Physiological Effects Of Estrogen Research Articles

Influence of the Onset of Menopause on the Risk of Developing Alzheimer's Disease.

Menopause is a natural phase marked by the permanent cessation of menstrual cycles, occurring when the production of reproductive hormones from the ovaries stops for at least 12 consecutive months. Studies have suggested a potential connection between menopause and a heightened risk of developing Alzheimer's disease (AD), underscoring the significant role of reduced estrogen levels in the development of AD. Estrogen plays a crucial role in brain metabolism, influencing energy metabolism, synaptic plasticity, and cognitive functions. The cognitive benefits associated with hormone replacement therapy (HRT) are believed to be linked to estrogen's neuroprotective effects, either through direct action on the brain or indirectly by improving cardiovascular health. Extensive literature supports the positive impact of estrogen on brain cells. While the physiological effects of estrogen on the brain have not been consistently replicated in clinical trials, further research is crucial to provide more definitive recommendations to menopausal patients regarding the influence of HRT on AD. This review aims to comprehensively explore the interplay between menopause and AD, as well as the potential of HRT to mitigate cognitive decline in post-menopausal individuals.

Opposite estrogen effects of estrone and 2-hydroxyestrone on MCF-7 sensitivity to the cytotoxic action of cell growth, oxidative stress and inflammation activity

There are many kinds of estrogens, and endogenous estrogens produce a variety of estrogen metabolites with similar structure but with different physiological effects after metabolism in vivo. Studies have shown that estrone (E1) widely occurs in the environment and animal-derived food. Because of its estrogen effect, E1 can have adverse effects on the human body as an endocrine disruptor. In this study, we found that E1 and 2-hydroxyestrone (2-OH-E1), the hydroxylation metabolite of estrogen, have opposite proliferative effects on breast cancer cells (MCF-7) through cell proliferation experiments and comparison of their effects by molecular docking and detection of ROS, Ca2+, and cell pathway proteins. The effects of 2-methoxyestrone (2-MeO-E1) and 16α-hydroxyestrone (16α-OH-E1) on the biochemical and protein levels of MCF-7 were further studied to compare the effects of metabolic sites and modes on estrogen effects. Hydroxylation of E1 at the C2 site weakened the estrogen effect, down-regulated the expression of the mammalian target of rapamycin (mTOR) and protein kinase B (Akt) pathway proteins, inhibited the proliferation of cancer cells, and enhanced anti-oxidative stress and anti-inflammation. Methoxylation at the C2 position also inhibited the expression of inflammatory and oxidative stress pathway proteins but did not greatly affect the estrogen effects. However, hydroxylation on C16 had no significant effect on the biological effects of estrogen. Therefore, the structural changes of estrogen on C2 are important reasons for the different physiological effects of estrogen and its metabolites. Thus, by regulating the gene Cytochrome P450 1B1(CYP1B1), which affects the hydroxylation metabolism of estrogen, and promoting the hydroxylation of estrone at the C2 position, the estrogen effect of estrone can be effectively reduced, thus reducing the harm its poses in food and the environment.

PO-254 G protein-coupled oestrogen receptor activation decreases prostate cancer cells viability concomitantly with altered proliferation, apoptosis, and metabolic profile

