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Year : 2004  |  Volume : 36  |  Issue : 2  |  Page : 98-99

Is oestrogen a ‘biological neuroprotective’?

Medical Officer, B. C. Roy Technology Hospital, Indian Institute of Technology, Kharagpur - 721302, India

Correspondence Address:
Medical Officer, B. C. Roy Technology Hospital, Indian Institute of Technology, Kharagpur - 721302, India
[email protected]

How to cite this article:
Chattopadhyay S. Is oestrogen a ‘biological neuroprotective’?. Indian J Pharmacol 2004;36:98-9

How to cite this URL:
Chattopadhyay S. Is oestrogen a ‘biological neuroprotective’?. Indian J Pharmacol [serial online] 2004 [cited 2023 Jun 3];36:98-9. Available from: https://www.ijp-online.com/text.asp?2004/36/2/98/6771

The present article outlines two interesting observations related to schizophrenia research:
A. The biological 'sex bias' i.e. males usually develop the illness early,[1] sustain a more vulnerable course and often have poorer prognosis than females.[2] On the other hand, females develop the illness during their lifetime when the serum estrogen level is low, for example at a particular phase of the menstrual cycle,[3] after childbirth[4] and after menopause.[5]
B. Despite equal exposure to birth-related complications male babies are more vulnerable to schizophrenia than females.[6]

Therefore, it would be appropriate to surmise that females are blessed with some 'biological boon' which is absent in males. Researchers have studied many factors (genetic, anatomical, epidemiological, socio-cultural and biological) that could be involved in such male-female heterogeneity in the schizophrenic population. This article emphasizes the possible role of estrogen as a biological variable in the pathophysiology of schizophrenia.
Estrogen is known to influence the pathophysiology of several diseases including psychiatric illnesses through its nuclear receptor gene expression. Genetic studies of estrogen metabolism show that estrogen is responsible for breast, endometrial and colorectal cancers, polycystic ovarian disease (PCOD), Parkinson's disease, alcoholism and schizophrenia.[7]
Studies have also shown the symptom-alleviating roles of oral estrogen therapy in postmenopausal females,[8] of transdermal estrogen in puerperal psychosis[9] and female schizophrenics,[10] and of estrogen-progesterone combined pills in schizophrenic females having PCOD[11] and premenstrual tension.[12]
Many studies have shown that the level of serum estrogen has got a strong correlation with cognitive function, especially global cognition, verbal, spatial deceleration, memory and perceptual motor speech. Further, higher estrogen levels in female schizophrenics are associated with better cognitive ability.[13]
While evaluating the molecular process of such benefits of estrogen in the brain, it has been observed that estrogen prevents toxin-related neuronal degenerations, maintains normal neuronal growth and thus may have tremendous implications in alcoholism, Alzheimer's disease, mood disorders and schizophrenia.[14] It has also been found that estrogen prevents several neurodegenerative processes by virtue of its nuclear receptor-mediated-alteration of estrogen-responsive-gene-expression that modulates the rate of apoptosis, axonal degeneration and offers a generalized support to the neurons.[15] A recent study has found that synthetic conjugated estrogens exert some neuroprotective effects in the brain and prevent the insult related to Alzheimer's disease.[16] Another study has shown that estrogen also protects retinal ganglionic cell lines from ischemia-induced-damage observed especially in sickle cell disease and diabetes-induced retinopathies.[17] Moreover, it is also seen that estrogen has a potent antioxidant effect as it moderates the potency of superoxide dismutase (an antioxidant enzyme) in the circulating monocytes and reduces the amount of free radicals.[18] Therefore, it can be inferred that estrogen physiologically confers a neuroprotective effect on the female brain due to its biological abundance.
Detailed studies on the pathophysiology of schizophrenia hypothesize excessive dopaminergic activity in the mesolimbic and mesocortical regions of the brain along with other neurotransmitters, like serotonin and GABA.[19] In this context, a large number of studies have shown that estrogen has modulating roles on dopamine and serotonin receptors in the relevant part of the brain affected in schizophrenia. In support of such postulations and to understand the molecular mechanisms of estrogenic action at the cerebral neurotransmitter level the following animal studies have been reviewed.
Studies on animal models have shown that estrogen is a potent dopamine receptor blocker, especially D1 and D2.[20] A few studies had also mentioned that estrogen is a potent GABA-A receptor manipulator and thus reduces the load of tardive dyskinesia due to antipsychotic drugs.[20] A series of studies have documented that apart from dopamine and GABA, estrogen can also block serotonin receptors, especially 5-HT1A and 5-HT2A.[21],[22],[23],[24],[25]
One study has shown that progesterone also expresses D5 receptors in the atrial natriuretic peptide neurons in the hypothalamus although the effect is less potent than estrogen.[26] The authors mention that there might be a possibility that progesterone could enhance the effect of estrogen[26] and thus it could lead to an estrogen-progesterone combination therapy in schizophrenia!
It is possible to infer that estrogen is a natural neuroprotectant and by blocking dopamine and serotonin neuroreceptors in the brain, probably acts in a manner similar to neuroleptics, which are either purely dopamine blockers (e.g. chlorpromazine, haloperidol and clozapine) or dopamine plus serotonin blockers (e.g. risperidone). Estrogen is thus better called a schizoprotectant, as it not only prevents the development of schizophrenia but also improves the external psychological functioning in the patients. Although a large body of studies has substantiated this view, it needs to be tested further on a large sample of first-onset drug-naďve female schizophrenics (preferably post-menopausal) using an interdisciplinary program. 

