Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The central nervous system is an important target for sex steroid hormones. During the climateric period the rapid decline of gonadal steroids causes neuroendocrine changes in different areas of the brain. The failure of gonadal hormone production brings specific symptoms due to the central nervous system derangement. At the hypotalamic level estrogen withdrawal gives rise to vasomotor symptoms, eating behavior disorders and altered blood pressure control. Psychological disturbances such as depression, anxiety, irritability and mood fluctuation are related to estrogen-induced changes in the lymbic system. The hypothesis of specific neuroanatomical and neurophysiological effects of estrogen on the brain may also explain the correlation between estrogen deficiency and cognitive disturbances such as Alzheimer's type dementia (AD). The increasing interest in the influence of sex steroids on brain function has focused attention on hormonal replacement therapy. Clinical and epidemiological studies have demonstrated that estrogen therapy exerts a positive effect on vasomotor instability and improves psychological disturbances. The positive effects of estrogen on mood are probably related to its stimulatory action on adrenergic and serotoninergic tone. Estrogen may influence the cognitive function through different biological actions. Estrogen administration increases total cerebral and cerebellar blood flow, cerebral glucose administration and improves cholinergic tone, a key neurotransmitter in learning and memory. The evidence suggests that hormone replacement therapy may reduce the relative risk of developing AD. Progestagens and androgen may also have a role in the control of mood disorders. At present, few data are available regarding the influence that selective estrogen receptor modulators, a new class of compounds, can exert on the brain.
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PMID:Menopause and the central nervous system: intervention options. 1022 2

Catechol-O-methyltransferase (COMT, EC 2.1.1.6) is a ubiquitous enzyme that is crucial to the metabolism of carcinogenic catechols and catecholamines. Regulation of human COMT gene expression may be important in the pathophysiology of various human disorders including estrogen-induced cancers, Parkinson's disease, depression, and hypertension. The gender difference in human COMT activity and variations in rat COMT activity during the estrous cycle led us to explore whether estrogen can regulate human COMT gene transcription. Our Northern analyses showed that physiological concentrations of 17-beta-estradiol (10(-9)-10(-7) M) could decrease human 1. 3-kilobase COMT mRNA levels in MCF-7 cells in a time- and dose-dependent manner through an estrogen receptor-dependent mechanism. Two DNA fragments immediately 5' to the published human COMT gene proximal and distal promoters were cloned. Sequence analyses revealed several half-palindromic estrogen response elements and CCAAT/enhancer binding protein sites. By cotransfecting COMT promoter-chloramphenicol acetyltransferase reporter genes with human estrogen receptor cDNA and pSV-beta-galactosidase plasmids into COS-7 cells, we showed that 17-beta-estradiol could down-regulate chloramphenicol acetyltransferase activities, and COMT promoter activities dose-dependently. Functional deletion analyses of COMT promoters also showed that this estrogenic effect was mediated by a 280 base pair fragment with two putative half-palindromic estrogen response elements in the proximal promoter and a 323-base pair fragment with two putative CCAAT/enhancer binding protein sites in the distal promoter. Our findings provide the first evidence and molecular mechanism for estrogen to inhibit COMT gene transcription, which may shed new insight into the role of estrogen in the pathophysiology of different human disorders.
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PMID:Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. 1038 81

The possible link between estrogen and serotonin (5-HT) in depression was investigated using a genetic animal model of depression, the Flinders Sensitive Line (FSL) rats, in comparison to control Flinders Resistant Line rats. The mRNA levels of the estrogen receptor (ER) alpha and beta subtypes and the 5-HT(1A) and 5-HT(2A) receptors were analyzed in several limbic-related areas of ovariectomized FSL and FRL rats treated with 17beta-estradiol (0.15 microg/g) or vehicle. The FSL animals were shown to express significantly lower levels of the 5-HT(2A) receptor transcripts in the perirhinal cortex, piriform cortex, and medial anterodorsal amygdala and higher levels in the CA 2-3 region of the hippocampus. The only significant difference between the rat lines in ER mRNA expression was found in the medial posterodorsal amygdala, where the FSL rats showed lower ERalpha expression levels. Overall, estradiol treatment increased 5-HT(2A) and decreased 5-HT(1A) receptor mRNA levels in several of the examined regions of both lines. Thus, in many areas, estradiol was found to regulate the 5-HT receptor mRNA expression in the opposite direction to the alterations found in the FSL rats. These findings further support the implication of 5-HT receptors, in particular the 5-HT(2A) subtype, in the etiology of affective disorders. Moreover, the ability of estradiol to regulate the expression of the 5-HT(1A) and 5-HT(2A) receptor genes might account for the reported influence of gonadal hormones in mood and depression.
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PMID:The flinders sensitive line rats, a genetic model of depression, show abnormal serotonin receptor mRNA expression in the brain that is reversed by 17beta-estradiol. 1064 Jun 86

