Chronic Estrogen Administration Research Articles

Androgens Enhance Recognition Memory and Dendritic Spine Density in the Hippocampus and Prefrontal Cortex of Ovariectomized Female Rats

Estrogen replacement has been repeatedly shown to enhance memory and increase dendritic spine density in the hippocampus and prefrontal cortex of ovariectomized (OVX) female rats. Given the potential deleterious effects of chronic estrogen administration, the present study assessed cognitive function using recognition memory tasks and measured dendritic spine density in the CA1 region of the hippocampus and medial prefrontal cortex after subchronic androgen replacement to adult OVX female rats. All androgens enhanced recognition memory in OVX rats, but object placement (OP) and object recognition (OR) results differed. Only testosterone enhanced OR. Testosterone had no effect on OP while dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT) and androstenedione (AD) enhanced OP. Dendritic spine density was increased by both TP and DHEA in both brain areas (DHT and AD were not tested). Lastly, we used the aromatase inhibitor, letrozole, to discriminate between potential androgenic and estrogenic effects of androgens on behavior. Letrozole alone did not alter recognition memory in OVX rats and did not block the effects of either TP or DHEA on recognition memory suggesting that effects were mediated via androgenic mechanisms. The present results expand previous information on gonadal hormone actions and show that, in addition to estrogens, androgens also improve memory and increase spine density in brains of OVX female rats. While requiring further investigation, these observations provide a basis for therapeutic interventions in the treatment of menopausal, age or disease related memory loss.

Effects chronic administration of corticosterone and estrogen on HPA axis activity and telomere length in brain areas of female rats

Chronic stress is related to the acceleration of telomere shortening. Recent work showed a correlation between chronic psychosocial stress and reduced telomere length in certain cells. The exposure of T lymphocytes to cortisol promoted a significant reduction in telomerase activity. Although stress can promote changes in telomere length, whether increased glucocorticoid concentrations alter telomere length in brain tissue cells is unclear. In addition to modulating the activity of the stress system, estrogen also influences telomere length. The objective of this study was to verify whether chronic exposure to glucocorticoids promotes changes in the telomere length of encephalic areas involved in the control of HPA axis activity and whether estrogen affects these changes. Wistar rats were ovariectomized and treated with estradiol cypionate [(50 or 100 μg/kg, subcutaneously)] or oil and 20 mg/kg corticosterone or vehicle (isotonic saline with 2% Tween 80, subcutaneously) for 28 days. On the day after the end of the hormonal treatment, the animals were euthanized for collection of blood, brain and pituitary gland samples. Estrogen modulated the activity of the HPA axis. CRH, AVP and POMC mRNA levels were reduced by estrogen. At least in doses and treatment time used, there was no correlation between effects of exposure to glucocorticoids and estrogen on telomere length in the brain areas of female rats. However, estrogen treatment reduced the telomere length in the central amygdala and dorsal hippocampus, but not in the PVN, indicating a variation of reaction of telomeres for estrogen in different brain areas.

Oestrogen receptor ERα and ERβ agonists ameliorate oxidative brain injury and improve memory dysfunction in rats with an epileptic seizure.