IntroductionA panoply of studies have been indicating that estrogens are protective agents in prostate carcinogenesis. However, the physiological effects of estrogens in PCa mainly have been associated with the differential activation of the nuclear estrogens receptors (ER), with much less knowledge existing on the membrane ER. The G protein-coupled ER (GPER), known to be involved in the rapid nongenomic responses, has been linked to antiproliferative and proapoptotic effects and is a likely candidate mediating the ‘anti-carcinogenic’ actions of estrogens. This work aims to characterise the GPER’ role controlling proliferation, apoptosis and metabolism of PCa cells.Material and methodsThe nonneoplastic PNT1A cell line and neoplastic LNCaP, DU145 and PC3 cell lines were maintained in culture in RPMI 1640 medium. GPER expression pattern was characterised by Western blot. Fluorescent immunocytochemistry allowed determining the subcellular localization of GPER by colocalization with wheat germ agglutinin, calnexin, and hoescht. PNT1A, LNCaP, DU145 and PC3 cells were treated with the GPER specific agonist G1 (1 µM) for 24 hour. Cell viability was assessed by the MTT assay. The effect of GPER activation on cell proliferation, apoptosis and metabolism was assessed by analysing the expression of key proteins in each process. Also, the enzymatic activity of caspase-3 and LHD was measured. Glucose consumption and lactate production were determined using commercial kits.Results and discussionsGPER was differentially expressed in PCa cell line models depending on their aggressiveness and disease status. GPER expression was highest in the androgen-sensitive and less aggressive LNCaP cells and decreased in the more aggressive castration-resistant cell line models (DU145 and PC3). GPER was located at the cell membrane, endoplasmic reticulum, and also in the nucleus. The activation of GPER by G1 decreased PCa cells viability, concomitantly with altered expression of key regulators of proliferation and apoptosis. Furthermore, G1-stimulated cells displayed augmented caspase-3 activity comparatively to the control group. G1 treatment also modulated PCa cell metabolism with altered glucose consumption and lactate production.ConclusionGPER activation decreased viability of PCa cells whereas enhancing apoptosis. Also, PCa metabolic profile was altered in response to G1. These findings stimulate further research to ascertain the role of GPER as a therapeutic target.

Role of Estrogen Receptors and G Protein-Coupled Estrogen Receptor in Regulation of Hypothalamus–Pituitary–Testis Axis and Spermatogenesis

Male reproductive function is under the control of both gonadotropins and androgens through a negative feedback loop that involves the hypothalamus, pituitary, and testis known as hypothalamus–pituitary–gonadal axis (HPG). Indeed, estrogens also play an important role in regulating HPG axis but the study on relative contribution to the inhibition of gonadotropins secretion exerted by the amount of estrogens produced within the hypothalamus and/or the pituitary or by the amount of circulating estrogens is still ongoing. Moreover, it is known that the maintenance of spermatogenesis is controlled by gonadotropins and testosterone, the effects of which are modulated by a complex network of locally produced factors, including estrogens. Physiological effects of estrogens are mediated by the classical nuclear estrogen receptor alpha and estrogen receptor beta, which mediate both genomic and rapid signaling events. In addition, estrogens induce rapid non-genomic responses through a membrane-associated G protein-coupled estrogen receptor (GPER). Ours and other studies reported that, in the testis, GPER is expressed in both normal germ cells and somatic cells and it is involved in mediating the estrogen action in spermatogenesis controlling proliferative and/or apoptotic events. Interestingly, GPER expression has been revealed also in the hypothalamus and pituitary. However, its role in mediating estrogen rapid actions in this context is under investigation. Recent studies indicate that GPER is involved in modulating gonadotropin-releasing hormone (GnRH) release as well as gonadotropins secretion. In this review, we will summarize the current knowledge concerning the role of estrogen/estrogen receptors molecular pathways in regulating GnRH, follicle-stimulating hormone, and luteinizing hormone release at the hypothalamic and pituitary levels in males as well as in controlling specific testicular functions such as spermatogenesis, focusing our attention mainly on estrogen signaling mediated by GPER.

GPER signaling in spermatogenesis and testicular tumors

Estrogens play important roles in the regulation of testis development and spermatogenesis. Moreover, several evidences suggest that estrogen signaling can be involved in testicular tumorigenesis. The physiological effects of estrogen are mediated by the classical nuclear estrogen receptors ESR1 and 2, which regulate both genomic and rapid signaling events. In the recent years, a member of the seven-transmembrane G protein-coupled receptor family, GPR30 (GPER), has been identified to promote estrogen action in target cells including testicular cells. Ours and other studies reported that GPER is expressed in normal germ cells (spermatogonia, spermatocytes, spermatids), somatic cells (Sertoli and Leydig cells), and it is also involved in mediating estrogen action during spermatogenesis and testis development. In addition, GPER seems to be involved in modulating estrogen-dependent testicular cancer cell growth. However, in this context, the effects of GPER stimulation on cell survival and proliferation appear to be cell type specific. This review summarizes the current knowledge on the functions regulated by estrogens and mediated by GPER in normal and tumor testicular cells.

