Spa treatment can effectively reestablish mood balance in patients with psychiatric disorders. In light of the adrenal gland's role as a crossroad of psychosomatic medicine, this study evaluated changes in 88 circulating steroids and their relationships with a consolidation of somatic, psychosomatic and psychiatric components from a modified N-5 neurotic questionnaire in 46 postmenopausal 50+ women with anxiety-depressive complaints. The patients underwent a standardized one-month intervention therapy with physical activity and an optimized daily regimen in a spa in the Czech Republic. All participants were on medication with selective serotonin reuptake inhibitors. An increase of adrenal steroidogenesis after intervention indicated a reinstatement of the hypothalamic-pituitary-adrenal axis. The increases of many of these steroids were likely beneficial to patients, including immunoprotective adrenal androgens and their metabolites, neuroactive steroids that stimulate mental activity but protect from excitotoxicity, steroids that suppress pain perception and fear, steroids that consolidate insulin secretion, and steroids that improve xenobiotic clearance. The positive associations between the initial values of neurotic symptoms and their declines after the intervention, as well as between initial adrenal activity and the decline of neurotic symptoms, indicate that neurotic impairment may be alleviated by such therapy provided that the initial adrenal activity is not seriously disrupted.

College of Physical Education and Sport Palestra 19700 Prague Czech Republic

Department of Rehabilitation Medicine 3rd Faculty of Medicine Charles University 12808 Prague Czech Republic

Institute of Endocrinology 11694 Prague Czech Republic

Priessnitz Spa Resort Jeseník 79003 Jeseník Czech Republic

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McRae R.I. The adrenal gland. A crossroad of psychosomatic medicine. J. Am. Osteop. Assoc. 1950;50:193–196. PubMed

Fava G.A., Sonino N. Psychosomatic medicine. Int. J. Clin. Pract. 2010;64:1155–1161. doi: 10.1111/j.1742-1241.2009.02266.x. PubMed DOI

Oken D. Multiaxial diagnosis and the psychosomatic model of disease. Psychosom. Med. 2000;62:171–175. doi: 10.1097/00006842-200003000-00002. PubMed DOI

Contoreggi C., Rice K.C., Chrousos G. Nonpeptide corticotropin-releasing hormone receptor type 1 antagonists and their applications in psychosomatic disorders. Neuroendocrinology. 2004;80:111–123. doi: 10.1159/000081785. PubMed DOI

Florio P., Zatelli M.C., Reis F.M., degli Uberti E.C., Petraglia F. Corticotropin releasing hormone: A diagnostic marker for behavioral and reproductive disorders? Front. Biosci. 2007;12:551–560. doi: 10.2741/2081. PubMed DOI

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:S433–S442. PubMed

Mastorakos G., Karoutsou E.I., Mizamtsidi M. Corticotropin releasing hormone and the immune/inflammatory response. Eur. J. Endocrinol. 2006;155:S77–S84. doi: 10.1530/eje.1.02243. DOI

Ibanez L., Potau N., Marcos M.V., de Zegher F. Corticotropin-releasing hormone as adrenal androgen secretagogue. Pediatr. Res. 1999;46:351–353. doi: 10.1203/00006450-199909000-00018. PubMed DOI

Dharia S., Parker C.R., Jr. Adrenal androgens and aging. Semin. Reprod. Med. 2004;22:361–368. doi: 10.1055/s-2004-861552. PubMed DOI

Swaab D.F., Bao A.M., Lucassen P.J. The stress system in the human brain in depression and neurodegeneration. Ageing Res. Rev. 2005;4:141–194. doi: 10.1016/j.arr.2005.03.003. PubMed DOI

Mastorakos G., Pavlatou M.G., Mizamtsidi M. The hypothalamic-pituitary-adrenal and the hypothalamic- pituitary-gonadal axes interplay. Pediatr. Endocrinol. Rev. 2006;3:172–181. PubMed

Willenberg H.S., Haase M., Papewalis C., Schott M., Scherbaum W.A., Bornstein S.R. Corticotropin-releasing hormone receptor expression on normal and tumorous human adrenocortical cells. Neuroendocrinology. 2005;82:274–281. doi: 10.1159/000093126. PubMed DOI

