Abstract
Several endocrine glands produce steroid hormones. Thanks to the work of chemists and biochemists, the main synthetic as well as metabolic pathways of steroid hormones were included in the textbooks more than 50 years ago and the classical endocrine gland functions were identified. Later on, evidence of steroid hormone effects beyond the classical endocrine gland function has been accumulating. Testosterone was shown to participate in the stress response and may influence coping with stressors. We have shown a decrease in testosterone concentrations in saliva in children undergoing a school exam compared to values on a non-exam school day. Testosterone has been associated with different cognitive functions in both adults and children. Circulating testosterone has been linked to negative symptoms of schizophrenia. Aldosterone is acting via mineralocorticoid receptors, which are thought to be fully occupied by glucocorticoids in the brain. Until now, an action of aldosterone in the brain has not been considered at all, because the enzyme 11-beta-hydroxysteroid dehydrogenase type 2, which would enable aldosterone to bind to receptors is absent in most of the brain areas. We have brought evidence that aldosterone can act in the brain and produce anxiogenic and depressogenic effects. To facilitate the translation of animal findings into clinical research, we have developed methodology for measurement of salivary aldosterone and obtained first data on a relationship between salivary aldosterone and trait anxiety. We have shown that salivary aldosterone concentrations reflect treatment outcome in patients with major depressive disorder.
Keywords: Androgens, mineralocorticoid, stress, cognition, children, psychiatric disorders.
Graphical Abstract
[2]
Melmed, S.; Polonsky, K.S.; Larsen, R.L.; Kronenberg, H.M. Williams Textbook of Endocrinology, 13th ed; Elsevier Health Sciences, 2015.
[3]
Beato, M.; Klug, J. Steroid hormone receptors: An update. Hum. Reprod. Update, 2000, 6(3), 225-236.
[4]
Melmed, S.; Polonsky, K.S.; Larsen, P.R.; Kronenberg, H.M. Williams Textbook of Endocrinology, 13th ed; Elsevier: Philadelphia, 2016.
[5]
Fatranska, M.; Repcekova-Jezova, D.; Jurcovicova, J.; Vigas, M. LH and testosterone response to LH-RH in blind men. Horm. Metab. Res., 1978, 10(1), 82-83.
[6]
Jezova, D.; Komadel, L.; Mikulaj, L. Plasma testosterone response to repeated human chorionic gonadotropin administration is increased in trained athletes. Endocrinol. Exp., 1987, 21(2), 143-147.
[7]
Repcekova, D.; Mikulaj, L. Plasma testosterone response to HCG in normal men without and after administration of anabolic drug. Endokrinologie, 1977, 69(1), 115-118.
[8]
Repcekova, D.; Mikulaj, L. Plasma testosterone of rats subjected to immobilization stress and/or HCG administration. Horm. Res., 1977, 8(1), 51-57.
[9]
Taché, Y.; Ducharme, J.R.; Charpenet, G.; Haour, F.; Saez, J.; Collu, R. Effect of chronic intermittent immobilization stress on hypophyso-gonadal function of rats. Acta Endocrinol. (Copenh.), 1980, 93(2), 168-174.
[10]
Jezova, D.; Vigas, M. Testosterone response to exercise during blockade and stimulation of adrenergic receptors in man. Horm. Res., 1981, 15(3), 141-147.
[11]
Jezova-Repcekova, D.; Vigas, M.; Mikulaj, L.; Jurcovicova, J. Plasma testosterone during bicycle ergometer exercise without and after L-dopa pretreatment. Endocrinol. Exp., 1982, 16(1), 3-8.
[12]
Jezova, D.; Vigas, M.; Tatar, P.; Kvetnansky, R.; Nazar, K.; Kaciuba-Uścilko, H.; Kozlowski, S. Plasma testosterone and catecholamine responses to physical exercise of different intensities in men. Eur. J. Appl. Physiol. Occup. Physiol., 1985, 54(1), 62-66.
[13]
Daly, W.; Seegers, C.A.; Rubin, D.A.; Dobridge, J.D.; Hackney, A.C. Relationship between stress hormones and testosterone with prolonged endurance exercise. Eur. J. Appl. Physiol., 2005, 93(4), 375-380.