 » References Top

1.Chaves AC, Seman MV, Mari JJ, Maluf A. Schizophrenia: impact of positive symptoms on gender social role. Schizophr Res 1993;11:41-5.  Back to cited text no. 1    
2.Meyer C, Kelterborn G, Naber D. Age of onset in schizophrenia: relations to psychopathology and gender. Br J Psychiatry 1993;162:665-71.  Back to cited text no. 2    
3.Riecher-Rossler A, Hafner H, Stumbaum M, Maurer K, Schmidt R. Can estradiol modulate schizophrenic symptomatology? Schizophr Bull 1994;20:203-14.  Back to cited text no. 3    
4.Davies A, McIvor RJ, Kumar RC. Impact of childbirth on a series of schizophrenic mothers: a comment on the possible influence of oestrogen on schizophrenia. Schizophr Res 1995:16:25-31.  Back to cited text no. 4    
5.Hafner H, an der Heiden W, Hambrecht M, Riecher-Rossler A, Maurer K, Loffler W. A chapter in systematic schizophrenia research-the search for causal explanations for sex differences in age of onset. Nervenartz 1993;64:706-16.  Back to cited text no. 5    
6.Chattopadhyay S, Mandal MK. Schizophrenia and obstetrical complications: Are they related? In: Mandal MK, Haque-Nizamie S, editors. Current developments in schizophrenia. 1st ed. New Delhi: Allied Publishers; 2001.  Back to cited text no. 6    
7.Huber JC, Schneeberger C, Tempfer CB. Genetic modelling of the estrogen metabolism as a risk factor of hormone-dependent disorders. Maturitas 2002;42:1-12.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Ozsoy M, Oral B, Ozsoy D. Clinical equivalence of intranasal estradiol and oral estrogens for postmenopausal symptoms. Int J Gynaecol Obstet 2002;79:143-6.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Gregoire AJ, Kumar R, Everitt B, Henderson AF, Studd JW. Transdermal oestrogen for treatment of severe postnatal depression. Lancet 1996;347:930-3.  Back to cited text no. 9  [PUBMED]  
10.Kulkarni J, Riedel A, de Castella AR, Fitzgerald PB, Rolfe TJ, Taffe J. A clinical trial of adjunctive oestrogen treatment in women with schizophrenia. Arch Women Ment Health 2002;5:99-104.  Back to cited text no. 10    
11.Kopala LC, Lewine R, Good KP, Fluker M, Martzke JS, Honer WG. Clinical features of schizophrenia in woman with hyperandrogenism. J Psychiatry Neurosci 1997;22:56-60.  Back to cited text no. 11    
12.Tiemstra JD, Patel K. Hormonal therapy in the management of premenstrual syndrome. J Am Board Fam Pract 1998;11:378-81.  Back to cited text no. 12  [PUBMED]  
