UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Postmenopausal patients with metastatic breast cancer were treated with medroxyprogesterone acetate (MPA) (Clinovir) in dosages between 500 and 1500 mg orally per day. The relation of MPA plasma concentrations and endocrine effects were studied in a longitudinal fashion. MPA exerted suppressive effects on the basal and gonadotropin-releasing hormone (GnRH) stimulated gonadotropin secretion, cortisol, dehydroepiandrosterone (DHEA), and estradiol (E2) in a dose-dependent manner leading to a complete suppression with 1500 mg orally per day. The depression of thyroid hormones (T3 and T4) coincided with a depression of the thyroxine-binding index (TBI). MPA did not affect human growth hormone (hGH), basal and thyrotropin-releasing hormone (TRH) stimulated thyroid-stimulating hormone (TSH) and aldosterone. Basal and TRH-stimulated prolactin (PRL) secretion showed a slight but distinct elevation. From these data it is concluded that in postmenopausal patients MPA exerts its antitumor activity by an interference with the hypothalamo-pituitary adrenal axis in the sense of a selective pharmacologic hypophysectomy leading to complete suppression of adrenal steroid secretion. Additionally, MPA inhibits tumor cell growth through the progesterone receptor. A dual mechanism for the antitumor activity of high dose is postulated MPA: ablative through suppression of the hypothalamo-pituitary-adrenal axis and subsequent estrogen deprivation, and additive via the progesterone receptor directly on the tumor cell. The significance of gonadotropin suppression in the postmenopause for breast cancer growth is unclear. The depression of T3 and T4 is due to a depression of thyroid hormone-binding proteins. The elevation of PRL secretion may be explained by a slight estrogenic activity of MPA metabolites.
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PMID:Pharmacokinetic and pharmacodynamic basis for the treatment of metastatic breast cancer with high-dose medroxyprogesterone acetate. 608 20

High doses of estrogen (5-500 micrograms) induce regression of hormone-dependent DMBA mammary tumors in rats at the same rate and degree as treatment with the antiestrogen C1628 (Parke-Davis). In contrast, high dose estrogen stimulated growth of uteri in tumor-bearing rats, while C1628 was antiuterotrophic. Within 72 h following treatment with estrogen, diethylstilbestrol (DES), or C1628, changes in the levels of estrogen receptor (ER) and progesterone receptor (PgR) were evident in both uterine and mammary tumor tissue. Both estrogen and antiestrogen induced depression of the total cytosolic ER and altered the 8S/4S receptor ratio. The tumor cytosolic ER levels of DES- and C1628-treated rats were 4.67 +/- 1.7 fmol/mg protein and 15.89 +/- 3.1 fmol/mg protein, respectively, compared to 48.89 +/- 13.6 fmol/mg protein in tumors of untreated rats. In spite of reduced levels of cytosolic ER, there was an apparent increase in the 8S/4S ratio (62% increase in 8S/4S ER ratio compared to control 8S/4S ratio; p less than 0.05). Total uterine cytosolic ER was low after treatments with DES (5.69 +/- 2.08 fmol/mg protein) or C1628 (94.76 fmol/mg +/- 30.3 fmol/mg protein), as compared to untreated controls (188.2 +/- 7.6 fmol/mg protein). The cytosolic PgR was consistently high in tumors of control rats (42.99 +/- 11.9 fmol/mg protein) and in castrated rats treated with high doses of DES or C1628 (DES, 55.15 +/- 27.0; C1628, 65.07 +/- 9.8 protein).
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PMID:Effect of high-dose estrogen on growth and steroid receptor activity in DMBA-induced mammary tumors and uteri of rats. 634 12