Estrogen receptor-mediated transcription involves the activation of multiple kinase pathways in neuroblastoma cells

While many physiological effects of estrogens (E) are due to regulation of gene transcription by liganded estrogen receptors (ERs), several effects are also mediated, at least in part, by rapid non-genomic actions of E. Though the relative importance of rapid versus genomic effects in the central nervous system is controversial, we showed previously that membrane-limited effects of E, initiated by an estradiol bovine serum albumin conjugate (E2-BSA), could potentiate transcriptional effects of 17β-estradiol from an estrogen response element (ERE)-reporter in neuroblastoma cells. Here, using specific inhibitors and activators in a pharmacological approach, we show that activation of phosphatidylinositol-3-phosphate kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways, dependent on a Gαq coupled receptor signaling are important in this transcriptional potentiation. We further demonstrate, using ERα phospho-deficient mutants, that E2-BSA mediated phosphorylation of ERα is one mechanism to potentiate transcription from an ERE reporter construct. This study provides a possible mechanism by which signaling from the membrane is coupled to transcription in the nucleus, providing an integrated view of hormone signaling in the brain.

The Dynamic Structure of the Estrogen Receptor

The estrogen receptor (ER) mediates most of the biological effects of estrogens at the level of gene regulation by interacting through its site-specific DNA and with other coregulatory proteins. In recent years, new information regarding the dynamic structural nature of ER has emerged. The physiological effects of estrogen are manifested through ER's two isoforms, ERα and ERβ. These two isoforms (ERα and ERβ) display distinct regions of sequence homology. The three-dimensional structures of the DNA-binding domain (DBD) and ligand-binding domain (LBD) have been solved, whereas no three-dimensional natively folded structure for the ER N-terminal domain (NTD) is available to date. However, insights about the structural and functional correlations regarding the ER NTD have recently emerged. In this paper, we discuss the knowledge about the structural characteristics of the ER in general and how the structural features of the two isoforms differ, and its subsequent role in gene regulation.

Residential Exposure of Environment Toxic Substance Outcome during Menstrual Cycle

Problem statement: It was intended to diagnose and treat the disorders of female reproductive system where they are exposed to environmentally toxic pesticides and estrogenic compounds like bisphenol A which are the main reason for the infertility problems. Approach: Human saliva contains arrays of proteins that have distinct biological functions. Results: Salivary hormones concentrations of luteinising hormone, follicle stimulating hormone, estrogen as well as estrone-1-glucuronide, were assayed in 20 normal menstruating women who were among the reproductive phases like preovulatory phase (6-12 days); Ovulatory phase (13-14 days) and Postovulatory phase (15-26 days). It was intended to diagnose and treat the disorders of female reproductive system where they are exposed to environmentally toxic pesticides and estrogenic compounds like bisphenol A which are the main reason for the infertility problems. In this context, the detection of fertile period suggests that the mean value of luteinising hormone (56.58±12.96 mIU L-1) indicates the surge during the time of ovulation. Identifying the period of ovulation would be the easiest way to detect other constituents like follicle stimulating hormone, estrogen and its conjugate like estrone-1-glucuronide are extensively high (p<0.05) was observed. Conclusion: Our results indicated that the salivary hormones like estrogen and its conjugate indicates decrease in ovulatory and postovulatory phase. Further, the environmental toxic materials can also cause problems like infertility. The conclusion is that any physiological effects of estrogen from drinking water will be undetectable in people. The results from hormones suggested that they may be considered in the diagnosis and treatment of ovulation using saliva as the noninvasive specimen.

