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The estrogen receptors ERα and ERβ are the main mediatorsof estrogen action and estrogens play an important role in avariety of aspects of physiology besides their wellacknowledged function in reproduction. In vivo and in vitrostudies indicate that the estrogen receptors are mechanisticallyimplicated in endocrine-related diseases. Recent studies withestrogen receptor knockout mice have helped to unravel therole of the estrogen receptors in brain degeneration,osteoporosis, cardiovascular diseases and obesity.

Addresses*Merck KGaA, Institute of Toxicology, 64271 Darmstadt, Germany; e-mail: stefan.o.mueller@merck.de†Laboratory of Reproductive and Developmental Toxicology, NationalInstitute of Environmental Health Sciences, National Institutes ofHealth, MD B3-02, PO Box 12233, Research Triangle Park,NC 27709, USA; e-mail: korach@niehs.nih.gov.

Current Opinion in Pharmacology 2001, 1:613–619

1471-4892/01/$ — see front matter© 2001 Elsevier Science Ltd. All rights reserved.

AbbreviationsAF activation functionERE estrogen responsive elementERKO estrogen receptor knockouteNOS endothelial nitric oxide synthaseHRT hormone replacement therapyLDL low-density lipoproteinSERM tissue-selective estrogen receptor modulator

IntroductionIt is now well established that estrogens play importantroles not only in the development and function of thereproductive system and the female mammary gland butalso in so-called non-classical target tissues, such as thebrain, bone, cardiovascular system and adipose tissue(Figure 1). In vivo and in vitro studies have provided evidence that the main mediator of estrogen action, theestrogen receptor, may also be mechanistically involved inbrain function and injury protection, bone maintenance,prevention of cardiovascular diseases and modulating fatdistribution and accumulation. However, estrogens alsohave mitogenic effects on breast and uterine tissues andare therefore implicated in breast and uterine tumor pro-gression in women [1]. Consequently, targeting estrogenreceptors with tissue-selective estrogen receptor modula-tors (SERMs) devoid of the mitogenic effects may be asuitable approach to treat related endocrine diseases [2].

A useful tool to study the role of estrogen receptors inphysiology and disease in vivo is the estrogen receptorknockout mouse (reviewed in [3]). This review focuses onrecent studies with estrogen receptor knockout mice thathave helped to unravel the role of estrogen receptors in

brain degeneration, osteoporosis, cardiovascular diseasesand obesity.

The estrogen receptors and their murineknockout modelsEstrogen receptor activityThe actions of estrogens are mediated in part by its cognate receptor, the estrogen receptor. Two distinct subtypes of estrogen receptor are now known to exist; themolecular mechanism by which both subtypes, ERα andERβ, elicit their effects is depicted schematically inFigure 2. The estrogen receptor is a member of the nuclearreceptor superfamily and regulates target gene expressionas a ligand-inducible transcription factor. Once agonist bindsto the estrogen receptor it dimerizes with another estrogenreceptor and binds, via the receptor’s DNA-binding

Estrogen receptors and endocrine diseases: lessons fromestrogen receptor knockout miceStefan O Mueller* and Kenneth S Korach†

Figure 1

Sites of estrogen action. This schematic shows the tissues reported inthe literature to express estrogen receptors ERα and/or ERβ andwhich represent potential sites of estrogen action in men and women.

Brain Hypothalamus Pituitary

Immune Thymus

Cardiovascular

Mammary gland

MaleFemale

Reproductive tract

Bone

MaleFemale

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Liver

Adipose tissue

domains (DBDs), to specific sequences termed estrogenresponsive elements (EREs) that are located within thepromoter sequence of the target gene (Figures 2 and 3).Subsequent interaction of the activation functions 1 and 2(AF-1 and AF-2) in the estrogen receptor protein with tissue-specific coactivators and the general transcriptionapparatus leads to targeted gene expression [4] (Figures 2and 3).