Sex hormone, an essential hormone in reproduction, acts upon the tissues through binding to its receptors. Thus, the study on the receptors is essential for understanding the reproductive processes, physiologically or pathologically. With the advent of molecular biology, receptorology in our field has rapidly developed. In this lecture, we presented our recent findings on the receptor and its gene expression, together with some brief overview on the development of the receptor study, basically or clinically. I. Basic study. 1) Methology: A specific and highly sensitive quantitative RT-PCR assay for measurement of the steroid hormone receptor (SHR) mRNA was developed. 2) Rat progesterone receptor (PR) cDNA, especially PR-BcDNA, was partially cloned. Using primers designed upon the cloned cDNA, two distinct different promoters was found to exist in PR-A and B gene expression in the rat. 3) Tissue specificity of gene expression of the SHRs in the central and peripheral tissues: The synthesis of the receptor protein was regulated mostly on the level of transcription. In some tissues, however, the receptor synthesis was regulated posttranscriptionally. Gene expression of the SHRs was widely distributed even in non-target tissue, indicating the existence of 'basic action' of SH on the tissues. 4) Primate monkey studies: SHR, especially PR, was localized mostly in the preoptic hypothalamic region and hypophysis in contrast with its wide distribution in the rat brain, suggesting the more limited feedback site of progesterone in women. 5) Brain sex differentiation and acquisition of steroid sensitivity: Region-specific and dynamic appearance of SHRs during peri- and postnatal development seemed to a major determinant of sex differentiation and hormone sensitivity' acquisition in female rats. Based upon analysis of PR-A and B mRNAs, gene expression of PR-B was first 'turn on', followed by PR-B gene expression. Progesterone seemed to be associated with 'termination' of the critical period of sex differentiation in the brain. 6) Thyroid hormone may be a regulator of synthesis and gene expression of the PR in rat cerebral cortex. Arachidonic acid, released from cell membrane, regulated SHRs in a non-competitive way, indicating some 'second messenger' role. Cross-talk might exist between the membrane factor and SHR. 7) Antisense mRNA against GnRHmRNA, SH2RNA, was identified in rat brain. Most interestingly, there was a reciprocal relationship between GnRHmRNA and SH2RNA, suggesting some GnRHmRNA regulatory mechanism other than previously thought. 8) Depression of the GnRH receptor (GnRHR)mRNA level by GnRH agonist indicated another mechanism on down-regulation of GnRHR.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Basic and clinical studies on sex hormone receptors]. 808 3

Antiprogestogens, which block the action of progesterone at the cellular level through binding to the progesterone receptor, are proving to be one of the most significant developments in endocrinology in recent years. Several hundreds of such compounds have been synthesized, but only a few of them have been evaluated to any significant extent in biological screening models and, to our knowledge, only three compounds, namely mifepristone, lilopristone (ZK 98.734) and onapristone (ZK 98.299) have been given to humans. Most of the clinical research to date has focused on the use of mifepristone given in combination with prostaglandin for termination of early pregnancy, an indication for which the compound is being used routinely in four countries so far, i.e. China, France, the UK and Sweden. The gynaecological and obstetrical applications in which antiprogestogens have been shown to be of value to date include ripening of the pregnant cervix prior to pregnancy termination, sensitization of the uterus to prostaglandins in second-trimester abortion, and induction of labour. Available data suggest that antiprogestogens have no place in the conservative treatment of ectopic pregnancy or in the treatment of premenstrual tension. In fertility regulation, the sequential combination regimen of mifepristone plus prostaglandin as used for inducing abortion has proved to be effective also for menses induction and can be expected to be an efficacious once-a-month contraceptive. Mifepristone alone, without adjuvant prostaglandin, has yielded promising results as an anti-implantation agent and in emergency contraception. Other potential uses include once-a-week contraception, ovulation inhibition (in a sequential regimen with a progestogen), and as a daily mini-pill. Mifepristone, and other antiprogestogens for which biological data have been reported also bind to the cellular receptors for glucocorticoid hormones and, consequently, possess antiglucocorticoid in addition to their antiprogestational activity. Because of this antiglucocorticoid effect, mifepristone has been employed successfully in the palliative treatment of hypercortisolism due to Cushing's syndrome, and its use has been proposed for treating certain forms of depression and of glaucoma, and in wound healing. However, for scientific and practical reasons, it would be preferable if molecules were developed that have only the antiprogestational or the antiglucocorticoid activity rather than both.
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PMID:Clinical uses of antiprogestogens. 908 Feb 4

