Indirect Effects Of Estrogen Research Articles

Calcium and bone metabolism across women's life stages. Molecular mechanisms underlying bone metabolism by estrogen.

Osteoporosis, which patients are estimated as more than 13 million in Japan, is mainly caused by postmenopausal osteoporosis. Estrogen deficiency induced by menopause can disturb endocrine feedback and homeostasis, followed by bone loss by increased bone resorption with high bone turnover. Recent studies using systemic or conditional Estrogen Receptor α(ERα)gene knockout mice have unveiled molecular mechanisms underlying bone metabolism. In this review, it will be discussed that direct and indirect effects of estrogen and its metabolites for bone metabolism.

The influence of aging and estradiol to progesterone ratio on rat macrophage phenotypic profile and NO and TNF-α production

The phenotype and function of tissue macrophages substantially depend on the cellular milieu and biological effector molecules, such as steroid hormones, to which they are exposed. Furthermore, in female rats, aging is associated with the altered macrophage functioning and the increased estrogen level is followed by a decrease in that of progesterone. Therefore, the present study aimed to investigate the influence of estradiol/progesterone balance on rat macrophage function and phenotype throughout whole adult lifespan. We ovariectomized rats at the late prepubertal age or at the very end of reproductive lifespan, and examined the expression of ED2 (CD163, a marker of mature resident macrophages related to secretion of inflammatory mediators) on peritoneal macrophages and their ability to produce TNF-α and NO upon LPS-stimulation at different age points. In addition, to delineate direct and indirect effects of estrogen, we assessed the in vitro influence of different concentrations of 17β-estradiol on LPS-induced macrophage TNF-α and NO production. Results showed that: (a) the low frequency of ED2high cells amongst peritoneal macrophages of aged rats was accompanied with the reduced TNF-α, but not NO production; (b) estradiol level gradually increased following ovariectomy; (c) macrophage ED2 expression and TNF-α production were dependent on estradiol/progesterone balance and they changed in the same direction; (d) changes in estradiol/progesterone balance differentially affected macrophages TNF-α and NO production; and (e) estradiol exerted pro-inflammatory and anti-inflammatory effects on macrophages in vivo and in vitro, respectively. Overall, our study discloses that estradiol/progesterone balance contributes to the fine-tuning of rat macrophage secretory capacity, and adds to a better understanding of the ovarian steroid hormone role in the regulation of macrophage function, and its significance for the age-associated changes in innate immunity.

Estrogens and bone disease in chronic kidney disease: role of FGF23

To describe the direct and indirect effects of estrogen on bone with special emphasis on the analysis of the recent findings related to the putative role of FGF23 in the estrogen-dependent parathyroid hormone (PTH) suppression. Estrogens act directly on bone cells, downregulating osteoclast precursors and differentiation, increasing osteoclast apoptosis and stimulating osteoblast proliferation and differentiation. However, estrogens can also act indirectly on bone, modulating the calcium-phosphorus-vitamin D-PTH axis. It has been recently demonstrated that estrogens suppress PTH synthesis and secretion in a dose-dependent manner and reduce serum calcitriol and phosphorus levels by an indirect mechanism. In-vivo and in-vitro experiments demonstrated that FGF23 positively correlated, also in a dose-dependent manner, with the dose of estrogens and with the observed changes in calcitriol and phosphorus. These new findings support the importance of the indirect effects of estrogens on bone, suggesting a role for FGF23 in the regulation of PTH by estrogens.

Estrogen Regulates Estrogen Receptors and Antioxidant Gene Expression in Mouse Skeletal Muscle

BackgroundEstrogens are associated with the loss of skeletal muscle strength in women with age. Ovarian hormone removal by ovariectomy in mice leads to a loss of muscle strength, which is reversed with 17β-estradiol replacement. Aging is also associated with an increase in antioxidant stress, and estrogens can improve antioxidant status via their interaction with estrogen receptors (ER) to regulate antioxidant gene expression. The purpose of this study was to determine if ER and antioxidant gene expression in skeletal muscle are responsive to changes in circulating estradiol, and if ERs regulate antioxidant gene expression in this tissue.Methodology/Principal FindingsAdult C57BL/6 mice underwent ovariectomies or sham surgeries to remove circulating estrogens. These mice were implanted with placebo or 17β-estradiol pellets acutely or chronically. A separate experiment examined mice that received weekly injections of Faslodex to chronically block ERs. Skeletal muscles were analyzed for expression of ER genes and proteins and antioxidant genes. ERα was the most abundant, followed by Gper and ERβ in both soleus and EDL muscles. The loss of estrogens through ovariectomy induced ERα gene and protein expression in the soleus, EDL, and TA muscles at both the acute and chronic time points. Gpx3 mRNA was also induced both acutely and chronically in all 3 muscles in mice receiving 17β-estradiol. When ERs were blocked using Faslodex, Gpx3 mRNA was downregulated in the soleus muscle, but not the EDL and TA muscles.Conclusions/SignificanceThese data suggest that Gpx3 and ERα gene expression are sensitive to circulating estrogens in skeletal muscle. ERs may regulate Gpx3 gene expression in the soleus muscle, but skeletal muscle regulation of Gpx3 via ERs is dependent upon muscle type. Further work is needed to determine the indirect effects of estrogen and ERα on Gpx3 expression in skeletal muscle, and their importance in the aging process.