[14]
Afrisham, R.; Sadegh-Nejadi, S. SoliemaniFar, O.; Kooti, W.; Ashtary-Larky, D.; Alamiri, F.; Aberomand, M.; Najjar-Asl, S.; Khaneh-Keshi, A. Salivary testosterone levels under psychological stress and its relationship with rumination and five personality traits in medical students. Psychiatry Investig., 2016, 13(6), 637-643.
[15]
Kuusi, T.; Kostiainen, E.; Vartiainen, E.; Pitkänen, L.; Ehnholm, C.; Korhonen, H.J.; Nissinen, A.; Puska, P. Acute effects of marathon running on levels of serum lipoproteins and androgenic hormones in healthy males. Metabolism, 1984, 33(6), 527-531.
[16]
Tauler, P.; Martinez, S.; Moreno, C.; Martínez, P.; Aguilo, A. Changes in salivary hormones, immunoglobulin A, and C-reactive protein in response to ultra-endurance exercises. Appl. Physiol. Nutr. Metab., 2014, 39, 560-565.
[17]
Kapsdorfer, D.; Hlavacova, N.; Vondrova, D.; Argalasova, L.; Sevcikova, L.; Jezova, D. Neuroendocrine response to school load in prepubertal children: Focus on trait anxiety. Cell. Mol. Neurobiol., 2018, 38(1), 155-162.
[18]
Gerra, G.; Zaimovic, A.; Zambelli, U.; Timpano, M.; Reali, N.; Bernasconi, S.; Brambilla, F. Neuroendocrine responses to psychological stress in adolescents with anxiety disorder. Neuropsychobiology, 2000, 42(2), 82-92.
[19]
Wegner, M.; Koedijker, J.M.; Budde, H. The effect of acute exercise and psychosocial stress on fine motor skills and testosterone concentration in the saliva of high school students. PLoS One, 2014, 9(3)e92953
[20]
Prastyo, D.B.; Deliana, M.; Dimyati, Y.; Arto, K.S. The effect of psychological stress on salivary testosterone in puberty children. Open Access Maced. J. Med. Sci., 2018, 6(9), 1611-1616.
[21]
Crewther, B.T.; Obmiński, Z.; Orysiak, J.; Al-Dujaili, E.A.S. The utility of salivary testosterone and cortisol concentration measures for assessing the stress responses of junior athletes during a sporting competition. J. Clin. Lab. Anal., 2018, 32(1), [Epub 2017 Mar
13]. DOI: 10.1002/jcla.22197.,
[22]
Davis, S.R.; Wahlin-Jacobsen, S. Testosterone in women--the clinical significance. Lancet Diabetes Endocrinol., 2015, 3(12), 980-992.
[23]
Drake, E.B.; Henderson, V.W.; Stanczyk, F.Z.; McCleary, C.A.; Brown, W.S.; Smith, C.A.; Rizzo, A.A.; Murdock, G.A.; Buckwalter, J.G. Associations between circulating sex steroid hormones and cognition in normal elderly women. Neurology, 2000, 54(3), 599-603.
[24]
Wolf, O.T.; Kirschbaum, C. Endogenous estradiol and testosterone levels are associated with cognitive performance in older women and men. Horm. Behav., 2002, 41(3), 259-266.
[25]
Kocoska-Maras, L.; Rådestad, A.F.; Carlström, K.; Bäckström, T.; von Schoultz, B.; Hirschberg, A.L. Cognitive function in association with sex hormones in postmenopausal women. Gynecol. Endocrinol., 2013, 29(1), 59-62.
[26]
Cherrier, M.M.; Anderson, K.; Shofer, J.; Millard, S.; Matsumoto, A.M. Testosterone treatment of men with mild cognitive impairment and low testosterone levels. Am. J. Alzheimers Dis. Other Demen., 2015, 30(4), 421-430.