What is the central question of this study? Could different hormonally active substances, including oestrogen receptor (ER) agonists, protect against oxidative brain damage and memory impairment induced by a single epileptic seizure in rats? If so, which signalling mechanisms are involved in their anti-inflammatory effects? What is the main finding and its importance? Chronic administration of oestrogen, progesterone, ER modulators/agonists or blockade of testosterone exhibited anti-inflammatory and antioxidant actions on single seizure-induced neuronal injury, while ER agonists additionally improved memory function and up-regulated CREB signalling and hippocampal GABA(A)α1 receptor density, suggesting that ERα or ERβ receptor activation may be beneficial in protecting against seizure-related oxidative brain injury and cognitive dysfunction. The susceptibility to epileptic seizures is dependent on sex as well as fluctuations in oestrogen levels, while exogenous oestrogen was shown to have no effect or to facilitate or to inhibit seizure activity. Oestrogen receptors (ERs) mediate antioxidant and anti-inflammatory actions in several inflammatory models, but the involvement of ERs in seizure-induced neuronal injury has not been evaluated previously. In order to assess the effects of resveratrol, progesterone, oestradiol (E2), an anti-testosterone (cyproterone acetate; CPA), a selective ER modulator (tamoxifen; TMX) and ERα/ERβ agonists (propyl pyrazole triol (PPT), diarylpropionitrile (DPN)) on oxidative brain damage and memory impairment due to epileptic seizure, male Wistar rats (n=120) received one of the treatment choices either in drinking water or intraperitoneally for 31 days, and epileptic seizure was induced on the 28th day by injection of a single-dose of pentylenetetrazole (45mgkg-1 ). The results demonstrate that chronic pretreatment with resveratrol, progesterone, E2, CPA or TMX suppressed most of the inflammatory parameters indicative of oxidative neuronal injury, while treatment with the ER agonists DPN or PPT were found to be even more effective in limiting the oxidative damage. Treatment with DPN resulted in the up-regulation of cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) expression, while PPT up-regulated expression of CREB without affecting BDNF levels. Moreover, both ER agonists provided protection against seizure-induced memory loss with a concomitant increase in hippocampal GABA(A)α1-positive cells. In conclusion, ER agonists, and more specifically ERβ agonist, appear to provide maximum protection against seizure-induced oxidative brain injury and associated memory dysfunction by up-regulating the expression of CREB, BDNF and GABA(A)α1 receptors.

Abstract 16806: Mechanisms of Sex Differences in Exercise Capacity

The current policy for NIH grants involves rigor, which not only includes adequate statistics, but also examination of both males and females. The reason for the priority to examine sex differences is because male rodents have been used almost exclusively in pre-clinical studies, which allows for biases to arise. Accordingly, the goal of this investigation was to determine sex differences in exercise capacity in mice and the mechanisms mediating these differences. C57 female wild-type (WT) mice (5 months old) exhibited greater, p<0.05, maximal exercise capacity for running distance (469 ± 24 m; n=7) than age-matched male WT mice (337 ± 14 m; n=8) as well as a 21% improvement in work to exhaustion. The first goal was to look at the effect of physical factors, such as weight and muscle mass, on exercise capacity. When matched for weight females still out-performed males in both running distance (541 ± 21 vs. 456 ± 18m, p<0.05; n=10/group) and demonstrated an 18% improvement in work to exhaustion. Similar outcomes were observed when matching for hind-limb muscle mass. The second goal was to study the effects of estrogen on exercise capacity. After ovariectomy (OVX), female mice no longer demonstrated enhanced exercise compared with males. Conversely, chronic administration of estrogen to male mice improved capacity in running distance and work to exhaustion by 35% after 4 weeks of treatment. Next, we investigated nitric oxide (NO), a downstream target of estrogen, a mechanism which has not been examined previously for mediating sex differences in exercise capacity. Total NO synthase (NOS) activity was higher in female mice compared with male mice (207 ± 14 U/mg vs. 138 ± 4 U/mg, p<0.05), but was no longer different after OVX. Furthermore, males chronically treated with estrogen exhibited a 47% increase in NOS activity. NO blockade with L-NAME eliminated the enhanced exercise capacity observed in both females and males treated with estrogen. Thus, as expected, estrogen is a key mechanism mediating the enhanced exercise capacity in female mice. However, this investigation also demonstrated another, novel key mechanism, increased nitric oxide activity.