The discovery of a second estrogen receptor (ER), ERbeta, has led to a complete change in our views on estrogen action. The previous dogmatic view that ERalpha represented the only estrogen receptor led to a static and simplistic concept of mechanisms of estrogen action with conceptual limitations in the development of novel estrogenic and antiestrogenic drugs. It is now realized that estrogen signaling represents a complex and multi facetted signal transduction pathway with, at least in many cases, quite different roles of ERalpha and ERbeta. For instance, the two receptors appear to behave quite differently on AP1, antioxidant and Sp1-response elements where ERbeta mediates positive regulation by antiestrogens whereas ERalpha is silent under these conditions. ERalpha and ERbeta also appear to be differentially distributed in the body and within tissues. They are regulated differently and seem to have distinct biological roles, at least in certain contexts. Data are currently rapidly generated with respect to these issues from knockout animals with either of the two receptors deleted. Also double knockouts have been generated and apparently survive. ERbeta may well have significant roles in the etiology of the following diseases and symptoms: prostate cancer, osteoporosis, depression, as well as urinary incontinence in postmenopausal women. Attempts are ongoing in several labs to develop specific ligands to the two receptors. Such ligands may well turn out to be extremely important in treating the mentioned diseases and symptoms as well as possibly others.
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PMID:An update on estrogen receptors. 1070 63

To evaluate the usefulness of 16alpha-[18F]-fluoro-17beta-estradiol (FES) for the assessment of estrogen receptor (ER), we examined the tissue distribution and kinetics of FES in immature female Sprague-Dawley rats and then examined FES uptake in rat breast tumors induced by 7,12-dimethylbenz(a) anthracene (DMBA). The FES uptake by the uterus, an ER-rich tissue, was highly selective and it was 3.34 +/- 0.79%ID/g at 60 minutes and 1.57 +/- 0.57%ID/g at 120 minutes after injection. The FES uptakes in ER-negative tissues were 0.12 +/- 0.05%ID/g or less and 0.05 +/- 0.03%ID/g or less, respectively. Coadministration of unlabeled beta-estradiol showed marked depression of uterine FES uptake. The FES uptake by rat breast tumors was 0.14 +/- 0.06%ID/g at 60 min and 0.12 +/- 0.09%ID/g at 120 min. The FES uptake by rat breast tumors correlated with the ER concentration (r = 0.45, p < 0.05). In conclusion, these results suggest that the FES uptake by tissue is mainly ER mediated and FES is thus useful for detecting ER positive breast tumors.
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PMID:Biodistribution and breast tumor uptake of 16alpha-[18F]-fluoro-17beta-estradiol in rat. 1083 May 31