Sirianni R., Mayhew B.A., Carr B.R., Parker C.R., Jr., Rainey W.E. Corticotropin-releasing hormone (CRH) and urocortin act through type 1 CRH receptors to stimulate dehydroepiandrosterone sulfate production in human fetal adrenal cells. J. Clin. Endocrinol. Metab. 2005;90:5393–5400. doi: 10.1210/jc.2005-0680. PubMed DOI

Giatti S., Garcia-Segura L.M., Barreto G.E., Melcangi R.C. Neuroactive steroids, neurosteroidogenesis and sex. Progr. Neurobiol. 2019;176:1–17. doi: 10.1016/j.pneurobio.2018.06.007. PubMed DOI

Bansal R., Singh R. Exploring the potential of natural and synthetic neuroprotective steroids against neurodegenerative disorders: A literature review. Med. Res. Rev. 2018;38:1126–1158. doi: 10.1002/med.21458. PubMed DOI

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

Hill M., Ripova D., Mohr P., Kratochvilova Z., Velikova M., Duskova M., Bicikova M., Starka L. Circulating C19 steroids and progesterone metabolites in women with acute depression and anxiety disorders. Horm. Mol. Biol. Clin. Investig. 2016;26:153–164. doi: 10.1515/hmbci-2016-0002. PubMed DOI

Sramkova M., Duskova M., Hill M., Bicikova M., Ripova D., Mohr P., Starka L. The role of steroids in the prediction of affective disorders in adult men. Steroids. 2017;121:47–53. doi: 10.1016/j.steroids.2016.11.004. PubMed DOI

Bicikova M., Macova L., Kolatorova L., Hill M., Novotny J., Jandova D., Starka L. Physiological changes after spa treatment—A focus on endocrinology. Physiol. Res. 2018;67:S525–S530. PubMed

Engelsmann F., Drdkova S. [Neurotic quastionnaires N-5 and life satisfaction] Ceskoslovenska Psychologie. 1964;8:340–348.

Novotny J., Jandova D., Kubanek J., Vareka J. [Possibilities in use of self-evaluation scale N-5 in diagnostic practises] Paktick. Lékař. 2005;85:575–576.

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., 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

Storbeck K.H., Swart P., Africander D., Conradie R., Louw R., Swart A.C. 16α-hydroxyprogesterone: Origin, biosynthesis and receptor interaction. Mol. Cell Endocrinol. 2011;336:92–101. doi: 10.1016/j.mce.2010.11.016. PubMed DOI

Attardi B.J., Zeleznik A., Simhan H., Chiao J.P., Mattison D.R., Caritis S.N., Obstetric–Fetal Pharmacology Research Unit Network Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17-α hydroxyprogesterone caproate, and related progestins. Am. J. Obstet. Gynecol. 2007;197:599.e1–599.e7. doi: 10.1016/j.ajog.2007.05.024. PubMed DOI PMC

Rupprecht R., Reul J.M., Trapp T., van Steensel B., Wetzel C., Damm K., Zieglgansberger W., Holsboer F. Progesterone receptor-mediated effects of neuroactive steroids. Neuron. 1993;11:523–530. doi: 10.1016/0896-6273(93)90156-L. PubMed DOI

Katzung B.G. Basic and Clinical Pharmacology 14th Edition. McGraw-Hill Education; New York, NY, USA: 2017. p. 728.

Sterzl I., Hampl R., Sterzl J., Votruba J., Starka L. 7β-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., Montes M., Favre-Reguillon A., Chermette H., Ferroud C., Morfin R. Epimerase activity of the human 11β-hydroxysteroid dehydrogenase type 1 on 7-hydroxylated C19-steroids. J. Steroid Biochem. Mol. Biol. 2009;114:57–63. doi: 10.1016/j.jsbmb.2008.12.015. PubMed DOI

Ahlem C.N., Auci D.L., Nicoletti F., Pieters R., Kennedy M.R., Page T.M., Reading C.L., Enioutina E.Y., Frincke J.M. Pharmacology and immune modulating properties of 5-androstene-3β,7β,17β-triol, a DHEA metabolite in the human metabolome. J. Steroid Biochem. Mol. Biol. 2011;126:87–94. doi: 10.1016/j.jsbmb.2011.04.010. PubMed DOI

Hampl R., Starka L., Jansky L. Steroids and thermogenesis. Physiol. Res. 2006;55:123–131. PubMed

