Ovarian hormones and cognition in the aged female rat: I. Long-term, but not short-term, ovariectomy enhances spatial performance

Although research suggests that ovariectomy (ovx) is detrimental to spatial cognition in young rats, little work has evaluated the cognitive effects of ovx in aged rats. The authors investigated the effects of ovx in aged rats using the water radial-arm maze. In Study 1, young rats and aged rats receiving ovx 1.5 months before testing outperformed aged rats receiving sham surgery or ovx 21 days before testing. In Study 2, young rats and aged rats receiving ovx 2.0 or 6.0 months before testing outperformed aged sham rats. Aged rats exhibited estradiol and elevated progesterone levels comparable to those of young rats. The findings suggest that 1.5-6.0 months, but not 21 days, of ovx improves spatial memory in aged rats. The hypothesis that long-term ovarian hormone loss is detrimental to spatial memory in aged rats was not supported. The authors hypothesize that removal of elevated progesterone levels is related to the ovx-induced cognitive enhancement.     

Ovarian hormones and meal patterns in rats: effects of progesterone and role of gastrointestinal transit

Three experiments determined: (1) whether progesterone treatment would reverse the effects of estradiol benzoate (EB) on meal patterns of ovariectomized (OVX) rats, and (2) whether changes in gastrointestinal transit were responsible for the EB-induced changes in meal patterns. Progesterone (5 mg/day) reversed the effects of EB by increasing meal size and decreasing meal frequency in OVX, EB-treated rats. Progesterone had no effect on these measures in OVX rats that were not given EB. In a comparison of the rate of gastrointestinal transit, the rate of gastrointestinal transit was found to be faster in OVX rats injected with EB daily for two weeks than in OVX, oil-treated controls as measured under anesthesia with infusion of ten ml of liquid diet. However, this alteration in gastrointestinal transit does not appear to be responsible for the decreased meal size of EB-treated, OVX-rats, because the gastrointestinal changes are not observed 34-38 hr after an EB injection, a time at which meal size is already affected.     

Ovarian hormone effects on activity, glucoregulation and thyroid hormones in the rat

Ovarian hormonal influences on the range of physiological and behavioral variables which combine to affect overall energy balance are poorly delineated. In the present study 4 groups of virgin, female rats (intact, ovariectomized, ovariectomized with estrogen replacement and ovariectomized with estrogen plus progesterone) were allowed access to running wheels and activity; food intake and weight gain were measured initially under food restricted, then under ad lib conditions. Serum insulin, glucose, thyroxine (T4) and triiodothyronine (T3) were determined on trunk blood samples obtained at the end of the experiment. Ovariectomy resulted in an increased rate of weight gain through reduced activity and T3 but food intake was unchanged. Insulin levels were greatly reduced. Estrogen replacement restored activity to the intact group's level and normalized weight gain. Insulin and T3 were also raised to control levels but T4 was reduced as was serum glucose. Estrogen plus progesterone replacement reduced weight gain markedly and increased T3 with normal T4. Despite the lower body weight this group was hyperglycemic and hyperinsulinemic suggesting insulin resistance. The results have important implications for the glucoregulatory and energy balance perturbations of ovarian hormone fluctuations and focus particularly on progesterone.     

Ovarian steroid hormones: effects on immune responses and Chlamydia trachomatis infections of the female genital tract

Female sex hormones are known to regulate the adaptive and innate immune functions of the female reproductive tract. This review aims to update our current knowledge of the effects of the sex hormones estradiol and progesterone in the female reproductive tract on innate immunity, antigen presentation, specific immune responses, antibody secretion, genital tract infections caused by Chlamydia trachomatis, and vaccine-induced immunity.     

Anabolic hormones in aging women: effects of supplementation vs. physical activity.

