Physiological Role Of Estrogen Research Articles

Estrogen Receptor Function: Impact on the Human Endometrium.

The physiological role of estrogen in the female endometrium is well established. On the basis of responses to steroid hormones (progesterone, androgen, and estrogen), the endometrium is considered to have proliferative and secretory phases. Estrogen can act in the endometrium by interacting with estrogen receptors (ERs) to induce mucosal proliferation during the proliferative phase and progesterone receptor (PR) synthesis, which prepare the endometrium for the secretory phase. Mouse knockout studies have shown that ER expression, including ERα, ERβ, and G-protein-coupled estrogen receptor (GPER) in the endometrium is critical for normal menstrual cycles and subsequent pregnancy. Incorrect expression of ERs can produce many diseases that can cause endometriosis, endometrial hyperplasia (EH), and endometrial cancer (EC), which affect numerous women of reproductive age. ERα promotes uterine cell proliferation and is strongly associated with an increased risk of EC, while ERβ has the opposite effects on ERα function. GPER is highly expressed in abnormal EH, but its expression in EC patients is paradoxical. Effective treatments for endometrium-related diseases depend on understanding the physiological function of ERs; however, much less is known about the signaling pathways through which ERs functions in the normal endometrium or in endometrial diseases. Given the important roles of ERs in the endometrium, we reviewed the published literature to elaborate the regulatory role of estrogen and its nuclear and membrane-associated receptors in maintaining the function of endometrium and to provide references for protecting female reproduction. Additionally, the role of drugs such as tamoxifen, raloxifene, fulvestrant and G-15 in the endometrium are also described. Future studies should focus on evaluating new therapeutic strategies that precisely target specific ERs and their related growth factor signaling pathways.

The biological and clinical relevance of estrogen metabolome

Considerable knowledge has been gathered on the physiological role of estrogens. However, fairly little information is available on the role of compounds produced in the breakdown process of estrone and estradiol wich may play a role in various diseases associated with estrogen impact. To date, approximately 15 extragonadal estrogen-related compounds have been identified. These metabolites may exert protective, or, instead, pro-inflammatory and/or pro-oncogenic activity in a tissue-specific manner. Systemic and local estrogen metabolite levels are not necesserily correlated, which may promote the diagnostic significance of the locally produced estrogen metabolites in the future. The aim of the present study is a bibliographic review of the extragonadal metabolome in peripheral tissues, and to highlight the role of the peripheral tissue homeostasis of estrogens as well as the non-hormonal biological activity and clinical significance of the estrogen metabolome. Orv Hetil. 2017; 158(24): 929-937.

Endocrine changes, fetal growth, and uterine artery hemodynamics after chronic estrogen suppression during the last trimester of equine pregnancy.

Equine pregnancy is characterized by very high circulating concentrations of estrogens. The physiological roles of estrogens during equine gestation are largely unknown, although some studies suggest a role in the regulation of uterine artery hemodynamics and a relationship between low circulating estrogen concentrations and late pregnancy loss. The objectives of this experiment were to evaluate the effects of estrogen suppression on uterine artery hemodynamics and on pregnancy outcome. Estrogen synthesis was suppressed using letrozole, a potent aromatase inhibitor. Twelve pregnant mares were randomly assigned to a control (n = 6) or treatment (n = 6; 500 mg letrozole orally every 4 days) group with treatment starting at 240 days of gestation and continuing until parturition. Weekly serum samples were analyzed to determine testosterone, dehydroepiandrosterone sulfate, estradiol, estrone sulfate, progestins, and prostaglandin F2α metabolite concentrations. Ultrasonographic examinations were performed biweekly and measurements included uterine artery hemodynamics (diameter, pulsatility, and resistance indices), fetal growth using the diameter of the fetal eye, and placental evaluation using the combined thickness of the uterus and placenta. At parturition, gestational length, foal weight, and neonatal viability were determined. Letrozole suppressed estrogen synthesis during gestation by approximately 90% compared to control values. This large reduction in circulating estrogens had no effect on uterine artery hemodynamics, normal placental development, maintenance of pregnancy, or neonatal viability. However, neonates from letrozole-treated mares had lower (P < 0.05) birth weights than controls, suggesting that estrogens may play a role in fetal growth that is not mediated through regulation of uterine blood flow.