Lardy H., Kneer N., Wei Y., Partridge B., Marwah P. Ergosteroids. II: Biologically active metabolites and synthetic derivatives of dehydroepiandrosterone. Steroids. 1998;63:158–165. doi: 10.1016/S0039-128X(97)00159-1. PubMed DOI

Dillard G.M., Bodel P. Studies on steroid fever. II. Pyrogenic and anti-pyrogenic activity in vitro of some endogenous steroids of man. J. Clin. Investig. 1970;49:2418–2426. doi: 10.1172/JCI106461. PubMed DOI PMC

Johansson T., Frandberg P.A., Nyberg F., Le Greves P. Molecular mechanisms for nanomolar concentrations of neurosteroids at NR1/NR2B receptors. J. Pharmacol. Exp. Ther. 2008;324:759–768. doi: 10.1124/jpet.107.130518. PubMed DOI

Petrovic M., Sedlacek M., Cais O., Horak M., Chodounska H., Vyklicky L., Jr. Pregnenolone sulfate modulation of N-methyl-D-aspartate receptors is phosphorylation dependent. Neuroscience. 2009;160:616–628. doi: 10.1016/j.neuroscience.2009.02.052. PubMed DOI

Horak M., Vlcek K., Chodounska H., Vyklicky L., Jr. Subtype-dependence of N-methyl-d-aspartate receptor modulation by pregnenolone sulfate. Neuroscience. 2006;137:93–102. doi: 10.1016/j.neuroscience.2005.08.058. PubMed DOI

Adamusova E., Cais O., Vyklicky V., Kudova E., Chodounska H., Horak M., Vyklicky L., Jr. Pregnenolone sulfate activates NMDA receptor channels. Physiol. Res. 2013;62:731–736. PubMed

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

Meyer D.A., Carta M., Partridge L.D., Covey D.F., Valenzuela C.F. Neurosteroids enhance spontaneous glutamate release in hippocampal neurons. Possible role of metabotropic sigma1-like receptors. J. Biol. Chem. 2002;277:28725–28732. doi: 10.1074/jbc.M202592200. PubMed DOI

Irwin R.P., Lin S.Z., Rogawski M.A., Purdy R.H., Paul S.M. Steroid potentiation and inhibition of N-methyl-d-aspartate receptor-mediated intracellular Ca++ responses: Structure-activity studies. J. Pharmacol. Exp. Ther. 1994;271:677–682. PubMed

Sedlacek M., Korinek M., Petrovic M., Cais O., Adamusova E., Chodounska H., Vyklicky L., Jr. Neurosteroid modulation of ionotropic glutamate receptors and excitatory synaptic transmission. Physiol. Res. 2008;57:S49–S57. PubMed

Petrovic M., Sedlacek M., Horak M., Chodounska H., Vyklicky L., Jr. 20-oxo-5β-pregnan-3α-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

Vales K., Rambousek L., Holubova K., Svoboda J., Bubenikova-Valesova V., Chodounska H., Vyklicky L., Stuchlik A. 3α5β-Pregnanolone glutamate, a use-dependent NMDA antagonist, reversed spatial learning deficit in an animal model of schizophrenia. Behav. Brain Res. 2012;235:82–88. doi: 10.1016/j.bbr.2012.07.020. PubMed DOI

Yaghoubi N., Malayev A., Russek S.J., Gibbs T.T., Farb D.H. Neurosteroid modulation of recombinant ionotropic glutamate receptors. Brain Res. 1998;803:153–160. doi: 10.1016/S0006-8993(98)00644-1. PubMed DOI

Yu R., Xu X.H., Sheng M.P. Differential effects of allopregnanolone and GABA on kainate-induced lactate dehydrogenase release in cultured rat cerebral cortical cells. Acta Pharmacol. Sin. 2002;23:680–684. PubMed

Morali G., Montes P., Hernandez-Morales L., Monfil T., Espinosa-Garcia C., Cervantes M. Neuroprotective effects of progesterone and allopregnanolone on long-term cognitive outcome after global cerebral ischemia. Restorat. Neurol. Neurosci. 2011;29:1–15. PubMed

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

Kokate T.G., Svensson B.E., Rogawski M.A. Anticonvulsant activity of neurosteroids: Correlation with γ-aminobutyric acid-evoked chloride current potentiation. J. Pharmacol. Exp. Ther. 1994;270:1223–1229. PubMed