Ligand-dependent interaction between estrogen receptor and adenomatous polyposis coli

Numerous independent clinical and experimental studies indicate that estrogens confer a protective effect against development of intestinal tumors, however the molecular mechanisms involved remain unclear. Physiological effects of estrogens are predominantly mediated by the action of nuclear estrogen receptors (ERs). A multifunctional protein adenomatous polyposis coli (APC) is a tumor suppressor and thought to act as a gatekeeper in colon tumorigenesis, as loss of function APC mutations trigger the development of colorectal cancer. Here we report that APC physically associates with ERa in the ligand-dependent manner. We have shown in the endogenous setting that the ligand-activated ERa recruits APC to the promoters in ER target genes and that increased levels of ER-dependent recruitment of APC enhances the ER transactivation through stimulation of histone acetylation. Found in majority of human colon tumors APC truncation mutants lost the ability to interact with ER. Thus, here we present the first evidence of a functional interaction between APC and ER that may be accounted for a tumor protective action of estrogens.

Homologous regulation of estrogen receptor subtypes in goldfish (Carassius auratus)

While considerable information is available on the physiological effects of estrogen, much less is known about the regulation of estrogen receptor (ER) subtypes, particularly in non-mammalian vertebrates. Using goldfish as primary experimental model, we investigated sex- and tissue-specific homologous regulation of ER subtypes (ERalpha, ERbetaI, and ERbetaII) by estradiol in vivo, in the liver and gonads. Treatment with estradiol, significantly upregulated transcript levels for all three types of ERs (ERalpha, ERbetaI, and ERbetaII) in the goldfish ovary and testis. In the goldfish liver, treatment with estradiol significantly increased ERalpha, ERbetaI transcript levels without affecting ERbetaII. In all cases increased ER transcript level was correlated with increased ER protein level determined by Western blot analysis, although we are not able to distinguish between ER subtypes. The results provide strong support for the hypothesis that homologous regulation of ERs is tissue- and gender-specific, and may be a mechanism for estrogen-mediated regulation of reproduction in goldfish.

ERβ shifts from mitochondria to nucleus during estrogen-induced neoplastic transformation of human breast epithelial cells and is involved in estrogen-induced synthesis of mitochondrial respiratory chain proteins

Both estrogen receptors (ER) alpha (ERα) and beta (ERβ) are localized in the nucleus, plasma membrane, and mitochondria, where they mediate the different physiological effects of estrogens. It has been observed that the relative subcellular localization of ERs is altered in several cancer cells. We have demonstrated that MCF-10F cells, the immortal and non-tumorigenic human breast epithelial cells (HBEC) that are ERα-negative and ERβ-positive, are transformed in vitro by 17β-estradiol (E 2), generating highly invasive cells that are tumorigenic in severe combined immunodeficient mice. E 2-transformed MCF-10F (trMCF) cells exhibit progressive loss of ductulogenesis, invasive (bsMCF) and tumorigenic (caMCF) phenotypes. Immunolocalization of ERβ by confocal fluorescent microscopy and electron microscopy revealed that ERβ is predominantly localized in mitochondria of MCF-10F and trMCF cells. Silencing ERβ expression with ERβ-specific small interference RNA (siRNA-ERβ) markedly diminishes both nuclear and mitochondrial ERβ in MCF-10F cells. The ERβ shifts from its predominant localization in the mitochondria of MCF-10F and trMCF cells to the nucleus of bsMCF cells, becoming predominantly nuclear in caMCF cells. Furthermore, we demonstrated that the mitochondrial ERβ in MCF-10F cells is involved in E 2-induced expression of mitochondrial DNA (mtDNA)-encoded respiratory chain (MRC) proteins. This is the first report of an association of changes in the subcellular localization of ERβ with various stages of E 2-induced transformation of HBEC and a functional role of mitochondrial ERβ in mediating E 2-induced MRC protein synthesis. Our findings provide a new insight into one of the potential roles of ERβ in human breast cancer.

