Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We found in a representative sample of 392 first hospital admissions for schizophrenia a higher mean age at onset in females by 3.2 to 3.9 years, whereas the lifetime risk was equal for both sexes. In males the rates of onset show a steep increase reaching the maximum value in the age group 15-24 years, followed then by a steady decrease. Females reach the first peak with a clear delay between 20 and 29 years. After the decrease a second smaller peak is observed consistently in females within the age group 45-49 years and over. After having excluded alternative explanations for this gender differences (for example, diagnosis artefacts, sociocultural factors), we hypothesized that the effect of oestradiol on the dopaminergic system enhances the vulnerability threshold for schizophrenia, which is lowered again during the menopause. Alternatively we assumed that testosterone reduces the vulnerability threshold and thus furthers the earlier onset of schizophrenia in males. We tested these hypotheses in animal models by investigating the effects of the gonadal hormones on haloperidol-induced catalepsy and on apomorphine-induced stereotypies in both neonatal and adult rats. Testosterone showed no clear influence on the tested dopamine-mediated behaviour. Oestradiol caused a significant reduction on both dopamine-agonist and dopamine-antagonist induced behaviour. These effects were stronger in neonatal animals. Since oestradiol caused a 2.8-fold reduction of dopamine receptor affinity for sulpiride, we assumed that the behavioural changes caused by oestradiol were accounted for by a down-regulation of the dopaminergic system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Estradiol inhibits dopamine mediated behavior in rats--an animal model of sex-specific differences in schizophrenia]. 131 53

In a representative sample of 392 first hospital admissions for schizophrenia from a population of 1.5 million we assessed the "true" age of onset by a semi-standardized interview "IRAOS". We demonstrated that the mean age at onset of the disease is 3-4 years higher in females than in males, with the lifetime risk being exactly equal. In males, the rates of onset show a steep increase - starting from school age and reaching their maximum value in the age group 15-24 years - followed by a steady decrease. Females reach the first peak with a clear delay between 20 and 29 years. After the decrease, a second smaller peak is observed consistently in females within the age group 45-49 years and over. After having excluded competing explanations, we hypothesized that the effect of oestradiol on the dopaminergic system enhances the vulnerability threshold, which is lowered again during the menopause. Alternatively, we assumed that testosterone reduces the vulnerability threshold and thus furthers the earlier onset of the disease in males. We tested the hypotheses in three animal models by examining the effect of gonadal hormones on haloperidol-induced catalepsy and on apomorphine-induced stereotypies in both neonatal and adult rats. No clear influence by testosterone was shown. Oestradiol caused a significant reduction of both dopamine-agonist and dopamine-antagonist induced behaviour. The effects were stronger in neonatal rats. Since oestradiol caused the dopamine (DA) receptor affinity for sulpiride to be reduced by a factor of 2.8, we assumed that the behavioural changes due to oestradiol were accounted for by a down-regulation of DA receptor sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oestradiol enhances the vulnerability threshold for schizophrenia in women by an early effect on dopaminergic neurotransmission. Evidence from an epidemiological study and from animal experiments. 165 19

Schizophrenic women have been consistently found to have a later age of onset and a less severe clinical course of illness as compared with schizophrenic men. Because these differences are not explained by diagnostic artifacts or sociocultural factors, we tested the hypothesis that they are determined by the influence of the gonadal hormones testosterone and estradiol on dopaminergic (DA) neurotransmission. We used animal models in which the effects of the hormones on behavioral changes induced by the DA antagonist haloperidol (catalepsy) and by the DA agonist apomorphine (oral stereotypies, grooming and sitting behavior) were investigated in neonatal and in adult treated rats. No consistent effects of testosterone were observed. Estradiol significantly reduced the behavioral changes induced by both haloperidol and apomorphine, and this effect was more pronounced in neonatally treated animals. These results suggest a downward regulation of DA neurotransmission by estradiol, which is supported by the results of 3H-sulpiride binding determinations in brain homogenates from the same animals: estradiol caused a 2.8-fold reduction of DA receptor affinity to sulpiride. Our findings suggest that estradiol might act as a protective modulator in schizophrenia by enhancing the vulnerability threshold for psychosis through the downward regulation of DA neurotransmission. Such mechanism could explain, at least in part, the later onset and the more favorable course of schizophrenia in female patients.
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PMID:An animal model for the effects of estradiol on dopamine-mediated behavior: implications for sex differences in schizophrenia. 175 27