Estrogen signaling in the proliferative endometrium: implications in endometriosis.

Even though the physiological role of estrogen in the female reproductive cycle and endometrial proliferative phase is well established, the signaling pathways by which estrogen exerts its action in the endometrial tissue are still little known. In this regard, advancements in cell culture techniques and maintenance of endometrial cells in cultures enabled the discovery of new signaling mechanisms activated by estrogen in the normal endometrium and in endometriosis. This review aims to present the recent findings in the genomic and non-genomic estrogen signaling pathways in the proliferative human endometrium specifically associated with the pathogenesis and development of endometriosis.

Inhibition of estrogen synthesis during the last trimester of gestation: changes in endocrine patterns, fetal growth and uterine artery hemodynamics in mares

Equine gestation is characterized by very high circulating concentrations of estrogens in the dam. The physiological roles of estrogens during late gestation are largely unknown, although some studies suggest a relationship between low circulating estrogen concentrations and late term pregnancy loss in the mare. Letrozole is a potent aromatase inhibitor that prevents the conversion of androgens to estrogens in the equine placenta. The objective of this study was to evaluate the effect of letrozole on circulating concentrations of estrogens, androgens, and progestins, and on uterine hemodynamics during the last trimester of pregnancy in mares, as well as the effect on fetal development. Multiparous mares of mixed breeds were randomly assigned to control (n1⁄46) or treatment (n1⁄46) groups. Treated mares received 500 mg of letrozole orally every 4 days starting at 240 days of gestation until parturition. Weekly, serum samples were analyzed using enzyme immunoassays to determine estrone sulfate (ES), progestins (P), testosterone (T) and dehydroepiandrosterone sulfate (DHEA-S) concentrations. To monitor the status of pregnancy: 1) the mean diameter of the fetal eye was measured as an estimate of fetal growth, 2) uterine artery (UA) diameters and 3) Doppler resistance and pulsatility indices (RI and PI) were determined in both uterine arteries by transrectal Doppler ultrasound every second week. Fetal development was evaluated based on foal weight and

Estrogen-Regulated Prohibitin Is Required for Mouse Uterine Development and Adult Function

Estrogen signaling is pivotal for maintenance of female reproductive function in mammals. The physiological role of estrogen is mediated by estrogen receptors (ERs) and the steroid receptor coactivator family of transcriptional coregulators. Ablation of steroid receptor coactivator and ER coactivators in mice causes impaired female reproductive function. Recently we reported that prohibitin (PHB) can function as a corepressor for ERs in cultured cells. In this study, we demonstrate that PHB is an estrogen-regulated gene in vitro and in vivo, and its expression is induced by estrogen in the uterus, suggesting the existence of feedback regulatory loops. A conditional PHB knockout mouse model was generated by gene targeting to assess its in vivo function. Female mice with selective ablation of the PHB allele in the uterus were sterile, and their uteri were severely hypoplastic, indicating PHB is required for uterine development. Moreover, expression of ER and progesterone receptor target genes was selectively altered in response to hormone treatment. In summary, this study demonstrates that PHB is an estrogen-regulated gene and that PHB is essential for mouse uterine development and adult function and selectively required for estrogen-regulated gene expression.

Symptome und Diagnostik innerer Krankheiten

The possible physiological role of estrogen in the epididymis and ventral prostate of rat was investigated. In prepubertal rats castrated for 7 days, treatment with estradiol (1.0 micrograms) for 7 days (35-day-old at autopsy) resulted in a marked increase in the weight and content of glyceryl-phosphorylcholine and sialic acid in the epididymis; estradiol and dihydrotestosterone were equipotent in causing an increase in sialic acid concentration. Estradiol showed a synergistic effect in influencing the androgen action on the growth of the prepubertal rat prostate while no such synergism was evident in stimulating the secretory function of the epididymis. The duality of epididymal response to the two sex steroids suggests that the two hormones may be acting in concert at physiological levels as regulators of epididymal secretory function; the need for identifying estrogen specific biochemical indices in the epididymis is discussed.