Estrogen Receptors α and β Mediate Distinct Pathways of Vascular Gene Expression, Including Genes Involved in Mitochondrial Electron Transport and Generation of Reactive Oxygen Species

Estrogen plays an important role in the regulation of vascular tone and in the pathophysiology of cardiovascular disease. Physiological effects of estrogen are mediated through estrogen receptors alpha (ERalpha) and beta (ERbeta), which are both expressed in vascular smooth muscle and endothelial cells. However, the molecular pathways mediating estrogen effects in blood vessels are not well defined. We have performed gene expression profiling in the mouse aorta to identify comprehensive gene sets the expression of which is regulated by long-term (1 wk) estrogen treatment. The ER subtype dependence of the alterations in gene expression was characterized by parallel gene expression profiling experiments in ERalpha-deficient [ERalpha knockout (ERalphaKO)] and ERbeta-deficient (ERbetaKO) mice. Importantly, these data revealed that ERalpha- and ERbeta-dependent pathways regulate distinct and largely nonoverlapping sets of genes. Whereas ERalpha is essential for most of the estrogen-mediated increase in gene expression in wild-type aortas, ERbeta mediates the large majority (nearly 90%) of estrogen-mediated decreases in gene expression. Biological functions of the estrogen-regulated genes include extracellular matrix synthesis, in addition to electron transport in the mitochondrion and reactive oxygen species pathways. Of note, the estrogen/ERbeta pathway mediates down-regulation of mRNAs for nuclear-encoded subunits in each of the major complexes of the mitochondrial respiratory chain. Several estrogen-regulated genes also encode transcription factors. Computational analysis of promoters from coexpressed genes revealed overrepresentation of binding sites for such factors, lending support for an estrogen-regulatory transcriptional network in the vasculature. Overall, these findings provide a foundation for understanding the molecular basis for estrogen effects on vasculature gene expression.

Estrogens and Urinary‐Tract Infection

The effects of estrogen on the risk of urinary-tract infection (UTI) in women has been the subject of many studies in both humans and experimental animals. Often, these studies have come to seemingly contradictory results: some have suggested an increased risk attributable to estrogen and others that estrogens may be preventative. In part, this confusion arises because the physiological effects of estrogen on different anatomic parts of the urinary tract differ depending on the specific effect and the outcome measured. For example, in the absence of estrogen, the periurethral and vaginal microflora, which is usually predominated by hydrogen peroxide-producing lactobacilli and few Escherichia coli, changes dramatically to a flora with few or no lactobacilli but many E. coli [1]. This change in flora is associated with a markedly increased risk of recurrent E. colibladder infections. In a randomized, placebo-controlled trial of topical intravaginal estrogen cream in such women, both the reestablishment of the normal lactobacillus-dominant vaginal flora and reduced rates of UTI were demonstrated in estro-

Sex steroid receptor evolution and signalling in aquatic invertebrates

In vertebrate reproductive endocrinology sex steroids play a pivotal role via binding to receptors. However, information on the origin and relevance of sex steroids in invertebrates is limited. This review highlights current literature on steroid receptors in aquatic invertebrates and reports on some new findings. It has been shown that invertebrates of the deuterostome clade, such as Acrania and Echinodermata, respond to estrogens and androgens and, at least in Branchiostoma, an estrogen receptor has been cloned. Within the protostomes, most findings are related to aquatic molluscs. Sex steroid receptor-like proteins are abundant in gastropods, bivalves and cephalopods and also sex hormone signalling shows partial similarity to the deuterostomes. In ecdysozoans, however, the impact of sex steroids is still a matter of debate even though there is evidence on the presence of estrogen receptor-like proteins in Crustacea and on physiological effects of estrogens in both Nematoda and Crustacea. Recent findings suggest the presence of an estrogen receptor alpha-like protein of unclear physiological role in Gammarus fossarum (Crustacea). Binding studies revealed the crustacean Hyalella azteca to possess specific binding sites only for androgens but not for estrogens suggesting a possible limitation to functional androgen receptors in this species. Further studies have to be conducted to shed more light into the discussion about the controversy about sex steroid receptors in invertebrates.

