Estradiol valerate and alcohol intake: dose-response assessments

Background

An injection of estradiol valerate (EV) provides estradiol for a prolonged period. Recent research indicates that a single 2.0 mg injection of EV modifies a female rat's appetite for alcoholic beverages. This research extends the initial research by assessing 8 doses of EV (from.001 to 2.0 mg/female rat), as well assessing the effects of 2.0 mg EV in females with ovariectomies.

Results

With the administration of EV, there was a dose-related loss of bodyweight reaching the maximum loss, when it occurred, at about 4 days after injections. Subsequently, rats returned to gaining weight regularly. Of the doses tested, only the 2.0 mg dose produced a consistent increase in intake of ethanol during the time previous research indicated that the rats would show enhanced intakes. There was, however, a dose-related trend for smaller doses to enhance intakes. Rats with ovariectomies showed a similar pattern of effects, to intact rats, with the 2 mg dose. After extensive histories of intake of alcohol, both placebo and EV-treated females had estradiol levels below the average measured in females without a history of alcohol-intake.

Conclusion

The data support the conclusion that pharmacological doses of estradiol can produce enduring changes that are manifest as an enhanced appetite for alcoholic beverages. The effect can occur among females without ovaries.     

Estradiol valerate/dienogest

Estradiol valerate 2mg/dienogest 2mg is an oral estrogen/ progestogen formulation that has been approved throughout the European Union for the treatment of climacteric symptoms in postmenopausal women. Dienogest is a progestogen that combines the properties of both progesterone and 19-nortestosterone derivatives. It has moderate affinity for the progesterone receptor, significant antiproliferative and antiandrogenic activity, and produces secretory transformation of the endometrium. Estradiol valerate is an esterified form of natural 17beta-estradiol, the most potent endogenous human ovarian estrogen, and is hydrolysed to estradiol soon after oral administration. Results from a randomised, double-blind, multicentre trial showed that oral estradiol valerate 2mg/dienogest 2mg and estradiol valerate 2mg/dienogest 3mg once daily for 1 year were each as effective as estradiol 2mg/estriol 1mg/norethisterone acetate 1mg in the treatment of climacteric symptoms in 581 postmenopausal women; reductions from baseline in Kupperman Index scores were 78.5, 74.5 and 75.0%, respectively. The number of days without any type of bleeding was lowest in patients treated with estradiol valerate 2mg/dienogest 2mg (8.7 days), and highest in the estradiol valerate 2mg/ dienogest 3mg group (12.1 days). During the twelfth month of treatment with estradiol valerate 2mg/dienogest 2mg, the percentage of patients who reported bleeding was 14.5%. Endometrial biopsy results were similar in patients treated with estradiol valerate 2mg/dienogest 2mg, estradiol valerate 2mg/dienogest 3mg or estradiol 2mg/estriol 1mg/norethisterone acetate 1mg once daily for 1 year; 90.8, 87.4 and 87.5% of samples, respectively, contained atrophic material. Proliferative material was found in 4.2, 2.5 and 4.4% of the biopsies, respectively; there was no incidence of hyperplasia in any of the treatment groups. A noncomparative multicentre study in 1501 postmenopausal women demonstrated that adverse events associated with estradiol valerate 2mg/dienogest 2mg once daily for 48 weeks included breakthrough bleeding, mastalgia, headache, abdominal pain, hypertension, thrush, migraine, weight gain, increase in endometrial thickness and metrorrhagia.     

Estradiol valerate and tibolone: effects on memory

This study investigated the effects of estradiol valerate (EV) and tibolone (TB) treatments on some memory parameters of ovariectomized young (2 months), adult (8 months) and old (20 months) female rats. A Sham-operated group was used as control and the animals were treated daily, by oral gavage, with saline (Sham and placebo NR group), EV (0.3 mg/kg) or TB (0.5 or 1 mg/kg, TB1 and TB2, respectively). In step-down inhibitory avoidance task, the latency of old TB2-treated females in the short-term test was significantly inferior (p<0.05), compared to TB2 adults. In the elevated plus maze, adult NR females spent significantly less time (p<0.05) in the open arms as compared with EV and TB2-treated animals. Additionally, adult TB2-treated females spent significantly less time in the closed arms compared to Sham, NR and TB1 groups. Finally, in the water maze retention test, young TB1-treated animals performed worse when compared to Sham, EV and TB2 females. In the old animals, EV treatment hampered subject performance as compared to all other treatments. Taken together, these results indicate that ovarian hormones differently affect female memory in an age-dependent manner.     