We investigated the effect of 10 months ovariectomy and a correction therapy, 2 weeks before the rats were killed, of oestradiol, progesterone or their combination on NMDA and AMPA receptor binding in the hippocampus, dentate gyrus, striatum, nucleus accumbens and frontal cortex of the rat brain as well as on amino acid levels in frontal cortex. NMDA and AMPA binding densities were assayed by autoradiography using, respectively, L-[3H]glutamate and [3H]AMPA; amino acid concentrations were measured by high performance liquid chromatograhy (HPLC) coupled with UV detection. Ovariectomy was without effect on NMDA and AMPA binding density in all brain regions assayed except in the hippocampal CA1 region and dentate gyrus where it decreased NMDA binding density compared to intact rats values. Oestradiol restored and increased NMDA binding density in the CA1 subfield and the dentate gyrus of ovariectomized rats but, by contrast, it decreased binding density in the striatum and in the frontal cortex while having no effect in the CA2/3 subfield of the hippocampus and in the nucleus accumbens. Oestradiol was without effect on AMPA binding density in the hippocampus and the dentate gyrus but it reduced AMPA binding density in the striatum, the frontal cortex and the nucleus accumbens. Progesterone, and oestradiol combined with progesterone, decreased NMDA but not AMPA binding density in the frontal cortex of ovariectomized rats, and they were without effect on these receptors in the other brain regions assayed. Amino acid concentrations in the frontal cortex were unchanged after ovariectomy or steroid treatments. The effect of oestradiol in the hippocampus confirmed in the present study and our novel findings in the frontal cortex, striatum and nucleus accumbens may have functional significance for schizophrenia and neurodegenerative diseases.
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PMID:Regional and selective effects of oestradiol and progesterone on NMDA and AMPA receptors in the rat brain. 1079 84

Estradiol has been postulated to constitute a protective factor for schizophrenia, which could provide women at risk to experience a psychotic episode with a relative protection in phases of high estradiol levels, i.e. before menopause and during the peri- and postovulatory phases of their cycle. Women suffering from schizophrenia have been reported to show significantly lower estradiol levels than the normal population and to experience first onset or recurrence of a psychotic episode significantly more often in low estrogen phases of the cycle with low estradiol levels. We examined estradiol levels in an open prospective study in 43 women admitted with a diagnosis of an acute psychotic episode and could confirm these findings for schizophrenia as well as other psychotic disorders. Only 28% of the women exhibited estradiol and progesterone levels indicating a peri- or postovulatory phase and all of the estradiol levels on admission were either within the lower part of the cycle-dependent normal range or below normal; comparison with a control group of healthy volunteers and patients admitted with different psychiatric diagnoses confirmed their estradiol levels to be significantly higher. However, when splitting this control group, the statistical difference would only hold between the study group of psychotic patients and the healthy control group. The group of patients with other diagnoses than a psychotic episode fell in between of the other two groups and did not differ significantly from either. Thus, an unspecific effect, i.e. a hypothalamic downregulation due to the stress of acute hospitalization must be born in mind when assessing hormone levels in acutely psychotic women.
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PMID:Estradiol levels in psychotic disorders. 1107 Mar 32

Epidemiological studies have shown gender differences in the age of onset and symptoms of schizophrenia. Because sensorimotor gating mechanisms are deficient in schizophrenia, we studied the effect of administration of estrogen on prepulse inhibition of startle in rats, an animal model of sensorimotor gating. Rats were tested in an automated startle apparatus for their responses to random combinations of 115-dB sound pulses and prepulses of various intensity. Startle responses were reduced by increasing intensities of prepulses, indicating prepulse inhibition. Repeated administration of startle pulses caused gradual habituation of startle responses. Ovariectomy did not induce significant changes in either habituation of the startle response or prepulse inhibition of startle. Treatment with 17beta-estradiol caused an increase in percentage prepulse inhibition at all prepulse intensities at 18 h, but only at higher prepulse intensities at 30 min after injection. Habituation of startle responses was not affected. The enhancing effect of estradiol on prepulse inhibition was mimicked by testosterone, but not by dihydrotestosterone. Estradiol treatment increased prepulse inhibition similarly in controls or after disruption of prepulse inhibition induced by treatment with apomorphine or dizocilpine (MK-801). Our results may help to explain gender differences in schizophrenia and some of the beneficial clinical effects of estrogen treatment in this disease.
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PMID:Estrogen increases prepulse inhibition of acoustic startle in rats. 1167 72

Estradiol is a pleiotropic hormone, involved in the etiology of a wide variety of diseases. Over the last decade individual genetic variability of the estradiol metabolism has been described as a significant contributor to disease susceptibility with variations depending on ethnic background. Among others, genetic variations of genes encoding cytochrome P450 (CYP) enzymes play an important role in this regard. Mutant alleles of the CYP 1A1 gene are major modulators of lung cancer risk among smokers, mediate gender differences in lung cancer susceptibility, and have been associated with an elevated risk for breast, prostate, colorectal, and oral squamous cell cancer. Variants of the CYP 1B1 gene modulate the risk for prostate, ovarian, lung, and breast cancer. Also, mutations in the CYP 1B1 gene are the major genetic determinant of congenital glaucoma. Mutant CYP 17 alleles are associated with serum and plasma levels of steroid hormones, use of hormone replacement therapy, and endometrial, prostate, and breast cancer. Available data indicate that the protective effect of a later age at menarche is limited to mutant CYP 17 allele carriers. Among women with the Polycystic Ovary (PCO) syndrome, mutant CYP 17 alleles are sufficient to aggravate the clinical presentation of the disease. Molecular variants of the CYP 19 gene are associated with an increased risk for breast cancer, advanced disease stage, and tumor aromatase production. Carriage of a mutant catechol-O-methyltransferase (COMT) allele is associated with breast cancer, neurologic disorders such as Parkinson's disease, and modulates behavior among patients with schizophrenia, alcoholics and the general population. In summary, the available evidence points to estrogen metabolising genes as strong hereditary determinants of the susceptibility to benign and malignant conditions.
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PMID:Genetic modeling of estrogen metabolism as a risk factor of hormone-dependent disorders. 1195 95