Clinical and laboratory studies suggest that progesterone reduces epileptic seizure activity. The mechanisms underlying this effect are not known. The present study determined the effects of progesterone on extracellular evoked responses recorded in the CA1 field of hippocampal slices, as well as epileptiform responses recorded from tetanized slices. Slices were prepared from ovariectomized rats, with or without estrogen replacement. Hippocampal slices were superfused in vitro with one of the following treatments: progesterone with or without RU486 (a progesterone receptor antagonist); allopregnanolone (a progesterone metabolite that potentiates GABA action at GABA(A) receptors); RU5020 (a high-affinity progesterone receptor agonist); or cholesterol (control). In non-tetanized slices, a twofold increase in the excitatory postsynaptic field potential and population spike amplitude occurred during both cholesterol and progesterone superfusion. In contrast, under the same conditions, exposure to allopreganolone caused a 25% reduction in both field potential and population spike amplitude of evoked responses within 30min of treatment. In tetanized slices, progesterone and RU5020, but not allopregnanolone or cholesterol, caused significant reductions in the field potential and population spike amplitude of evoked responses. Progesterone and RU5020 also significantly reduced the duration of tetanic stimulus-induced afterdischarges and the frequency of spontaneous interictal discharges. The effects of allopregnanolone were restricted to a reduction in the primary afterdischarge duration. Estrogen replacement slightly attenuated progesterone's suppression of spontaneous discharges and depression of evoked responses. All responses to progesterone were blocked by prior or concurrent exposure to RU486. These data indicate that allopregnanolone suppresses evoked potentials in non-tetanized hippocampal slices, consistent with previous reports that this neurosteroid has marked anxiolytic and anticonvulsant effects. After tetanization, however, progesterone receptor-mediated responses become quantitatively more important as a mechanism for suppressing hippocampal electrical activity.
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PMID:Progestin receptors mediate progesterone suppression of epileptiform activity in tetanized hippocampal slices in vitro. 1111 38

Besides their binding to cognate intracellular receptors gonadal steroids may also act as functional antagonists at the 5-HT3 receptor. A structure-activity relationship for the actions of a variety of steroids at the 5-HT3 receptor was elaborated that differed considerably from that known for GABA(A) receptors. Steroids appear to interact allosterically with ligand-gated ion channels at the receptor membrane interface. The functional antagonism of gonadal steroids at the 5-HT3 receptor may play a role for the development and course of nausea during pregnancy and of psychiatric disorders. Moreover, we could demonstrate that 3alpha-reduced neuroactive steroids concurrently modulate the GABA(A) receptor and regulate gene expression via the progesterone receptor after intracellular oxidation. Animal studies showed that progesterone is converted rapidly into GABAergic neuroactive steroids in vivo. Progesterone reduces locomotor activity in a dose dependent fashion in male Wister rats. Moreover, progesterone and 3alpha,5alpha-tetrahydroprogesterone produce a benzodiazepine-like sleep EEG profile in rats and humans. In addition, there is a dysequilibrium of such 3alpha-reduced neuroactive steroids during major depression which is corrected by successful treatment with antidepressants. Neuroactive steroids may further be involved in the treatment of depression and anxiety with antidepressants in patients during ethanol withdrawal. First studies in patients with panic disorder suggest that neuroactive steroids may also play a pivotal role in human anxiety. The genomic and non-genomic effects of steroids in the brain contribute to the pathophysiology of psychiatric disorders and the mechanisms of action of antidepressants. Neuroactive steroids affect a broad spectrum of behavioral functions through their unique molecular properties and may constitute a yet unexploited class of drugs.
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PMID:Neuroactive steroids: molecular mechanisms of action and implications for neuropsychopharmacology. 1174 74

Steroids influence neuronal function through binding to cognate intracellular receptors which may act as transcription factors in the regulation of gene expression. In addition, certain so-called neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially distinct 3alpha-reduced metabolites of progesterone and deoxycorticosterone are potent positive allosteric modulators of gamma-aminobutyric acid type A (GABA(A)) receptors. However, also classical steroid hormones such as 17beta-estradiol, testosterone and progesterone are neuroactive steroids because they may act as functional antagonists at the 5-hydroxytryptamine type 3 (5-HT(3)) receptor, a ligand-gated ion channel or distinct glutamate receptors. A structure-activity relationship for the actions of a variety of steroids at the 5-HT(3) receptor was elaborated that differed considerably from that known for GABA(A) receptors. Although a bindings site for steroids at GABA(A) receptors is still a matter of debate, meanwhile there is also evidence that steroids interact allosterically with ligand-gated ion channels at the receptor membrane interface. On the other hand, also 3alpha-reduced neuroactive steroids may regulate gene expression via the progesterone receptor after intracellular oxidation into 5alpha-pregnane steroids. Animal studies showed that progesterone is converted rapidly into GABAergic neuroactive steroids in vivo. Progesterone reduces locomotor activity in a dose-dependent fashion in male Wistar rats. Moreover, progesterone and 3alpha-reduced neuroactive steroids produce a benzodiazepine-like sleep EEG profile in rats and humans. During major depression, there is a disequilibrium of such 3alpha-reduced neuroactive steroids which is corrected by successful treatment with antidepressant drugs. Neuroactive steroids may further be involved in the treatment of depression and anxiety with antidepressants in patients during ethanol withdrawal. Studies in patients with panic disorder suggest that neuroactive steroids may also play a role in modulating human anxiety. Both the genomic and non-genomic effects of steroids in the brain may contribute to the pathophysiology of psychiatric disorders and the mechanisms of action of antidepressants. Neuroactive steroids affect a broad spectrum of behavioral functions through their unique molecular properties and may represent a new treatment strategy for neuropsychiatric disorders.
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PMID:Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. 1251 9

