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Isolation and characterization of an estrogen binding protein which may integrate the plethora of estrogenic actions in nonreproductive organs
Abstract
A putative estrogen receptor (pER) from mouse liver has been characterized. The heterodimer protein (81-84 kDa) consists of two covalently bound subunits (61-67 and 17-27 kDa) with following characteristics: sedimentation constant--4.9 S; IP--4.8; dissociation constant (Kd) for estradiol-17beta binding--0.7 nmol; binding sites--0.746 pmol/mg protein; relative binding affinity--estradiol-17beta--100, estrone--80 and estriol--30; specificity--does not bind, other natural steroids, synthetic estrogens, antiestrogens and bioflavonoids. Importantly, immunosuppressants, neuroleptic and carcinogens influence 3H-estradiol-17beta binding to pER. Interestingly, pER is a serine phosphatase and this may have relevancy to estrogen action in Alzheimer's disease. The polyclonal anti-pER antibody does not react with estrogen receptors (ER). ER antibody does not react with pER. Remarkably, anti-pER antibody reacts with calcineurin, a brain phosphatase and anti-calcineurin antibody reacts with pER. Immunohistochemical analyses showed that pER is undetectable in reproductive organs (except ovary). It is localized on the plasma or the nuclear membranes in some, in cytoplasm and/or nucleus in other cells of non-reproductive organs (skeletal, neural, vascular, hair and retina), and in tumors (mammary, endometrial and prostate cancers, and prostatic hyperplasia). The information presented justifies the proposition that pER may mediate the estrogenic actions in non-reproductive organs.
... A heterodimeric estrogen-binding protein, referred to as the putative ER (pER), was reported to bind to E2β at a sub-nanomolar affinity but was unable to bind other estrogens or anti-estrogens. Depending on cell types, pER is expressed on the plasma and/or nuclear membranes or in the cytoplasm and the nucleus (Rao, 1998). Since the polyclonal anti-pER antibody failed to react with ERs and was unable to detect pER expression in reproductive organs (Rao, 1998), the role of this putative ER in rapid estrogen signaling of breast cancer cells remains elusive. ...
... Depending on cell types, pER is expressed on the plasma and/or nuclear membranes or in the cytoplasm and the nucleus (Rao, 1998). Since the polyclonal anti-pER antibody failed to react with ERs and was unable to detect pER expression in reproductive organs (Rao, 1998), the role of this putative ER in rapid estrogen signaling of breast cancer cells remains elusive. ...
Prevailing wisdom is that estrogen receptor (ER)-α mediated genomic estrogen signaling is responsible for estrogen-stimulated cell proliferation and development of ER-positive breast cancer. However, accumulating evidence indicates that another estrogen signaling pathway, non-genomic or rapid estrogen signaling, also plays an important role in mitogenic estrogen signaling. Previously, our laboratory cloned a 36 kDa variant of ER-α, ER-α36, and found that ER-α36 is mainly expressed in the cytoplasm and at the plasma membrane. ER-α36 mediates rapid estrogen signaling and inhibits genomic estrogen signaling. In this review, we review and update the biological function of ER-α36 in ER-positive and -negative breast cancer, breast cancer stem/progenitor cells and tamoxifen resistance, potential interaction and cross-talk of ER-α36 with other ERs and growth factor receptors, and intracellular pathways of ER-α36-mediated rapid estrogen signaling. The potential function and underling mechanism of ER-α in development of ER-positive breast cancer will also be discussed.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
... As with the brain, the retina is a steroid target but also contains a system for its synthesis [10]. Several studies have shown the existence of retinal hormone receptors and steroid enzymes for the formation of ex novo steroids or neurosteroids [9,11,12]. In addition, the role of these neurosteroids in the visual function physiology and pathology has been confirmed both in humans and animal models [13,14]. ...
The interactions between steroid gonadal hormones and the retina (a part of the visual system and the central nervous system (CNS)) have received limited attention and beneficial effects of these hormones in retinal diseases is controversial. Retinitis pigmentosa (RP) is the most common cause of retinal hereditary blindness and to date no treatment is available. However, results regarding the effects of progesterone on the progression of RP are promising. With the idea of demonstrating if the progesterone retinal protection in RP is related to its possible anti-inflammatory properties, we have administered orally progesterone to rd10 mice, an animal model of RP. We observed that progesterone decreased photoreceptors cell death, reactive gliosis and the increase in microglial cells caused by RP. We also examined the expression of neuronal and inducible nitric oxide synthase (nNOS and iNOS), the enzyme responsible for NO production. The results demonstrated a decrease in nNOS expression only in control mice treated with progesterone. Inflammation has been related with an increase in lipid peroxidation. Noticeably progesterone administration was able to diminish retinal malondialdehyde (MDA, a lipid peroxidation product) concentrations in rd10 mice. Altogether, we can conclude that progesterone could be a good therapeutic option not only in RP but also for other retinal diseases that have been associated with inflammation and lipid peroxidation.
... Par exemple, la ciclosporine et le tacrolimus augmentent les taux d'estrogè nes en agissant par compé tition avec leur ré cepteur pouvant entraîner l'apparition de kystes fonctionnels et alté rer l'ovulation [37,43]. Les glucocorticoïdes diminuent la pulsatilité de la GnRH et font baisser les taux de LH et de FSH, de plus ils diminuent la synthè se des androgè nes surré naliens. ...
Chronic renal failure leads to many metabolic disorders affecting reproductive function. For men, hypergonadotropic hypogonadism, hyperprolactinemia, spermatic alterations, decreased libido and erectile dysfunction are described. Kidney transplantation improves sperm parameters and hormonal function within 2 years. But sperm alterations may persist with the use of immunosuppressive drugs. In women, hypothalamic-pituitary-ovarian axis dysfunction due to chronic renal failure results in menstrual irregularities, anovulation and infertility. After kidney transplantation, regular menstruations usually start 1 to 12 months after transplantation. Fertility can be restored but luteal insufficiency can persist. Moreover, 4 to 20% of women with renal transplantation suffer from premature ovarian failure syndrome. In some cases, assisted reproductive technologies can be required and imply risks of ovarian hyperstimulation syndrome and must be performed with caution. Pregnancy risks for mother, fetus and transplant are added to assisted reproductive technologies ones. Only 7 authors have described assisted reproductive technologies for patients with kidney transplantation. No cases of haemodialysis patients have been described yet. So, assisted reproductive technologies management requires a multidisciplinary approach with obstetrics, nephrology and reproductive medicine teams' agreement.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
... Par exemple, la ciclosporine et le tacrolimus augmentent les taux d'estrogè nes en agissant par compé tition avec leur ré cepteur pouvant entraîner l'apparition de kystes fonctionnels et alté rer l'ovulation [37,43]. Les glucocorticoïdes diminuent la pulsatilité de la GnRH et font baisser les taux de LH et de FSH, de plus ils diminuent la synthè se des androgè nes surré naliens. ...
Chronic renal failure leads to many metabolic disorders affecting reproductive function. For men, hypergonadotropic hypogonadism, hyperprolactinemia, spermatic alterations, decreased libido and erectile dysfunction are described. Kidney transplantation improves sperm parameters and hormonal function within 2 years. But sperm alterations may persist with the use of immunosuppressive drugs. In women, hypothalamic-pituitary-ovarian axis dysfunction due to chronic renal failure results in menstrual irregularities, anovulation and infertility. After kidney transplantation, regular menstruations usually start 1 to 12 months after transplantation. Fertility can be restored but luteal insufficiency can persist. Moreover, 4 to 20% of women with renal transplantation suffer from premature ovarian failure syndrome. In some cases, assisted reproductive technologies can be required and imply risks of ovarian hyperstimulation syndrome and must be performed with caution. Pregnancy risks for mother, fetus and transplant are added to assisted reproductive technologies ones. Only 7 authors have described assisted reproductive technologies for patients with kidney transplantation. No cases of haemodialysis patients have been described yet. So, assisted reproductive technologies management requires a multidisciplinary approach with obstetrics, nephrology and reproductive medicine teams’ agreement.
... A higher mER migrating at approximately 80 kDa was also recognized. This band has also been observed in previous studies (Rao, 1998;Marin et al., 2005;González et al., 2007), and may be the result of the duplication of two exons within the ERα gene, as previously reported in cancer cells (Pink et al., 1996). Although not shown here, a battery of antibodies directed to distinct epitopes of ERα consistently reproduced these results, indicating that this receptor is a high homologue to ERα, which is in agreement with previous studies in immortalized cells and neuronal tissues (reviewed in Marin et al., 2009). ...
Membrane estrogen receptor Caveolae Caveolin-1 Human brain Alzheimer's disease Voltage-dependent anion channel (VDAC) is a mitochondrial porin also found in the neuronal membrane (pl-VDAC), where its function may be related to redox homeostasis and apoptosis. Murine models have evidenced pl-VDAC into caveolae in a complex with estrogen receptor alpha (mERα), which participates in neuroprotection against amyloid beta (Aβ), and whose integration into this hydrophobic domain remains unclear. Here, we have demonstrated in caveolae of human cortex and hippocampus the presence of pl-VDAC and mERα, in a complex with scaffolding caveolin-1 which likely provides mERα stability at the plasma membrane. In Alzheimer's disease (AD) brains, VDAC was accumulated in caveolae, and it was observed in dystrophic neurites of senile plaques, whereas ERα was expressed in astrocytes surrounding the plaques. Together with previous data in murine neurons demonstrating the participation of pl-VDAC in Aβ-induced neurotoxicity, these data suggest that the channel may be involved in membrane dysfunctioning observed in AD neuropathology.
... A higher mER migrating at approximately 80 kDa was also recognized. This band has also been observed in previous studies (Rao, 1998;Marin et al., 2005;González et al., 2007), and may be the result of the duplication of two exons within the ERα gene, as previously reported in cancer cells (Pink et al., 1996). Although not shown here, a battery of antibodies directed to distinct epitopes of ERα consistently reproduced these results, indicating that this receptor is a high homologue to ERα, which is in agreement with previous studies in immortalized cells and neuronal tissues (reviewed in Marin et al., 2009). ...
Membrane estrogen receptor Caveolae Caveolin-1 Human brain Alzheimer's disease Voltage-dependent anion channel (VDAC) is a mitochondrial porin also found in the neuronal membrane (pl-VDAC), where its function may be related to redox homeostasis and apoptosis. Murine models have evidenced pl-VDAC into caveolae in a complex with estrogen receptor alpha (mERα), which participates in neuroprotection against amyloid beta (Aβ), and whose integration into this hydrophobic domain remains unclear. Here, we have demonstrated in caveolae of human cortex and hippocampus the presence of pl-VDAC and mERα, in a complex with scaffolding caveolin-1 which likely provides mERα stability at the plasma membrane. In Alzheimer's disease (AD) brains, VDAC was accumulated in caveolae, and it was observed in dystrophic neurites of senile plaques, whereas ERα was expressed in astrocytes surrounding the plaques. Together with previous data in murine neurons demonstrating the participation of pl-VDAC in Aβ-induced neurotoxicity, these data suggest that the channel may be involved in membrane dysfunctioning observed in AD neuropathology.
... Studies indicate that estrogens and estrogen receptors play important physiological roles in cardiovascular disease [1]. Estrogens act by controlling expression of specific genes in target cells [2,3]. Their transcriptional activity is mediated by two estrogen receptors, ER-and ER-, similar in structure and function. ...
... 34 Pregnenolone sulfate is the most abundant neurosteroid found in the brain and retina, and estrogen receptors have been demonstrated on the rods, cones, and neuronal cells of the retina. [35][36][37] Potential mechanisms for steroid-induced apoptosis include induction of increased glutamate levels, which are excitotoxic and could trigger apoptosis. 5, 10,38 Glutamate has been shown to be increased in SARDSaffected eyes compared to eyes affected with progressive retinal atrophy. ...