Estrogen receptor knockout mice: phenotypes in the female reproductive tract

There is a broad spectrum of organ systems that respond to estrogen hormones ,including the female and male reproductive tracts ,mammary gland ,the skeleton ,cardiovascular system and central nervous system. The physiological effects of estrogens are mediated by the estrogen receptor ,a member of the nuclear receptor superfamily of transcription factors. Two estrogen receptors have been identified: the originally described estrogen receptor α (ERα) and the more recently discovered estrogen receptor β (ERβ). Three different estrogen receptor knockout (ERKO) mouse models were generated ,carrying a null mutation in the ERα gene (αERKO) ,the ERβ gene (βERKO) or both genes (αβERKO). The generation of the different ERKO mice provides ideal models for studying the physiological consequences of the complete lack of estrogen receptor activity and the distinct roles of both estrogen receptors in various tissues. This review summarizes the phenotypes principally seen in the female reproductive system of the different ERKO mice.

Estrogen receptor knockout mice: phenotypes in the female reproductive tract

There is a broad spectrum of organ systems that respond to estrogen hormones ,including the female and male reproductive tracts ,mammary gland ,the skeleton ,cardiovascular system and central nervous system.The physiological effects of estrogens are mediated by the estrogen receptor ,a member of the nuclear receptor superfamily of transcription factors. Two estrogen receptors have been identified: the originallydescribed estrogen receptor α (ERα) and the more recently discovered estrogen receptor β (ERβ). Three different estrogen receptor knockout (ERKO) mouse models were generated ,carrying a nullmutation in the ERα gene (αERKO) ,the ERβ gene (βERKO) or both genes (αβERKO). The generation of the different ERKO mice provides ideal models for studying the physiologicalconsequences of the complete lack of estrogen receptor activity and the distinct roles of both estrogen receptors in various tissues. This review summarizes the phenotypes principally seen in the femalereproductive system of the different ERKO mice.

Activation of estrogen receptor β is a prerequisite for estrogen-dependent upregulation of nitric oxide synthases in neonatal rat cardiac myocytes

Physiological effects of estrogen on myocardium are mediated by two intracellular estrogen receptors, ERα and ERβ, that regulate transcription of target genes through binding to specific DNA target sequences. To define the role of ERβ in the transcriptional activation of both endothelial (eNOS) and inducible nitric oxide synthase (iNOS) in cardiac myocytes, we used the complete ERβ-specific antagonist R, R-tetrahydrochrysene ( R, R-THC). R, R-THC inhibited activation of iNOS/eNOS promoter-luciferase reporter constructs (iNOS/eNOS-Luc) in a dose-dependent fashion in COS7 cells selectively transfected with ERβ, but failed to influence ERα-mediated increase of iNOS/eNOS-Luc. In neonatal rat cardiomyocytes transfected with eNOS-Luc or iNOS-Luc, incubation with 17β-estradiol (E2, 10 −8 M) for 24 h stimulated expression of eNOS and iNOS. R, R-THC (10 −5 M) completely inhibited this effect. Furthermore, eNOS and iNOS protein expression in cardiac myocytes induced by E2 was completely blocked by R, R-THC as shown by immunoblot analysis. Taken together, these results show that ERβ mediates transcriptional activation of eNOS and iNOS by E2.

Estrogen receptor beta acts as a dominant regulator of estrogen signaling.

The physiological effects of estrogens are mediated by two intracellular transcription factors, the estrogen receptors (ERs), that regulate transcription of target genes through binding to specific DNA target sequences. Here we describe alterations in cellular responses to different ER agonists and to the anti-estrogenic compound tamoxifen resulting from co-expression of the two ERs in transient co-transfection experiments. Our results demonstrate that ERbeta can act as a negative or positive dominant regulator of ER activity. This is manifested through reduced transcriptional activity at low concentrations of estradiol (E2); increased antagonistic effects of tamoxifen on E2 stimulated activity; and enhanced agonistic action of the phytoestrogenic compound genistein. Furthermore, using chimeric proteins lacking the N-terminal activation function 1 (AF-1), we show that the differential responses of ERalpha and ERbeta to different agonists and antagonists are primarily dictated by inherent differences in the C-terminal ligand-binding domains of the receptors, whereas the magnitude of transcriptional activity is influenced by ERalpha AF-1, but not ERbeta AF-1. The ERalpha AF-1 activity appears to be modulated upon co-expression of both ERs. The alterations in transcriptional activity resulting from co-expression of ERalpha and ERbeta are probably due to the formation of alpha/beta heterodimeric complexes. This study demonstrates that co-localization and subsequent heterodimerization of ERalpha and ERbeta may result in receptor activity distinct from that of ER homodimers.