[27]
Wahjoepramono, E.J.; Asih, P.R.; Aniwiyanti, V.; Taddei, K.; Dhaliwal, S.S.; Fuller, S.J.; Foster, J.; Carruthers, M.; Verdile, G.; Sohrabi, H.R.; Martins, R.N. The effects of testosterone supplementation on cognitive functioning in older men. CNS Neurol. Disord. Drug Targets, 2016, 15(3), 337-343.
[28]
Hampson, E. Endocrine contributions to sex differences in visuospatial perception and cognition.In: Sex differences in the brain: From genes to behavior; Becker, J.B.; Berkley, K.J.; Geary, N.; Hampson, E.; Herman, J.; Young, E., Eds.; Oxford University Press: New York, 2007, pp. 311-325.
[29]
Quaiser-Pohl, C.; Jansen, P.; Lehmann, J.; Kudielka, B.M. Is there a relationship between the performance in a chronometric mental-rotations test and salivary testosterone and estradiol levels in children aged 9-14 years? Dev. Psychobiol., 2016, 58(1), 120-128.
[30]
Ostatnikova, D.; Dohnanyiova, M.; Mataseje, A.; Putz, Z.; Laznibatova, J.; Hajek, J. Salivary testosterone and cognitive ability in children. Bratisl. Lek Listy, 2000, 101(8), 470-473. [Slovak.].
[31]
Ostatnikova, D.; Celec, P.; Putz, Z.; Hodosy, J.; Schmidt, F.; Laznibatova, J.; Kudela, M. Intelligence and salivary testosterone levels in prepubertal children. Neuropsychologia, 2007, 45(7), 1378-1385.
[32]
Celec, P.; Tretinarova, D.; Minarik, G.; Ficek, A.; Szemes, T.; Lakatosova, S.; Schmidtova, E.; Turňa, J.; Kádaši, Ľ.; Ostatnikova, D. Genetic polymorphisms related to testosterone metabolism in intellectually gifted boys. PLoS One, 2013, 8(1)e54751
[33]
Shores, M.M.; Moceri, V.M.; Sloan, K.L.; Matsumoto, A.M.; Kivlahan, D.R. Low testosterone levels predict incident depressive illness in older men: effects of age and medical morbidity. J. Clin. Psychiatry, 2005, 66(1), 7-14.
[34]
McIntyre, R.S.; Mancini, D.; Eisfeld, B.S.; Soczynska, J.K.; Grupp, L.; Konarski, J.Z.; Kennedy, S.H. Calculated bioavailable testosterone levels and depression in middle-aged men. Psychoneuroendocrinology, 2006, 31(9), 1029-1035.
[35]
Aydogan, U.; Aydogdu, A.; Akbulut, H.; Sonmez, A.; Yuksel, S.; Basaran, Y.; Uzun, O.; Bolu, E.; Saglam, K. Increased frequency of anxiety, depression, quality of life and sexual life in young hypogonadotropic hypogonadal males and impacts of testosterone replacement therapy on these conditions. Endocr. J., 2012, 59(12), 1099-1105.
[36]
Ji, E.; Weickert, C.S.; Lenroot, R.; Catts, S.V.; Vercammen, A.; White, C.; Gur, R.E.; Weickert, T.W. Endogenous testosterone levels are associated with neural activity in men with schizophrenia during facial emotion processing. Behav. Brain Res., 2015, 286, 338-346.
[37]
Li, J.; Xiao, W.; Sha, W.; Xian, K.; Tang, X.; Zhang, X. Relationship of serum testosterone levels with cognitive function in chronic antipsychotic-treated male patients with schizophrenia. Asia-Pac. Psychiatry, 2015, 7(3), 323-329.
[38]
Moore, L.; Kyaw, M.; Vercammen, A.; Lenroot, R.; Kulkarni, J.; Curtis, J.; O’Donnell, M.; Carr, V.J.; Shannon Weickert, C.; Weickert, T.W. Serum testosterone levels are related to cognitive function in men with schizophrenia. Psychoneuroendocrinology, 2013, 38(9), 1717-1728.