Mechanisms of Gender Differences in Exercise Capacity

The examination of gender differences has been a recent priority of the NIH. It is well documented that female rodents exhibit higher exercise capacity than their male counterparts. We confirmed this in C57 wild‐type(WT) mice, where female mice exhibited greater, p<0.05, maximal exercise capacity for running distance (469 ± 24 m) than age‐matched male WT mice (337 ± 14 m). The first goal was to examine whether these differences persisted with models of enhanced exercise capacity, e.g. exercise training and the adenylyl cyclase type 5 knockout (AC5 KO) mouse. When WT mice underwent chronic exercise‐training, female mice maintained their superiority over males, with females running a 32% greater distance (p<0.05) than age‐matched trained males. However, AC5 KO mice, which demonstrated enhanced exercise capacity, did not exhibit a gender difference, with female AC5 KO mice (695 ± 51 m) running similar distances to male AC5 KO mice (661 ± 45 m). The next goal was to determine mechanisms mediating these differences. After ovariectomy, WT female mice no longer demonstrated enhanced exercise compared with males. Conversely, chronic administration of estrogen to male mice improved their exercise performance and eliminated the gender differences with exercise. Next we investigated nitric oxide (NO), a downstream target of estrogen. Total NO synthase (NOS) activity was higher in female mice compared with male mice in both sedentary (207 ± 14 U/mg vs. 138 ± 4 U/mg, p<0.05) and exercise trained groups (338 ± 42 vs. 193 ± 15 U/mg, p<0.05). Ovariectomized females exhibited nitric oxide levels similar to males (165 ± 11 U/mg). Administration of L‐NAME, resulting in NO blockade, eliminated the gender differences in exercise performance. In AC5 KO mice NOS activity was not different in male and female mice and similar exercise performance in males and females was still observed after treatment with L‐NAME. Thus, both estrogen and nitric oxide are key mechanisms mediating the enhanced exercise performance in female mice.Support or Funding InformationThis study was supported by the National Institute of Health grant R01HL106511This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of Chronic Estrogen Administration in the Ventromedial Nucleus of the Hypothalamus (VMH) on Fat and Bone Metabolism in Ovariectomized Rats.

Estrogen deficiency after ovariectomy (OVX) results in increased adiposity and bone loss, which can be prevented by systemic 17-β estradiol (E2) replacement. Studies in transgenic mice suggested that in addition to direct actions of estrogen in peripheral tissues, also estrogen signaling in the hypothalamus regulates fat distribution and bone metabolism. We hypothesized that the protective effect of systemic E2 on fat and bone metabolism in the OVX model is partly mediated through the ventromedial nucleus of the hypothalamus (VMH). To test this hypothesis, we determined the effect of systemic, central, and targeted VMH administration of E2 on fat and bone metabolism in OVX rats. Subcutaneous administration of E2 for 4 weeks decreased body weight, gonadal and perirenal fat, and bone formation rate in OVX rats. This effect was completely mimicked by intracerebroventricular injections of E2, once every 4 days for 4 weeks. Administration of E2 locally in the VMH by retromicrodialysis (3 h) acutely increased expression of the lipolytic gene hormone-sensitive lipase in gonadal and perirenal fat. Finally, chronic administration of E2 in the VMH for 8 weeks decreased perirenal fat but did not affect body weight, trabecular bone volume, or cortical thickness. In conclusion, we demonstrated that intracerebroventricular E2 replacement reduces body weight gain, ameliorates intraabdominal fat accumulation, and reduces bone formation in the OVX rats. E2 administration selectively in the VMH also reduced intraabdominal fat but did not affect bone metabolism.

Effect of Sex and Estrogens on Neuronal Activation in an Animal Model of Migraine

In this study, we evaluated the influence of sex and estrogen treatment on nitroglycerin (NTG)-induced neuronal activation in the rat brain. Systemic NTG activates cerebral nuclei of rat involved in nociceptive transmission, as well as in neuroendocrine and autonomic functions. These changes are considered relevant for migraine, since NTG consistently induces spontaneous-like attacks in migraineurs. Intact and castrated male and female rats, and castrated female rats treated with estradiol benzoate (or placebo) were injected with NTG and sacrificed after 4 hours. Rats were perfused, and their brains were processed for Fos protein, a marker of neuronal activation. Data showed a reduced expression of NTG-induced Fos protein in the paraventricular nucleus (PVH), supraoptic nucleus (SON), and nucleus trigeminalis caudalis (SPVC) of male rats in comparison with female rats. Furthermore, in castrated female rats, NTG-induced neuronal activation was reduced in PVH, SON, central nucleus of the amygdala (AMI), nucleus tractus solitarius (NTS), area postrema (AP), and SPVC, while in castrated male rats Fos expression was reduced uniquely in the SPVC. Chronic administration of estrogens restored Fos protein expression in PVH, SON, AMI, NTS, AP, and SPVC in castrated female rats. These data provide a support for the existence of a sexual dimorphism in NTG-induced neuronal activation, and they prompt a specific model for evaluating and modulating the influence of estrogens upon the cerebral structures implicated in the pathophysiology of migraine.