The intention of this review is to summarize the current knowledge on the bidirectional interaction between sleep EEG and the secretion of corticotropin (ACTH) and cortisol. The administration of various hypothalamic-pituitary- adrenocortical (HPA) hormones and their antagonists exerts specific sleep-EEG changes in several species including humans. It is well documented that corticotropin releasing hormone (CRH) impairs sleep and enhances vigilance. In addition, it may promote REM sleep. Changes in the growth hormone-releasing hormone (GHRH):CRH ratio in favour of CRH appear to contribute to shallow sleep, elevated cortisol levels and blunted GH in depression and ageing. On the other hand, in women GHRH appears to exert CRH-like effects on sleep. Acute cortisol administration increases slow-wave sleep (SWS) and GH, probably due to feedback inhibition of CRH, and inhibits REM sleep. With the mixed glucocorticoid and progesterone receptor antagonist mifepriston sleep is disrupted. Subchronic administration of the glucocorticoid agonist methylprednisolone desinhibited REM sleep. A synergism of elevated CRH and cortisol activity may contribute to REM disinhibition during depression. Also ACTH and vasopressin modulate sleep specifically but their physiological role remains unclear. For example acute icv vasopressin enhances wakefulness in rats, whereas its long-term administration increases SWS in the elderly. In various studies the interaction of sleep EEG and HPA hormones has been investigated at the baseline, after manipulation of sleep-wake behaviour and after environmental changes. Most studies agree that the circadian pattern of cortisol is relatively independent from sleep and environmental influences. Some data suggest a major effect of light on cortisol secretion. Sleeping is widely associated with blunting and awakenings are linked with increases of HPA hormones.
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PMID:Sleep and the hypothalamo-pituitary-adrenocortical system. 1253 Nov 48

BACKGROUND. Little information is available regarding depression among Asian breast cancer survivors. METHODS. We estimated the prevalence of depression and its correlates among 1400 participants of a population-based cohort study of women with stage 0-IV breast cancer in Shanghai, China. Through in-person interviews conducted at 6 months and 18 months post-diagnosis and review of medical charts, information on sociodemographic and clinical factors and quality of life (QOL) was collected. Depression was measured by the 20-item Center for Epidemiologic Studies Depression Scale at 18 months post-diagnosis. RESULTS. Approximately 26% of participants had mild to severe depression and 13% fulfilled the criteria of clinical depression at 18 months post-diagnosis. Women with lower income were more likely to have depression than women with higher income (prevalence: 16.6% vs. 6.9% for mild depression and 17.1% vs. 5.5% for clinical depression, respectively). Depression was more common among women who were widowed (18.9%) or divorced/separated/single (16.4%) than among women who were married (11.8%). Women with comorbidity were more likely to have clinical depression (17.3% vs 11.2%). Multivariate analysis showed that low income, marital status, comorbidity, and low QOL scores were independent predictors for depression. We did not find that prevalence of depression differed by menopausal status, estrogen or progesterone receptor status, disease stage, or cancer-related treatments. CONCLUSION. Depression is common among Asian women with breast cancer. Routine screening and prevention of depression are warranted among women with breast cancer.
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PMID:Prevalence of depression and its related factors among Chinese women with breast cancer. 1986 20

Progesterone withdrawal has been proposed as an underlying factor in premenstrual syndrome and postpartum depression. Progesterone withdrawal induces forced swim test (FST) immobility in mice, a depression-like behavior, but the contribution of specific receptors to this effect is unclear. The role of progesterone's GABA(A) receptor-modulating metabolite allopregnanolone in depression- and anxiety-related behaviors has been extensively documented, but little attention has been paid to the role of progesterone receptors. We administered the classic progesterone receptor antagonist mifepristone (RU-38486) and the specific progesterone receptor antagonist CDB-4124 to mice that had been primed with progesterone for five days, and found that both compounds induced FST immobility reliably, robustly, and in a dose-dependent fashion. Although CDB-4124 increased FST immobility, it did not suppress initial activity in a locomotor test. These findings suggest that decreased progesterone receptor activity contributes to depression-like behavior in mice, consistent with the hypothesis that progesterone withdrawal may contribute to the symptoms of premenstrual syndrome or postpartum depression.
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PMID:Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability. 2116 82

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