[39]
Sisek-Šprem, M.; Križaj, A.; Jukić, V.; Milošević, M.; Petrović, Z.; Herceg, M. Testosterone levels and clinical features of schizophrenia with emphasis on negative symptoms and aggression. Nord. J. Psychiatry, 2015, 69(2), 102-109.
[40]
Paipa, N.; Stephan-Otto, C.; Cuevas-Esteban, J.; Núñez-Navarro, A.; Usall, J.; Brébion, G. Second-to-fourth digit length ratio is associated with negative and affective symptoms in schizophrenia patients. Schizophr. Res., 2018, 199, 297-303.
[41]
Misiak, B.; Frydecka, D.; Loska, O.; Moustafa, A.A.; Samochowiec, J.; Kasznia, J.; Stańczykiewicz, B. Testosterone, DHEA and DHEA-S in patients with schizophrenia: A systematic review and meta-analysis. Psychoneuroendocrinology, 2018, 89, 92-102.
[42]
Fuller, P.J.; Lim-Tio, S.S.; Brennan, F.E. Specificity in mineralocorticoid versus glucocorticoid action. Kidney Int., 2000, 57(4), 1256-1264.
[43]
Taddei, S.; Virdis, A.; Mattei, P.; Salvetti, A. Vasodilation to acetylcholine in primary and secondary forms of human hypertension. Hypertension, 1993, 21(6 Pt2), 929-933.
[44]
Golembiewska, E.; Machowska, A.; Stenvinkel, P.; Lindholm, B. Prognostic value of copeptin in chronic kidney disease: from general population to end-stage renal disease. Curr. Protein Pept. Sci., 2017, 18(12), 1232-1243.
[45]
DiBona, G.F. Central angiotensin modulation of baroreflex control of renal sympathetic nerve activity in the rat: Influence of dietary sodium. Acta Physiol. Scand., 2003, 177(3), 285-289.
[46]
El Ghorayeb, N.; Bourdeau, I.; Lacroix, A. Role of ACTH and other hormones in the regulation of aldosterone production in primary aldosteronism. Front. Endocrinol., 2016, 7, 72.
[47]
Murck, H.; Büttner, M.; Kircher, T.; Konrad, C. Genetic, molecular and clinical determinants for the involvement of aldosterone and its receptors in major depression. Nephron, Physiol., 2014, 128(1-2), 17-25.
[48]
Korte, S.M. Corticosteroids in relation to fear, anxiety and psychopathology. Neurosci. Biobehav. Rev., 2001, 25(2), 117-142.
[49]
Jezova, D. Control of ACTH secretion by excitatory amino acids: Functional significance and clinical implications. Endocrine, 2005, 28(3), 287-294.
[50]
Stier, C.T., Jr; Serova, L.I.; Singh, G.; Sabban, E.L. Stress triggered rise in plasma aldosterone is lessened by chronic nicotine infusion. Eur. J. Pharmacol., 2004, 495(2-3), 167-170.
[51]
Moncek, F.; Aguilera, G.; Jezova, D. Insufficient activation of adrenocortical but not adrenomedullary hormones during stress in rats subjected to repeated immune challenge. J. Neuroimmunol., 2003, 142(1-2), 86-92.
[52]
Kajihara, H.; Malliwah, J.A.; Matsumura, M.; Taguchi, K.; Iijima, S. Changes in blood cortisol and aldosterone levels and ultrastructure of the adrenal cortex during hemorrhagic shock. Pathol. Res. Pract., 1983, 176(2-4), 324-340.
[53]
Belyakova, E.I.; Mendzheritskii, A.M. Adrenocortical and thyroid systems of rats during the initial period of nociceptive influences. Neurosci. Behav. Physiol., 2006, 36(5), 561-564.
[54]
Varga, J.; Ferenczi, S.; Kovács, K.J.; Garafova, A.; Jezova, D.; Zelena, D. Comparison of stress-induced changes in adults and pups: Is aldosterone the main adrenocortical stress hormone during the perinatal period in rats? PLoS One, 2013, 8(9)e72313
[55]
Csanova, A.; Hlavacova, N.; Hasiec, M.; Pokusa, M.; Prokopova, B.; Jezova, D. β(3)-Adrenergic receptors, adipokines and neuroendocrine activation during stress induced by repeated immune challenge in male and female rats. Stress, 2017, 20(3), 294-302.