戊酸雌二醇联合地屈孕酮治疗非器质性月经过多的疗效观察

目的观察戊酸雌二醇联合地屈孕酮治疗非器质性月经过多的临床疗效及安全性。方法选取86例非器质性月经过多患者,采用信封法随机分为2组,每组43例。对照组患者采用戊酸雌二醇联合安宫黄体酮治疗,观察组采用戊酸雌二醇联合地屈孕酮治疗,两组患者均给予补充铁剂、加强营养、注意休息等对症支持治疗,均连续治疗3个周期。按照月经失血图评分法(PBAC)评估两组患者经血量,评分>100分(经血量>80 mL)为月经过多。记录两组患者用药后出血控制时间、出血停止时间,并根据两组患者阴道出血情况进行疗效评定。治疗期间严密观察两组患者不良反应发生情况。结果观察组、对照组的总有效率分别为95.35%、81.40%,两组比较差异有统计学意义(P<0.05)。观察组、对照组的出血控制时间分别为(16.5±2.0)d、(25.6±3.0)d,出血停止时间分别为(23.5±3.8)d、(40.5±5.0)d,两组比较差异均有统计学意义(P<0.05)。观察组治疗1个周期、2个周期、3个周期后,PABC评分明显低于对照组(P<0.05)。观察组、对照组分别有4例(9.30%)、5例(11.63%)发生不良反应,两组比较差异无统计学意义(P>0.05)。结论采用戊酸雌二醇联合地屈孕酮治疗非器质性月经过多,可迅速控制出血,减少月经出血量,不良反应少而轻微。     

One injection of estradiol valerate induces dramatic changes in rats' intake of alcoholic beverages

A series of experiments investigated the effects of a single injection of estradiol valerate (EV) on female rats' consumption of alcoholic beverages. EV provides sustained release of estradiol. Just after an injection of EV, rats' intake of a palatable alcoholic beverage, which had been taken regularly before, is reduced dramatically. Subsequently, rats' intake of alcoholic beverage returns to baseline levels. With continued opportunity to drink, rats take more ethanol than controls. When EV was given 15 and 31 days before the first opportunity to drink an alcoholic beverage, female rats markedly enhanced their intake of ethanol. Once enhanced intakes emerged, they were observed with different kinds of alcoholic beverages and endured for months.     

Repeated binge ethanol administration during adolescence enhances voluntary sweetened ethanol intake in young adulthood in male and female rats

Binge alcohol consumption is a rising concern in the United States, especially among adolescents. During this developmental period alcohol use is usually initiated and has been shown to cause detrimental effects on brain structure and function as well as cognitive/behavioral impairments in rats. Binge models, where animals are repeatedly administered high doses of ethanol typically over a period of three or four days cause these effects. There has been little work conducted aimed at investigating the long-term behavioral consequences of repeated binge administration during adolescence on later ethanol-induced behavior in young adulthood and adulthood. The repeated four-day binge model may serve as a good approximate for patterns of human adolescent alcohol consumption as this is similar to a “bender” in human alcoholics. The present set of experiments examined the dose-response and sex-related differences induced by repeated binge ethanol administration during adolescence on sweetened ethanol (Experiment 1) or saccharin (Experiment 2) intake in young adulthood. In both experiments, on postnatal days (PND) 28-31, PND 35-38 and PND 42-45, ethanol (1.5, 3.0 or 5.0 g/kg) or water was administered intragastrically to adolescent rats. Rats underwent abstinence from PND 46-59. Subsequently, in young adulthood, ethanol and saccharin intake were assessed. Exposure to any dose of ethanol during adolescence significantly enhanced ethanol intake in adulthood. However, while female rats had higher overall g/kg intake, males appear to be more vulnerable to the impact of adolescent ethanol exposure on subsequently increased ethanol intake in young adulthood. Exposure to ethanol during adolescence did not alter saccharin consumption in young adulthood in male or female rats. Considering that adolescence is the developmental period in which ethanol experimentation and consumption is usually initiated, the present set of experiments demonstrate the importance of elucidating the impact of early binge-pattern ethanol exposure on the subsequent predisposition to drink later in life.     