In vitro generation of three-dimensional functional ovarian structures

INTRODUCTION: The ovary contains cells that secrete hormones, which maintain female sexual characteristics as well as egg production. Loss of ovarian tissue function due to various endocrine and fertility disorders requires chronic estrogen and progesterone administration. While conventional hormone replacement therapy is able to maintain female sexual characteristics, this therapy is unable to restore ovarian tissue function, which includes the production of eggs. This is critical for premenopausal women who desire to conceive.

Estrogen in ischaemic stroke: the debate continues

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Effect of chronic oestrogen administration on androgen receptor expression in reproductive organs and pituitary of adult male rat

Following chronic (15 or 30 days) treatment with oestradiol 3-benzoate (75 microg rat(-1) day(-1) in 100 microl of olive oil) to adult rats, androgen receptor (AR) expression was analysed simultaneously in testis, epididymis, seminal vesicle, prostate and pituitary utilising three independent tools i.e. immunohistochemistry, Western blotting and RT-PCR. All the five organs showed higher AR transcriptional activity gradually increasing from 15 to 30 days of oestrogen treatment. However, the AR protein expression either through immunostaining or Western blotting demonstrated a significant decline in all the reproductive organs. In the pituitary, on the other hand, the decline coincided with a distinct breakdown of the AR protein into two bands with increasing duration of treatment. Serum and intra-testicular testosterone levels were found significantly lowered. Spermatogenesis was adversely affected with concurrent decrease in weights of testis and accessory sex organs. Decrease in testis weight was consistent with the reduction in the number of maturing germ cells per tubule. Despite the decrease in weight, accessory sex organs like epididymis, seminal vesicle and prostate were completely devoid of any apoptotic cells which were characterised only in testis and pituitary. Seminiferous epithelium demonstrated a marked increase in the number of germ cells undergoing apoptosis. However, the rate of cell apoptosis was much higher in the pituitary than in the testis at the end of 30 days treatment. It is therefore concluded that degradation of AR protein expression after oestrogen treatment is probably directly linked to an increase in cell apoptosis both in testis and pituitary.

Evidence of a Parathyroid Hormone-independent Chronic Effect of Estrogen on Renal Phosphate Handling and Sodium-dependent Phosphate Cotransporter Type IIa Expression

The effects of estrogen on phosphate metabolism are not well understood. To better define the chronic effects of estrogen on phosphate balance and on renal phosphate handling, the following groups were examined: A. young male and female rats, age- and weight-matched (age 8-10 weeks, 1 (st) study), and B. ovariectomized female rats (OVX), 22 weeks old, ovariectomized aged-matched rats receiving estrogen replacement (15 micromol x 3/week) for 14 weeks (OVX+E), control female rats (intact ovaries), and male rats, both age matched to OVX and OVX+E (2 (nd) Study). In younger females (1 (st) study), plasma phosphate was lower, whereas the urinary excretion of phosphate was higher than in males. In adult intact females and in OVX+E urinary excretion of phosphate was higher than in males and OVX (2 (nd) Study). In these rats, a significant correlation between plasma phosphate and estrogen level was found. Sodium-dependent phosphate cotransporter (NaPiIIa) mRNA expression and protein abundance were higher in the renal cortex of younger male rats than in age- and weight-matched females. In adult rats, NaPiIIa mRNA and protein abundance were higher in OVX than in OVX+E, and in mature males as compared with age-matched females. These differences were not related to the parathyroid hormone (PTH) levels. Chronic estrogen administration was also associated with increased plasma calcium level and urinary calcium excretion. These results suggest that chronic estrogen treatment is associated with an inhibitory, PTH-independent effect on the expression of NaPiIIa in the kidney, leading to sex-related differences in phosphate balance.