Aging is associated with a decline in bone mass, muscle mass, strength, and physical function, and women are more likely to suffer from these physical changes than men. The model presented in this paper illustrates the age related changes in anabolic hormones and how this may partly explain the diminished physical function of older women. The model can also be used to identify potential sites of intervention that could delay the atrophy of the musculoskeletal system. Various pharmacological hormone therapies have been shown to be beneficial, but there may be health risks associated with their use. There is evidence that regular physical activity is related to higher levels of anabolic hormones in older persons, therefore exercise could be an alternative to drugs for slowing the age related changes in the endocrine system. However, some research suggests that the hormone response to exercise is blunted in older women. This lower hormonal response may not be a consequence of aging per se but instead may result from secondary characteristics of aging such as a decline in physical fitness and exercise intensity or changes in body composition. Further research is needed to determine whether exercise-induced increases in endogenous hormones have clinical significance in improving muscle or bone mass in aging women.     

Ovarian hormones regulating sexual and social behaviors in female prairie voles, Microtus ochrogaster.

In the induced ovulator, Microtus ochrogaster (the prairie vole), daily injections of estradiol benzoate (EB 0.5 μg or 5.0 μg) facilitated high levels of sexual receptivity in ovariectomized females withing 48 hr of the onset of treatment. A lower level of EB (0.05 μg) with or without progesterone (0.5 mg) for five days did not induce lordosis. Four hr after sexually receptive EB-primed females received progesterone (0.5 mg) they either continued to show lordosis (EB 5.0 μg group) or showed an inhibition of lordosis (EB 0.5 μg group). Within 24 hr lordosis was markedly reduced in both groups. Progesterone-associated inhibitions were no longer apparent 48 hr after progesterone was discontinued. This general pattern of response to ovarian hormones is consistent with data described for other induced ovulators.     

Hypothalamic self-stimulation in the female rat: effects of oestrus and food deprivation.

Natural oestrus (147 cycles) had no overall effect in a longitudinal study of self-stimulation in a group of rats with hypothalamic electrodes (n = 20), though some individual animals showed significant increases in response rate at oestrus or at dioestrus. Animals were significantly more likely to show peak rates at prooestrus or oestrus if their electrodes were located in hypothalamic feeding areas; the effects in these rats were therefore probably indirect and non-sexual, caused by the decrease in food intake that accompanies oestrus. In ovariectomized rats, however, self-stimulation of feeding areas was usually unaffected by oestradiol injections, and increases in response rate reported after oestradiol injections in ovariectomized animals may therefore be a direct effect of the hormone; replicated study of the only animal showing unequivocal oestrogen-sensitive enhancement of self-stimulation showed that the effect was specific to oestrogenic (and not androgenic) steroids, and that the minimum effective dose was within the physiological range. These findings indicate both direct and indirect effects of oestrus on hypothalamic self-stimulation.     

Neonatal gonadal hormones: Effect on maternal and sexual behavior in the female rat

It has been found that significant differences exist between male and female rats of the Long-Evans strain on maternal behavior when the animals were presented with rat pups for seven consecutive days. The presence of ovarian or testicular products at the time of maternal testing did not have a facilitating or suppressing effect on maternal behavior in the Long-Evans rat. Females given 100 μg or 1 mg of testosterone propionate (TP) four days after birth and gonadectomized at 25 days of age behaved like control females (oil injected four days after birth and gonadectomized at 25 days of age) on measures of maternal behavior, but showed significantly lower sexual receptivity when primed with estrogen and progesterone. Thus the female sexual behavior system was suppressed by neonatal TP, but the maternal mediating system was not suppressed by the same treatment. It is concluded that the critical periods of differentiation may be different for sex and maternal behavior.     

Some effects of ovariectomy and estrogen replacement on body composition in the rat

Sprague-Dawley rats were ovariectomized (OvX) at 3 ages, day 2 (D2), week 4 (W4) and week 7 (W7); a group of OvX W7 rats were treated daily with estrogen (OB; 2 μg for 2 or 5 weeks from 10 weeks of age). Rats were slaughtered at 4 ages, weeks 7, 9, 12 and 15, for the chemical analysis of carcass and skin. Chemical compositions were analysed as % wet weight and as component weights by two-way analysis of variance. Component weights were also analysed by allometry, regressing against nose-anal length. Ovariectomy increased overall body weight without causing obesity. The weight gain of the OvX rat was mainly a true growth response but OvX affected body proportions so that at a given body length the OvX rat had a larger skin and carcass than controls. Ovariectomy at the earliest age (D2) produced the smallest response in body weight and body length but produced the greatest fat redistribution towards the skin and away from the carcass; there was no net change in whole body fat levels following OvX. Long-term daily OB treatment increased fat reserves but slowed the growth of other body components, including the axial skeleton. Whereas OvX redistributed components between skin and carcass, OB treatment reversed this process.     