Belelli D., Lambert J.J., Peters J.A., Gee K.W., Lan N.C. Modulation of human recombinant GABAA receptors by pregnanediols. Neuropharmacology. 1996;35:1223–1231. doi: 10.1016/S0028-3908(96)00066-4. PubMed DOI

Lundgren P., Stromberg J., Backstrom T., Wang M. Allopregnanolone-stimulated GABA-mediated chloride ion flux is inhibited by 3β-hydroxy-5α-pregnan-20-one (isoallopregnanolone) Brain Res. 2003;982:45–53. doi: 10.1016/S0006-8993(03)02939-1. PubMed DOI

Wang M.D., Borra V.B., Stromberg J., Lundgren P., Haage D., Backstrom T. Neurosteroids 3β, 20 (R/S)-pregnandiols decrease offset rate of the GABA-site activation at the recombinant GABA A receptor. Eur. J. Pharmacol. 2008;586:67–73. doi: 10.1016/j.ejphar.2008.02.063. PubMed DOI

Rahman M., Lindblad C., Johansson I.M., Backstrom T., Wang M.D. Neurosteroid modulation of recombinant rat α5β2γ2L and α1β2γ2L GABA(A) receptors in Xenopus oocyte. Eur. J. Pharmacol. 2006;547:37–44. doi: 10.1016/j.ejphar.2006.07.039. PubMed DOI

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

Mtchedlishvili Z., Kapur J. A presynaptic action of the neurosteroid pregnenolone sulfate on GABAergic synaptic transmission. Mol. Pharmacol. 2003;64:857–864. doi: 10.1124/mol.64.4.857. PubMed DOI

Wang M., He Y., Eisenman L.N., Fields C., Zeng C.M., Mathews J., Benz A., Fu T., Zorumski E., Steinbach J.H., et al. 3β-hydroxypregnane steroids are pregnenolone sulfate-like GABAA receptor antagonists. J. Neurosci. 2002;22:3366–3375. doi: 10.1523/JNEUROSCI.22-09-03366.2002. PubMed DOI PMC

Maksay G., Laube B., Betz H. Subunit-specific modulation of glycine receptors by neurosteroids. Neuropharmacology. 2001;41:369–376. doi: 10.1016/S0028-3908(01)00071-5. PubMed DOI

Wu F.S., Chen S.C., Tsai J.J. Competitive inhibition of the glycine-induced current by pregnenolone sulfate in cultured chick spinal cord neurons. Brain Res. 1997;750:318–320. doi: 10.1016/S0006-8993(97)00053-X. PubMed DOI

Weir C.J., Ling A.T., Belelli D., Wildsmith J.A., Peters J.A., Lambert J.J. The interaction of anaesthetic steroids with recombinant glycine and GABAA receptors. Br. J. Anaesth. 2004;92:704–711. doi: 10.1093/bja/aeh125. PubMed DOI

ffrench-Mullen J.M., Danks P., Spence K.T. Neurosteroids modulate calcium currents in hippocampal CA1 neurons via a pertussis toxin-sensitive G-protein-coupled mechanism. J. Neurosci. 1994;14:1963–1977. doi: 10.1523/JNEUROSCI.14-04-01963.1994. PubMed DOI PMC

Bukusoglu C., Sarlak F. Pregnenolone sulfate increases intracellular Ca2+ levels in a pituitary cell line. Eur. J. Pharmacol. 1996;298:79–85. doi: 10.1016/0014-2999(95)00772-5. PubMed DOI

Dayanithi G., Tapia-Arancibia L. Rise in intracellular calcium via a nongenomic effect of allopregnanolone in fetal rat hypothalamic neurons. J. Neurosci. 1996;16:130–136. doi: 10.1523/JNEUROSCI.16-01-00130.1996. PubMed DOI PMC

Wang J.M., Brinton R.D. Allopregnanolone-induced rise in intracellular calcium in embryonic hippocampal neurons parallels their proliferative potential. BMC Neurosci. 2008;9:S11. doi: 10.1186/1471-2202-9-S2-S11. PubMed DOI PMC

Perusquia M., Villalon C.M. The relaxant effect of sex steroids in rat myometrium is independent of the γ-amino butyric acid system. Life Sci. 1996;58:913–926. doi: 10.1016/0024-3205(96)00034-3. PubMed DOI

