Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0600142 (hot flushes)
 1,242 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hot flushes are experienced in those periods of the female life when estrogen levels are low. Hormone replacement therapy is thus the first choice for treatment of hot flushes. However this treatment is not always accepted or contraindicated for a variety of reasons. Estrogen (and progestogen) strongly interact with a number of neurotransmitters and this has led to a range of non-hormonal treatments including compounds that act via the noradrenergic or dopaminergic systems as well as herbal remedies. These treatments (which are shortly reviewed) are not always successful. Surprisingly, apart from treatment with some selective serotonin (5-HT) reuptake inhibitors (SSRI's), up till now, little attention is given to the strong interaction of estrogens with the serotonergic system. These interactions are shortly reviewed. Based on these interactions, a hypothesis on the genesis of hot flushes is postulated. Especially the 5-HT(2A) receptor subtype may play a key role in the occurrence of hot flushes. A number of arguments that support this hypothesis are discussed.
 ...
PMID:The role of serotonin in hot flushes. 1106 96

The purpose of the present study was to further evaluate the tail-temperature test as a tool to test potential steroidal and non-steroidal compounds for the treatment of hot flushes. Ovariectomized rats were implanted with a temperature sensitive probe. After a recovery period of 5 weeks, the effect of oestradiol (given via a silastic tube) and the 5-HT(2) receptor antagonist mirtazapine (10 mg/kg i.p.) on the tail-temperature in the active phase of the animals was measured. Oestradiol completely restored the disturbed tail temperature after 3 days. Treatment with mirtazapine also restored the oestrogen withdrawal-induced disturbed tail-temperature. The effect of mirtazapine was already seen on the first day of treatment. These experiments confirm and extend the idea that measuring the oestradiol withdrawal-induced disturbance of tail-temperature may be a useful tool to select compounds that might have beneficial effects in the treatment of hot flushes. Blockade of the 5-HT(2A) receptors prevented or reduced the ovariectomy-induced disturbance of the rat tail-temperature, which may validate this model to evaluate the effect of compounds on hot flushes.
 ...
PMID:Oestradiol and mirtazapine restore the disturbed tail-temperature of oestrogen-deficient rats. 1466 40

The aim of the present study was to develop an experimental paradigm for the study of serotonergic neurotransmission in humans using positron emission tomography and the 5-HT2A selective radioligand [18F]altanserin. [18F]altanserin studies were conducted in seven subjects using the bolus/infusion approach designed for attaining steady state in blood and brain 2 hours after the initial [18F]altanserin administration. Three hours after commencement of radiotracer administration, 0.25 mg/kg of the selective serotonin reuptake inhibitor, citalopram (Lundbeck, Valby, Denmark), was administered to all subjects as a constant infusion for 20 minutes. To reduce 5-HT1A-mediated autoinhibition of cortical 5-HT release, four of the seven subjects were pretreated with the partial 5-HT1A agonist pindolol for 3 days at an increasing oral dose (25 mg on the day of scanning). In each subject, the baseline condition (120 to 180 minutes) was compared with the stimulated condition (195 to 300 minutes). Despite a pronounced increase in plasma prolactin and two subjects reporting hot flushes compatible with an 5-HT-induced adverse effect, cortical [18F]altanserin binding was insensitive to the citalopram challenge, even after pindolol pretreatment. The biochemical and cellular events possibly affecting the unsuccessful translation of the citalopram/pindolol challenge into a change in 5-HT2A receptor binding of [18F]altanserin are discussed.
 ...
PMID:[18F]altanserin binding to human 5HT2A receptors is unaltered after citalopram and pindolol challenge. 1535 24

Menopause-associated thermoregulatory dysfunction, including hot flushes and night sweats, is effectively treated by hormonal therapies that include estrogens. Evidence suggests that estrogen regulates serotonin 2A (5-HT(2A)) receptor expression and that 5-HT(2A) receptors are involved in thermoregulation. Therefore, the role of 5-HT(2A) receptors in thermoregulation was assessed in two rat models of ovariectomy-induced thermoregulatory dysfunction. The first model is based on measurement of the tail-skin temperature (TST) increase following naloxone-induced withdrawal in morphine-dependent ovariectomized (OVX) rats (MD model), while the second model relies on telemetric assessment of diurnal TST changes in ovariectomized rats (telemetry model). Treatment with a 5-HT(2A/2C) receptor agonist, (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), prevented the naloxone-induced TST increase in the MD model and restored normal active-phase TST in the telemetry model. The selective 5-HT(2A) receptor antagonist, MDL-100907, had no effect on the naloxone-induced flush when administered alone in the MD model, but it decreased DOI's ability to abate the flush. In the telemetry model, MDL-100907 attenuated the DOI-induced decrease in active-phase TST. Interestingly, MDL-100907 increased TST in both models when given alone, with the TST increase occurring prior to the naloxone-induced flush in the MD model. To evaluate the role of central nervous system (CNS) 5-HT(2A) receptors in TST regulation, DOI was administered in combination with a known peripheral 5-HT(2A/2C) receptor antagonist, xylamidine, in the MD model. Xylamidine had no effect on DOI's ability to abate the naloxone-induced flush. These results indicate that activation of central 5-HT(2A) receptors restores temperature regulation in two rodent models of ovariectomy-induced thermoregulatory dysfunction.
 ...
PMID:Serotonin 2A receptors modulate tail-skin temperature in two rodent models of estrogen deficiency-related thermoregulatory dysfunction. 1552 44