Estradiol is a pleiotropic hormone, involved in the etiology of a wide variety of diseases. Over the last decade individual genetic variability of the estradiol metabolism has been described as a significant contributor to disease susceptibility with variations depending on ethnic background. Among others, genetic variations of genes encoding cytochrome P450 (CYP) enzymes play an important role in this regard. Mutant alleles of the CYP 1A1 gene are major modulators of lung cancer risk among smokers, mediate gender differences in lung cancer susceptibility, and have been associated with an elevated risk for developing breast, prostate, colorectal, and oral squamous cell cancer. Variants of the CYP 1B1 gene modulate the risk for developing prostate, ovarian, lung, and breast cancer. Also, mutations in the CYP 1B1 gene are the major genetic determinant of congenital glaucoma. Mutant CYP 17 alleles are associated with serum and plasma levels of steroid hormones, use of hormone replacement therapy, and the development of endometrial, prostate, and breast cancer. Available data indicate that the protective effect against breast cancer of a later age at menarche is limited to wild-type CYP 17 allele carriers. Among women with the polycystic ovary syndrome, carriage of mutant CYP 17 alleles is sufficient to aggravate the clinical presentation of the disease. Molecular variants of the CYP 19 gene are associated with an increased risk for developing breast cancer, advanced breast cancer stages, and tumor aromatase production. Carriage of a mutant catechol-O-methyltransferase allele is associated with breast cancer, neurologic disorders such as Parkinson's disease, and modulates behavior among patients with schizophrenia, alcoholics and the general population. In summary, the available evidence points to genes that encode estrogen-metabolizing enzymes as strong hereditary determinants of the susceptibility to benign as well as malignant conditions.
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PMID:Genetic modelling of the estrogen metabolism as a risk factor of hormone-dependent disorders. 1202 Sep 74

Estradiol-17beta is the most potent female sex hormone. In addition to its role in the control of primary and secondary sexual characteristics, it also influences the development of the brain. Furthermore, estradiol-17beta possesses neuroprotective properties that are mediated via receptor action and also independently of receptors. Several processes that are regulated by estradiol-17beta might influence the expression of Alzheimer's disease and schizophrenia. Differences between the sexes have been described in both disorders, and it has been suggested that these may be due to the action of oestrogens. Long-term oestrogen replacement has proved to be beneficial in the prevention and treatment of Alzheimer's disease and schizophrenia. The results, however, are controversial. Preliminary in vitro and in vivo findings, which are summarised in this review, encourage further studies with estradiol-17beta or its analogues as potential adjunctive interventions particularly in "negative syndrome" schizophrenia and in Alzheimer's disease.
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PMID:Neuroprotective effects of estradiol-17beta: implications for psychiatric disorders. 1251 Feb 13

Increasing evidence during the last few years suggests that there are gender-specific differences in schizophrenia, influencing the age of onset, treatment outcome and the prevalence of negative symptoms. With respect to the latter in postmortem brain and cerebrospinal fluid of schizophrenic patients with negative symptoms a reduction of dopaminergic activity became evident. Measures of noradrenergic activity, dopamine beta-hydroxylase and the metabolite MHPG, appear to decrease with brain atrophy seen in patients with negative symptoms. Serotonergic activity tends to be low in patients with impaired cognitive function as is seen in negative schizophrenia. In these patients ventricular enlargement is associated with the severity of negative symptoms, low monoamine activity and low cerebral glucose metabolism. On the other hand atypical antipsychotic drugs that modulate also glutamate receptor activity, suggest an additional alternative mechanism of antipsychotic action beyond aminergic neurotransmitters. These drugs improve glutamatergic transmission and decrease negative symptoms; this suggests a glutamatergic deficiency as an extension of the dopamine model. The glutamate-dopamine interaction illustrates the importance of cross-talk between projections to the cortex, striatum, and lower brainstem for the expression of negative symptomatology. On the other hand, estradiol-17beta the most potent female sex hormone influences not only primary and secondary sexual characteristics but also embryonal and fetal growth as well as development of the brain aminergic networks, which are involved in schizophrenia. Estradiol-l7beta possesses neuroprotective properties, which are relevant for the course of schizophrenia and this may explain the pronounced gender differences with respect to progression and therapeutic response of schizophrenia. The present review attempts an update and synthesis of the information about the hormonal influence on neuronal pathways in negative symptoms of schizophrenia. It shows that estradiol-l7beta influences transporters and receptors as well as the morphological appearance of neuronal systems and that it may be an integral part of the neuroprotective system ameliorating schizophrenia.
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PMID:Effects of estrogen on brain development and neuroprotection--implications for negative symptoms in schizophrenia. 1265 Jun 83


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