Estrogens and progestins: molecular effects on brain cells.

Sex steroids are known to regulate brain function and their role is so important that several diseases are strictly correlated with the onset of menopause when estrogen-progesterone deficiency makes neural cells much more vulnerable to toxic stimuli. Although in the past years several scientists have focused their studies on in vitro and in vivo effects of sex steroids on the brain, we are still far from complete knowledge. Indeed, contrasting results from large clinical trials have made the entire issue much more complicated. Currently we know that protective effects exerted by sex steroids depend on several factors among which the dose, the health of the cells and the type of molecule being used. In this review, we present an overview of the direct and indirect effects of estrogen and progesterone on the brain with specific focus on the molecular mechanisms by which these molecules act on neural cells.

Sex and drugs: Comment on “Evidence for involvement of erβ and rgs9-2 in 17-β estradiol enhancement of amphetamine-induced place preference behavior” by Silverman and Koenig

Sex and drugs: Comment on “Evidence for involvement of erβ and rgs9-2 in 17-β estradiol enhancement of amphetamine-induced place preference behavior” by Silverman and Koenig

Direct and indirect effects of estrogen on rat hippocampus

Estrogen-induced synaptic plasticity was frequently shown by an increase of spines at apical dendrites of CA1 pyramidal neurons after systemic application of estradiol to ovariectomized rats. Recent findings question this direct endocrine regulation of synaptogenesis by estradiol. We have shown, for the first time, that estrogens are synthesized de novo in rat hippocampal neurons. By using letrozole, an inhibitor of aromatase, estradiol levels in hippocampal dispersion cultures as well as in hippocampal slice cultures were significantly suppressed. Letrozole treatment resulted in a significant decrease in the density of spines and spine synapses and in the number of presynaptic boutons. Quantitative immunohistochemistry revealed a dose-dependent downregulation of spinophilin, a spine marker, and of synaptophysin, a presynaptic marker, in the hippocampus. Surprisingly, exogenous application of estradiol to the cultures had no effect. Indirect effects of estrogens, mediated via subcortical nuclei, may help to explain this phenomenon. Implantation of estrogen-filled cannulae into the median raphe, which projects to the hippocampus, resulted in a significant increase in spine density in the hippocampus after seven days of treatment. This increase was paralleled by a decrease in the density of serotonergic innervation of the strata lacunosum moleculare and radiatum of the CA1 region. Apart from direct endocrine mechanisms our findings suggest that estradiol-induced spinogenesis in the hippocampus is also mediated by indirect mechanisms and is furthermore regulated endogenously, in a paracrine manner.

Effect of estrogen on scavenger receptor BI expression in the rat.

High-dose 17alpha-ethinyl estradiol treatment is associated with increased adrenal and decreased hepatic levels of scavenger receptor class B type 1 (SR-BI) in rats. In this paper we explored the mechanisms responsible for the differential regulation of SR-BI by estrogen in these two tIssues. Previously it was shown that estrogen-treated rats are profoundly hypolipidemic due to increased hepatic low density lipoprotein receptor (LDLR) activity, and that this effect is not maintained with hypophysectomy. To determine if the reduction in hepatic SR-BI was a direct or indirect effect of estrogen, we treated hypophysectomized rats with high-dose estrogen; the levels of SR-BI expression did not change in the livers or adrenals of these animals. To determine if the absence of response to estrogen in the adrenals of hypophysectomized animals was due to the absence of adrenocorticotropic hormone (ACTH), we examined the effect of estrogen treatment on SR-BI expression in animals treated with dexamethasone, which inhibits endogenous ACTH production. The administration of dexamethasone completely inhibited the increase in SR-BI expression in the adrenals of estrogen-treated rats. From these studies we conclude that estrogen does not have a direct effect on SR-BI expression in either the liver or the adrenals. In the liver, the decrease in SR-BI is dependent on the estrogen-induced increase in LDLR activity, and in the adrenal glands, ACTH is required for the estrogen-associated increase in expression of SR-BI.

Cell-specific distribution of oestrogen receptor-alpha in the bovine ovary.