Genes related to estrogen action in reproduction and breast cancer

Estrogen is an important steroid hormone with diverse functions in different parts of the human body. The developmental and physiological role of estrogen is mediated by estrogen receptor alpha (ER-alpha) and newly identified ER-beta. Regulation of expression of various important cellular oncogenes and tumor suppressor genes is a key component of estrogen and ER action. The expression of these genes is crucial in various processes such as cell cycle progression, mammary gland development, growth factor pathways and apoptosis. A very precise and accurate control of these genes is required for normal growth and functioning of cells. Aberrant expression of these genes through elevated expression, gene amplification or mutation may lead to induction and/or progression of different cancers including estrogen-dependent breast cancers. This review briefly describes the role of different genes that are regulated by estrogen in female reproductive tissues and breast cancer.

Human ejaculated spermatozoa contain active P450 aromatase.

The generation of cytochrome P450 aromatase (P450arom) and estrogen receptor (ER) knockout mice has raised new interest in the physiological role of estrogens in male reproduction. Testicular expression of P450arom, the enzyme that converts androgens into estrogens, has been shown in both somatic and germ cell types in several species, whereas in humans, testicular expression is confined to the somatic cells. The aim of this study was to determine whether P450arom is present in human ejaculated spermatozoa. Using RT-PCR and specific primers, we amplified the highly conserved helical, aromatic, and heme-binding sequences of the conventional human P450arom from RNA isolated from human spermatozoa. Employing a rabbit polyclonal antiserum directed against human placental P450arom, immunoblotting analysis demonstrated aromatase protein expression, which was localized primarily to the tail and midpiece of spermatozoa. Measurement of enzymatic activity using a sensitive (3)H(2)O aromatase assay revealed that activity was enhanced by the 2'-O-dibutyryl cAMP and completely inhibited in the presence of the specific aromatase inhibitor, letrozole. These results represent the first demonstration that human spermatozoa are a potential site of estrogen biosynthesis. The physiological relevance of estrogen synthesis in spermatozoa remains to be elucidated and opens a new area of investigation in male fertility.

Human Ejaculated Spermatozoa Contain Active P450 Aromatase

The generation of cytochrome P450 aromatase (P450arom) and estrogen receptor (ER) knockout mice has raised new interest in the physiological role of estrogens in male reproduction. Testicular expression of P450arom, the enzyme that converts androgens into estrogens, has been shown in both somatic and germ cell types in several species, whereas in humans, testicular expression is confined to the somatic cells. The aim of this study was to determine whether P450arom is present in human ejaculated spermatozoa. Using RT-PCR and specific primers, we amplified the highly conserved helical, aromatic, and heme-binding sequences of the conventional human P450arom from RNA isolated from human spermatozoa. Employing a rabbit polyclonal antiserum directed against human placental P450arom, immunoblotting analysis demonstrated aromatase protein expression, which was localized primarily to the tail and midpiece of spermatozoa. Measurement of enzymatic activity using a sensitive 3H2O aromatase assay revealed that activity was enhanced by the 2′-O-dibutyryl cAMP and completely inhibited in the presence of the specific aromatase inhibitor, letrozole. These results represent the first demonstration that human spermatozoa are a potential site of estrogen biosynthesis. The physiological relevance of estrogen synthesis in spermatozoa remains to be elucidated and opens a new area of investigation in male fertility.

Estrogen depletion induces NaCl-sensitive hypertension in female spontaneously hypertensive rats.