Hidalgo A., Suzano R.C., Revuelta M.P., Sanchez-Diaz C., Baamonde A., Cantabrana B. Calcium and depolarization-dependent effect of pregnenolone derivatives on uterine smooth muscle. Gen. Pharmacol. 1996;27:879–885. doi: 10.1016/0306-3623(95)02131-0. PubMed DOI

Pathirathna S., Brimelow B.C., Jagodic M.M., Krishnan K., Jiang X., Zorumski C.F., Mennerick S., Covey D.F., Todorovic S.M., Jevtovic-Todorovic V. New evidence that both T-type calcium channels and GABAA channels are responsible for the potent peripheral analgesic effects of 5α-reduced neuroactive steroids. Pain. 2005;114:429–443. doi: 10.1016/j.pain.2005.01.009. PubMed DOI

Todorovic S.M., Pathirathna S., Brimelow B.C., Jagodic M.M., Ko S.H., Jiang X., Nilsson K.R., Zorumski C.F., Covey D.F., Jevtovic-Todorovic V. 5β-reduced neuroactive steroids are novel voltage-dependent blockers of T-type Ca2+ channels in rat sensory neurons in vitro and potent peripheral analgesics in vivo. Mol. Pharmacol. 2004;66:1223–1235. doi: 10.1124/mol.104.002402. PubMed DOI

Chen S.C., Wu F.S. Mechanism underlying inhibition of the capsaicin receptor-mediated current by pregnenolone sulfate in rat dorsal root ganglion neurons. Brain Res. 2004;1027:196–200. doi: 10.1016/j.brainres.2004.08.053. PubMed DOI

Chen S.C., Chang T.J., Wu F.S. Competitive inhibition of the capsaicin receptor-mediated current by dehydroepiandrosterone in rat dorsal root ganglion neurons. J. Pharmacol. Exp. Ther. 2004;311:529–536. doi: 10.1124/jpet.104.069096. PubMed DOI

Majeed Y., Amer M.S., Agarwal A.K., McKeown L., Porter K.E., O’Regan D.J., Naylor J., Fishwick C.W., Muraki K., Beech D.J. Stereo-selective inhibition of transient receptor potential TRPC5 cation channels by neuroactive steroids. Br. J. Pharmacol. 2011;162:1509–1520. doi: 10.1111/j.1476-5381.2010.01136.x. PubMed DOI PMC

Wagner T.F., Loch S., Lambert S., Straub I., Mannebach S., Mathar I., Dufer M., Lis A., Flockerzi V., Philipp S.E., et al. Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic β cells. Nat. Cell Biol. 2008;10:1421–1430. doi: 10.1038/ncb1801. PubMed DOI

Majeed Y., Agarwal A.K., Naylor J., Seymour V.A., Jiang S., Muraki K., Fishwick C.W., Beech D.J. Cis-isomerism and other chemical requirements of steroidal agonists and partial agonists acting at TRPM3 channels. Br. J. Pharmacol. 2010;161:430–441. doi: 10.1111/j.1476-5381.2010.00892.x. PubMed DOI PMC

Naylor J., Li J., Milligan C.J., Zeng F., Sukumar P., Hou B., Sedo A., Yuldasheva N., Majeed Y., Beri D., et al. Pregnenolone sulphate- and cholesterol-regulated TRPM3 channels coupled to vascular smooth muscle secretion and contraction. Circ. Res. 2010;106:1507–1515. doi: 10.1161/CIRCRESAHA.110.219329. PubMed DOI PMC

Ekins S., Reschly E.J., Hagey L.R., Krasowski M.D. Evolution of pharmacologic specificity in the pregnane X receptor. BMC Evol. Biol. 2008;8:103. doi: 10.1186/1471-2148-8-103. PubMed DOI PMC

Bloem L.M., Storbeck K.H., Schloms L., Swart A.C. 11β-hydroxyandrostenedione returns to the steroid arena: Biosynthesis, metabolism and function. Molecules. 2013;18:13228–13244. doi: 10.3390/molecules181113228. PubMed DOI PMC

Sulcova J., Hill M., Hampl R., Starka L. Age and sex related differences in serum levels of unconjugated dehydroepiandrosterone and its sulphate in normal subjects. J. Endocrinol. 1997;154:57–62. doi: 10.1677/joe.0.1540057. PubMed DOI