In this study, the expression of estrogen receptor alpha (ERalpha) in the bovine ovary is described. ERalpha was visualized by immunohistochemistry on paraffin sections of ovaries obtained from 11 non-pregnant and 2 pregnant animals. In general, ERalpha was not observed in cells of primordial, primary and secondary follicles, whereas weak expression was noticed in cells of healthy and arteric tertiary follicles. In corpora lutea cells the expression of ERalpha was obvious. Intermediate to high ERalpha expression was present in thecal cells and in cells of the superficial and deep stroma, tunica albuginea and surface epithelium. Furthermore, the expression of ERalpha in stroma and tunica albuginea cells was in general, highest in cows with the lowest plasma progesterone levels, and lowest in cows with the highest plasma progesterone levels. Remarkably, the ERalpha expression in pregnant cows was in general, lower than in non-pregnant cows with similar plasma progesterone levels. The relatively high expression of ERalpha in thecal and stromal cells in comparison with that in follicle cells suggests an indirect effect of estrogen on the follicular development. However, the exact function of ERalpha in the bovine ovary together with the cycle-dependent variations in ERalpha expression remain to be elucidated.

Non-nuclear actions of estrogen: new targets for prevention and treatment of cardiovascular disease.

Gender-based differences in the incidence of hypertensive and coronary artery disease, the development of atherosclerosis, and myocardial remodeling after infarction are attributable to the indirect effect of estrogen on risk factor profiles, such as cholesterol levels, glucose metabolism, and insulin levels. More recent evidence, however, suggests that activated estrogen receptor (ER) mediates signaling cascades that culminate in direct protective effects such as vasodilation, inhibition of response to vessel injury, limiting myocardial injury after infarction, and attenuating cardiac hypertrophy. Although the ER is usually thought of as a ligand-dependent transcription factor, it can also rapidly mobilize signals at the plasma membrane and in the cytoplasm. Thus, a greater understanding of ER function and regulation may lead to the development of highly specific therapeutics that mediate the prevention and treatment of cardiovascular diseases.

Estrogen receptor transcription and transactivation: Estrogen receptor knockout mice: what their phenotypes reveal about mechanisms of estrogen action.

Natural, synthetic and environmental estrogens have numerous effects on the development and physiology of mammals. Estrogen is primarily known for its role in the development and functioning of the female reproductive system. However, roles for estrogen in male fertility, bone, the circulatory system and immune system have been established by clinical observations regarding sex differences in pathologies, as well as observations following menopause or castration. The primary mechanism of estrogen action is via binding and modulation of activity of the estrogen receptors (ERs), which are ligand-dependent nuclear transcription factors. ERs are found in highest levels in female tissues critical to reproduction, including the ovaries, uterus, cervix, mammary glands and pituitary gland. Since other affected tissues have extremely low levels of ER, indirect effects of estrogen, for example induction of pituitary hormones that affect the bone, have been proposed. The development of transgenic mouse models that lack either estrogen or ER have proven to be valuable tools in defining the mechanisms by which estrogen exerts its effects in various systems. The aim of this article is to review the mouse models with disrupted estrogen signaling and describe the associated phenotypes.

Estrogen-induced rat pituitary tumor is associated with loss of retinoblastoma susceptibility gene product

Chronic treatment of rats with the estrogens 17 β-estradiol or diethylstilbestrol (DES) induces pituitary tumors in Fischer 344 but not Brown–Norway or Sprague–Dawley rats. Functional loss of retinoblastoma susceptibility gene product (pRb), a major regulatory protein for the G1 to S transition of the cell cycle, has been shown in several tumors. Here we report a decreased level of pRb in pituitary tumors of the Fischer 344 rat as compared with resistant Sprague–Dawley and Brown–Norway strains. pRb protein levels decreased 70% in Fischer 344 rats that were treated with diethylstilbestrol for 10 weeks as compared with tumor resistant control animals. Interestingly, the F1 hybrid (Fischer 344×Norway) showed an intermediate range of pRb protein expression as compared with those of the parental strains. pRb expression levels in nonhemmorhagic F2 (F1×F1) rats correlated with the size of the tumors. One week withdrawal of DES increased pRb levels as compared with continuously treated rats. Also, there was a decreased association of cyclin D and cyclin dependent kinase in susceptible tumors, supporting the hypothesis of a physical and possibly functional loss of pRb in the diethylstilbestrol-induced pituitary tumor. These results suggest that the difference in pRb regulation, whether it is a direct or indirect effect of estrogen, is related to tumor resistance or susceptibility in these two rat strains.

Estrogen: Effects on the cardiovascular tree

My objective is to review the current literature with respect to basic science aspects concerning the effects of both endogenous and exogenous sex steroids on the vascular system. For simplification in this complex, burgeoning field, generalizations are made and mechanisms are highlighted. Major landmark studies in the English language over the past 25 years are reviewed. Cardiovascular, endocrinologic, and gynecologic references are targeted. Investigations by leading authorities are emphasized with an intent to bridge clinical significance with in vitro studies, in vivo data (both animal and human), and current epidemiologic information. Study results indicate that atherosclerotic lesions can stabilize, and occlusion can regress. The combined effects of estrogen in preventing atherosclerosis and maintaining arterial tone and integrity indicate that the circulatory system is a major target for estrogen action. A number of direct and indirect effects of estrogen have been shown to be beneficial.