The effects of d-fenfluramine on saccharin intake and preference, and on food and water intake

The effects of d-fenfluramine on saccharin intake and preference were examined to investigate whether the reduced rate of eating induced by this compound reflects a reduction in the palatability of foods. In two separate experiments, water deprived rats were offered a choice between a 0.05% solution of saccharin and water, or a 0.2% saccharin solution and water. Injection of d-fenfluramine at doses which reliably decreased food intake resulted in dose dependent reductions in total fluid intake and saccharin intake. A trend towards reduced water intake was observed also, and this together with the reduced saccharin intake resulted in no overall change in saccharin preference. In a further experiment, d-fenfluramine reduced the water intake of water deprived rats to the same extent as it reduced total fluid intake in the choice tests. Since d-fenfluramine failed to alter saccharin preference, it is unlikely that the slowed eating rate induced by this compound indicates a reduction in food palatability. Instead, it is likely that this behaviour results from a subtle motor deficit, such that fenfluramine treated animals are unable to maintain ingestion at the same rate as non-drugged animals. This explanation could account for the reduction in the consumption of non-nutritive saccharin solutions and water in water deprived animals. The relevance of this action to the anorectic effect of fenfluramine is discussed.     

Estradiol and Dydrogesterone

Drugs & Aging - The focus of this review is hormone replacement therapy (HRT) with continuous oral 17β-estradiol (herein referred to as estradiol) 2 mg/day plus sequential oral...     

Reducing added sugar intake in Norway by replacing sugar sweetened beverages with beverages containing intense sweeteners - A risk benefit assessment

A risk benefit assessment in Norway on the intake of added sugar, intense sweeteners and benzoic acid from beverages, and the influence of changing from sugar sweetened to diet beverages was performed. National dietary surveys were used in the exposure assessment, and the content of added sugar and food additives were calculated based on actual contents used in beverages and sales volumes provided by the manufactures. The daily intake of sugar, intense sweeteners and benzoic acid were estimated for children (1- to 13-years-old) and adults according to the current intake level and a substitution scenario where it was assumed that all consumed beverages contained intense sweeteners. The change from sugar sweetened to diet beverages reduced the total intake of added sugar for all age groups but especially for adolescent. This change did not result in intake of intense sweeteners from beverages above the respective ADIs. However, the intake of acesulfame K approached ADI for small children and the total intake of benzoic acid was increased to above ADI for most age groups. The highest intake of benzoic acid was observed for 1- to 2-year-old children, and benzoic acid intake in Norwegian children is therefore considered to be of special concern.     

Attenuation of angiotensin-induced water intake in estrogen-treated rats

Chronic treatment with either estradiol benzoate (31 and 57 μg/kg/day) or ethynyl estradiol (30 and 72 μg/kg/day) attenuated the drinking responses of female rats to acute administration of either isoproterenol (25 μg/kg, SC) or synthetic angiotensin II (100 and 200 μg/kg, IP). While these studies do not rule out the possibility that attenuation of isoproterenol-induced drink in estrogen-treated rats may be associated with a defect in renin release, attenuation is also apparently associated with a reduced responsiveness to angiotensin II. This may be related to reduced permeability of angiotensin II at the level of the circumventricular organs of the brain; to hyporesponsiveness of receptors for angiotensin II mediating thirst in the central nervous system, or to mechanisms beyond the receptor that are responsible for the conscious behavioral changes which normally accompany angiotensin II-induced thirst.     