Effect of acute and chronic administration of progesterone, estrogen, FSH and LH on oxidant and antioxidant parameters in rat gastric tissue

This study was conducted to investigate whether gastro-protective and gastro-toxic effects of acute and chronic administration of progesterone, estrogen, FSH and LH were related to oxidant and antioxidant parameters. Chronic administration of progesterone at a low dose (1 mg/kg), which probably could not stimulate progesterone receptors (PRs), inhibited oxidative stress of FSH in gastric tissue by suppressing FSH. Progesterone (5 mg/kg) may have been caused oxidative stress as reflected by PR stimulation. FSH may have decreased antioxidant parameters and increased oxidant parameters via PRs. Chronic administration of low dose of estrogen (1 mg/kg) inhibited LH and but could not stimulate α-2 adrenergic receptors, which resulted in oxidative stress in gastric tissue. The higher dose of estrogen (5 mg/kg), however, could stimulate α-2 receptors, exhibited antioxidant activity in acute and chronic administration. While antioxidant activity of estrogen and LH was blocked with yohimbine (an α-2 adrenergic receptor blocker), mifepristone prevented the oxidative stress of progesterone and FSH in gastric tissue. It is concluded that low doses of progesterone may inhibit FSH, whereas high doses of estrogen may stimulate α-2 receptors, suggesting that LH could have protective and antioxidant hormone effects.

Ovarian hormones are not required for PRL-induced mammary tumorigenesis, but estrogen enhances neoplastic processes

Epidemiologic studies have demonstrated that increased prolactin (PRL) exposure raises the risk of invasive estrogen receptor alpha (ERalpha)-positive breast cancer in women. However, the mechanism(s) whereby this occurs and the interactions with estrogen itself in this disease remain poorly understood. In order to investigate the role of ovarian hormones in the disease process, we employed a transgenic model neu-related lipocalin (NRL)-PRL in which transgenic PRL is directed to mammary epithelial cells by the PRL- and estrogen-insensitive NRL promoter, mimicking the endogenous PRL expression within the breast observed in women. This high local exposure leads to mammary lesion development and eventually carcinomas. Ovariectomy (ovx), shortly after puberty, did not alter the incidence or latency of PRL-induced mammary carcinomas, consistent with the independence of PRL from circulating estrogens as a risk factor for invasive breast cancer in women. However, chronic estrogen administration to ovx NRL-PRL females decreased the latency of both ERalpha-positive and -negative tumors. We identified multiple mechanisms that may underlie this observation. Elevated estrogen exposure cooperated with PRL to increase epithelial proliferation and myoepithelial abnormalities, increasing the incidence of preneoplastic lesions. Critical components of the extracellular matrix secreted by the myoepithelium were reduced with age, and transgenic PRL raised transcripts for tenascin-C and maspin, both associated with tumor progression and poor prognosis in subclasses of clinical breast tumors. Mammary pERK1/2 and pAkt, but not phosphorylated Stat5, were markedly elevated by local PRL. Together, these findings indicate that PRL employs multiple mechanisms to promote mammary tumorigenesis.

Hormonal regulation of pro-inflammatory and lipid peroxidation processes in liver of old ovariectomized female rats

There is now a large body of evidence suggesting that the decline in ovarian function with menopause is associated with spontaneous increases in pro-inflammatory cytokines. On the other hand, oxidative stress has been implicated in the pathogenesis of several alterations due to menopause, and can arise through the increased production of lipid peroxides (LPO) and/or a deficiency of antioxidant defense. The aim of the present study was to investigate the effect of aging and ovariectomy on various physiological parameters related to inflammation and oxidative stress in livers obtained from old female rats and the influence of chronic exogenous administration of estrogens, phytoestrogens and growth hormone on these. Thirty-six female Wistar rats of 22 months of age were used in the present study. Twelve of them remained intact, and the other 24 had been ovariectomized at 12 months of age. Intact animals were divided into two groups and treated for 10 weeks with GH or saline, and ovariectomized animals were divided into four groups and treated for the same time with GH, estrogens, phytoestrogens or saline. A group of 2 month old intact female rats was used as young control. Protein expression of iNOS, HO-1, IL-6, TNFalpha, and IL-1beta were determined by Western blot analysis. The levels of NO( x ), LPO, TNFalpha, IL-1beta, IL-6 and IL-10 were determined in different fractions of the liver. Levels of LPO in the liver homogenates as well as iNOS protein expression and NO( x ) levels were increased in old rats as compared to young animals; this effect was more evident in ovariectomized animals. Pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6 were significantly increased and anti-inflammatory IL-10 decreased during ageing and after ovariectomy. Aging also significantly increased expression of HO-1 protein and ovariectomized rats showed an additional increase. Hormonal administration to the ovariectomized groups decreased NO( x ), LPO levels and pro-inflammatory cytokines as compared with untreated rats. Significant rise in IL-10 and reductions in the iNOS, IL-6, TNFalpha and IL-1beta proteins expression were also found. Oxidative stress and inflammation induced during aging in the liver are more marked in castrated than in intact old females. Administration of the different hormonal replacement therapies was able to inhibit the induction of pro-inflammatory cytokines and iNOS, decreased the levels of oxidative stress markers and had therapeutic potential in the prevention of liver injury.