Basic science and clinical studies have investigated the potential neuroprotective effects of estrogen. One apparent area of convergence in these studies is the selective benefits of estrogen on cognitive tasks mediated by the hippocampus and frontal lobes. Findings in non-human primates parallel findings from neuroimaging and behavioral studies in humans and suggest that estrogen might influence memory tasks mediated by the hippocampus as well as working memory tasks mediated by the prefrontal cortex. This evidence provides a framework for the design of future hormone studies, wherein such tasks can serve as primary outcomes. In studies of symptomatic women, hormone therapy can benefit a broader range of cognitive domains, particularly effortful tests that are sensitive to remittance of dysphoria, sleep difficulty, and hot flushes. Serotonin might play a critical role in these potential indirect benefits, and therapies that target these symptoms, even those without estrogenic actions, might have indirect benefits on cognition.
 ...
PMID:Estrogen effects on the hippocampus and frontal lobes. 1633 13

Thermoregulation is a complex intercommunicative function requiring coordination between core body temperature (CBT), the central nervous system, and peripheral vasculature. In menopausal women, dysregulation of thermoregulatory mechanisms leads to hot flushes and night sweats. A previous study in ovariectomized (OVX) rats has suggested that mirtazapine can alleviate thermoregulatory dysfunction by blocking 5-HT(2A) receptor signaling. This is in opposition to other work in which 5-HT(2A) receptor blockade appeared to exacerbate thermoregulatory dysfunction in OVX rats. Thus, the goals of the present study were to reexamine the effects of mirtazapine on temperature regulation in OVX rat models and explore further the role of 5-HT(2A) receptor blockade. Mirtazapine exhibited potent functional antagonism (EC(50)=0.62 nM) at the cloned human 5-HT(2A) receptor. In the morphine-dependent model of thermoregulatory dysfunction, mirtazapine (10 mg/kg, i.p.) induced an increase in tail-skin temperature (TST) prior to naloxone administration. In the telemetry model, mirtazapine (0.3-3 mg/kg, i.p.) caused an increase in TST. However, at the highest dose tested (10 mg/kg, i.p.), mirtazapine induced a small but significant decrease in TST followed by an increase in TST. To examine this finding further, mirtazapine's effect on CBT was determined. Administration of mirtazapine (1-3 mg/kg, i.p.) resulted in a slight decrease in CBT but at the 10 mg/kg dose a dramatic decrease (-3.6 degrees C) in CBT was observed. These data support the concept that 5-HT(2A) receptors play a role in temperature regulation but that functional blockade of these receptors by mirtazapine is not a likely mechanism for restoring thermoregulatory processes in OVX rats.
 ...
PMID:Effects of the 5-HT2A antagonist mirtazapine in rat models of thermoregulation. 1706 60

Thermoregulation is an integrated network of neuroendocrine, autonomic and somatosensory responses. Thermoregulatory dysfunction occurs during fluctuations or decline of gonadal hormone levels and results in vasomotor symptoms such as hot flushes and/or night-time sweating. The neurotransmitter serotonin (5-HT), has been reported to play a role in thermoregulation via changes in extracellular 5-HT levels and/or activation of various 5-HT receptors. The purpose of this study was to evaluate the role of the selective 5-HT reuptake inhibitor (SSRI), fluoxetine (FLX), on temperature regulation using ovariectomized (OVX) rodent models of thermoregulation. Single, subcutaneous (s.c.) administration of FLX (3, 10, 30 and 60 mg/kg) dose-dependently reduced core body temperature (CBT). FLX at 3 and 10 mg/kg s.c. showed no statistically significant decrease on tail-skin temperature (TST), whereas at higher doses (30 and 60 mg/kg) a significant decrease in TST was noted in the telemetry model. To mimic chronic SSRI treatment, a 5-HT(1A) antagonist (WAY-100635; 0.3 mg/kg) was administered 20 min prior to FLX (10 mg/kg). This combination showed no significant improvement on temperature dysfunction compared to FLX alone. Similarly, in a morphine-dependent model of temperature dysfunction FLX, was inactive at 10 mg/kg whereas the 30 and 60 mg/kg s.c. dose abated the naloxone-induced increase in TST by 55 and 81%, respectively. In summary, FLX affected CBT at all doses, but alleviated thermoregulatory dysfunction only at higher doses that are non-selective for the 5-HT system.
 ...
PMID:The role of the selective serotonin reuptake inhibitor fluoxetine in temperature regulation in ovariectomized rat models. 1719 1