Anti-arrhythmia activity of estradiol valerate and estradiol nitrate

Estradiol valerate and estradiol nitrate exhibit significant antiarrhythmic activity of on the aconitine arrhythmia model in rats. In both cases, the maximum effect was observed in a dose of 0.5 mg/kg.     

Oral self-administration of sweetened nicotine solutions by rats

Oral self-administration of sweetened nicotine solutions in rats was studied in two ways. In the first experiment, one group had continuous access to a water bottle containing a sucrose solution and nicotine (10 μg/ml), while another group had access to an identical sucrose solution without nicotine. All rats had continuous access to water. While consumption of nicotine increased with increasing concentrations of sucrose, consumption of the sucrose + nicotine solution never exceeded the intake of sucrose alone. In subsequent experiments, the delivery of the solutions was made contingent upon an operant response. The sucrose + nicotine solution was found to maintain responding to higher response/reinforcer ratiosthan the sucrose only solution. These data demonstrate that rats will self-administer sweetened nicotine solutions and that sucrose + nicotine solutions are more reinforcing than sucrose solutions alone. Free accessconsumption is not a good predictor of the response maintaining properties of nicotine solutions.     

Time of day and access to food alter water intake in rats after water deprivation

1. Drinking behaviour after water deprivation is one of the standard tests used to study thirst in humans and animals. Diurnal cycle and food availability are known to influence water intake, but have not been considered in previous studies of thirst after water deprivation. In the present study, we examined the effects of diurnal variation and food availability on water intake after 24 h water deprivation in rats. 2. All rats cycled through four treatments in varying order. These treatments were: (i) 24 h water deprivation with free access to food from 1900 h one day to 1900 h the next day, followed by free access to both food and water (Night-with-Food); (ii) 24 h water deprivation with free access to food from from 1900 h one day to 1900 h the next day, followed by free access to water but not food (Night-without-Food); (iii) 24 h water deprivation with free access to food from 0700 h one day to 0700 h the next day, followed by free access to both food and water (Day-with-Food); or (iv) 24 h water deprivation with free access to food from 0700 h one day to 0700 h the next day, followed by free access to water but not food (Day-without-Food). The amount of water consumed during the first 6 h, post-24 h water deprivation, was examined under each condition. 3. There was a significant diurnal effect (P < 0.001) and a significant food availability effect (P = 0.007) on the water consumed in the 6 h period after water deprivation. Most water was consumed by the Night-with-Food group and the least amount of water was consumed by the Day-without-Food group. These effects persisted after correction for water intake during 6 h periods from 0700 and 1900 h with and without food but without previous water deprivation. The diurnal and food availability effects on water consumption were independent (P = 0.5). 4. The coefficient of variability for each group suggests that the most sensitive measurements of water intake are obtained during the day in the absence of food. 5. We conclude that both the time of day and access to food independently alter water intake in rats subjected to a previous 24 h water deprivation. Our study also supports the validity of performing water intake measurements in thirst studies in rats during the day.     

Effects of the dopamine D-1 antagonist SCH 23390 on water intake, water-rewarded operant responding and apomorphine-induced decrease of water intake in rats

The specific dopamine (DA) D-1 receptor antagonist SCH 23390 was found to attenuate operant lever-pressing with water as reward in a dose-dependent manner and more potently than drinking itself. This effect occurred in the same fashion as previously reported for DA D-2 antagonists. In contrast to the DA D-2 antagonist haloperidol, the attenuated operant lever-pressing induced by the DA D-1 antagonist SCH 23390 was not counteracted by the anticholinergic drug scopolamine. The decreased water intake in thirsty animals caused by a low dose of apomorphine was not antagonised by SCH 23390. This has previously been found with DA D-2 antagonists, such as haloperidol and sulpiride. The results show that in spite of some similarities in the behavioural effects of DA D-1 and D-2 antagonists, a closer pharmacological analysis is able to reveal pronounced differences.     