Hampl R., Hill M., Starka L. 7-Hydroxydehydroepiandrosterone epimers in the life span. J. Steroid Biochem. Mol. Biol. 2001;78:367–372. doi: 10.1016/S0960-0760(01)00108-X. PubMed DOI

Staton B.A., Mixon R.L., Dharia S., Brissie R.M., Parker C.R., Jr. Is reduced cell size the mechanism for shrinkage of the adrenal zona reticularis in aging? Endocr. Res. 2004;30:529–534. doi: 10.1081/ERC-200043617. PubMed DOI

Maninger N., Wolkowitz O.M., Reus V.I., Epel E.S., Mellon S.H. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) Front. Neuroendocrinol. 2009;30:65–91. doi: 10.1016/j.yfrne.2008.11.002. PubMed DOI PMC

Rammouz G., Lecanu L., Aisen P., Papadopoulos V. A lead study on oxidative stress-mediated dehydroepiandrosterone formation in serum: The biochemical basis for a diagnosis of Alzheimer’s disease. J. Alzheimer’s Dis. 2011;24:5–16. doi: 10.3233/JAD-2011-101941. PubMed DOI

Asaba H., Hosoya K., Takanaga H., Ohtsuki S., Tamura E., Takizawa T., Terasaki T. Blood-brain barrier is involved in the efflux transport of a neuroactive steroid, dehydroepiandrosterone sulfate, via organic anion transporting polypeptide 2. J. Neurochem. 2000;75:1907–1916. doi: 10.1046/j.1471-4159.2000.0751907.x. PubMed DOI

Wang M.D., Wahlstrom G., Backstrom T. The regional brain distribution of the neurosteroids pregnenolone and pregnenolone sulfate following intravenous infusion. J. Steroid Biochem. Mol. Biol. 1997;62:299–306. doi: 10.1016/S0960-0760(97)00041-1. 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

Kriz L., Bicikova M., Mohapl M., Hill M., Cerny I., Hampl R. Steroid sulfatase and sulfuryl transferase activities in human brain tumors. J. Steroid Biochem. Mol. Biol. 2008;109:31–39. doi: 10.1016/j.jsbmb.2007.12.004. PubMed DOI

Kriz L., Bicikova M., Hill M., Hampl R. Steroid sulfatase and sulfuryl transferase activity in monkey brain tissue. Steroids. 2005;70:960–969. doi: 10.1016/j.steroids.2005.07.005. 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

BioGPS In 2011/11/13 ed.; Affymetrix: 2015. [(accessed on 26 July 2019)]; Available online: http://biogps.org/#goto=welcome.

Uno Y., Hosaka S., Yamazaki H. Identifcation and Analysis of CYP7A1, CYP17A1, CYP20A1, CYP27A1 and CYP51A1 in Cynomolgus Macaques. Jpn. Soc. Vet. Sci. 2014;76:1647–1650. PubMed PMC

Scotney H., Symonds M.E., Law J., Budge H., Sharkey D., Manolopoulos K.N. Glucocorticoids modulate human brown adipose tissue thermogenesis in vivo. Metab. Clin. Exp. 2017;70:125–132. doi: 10.1016/j.metabol.2017.01.024. PubMed DOI PMC

De Kloet E.R., Meijer O.C., de Nicola A.F., de Rijk R.H., Joels M. Importance of the brain corticosteroid receptor balance in metaplasticity, cognitive performance and neuro-inflammation. Front. Neuroendocrinol. 2018;49:124–145. doi: 10.1016/j.yfrne.2018.02.003. PubMed DOI

Yiallouris A., Tsioutis C., Agapidaki E., Zafeiri M., Agouridis A.P., Ntourakis D., Johnson E.O. Adrenal Aging and Its Implications on Stress Responsiveness in Humans. Front. Endocrinol. 2019;10:54. doi: 10.3389/fendo.2019.00054. PubMed DOI PMC

Roelfsema F., van Heemst D., Iranmanesh A., Takahashi P., Yang R., Veldhuis J.D. Impact of age, sex and body mass index on cortisol secretion in 143 healthy adults. Endocr. Connect. 2017;6:500–509. doi: 10.1530/EC-17-0160. PubMed DOI PMC

Herbert J. Cortisol and depression: Three questions for psychiatry. Psychol. Med. 2013;43:449–469. doi: 10.1017/S0033291712000955. PubMed DOI