13.Hoff Al, Kremen WS, Wieneke MH, Lauriello J, Blankfeld HM, Faustman WO, et al. Association of oestrogen levels with neuropsychological performance in women with schizophrenia. Am J Psychiatry 2001;158:1134-9.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Seeman MV. Psychopathology in women and men: focus on female hormones. Am J Psychiatry 1997;154:1641-7.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Garcia-Segura LM, Azcoitia I, DonCarlos LL. Neuro-protection by estradiol. Prog Neurobiol 2001;63:29-60.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Zhao L, Chen S, Brinton RD. An estrogen replacement therapy containing nine synthetic plant-based conjugated estrogens promotes neuronal survival. Exp Biol Med 2003; 228:823-35.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Kaja S, Yang SH, Wei J, Fujitani K, Liu R, Brun-Zinkernagel AM, et al. Estrogen protects the inner retina from apoptosis and ischemia-induced loss of Vesl-1L/Homer 1c immunoreactive synaptic connections. Invest Ophthalmol Vis Sci 2003;44:3155-62.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Strehlow K, Rotter S, Wassmann S, Adam O, Grohe C, Laufs K, et al. Modulation of antioxidant enzyme expression and function by estrogen. Circ Res 2003;93:170-7.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]
19.Victor IR. Mental Disorders. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, editors. Harrison's Principles of Internal Medicine. 15th ed. New York: McGraw-Hill Companies Inc; 2001. Vol 2. p. 2555.  Back to cited text no. 19    
20.Bosse R, DiPaolo T. The modulation of brain dopamine and GABA A receptors by estradiol: a clue for CNS changes occurring at menopause. Cell Mol Neurobiol 1996;16:199-212.  Back to cited text no. 20  [PUBMED]  
21.Fink G, Summer BE, Rosie R, Grace O, Quinn JP. Estrogen control of central neurotransmission: effect on mood, mental state and memory. Cell Mol Neurobiol 1996;16:325-44.  Back to cited text no. 21    
22.Fink G, Summer BE, McQueen JK, Wilson H, Rosie R. Sex steroid control of mood, mental state and memory. Clin Exp Pharmacol Physiol 1998;25:  Back to cited text no. 22    
23.764-75.  Back to cited text no. 23    
24.Summer BE, Fink G. Testosterone as well as estrogen increases serotonin 2A receptor mRNA and binding site densities in the male rat brain. Brain Res Mol Brain Res 1998;59:205-14.  Back to cited text no. 24    
25.Fink G, Summer BE, Rosie R, Wilson H, McQueen J. Androgen actions on central serotonin neurotransmission: relevance for mood, mental state and memory. Behav Brain Res 1999;105:53-68.  Back to cited text no. 25    
26.Osterlund MK, Halldin C, Hurd YL. Effects of chronic 17-beta-estradiol treatment on the serotonin 5-HT (1A) receptor mRNA and binding levels in the rat brain. Synapse 2000;35:39-44.  Back to cited text no. 26  [PUBMED]  [FULLTEXT]
27.Lee D, Wang L, Dong P, Tran T, Copolov D, Lim AT. Progesterone modulation of D5 receptor expression in hypothalamic ANP neurons, the role of estrogen. Mol Psychiatry 2001;6:112-7.  Back to cited text no. 27  [PUBMED]  
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