[56]
Kubzansky, L.D.; Adler, G.K. Aldosterone: a forgotten mediator of the relationship between psychological stress and heart disease. Neurosci. Biobehav. Rev., 2010, 34(1), 80-86.
[57]
Makatsori, A.; Duncko, R.; Moncek, F.; Loder, I.; Katina, S.; Jezova, D. Modulation of neuroendocrine response and non-verbal behavior during psychosocial stress in healthy volunteers by the glutamate release-inhibiting drug lamotrigine. Neuroendocrinology, 2004, 79(1), 34-42.
[58]
Bae, Y.J.; Reinelt, J.; Netto, J.; Uhlig, M.; Willenberg, A.; Ceglarek, U.; Villringer, T.J.; Gaebler, M.; Kratzsch, J. Salivary cortisone, as a biomarker for psychosocial stress, is associated with state anxiety and heart rate. Psychoneuroendocrinology, 2018, 101, 35-41.
[59]
Hlavacova, N.; Solarikova, P.; Marko, M.; Brezina, I.; Jezova, D. Blunted cortisol response to psychosocial stress in atopic patients is associated with decrease in salivary alpha-amylase and aldosterone: Focus on sex and menstrual cycle phase. Psychoneuroendocrinology, 2017, 78, 31-38.
[60]
Hlavacova, N.; Wes, P.D.; Ondrejcakova, M.; Flynn, M.E.; Poundstone, P.K.; Babic, S.; Murck, H.; Jezova, D. Subchronic treatment with aldosterone induces depression-like behaviours and gene expression changes relevant to major depressive disorder. Int. J. Neuropsychopharmacol., 2012, 15(2), 247-265.
[61]
Aguilera, G.; Kiss, A.; Luo, X.; Akbasak, B.S. The renin angiotensin system and the stress response. Ann. N. Y. Acad. Sci., 1995, 771, 173-186.
[62]
Grippo, A.J.; Johnson, A.K. Stress, depression and cardiovascular dysregulation: A review of neurobiological mechanisms and the integration of research from preclinical disease models. Stress, 2009, 12(1), 1-21.
[64]
Garg, R.; Adler, G.K. Aldosterone and the mineralocorticoid receptor: Risk factors for cardiometabolic disorders. Curr. Hypertens. Rep., 2015, 17(7), 52.
[65]
Gilbert, K.C.; Brown, N.J. Aldosterone and inflammation. Curr. Opin. Endocrinol. Diabetes Obes., 2010, 17(3), 199-204.
[66]
Bruder-Nascimento, T.; da Silva, M.A.; Tostes, R.C. The involvement of aldosterone on vascular insulin resistance: Implications in obesity and type 2 diabetes. Diabetol. Metab. Syndr., 2014, 6(1), 90.
[67]
Geerling, J.C.; Loewy, A.D. Aldosterone in the brain. Am. J. Physiol. Renal Physiol., 2009, 297(3), F559-F576.
[68]
Huang, B.S.; Leenen, F.H. Mineralocorticoid actions in the brain and hypertension. Curr. Hypertens. Rep., 2011, 13(3), 214-220.
[69]
Hlavacova, N.; Jezova, D. Chronic treatment with the mineralocorticoid hormone aldosterone results in increased anxiety-like behavior. Horm. Behav., 2008, 54, 90-97.
[70]
Franklin, M.; Hlavacova, N.; Babic, S.; Pokusa, M.; Bermudez, I.; Jezova, D. Aldosterone signals the onset of depressive behaviour in a female rat model of depression along with SSRI treatment resistance. Neuroendocrinology, 2015, 102(4), 274-287.
[71]
Sonino, N.; Fallo, F.; Fava, G.A. Psychological aspects of primary aldosteronism. Psychother. Psychosom., 2006, 75, 327-330.
[72]
Künzel, H.E. Psychopathological symptoms in patients with primary hyperaldosteronism--possible pathways. Horm. Metab. Res., 2012, 44(3), 202-207.