We investigated the clinical efficacy of milnacipran (Serotonin-Noradrenalin Reuptake Inhibitor: SNRI) in prostate cancer patients who suffer from hot flushes. Our study included 12 patients who had taken hormone therapy for at least 3 months prior to the trial entry. All patients had severe hot flushes at least 3 times daily. Among 12 patients, 7 subjects received milnacipran 25 mg orally once a day and 5 subjects received 50mg once a day. The questionnaire was used to measure the frequency and severity of hot flushes at baseline, and at 6 and 12 weeks. At 12 weeks, 9 patients were available for the evaluation. Four patients received 50 mg per day and 5 patients received 25 mg per day. The patients with > or =50% decrease in baseline hot flash score were observed in 3 out of 4 who received 50 mg and 2 out of 5 who received 25 mg per day. The frequency of hot flushes had significantly decreased at the 12 weeks period than the baseline in the milnacipran 50 mg per day treatment group (p < 0.05, paired t-test). Adverse events were observed in 3 patients: 2 cases of nausea and 1 case of constipation. However, all of them were mild to moderate. These results indicated that milnacipran 50 mg per day therapy is effective in the treatment of hot flushes, which is the side effect of hormone therapy for prostate cancer.
 ...
PMID:[The clinical efficacy of SNRI milnacipran in the treatment of hot flushes with prostate cancer hormonally treated]. 1762 34

Menopausal syndromes can seriously disturb the quality of women's life. In this work, we have investigated transdermal administration of buspirone, a 5-HT(1A) receptor agonist, for treatment of the major menopausal syndrome, hot flushes. To the best of our knowledge, this is the first time buspirone has been proposed for the treatment of hot flushes. We designed a buspirone transdermal system containing the drug in an ethosomal carrier. Pharmacokinetic data in rats following transdermal administration indicate that buspirone was present in plasma for 12 h, reaching a C(max) value of 120.07+/-86.97 ng/ml after 2 h. A F(rel) value of 0.89 was estimated for transdermal vs. oral buspirone. The effect of transdermal buspirone on hot flushes was evaluated in ovariectomized rats by monitoring tail skin temperature changes. Temperature alleviation (1.6+/-0.7 degrees C) to normal values was observed 3 h post-buspirone administration with the effect lasting for at least 3 h. Histological examination of the skin at the application site indicated that transdermal ethosomal buspirone is safe. The significant findings presented here encourage further studies with ethosomal buspirone transdermal system for treatment of menopausal syndromes.
 ...
PMID:Buspirone transdermal administration for menopausal syndromes, in vitro and in animal model studies. 1996 12

Perimenopausal syndromes begin as ovarian function ceases and the most common symptoms are hot flushes. Data indicate that the projections of serotonin to hypothalamus may be involved in the mechanism of hot flushes. Therefore, the aim of this study is to investigate the potential role of the serotonin dorsal raphe-preoptic hypothalamus pathway for hot flushes in an animal model of menopause. We determined the changes in serotonin expression in the dorsal raphe (DR) and preoptic anterior hypothalamus (POAH) in ovariectomized rats. We also explored the therapeutical effects of estradiol valerate and Remifemin in this model. Eighty female Sprague-Dawley rats were randomly assigned to sham-operated (SHAM) group, ovariectomy (OVX) group with vehicle, ovariectomy with estradiol valerate treatment (OVX+E) group and ovariectomy with Remifemin (OVX+ICR) group. Serotonin expression was evaluated in the DR and POAH using immunofluorescence and quantified in the DR using an enzyme-linked immunosorbent assay (ELISA). Apoptosis was analyzed in the DR by TUNEL assay. The number of serotonin immunoreactive neurons and the level of serotonin expression in the DR decreased significantly following OVX compared to the SHAM group. No TUNEL-positive cells were detected in the DR in any group. In addition, following OVX, the number of serotonin-positive fibers decreased significantly in the ventromedial preoptic nucleus (VMPO), especially in the ventrolateral preoptic nucleus (VLPO). Treatment with either estradiol or Remifemin for 4 weeks countered the OVX-induced decreases in serotonin levels in both the DR and the hypothalamus, with levels in the treated rats similar to those in the SHAM group. A fluorescently labeled retrograde tracer was injected into the VLPO at the 4-week time point. A significantly lower percentage of serotonin with CTB double-labeled neurons in CTB-labeled neurons was demonstrated after ovariectomy, and both estradiol and Remifemin countered this OVX-induced decrease. We conclude that serotonin pathway is changed after ovariectomy, including the serotonin synthesis in DR and serotonin fibers in PO/AH, both E and Remifemin have an equivalent therapeutic effect on it.
 ...
PMID:Estradiol Valerate and Remifemin ameliorate ovariectomy-induced decrease in a serotonin dorsal raphe-preoptic hypothalamus pathway in rats. 2756 57


1 2 Next >>