In women, arterial pressure generally increases after menopause, but several studies suggest that women who eat large amounts of plant estrogens (phytoestrogens) experience a slower rise in the incidence of postmenopausal hypertension. This suggests that both ovarian hormones (principally estrogen) and phytoestrogens may protect at least some women from hypertension. The present study tests the hypothesis that phytoestrogens blunt hypertension in estrogen-depleted female spontaneously hypertensive rats (SHR). Three-week-old ovariectomized SHR were fed one of four diets that contained basal (0.6%) or high (8%) NaCl with or without dietary phytoestrogens for 9 wk. In SHR on the basal NaCl diet, arterial pressure was unaffected by the removal of dietary phytoestrogens. In contrast, in SHR on the high-NaCl diet, arterial pressure was significantly higher in rats on the phytoestrogen-free (204 +/- 4 mmHg) compared with the phytoestrogen-replete (153 +/- 4 mmHg) diet. Ganglionic blockade resulted in reductions in arterial pressure that were directly related to the dietary NaCl-induced increases in arterial pressure. Together, these data indicate that dietary phytoestrogens protect ovariectomized female SHR from dietary NaCl-sensitive hypertension and that the sympathetic nervous system plays an important role in this effect. Furthermore, these results demonstrate that dietary phytoestrogens can have a major impact on the interpretation of studies into the physiological role of estrogen in females.

Matters of Sex

Despite the popular concept that heart disease preferentially affects the male population, in every year for the past 16 years, cardiovascular disease has killed more women than men.1 Unfortunately, a disparity still exists between men and women in the diagnosis and aggressive treatment of heart disease. The perception that women are relatively protected is reflected by the fact that women are much more fearful of dying from some form of cancer than from cardiovascular disease.1 Understanding any risk factors that predispose or protect the female population from cardiovascular and coronary disease is therefore a compelling goal for the research community. See p 1419 Left ventricular hypertrophy is a compensatory response of the heart to a variety of stresses, and it is a strong predictor of morbidity and mortality in individuals whether or not they have been diagnosed with cardiovascular disease. Sex differences in the development of this disease over time have been suggested by clinical studies dealing with patients who suffer from aortic stenosis or hypertension.2,3 For example, older female patients with aortic stenosis tend to have increased hypertrophy accompanied by greater concentric remodeling and preserved left ventricular function when compared with male patients. Premenopausal women, in fact, exhibit a thinner posterior wall, smaller left ventricular mass, and better load-dependent and load-independent cardiac function than age-matched men under conditions of mild essential hypertension.4 Population studies have shown an age-dependent increase in left ventricular mass in healthy normotensive women that is not seen in men, as determined by echocardiography.5 These and many other studies in both humans and animals suggest that estrogens can affect the remodeling of the heart. Estrogens are potent vasodilators; they act in this capacity by increasing nitric oxide production. However, recent findings indicate that estrogens have direct actions on the myocardium as …

Biphasic effects of the natural estrogen 17beta-estradiol on hepatic cholesterol metabolism in intact female rats.

The protective influence of estrogens in cardiovascular disease is believed to be partly due to beneficial effects on cholesterol metabolism. Much of the experimental data are based on models in which synthetic estrogens have been used in pharmacological doses, and therefore, the physiological role of estrogens in cholesterol metabolism is uncertain. To evaluate this important issue, we performed experiments in intact female rats with use of the natural estrogen 17beta-estradiol (E2) administered either subcutaneously or orally. After physiological doses of E2 (< or =0.04 mg. kg(-1). d(-1)) were administered, plasma levels of high density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I were increased. In the liver, 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol 7alpha-hydroxylase activities were increased, as well as cholesterol 7alpha-hydroxylase mRNA levels. These effects were abolished during treatment with higher doses of E2, whereas apo A-I mRNA increased in a dose-dependent way. After treatment with pharmacological doses of E2 (> or =0.2 mg. kg(-1). d(-1)), the number of hepatic low density lipoprotein receptors increased and plasma cholesterol was reduced. These effects were similar after both oral and subcutaneous administration of E2. Our results show that the responses to E2 are biphasic: plasma HDL, apo A-I, and hepatic enzyme activities governing bile acid and cholesterol synthesis increased only at physiological doses of E2. At pharmacological doses of E2, hepatic low density lipoprotein receptors are stimulated and plasma cholesterol is reduced. Therefore, under physiological conditions, E2 exerts its major effects on hepatic cholesterol metabolism through mechanisms other than stimulation of low density lipoprotein receptor expression.

Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens

Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens

Endogenous protein kinase-C activation in osteoblast-like cells modulates responsiveness to estrogen and estrogen receptor levels.

The osteoblast-like osteosarcoma cell line ROS 17/2.8, which expresses very low levels of estrogen receptor (ER), was stably transfected with the mouse ER in order to more easily evaluate the physiological role of estrogens in bone cell homeostasis. These transfected ROS.SMER 14 cells are highly responsive to estrogenic stimulation at subconfluence, but become refractory to estrogenic stimulation when postconfluency is reached. The purpose of these studies was to determine the mechanisms underlying this loss of responsiveness in these ER stably transfected cells at postconfluence. When proliferative capacity was evaluated by bromodeoxyuridine immunocytochemistry, approximately 70% of the subconfluent cells were actively dividing, whereas none of the postconfluent cells underwent division. Subconfluent cells were found to contain 2500-3000 ER-binding sites/cell, whereas the ER in postconfluent cells was low and often undetectable. Steady state ER mRNA levels were not significantly modified by postconfluency. ER protein levels were also unaffected by confluency status. Since protein kinase-C (PKC) has been reported to influence cell proliferation and steroid hormone receptor binding, PKC activity was measured in sub- and postconfluent cells. Calcium-dependent PKC activity was approximately about 2-fold higher in postconfluent compared to subconfluent cells, whereas no differences were discerned in calcium-independent PKC activity. In an effort to examine the role of PKC in greater detail, postconfluent cells were treated with PKC inhibitors (H-7 or staurosporine) or with the tumor promoter TPA (12-O-tetradecanoylphorbol-13-acetate) to down-regulate PKC activity, and changes in ER were evaluated. Inhibition or down-regulation of the PKC activity in postconfluent cells enhanced ER-binding capacity in a dose-dependent manner and estrogen responsiveness of an exogenous reporter gene and of the endogenous alkaline phosphatase, representing an endogenous estrogen-stimulated gene. These data indicate that there is an interaction between the PKC and ER signaling systems in bone cells and that this interaction may be influenced by the proliferative and/or differentiative state of the cells, resulting in modulation of hormone responsiveness.

Androgen-Estrogen Synergy in the Regulation of Energy Metabolism in Epididymis and Vas Deferens of Rhesus Monkey

The possible physiological role of estrogen in the regulation of energy metabolism of epididymis and vas deferens of rhesus monkey was investigated. A few selected key enzymes of glycolysis (hexokinase, phosphofructokinase and pyruvate kinase) and TCA cycle (succinate dehydrogenase and malate dehydrogenase) were measured in these two organs of (a) castrated estrogen treated, (b) castrated estrogen + dihydrotestosterone (DHT) treated animals and compared with those in castrated and castrated + DHT treated animals. Results reveal that DHT stimulated the activities of all these enzymes whereas estrogen failed to stimulate any of the enzymes in castrated animals. However, estrogen in combination with DHT caused a marked stimulation of the enzymes and the response of the epididymis and vas deferens to combination treatment was significantly more than that caused by DHT alone. The results suggest that circulating estrogen in male has a physiological role and acts synergistically with androgen in regulating accessory sex organ function.