Borges S., Gayer-Anderson C., Mondelli V. A systematic review of the activity of the hypothalamic-pituitary-adrenal axis in first episode psychosis. Psychoneuroendocrinology. 2013;38:603–611. doi: 10.1016/j.psyneuen.2012.12.025. PubMed DOI

Papadopoulos A.S., Cleare A.J. Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome. Nat. Rev. Endocrinol. 2011;8:22–32. doi: 10.1038/nrendo.2011.153. PubMed DOI

Traustadottir T., Bosch P.R., Matt K.S. The HPA axis response to stress in women: Effects of aging and fitness. Psychoneuroendocrinology. 2005;30:392–402. doi: 10.1016/j.psyneuen.2004.11.002. PubMed DOI

Schumacher M., Denier C., Oudinet J.P., Adams D., Guennoun R. Progesterone neuroprotection: The background of clinical trial failure. J. Steroid Biochem. Mol. Biol. 2016;160:53–66. doi: 10.1016/j.jsbmb.2015.11.010. PubMed DOI

Monnet F.P., Mahe V., Robel P., Baulieu E.E. Neurosteroids, via sigma receptors, modulate the [3H]norepinephrine release evoked by N-methyl-d-aspartate in the rat hippocampus. Proc. Natl. Acad. Sci. USA. 1995;92:3774–3778. doi: 10.1073/pnas.92.9.3774. PubMed DOI PMC

Shirakawa H., Katsuki H., Kume T., Kaneko S., Akaike A. Pregnenolone sulphate attenuates AMPA cytotoxicity on rat cortical neurons. Eur. J. Neurosci. 2005;21:2329–2335. doi: 10.1111/j.1460-9568.2005.04079.x. PubMed DOI

Bender C., Rassetto M., de Olmos J.S., de Olmos S., Lorenzo A. Involvement of AMPA/kainate-excitotoxicity in MK801-induced neuronal death in the retrosplenial cortex. Neuroscience. 2010;169:720–732. doi: 10.1016/j.neuroscience.2010.05.007. PubMed DOI

Egbenya D.L., Hussain S., Lai Y.C., Xia J., Anderson A.E., Davanger S. Changes in synaptic AMPA receptor concentration and composition in chronic temporal lobe epilepsy. Mol. Cell. Neurosci. 2018;92:93–103. doi: 10.1016/j.mcn.2018.07.004. PubMed DOI

Weiss J.H. Ca permeable AMPA channels in diseases of the nervous system. Front. Mol. Neurosci. 2011;4:42. doi: 10.3389/fnmol.2011.00042. PubMed DOI PMC

Kuhse J., Betz H., Kirsch J. The inhibitory glycine receptor: Architecture, synaptic localization and molecular pathology of a postsynaptic ion-channel complex. Curr. Opin. Neurobiol. 1995;5:318–323. doi: 10.1016/0959-4388(95)80044-1. PubMed DOI

Lynch J.W., Callister R.J. Glycine receptors: A new therapeutic target in pain pathways. Curr. Opin. Investig. Drugs. 2006;7:48–53. PubMed

Felizola S.J., Maekawa T., Nakamura Y., Satoh F., Ono Y., Kikuchi K., Aritomi S., Ikeda K., Yoshimura M., Tojo K., et al. Voltage-gated calcium channels in the human adrenal and primary aldosteronism. Pt BJ. Steroid Biochem. Mol. Biol. 2014;144:410–416. doi: 10.1016/j.jsbmb.2014.08.012. PubMed DOI

Caterina M.J., Julius D. The vanilloid receptor: A molecular gateway to the pain pathway. Annu. Rev. Neurosci. 2001;24:487–517. doi: 10.1146/annurev.neuro.24.1.487. PubMed DOI

Riccio A., Li Y., Moon J., Kim K.S., Smith K.S., Rudolph U., Gapon S., Yao G.L., Tsvetkov E., Rodig S.J., et al. Essential role for TRPC5 in amygdala function and fear-related behavior. Cell. 2009;137:761–772. doi: 10.1016/j.cell.2009.03.039. PubMed DOI PMC

Kliewer S.A., Goodwin B., Willson T.M. The nuclear pregnane X receptor: A key regulator of xenobiotic metabolism. Endocr. Rev. 2002;23:687–702. doi: 10.1210/er.2001-0038. PubMed DOI