Introduction and Objectives: Raloxifene, a novel selective estrogen receptor modulator (SERM), is under investigation for the prevention of osteoporosis in postmenopausal women. Like traditional estrogen replacement therapy, raloxifene has beneficial effects on bone and on serum lipids whereas, in contrast to estrogen's adverse effects in the breast and uterus, raloxifene is an estrogen antagonist in the breast and is nonstimulatory in the uterus. This study examines the effects of raloxifene 60 mg/day compared with placebo on: 1) the incidence of vasomotor symptoms: hot flashes (flushing) and sweating (including night sweats), 2) the severity and time course of hot flashes, and 3) the relation of hot flashes to baseline subject characteristics and study discontinuations. Additionally, the study explores the effects of raloxifene 60 mg/day compared with placebo on other climacteric symptoms that affect the quality of life of postmenopausal women, such as depression, insomnia, mood lability and genitourinary complaints.Methods: Integrated data from five randomized, placebo-controlled studies involving 1,165 healthy, postmenopausal women, with up to 30 months of study drug exposure, were analyzed. The incidence and severity of hot flashes and other climacteric symptoms were compared in patients treated with placebo or raloxifene (60 mg/day) via open-ended, non-directed subject self-assessment questionnaires. Data were analyzed for subgroup-by-therapy interactions using many baseline subject characteristics such as age, body mass index, smoking, alcohol, and years post-menopause, as well as preexisting conditions such as hot flashes, sweating, insomnia, depression, and history of hysterectomy. The overall incidence of other climacteric symptoms were reported as adverse events.Results: The increase in overall incidence of hot flashes in raloxifene-treated (24.6%) and placebo-treated (18.3%) subjects was modest, but statistically significant. However, this difference was significant only during the first 6 months of therapy, raloxifene (20.1%) compared with placebo (14.4%). After 6 months of treatment, there was no statistically significant difference in the incidence of hot flashes between the two treatment groups. The majority of hot flashes in raloxifene-treated subjects were subject-assessed as "mild-to-moderate" in severity (89%). The incidence of hot flashes reported as "severe" did not differ significantly in raloxifene- or placebo-treated subjects. Subgroup analyses revealed the overall incidence of hot flashes to be highest for both raloxifene and placebo-treated subjects, in younger (age < 55 years) women (P =.004), in women who had previously experienced hot flashes (P =.031), and in women having had hysterectomies (P <.001). Within each of these subgroups, there was no statistical difference in the incidence of hot flashes between the raloxifene and placebo groups. Between the two treatment groups, there was no difference in the overall incidence of subject discontinuations from study due to hot flashes. The occurrence of the other common vasomotor symptom, sweating (which includes night sweats), was not statistically different for the raloxifene- or placebo-treated subjects.Genitourinary complaints are often symptoms related to vaginal dryness, such as dyspareunia and decreased libido, as well as other symptoms of vaginitis and leukorrhea. No statistically significant differences occurred for raloxifene- or placebo-treated subjects in reports of these genitourinary symptoms. Similarly, for the other common climacteric symptoms; depression, insomnia, and mood lability, no significant differences in incidence between the raloxifene and placebo treatment groups were observed.Conclusions: Raloxifene (60 mg/day) treatment modestly increased the incidence of hot flashes compared with placebo, however, this difference was only statistically significant during the first 6 months of treatment. There were no differences in the severity of hot flashes between treatment groups, and this symptom did not adversely affect subjects' study participation. In both the raloxifene and placebo treatment groups, young postmenopausal women (age < 55), those with baseline hot flashes, and those with histories of hysterectomy were most likely to experience hot flashes. Raloxifene therapy did not affect the occurrence of other climacteric symptoms commonly affecting the quality of life of women after menopause.
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PMID:Raloxifene effects on vasomotor and other climacteric symptoms in postmenopausal women. 1083 11

Numerous reports, ranging from molecular investigations to clinical studies, demonstrate the potency of estrogens to modulate brain function and their implications in schizophrenia and depression. Alterations of dopaminergic, cholinergic, GABAergic, glutamatergic and serotonergic neurotransmission through estrogen-mediated mechanisms have been consistently established. Moreover, studies using in vivo and in vitro models as well as epidemiological data suggest that estrogens provide neuroprotection of central nervous system (CNS) cells implicated in the etiology of neurodegenerative disorders such as Alzheimer s (AD) and Parkinson s (PD) diseases. Numerous genomic or non-genomic mechanisms of actions of estrogens in the brain have been documented implicating classical nuclear estrogen receptors as well as possible estrogen membrane receptors, antioxidant activity of steroids, their effect on fluidity as well as on antiapoptotic proteins and growth factors. Selective estrogen receptor modulators (SERMs) have estrogenic and/or antiestrogenic activity depending on the target tissue. Hence, SERMs have the same beneficial effect as estrogen in skeleton and cardiovascular systems but act as antagonists in breast and uterus. The finding of beneficial side effects of SERMs in the CNS might improve their risk-benefit ratio in traditional indications. In this review, we will survey schizophrenia and depression as examples of mental diseases and AD and PD as neurodegenerative diseases. We will review brain effects of estrogens, steroids possibly acting as pro-drugs of estrogens such as testosterone and dehydroepiandrosterone (DHEA) and present novel findings with SERMs. Drugs with estrogen activity in the brain may have therapeutic potential either by modulating brain neurotransmitter transmission or through neuroprotective activity.
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PMID:Drugs with estrogen-like potency and brain activity: potential therapeutic application for the CNS. 1090 93

