Estrogen hormones play an important regulatory role in the human body. They contribute to sexual differentiation, reproductive function and behavior, as well as to memory, neuronal survival, homeostasis and metabolic rate. The menopausal period in a woman's life is accompanied by changes associated with decreased levels of gonadal hormones. Decreased estrogen levels are considered to be one of the potential factors in the pathogenesis of affective disorders and cognitive dysfunctions. This review summarizes the available literature data on behavioral changes in animals with ovariectomy-induced estrogen deficit.
Almey A; Milner TA.; Brake WG. Estrogen receptors in the central nervous system and their implication for dopaminedependent cognition in females. Horm. Behav. 2015; 74:125–138.
Amandusson A, Blomqvist A. Estrogen receptors can regulate pain sensitivity. Possible explanation of certain chronic pain ditions. Lakartidningen. 2001;98,1774-1778.
Amandusson A, Blomqvist A. Estrogenic influences in pain processing. Front Neuroendocrinol. 2013;34:329–349.
Ansonoff MA, Etgen, AM. Evidence that oestradiol attenuates beta-adrenoceptor func-tion in the hypothalamus of female rats by altering receptor phosphorylation and seques-tration. J. Neuroendocrinol. 2000;12:1060–1066.
Azcoitia I, Arevalo MA, De Nicola AF, Garcia-Segura LM. Neuroprotective actions of estradiol revisited. Trends Endocrinol. Metab. 2011;22:467–473.
Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38(8):1083-1152.
Barth C., Villringer A., Sacher J. Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods. Front. Neurosci. 2015;9:37.
Behl C, Skutella T, Lezoualc'h F, Post A, Widmann M, Newton CJ, et al, Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Molecular Pharmacology. 1997;51(4):535–541.
Bekko N, Yoshimura H. Animal model of menopausal depressive-like state female mice: prolongation of immobility time in the forced swimming test following ovariectomy. Psychopharmacology. 2005;187(3):300-307.
Bekku N, Yoshimura H, Araki H .Factors producing a menopausal depressive-like state in mice following ovariectomy. Psychopharmacology (Berl). 2006; 187:170–180.
Borrás C, Gambini J, López-Grueso R, Federico V, Pallardó V, Viña J. Direct antioxidant and protective effect of estradiol on isolated mitochondria. Direct antioxi-dant and protective effect of estradiol on isolated mitochondria. Biochemical et Biophys-ical Acta, 2010;1802:205–211.
Borrow AP, Handa RJ. Estrogen receptors modulation of anxiety-like behavior. Vitam Horm. 2017;103:27–52.
Bosse R, Di Paolo T. The modulation of brain dopamine and GABAA receptors by estradiol: a clue for CNS changes occurring at menopause. Cell Mol Neurobiol. 1996;16(2):199-212.
Bouayed J, Rammal H, Soulimani R. Oxidative stress and anxiety. Oxidative Medicine and Cellular Longevity. 2009;2(2):63-67.
Buckwalter JG, Stanczyk FZ, McCleary CA, Bluestein BW, Buckwalter DK, Rankin KP, et al. Pregnancy, the postpartum, and steroid hormones: effects on cognition and mood. Psychoneuroendocrinology. 1999;24(1):69-84.
Chakravorty SG, Halbreich U. The influence of estrogen on monoamine oxidase activity. Psychopharmacology bulletin. 1997;33(2):229–233.
Chen Q, Zhang W, Sadana N, Chen X. Estrogen receptors in pain modulation:cellular signaling. Biol Sex Differ. 2021; 12: 22.
Colzato LS; Hommel B. Effects of estrogen on higher-order cognitive functions in unstressed human females may depend on individual variation in dopamine baseline levels. Front. Neurosci. 2014;8:65.
Craft RM. Modulation of pain by estrogens. Pain. 2007;132(1):3–12.
Creutz LM, Kritzer MF. Estrogen receptor-beta immunoreactivity in the midbrain of adult rats: regional, subregional, and cellular localization in the A10, A9, and A8 dopamine cell groups. The Journal of comparative neurology. 2002;446(3):288–300.
Crispino M, Stone DJ, Wei M, Anderson CP, Tocco G, Finch CE, at al.. Variations of synaptotagmin I, synaptotagmin IV, and synaptophysin mRNA levels in rat hippocampus during the estrous cycle. Exp Neurol. 1999;159:574–583.
Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med. 2013;19:197–209.
Cyr M; Bossé R, Di Paolo T. Gonadal hormones modulate 5-hydroxytryptamine2A receptors: Emphasis on the rat frontal cortex. Neuroscience 1998;83:829–836.
Cyr M, Calon F, Morissette M, Grandbois M, Di Paolo T, Callier S. Drugs with estrogen-like potency and brain activity: potential therapeutic application for the CNS. Curr Pharm Des. 2000;6(12):1287-312.
Dalla C, Antoniou K, Drossopoulou G, Xagoraris M, Kokras N, Sfikakis A, et al. Chronic mild stress impact: are females more vulnerable? Neuroscience. 2005;135(3):703-714.
Dawson-Basoa M, Gintzler AR. Gestational and ovarian sex steroid antinociception: synergy between spinal kappa and delta opioid systems. Brain Research.1998;794:61-67.
De Chaves G, Moretti M, Castro AA, DagostinW, da Silva GG, Boeck CR, et al. Effect of long-term ovariectomy on anxiety and behavioral despair in rats. Phisiol Behav. 2009;97:420-425.
Denley MCS, Gatford NJF, Sellers KJ., Srivastava DP. Estradiol and the Development of the Cerebral Cortex: An Unexpected Role? Front. Neurosci. 2018;12:245.
Devall AJ, Santos JM, Lovick TA. Estrous cycle stage influences on neuronal responsiveness to repeated anxiogenic stress in female rats. Behav Brain Res. 2011;225: 334–340.
Diaz Brinton R. Minireview: translational animal model of human menopause: challenges and emerging opportunities. Endocrinology. 2012;153:3571-3578.
Dickinson SL, Curzon G. 5-Hydroxytryptamine-mediated behaviour in male and female rats. Neuropharmacology. 1986;25(7):771–776.
Dotlic J, Radovanovic S, Rancic B, Milosevic B, Nicevic S, Kurtagic I, et al. Mental health aspect of quality of life in themenopausal transition. J Psychosom Obstet Gynecol. 2020;4:1−10.
Estrada-Camarena E, Fernandez-Guasti A, Lopez-Rubalcava C. Antidepressant-like effect of different estrogenic compounds in the forced swimming test. Neuropsychopharmacology. 2003;28:830–838.
Etgen, AM. and Karkanias, GB. Estrogen regulation of noradrenergic signaling in the hypothalamus. Psychoneuroendocrinology. 1994;19:603–610.
Fedotova J, Puvina S, Susjko A. Effect of chronic vitamin D3 hormone administration on anxiety-like behavior in adult female rats after long- term ovaryectomy. Nutrients. 2017;9:28.
Freeman EW. Association of depression with the transition to menopause. Menopause 2010;17:823-827.
Frey et al. Frye CA, Walf AA. Estrogen and/or progesterone administered systemically or to the amygdala can have anxiety-, fear-, and pain-reducing effects in ovariectomized rats. Behavioral neuroscience. 2004;118(2):306–313.
Frizell B; Dumas JA. Examining the Relationship Between Neurosteroids, Cognition, and Menopause with Neuroimaging Methods. Curr. Psychiatry Rep. 2018;20:96.
Garcia-Segura LM, Cardona-Gomez P, Naftolin F, Chowen JA. Estradiol up-regulates Bcl-2 expression in adult brain neurons. Neuroreport 1998;9:593–597.
Gasbarri A, Tavares MC, Rodrigues RC, Tomaz C, Pom pili A. Estrogen, cognitive functions and emotion: an overview on humans, non-human primates and rodents in reproductive years. Rev Neurosci. 2012;23:587–606.
Genazzani, AR., Pluchino N, Luisi S, Luisi M. Estrogen, cognition and female ageing. Update. Hum. Reprod. 2007;13:175–187.
Gundlah C, Pecins-Thompson M, Schutzer WE, Be-thea CL.Ovarian steroid effects on serotonin 1A, 2A, and 2Creceptor mRNA in macaque hypothalamus. Brain Res MolBrain Res. 1999;63:325–339.
Gundlah C, Alves SE, Clark JA, Pai LY, Schaeffer JM, Rohrer SP. Estrogen receptor-beta regulates tryptophan hydroxylase-1 expression in the murine midbrain raphe. Biol. Psychiatry. 2005;57:938–942.