Effect of chronic intake of arsenic-contaminated water on liver

The hepatotoxic effect of arsenic when used in therapeutic dose has long been recognized. We described the nature and degree of liver involvement and its pathogenesis due to prolonged drinking of arsenic-contaminated water in West Bengal, India. From hospital-based studies on 248 cases of arsenicosis, hepatomegaly was found in 190 patients (76.6%). Non cirrhotic portal fibrosis was the predominant lesions in 63 out of 69 cases who underwent liver biopsy. The portal fibrosis was characterized by expansion of portal zones with streaky fibrosis, a few of which contained leash of vessels. However, portal hypertension was found in smaller number of cases. A cross-sectional epidemiological study was carried out on 7683 people residing in arsenic-affected districts of West Bengal. Out of these, 3467 and 4216 people consumed water-containing arsenic below and above 0.05 mg/l, respectively. Prevalence of hepatomegaly was significantly higher in arsenic-exposed people (10.2%) compared to controls (2.99%, P < 0.001). The incidence of hepatomegaly was found to have a linear relationship proportionate to increasing exposure of arsenic in drinking water in both sexes (P < 0.001). In an experimental study, BALB/C mice were given water contaminated with arsenic (3.2 mg/l) ad libitum for 15 months, the animals being sacrificed at 3-month intervals. We observed progressive reduction of hepatic glutathione and enzymes of anti-oxidative defense system associated with lipid peroxidation. Liver histology showed fatty infiltration at 12 months and hepatic fibrosis at 15 months. Our studies show that prolong drinking of arsenic-contaminated water is associated with hepatomegaly. Predominant lesion of hepatic fibrosis appears to be caused by arsenic induced oxystress.     

Effect of indomethacin on water intake of the rat

Indomethacin stimulated water intake in intact rats. This effect could also be demonstrated in bilaterally ureteral ligated rats, but it was totally abolished after bilateral nephrectomy. It is suggested that the stimulatory effect of indomathacin on water consumption is mediated by a renal factor.     

Bioavailability of mefenamic acid: influence of food and water intake

The influence of food and water intake on mefenamic acid (N-2,3-xylylanthranilic acid) bioavailability from commercial capsules of high bioavailability was studied in four healthy male volunteers. The drug was administered as a single oral dose of 250 mg, under fasting or nonfasting conditions, and a 4 X 4 Latin-square design was used. Eight blood samples were collected over a 24-h period following drug administration, and the drug plasma concentrations were determined by HPLC. The bioavailability of mefenamic acid from capsules was markedly influenced in the fasting subjects by the water but not by the food intake. A good correlation was found between the bioavailability and amount of water ingested with the drug in the fasting subjects. The area under the plasma concentration-time curve (AUC0-infinity) of mefenamic acid was highest when the capsule was taken with 50 mL of water or immediately after a meal. Increasing the amount of water from 50 to 500 mL in the fasting subjects caused a significant reduction in AUC0-infinity.     

Regulation of drug and water intake in rats dependent on morphine

Rats were made dependent on morphine by training them to drink solutions of the drug even when water was available as an alternative. Experiments were carried out to examine the reliability of the technique. Drinking was recorded in two ways, and it was found that there was close agreement between the numbers of laps (drinkometer counts) and the volumes of fluids removed from the drinking bottles. When dependent rats were allowed to partially satisfy their needs for morphine and/or water shortly before morphine: water choice trials, they made appropriate adjustments in their subsequent consummatory responses. However, the value of using quinine solutions to control for effects due to the bitter taste of morphine was more limited than has sometimes been supposed; the relative palatabilities of the two drugs seemed to vary across experiments. Considered as a whole, the results support the view that preferences for morphine in rats can provide a valid measure of their need for the drug.     

Bombesin potently stimulates water intake in the pigeon

Bombesin, injected intracerebroventricularly, evoked a potent dipsogenic response in the pigeon.The effect was dose-dependent and apparently specific since no other behavioural alteration was ever observed. The findings suggest that endogenous bombesin-like peptides may be involved in the control of water intake in the pigeon.