Hormone-dependent aggression in the female rat: testosterone plus estradiol implants prevent the decline in aggression following ovariectomy

Female rats were individually housed with a sterile male for the duration of the experiment. Beginning 7 to 10 weeks after the start of cohabitation, each female was tested for aggression toward an unfamiliar female at weekly intervals for 3 weeks. Females that displayed consistent and substantial aggression were given one of the following treatments: ovariectomy followed by both testosterone and estradiol implants, ovariectomy followed by 2 empty implants, or sham ovariectomy followed by 2 empty implants. The implants were subcutaneously placed hormone-filled Silastic capsules. They were expected to produce a serum testosterone concentration of 0.5 ng/ml and an estradiol concentration of 15 pg/ml. Postoperatively, the aggression of each female continued to be assessed on a weekly basis for 3 weeks. Ovariectomized females with hormone implants displayed a level of aggression postoperatively similar to that of sham-ovariectomized females and significantly greater than that of ovariectomized females with empty implants. These results, together with others, suggest that estradiol and testosterone act together to form the hormonal foundation of hormone-dependent aggression by females cohabiting with a sterile male.     

Prolactin reduces the damaging effects of excitotoxicity in the dorsal hippocampus of the female rat independently of ovarian hormones

We reported previously that lactation prevents the cell damage induced by kainic acid (KA) excitotoxicity in the CA1, CA3, and CA4 areas of the dorsal hippocampus compared to rats in diestrus phase, and hypothesize that pronounced fluctuations of hormones, such as ovarian steroids and prolactin (PRL), have a role in the neuroprotection of the dorsal hippocampus during lactation. PRL is thought to be involved in modulating neural excitability and seizure activity. To investigate actions of prolactin that minimize KA-induced cell damage in the hippocampus, female intact and ovariectomized (OVX) rats were treated for 4 days with a daily dose of 100 μg of prolactin or vehicle. On the third day of prolactin treatment, rats received a systemic dose of 7.5 mg/kg of KA and were sacrificed 48 h later. Immunostaining for Neu-N revealed a significant decrease in cell number in the CA1, CA3 and CA4 areas of intact or OVX, vehicle-treated rats after KA, whereas prolactin treatment prevented cell loss in the CA3 area of intact, and in the CA1, CA3, and CA4 of OVX rats. Fluoro-Jade C staining confirmed these observations. Kainate-induced seizure behavior progressed further in OVX rats, but was attenuated in prolactin-treated rats, both intact and OVX, compared to vehicle-treated rats. These data indicate that prolactin diminishes the damaging actions of excitotoxicity in the kainate model of epilepsy.     

Positive effects of deprenyl and estradiol on spatial memory and oxidant stress in aged female rat brains

Increasing age decreases spatial learning and memory. Spatial learning is coordinated with different brain regions. Since the oxidative damage may play a role in the aging process, including the associated cognitive decline, age-related impairment in spatial learning and memory may be alleviated by antioxidant treatment. The present study examined the effects of the monoamine oxidase B inhibitor L-deprenyl, alone and in combination with estradiol, on spatial memory using the Morris water maze and oxidant stress in aged female rat brains. We demonstrated that co-administration of deprenyl and estradiol caused a synergistic effect on spatial memory. However, use of either deprenyl or estradiol alone increased antioxidant enzyme activities in brain and reduced lipid peroxidation. Therefore, positive effects of deprenyl and estradiol on spatial memory may occur due not only to their antioxidant activities but also to the different actions.     