Halbreich U, Rojansky N, Palter S, Tworek H, Hissin P, Wang K. Estrogen augments serotonergic activity in postmenopausal women. Biological psychiatry. 1995 1;37(7):434–441.
Hall J, Thomas KL, Everitt BJ: Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat Neurosci. 2000;3:533 535.
Handley SL, McBlane JW, Critchley MA, Njung’e K. Multiple serotonin mechanisms in animal models of anxiety: Environmental, emotional and cognitive factors. Behavioural Brain Research. 1993;58(1–2):203–210. .
Hiroi R, McDevitt RA, Neumaier JF. Estrogen selectively increases tryptophan hydroxylase-2 mRNA expression in distinct subregions of rat midbrain raphe nucleus: association between gene expression and anxiety behavior in the open field. Biol Psychiatry. 2006;60:288–295.
Holschneider DP, Kumazawa T, Chen K, Shih JC. Tissue-specific effects of estrogen on monoamine oxidase A and B in the rat. Life Sci. 1998;63:155–160.
Hu S, Lu SF, Kaplan JR, Adams MR, Simon NG. ERbeta protein expression in female cynomolgus monkey and CF-1 mouse brain: Western analysis. J Neurobiol. 2005;64:298–309.
Imwalle DB, Gustafsson JA, Rissman EF. Lack of functional estrogen receptor beta influences anxiety behavior and serotonin content in female mice. Physiol Behav. 2005;84:157–163
Khariv V, Acioglu C, Ni L, Ratnayake A, Li L, Tao YX, et al. A link between plasma membrane calcium ATPase 2 (PMCA2), estrogen and estrogen receptor α signaling in mechanical pain. Sci Rep. 2018;8(1):17260.
Kiss A, Delattre AM, Pereira SI, Carolino RG, Szawka RE, Anselmo-Franci JA et al. 17-β-estradiol replacement in young, adult and middle-aged female ovariectomized rats promotes improvement of spatial reference memory and antidepressant effect and alters monoamines and BDNF levels in memory- and depression related brain areas. Behav Brain Res. 2012;227:100-108.
Koonce CJ, Walf AA, Frye CA. Trilostane exerts antidepressive effects among wild-type, but not estrogen receptor [beta] knockout mice. Neuroreport. 2009;20:1047–1050.
Krezel W, Dupont S, Krust A, Chambon P, Chapman PF. Increased anxiety and synaptic plasticity in estrogen receptor beta -deficient mice. Proc.Natl.Acad.Sci USA. 2001;98:12278–12282.
Leuner B, Mendolia-Loffredo S, Shors TJ. High levels of estrogen enhance associative memory formation in ovariectomized females. Psychoneuroendocrinology. 2004;29(7):883–890.
Li J, Xu Y, Hu W, Gao Y, Ni X, Sheng H, et al. Exercise ameliorates depression-like be-havior and increases hippocampal BDNF level in ovariectomized rats. Neurosci Lett. 2014; 573:13-18.
Li LH, Wang ZC, Jin Y, Zhang YO. Ovariectomy results in variable changes in nocicep-tion, mood and depression in adult female rats. PLoS ONE 2014;9(4):e943120.
Li XH, Liu NB, Zhang MH, Zhou YL, Liao JW, Liu XQ, et al. Effects of chronic multiple stress on learning and memory and the expression of Fyn, BDNF, TrkB in the hippocampus of rats. Chin Med J (Engl). 2007;120:669–674.
Liu F, Day M, Muñiz LC, Bitran D, Arias R, Revilla-Sanchez R, et al. Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci. 2008;11:334–343.
Luine VN. Estradiol and cognitive function: past, present and future. Horm Behav. 2014;66(4):602–618.
Maggiolini M, Picard D. The unfolding stories of GPR30, a new membrane-bound estrogen receptor. J Endocrinol. 2010; 204:105–114.
Marchev S, Temelkova K, Todorova M, Eftimov M, Georgieva A, Kuzmanov K, Kuz-manov A, et al. Effects of antioxidants from Aronia melanocarpa and Apium graveolens on experimental model of osteoporosis. Osteoporoc Int. 2018;29(1):60.
Mauvais-Jarvis F,Clegg DJ, Hevener AL. The role of estrogens in control of energy balance and glucose homeostasis. Endocrine Reviews. 2013;34:309–338.