Dogs diagnosed with sudden acquired retinal degeneration syndrome (SARDS) commonly are presented with concurrent clinical, physical, and historical findings consistent with hyperadreno-corticism (HAC) at the time of vision loss. Thirteen dogs diagnosed with SARDS on the basis of complete ophthalmic examination and extinguished bright-flash electroretinogram were evaluated for steroid hormonal abnormalities. Signalment, case history, physical examination, and clinicopathological findings were recorded. Serum cortisol and sex-hormone concentrations were measured before and after adrenocorticotropic hormone (ACTH) stimulation. Clinical signs of HAC, systemic hypertension, and proteinuria were commonly found in dogs with SARDS. Elevations in one or more sex hormones were found in 11 (85%) of 13 dogs (95% confidence interval [CI] 65% to 100%); cortisol was elevated in nine (69%) of 13 dogs (95% CI 44% to 94%). A minority of dogs (three [23%] of 13; 95% CI 0.2% to 46%) exhibited only an increase in adrenal sex hormones. Only one dog had completely normal ACTH stimulation test results. Symptoms of HAC were associated with abnormal ACTH stimulation results. Routine ACTH stimulation testing to evaluate cortisol and sex hormones, blood pressure screening, and urinalysis are recommended in these animals.
... We also identified higher molecular weight ERs at ~80 kDa and ~110-120 kDa, but like lower molecular weight proteins, it is unclear whether these represent functional ERs. It has been suggested that higher molecular weight ER-like proteins are similar to those described in rodent cortical and liver tissue (Asaithambi et al., 1997;Rao, 1998) and may be products of post-transcriptional modifications (Marin et al., 2006). ...
17-beta-Estradiol (E2) is a steroid hormone involved in numerous bodily functions, including several brain functions. In particular, E2 is neuroprotective against excitotoxicity and other forms of brain injuries, a property that requires the extracellular signal-regulated kinase (ERK) pathway and possibly that of other signaling molecules. The mechanism and identity of the receptor(s) involved remain unclear, although it has been suggested that E2 receptor alpha (ERalpha) and G proteins are involved. We, therefore, investigated whether E2-mediated neuroprotection and ERK activation were linked to pertussis toxin (PTX)-sensitive G-protein-coupled effector systems. Biochemical and image analysis of organotypic hippocampal slices and cortical neuronal cultures showed that E2-mediated neuroprotection as well as E2-induced ERK activation were sensitive to PTX. The sensitivity to PTX suggested a possible role of G-protein- and beta-arrestin-mediated mechanisms. Western immunoblots from E2-treated cortical neuronal cultures revealed an increase in phosphorylation of both G-protein-coupled receptor-kinase 2 and beta-arrestin-1, a G-protein-coupled receptor adaptor protein. Transfection of neurons with beta-arrestin-1 small interfering RNA prevented E2-induced ERK activation. Coimmunoprecipitation experiments indicated that E2 increased the recruitment of beta-arrestin-1 and c-Src to ERalpha. These findings suggested that ERalpha is regulated by a mechanism associated with receptor desensitization and downregulation. In support of this idea, we found that E2 treatment of cortical synaptoneurosomes resulted in internalization of ERalpha, whereas treatment of cortical neurons with the ER agonists E-6-BSA-FITC [beta-estradiol-6-(O-carboxymethyl)oxime-bovine serum albumin conjugated with fluorescein isothiocyanate] and E-6-biotin [1,3,5(10)-estratrien-3,17beta-diol-6-one-6-carboxymethloxime-NH-propyl-biotin] resulted in agonist internalization. These results demonstrate that E2-mediated neuroprotection and ERK activation involve ERalpha activation of G-protein- and beta-arrestin-mediated mechanisms.
... It is also known that there are sex hormone-mediated gender differences in cardiovascular and immune system functions (16,26). In this regard, 17-estradiol (E 2 ) plays an important role in blood vessel dilation and improvement in organ perfusion and function after trauma-hemorrhage and resuscitation (T-H/R) or vascular injury (2,10,15,17,18,20,21,24,25,27,29). The mechanism of action of E 2 appears to be multifactorial and related to improved circulation via nitric oxide (NO)-induced vasodilation and decreased synthesis of vasoconstricting molecules, such as endothelin (ET) and angiotensin II (2,4,20,22). ...
Although endothelin-1 (ET-1)-induced organ hypoperfusion after trauma-hemorrhage is improved by estrogen administration, it remains unclear whether estrogen receptor (ER) subtypes play any role in the attenuation of ET-1-induced vasoconstriction in any specific organ bed. To investigate this, isolated perfusion experiments in the heart, liver, small intestine, kidney, and lung were carried out in sham, at the time of maximum bleedout (MBO; i.e., 5-cm midline incision, with removal of 60% of circulating blood volume over 45 min to maintain a mean blood pressure of 40 mmHg), and 2 h after trauma-hemorrhage and resuscitation (T-H/R). Organ-specific ET-1-induced vasoconstriction was evaluated, and the effects of 17beta-estradiol (E2) and ER-specific agonists propylpyrazole triol (PPT; ERalpha agonist) and diarylpropionitrile (DPN; ERbeta agonist) were determined. ET-1 induced the greatest vasoconstriction in sham animals, with the strongest response in the kidneys, followed by the small intestine and liver. ET-1-induced responses were weakest in the heart and lungs. ET-1-induced vasoconstriction was evident at the time of MBO but was significantly decreased at 2 h after T-H/R. ERbeta plays an important role in cardiac performance, as evidenced by improved heart performance (+dP/dt) in the presence of DPN. DPN also induced a greater effect than PPT in the reduction of ET-1-induced vasoconstriction in the kidneys and lungs. In contrast, PPT attenuated ET-1-induced vasoconstriction in the liver, whereas both DPN and PPT were equally effective in the small intestine. The increased +dP/dt values induced by E2, DPN, or PPT were evident at the time of MBO but were significantly decreased at 2 h after T-H/R. These data indicate that the effects of ET-1 on vasoconstriction and the role of ER subtypes in estrogen-induced vasorelaxation are organ specific and temporally specific after trauma-hemorrhage.
... In 1998 new putative estrogen receptor (pER) or ER-gamma has been isolated and purified from mouse liver (RAO 1998). Immunohistochemical analyses detected pER in the ovary, non-reproductive organs (skeletal, neural, vascular, hair and retina cells) and endometrial, prostatic and mammary tumours. ...
Key Words: Ligand inducible transcription factors Nuclear receptors Estrogen receptors Steroid/thyroid receptor superfamily Hormone responsive element Review 1. Nuclear receptor superfamily Members of the nuclear receptor superfamily can be divided into four classes according to their inter-actions with heat-shock proteins, their tendency to form homodimers or heterodimers, and DNA bind-ing specificity. Class Iconsists of the steroid recep-tors with alonger A/B domain (estrogens ERs, glu-cocorticoids GRs, mineralocorticoids MRs, progestins PRs, androgens ARs) which in the absence of bound ligands are sequestered in 9S het-erocomplexes that contain heat-shock proteins (e. g. hsp90, hsp70, p23, p60), immunophilins (e. g. CyP40, .KBP52) and other chaperones (PRATT et al. 1997; KNOBLAUCH et al. 1999). Upon aligand binding, the protease-resistant conformation changes lead to the dissociation of heat-shock proteins and the recep-tors sediment as a4S complex. After dimerization, receptors bind to target hormone responsive elements (HREs) in the promoter region of target genes and they modulate the rate of their transcription (DECHER-ING et al. 2000). In the absence of ligand, the recep-tors shuttle between nucleus and cytoplasm with the constitutive amount of cytoplasmic receptor depen-dent upon the receptor type (DE .RANCO 1991). Class II receptors (thyroid hormone TR, dihydroxyvita-min D 3 VDR, all-trans retinoic acid RAR, 9-cis retinoic acid RXR, and most of the orphan recep-tors) have ashort A/B domain and they do not asso-ciate with heat-shock proteins. They bind tightly to DNA elements consisting of half sites in direct re-peats as homodimers and occasionally as monomers, but they preferentially heterodimerize with RXR in the absence of ligand thus awaiting aconformational activation by ligands in situ (BRTKO et al. 1994a; BRTKO et al. 1994b; PARKER 1995). Class III recep-tors e.g. steroidogenic factor (S.-1) function prima-rily as monomers and cause constitutive transcrip-tion, although some receptors heterodimerize with RXR (JIANG et al. 1997). Class IV receptors such as an orphan receptor hepatocyte nuclear factor 4 (HN.-4) show characteristics of both class Iand class II receptors; since they bind DNA exclusively as monomers and bind half sites in direct repeats (JIANG et al. 1997).
... Estradiol (E) exerts pleiotropic effects on its target tissues. Adding to this pleiotropism are the various kinds of receptors, which are being found and the way in which they interact with each other or other factors [1][2][3][4][5][6][7]. Of these estrogen receptors (ER), alpha and beta (ER␣ and ER) are known to be cytosolic/nuclear and serve as the transcription factors mediating estrogen-induced changes in the gene expression [8]. ...
Estrogens induce rapid (non-genomic) and delayed (genomic) effects on the target cells. The early effects include induction of signal transduction pathway within seconds, whereas the delayed responses require hours and involve transcription and translation. The rapid effects of estradiol (E) on the vaginal epithelial cells (VEC) involved calcium uptake within seconds via the induction of phosphoinositol lipid metabolism as reported in our earlier studies. In this study, we demonstrate the presence of classical estrogen receptors (ER) on the plasma membrane of VEC of the rats. Immunoreactive bands of 67, 56 and 35 kDa are detectable in the membrane fractions (mf) using antibodies recognizing different epitopes of ER alpha. We have also been able to purify a protein having a mass of 67 kDa from the detergent-soluble fraction of the plasma membrane of VEC, which shows properties identical to the classical receptor purified from the cytosolic fraction of the cells. The membrane receptors get dissociated upon binding to the ligand. Besides a role in signal transduction events induced by estradiol, the membrane estrogen receptors may have an important role to play in translocation of the steroid to the cytosolic compartment.
... It is noteworthy that CLMs appear to have an important role in different aspects of neuronal response to injury, such as upregulation of ERα-mediated modulation of caveolin expression (Zschocke et al., 2002), or amyloid precursor protein (APP) accumulation (Bouillot et al., 1996). Adding more complexity to this matter, other relatives of mER with different MWs have been also reported: three estrogen-binding proteins of 55, 37, and 23 kDa in the rat brain, probably related to cytoskeletal function and synaptic remodelling (Zheng and Ramirez, 1997; Ramirez et al., 2001); a 112-kDa cytosolic and nuclear receptor in mouse brain cortex that seems to be regulated in an age-specific manner (Asaithambi et al., 1997); and a heterodimer serine phosphatase (pER) in human and rat neurons with an apparent MW of 81-84 kDa that is not recognised by antibodies to ERα or ERβ, and that has been suggested to participate in non-reproductive estrogenic functions (Rao, 1998). It has also been observed in the plasma membrane of, both, SN56 murine septal and hippocampal-derived HT22 cells, the presence of an 80-kDa protein (Marin et al ., 2003b;Fig. ...
Evidence for a protective role of estradiol in neurodegenerative diseases has steadily increased over the past decade, though the mechanisms of action and the participation of true estrogen receptors (ERs) have proven a complex score. The protective effects of estrogens take place partly through pathways involving canonical ER activation, which is constitutively expressed in many brain regions and is able to initiate gene transcription after specifically binding to estradiol. In addition, non-genomic (or alternative) signalling pathways, involving extranuclear ERs, respond to physiological concentration of estrogens to elicit neuroprotection. Often, rapid activation of intracellular signallers such as mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K) underlie alternative estrogen-induced neuroprotection upon activation of specific binding sites at the plasma membrane. Although the molecular characteristics of these unconventional ERs are still largely unknown, the generally held view maintains that plasma membrane ER (mER) originates from, or is related to, classical nuclear ERs. The present article will review some of the most recent evidence revealing the relevance of alternative mechanisms in estrogen-dependent neuroprotection. Special emphasis will be paid to cellular models of amyloid-beta toxicity where classical and alternative pathways activated by estrogens seem to coexist to orchestrate neuroprotection.