Regulation of pituitary and brain enkephalin systems by estrogen

The roles of estrogen in the regulation of pituitary and brain enkephalin systems were studied. A sex-related difference in the levels of enkephalins was observed in the anterior lobe of rat pituitary. Administration of estradiol to male rats caused a marked reduction in the levels of enkephalins in the anterior lobe. Ovariectomy produced a significant increase in the enkephalin levels of the same region but this increase was completely prevented by replacement with estradiol. These results suggest a physiological role of estrogen in the regulation of pituitary enkephalin systems. Repeated injections of haloperidol elicited effects similar to those of estrogen on the pituitary and brain enkephalin levels; namely, striatal enkephalin levels were increased whereas pituitary enkephalin levels were decreased after long-term treatment with these two compounds. These results raise the possibility that the regulation of estrogen on enkephalin systems may in part be mediated through a dopaminergic mechanism.

Cytoplasmic and nuclear estradiol-17β binding in male and female rat brain: Regional distribution, temporal aspects and metabolism

A study was conducted in which we simultaneously measured absolute levels of cell nuclear estradiol-17β (E 2) retention and cytosol E 2 saturation binding capacities in various neural tissues from adult gonadectomized-adrenalectomized (GX-ADX) male and female rats, at various times after a saturating dose of [ 3H]E 2. The results indicate that, with minor exceptions, the basic properties of E 2 metabolism and E 2 retention kinetics in target brain tissues and corresponding cell nuclear and cytosol fractions are quite similar in GX-ADX male and female rats. The results do not, however, rule out the possibility of subtle sex differences in estrogen binding in at least some brain regions which were studied. The present demonstration of E 2 binding in various regions of the male brain is consistent with a physiological role of estrogen in the male; however, the similarities in these E 2 binding parameters between the sexes unfortunately sheds little light on the marked neuroendocrine sex differences which have been documented. At times of maximal nuclear E 2 retention (2 h post-injection), pituitary cytosol was markedly depleted of E 2 binding sites, while cytosols obtained from the preoptic area, hypothalamus and amygdala were only moderately depleted. These observations suggest that within the brain the relationship between cytoplasmic and cell nuclear estrogen binding may be different from that observed in non-neural tissues. In all tissues, E 2 cytosol binding was replinished to normal levels 24 h after [ 3H]E 2 administration.

Estrogens and the human male.

Literature on the role of estrogens in men is reviewed. The primary active estrogens in males and females are estradiol-17beta (E2), estrone (E1), and estriol (E3). The active constituents of serum E2 and testosterone (T) are those which are not bound by testosterone-estrogen binding globulin (TEBG). The concentration of TEBG is stimulated by estrogen and suppressed by androgens. Both E1 and E2 appear to be derived from the peripheral metabolism of T and androstenedione. The metabolism and physiological roles of estrogens in men are briefly discussed. The association of gynecomastia with puberty, cirrhosis of the liver, hyperthyroidism, chronic renal failure, refeeding gynecomastia, administration of digitalis and diuretics, neoplasms, and hypergonadotropic hypogonadism is reviewed. In older men, the ratio of free E2:T is increased. The relationship of andorgens, estrogens, and male sex behavior is briefly reviewed. Areas for future research include the mechanisms by which estrogens and androgens exert antagonistic effects on similar tissues, variations in the fractional conversionr ate of androgens to estrogens, the etiology of pubertal gynecomastia, the role of the free E2:T ratio in male social and sexual behavior, and the interrelation between behavior, nutrition, hormone secretion, and degenerative changes such as benign prostatic hyperplasia.

Feeding Estrogen (Dianisylhexene) to Laying Hens

THE physiological role of estrogen (female sex hormone) in promoting the development and the secretion of the various component parts of the egg is gradually being determined. Not only does the secretion of estrogen by the developing ovary stimulate the growth and functional activity of the oviduct but it has been shown to influence the composition of the blood and the metabolism of the egg precursors.Lawrence and Riddle (1916) reported that the lipids of the blood of fowls increase during the period of lay. This observation was confirmed by Lorenz et al., (1938) who then showed that estrogen administration could cause a similar rise in blood lipids in the immature fowl. (Lorenz et al., 1938).Buckner et al., (1930), Macowan (1932), and Charles and Hogben (1933) found the serum calcium level of laying hens markedly above that in non-laying and immature birds. Riddle and Dotti (1936) demonstrated that estrogens .