The response of the uterine surface to ovarian hormones in the aged rat

Summary By scanning electron microscopy uterine luminal epithelium of the rat was studied to determine whether aging alters ovarian hormone stimulated ultrastructural changes in that portion of the endometrial surface into which implantation takes place in the younger animal. Results show that in the aged rat this surface differentiates in response to ovarian hormones in a manner qualitatively similar to that which occurs in the young animal. Epithelial cells of ovariectomized rats, both young and aged, were polygonal in outline, flattened, or even somewhat concave, and had short microvilli. Following estrogen treatment cells of both groups were round or oval and bulged into the lumen. Cells of young rats were covered with long microvilli. Most cells of aged rats had microvilli of equal or greater length; a small number of epithelial cells had fewer and shorter microvilli. Cells of progesterone-treated young and aged animals both were covered with short microvilli and bore membrane protrusions. The protrusions varied in size, shape and numbers both within and between age groups. These findings suggest that differences in the surface ultrastructure of the aged uterus reflect age-related changes in hormone levels.     

Pituitary-adrenal hormones and effects of partial reinforcement on appetitive behaviour in the rat.

Rats ran in a straight alley with food reward on continuous (CR) or partial (PR) reinforcement. They received during training placebo, 80 μg ACTH 4–10, 80 μg ACTH 4–10 (7-D-Phe), 1 or 2.5 mg corticosterone. None of these treatments affected performance during training itself. The rats were tested during extinction without hormone treatment. The partial reinforcement extinction effect (PREE) was decreased by ACTH 4–10 and increased by ACTH 4–10 (7-D-Phe), both these changes being due to altered running speeds in the peptide-treated PR groups. One mg corticosterone was without effect on the PREE. 2.5 mg corticosterone caused the PREE to be larger early in extinction (due to changed running speeds in the hormone-treated PR group). These and previous results suggest that ACTH 4–10 attenuates the behavioural effects of nonreward, ACTH 4–10 (7-D-Phe) increases them, and corticosterone has little influence on them.     

Interaction of estradiol, testosterone, and progesterone in the modulation of hormone-dependent aggression in the female rat.

Female rats that had become aggressive as a result of cohabiting with a sterile male were ovariectomized and implanted with Silastic tubes of estradiol, testosterone, and progesterone, estradiol and testosterone alone, or with empty tubes. The implants were designed to model serum concentrations present during the last week of pregnancy (estradiol, 0.06 ng/ml; testosterone, 2.6 ng/ml; progesterone, 70 ng/ml). Following a test of aggression 1 week postoperatively, estradiol and testosterone implants were replaced with ones designed to maintain the lower hormone levels present following parturition (0.02 ng/ml; 0.6 ng/ml, respectively). Progesterone was not replaced. At the first aggression test, females with estradiol and testosterone alone displayed significantly more aggression than females with these hormones plus progesterone. Both groups were more aggressive than females without hormone replacement. Following the exchange of large implants for small ones, females that previously had progesterone increased in aggression while females that previously had only estradiol and testosterone decreased in aggression. Both groups continued to be more aggressive than the group without hormone replacement. High serum progesterone present near the end of pregnancy appears to moderate the expression of aggression supported by estradiol and testosterone. Conversely, progesterone's decline at parturition appears to produce a rebound facilitation of aggression even though serum estradiol and testosterone simultaneously decline.     

Effect of estradiol and progesterone on the low-dose endotoxin-induced glomerular inflammatory response of the female rat.

PROBLEM: Is the endotoxin-induced glomerular inflammatory response of the female rat under ovarian control? METHOD OF STUDY: Ovariectomized rats (OVX), with or without progesterone (OVX-P) or estradiol (OVX-E) treatment, as well as rats in the follicular or luteal phase of the ovulatory cycle were infused with endotoxin or saline and sacrificed 3 days later. Cryostat kidney sections were immunohistologically stained for the presence of neutrophils and monocytes (MØ) and the expression of adhesion molecules. RESULTS: After endotoxin, the glomerular number of neutrophils and the number of MAC-1 positive cells were increased in luteal-phase and in OVX-P rats, and the number of glomerular MØ was increased in luteal-phase, OVX, OVX-E, and OVX-P rats. Endotoxin increased ICAM-1 expression in all groups of rats, except in follicular-phase rats. The glomerular number of LFA-1– and VLA-4-positive cells following endotoxin were only increased in OVX rats. CONCLUSIONS: It is concluded that endotoxin-induced monocyte infiltration and ICAM-1 expression are inhibited by a factor produced during the follicular phase, probably by developing follicles. Infiltration of neutrophils and expression of MAC-1, LFA-1, VLA-4 seem to be under control of progesterone or estradiol.     

Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition

Omega-3 fatty acids (i.e. docosahexaenoic acid; DHA), similar to exercise, improve cognitive function, promote neuroplasticity, and protect against neurological lesion. In this study, we investigated a possible synergistic action between DHA dietary supplementation and voluntary exercise on modulating synaptic plasticity and cognition. Rats received DHA dietary supplementation (1.25% DHA) with or without voluntary exercise for 12 days. We found that the DHA-enriched diet significantly increased spatial learning ability, and these effects were enhanced by exercise. The DHA-enriched diet increased levels of pro-brain-derived neurotrophic factor (BDNF) and mature BDNF, whereas the additional application of exercise boosted the levels of both. Furthermore, the levels of the activated forms of CREB and synapsin I were incremented by the DHA-enriched diet with greater elevation by the concurrent application of exercise. While the DHA diet reduced hippocampal oxidized protein levels, a combination of a DHA diet and exercise resulted in a greater reduction rate. The levels of activated forms of hippocampal Akt and CaMKII were increased by the DHA-enriched diet, and with even greater elevation by a combination of diet and exercise. Akt and CaMKII signaling are crucial step by which BDNF exerts its action on synaptic plasticity and learning and memory. These results indicate that the DHA diet enhanced the effects of exercise on cognition and BDNF-related synaptic plasticity, a capacity that may be used to promote mental health and reduce risk of neurological disorders.     

Prolactin binding sites in rat brain and liver: effects of long-term ovariectomy and ovarian steroids

The effects of long-term ovariectomy on the levels of brain and liver lactogenic binding sites as well as plasma and liver prolactin (PRL) have been investigated in sham-operated and ovariectomized rats receiving either 17β estradiol (OVX-E), progesterone (OVX-P), or vehicle (OVX-V). The levels of lactogenic binding sites in the parietal and piriform cortices, amygdala, thalamus, hypothalamus, as well as in the liver were significantly decreased after long-term ovariectomy. Moreover, the levels of plasma and liver PRL were also significantly decreased. Exogenous estradiol and progesterone replacement restored the levels of lactogenic binding sites in the parietal cortex and hypothalamus as well as in the liver. However, plasma and liver PRL levels were significantly increased by estradiol but only restored by progesterone. These results suggest that ovarian steroids influence the levels of lactogenic binding sites and prolactin.     

The metabolic effects of estriol in female rat liver.

The effects of estriol on oxygen uptake, glucose release, lactate and pyruvate production, beta-hydroxybutyrate and acetoacetate production in perfused rat liver as well as, carbon uptake in rat liver and intracellular calcium in isolated Kupffer cells were investigated. Basal oxygen consumption of perfused liver increased significantly in estriol or ethanol-treated rats. But these increased effects were blocked by gadolinium chloride pretreatment. In a metabolic study, pretreatment with estriol resulted in a decrease in glucose production and in glycolysis while an increase in ketogenesis. A more oxidized redox state of the mitochondria was indicated by increased ratios of perfusate [lactate]/[pyruvate] and decreased ratios of perfusate [beta-hydroxybutyrate]/[acetoacetate]. Carbon uptake of Kupffer-cell increased significantly in estriol-treated rats. But these increased uptake were not shown in rats pre-treated by gadolinium chloride blocking phagocytosis. In isolated Kupffer cells from estriol-treated rats, intracellular calcium was more significantly increased after addition of lipopolysaccharide (LPS) than in controls. These findings suggest that the metabolic effects of estriol (two mg per 100 mg body wt) can be summarized to be highly toxic in rat liver, and these findings suggest that oral administration of estrogens may induce hepatic dysfunctions and play a role in the development of liver disease.