... In addition to a mER␣-like with identical Mw to ER␣ (67 kDa), Western blot analysis of septal and hippocampal neurons also revealed specific higher bands at 80 and 97 kDa that were recognized by most of anti-ER␣ antibodies used. Other examples of extranuclear ERs with high Mw variously sized have been reported in mouse brain cortex (112-kDa) [1], and in human and rat neurons (80-kDa) [16]. A reasonable explanation for the existence of higher bands with immunoaffinity for nuclear ER␣ antibodies may be that mERs could result from post-transcriptional modifications such as glycosylation, which may allow the receptor to be inserted into the plasma membrane. ...
Although it is widely accepted the existence of putative estrogen receptors (ERs) localized at extranuclear domains in the brain, their molecular identity is still unclear. We have previously demonstrated in a murine septal cell line the existence of a membrane-related ER (mER) that participates in estrogen-mediated neuroprotection. To investigate the molecular structure of mER, we have used a battery of antibodies raised against different domains of the classical ERalpha to immunoblot with plasma membrane fractions from septal SN56 and hippocampal HT22 cell lines, and microsomal fractions of mouse septal and hippocampal tissues. The results confirmed that mER is the homologue of its intracellular counterpart ERalpha, suggesting the possibility that both nuclear and extranuclear receptors may share a common origin.
... To date, three ER subunits have been identified: ER-␣, ER-, and ER-␥. The biological relevance for only the ER-␣ and ER- subtypes has been described (16,22,28), whereas very little is known about ER-␥. Vascular endothelium and myocytes express both ER-␣ and ER-, and their local distribution is dependent on both sex difference and anatomical location. ...
Although endothelin-1 (ET-1) induces vasoconstriction, it remains unknown whether 17beta-estradiol (E(2)) treatment following trauma-hemorrhage alters these ET-1-induced vasoconstrictive effects. In addition, the role of the specific estrogen receptor (ER) subtypes (ER-alpha and ER-beta) and the endothelium-localized downstream mechanisms of actions of E(2) remain unclear. We hypothesized that E(2) attenuates increased ET-1-induced vasoconstriction following trauma-hemorrhage via an ER-beta-mediated pathway. To study this, aortic rings were isolated from male Sprague-Dawley rats following trauma-hemorrhage with or without E(2) treatment, and alterations in tension were determined in vitro. Dose-response curves to ET-1 were determined, and the vasoactive properties of E(2), propylpyrazole triol (PPT, ER-alpha agonist), and diarylpropionitrile (DPN, ER-beta agonist) were determined. The results showed that trauma-hemorrhage significantly increased ET-1-induced vasoconstriction; however, administration of E(2) normalized ET-1-induced vasoconstriction in trauma-hemorrhage vessels to the sham-operated control level. The ER-beta agonist DPN counteracted ET-1-induced vasoconstriction, whereas the ER-alpha agonist PPT was ineffective. Moreover, the vasorelaxing effects of E(2) were not observed in endothelium-denuded aortic rings or by pretreatment of the rings with a nitric oxide (NO) synthase inhibitor. Cyclooxygenase inhibition with indomethacin had no effect on the action of E(2). Thus, E(2) administration attenuates ET-1-induced vasoconstriction following trauma-hemorrhage via an ER-beta-mediated pathway that is dependent on endothelium-derived NO synthesis.
... A recent identification of estrogen-binding protein, called putative ER, which has been identified in the brain (Rao 1998), documents the complexity of the estrogen's effects. ...
Estrogens are essential for normal brain function throughout life. The source of estrogens is not only from the periphery, but local production has also been demonstrated in the CNS. Actions of estrogens involve a variety of effects, which include modulation of gene expression, regulation of neurotransmitter release, or direct inter-actions with neurotransmitter receptors. By these effects, estrogens affect neuronal excitability and thus may play an important role in seizure disorders. Although the original clinical as well as animal studies suggest that estrogens have exclusively proconvulsant properties, it has now become clear that estrogens also produce anticonvulsant effects. These opposite effects of estrogens on seizures may depend on treatment duration, latency prior to seizure testing, mode of administration, estrogen dose and hormonal status, estrogenic species, the region/neurotransmitter system involved, seizure type/model used, and sex. Animal data also suggest that estrogens, specifically beta-estradiol, have neuroprotective effects on seizure-induced hippocampal damage. Further studies are necessary to understand the role of estrogens in seizure disorders. Such under-standing is important, especially for women with epilepsy, to make qualified decisions regarding administration of contraceptives and hormonal replacement therapy as well as for the design of new therapeutic strategies for better seizure control and prevention of seizure-induced neuronal damage.
... Complicating matters is the recent identification in the brain and other tissues of a heterodimeric estrogen binding protein, termed the putative ER (pER) (81-84 kDa) (68). pER consists of two covalently bound subunits (61-67 kDa and 17-27 kDa) and has been localized on the plasma or nuclear membrane of some cells; in the cytoplasm and/or nucleus of others. ...
Until 1996, when estrogen receptor (ER)-beta was discovered, life seemed simple. The gonadal steroid hormone 17 beta-estradiol had one receptor, the ER, a ligand-inducible nuclear transcription factor. ER variants, the result of base pair insertions, transitions, and deletions, as well as alternative splicing, were considered abnormal and a prominent feature of breast cancer. Since then, like many other scientific beliefs, this concept has increased dramatically in complexity, and we are now faced with an ever-increasing array of estrogen-binding proteins, putative ERs, in the brain as well as in the extraneural targets of estrogen. The end is unlikely to be in sight. Some of these putative receptors have been localized to plasma or nuclear membranes, and others to the cytoplasm and/or nucleus. The molecular characteristics of membrane ERs are still in question, and, in most instances, the proteins have not been sequenced or cloned. However, based on transfection and immunohistochemistry, the generally held view, if not dogma, maintains that both nuclear and plasma membrane-associated ERs probably originate from the same gene and transcript that produce the classical intranuclear receptors ER-alpha and ER-beta. However, the physiological relatedness of this observation remains open to question. This review addresses evidence that, in addition to ER-alpha and ER-beta, there exist a variety of non-ER-alpha/non-ER-beta nuclear, cytoplasmic, and plasma membrane ERs in the brain, including G protein-coupled receptors; a novel, developmentally regulated, membrane-associated ER, ER-X; a functional, truncated ER-alpha variant, ER-46; and a putative ER that is immunochemically, structurally, and functionally completely distinct from ER-alpha and ER-beta.
... Furthermore, other ERs with different molecular features have also been identified, such as ER-X [9] and GPR30, a seven-transmembrane G-protein-coupled receptor localized at the endoplasmic reticulum [10]. In addition, some examples, including our own, in different neuronal types have detected multiple bands of higher Mw than classical ER␣ that are also recognized by anti-ER␣ antibodies [11,12]. Empirically, these bands may be explained by post-transcriptional modifications, such as glycosylation, which may facilitate ER insertion at the plasma membrane, although the 80-kDa receptor observed in septal and hippocampal cells is neither a glycoprotein [8] nor the product of ubiquitin-or SUMO-binding (unpublished data). ...
Some evidences have demonstrated the participation of estrogen receptors (ERs) in rapid, non-genomic actions of estrogen to promote neuroprotection against different toxic agents. However, there is still very little information about the structural nature of these receptors and the manner these proteins may be integrated into the plasma membrane. One of the plausible possibilities is that they may be localized in lipid rafts microstructures where they would be associated with other, still unknown, molecules which may modulate their physiological activities related to cell survival. In this work, we have identified in caveolar fractions of murine septal and hippocampal neurons a membrane-related ER shown to physically interact with, both, a voltage-dependent anion channel and scaffold protein caveolin-1.
... To date, three subtypes of ERs have been identified: ER-!, ER-", and ER-+. The biological relevance of the ER-! and ER-" subunits has been described (23,24); however, little is known regarding ER-+. ...
Although 17beta-estradiol (estrogen) and estrogen receptor (ER) agonist administration after trauma-hemorrhage improves cardiac function, it remains unknown what the optimal estrogen or ER agonist dosage is to elicit this beneficial effect. To study this, the dose-dependent effects of estrogen, propylpyrazole triol (ER-alpha agonist), and diarylpropionitrile (DPN; ER-beta agonist) on heart performance (+dP/dt) were determined in sham rats and in experimental animals at the time of maximal bleedout (MBO) or at 2 h after trauma-hemorrhage. The results showed that estrogen and DPN induced dose-dependent increases in the maximal rate of left ventricular pressure increase (+dP/dt) in all groups, whereas propylpyrazole triol was ineffective at all doses. The maximal dose and the 50% effective dose of DPN were approximately 100-fold lower than those of estrogen. The half-life of estrogen in plasma was approximately 25 min in sham and MBO groups. A positive correlation between the estrogen-induced increase in +dP/dt and survival in MBO rats were observed. These results collectively suggest that the salutary effects of estrogen on cardiac performance are dose-dependent and mediated via ER-beta.
Background and objectives
Menstrual abnormalities and shortened reproductive lifespan are associated with shorter life expectancy and higher cardiovascular and osteoporosis risk in the general population, although the magnitude of these reproductive factor irregularities in females with CKD is unclear. This systematic review and meta-analysis aimed to summarize the current knowledge regarding menstrual abnormalities and reproductive lifespan among females with CKD.
Design, setting, participants, & measurements
A comprehensive bibliographic search (MEDLINE, Embase, and Cumulative Index to Nursing and Allied Health Literature [CINAHL]) was completed from database inception to February 2022 to identify all original articles reporting on females of reproductive age with nondialysis-dependent/nonkidney transplant CKD, dialysis-dependent CKD, or kidney transplantation and menstruation patterns, age of menarche, and/or menopause. Data extraction and study quality assessment were completed in duplicate. Random effects meta-analyses were used to derive pooled proportions estimates.
Results
Forty-six studies were identified, and 35 were meta-analyzed, stratified by KRT modality and reported outcome. Menstrual abnormalities were present in 19%–47% of patients on hemodialysis and 75% of patients on peritoneal dialysis. Kidney transplantation was associated with a 7%–30% decrease in menstrual abnormalities. Reproductive lifespan was 32 years (95% confidence interval, 30 to 34 years). Although significant heterogeneity was present, study quality ranged from fair to good, and no evidence of publication bias was noted.
Conclusions
Menstrual abnormalities and shorter reproductive lifespan are common in females with CKD, although kidney transplantation may improve menstrual health.
Estrogens are hormones with wide-ranging and significant biological effects on many tissues. Major target organs are the reproductive tract, genitals, bone, blood vessels, and skin. In humans, estrogens influence all skin elements in various ways, but mostly the dermal papilla (DP) and the connective tissue are affected. Estrogens increase overall skin thickness, increase the collagen content of the dermis, increase hair and skin pigmentation, enhance vascularization of the dermis [1], augment the mitotic activity of the epidermis [2], reduce the activity of the sebaceous glands, delay skin aging [3] and increase the water and hyaluronic acid content of the skin [4]. After menopause, the dramatic decrease in the amount of estrogens in the serum results in significant “catabolic” processes in the female skin and body. These include a decline by 1–2% per year of skin collagen content, reduction in skin thickness, in the metacarpal index, and forearm bone mineral content [5, 6]. However, there is still a huge disparity in our understanding of how estrogens exert their actions, particularly in non-reproductive tissues, such as the skin [3].