Qualitative Changes of Total Cytoplasmic RNA Size Patterns in Estrogen-Induced Adenoma in Female Rats

Estradiol was administered 2.5 mg once a week for 4, 8 and 16 weeks to female Wistar rats. Hyperprolactinemia corresponding to the size of the pituitary developed along the pituitary enlargement after 4 weeks and macroscopically apparent pituitary adenomas after 8 and 16 weeks of treatment. The total pituitary cytoplasmic RNA was isolated from treated and control animals and the size distribution pattern of total RNA was obtained by sucrose gradient centrifugation. Estrogen treatment did not change that pattern in the first 4 weeks of treatment, but considerable RNA size distribution changes mainly in the medium size molecular range occurred after 8 and 16 weeks of estrogen administration. It can be hypothesized that an effect of estrogens on pituitary lactotroph hypersecretion and proliferation is not identical with events of irreversible adenomatous cell transformation which occurs later on during chronic estrogen administration.

Differential effects of exogenous and endogenous estrogen on anxiety as measured by elevated T-maze in relation to the serotonergic system

The effects of estrogen on anxiety-like behaviors have been widely studied but the mechanisms responsible are still inconclusive. The purpose of the current study was to compare the effects of transient high levels of endogenous estrogen and chronic exogenous estrogen treatment on the anxiety-like behaviors using the elevated T-maze (ETM) test. In addition, serotonin (5-HT) and its metabolite (5-HIAA), serotonin reuptake transporter (SERT) and tryptophan hydroxylase enzyme (TPH) were measured at the end of the study and correlated to the task performances. Female sham-operated rats in proestrous phase (Sham-Pro) and ovariectomized rats treated with or without 17β-estradiol (10 μg/kg, s.c.; Ovx + E 2 or Ovx) for 4 weeks were used. In the ETM test, the Ovx + E 2 group had reduced inhibitory avoidance responses compared to others, suggesting that exogenous E 2 replacement is anxiolytic, while escape latency was prolonged in the Sham-Pro group suggesting endogenous E 2 is panicolytic. Further, the serotonin turnover rate (5-HIAA/5-HT ratio) in the hippocampus and nucleus accumbens was highest in the Ovx + E 2 group. While the TPH protein in the midbrain of Ovx rats was significantly higher than others, the SERT levels were not significantly different among groups in all measured brain areas. In conclusion, Ovx rats with chronic estrogen administration and Sham-Pro rats with naturally high levels of estrogen, demonstrated anxiolytic behavior by exhibiting different forms of anxiety that related to the changes in the function of serotonergic system.