Ontogenetic changes in the expression of estrogen receptor alpha and beta in rat pituitary gland detected by immunohistochemistry.

The physiological effects of estrogen on the pituitary, including cellular proliferation and regulation of hormone synthesis, are mediated by the nuclear estrogen receptor (ER). The purpose of this study was to determine ontogenetic expression of two types of ERs (ERalpha and ERbeta) in the pituitary using specific antibodies, monoclonal antibody (1D5) for ERalpha and polyclonal antibody generated against ERbeta. First, we confirmed the detection of 66- and 55-kDa bands for ERalpha and ERbeta, respectively, in the rat pituitary extract by Western blotting. Then immunostaining with these antibodies was performed using fetal and adult Wistar rat tissues, combined with PRL or LHbeta immunohistochemistry. Intense ERbeta signal was detected throughout the pituitary from day 12 of gestation. However, staining for ERalpha only became detectable from day 17 of gestation. In contrast with the fetal period, nuclei stained for ERalpha were widely distributed in the anterior lobe in the adult rat, whereas ERbeta-positive cells were restricted in the anterior lobe. LHbeta, but not PRL, was colocalized in ERbeta-positive cells. Our results indicated that the major population of ER subtypes in the rat pituitary gland has changed around the day of birth and that the expression of ERbeta may be involved in the differentiation of pituitary cell function to synthesize a specific hormone.

Estradiol and tamoxifen interactions with thyroid hormone in the ovariectomized-thyroidectomized rat.

Receptors for estrogens and thyroid hormone (T3) have related DNA-binding domains that interact with closely related DNA target sequences which enable transcriptional control. In vitro molecular studies have raised the possibility that estrogen and T3 receptors may compete for binding to certain DNA target sites (cross-talk). However, there have been no physiological studies evaluating the abilities of estrogens or T3 to mimic or inhibit each other in vivo in a manner consistent with a mechanism involving receptor cross-talk. To address this issue, the effects of estradiol, tamoxifen (an antiestrogen), and T3 were studied in an ovariectomized-thyroidectomized rat model designed to minimize hormone interplay occurring via neuroendocrine or pharmacokinetic mechanisms. The T3 responses examined included induction of GH, somatic growth, and hepatic malic enzyme, and suppression of TSH secretion. The estrogen responses examined included induction of pituitary kallikrein, PRL, and uterine weight; increases in serum triglycerides; and suppression of LH secretion. Estradiol and tamoxifen acted as partial T3 agonists on GH induction, with agonist or antagonist effects depending upon T3's presence. Estradiol and tamoxifen acted as pure T3 antagonists on T3 induction of somatic growth and malic enzyme. Similarly, estradiol blocked T3-evoked decreases in bone mineral density and had no effect on bone in T3's absence. In contrast, estradiol or tamoxifen did not alter T3 feedback inhibition of TSH release or T3 induction of PRL. T3 partially mimicked estrogen actions to suppress LH, but did not mimic or inhibit other estrogen responses. Interestingly, the effect of estradiol and tamoxifen to increase serum triglycerides was totally T3 dependent even though T3 tended to decrease triglyceride levels. The results indicate that physiological effects of estrogens on GH, somatic growth, bone, malic enzyme, and serum triglycerides exhibit properties suggestive of a mechanism involving cross-talk with T3 receptors. Tamoxifen fully mimicked the effects of estradiol arising by an apparent antagonism of T3 actions, but acted as an antiestrogen in other responses.