This chapter describes basic principles of receptor action including definitions of agonists, antagonists, inverse agonists, including basic pharmacology of receptor binding, activation and inhibition. All classes of receptors relevant to endocrinology are described, organized by receptor class, and sometimes subclass. Each class/subclass has a general description of receptor structure, expression, subcellular localization, binding, activation, downstream signaling, and deactivation. For a given class of receptors, nonendocrine receptors and ligands of the same class may be described where relevant. For example, in the description of G protein–coupled receptors the variety of ligands is described, both endocrine and nonendocrine including light, odorants and pheromones, small molecules, and proteins. Germline mutations of each receptor (whether activating or inactivating) are described along with the resulting endocrine disorder and its phenotype. In some cases germline mutations causing syndromes that do not have an endocrine phenotype are listed but not fully described. Genotype phenotype correlations are discussed where relevant. Treatment of each disorder may be briefly described but is not the focus of this chapter.
Normal pregnancy is associated with dramatic increases in uterine blood flow to facilitate the bidirectional maternal-fetal exchanges of respiratory gases and to provide the sole nutrient support for fetal growth and survival. The mechanism(s) underlying pregnancy-associated uterine vasodilation remains incompletely understood, but this is associated with elevated estrogens that stimulate specific estrogen receptors (ER)-dependent vasodilator production in uterine artery (UA). The classical ERs (ERα and ERβ) and the plasma-bound G protein-coupled ER (GPR30/GPER) are expressed in UA endothelial cells and smooth muscle cells, mediating the vasodilatory effects of estrogens through genomic and/or nongenomic pathways that are likely epigenetically modified. Activation of these three ERs by estrogens enhances endothelial production of nitric oxide (NO) that has been shown to play a key role in uterine vasodilation during pregnancy. However, local blockade of NO biosynthesis only partially attenuate estrogen-induced and pregnancy-associated uterine vasodilation, suggesting mechanisms other than NO exist to mediate uterine vasodilation. In this review, we summarized the literature on the role of NO in ER-mediated mechanisms controlling estrogen-induced and pregnancy-associated uterine vasodilation and our recent work on a "new" UA vasodilator hydrogen sulfide (H2S) that has dramatically changed our view of how estrogens regulate uterine vasodilation in pregnancy.
Intensive epidemiological studies have identified a number of genetic risk factors associated with breast cancer, including evidence of BRCA1 and BRCA2 susceptibility genes, familiar history of cancer in the breast, ovary or endometrium and individual history of breast diseases [1]. An increased risk has also been associated with early onset of menstruation, nulliparity or delayed first childbirth, short duration of breast feeding, late menopause, use of hormone replacement therapy and increased bone density [2–4]. A principal culprit common for all these endocrine-related risk factors is the prolonged exposure to female sex hormones [5–8]. The hormonal influences have been mainly attributed to unopposed exposure to elevated levels of estrogens [5], as has been indicated for a variety of female cancers, namely, vaginal, hepatic and cervical carcinomas [9–11]. Exposure to estrogens, particularly during the critical developmental periods (e.g., in utero, puberty, pregnancy, menopause), also affects affective behaviors (e.g., depression, aggression, alcohol intake) and increases breast cancer risk [12].
Numerous studies indicate that estrogens are crucial in normal brain functioning and preservation against different injuries. At the neuronal membrane, estrogens, binding to estrogen receptors (ERs) or other surface targets, exert rapid actions involving a plethora of signaling pathways that may converge in neuronal survival. Emerging work reveals that at least part of these actions may require the compartmentalization of ERs in signaling platforms, composed of macromolecular signaling proteins and particular lipid composition integrated in lipid rafts. These particular microstructures may provide the optimal microenvironment to trigger multiple ER interactions that may be crucial for neuroprotection against different brain impairments, such as Alzheimer's disease (AD). In this order of ideas, recent evidence has demonstrated that a membrane ER (mER) physically interacts with a voltage-dependent anion channel (VDAC) in lipid rafts from septal, hippocampal and cortical neurons, and these interactions may have important consequences in the alternative mechanisms developed by estrogens to achieve neuroprotection against amyloid beta (Aβ)-induced toxicity. This review includes a survey of some of the rapid mechanisms developed by estrogen to prevent neuronal death, and the ER interactions that are involved in the structural maintenance and signal transduction mechanisms important for neuronal survival against AD neuro-pathology. A special emphasis is put on the biological relevance of neuronal membrane VDAC in Aβ-related neurotoxicity, and the potential modulation of this channel as a part of a signaling complex with mER, which may be modified in AD brains.
The aim of this study was to explore the effects of applying force during the different stages of the estrous cycle on the dynamic expression of alpha estrogen receptors (ERα) and the rate of tooth movement, to provide insight into the timing of effective treatment. A repeated, intermittent force was loaded on the first upper molar of female rats five times during specific stages of the estrous cycle. The distance of tooth movement was measured. ERα protein and mRNA levels in the periodontal tissue were measured, and the data were analyzed by ANOVA, Student–Newman–Keuls (SNK) and cosinor analysis. The results showed that ERα expression varied among the subgroups that received force during different stages of the estrous cycle and exhibited an infradian rhythm in both groups. There were significant variations in the amount of tooth movement among the four subgroups (P < 0.01). We conclude that the highest ERα expression and the fastest periodontal remodeling were in the rats that received force during estrus.
End-stage renal disease is associated with severe abnormalities in reproductive function. However, the abnormalities are reversed by successful kidney transplantation. The aim of the present study was to compare hormonal levels between recipients with successful kidney transplantations and healthy women with the same gynecologic conditions.
The study group consisted of 31 women of reproductive age with end-stage renal disease who underwent successful kidney transplantation. The ratio of the control group, composed of healthy woman, to the study group was 3:1 matched for age and symptoms.
Abnormal bleeding (n = 14) and infertility were the most common gynecologic conditions in kidney transplant recipients. The levels of estrogen (E2) and follicle-stimulating hormone (FSH) in the study group were higher than in the control group, but the levels of progesterone (P4) and luteinizing hormone (LH) were lower in the study group than in the control group. There were no significant differences in prolactin and thyroid-stimulating hormone between the two groups. The incidence of infertility in patients who receive steroid was higher than those with no steroid use (P = .007).
Compared with healthy age- and symptom-matched women, female kidney transplant recipients have increased levels of E2 and FSH and decreased levels of P4 and LH. These differences in hormone profiles may predispose kidney transplant recipients to increased risk of gynecologic pathologies.
Estrogens exert a plethora of actions conducted to brain preservation and functioning. Some of these actions are initiated in lipid rafts, which are particular microstructures of the plasma membrane. Preservation of lipid raft structure in neurons is essential for signal transduction against different injuries, such as Alzheimer's disease (AD). These membrane structures appear to be disrupted as this neuropathology evolves, and that may largely contribute to dysfunction of raft resident proteins involved in intracellular signalling. This review includes a survey of some protein interactions that are involved in the structural maintenance and signal transduction mechanisms for neuronal survival against AD. Particularly relevant are the rapid mechanisms developed by estrogen to prevent neuronal death, through membrane estrogen receptors (mER) interactions with a voltage-dependent anion channel (VDAC) and other protein markers within neuronal lipid rafts. These interactions may have important consequences in estrogen mechanisms to achieve neuroprotection against amyloid beta (Abeta-induced toxicity).
This paper describes three distinct estrogen receptor (ER) subtypes: ERalpha, ERbeta, and a unique type, ERgamma, cloned from a teleost fish, the Atlantic croaker Micropogonias undulatus; the first identification of a third type of classical ER in vertebrate species. Phylogenetic analysis shows that ERgamma arose through gene duplication from ERbeta early in the teleost lineage and indicates that ERgamma is present in other teleosts, although it has not been recognized as such. The Atlantic croaker ERgamma shows amino acid differences in regions important for ligand binding and receptor activation that are conserved in all other ERgammas. The three ER subtypes are genetically distinct and have different distribution patterns in Atlantic croaker tissues. In addition, ERbeta and ERgamma fusion proteins can each bind estradiol-17beta with high affinity. The presence of three functional ERs in one species expands the role of ER multiplicity in estrogen signaling systems and provides a unique opportunity to investigate the dynamics and mechanisms of ER evolution.
The futile cycling of estrone sulfate (E(1)S) and estrone (E1) was investigated in the recirculating, perfused, rat liver preparation. Although E(1)S was not distributed into bovine erythrocytes, the compound was highly bound to albumin [4% bovine serum albumin (BSA), unbound fraction of 0.03 +/- 0.01]. By contrast, E1 was bound and metabolized to estradiol (E2) by bovine erythrocytes, with metabolic clearances of 0.061 to 0.069 ml/min when normalized to the hematocrit. Due to strong binding of E1 to albumin, BSA (4%) greatly reduced the red cell clearance to a minimum (0.0024 to 0.0031 ml/min/unit of hematocrit). Despite the low unbound fractions of E(1)S (0.027 +/- 0.004) and E1 (0.036 +/- 0.006), clearances of the simultaneously delivered tracers [(3)H]E(1)S and [(14)C]E1 in perfusate (4% BSA and 20% erythrocytes) by the recirculating, perfused rat liver (flow rate of 0.91 +/- 0.1 ml/min/g of liver) were high (0.53 +/- 0.08 and 0.85 +/- 0.2 ml/min/g of liver, respectively). Although low levels of [(3)H]E1 were observed following the tracer [(3)H]E(1)S, both parent and metabolite species displayed similar decay half-lives that were characteristic of compounds undergoing futile cycling. The same decay profile was observed for [(14)C]E(1)S but the half-life of administered [(14)C]E1 was shorter in comparison. A series-compartment liver model that incorporated previously noted heterogeneity in estrone sulfation and glucuronidation activities among periportal and perivenous hepatocytes, and homogeneity in sinusoidal transport and desulfation was used to explain the discrepant half-lives. The model described a high partitioning of E1 in the endoplasmic reticulum and the segregation of estrone sulfation activities in the cytosolic space from the desulfation and glucuronidation activities in the endoplasmic reticulum space.
Blood vessel homeostasis involves a complex interplay between inflammatory signals, hormones, and other mediators. Recent research suggests that although atherosclerosis is primarily a problem of impaired lipid regulation, the very processes of cholesterol and triglyceride metabolism are intrinsically tied to inflammatory and hormonal regulatory signals. Similarities between inflammatory and endocrine disturbances in systemic lupus and the predicted consequences for vascular regulation help explain the high incidence of premature atherosclerosis in lupus. Atherosclerosis in systemic lupus, then, may be a consequence of imbalances in what are intrinsic homeostatic mechanisms, rather than a result of externally superimposed pathologic changes.