Mazzucco CA, Lieblich SE, Bingham BI, Williamson MA, Viau V, Galea LA. Both estrogen receptor alpha and estrogen receptor beta agonists enhance cell proliferation in the dentate gyrus of adult female rats. Neuroscience. 2006;141:1793–1800.
McEwen BS, Alves SE, Bulloch K, al. Ovarian steroids and the brain: implications for cognition and aging. Neurology. 1997;48(7):8–15.
McEwen BS. Endocrine effects on the brain and their relationship to behavior. In: Basic neurochemistry: molecular, cellular and medical aspects. Siegel GJ, editor. 1989; pp. 893–913. New York: Raven. (Soares, 2013).
Milner TA, Thompson LI, Wang G, Kievits JA, Martin E, Zhou P, et al. Distribution of estrogen receptor beta containing cells in the brains of bacterial artificial chromosome transgenic mice. Brain research. 2010;1351:74–96.
Moses-Kolko EL, Berga, SL, Greer PJ, Smith G, Cidis Meltzer C, Drevets WC. Wide-spread increases of cortical serotonin type 2A receptor availability after hormone therapy in euthymic postmenopausal women. Fertil. Steril. 2004;80:554–559.
Naughton M, Mulrooney JB, Leonard BE. A review of the role of serotonin receptors in psychiatric disorders. Human Psychopharmacology. 2000;15(6):397–415.
Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Dermatol. 2001;45(3):116-124.
Numakawa T, Yokomaku D, Richards M, Hori H, Adachi N, Kunugi H. Functional in-teractions between steroid hormones and neurotrofin BDNF. World J Biol Chem. 2010;1:133-143.
Park JH, Lee JE, Shin IC, Koh HC. Autophagy regulates chlorpyrifos-induced apoptosis in SH-SY5Y cells. Toxicology and applied pharmacology. 2013;268:55-67.
Patki G, Allam FH, Atrooz F, Dao AT, Solanki N, Chugh G, et al. Grape powder intake prevents ovariectomy-indused anxiety-like behavior, memory impairment and high blood pressere in famile Wistar rats. PLoS ONE. 2013:8(9);e745220.
Peiffer A, Morale MC, Barden NB, Marchetti B. Modulation of glucocorticoid receptor gene expression in the thymus by the sex steroid hormone milieu and correlation with sexual dimorphism of immune response. Endocr J. 1994;2:181–192.
Protopopescu X, Butler T, Pan H, Root J, Altemus M, Polanecsky M, et al. Hippocampal structural changes across the menstrual cycle. Hippocampus. 2008;18(10):985–988.
Qu ZW, Liu TT, Ren C, Gan X, Qiu CY, Ren P, et al. 17β-estradiol enhances ASIC activity in primary sensory neurons to produce sex difference in acidosis-induced nociception. Endocrinology. 2015;156(12):4660–4671.
Renczés Е, Borbélyová V, Manuel Steinhardt M, Höpfner T, Stehle T, Ostatníková D, et al. The role of estrogen in anxiety-like behavior and memory of middle-aged female rats. Frontier in Endocrinology. 2020;11:570-560.
Rossi C, Angelucci A, Costantin L, Braschi C, Mazzantini M, Babbini F, et al. Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. Eur J Neurosci.2006;24:1850–1856.
Rubinow DR, Schmidt PJ, Roca CA.Estrogen-seroto-nin interactions: implications for affective regulation. Biol Psy-chiatry. 1998;4:839–850.
Rudolph LM, Cornil CA, Mittelman-Smith MA, Rainville JR, Remage-Healey L, Sinchak K, et al. Actions of steroids: new neurotroansmitters. The Journal of Neuroscience. 2016;36(45):11449-11458.
Sandstrom NJ, Williams CL. Spatial memory retention is enhanced by acute and continuous estradiol replacement. Horm Behav. 2004;45:128–135.
Savitz J, Lucki I, Drevets WC. 5-HT(1A) receptor function in major depressive disorder. Prog Neurobiol. 2009;88:17–31.
C Yilmaza, K Karalib,G Fodelianakia, A Gravanisb, T Chavakisa, I Charalampopoulosb et al. Neurosteroids as regulators of neuroinfammation. Frontiers in Neuroendocrinology. 2019; 55; 100788.