Laboratory experiments were conducted with male summer flounder to assess the value of selected measures of endocrine status in fish as indicators of exposure to endocrine-disrupting contaminants. Effects of 1,1,1-trichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl) ethane (o,p'-DDT), octylphenol and 1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene (p,p'-DDE) on hepatosomatic and gonadosomatic indices, plasma steroid hormone levels, vitellogenin production, and gonadal development were evaluated in laboratory-raised, juvenile male summer flounder. Flounder were injected twice with test chemical in a coconut oil carrier. Each chemical was tested at three different concentrations. Estrogenic (o,p'-DDT; octylphenol) and anti-androgenic (p,p'-DDE) chemicals were evaluated alone and in combination (octylphenol plus o,p'-DDT or p,p'-DDE). Additionally, some fish were treated with the natural ligand for the estrogen receptor, 17beta-estradiol. Blood and tissues from different fish in each treatment were sampled 4, 6 and 8 weeks after the first injection. Fish exposed to a combination of o,p'-DDT plus octylphenol were also sampled after 15 weeks. In all cases, responses of fish exposed to a test chemical were compared to control fish sampled at the same time. The following significant differences, relative to controls, were observed in at least one sampling time or at least one concentration of chemical. 17beta-Estradiol-treated flounder exhibited decreased gonadosomatic index (GSI), altered hepatosomatic index (HSI), elevated plasma estradiol, reduced plasma testosterone, and high levels of plasma vitellogenin. Fish treated with o,p'-DDT showed lower GSI, no change in HSI or plasma estradiol, depression of plasma testosterone, and induction of vitellogenesis. Octylphenol treatment resulted in lower GSI, no change in HSI, initially increased plasma estradiol and decreased testosterone, and no vitellogenin production. p,p'-DDE treatment did not significantly alter any indicator relative to controls. In experiments using combinations of chemicals, flounder receiving o,p'-DDT plus octylphenol had lower GSI after 8 weeks and elevated plasma estradiol after 15 weeks exposure. Fish treated with p,p'-DDE plus octylphenol for 8 weeks exhibited a significantly lower GSI. Overall, lower GSI and plasma testosterone levels, relative to controls, were consistent indicators of exposure to estrogenic chemicals in juvenile male flounder. No indicators were found that would identify exposure to the mammalian anti-androgen p,p'-DDE.
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PMID:Effects of estrogenic (o,p'-DDT; octylphenol) and anti-androgenic (p,p'-DDE) chemicals on indicators of endocrine status in juvenile male summer flounder (Paralichthys dentatus). 1116 37

Estrogen exerts profound effects on mood and mental state. The ability of estrogen to modulate serotonergic function raises the possibility that it may play a role in the mechanism associated with depression and its treatment. A cellular mechanism for estrogen to influence mood might be through the regulation of genes involved at various levels of the serotonin system. Here we report that estrogen can up-regulate the expression of the serotonin-1A receptor via a new mechanism involving synergistic activation by nuclear factor-kappa B (NF-kappa B) with estrogen receptor alpha. Interestingly, we observed that only estrogen receptor-alpha, and not -beta, was able to mediate this effect of estrogens. The partial antiestrogen, 4-hydroxytamoxifen, had the same effect as estrogen. In addition, mutation analysis showed that both the transactivation function of p65 and activation function 1 of estrogen receptor-alpha were essential for this synergistic regulation. Therefore, we propose that NF-kappa B complexes cooperate with estrogen receptor-alpha to recruit cofactors into the complex and thereby synergistically activate the serotonin-1A receptor promoter through nonclassical estrogen response elements by a mechanism that does not involve direct receptor binding to DNA.
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PMID:Synergistic activation of the serotonin-1A receptor by nuclear factor-kappa B and estrogen. 1126 6

The preventive effect of estrogen on Alzheimer's disease (AD) has become clear with epidemiological data. Therapeutic effects of estrogen have not yet been established. In this presentation, we report our new basic and clinical data. The estrogen receptor, (ER)alpha, and ERbeta mRNA were investigated in rat brain. Estradiol-17beta (E(2)) treatment following OVX reduced the levels of ERalpha mRNA in the hypothalamus. In the substantia innominata (SI), the number of choline acetyltransferase immunoreacive cells increased significantly in the estrogen treatment rat. The neurons in SI projecting to the forebrain cortex contained ERalpha. Increasing amounts of intracellular calcium, peroxidation, and apoptosis with amyloid beta were suppressed in neuronal cells from rat pheochromocytoma (PC12) cells with E(2). ERalpha cDNA transfected PC 12 cells elaborated more neurite-like processes with E(2). In clinics, we are currently preparing vaginal progesterone tablets, which essentially may concentrate in the endometrium to prevent endometrial cancer, with few general circulation of progesterone inviting less depression. The therapeutic effects of cyclic estrogen, such as its preventive effect, are suggested in these studies, at least on mild AD.
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PMID:Alzheimer's disease and estrogen. 1138 81


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