Estrogens play a crucial role in the development and evolution of human breast cancer. However, it is still unclear whether estrogens are carcinogenic to the human breast. There are three mechanisms that have been considered to be responsible for the carcinogenicity of estrogens: receptor-mediated hormonal activity, a cytochrome P450 (CYP)-mediated metabolic activation, which elicits direct genotoxic effects by increasing mutation rates, and the induction of aneuploidy by estrogen. To fully demonstrate that estrogens are carcinogenic in the human breast through one or more of the mechanisms explained above it will require an experimental system in which, estrogens by itself or one of the metabolites would induce transformation phenotypes indicative of neoplasia in HBEC in vitro and also induce genomic alterations similar to those observed in spontaneous malignancies. In order to mimic the intermittent exposure of HBEC to endogenous estrogens, MCF-10F cells that are ERalpha negative and ERbeta positive were first treated with 0, 0.007, 70 nM and 1 microM of 17beta-estradiol (E(2)), diethylstilbestrol (DES), benz(a)pyrene (BP), progesterone (P), 2-OH-E(2), 4-hydoxy estradiol (4-OH-E(2)) and 16-alpha-OH-E(2) at 72 h and 120 h post-plating. Treatment of HBEC with physiological doses of E(2), 2-OH-E(2), 4-OH-E(2) induce anchorage independent growth, colony formation in agar methocel, and reduced ductulogenic capacity in collagen gel, all phenotypes whose expression are indicative of neoplastic transformation, and that are induced by BP under the same culture conditions. The presence of ERbeta is the pathway used by E(2) to induce colony formation in agar methocel and loss of ductulogenic in collagen gel. This is supported by the fact that either tamoxifen or the pure antiestrogen ICI-182,780 (ICI) abrogated these phenotypes. However, the invasion phenotype, an important marker of tumorigenesis is not modified when the cells are treated in presence of tamoxifen or ICI, suggesting that other pathways may be involved. Although we cannot rule out the possibility, that 4-OH-E(2) may interact with other receptors still not identified, with the data presently available the direct effect of 4-OH-E(2) support the concept that metabolic activation of estrogens mediated by various cytochrome P450 complexes, generating through this pathway reactive intermediates that elicit direct genotoxic effects leading to transformation. This assumption was confirmed when we found that all the transformation phenotypes induced by 4-OH-E(2) were not abrogated when this compound was used in presence of the pure antiestrogen ICI. The novelty of these observations lies in the role of ERbeta in transformation and that this pathway can successfully bypassed by the estrogen metabolite 4-OH-E(2). Genomic DNA was analyzed for the detection of micro-satellite DNA polymorphism using 64 markers covering chromosomes (chr) 3, 11, 13 and 17. We have detected loss of heterozygosity (LOH) in ch13q12.2-12.3 (D13S893) and in ch17q21.1 (D17S800) in E(2), 2-OH-E(2), 4-OH-E(2), E(2) + ICI, E(2) + tamoxifen and BP-treated cells. LOH in ch17q21.1-21.2 (D17S806) was also observed in E(2), 4-OH-E(2), E(2)+ICI, E(2)+tamoxifen and BP-treated cells. MCF-10F cells treated with P or P+E(2) did not show LOH in the any of the markers studied. LOH was strongly associated with the invasion phenotype. Altogether our data indicate that E(2) and its metabolites induce in HBEC LOH in loci of chromosomes 13 and 17, that has been reported in primary breast cancer, that the changes are similar to those induced by the chemical carcinogen (BP) and that the genomic changes were not abrogated by antiestrogens.
This study examined the effects of long-term exposure to the endocrine-disrupting compounds (EDCs) Bisphenol-A (BPA) and Octylphenol (OP) on gonadotrophin secretion in pre-pubertal female sheep. Four-week-old, female lambs were randomly allocated to four groups (n=6), and twice each week treated with i.m. injections of either corn oil (vehicle controls), diethylstilbestrol (DES; 0.175mg/kg), BPA (3.5mg/kg) or OP (3.5mg/kg). After 5 weeks of treatment, animals were ovariectomized (ovx) and ovary weights recorded. Two weeks later, blood samples were collected from lambs every 15min for 6h, for LH pulse analysis. Animals were then euthanased and adrenal and kidney weight recorded. An age-related increase in tonic LH secretion was noted in Control, BPA- and OP-treated lambs, but was absent in DES-treated lambs. Following ovx, LH secretion increased in all except DES-treated lambs; FSH concentrations increased in all groups. BPA and DES significantly suppressed LH pulse frequency (C: 6.7+/-0.3pulses/6h, DES: 1.5+/-0.8pulses/6h, BPA: 2.3+/-0.8pulses/6h) and amplitude (C: 7.1+/-1.0ng/ml, DES: 1.9+/-0.6ng/ml, BPA: 1.6+/-0.4ng/ml). OP had no effect on LH secretion (Frequency: 5.8+/-0.5pulses/6h, amplitude: 8.0+/-2.0ng/ml). Ovary weight was similar among all groups. Results show that chronic in vivo exposure of prepubertal female lambs to BPA, at levels lower than those reported previously, can have significant effects on LH secretion that are comparable to those seen following exposure to the known xenoestrogen, DES. Exposure to an equal dose of the EDC OP, over the equivalent period of time was without effect on gonadotropin secretion in the prepubertal ewe lamb. These results indicate that exposure of prepubertal female lambs to the EDC BPA can induce significant effects on gonadotropin secretion, the potential long-term effects of exposure and the effects of these changes on reproductive performance and efficacy, therefore, merit further study.
This review summaries recent evidence from clinical and basic science studies on estrogen central nervous system. For decades, estrogen was thought of only as a "sex hormone" and plays a fundamental role in regulating behavioral and physiological events. In recent years, accumulated evidence shows that estrogen also plays very important roles in the brain. Recent basic science studies show that estrogen treatment decreases the neuronal response to various forms of insult through the regulation of both estrogen synthesis and estrogen receptor expression in the brain. Some clinical evidence also suggests that estrogen deprivation might be implicated as a risk factor in various neurodegenerative diseases. Estrogen may play a neuroprotective role through estrogen dependent alterations in cell survival, enhancement of synaptic transmission and neurogenesis. Some of the mechanisms underlying these effects are independent of the classical nuclear estrogen receptors and involve direct modulation of neurotransmitter receptor function, or anti-oxidant activities of estrogen. It is controversial whether estrogen is indicated in the prevention or treatment of various brain disorders such as Alzheimer's disease. The conflicting findings suggest that several variables, including age, estrogen dose and formulation, the length of treatment, may determine whether the potential benefits of estrogen treatment would outweigh the associated risks.
The effects of estrogen on responsive cells and organismic development have long been known and well documented. Estrogen binds to the estrogen receptor, a dimer of the complex translocates to the nucleus, binds specific DNA elements and regulates the transcription of particular genes, a process that takes some time to achieve. One of the curious findings of intense estrogen research-that some estrogen-dependent effects appear to occur immediately-has led to the conclusion that quick responses are mediated by an estrogen binding protein(s) in the cytoplasm or located at the plasma membrane. Hasbi et al. chart the course through which several characterized estrogen binding proteins (not necessarily sharing sequence similarity beyond the estrogen binding domain) were discovered, including most notably, the orphan G protein-coupled receptor GPR30. And what is to be made of differing accounts of GPR30's intracellular whereabouts?
Estrogen treatment during middle-age postpones memory impairments, which depend on the hippocampus. However, estrogen responsiveness diminishes with advanced age. The challenge remains to determine, which processes are important for delaying brain aging and the mechanisms for decreased sensitivity. Estrogen can influence transcription through estrogen receptors (e.g., ERalpha and ERbeta) and membrane effects on rapid signal transduction cascades ultimately influencing the phosphorylation state of transcription factors. In middle-aged animals, the membrane effects involve Ca2+ and G-protein cascades, which rapidly counteract senescent physiology. Moreover, estrogen induces transcription for elements of signal transduction cascades that decline with age. Together, the rapid and genomic influences promote synaptic transmission and cell growth. Thus, interruption of genomic/membrane interactions due to loss of ERs, disruption of the hormone cycle, or uncoupling of the hormone/receptor system associated with extended exposure to estrogen could contribute to a decline in these biological pathways during aging.
While it is undisputed that estrogens (17β-estradiol, E2) are mainly involved in skin physiology and operate as potent hair growth modulators, our knowledge about the estrogen target cells in skin and exact signaling pathways is still very limited. The current review provides an overview of estrogen effects on hair follicle cycling, cutaneous expression of estrogen receptors, and potential functions of estrogens in hair biology. We discuss potential target genes of estrogen receptor-mediated signaling in the skin, explore the interplay of estrogens with other hormones, growth factors and enzymes, and define major open questions in this intriguing and far too long neglected area of hair research.
Östrogene (17β-Östradiol, E2) haben maßgeblichen Einfluß auf die Physiologie der Haut und das Haarwachstum, es mangelt jedoch an grundlegenden Kenntnissen über die genauen Wirkungsmechanismen und Zielzellen, die diesen Einflüssen zugrunde liegen. Die Effekte von Östrogenen auf den Haarfollikelzyklus, die unterschiedlichen Expressionsmuster der Östrogenrezeptoren im Haarfollikel von Mensch und Maus, sowie bekannte und vermutete Funktionen der Östrogene in der Haarbiologie werden in dieser Arbeit vorgestellt. Potentielle Zielgene sowie die Einflüsse der zahlreichen Modulatoren, wie Wachstumsfaktoren, Hormone und Enzyme in der Vermittlung von Östrogen-Effekten auf die Haut und den Haarfollikel werden diskutiert und offene Fragen erörtert, deren Klärung für die Haarforschung von großer Bedeutung wäre.
One of the effects of an improved general health state after successful kidney transplantation in women of reproductive age is recurrence of regular menstrual function.
Sixty-three ovarian cycles in female kidney transplant recipient, aged from 18 to 44 years, at 1.5 to 15 years after transplantation, were compared with 50 cycles of healthy women. We monitored the menstrual cycle duration as well as follicle stimulation hormone (FSH), leutinizing hormone (LH), estradiol, progesterone, prolactin, creatinine, and testosterone serum concentrations as well as hematocrit and obtained sonographic observations of ovarian follicle growth and ovulation.
Of the recipients, 68.1% had regular menstrual cycles. Ovulatory cycles were observed in 45% of patients. Estradiol concentration established in the first phase of the cycle was significantly higher among the transplanted group (mean value 226.86 +/- 97.45 pg/mL vs 140.00 +/- 61.00 in the controls). A significantly lower level of progesterone (15.05 +/- 17.34 ng/mL vs 30.79 +/- 18.48 ng/mL in the controls) and of testosterone were observed in kidney recipients. Other hormonal parameters did not differ significantly between the groups.
Similar serum FSH, LH, and prolactin concentrations as well as increased levels of estrogens were observed in kidney transplant recipients compared with healthy nonrecipients. The rate of ovulatory cycles in regularly menstruated kidney graft recipients was similar to that of healthy women. Stabilization of graft function resulted in restoration of normal ovarian hormone metabolism and ovulatory cycles in female kidney transplanted recipients.
A high rate of endometrial hyperplasia, an estrogen-dependent premalignant lesion of the endometrium, has been observed among female kidney allograft recipients. The aim of the study was to evaluate the incidence of endometrial abnormalities among renal transplanted women with abnormal uterine bleedings.
A retrospective analysis compared 45 renal transplanted women who underwent dilatation and curettage for abnormal uterine bleeding between January 1999 and September 2004 with 90 consecutive, nontransplanted, control patients who underwent dilatation and curettage for the same reason in 2004.
Thirty-one cases (69%) of endometrial hyperplasia and one case (2%) of endometrial cancer were detected among the renal allograft recipients. The majority of transplant patients (28 cases, 62%) developed endometrial hyperplasia without atypia successfully treated with progestagens. There were 29 cases (32%) of hyperplasia without atypia, 2 cases (1%) of atypical hyperplasia, and 4 cases (4%) of endometrial cancer in the control group.
Renal transplanted women seem to have an extremely high risk of endometrial hyperplasia. The majority of cases may be successfully treated with progestagens. Immunocompromised renal graft recipients, however, show other risk factors for carcinogenesis. Thus, frequent clinical surveillance should be recommended in this group of patients, also because there is conflicting evidence with regard to the risk of progression to carcinoma among untreated patients.
End-stage renal failure is associated with amenorrhaea and extremely reduced fertility. After successful kidney transplantation restoration of menstrual function is observed. The aim of the study was to investigate ovarian function and menstrual cycles in kidney-transplanted women of reproductive age.
55 ovarian cycles in kidney transplanted women, aged 18-40 years, being one to five years after transplantation, were analyzed and compared with 50 cycles of healthy women. The duration of the cycles as well as FSH, LH, estradiol, progesterone, prolactin and testosterone serum concentrations were monitored. Simultaneously the presence of ovulation was evaluated with repeated sonographic examinations.