Effects of progesterone on FSH-stimulated indomethacin ulcers in rats

To investigate whether the balance between progesterone and FSH levels has a role in ulcer formation/inhibition. Animal study. Ataturk University, Faculty of Medicine, Laboratory of Pharmacology Department. One hundred thirty-two female Albino Wistar rats. Ovariectomy. Chronic administration of progesterone and estrogen to ovariectomized rats. Acute administration of progesterone to ovariectomized rats. Acute administration of progesterone and FSH to intact rats. Combined administration of mifepristone with progesterone or FSH to intact rats. Indomethacin administration to all rats. Gastric ulcer areas as mm(2). Indomethacin-induced ulcers were significantly higher in ovariectomized rats than in intact rats. Chronic progesterone (1 mg/kg) inhibited gastrointestinal system ulcers by 51.2%, whereas 2 and 5 mg/kg chronic progesterone and 1, 2, and 5 mg/kg chronic estrogen were not effective. Acute progesterone (5 mg/kg) increased indomethacin ulcers significantly in ovariectomized rats. FSH increased indomethacin ulcers significantly. In addition, progesterone increased indomethacin ulcers significantly in intact rats. Mifepristone antagonized the ulcerogenic effects of FSH and progesterone. Our data suggest that progesterone is not an antiulcer hormone, and produces ulcers via its own receptor. In addition, FSH may produce ulcerogenic effects via progesterone receptors. The low doses of progesterone (inhibits endogenous FSH) cannot stimulate its own receptors sufficiently for ulcer formation and prevent the ulcerogenic effects of FSH by decreasing FSH concentration.

G-Protein-Coupled Receptor 30 Mediates Estrogen's Nongenomic Effects after Hemorrhagic Shock and Trauma

G-Protein-Coupled Receptor 30 Mediates Estrogen's Nongenomic Effects after Hemorrhagic Shock and Trauma

Genetic mapping of loci controlling diethylstilbestrol-induced thymic atrophy in the Brown Norway rat

Chronic estrogen administration can lead to thymic atrophy in rodents. In this article we report that the Brown Norway (BN) rat is sensitive to thymic atrophy induced by the estrogen diethylstilbestrol (DES). By contrast, DES does not induce significant thymic atrophy in the August x Copenhagen-Irish (ACI) strain. The sensitivity of the BN rat to DES-induced thymic atrophy appears to segregate as an incompletely dominant trait in crosses between the BN and ACI strains. In a (BN x ACI)F(2) population, we find strong evidence for three major genetic determinants of sensitivity to DES-induced thymic atrophy on rat Chromosome (RNO) 10 and RNO2. Genotypes at these loci, termed Esta1, 2, and 3, do not have a significant impact on the ability of DES to induce pituitary tumorigenesis or inhibit growth of these F(2) rats. These data indicate that the genetic factors that control DES-induced thymic atrophy are distinct from those that control the effects of DES on pituitary mass and body mass. The Esta intervals on RNO10 and RNO2 overlap with loci that control sensitivity to radiation-induced thymocyte apoptosis, as well as susceptibility to a variety of allergic and autoimmune pathologies, including allergic encephalitis, arthritis, and glomerulonephritis in rodents. These observations suggest that common genetic determinants may control sensitivity to estrogen-induced thymic atrophy, maintenance of thymocyte homeostasis, and immune function.

Anxiolytic property of estrogen related to the changes of the monoamine levels in various brain regions of ovariectomized rats

Anxiety is a symptom reflecting the dysregulation of monoaminergic neurotransmitters which may be modulated by estrogen. In our current study, we investigated the effects of chronic estrogen administration (10 μg/kg, s.c. for 4 weeks) on anxiety-like behavior using the elevated plus-maze with the corresponding changes of monoamines in the brain regions contributing to anxiety. The behavioral test revealed that estrogen-treated rats (Ovx + E 2) spent more time in the open arm of the maze as well as a higher time/entry ratio in open arms than ovariectomized (Ovx) rats, indicating an anxiolytic property of estrogen. The increase in open arm time corresponded to an increase in uterine weight, indicated a correlation between the function of estrogen and its anxiolytic effect. Measurements of brain monoamines following estrogen treatment revealed decreases in norepinephrine, dopamine and serotonin in all of the brain regions studied, which also lead to an increase in turnover rates. The concentrations of norepinephrine in caudate putamen, of dopamine in nucleus accumbens, of serotonin in frontal cortex, hippocampus, caudate putamen, nucleus accumbens, and substantia nigra and of the serotonin metabolite, the 5-hydroxyindolacetic acid in substantia nigra of Ovx + E 2 rats were significantly lower than those of Ovx rats. Interestingly, the uterine weight was negatively correlated with the changes of dopamine and serotonin (with the exception of the hippocampus), suggesting a regulatory role of estrogen on these systems. From these data, we concluded that, in fact, there is a relationship between estrogen and monoamines (i.e. serotonin, dopamine) in modulating the anxiety-like behaviors in female rats.