Shoupe,D, Montz FJ, Lobo RA. The effects of estrogen and progestin on endogenous opioid activity in oophorectomized women. J Clin Endocrinol Metab. 1985;60(1):178-183.
Shughrue PJ, Lane MV, Merchenthaler I. Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol. 1997;388(4):507–525.
Solum DT, Handa RJ. Estrogen regulates the development of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus. J Neurosci. 2002;22: 2650-2659.
Sprague AH, Khalil RA.Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol. 2009;78(6):539-52.
Stahl SM. Effects of estrogen on the central nervous system. J Clin Psychiatry.2001; 62:317-318.
Stiedl O, Pappa E, Konradsson-Geuken A, Ogren SO. The role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and its interaction in emotional learning and memory. Fron-tiers in Pharmacology, 2015;6; article 162.
Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. J Neurosci. 1998;18(18):7394-7401.
Su Q, Cheng Y, Jin K, Cheng J, Lin Y, Lin Z, et al. Estrogen therapy increases BDNF expression and improves post-stroke depression in ovariectomy-treated rats. Exp Ther Med. 2016;12(3):1843-1848.
Ter Horst GJ, Wichmann R, Gerrits M, Westenbroek C, Lin Y. Sex differences in stress responses: focus on ovarian hormones. Physiol Behav. 2009;97:239–249.
Thompson TL, Moss RL. Estrogen regulation of dopamine release in the nucleus accumbens: genomic- and nongenomic-mediated effects. Journal of neurochemistry. 1994;62(5):1750–6.
Vandegrift BJ, You CH, Satta R, Mark S. Brodie MS, W. Lasek AW. Estradiol increases the sensitivity of ventral tegmental area dopamine neurons to dopamine and ethanol. PLoS ONE. 2017;12(11):e0187698.
Walf AA, Rhodes ME, Frye CA. Anti-depressant effects of ERβ selective estrogen receptor modulators in the forced swim test. Pharm Biochem Behav. 2004;78:523–529.
Walf AA, Frye CA. Administration of estrogen receptor beta-specific selective estrogen receptor modulators to the hippocampus decrease anxiety and depressive behavior of ovariectomized rats. Pharmacol Biochem Behav. 2007;86:407–414.
Walf AA, Paris JJ, Frie CA. Chronic estradiol replacement to aged female rats reduces anxiety-like and depression-like behavior and enhances cognitive performance. Psycho-endocrinology. 2009;34:909-916.
Walf AA, Frye C. Estradiol reduces anxiety- and depression-like behavior of aged female mice. Physiol Behav. 2010;99(2):169-174.
Wang AC, Hara Y, Janssen WG, Rapp PR, Morrison JH. Synaptic estrogen receptor-alpha levels in prefrontal cortex in female rhesus monkeys and their correlation with cognitive performance. J. Neurosci.2010;3:12770–12776.
Welshons WV, Lieberman ME, Gorski J. Nuclear localization of unoccupied oestrogen receptors. Nature. 1984;307:747-749.
Wharton W, Gleason CE, Olson SRMS, Carlsson CM, Asthana S. Neurobiological Underpinnings of the Estrogen – Mood Relationship. Curr Psychiatry Rev. 2012;8(3):247–256.
Woolley CS, Schwartzkroin PA. Hormonal effects on the brain. Epilepsia. 1998;39:2–8.
Woolley, C.S. Acute effects of estrogen on neuronal physiology. Annu. Rev. Pharmacol. Toxicol. 2007;47:657–680.
Yi H, Bao X, Tang X, Fan X, Xu H. Estrogen modulation of calretinin and BDNF expression in midbrain dopaminergic neurons of ovariectomized mice. J Chem Neuroanot. 2016;77:60-67.
Zhang YY, Liu MY, Liu Z, Zhao JK, Zhao YG, He L, et al. GPR30-mediated estro-genic regulation of action of actin polymerization and spatial memory involves SRC-1 and PI3K-Mtorc2 in the hippocampus of female mice. CNS Neurosci Ther. 2019;25:714-733.
Zsarnovszky A, Scalise TJ, Horvath TL, Naftolin F. Estrogen effects on tyrosine hydroxylase-immunoreactive cells in the ventral mesencephalon of the female rat: Further evidence for the two cell hypothesis of dopamine function. Brain Res. 2000; 868:363–366.