[73]
Apostolopoulou, K.; Künzel, H.E.; Gerum, S.; Merkle, K.; Schulz, S.; Fischer, E.; Pallauf, A.; Brand, V.; Bidlingmaier, M.; Endres, S.; Beuschlein, F.; Reincke, M. Gender differences in anxiety and depressive symptoms in patients with primary hyperaldosteronism: A cross-sectional study. World J. Biol. Psychiatry, 2014, 15(1), 26-35.
[74]
Murck, H.; Held, K.; Ziegenbein, M.; Künzel, H.; Koch, K.; Steiger, A. The renin-angiotensin-aldosterone system in patients with depression compared to controls-a sleep endocrine study. BMC Psychiatry, 2003, 3, 15.
[75]
Emanuele, E.; Geroldi, D.; Minoretti, P.; Coen, E.; Politi, P. Increased plasma aldosterone in patients with clinical depression. Arch. Med. Res., 2005, 36, 544-548.
[76]
Häfner, S.; Baumert, J.; Emeny, R.T.; Lacruz, M.E.; Bidlingmaier, M.; Reincke, M.; Kuenzel, H.; Holle, R.; Rupprecht, R.; Ladwig, K.H. To live alone and to be depressed, an alarming combination for the renin-angiotensin-aldosterone-system (RAAS). Psychoneuroendocrinology, 2012, 37, 230-237.
[77]
Häfner, S.; Baumert, J.; Emeny, R.T.; Lacruz, M.E.; Bidlingmaier, M.; Reincke, M.; Ladwig, K.H. Hypertension and depressed symptomatology: A cluster related to the activation of the renin-angiotensin-aldosterone system (RAAS). Findings from population based KORA F4 study. Psychoneuroendocrinology, 2013, 38, 2065-2074.
[78]
Segeda, V.; Izakova, L.; Hlavacova, N.; Bednarova, A.; Jezova, D. Aldosterone concentrations in saliva reflect the duration and severity of depressive episode in a sex dependent manner. J. Psychiatr. Res., 2017, 91, 164-168.
Call for Papers in Thematic Issues
31 December, 2024
Advancements in Proteomic and Peptidomic Approaches in Cancer Immunotherapy: Unveiling the Immune Microenvironment
The scope of this thematic issue centers on the integration of proteomic and peptidomic technologies into the field of cancer immunotherapy, with a particular emphasis on exploring the tumor immune microenvironment. This issue aims to gather contributions that illustrate the application of these advanced methodologies in unveiling the complex interplay ...read more
31 March, 2025
Nutrition and Metabolism in Musculoskeletal Diseases
The musculoskeletal system consists mainly of cartilage, bone, muscles, tendons, connective tissue and ligaments. Balanced metabolism is of vital importance for the homeostasis of the musculoskeletal system. A series of musculoskeletal diseases (for example, sarcopenia, osteoporosis) are resulted from the dysregulated metabolism of the musculoskeletal system. Furthermore, metabolic diseases (such ...read more
28 August, 2024
Protein Folding, Aggregation and Liquid-Liquid Phase Separation
Protein folding, misfolding and aggregation remain one of the main problems of interdisciplinary science not only because many questions are still open, but also because they are important from the point of view of practical application. Protein aggregation and formation of fibrillar structures, for example, is a hallmark of a ...read more
Related Books
In Vitro Propagation and Secondary Metabolite Production from Medicinal Plants: Current Trends (Part 2)
Micropropagation of Medicinal Plants
Software and Programming Tools in Pharmaceutical Research
Biotechnology and Drug Development for Targeting Human Diseases
In Vitro Propagation and Secondary Metabolite Production from Medicinal Plants: Current Trends (Part 1)
Molecular and Physiological Insights into Plant Stress Tolerance and Applications in Agriculture- Part 2
Micropropagation of Medicinal Plants
Genome Editing in Bacteria (Part 1)
Data Science for Agricultural Innovation and Productivity
Animal Models In Experimental Medicine
Article Metrics
56
2
1
1