Zhang B., Cheng Q., Ou Z., Lee J.H., Xu M., Kochhar U., Ren S., Huang M., Pflug B.R., Xie W. Pregnane X receptor as a therapeutic target to inhibit androgen activity. Endocrinology. 2010;151:5721–5729. doi: 10.1210/en.2010-0708. PubMed DOI PMC

Garg A., Zhao A., Erickson S.L., Mukherjee S., Lau A.J., Alston L., Chang T.K., Mani S., Hirota S.A. Pregnane X Receptor Activation Attenuates Inflammation-Associated Intestinal Epithelial Barrier Dysfunction by Inhibiting Cytokine-Induced Myosin Light-Chain Kinase Expression and c-Jun N-Terminal Kinase 1/2 Activation. J. Pharmacol. Exp. Ther. 2016;359:91–101. doi: 10.1124/jpet.116.234096. PubMed DOI PMC

Bicikova M., Kolatorova L., Macova L., Bestak J., Hill M., Formanova P., Jandova D., Moravek O., Novotny J. [Steroidal metabolomic biomarkers as an indicator of the effect of spa therapy and balneotherapy] Rehabilitace Fyzikální Lékařství. 2018;25:99–108.

Brochu M., Belanger A. Comparative study of plasma steroid and steroid glucuronide levels in normal men and in men with benign prostatic hyperplasia. Prostate. 1987;11:33–40. doi: 10.1002/pros.2990110105. PubMed DOI

Sanchez-Guijo A., Oji V., Hartmann M.F., Traupe H., Wudy S.A. Simultaneous quantification of cholesterol sulfate, androgen sulfates, and progestagen sulfates in human serum by LC-MS/MS. J. Lipid Res. 2015;56:1843–1851. doi: 10.1194/jlr.D061499. PubMed DOI PMC

Labrie F., Belanger A., Cusan L., Gomez J.L., Candas B. Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J. Clin. Endocrinol. Metab. 1997;82:2396–2402. doi: 10.1210/jcem.82.8.4160. PubMed DOI

Brochu M., Belanger A., Dupont A., Cusan L., Labrie F. Effects of flutamide and aminoglutethimide on plasma 5α-reduced steroid glucuronide concentrations in castrated patients with cancer of the prostate. J. Steroid Biochem. 1987;28:619–622. doi: 10.1016/0022-4731(87)90388-8. PubMed DOI

Abu-Hayyeh S., Papacleovoulou G., Lovgren-Sandblom A., Tahir M., Oduwole O., Jamaludin N.A., Ravat S., Nikolova V., Chambers J., Selden C., et al. Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype. Hepatology. 2013;57:716–726. doi: 10.1002/hep.26055. PubMed DOI PMC

Meng L.J., Reyes H., Axelson M., Palma J., Hernandez I., Ribalta J., Sjovall J. Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: Effect of ursodeoxycholic acid therapy. Hepatology. 1997;26:1573–1579. doi: 10.1002/hep.510260627. PubMed DOI

Tokushige K., Hashimoto E., Kodama K., Tobari M., Matsushita N., Kogiso T., Taniai M., Torii N., Shiratori K., Nishizaki Y., et al. Serum metabolomic profile and potential biomarkers for severity of fibrosis in nonalcoholic fatty liver disease. J. Gastroenterol. 2013;48:1392–1400. doi: 10.1007/s00535-013-0766-5. PubMed DOI PMC

Trygg J., Holmes E., Lundstedt T. Chemometrics in metabonomics. J. Proteome Res. 2007;6:469–479. doi: 10.1021/pr060594q. PubMed DOI

Trygg J., Wold S. Orthogonal projections to latent structure. J. Chemometr. 2002;16:119–128. doi: 10.1002/cem.695. DOI

Madsen R., Lundstedt T., Trygg J. Chemometrics in metabolomics—A review in human disease diagnosis. Anal. Chim. Acta. 2010;659:23–33. doi: 10.1016/j.aca.2009.11.042. PubMed DOI

Meloun M., Hill M., Militky J., Kupka K. Transformation in the PC-aided biochemical data analysis. Clin. Chem. Lab. Med. 2000;38:553–559. doi: 10.1515/CCLM.2000.081. PubMed DOI

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