Regular menstrual cycles were observed in 72.7% of kidney transplanted women. The rates of ovulatory cycles were similar in the study group and the control: 65% and 70% respectively. Mean estradiol level in the follicular phase of the cycle was significantly higher in transplant patients (205.9, SD 160.22 vs 135.9 pg/ml, SD 68.34 in the control). Significantly lower levels of progesterone (13.2 ng/ml, SD 14.2 vs 26.7 ng/ml, SD 14.1 in the control) and testosterone were observed in kidney recipients. Other hormonal parameters did not differ significantly between the groups.
The rate of ovulatory cycles in regularly menstruated kidney transplanted patients is similar to that of healthy women. Similar serum FSH, LH and PRL concentrations as well as increased levels of estrogens are observed in kidney graft recipients in comparison to healthy non-recipients. Increased levels of estrogens put that group of patients at risk of gynecological pathologies.
For many decades, androgens have dominated endocrine research in hair growth control. Androgen metabolism and the androgen receptor currently are the key targets for systemic, pharmacological hair growth control in clinical medicine. However, it has long been known that estrogens also profoundly alter hair follicle growth and cycling by binding to locally expressed high-affinity estrogen receptors (ERs). Besides altering the transcription of genes with estrogen-responsive elements, 17beta-estradiol (E2) also modifies androgen metabolism within distinct subunits of the pilosebaceous unit (i.e., hair follicle and sebaceous gland). The latter displays prominent aromatase activity, the key enzyme for androgen conversion to E2, and is both an estrogen source and target. Here, we chart the recent renaissance of estrogen research in hair research; explain why the hair follicle offers an ideal, clinically relevant test system for studying the role of sex steroids, their receptors, and interactions in neuroectodermal-mesodermal interaction systems in general; and illustrate how it can be exploited to identify novel functions and signaling cross talks of ER-mediated signaling. Emphasizing the long-underestimated complexity and species-, gender-, and site-dependence of E2-induced biological effects on the hair follicle, we explore targets for pharmacological intervention in clinically relevant hair cycle manipulation, ranging from androgenetic alopecia and hirsutism via telogen effluvium to chemotherapy-induced alopecia. While defining major open questions, unsolved clinical challenges, and particularly promising research avenues in this area, we argue that the time has come to pay estrogen-mediated signaling the full attention it deserves in future endocrinological therapy of common hair growth disorders.
The high rate of abnormal uterine bleeding associated with endometrial hyperplasia has been observed in women after kidney transplantation. The great majority of these premalignant lesions regress after conservative treatment, mostly with progestagens. There are cases, however, of persistent or recurrent hyperplasia requiring operative treatment.
We report seven cases of endometrial hyperplasia in kidney graft recipients treated with hysterectomy after failure of conservative treatment. The presence of typical risk factors of endometrial hyperplasia and cancer were analyzed as well as their clinical courses and treatment methods.
The age of the patients ranged from 35 to 50 years (mean, 42.7). Among typical risk factors, we observed obesity, diabetes, arterial hypertension, and nulliparity in the study group. All patients reported abnormal uterine bleeding and developed anemia. Women underwent two to four dilatation and curettage procedures. Progestagens (medroxyprogesterone or lynesterol) were administered for 3 to 9 months. The initial treatment was ineffective in two cases; in the remaining five cases endometrial hyperplasia recurred within 3 to 12 months. Pathologic findings after hysterectomy in all patients confirmed non-atypical endometrial hyperplasia.
Hysterectomy is the treatment of last resort for premalignant endometrial lesions. It should be considered in all cases of recurrent or persistent endometrial hyperplasia. It may protect immunocompromised kidney graft recipients from heavy bleeding, severe anemia, and most of all, the of endometrial cancer development.
Background
Oestrogen use by postmenopausal women has many health benefits, but findings on the effect of oestrogen in Alzheimer's disease are conflicting. Oestrogen promotes the growth and survival of cholinergic neurons and could decrease cerebral amyloid deposition, both of which may delay the onset or prevent Alzheimer's disease. To investigate whether use of oestrogen during the postmenopausal period affects the risk of Alzheimer's disease, we studied 1124 elderly women who were initially free of Alzheimer's disease, Parkinson's disease, and stroke, and who were taking part in a longitudinal study of ageing and health in a New York City community.
Methods
Relative risks and age-at-onset distributions were calculated from simple and adjusted Cox proportional hazards models. Standard annual clinical assessments and criterion-based diagnoses were used in follow-up (range 1–5 years).
Findings
Overall, 156 (12·5%) women reported taking oestrogen after onset of menopause. The age at onset of Alzheimer's disease was significantly later in women who had taken oestrogen than in those who did not and the relative risk of the disease was significantly reduced (9/156 [5·8%] oestrogen users vs 158/968 [16·3%] non-users; 0·40 [95% CI 0·22–0·85], p<0 01), even after adjustment for differences in education, ethnic origin, and apolipoprotein-E genotype. Women who had used oestrogen for longer than 1 year had a greater reduction in risk; none of 23 women who were taking oestrogen at study enrolment has developed Alzheimer's disease.
Interpretation
Oestrogen use in postmenopausal women may delay the onset and decrease the risk of Alzheimer's disease. Prospective studies are needed to establish the dose and duration of oestrogen required to provide this benefit and to assess its safety in elderly postmenopausal women.
Large numbers and large quantities of endocrine-disrupting chemicals have been released into the environment since World War II. Many of these chemicals can disturb development of the endocrine system and of the organs that respond to endocrine signals in organisms indirectly exposed during prenatal and/or early postnatal life; effects of exposure during development are permanent and irreversible. The risk to the developing organism can also stem from direct exposure of the offspring after birth or hatching. In addition, transgenerational exposure can result from the exposure of the mother to a chemical at any time throughout her life before producing offspring due to persistence of endocrine-disrupting chemicals in body fat, which is mobilized during egg laying or pregnancy and lactation. Mechanisms underlying the disruption of the development of vital systems, such as the endocrine, reproductive, and immune systems, are discussed with reference to wildlife, laboratory animals, and humans.
Spontaneous prostatic hyperplasia in the beagle appears to progress with age from a glandular to a cystic histological appearance. Prostatic hyperplasia can be induced in young beagles with intact testes by treatment for 4 mo with either dihydrotestosterone or 5 alpha-androstane-3 alpha, 17 beta-diol, alone, or with either of these steroids in combination with 17 beta-estradiol. In contrast, the induction of prostatic hyperplasia in young castrated beagles, in which the gland had been allowed to involute for 1 mo, requires the administration of both 17 beta-estradiol and either 5 alpha-androstane-3 alpha, 17 beta-diol or dihydrotestosterone. Testosterone and 17 beta-estradiol, either singly or in combination, did not produce the hyperplastic condition in intact or castrated beagles. The experimentally induced prostatic hyperplasia is identical in pathology to the glandular hyperplasia that occurs naturally in the aging dog with intact testes. However, cystic hyperplasia was not produced by any of the treatments tested in young animals.
The primary sequence of the microtubule-associated protein tau contains multiple repeats of the sequence -X-Ser/Thr-Pro-X-, the consensus sequence for the proline-directed protein kinase (p34cdc2/p58cyclin A). When phosphorylated by proline-directed protein kinase in vitro, tau was found to incorporate up to 4.4 mol of phosphate/mol of protein. Isoelectric focusing of the tryptic phosphopeptides demonstrated the presence of five distinct peptides with pI values of approximately 6.9, 6.5, 5.6-5.9, 4.7, and 3.6. Mapping of the tryptic phosphopeptides by high performance liquid chromatography techniques demonstrated three distinct peaks. Data from gas phase sequencing, amino acid analysis, and phosphoamino acid analysis suggest that proline-directed protein kinase phosphorylates tau at four sites. Each site demonstrates the presence of a proline residue on the carboxyl-terminal side of the phosphorylated residue. Two phosphorylation sites are located adjacent to the three-repeat microtubule-binding domain that has been found to be required for the in vivo co-localization of tau protein to microtubules. Two other putative phosphorylation sites are located within the identified epitope of the monoclonal antibody Tau-1. Phosphorylation of these sites altered the immunoreactivity of tau to Tau-1 antibody. Since the neuronal microtubule-associated protein tau is multiply phosphorylated in Alzheimer's disease, and Tau-1 immunoreactivity is similarly reduced in neurofibrillary tangles and enhanced after dephosphorylation, phosphorylation at one or more of these sites may correlate with abnormally phosphorylated sites in tau protein in Alzheimer's disease.
The effect of 17 beta-estradiol on interleukin-6 (IL-6) synthesis was examined in murine bone marrow-derived stromal cell lines, normal human bone-derived cells, and nontransformed osteoblast cell lines from mice and rats. In all these cell types IL-6 production was stimulated as much as 10,000-fold in response to the combination of recombinant interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha). Addition of 17 beta-estradiol in the cultures exerted a dose-dependent inhibition of IL-1-, TNF-, and IL-1 + TNF-induced production of bioassayable IL-6. Testosterone and progesterone (but not 17 alpha-estradiol) also inhibited IL-6, but their effective concentrations were two orders of magnitude higher than 17 beta-estradiol. 17 beta-estradiol also decreased the levels of the IL-6 mRNA. In addition, estradiol inhibited both TNF-induced IL-6 production and osteoclast development in primary bone cell cultures derived from neonatal murine calvaria. The TNF-stimulated osteoclast development was also suppressed by a neutralizing monoclonal anti-IL-6 antibody. This in vitro evidence suggests, for the first time, a mechanistic paradigm by which estrogens might exert at least part of their antiresorptive influence on the skeleton.
It is well established that osteoporosis is more common in women than men and fracture risk increases dramatically after menopause. Several different forms of estrogen are available for therapeutic use (e.g., estradiol, conjugated estrogen, esterified estrogens) as well as several routes of administration (e.g., oral, transdermal). Tamoxifen and functionally related compounds are classified as estrogen agonists/antagonists, and bind with estrogen receptors, activating estrogen pathways in some tissues and blocking them in others. However, several estrogen agonists/antagonists have fallen by the wayside, while a few have made it into Phase 3 trials for osteoporosis. In humans, calcitonin is a 32-amino acid peptide produced by specialized C cells in the thyroid. Osteoclasts express receptors for calcitonin and respond to calcitonin with a rapid decrease in resorptive capacity. An oral form of calcitonin is being studied as possible treatment for osteoarthritis and osteoporosis.
The last two decades have witnessed a growing number of experimental observations regarding the mineralocorticoid physiopathology, leading to a new understanding of the molecular basis of the aldosterone-induced target organ damage. As a matter of fact, although it has long been known that the combined administration of mineralocorticoids and salt leads to extensive vascular lesions in the target organs, the recognition that aldosterone is able to induce direct toxic effects on the various cell types that make up the cardiovascular organ has built up recently. Moreover, non-genomic effects have been attributed to aldosterone, i.e. effects which do not depend on the activation of the cellular transcription machinery, whose physiopathologic relevance is still being investigated. These advances in our understanding of aldosterone physiopathology have shed light on the biological reasons which are at the base of the impressive results obtained in clinical trials of aldosterone antagonism.
In seven strains of cultured normal human osteoblast-like cells, a mean of 1615 molecules of tritium-labeled 17 beta-estradiol
per cell nucleus could be bound to specific nuclear sites. The nuclear binding of the labeled steroid was temperature-dependent,
steroid-specific, saturable, and cell type-specific. These are characteristics of biologically active estrogen receptors.
Pretreatment with 10 nanomolar estradiol in vitro increased the specific nuclear binding of progesterone in four of six cell
strains, indicating an induction of functional progesterone receptors. RNA blot analysis demonstrated the presence of messenger
RNA for the human estrogen receptor. The data suggest that estrogen acts directly on human bone cells through a classical
estrogen receptor-mediated mechanism.