Implications of hormonal influences on sexual behavior for demographic models of reproduction.

In exploring the implications of hormonal influences on sexual behavior for reproduction, we have focused on androgens because of the convincing evidence for androgenic effects on female sexual motivation. We have been guided by the simple idea, based on clinical findings among hyperandrogenic women, that higher testosterone levels will increase female sexual motivation which in turn will result in increased coital frequency. However, careful consideration of the evidence fails to confirm such a role for testosterone in sexual behavior among normal women at any point in the reproductive span. While some amount of testosterone appears to be important in maintaining female sexual motivation, there is little evidence that variation in testosterone within the normal range is associated with variation in sexual motivation. Reported associations between testosterone and sexual behavior among married women cannot be interpreted as resulting from androgenic effects on sexual motivation. Thus we are left with the task of explaining why testosterone does not appear to play the same role in libido among hyperandrogenic and normal women. As mentioned earlier, some of the difference may attributable to the much higher levels of testosterone among hyperandrogenic women. Sherwin points out that the levels of sexual motivation decline with declining testosterone levels even while testosterone is well above normally occurring levels. It is possible that the brain is simply not sensitive to the variation in testosterone levels found in normal women. Other evidence suggests that the presence of intact ovaries may be equally important. A recent study of androgen replacement in naturally post-menopausal women failed to find a dramatic effect of testosterone on sexual motivation and behavior, despite levels similar to those in studies on surgically menopausal women, pointing to the importance of other factors associated with the presence of ovaries. A similar point can be made with regard to hyperandrogenism related to endogenous sources of testosterone, as in the case of PCOS. High levels of testosterone effectively disrupt ovarian function and interfere with other ovarian processes. Among hyperandrogenic women sexual behavior appears to be related to the direct effects of androgens on motivation, while the indirect effects of estrogen and progesterone are essentially eliminated. Among normal women, on the other hand, there is little evidence for such a dominating role of a direct androgenic effect on sexual behavior. Instead, other ovarian hormones, including estrogen and progesterone may also play a demonstrable role, despite the lack of strong evidence at this point.(ABSTRACT TRUNCATED AT 400 WORDS)

Estrogen Induction of Fatty Liver in Dairy Cattle

Two trials were conducted to determine if estrogen contributes to development of fatty liver in dairy cattle. During trial 1, eight late lactation, nonpregnant cows were assigned to 0 or 15mg estradiol-17β benzoate/d treatment. Days 1 to 3 of the trial were for baseline measurements, and treatments were given from d 4 to 21; on d 20 and 21 animals were fasted. Short-term feed deprivation resulted in increased plasma FFA concentrations and rapid accumulation of triglyceride into liver tissue obtained by biopsy. During starvation, plasma FFA concentration and liver triglyceride content were lower for cows receiving the estradiol-17β treatment relative to cows receiving control treatment. Very low density lipoprotein concentration in blood increased dramatically in three of four animals during estradiol-17β administration. Because of the decrease in milk production during estradiol-17β treatment, it was not known whether this represented a decrease in very low density lipoprotein clearance from blood or reflected a lipotropic response to estradiol-17β. Therefore, a second trial was conducted employing nonlactating cows, and control and estradiol-17β-treated animals were pair fed. The trial was 33 d with d 1 to 3 for baseline measurements, and treatments were administered from d 4 to 33. All animals were starved from d 19 to 23. Estradiol-17β increased hepatic lipid and triglyceride accumulation and plasma very low density lipoprotein concentration during starvation. Plasma FFA concentration was also increased by estradiol-17β during this time; therefore, a direct or indirect effect of estrogen on hepatic lipid metabolism could not be delineated.

The participation of pituitary gland in estrogenic effect on arginase activity in the rat prostates.

Estradiol-17β, estrone, estriol or diethylstilbesterol showed the increase in arginase activity of the dorsolateral prostate of intact adult male rats. Neither castration nor adrenalectomy modified the response of arginase activity by administration of estrogen. However, the arginase activity of the dorsolateral prostate of hypophysectomized male rats was significantly reduced regardless of estrogen treatment. On the other hand, almost the similar decrease was observed in the arginase activity of the ventral prostate from castrated, adrenalectomized or hypophysectomized rats, as well as from intact ones.From these results, it was concluded that the increase in arginase activity of the dorsolateral prostate after estrogen treatment might be due to some indirect effects of estrogen, and that pituitary the gland seemed to be involved in this estrogenic effect.