva R., Jemelkova J., Czernekova L., Kosztyu P., ZadraZil J., Matousovic K., et al. Patients with IgA nephropathy have altered levels of immunomodulatory C19 steroids. Glucocorticoid therapy with addition of adrenal androgens may be the choice. Physiol. Res. 2017;66((Suppl. S3)):S433–S442. doi: 10.33549/physiolres.933732. PubMed DOI

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. S4)):S617–S634. doi: 10.33549/physiolres.934794. PubMed DOI PMC

Wu H., Wu Z.G., Shi W.J., Gao H., Wu H.H., Bian F., Jia P.P., Hou Y.N. Effects of progesterone on glucose uptake in neurons of Alzheimer’s disease animals and cell models. Life Sci. 2019;238:116979. doi: 10.1016/j.lfs.2019.116979. PubMed DOI

Branisteanu D.D., Mathieu C. Progesterone in gestational diabetes mellitus: Guilty or not guilty? Trends Endocrinol. Metab. 2003;14:54–56. doi: 10.1016/S1043-2760(03)00003-1. PubMed DOI

Lu Y., Wang E., Chen Y., Zhou B., Zhao J., Xiang L., Qian Y., Jiang J., Zhao L., Xiong X., et al. Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor. J. Clin. Investig. 2020;130:3791–3804. doi: 10.1172/JCI134485. PubMed DOI PMC

Csernansky J.G., Dong H., Fagan A.M., Wang L., Xiong C., Holtzman D.M., Morris J.C. Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia. Am. J. Psychiatry. 2006;163:2164–2169. doi: 10.1176/ajp.2006.163.12.2164. PubMed DOI PMC

Green K.N., Billings L.M., Roozendaal B., McGaugh J.L., LaFerla F.M. Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer’s disease. J. Neurosci. 2006;26:9047–9056. doi: 10.1523/JNEUROSCI.2797-06.2006. PubMed DOI PMC

Chang N., Ying G., Wei L., Bin G., Chuan Y. Correlation between serum cortisol and chronic complications in patients with type 2 diabetes mellitus. J. New Med. 2021;52:260–264.

Kamba A., Daimon M., Murakami H., Otaka H., Matsuki K., Sato E., Tanabe J., Takayasu S., Matsuhashi Y., Yanagimachi M., et al. Association between Higher Serum Cortisol Levels and Decreased Insulin Secretion in a General Population. PLoS ONE. 2016;11:e0166077. doi: 10.1371/journal.pone.0166077. PubMed DOI PMC

Ortiz R., Kluwe B., Odei J.B., Echouffo Tcheugui J.B., Sims M., Kalyani R.R., Bertoni A.G., Golden S.H., Joseph J.J. The association of morning serum cortisol with glucose metabolism and diabetes: The Jackson Heart Study. Psychoneuroendocrinology. 2019;103:25–32. doi: 10.1016/j.psyneuen.2018.12.237. PubMed DOI PMC

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

Tok E.C., Ertunc D., Evruke C., Dilek S. The androgenic profile of women with non-insulin-dependent diabetes mellitus. J. Reprod. Med. 2004;49:746–752. PubMed

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

Janicki S.C., Schupf N. Hormonal influences on cognition and risk for Alzheimer’s disease. Curr. Neurol. Neurosci. Rep. 2010;10:359–366. doi: 10.1007/s11910-010-0122-6. PubMed DOI PMC

Ratnakumar A., Zimmerman S.E., Jordan B.A., Mar J.C. Estrogen activates Alzheimer’s disease genes. Alzheimer’s Dement. 2019;5:906–917. doi: 10.1016/j.trci.2019.09.004. PubMed DOI PMC

Li J., Lai H., Chen S., Zhu H., Lai S. Interaction of sex steroid hormones and obesity on insulin resistance and type 2 diabetes in men: The Third National Health and Nutrition Examination Survey. J. Diabetes Its Complicat. 2017;31:318–327. doi: 10.1016/j.jdiacomp.2016.10.022. PubMed DOI

Vikan T., Schirmer H., Njolstad I., Svartberg J. Low testosterone and sex hormone-binding globulin levels and high estradiol levels are independent predictors of type 2 diabetes in men. Eur. J. Endocrinol. 2010;162:747–754. doi: 10.1530/EJE-09-0943. PubMed DOI

Barry G., Ross I.L. Neurosteroids and sporadic Alzheimer’s diseas. Curr. Alzheimer Res. 2008;5:367–374. doi: 10.2174/156720508785132325. PubMed DOI

Munoz-Mayorga D., Guerra-Araiza C., Torner L., Morales T. Tau Phosphorylation in Female Neurodegeneration: Role of Estrogens, Progesterone, and Prolactin. Front. Endocrinol. 2018;9:133. doi: 10.3389/fendo.2018.00133. PubMed DOI PMC

Marx C.E., Trost W.T., Shampine L.J., Stevens R.D., Hulette C.M., Steffens D.C., Ervin J.F., Butterfield M.I., Blazer D.G., Massing M.W., et al. The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer’s disease. Biol. Psychiatry. 2006;60:1287–1294. doi: 10.1016/j.biopsych.2006.06.017. PubMed DOI

Afrazi S., Esmaeili-Mahani S., Sheibani V., Abbasnejad M. Neurosteroid allopregnanolone attenuates high glucose-induced apoptosis and prevents experimental diabetic neuropathic pain: In vitro and in vivo studies. J. Steroid Biochem. Mol. Biol. 2014;139:98–103. doi: 10.1016/j.jsbmb.2013.10.010. PubMed DOI

Bergman R.N. A better index of body adiposity. Obesity. 2012;20:1135. doi: 10.1038/oby.2012.99. PubMed DOI

Roberts W.C. The Friedewald-Levy-Fredrickson formula for calculating low-density lipoprotein cholesterol, the basis for lipid-lowering therapy. Am. J. Cardiol. 1988;62:345–346. doi: 10.1016/0002-9149(88)90248-2. PubMed DOI

Matthews D.R., Hosker J.P., Rudenski A.S., Naylor B.A., Treacher D.F., Turner R.C. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–419. doi: 10.1007/BF00280883. PubMed DOI

Hill M., Parizek A., Kancheva R., Duskova M., Velikova M., Kriz L., Klimkova M., Paskova A., Zizka Z., Matucha P., et al. Steroid metabolome in plasma from the umbilical artery, umbilical vein, maternal cubital vein and in amniotic fluid in normal and preterm labor. J. Steroid Biochem. Mol. Biol. 2010;121:594–610. doi: 10.1016/j.jsbmb.2009.10.012. PubMed DOI

Hill M., Hampl R., Lukac D., Lapcik O., Pouzar V., Sulcova J. Elimination of cross-reactivity by addition of an excess of cross-reactant for radioimmunoassay of 17alpha-hydroxypregnenolone. Steroids. 1999;64:341–355. doi: 10.1016/S0039-128X(99)00017-3. PubMed DOI

Vcelakova H., Hill M., Lapcik O., Parizek A. Determination of 17alpha-hydroxypregnenolone sulfate and its application in diagnostics. Steroids. 2007;72:323–327. doi: 10.1016/j.steroids.2006.11.026. PubMed DOI

Corticosteroids as Selective and Effective Modulators of Glycine Receptors