We have cloned a novel member of the nuclear receptor superfamily. The cDNA of clone 29 was isolated from a rat prostate cDNA library and it encodes a protein of 485 amino acid residues with a calculated molecular weight of 54.2 kDa. Clone 29 protein is unique in that it is highly homologous to the rat estrogen receptor (ER) protein, particularly in the DNA-binding domain (95%) and in the C-terminal ligand-binding domain (55%). Expression of clone 29 in rat tissues was investigated by in situ hybridization and prominent expression was found in prostate and ovary. In the prostate clone 29 is expressed in the epithelial cells of the secretory alveoli, whereas in the ovary the granulosa cells in primary, secondary, and mature follicles showed expression of clone 29. Saturation ligand-binding analysis of in vitro synthesized clone 29 protein revealed a single binding component for 17beta -estradiol (E2) with high affinity (Kd = 0.6 nM). In ligand-competition experiments the binding affinity decreased in the order E2 > diethylstilbestrol > estriol > estrone > 5alpha -androstane-3beta ,17beta -diol >> testosterone = progesterone = corticosterone = 5alpha -androstane-3alpha ,17beta -diol. In cotransfection experiments of Chinese hamster ovary cells with a clone 29 expression vector and an estrogen-regulated reporter gene, maximal stimulation (about 3-fold) of reporter gene activity was found during incubation with 10 nM of E2. Neither progesterone, testosterone, dexamethasone, thyroid hormone, all-trans-retinoic acid, nor 5alpha -androstane-3alpha ,17beta -diol could stimulate reporter gene activity, whereas estrone and 5alpha -androstane-3beta ,17beta -diol did. We conclude that clone 29 cDNA encodes a novel rat ER, which we suggest be named rat ERbeta to distinguish it from the previously cloned ER (ERalpha ) from rat uterus.
The rat estrogen receptor (ER) exists as two subtypes, ERα and ERβ, which differ in the C-terminal ligand binding domain and in the N-terminal transactivation domain. In this study we investigated the messenger RNA expression of both ER subtypes in rat tissues by RT-PCR and compared the ligand binding specificity of the ER subtypes.
Saturation ligand binding analysis of in vitro synthesized human ERα and rat ERβ protein revealed a single binding component for 16α-iodo-17β-estradiol with high affinity[ dissociation constant (Kd) = 0.1 nm for ERα protein and 0.4 nm for ERβ protein]. Most estrogenic substances or estrogenic antagonists compete with 16α-[125I]iodo-17β-estradiol for binding to both ER subtypes in a very similar preference and degree; that is, diethylstilbestrol > hexestrol > dienestrol > 4-OH-tamoxifen > 17β-estradiol > coumestrol, ICI-164384 > estrone, 17α-estradiol > nafoxidine, moxestrol > clomifene > estriol, 4-OH-estradiol > tamoxifen, 2-OH-estradiol, 5-androstene-3β,17β-diol, genistein for the ERα protein and dienestrol > 4-OH-tamoxifen > diethylstilbestrol > hexestrol > coumestrol, ICI-164384 > 17β-estradiol > estrone, genistein > estriol > nafoxidine, 5-androstene-3β,17β-diol > 17α-estradiol, clomifene, 2-OH-estradiol > 4-OH-estradiol, tamoxifen, moxestrol for the ERβ protein. The rat tissue distribution and/or the relative level of ERα and ERβ expression seems to be quite different, i.e. moderate to high expression in uterus, testis, pituitary, ovary, kidney, epididymis, and adrenal for ERα and prostate, ovary, lung, bladder, brain, uterus, and testis for ERβ. The described differences between the ER subtypes in relative ligand binding affinity and tissue distribution could contribute to the selective action of ER agonists and antagonists in different tissues.
AG-04875/AG/United States NIA
AR-41418/AR/United States NIAMS
AR-41652/AR/United States NIAMS
Journal Article
Research Support, U.S. Gov't, P.H.S.
Review
United states
This investigation is concerned with the prevalence of dysmenorrhoea and premenstrual symptoms in the general population and with their relationship to personality.
Many authors have expressed the opinion that such relationships exist, but we will confine our review here to those studies which have presented supporting data. Wittkower and Wilson (1940) studied 57 patients with primary dysmenorrhoea and found there was a history of childhood maladjustment four times as often in these patients as in a control group. They considered that patients with dysmenorrhoea could be classified into two main personality types: the first, “characterized by deep resentment of their feminine role”; the second, “obviously immature physically and either shy or shut-in or chronically anxious and complaintive”. Sainsbury (1960) observed a significantly raised neuroticism score on the Maudsley Personality Inventory for patients attending hospital for dysmenorrhoea. Such views as these are not universally held, and would certainly not be shared by many gynaecologists. Nor are they supported by the little evidence forthcoming from population studies.
Alistair Burns, Robert Howard, William Pettit Blackwell Science, pounds sterling19.50, pp 159 ISBN 0 632 03731 8Alzheimer's disease is rarely out of the news these days, whether through the revelations of public figures such as Ronald Reagan or Lord Wilson being affected (or not, in the case of Ernest Saunders) or the furore over the decision not to license tacrine for use in the United Kingdom. Public awareness has risen dramatically over the past decade, and Professor Burns and his colleagues have produced an authoritative, attractive, well designed monograph which should help general practitioners to keep abreast of the many developments influencing the diagnosis and management of patients …
Gender differences have long been described in the occurrence of several vascular disorders. Female hormones exert protective effects against some disease (e.g. coronary artery disease), and restoration of hormone levels improves symptoms in some disorders such as menstrual migraines and cardiac syndrome X. In other circumstances, alterations in female hormones may be linked to the onset of symptoms. The protective effects of female sex steroids may be related to their vasodilatory properties. Studies suggest that estradiol enhances vasodilation by stimulating endothelial NO and prostacyclin activity and by attenuating vascular smooth muscle cell responses to vasoconstrictors such as ET-1. Estradiol may also have an inhibitory effect on voltage-gated Ca++ channels. The influence of female hormones on the onset of symptoms or disease remains speculative and may include alterations in hormone levels and/or ratios. In certain vascular beds, however, estrogen and progesterone may also stimulate vasoconstrictor pathways by increasing α1-adrenergic activity and/or catecholamine release. The cellular mechanisms underlying these hormonal effects remain to be determined. Studies primarily conducted in nonvascular cell types support the likelihood that estrogen and progesterone can influence Ca++ homeostasis through genomic as well as nongenomic mechanisms of action. Research is needed to better define the effects of estrogen and progesterone in different vascular beds, the cellular mechanisms through which these effects are mediated, whether receptor-mediated induction of enzymes and proteins and/or immediate effects at the cell membrane are involved, and how the normal mechanisms are altered under conditions of vascular disease. In addition, studies are needed to determine the clinical relevance of many of these observations. For instance, does chronic estrogen replacement therapy enhance endothelial cell vasodilator/vasoconstrictor function? The effects of progesterone also require study since, thus far, the primary focus has been on the effects of estrogen alone. The cardiovascular effects of long-term use of progesterone-only contraceptives, such as Norplant, remain to be determined. Finally, studies on the effects of both hormones combined are important as rarely, if ever, is the level of only one altered in vivo.
Behavioral, neurochemical and pharmacological data have indicated a possible interaction between estrogen and dopamine. Treatment of ovariectomized rats with estradiol benzoate (EB) prior to testing for stereotyped behavior shifted the dose response curve for apomorphine to the right, increasing the median effective dose from 0.38 to 0.65 mg/kg. Ovariectomized rats treated chronically with EB for 14 days were more responsive than oil injected controls when challenged with apomorphine on the seventh day after cessation of EB treatment. Similarly long term ovariectomized rats also display an enhanced response to apomorphine in terms of development of stereotyped behavior. The reduced response to apomorphine following acute EB (3 days) can be interpreted as a possible decrease in either the number of affinity of dopamine receptors. Moreover the enhanced response to apomorphine after cessation of chronic EB treatment (14 days) may be explained on the basis of a decrease in the postsynaptic efficacy of dopamine during chronic treatment with EB, which is then over compensated for upon withdrawal from chronic treatment. The increased sensitivity to apomorphine in long term ovariectomized animals is also consistent with the chronic suppression of dopamine efficacy in the intact female animal.
The effects of androstanediol and estradiol on prostatic growth were investigated in castrate dogs. Estrogens along resulted in no significant change in prostatic weight, whereas androstanediol produced growth comparable to that in uncastrated controls. Androstanediol plus estradiol resulted in an even more striking increase in prostate growth. Approximately half the animals receiving androstanediol alone and all of those receiving androstanediol plus estradiol fulfill the weight and histological criteria for prostatic hypertrophy in the dog. Since both these steroid hormones are presumed to be normal secretory products of the testis, it is possible that they are involved in the pathogenesis of prostatic hypertrophy in the dog.
7,12-Dimethylbenz(a)anthracene-induced rat mammary tumors often contain high levels of the enzyme perioxidase, a putative marker of estrogen dependence. This enzyme can be effectively extracted with 0.5 M CaCl2, giving rise to a soluble peroxidase with a molecular weight of about 50,000 as determined by gel filtration. This is the same size as the estrogen-induced peroxidase of rat uterus but smaller than other mammalian peroxidases. Further purification of the rat mammary tumor peroxidase by concanavalin A-Sepharose chromatography and hydrophobic interaction chromatography on phenyl Sepharose provides a 640-fold purification of the enzyme.
The effect of administration of estrogens parenterally for 1 week was tested on apomorphine-induced circling in a group of castrated female rats with a lesion of the left entopednucluar nucleus. We observed a significant decrease in the number of turns per minute in estrogen-treated animals as compared with controls. Our tentative explanation is that estrogens decrease the sensitivity of dopamine receptors in the striatum.
Positive results are reported from a double-blind study of estrogen therapy administered to severely depressed, inpatient women who had failed to respond to various conventional treatments of depression. Large doses of oral conjugated estrogen were administered for a three-month period to 23 premenopausal and postmenopausal inpatient women. Placebos were administered for a comparable period to 17 similar patients. The posttreatment Hamilton ratings of depression were significantly reduced in the estrogen-treated group, but not in the placebo group. Possible physiological mechanisms are discussed. The risk-benefit ratio for estrogen therapy of depression in these patients was judged to be favorable. However, periodic endometrial biopsies are required to monitor the endometrial response of women receiving high doses of estrogens.
Primary cultures of rat pituitary cells respond to estradiol-17beta by increased incorporation of radiolabeled precursors into prolactin but not into the bulk of other cellular proteins. The rate of increase in prolactin synthesis is dose dependent, reaching maximal levels in the physiological range of estradiol. At a concentration of 1 nM, estradiol, diethylstilbestrol, and estriol are stimulatory whereas androgens, progesterone, and corticosterone are without significant effect. Exposure of pituitary cells to 10 nM estradiol resulted in a 500% increase in prolactin synthesis after 7 days of culture. The results indicate that estradiol can stimulate prolactin synthesis through direct action on the pituitary.
Hepatocytes were isolated by established procedures from freshly-excised livers of ovariectomized rats. Integrity of the cells was verified by DNA, protein, and calcium contents, and by dye exclusion. The cells also showed progressive increments in oxidation to 14CO2 of [26-14C]cholesterol during one to five hours' incubation. Analysis was undertaken of cellular reactivities toward estrogen and the hepatocarcinogen dibutylnitrosamine (DBN). Binding and retention of [3H]estradiol-17β (E2β) by isolated liver cells was specific for E2β, saturable, temperature-dependent, and maximal after 30-minute incubation. The apparent dissociation constant for the binding process at 22°C is 2 × 10−9 M, and the total number of binding-sites at saturation corresponds to approximately 3,400 E2β molecules per liver cell. To probe for steroid binding-sites at their external surfaces, cells were incubated 30 minutes with mounted 17β-estradiol-17-hemisuccinyl:albumin:nylon fibers. The covalentlyimmobilized estrogen (1 ng/mg albumin) was accessible for interaction with antiserum directed against 17β-estradiol-17-hemisuccinyl:albumin. Significant numbers of isolated liver cells were retained by estrogen-derivatized fibers at 22°C after extensive washes. Binding was markedly reduced by incubation at 4°C and by prior exposure to free E2β (× 10−8 M), but not to the relatively inert estradiol-17α (E2α). Fiber-bound cells could be dislodged by brief incubation in 150 mOsM saline with 2 × 10−7 M E2β or diethylstilbestrol, but not E2α, cortisol, progesterone, or testosterone, and recovered intact. Cells that had been retained by the fibers and those that were not adherent were collected and washed under identical conditions, then plated in serum-free, chemically-defined medium at 37°C. After 72 hours, specific binding of E2β by the fiber-binding cells during 30 minutes' incubation was 2.5-fold that of cells which had not bound the immobilized steroid. Similarly, stimulation of the oxidation to 14CO2 of [26-14C]cholesterol by E2β was greater in fiber-binding than in non-binding liver cells after three hours' incubation. In the absence of added mitogen, thymidine incorporation into macromolecular form (20 hours), and cell proliferation (48 hours) were significantly greater in fiber-binding cells as compared to non-binding hepatocytes. Moreover, in parallel experiments, when cells were exposed to 1 × 10−9 M estrogens or to 1 × 10−4 M nitrosamines to assess the capacities of these substances to increase basal thymidine incorporation, total DNA, and cell numbers, only those cells with estrogen-binding sites at their surfaces showed significant E2β- and DBN-induced increments in these parameters as compared with paired controls that had been treated with E2α or the noncarcinogen diphenylnitrosamine. These data indicate that the accessibility of hormone-binding components at the plasma membrane may contribute to the capacity of a given liver cell to respond to E2β, as well as to other known hepatocarcinogens.
Treatment of mice with sustained high levels of betarestradiol leads to a reduction in natural killer cell activity and genetic resistance to bone marrow transplantation. The loss of natural killing does not seem to result from either humoral or immune suppression. Natural killer cells are thought to depend on the bone marrow, and it is notable that estrogens reduce natural killing at approximately the same time that they produce a loss of ma-row due to osteoproliferation. Similarly, mice with congenital osteopetrosis are deficient in natural killing. However, changes in natural killing during and after treatment with estrogen do not correspond directly to changes in marrow volume. Estrogens are known to exacerbate spontaneous autoimmunity in NZB/NZW mice. The relationship between this effect and the effect of estrogen on natural killing is not clear. When natural killing is lowered in NZB/NZW mice by the in vivo administration of 89Sr, autoimmunity is reduced.
Prior incubation of rat anterior pituitary cells with 17beta-estradiol led to an almost complete reversal of the inhibitory
effect of two dopamine agonists, dihydroergocornine and RU 24213, on both basal prolactin release and thyrotropin releasing
hormone-induced prolactin release. These experiments thus demonstrate a direct interference of dopamine action by a peripheral
hormone. Prolactin secretion by pituitary cells in primary culture could possibly serve as an easily accessible model of a
system under dopaminergic control.
The α-methyltyrosine-induced decline of dopamine was increased in the median eminence of rats at 16 but not at 2 hours after the start of intraventricular injections of 0.2–2 μg of rat prolactin. Intraventricular injections of prolactin did not alter the α-methyltyrosine-induced decline of dopamine in the striatum or olfactory tubercle. These results suggest that prolactin in the cerebrospinal fluid can selectively increase the activity of tuberoinfundibular dopaminergic neurons.
The estrogen receptor binding properties of 3,9-dihydroxybenz[a]anthracene (3,9-diOHBA) were determined in uterine cytosol of immature Sprague-Dawley rats by competitive binding experiments with [3H]estradiol and sucrose density centrifugation. 3,9-DiOHBA inhibited estradiol binding to the 8S binding protein at a concentration (1.2 X 10(-5) M) approximately equal to that of nafoxidine-HCl (3 X 10(-5) M) required to inhibit estradiol-specific binding, and bioassay for estrogenic activity substantiated this finding.
OESTROGENS are more readily accumulated and retained in responsive cells
than in cells that are not their targets1. Cytoplasmic
macromolecules2 which specifically interact with oestradiol
and other steroid hormones seem to mediate transfer of the agonist to
the nuclear chromatin, where the complex is believed to promote
expression of the phenotypic effects3-6. It is generally
assumed that the hormone diffuses passively to ``cytoplasmic'' receptors
which determine the cellular specificity of response7. But
some experiments indicate that steroid hormones interact with components
of biological membranes and may enter their respective target cells by a
membrane-mediated process8-12 which is saturable and
temperature-dependent13-17. We have investigated
steroid-binding components associated with the plasma membranes of cells
isolated from endometrium, liver and intestinal mucosa. Endometrial and
liver cells show substantial binding to oestrogen immobilised by
covalent linkage to an inert support, while intestinal cells have no
such binding sites. The relative quantity of these steroid receptors at
the outer surfaces of cells from diverse tissues corresponds well with
the capacity of a given cell to accumulate and retain oestrogen.
Serum prolactin concentrations and dopamine turnover in the striatum and median eminence were studied in male rats after the administration of estradiol benzoate. The alpha-methyltyrosine-induced reduction of dopamine concentrations in these brain regions was used to evaluate relative rates of turnover. Steady state dopamine concentrations in the median eminence and striatum were not altered by 1, 3 or 5 days of estradiol treatment. However, 3 or 5 days of estradiol administration enhanced dopamine turnover in the median eminence but not in the striatum. Estradiol treatment failed to alter dopamine turnover in the median eminence of hypophysectomized rats. Estradiol increased serum prolactin concentrations at all of the times examined. Although alpha-methyltyrosine also increased serum prolactin, this increase was further enhanced in estradiol-treated rats. The increased prolactin response to alpha-methyltyrosine and increased dopamine turnover in the median eminence of estradiol-treated rats suggests that tuberoinfundibular dopaminergic neurons may be part of a hormonal-neuronal negative feedback loop which functions to regulate prolactin secretion.
A rat model for benign prostatic hyperplasia in man (BPH) was investigated. Citral treatment of male Copenhagen rats for 4 months via the transdermal route resulted in a marked hyperplasia of glandular epithelium and interglandular stroma in the ventral prostate. Despite the cellular hyperplasia there was not a significant increase in prostate weight. Investigations of the mechanism of action of citral showed that application of citral directly to the vagina in female, ovariectomized rats resulted in an increased proliferation of vaginal epithelium and a significant increase in the BrdUrd incorporation in vaginal epithelial cells, in short a similar effect to that of estrogen application. In an in vitro assay citral proved to inhibit estrogen binding to estrogen receptors, while no such inhibition was observed with testosterone for androgen receptors. These observations together with the estrogen implication in the BPH and the reported incidence of gynecomastia following exposure to geraniol, a precursor of citral, strongly suggest that the prostatic hyperplasia-inducing capacity of citral may be due to its estrogenic action.
The mammalian hair follicle is a treasure waiting to be discovered by more molecular geneticists. How can a tiny cluster of apparently uniform epithelial cells, adjacent to a tiny cluster of uniform mesenchymal cells, give rise to five or six concentric cylinders, each of which is composed of cells of a distinctive type that synthesize their own distinctive set of proteins? There is now evidence that several growth factors, cell adhesion molecules and other molecules play important roles in the regulation of this minute organ.
We investigated, in five cell strains per experiment, whether several cytokines known or believed to have effects on bone resorption were produced by nearly homogeneous strains of cultured normal human osteoblast-like (hOB) cells that display virtually the complete phenotype of the mature osteoblast. In unstimulated hOB cells, we detected constitutive production of interleukin-6 (IL-6) (mean +/- SE, 122 +/- 32 pg/ml) and IL-8 (135 +/- 39 pg/ml), but not of IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), or tumor necrosis factor-alpha (TNF alpha). IL-1 beta in doses from 1-100 U/ml stimulated dose-dependent increases in IL-6 (r = 0.87; P less than 0.001) and IL-8 (r = 0.95; P less than 0.001). Similar increases occurred after stimulation with TNF alpha in doses from 3-300 U/ml. IL-1 beta and TNF alpha also stimulated GM-CSF production, but only at higher doses. 17 beta-Estradiol (10(-8) M) had no significant effect on the secretion of any of these cytokines, either constitutively or after stimulation with IL-1 beta or TNF alpha. Stimulated production of IL-4 was not detected after treatment with IL-1 beta or TNF alpha, and that of TNF alpha was not detected after treatment with IL-1 beta. We conclude that IL-6, IL-8, and GM-CSF, but not IL-4 and TNF alpha, are produced by highly differentiated normal human cells of the osteoblast lineage, but their secretion is not regulated by estrogen. However, we cannot exclude the possibility that estrogen regulation of these cytokines may occur during early stages of osteoblast differentiation.
This article has no abstract; the first 100 words appear below.
THE potential for immunosuppressive agents to control the poorly understood pathophysiologic consequences of autoimmunity has intrigued clinical immunologists for decades. Unfortunately, the toxicity of these agents has often outweighed their clinical benefit. In the mid-1970s cyclosporine was shown to have pronounced immunosuppressive activity without causing myelotoxicity or other severe side effects, and it was quickly proved to be effective in a wide variety of animal models of transplantation and autoimmunity.¹ During the ensuing years, great strides have been made in understanding the basic immunopharmacology of cyclosporine and in demonstrating its effectiveness in human transplantation and autoimmune disorders.² In studies using . . .
C. Garrison Fathman, M.D.
Bryan D. Myers, M.D.
Stanford University Medical Center Stanford, CA 94305
Cyclosporine is an immunosuppressive drug that is used to treat patients with autoimmune disease as well as patients who have received allografts. The drug can cause renal damage, but the incidence of and risk factors for nephropathy in patients treated with cyclosporine for autoimmune or inflammatory diseases are not known.
We analyzed data from renal biopsies performed in 192 patients (129 adults and 63 children) who had been treated with cyclosporine for insulin-dependent diabetes mellitus of recent onset, uveitis, psoriasis, Sjögren's syndrome, or polychondritis. The mean (+/- SD) initial dose of cyclosporine was 8.2 +/- 2.8 mg per kilogram of body weight per day, and the duration of treatment was 4 to 39 months (median, 13).
Forty-one patients (37 adults and 4 children) had cyclosporine-induced nephropathy, defined as at least moderate focal interstitial fibrosis with tubular atrophy, arteriolar alterations, or both. As compared with patients in whom nephropathy did not develop, these patients received a larger initial dose of cyclosporine (9.3 +/- 2.8 vs. 8.0 +/- 2.8 mg per kilogram per day), had a larger maximal increase in the serum creatinine concentration above base-line values (101 +/- 77 percent vs. 50 +/- 33 percent), and were older (31 +/- 13 vs. 23 +/- 12 years). These three variables were shown by multivariate logistic-regression analysis to be significant risk factors. The duration of the elevation in the serum creatinine concentration and the occurrence of elevated blood pressure were not additional risk factors.
Nephropathy is an important potential effect of cyclosporine therapy. The risk of its development in patients with autoimmune diseases who are treated with cyclosporine can be minimized by allowing a dose no higher than 5 mg per kilogram per day and avoiding increases in serum creatinine of more than 30 percent above the patient's base-line value.
Binding of (3H)-estradiol labeled estrogen receptor from uterine cytosol to calmodulin was demonstrated by both affinity chromatography and sucrose gradient sedimentation. Triphenylethylene antiestrogens (tamoxifen family) with strong antagonistic activity against the calmodulin-dependent c-AMP phosphodiesterase largely reduced the binding of the receptor. Relevance of this observation with regard to the major antiproliferative activity (cytotoxicity) of these drugs is discussed.