Receptor distribution and specificityComparative analysis of tissue-specific expression of ERαand ERβ (Table 1) has provided valuable insights intodistinct roles of ERα and ERβ in physiology (reviewedin [3]). It is now acknowledged that the tissue specificityof estrogens and SERMs is determined in part by thespecific conformation the estrogen receptor assumes uponligand binding; this allows or prevents association of cell-type-specific coactivators to the liganded estrogen receptor

[5–7]. This is true for both ERα and ERβ, as the SERMstamoxifen and raloxifene induce a conformational changeof ERα and ERβ, respectively, that prevents coactivatorsfrom binding to the AF-2 domain of the receptor ([6,7]; seealso Figure 3). The N-terminal AF-1 of the estrogen receptor(Figure 3), however, may then be responsible for thetissue-specific estrogen receptor agonist activity ofSERMs observed in bone and the cardiovascular system(reviewed in [8]). In contrast, the potent estrogen receptoragonist diethylstilbestrol allows full coactivator binding atAF-2 that facilitates ligand-dependent activation of ERα[6]. In addition to the classical ERE-mediated estrogenreceptor action described above, other mechanisms thatlead to estrogen action are also known (Figure 4). Thesenon-classical pathways include non-genomic, ligand-independent and ERE-independent pathways of estrogenand estrogen receptor signaling (Figure 4; reviewed in [9]).

Receptor knockout modelsMice with a targeted disruption of either estrogen receptorgene, estrogen receptor knockout (ERKO) mice, providesuitable models to study the tissue-specific role of ERαand ERβ in a physiological context (reviewed in [3]). Withthe recently described double estrogen receptor knockoutmice, which lack both functional ERα and ERβ(αβERKO), all three possible knockout models (lackingERα, ERβ or both) are now available for more mechanisticstudies on the contribution of each estrogen receptor subtype and their cooperative role in endocrine diseasesand physiology [10,11].

Estrogen receptors in the brain ERα and ERβ are expressed in distinct brain regions ofrodents and humans ([12–14]) and epidemiological dataindicate that the onset of neurodegenerative disorders likeAlzheimer’s disease is delayed in women on hormonereplacement therapy (HRT) compared with untreatedwomen [15]. Based on these reports, it appears that estro-gens may play an important role in brain function and itsprotection. Understanding the exact mechanisms and

614 Endocrine and metabolic diseases

Figure 3

The modular domain structure of estrogen receptor protein. TheN-terminal domain contains the ligand-independent AF-1, whichmediates cell-specific and promoter-specific transactivation oftranscription. The DNA binding domain (DBD) is responsible forreceptor dimerization and DNA binding, and the ligand-binding domain(LBD) and the ligand-dependent AF-2 mediate coactivator binding andligand-dependent activation.

Cell-specific andpromoter-specific

transactivation

Ligand binding

Ligand-dependent, cell-specific andpromoter-specific transactivation

Binding of coactivators

AF-1 LBD AF-2DBD

DNA binding

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Figure 2

Molecular mechanism of estrogen receptormediated action. On agonist binding(estrogen, E), estrogen receptors (ER) in thecell nucleus, dimerize and bind to the ERE.Once bound, the receptors interact withcoactivators, which act as a bridge to thegeneral transcription machinery. Thecoactivators shown here are CBP/p300(CREB binding protein) and SRC-1 (steroidreceptor coactivator 1). Transcription factors(TF) can now be recruited, bind to theirpromoter sequence (e.g. the TATA boxthrough the TATA binding protein, TBP) andactivate transcription of the target gene byRNA polymerase (RNA Pol).

Genetranscription

RNAPol

TATA Target gene

mRNA

Coactivators

TBP

TF

CBP/p300

ER ER

EE

SRC-1

ERE

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determining which estrogen receptor mediates the biological actions of estrogens on brain function is an areaof active investigation.

A recent mechanistic study used neuroblastoma cells andanalyzed their morphological phenotypes after transfectionof ERα or ERβ cDNA and treatment with estradiol [16].ERα mediated elongation of cells and an increase in neurite number whereas ERβ induced only neurite elongation, indicating distinct properties of ERα and ERβin the brain. The protective role of the estrogen receptorsin brain ischemia has been investigated using ERKO mice[17•]. Physiological serum levels of estradiol reduced theextent of infarct in all regions of the brain in wild-typemice and ERβ-deficient mice, whereas deletion of ERαcompletely abolished the protective effects of estradiol,indicating that ERα but not ERβ mediates estradiol-induced brain protection [17•]. However, analysis ofexperimentally-induced stroke in αERKO and wild-typemice revealed no propensity for stroke in ERα-deficientmice [18]. Mechanistic studies have demonstrated rapidphosphorylation and kinase activation in the brain ofαERKO and βERKO mice, suggesting that non-genomic,estrogen receptor independent effects contribute to estra-diol’s brain-protective effects [19]. One likely mechanismof estradiol’s protective role in neurodegeneration is theinhibition of apoptosis. Estradiol has been shown to inducethe expression of nip2, a gene encoding a pro-apoptoticprotein, in human neural cells expressing ERα [20].Estradiol has also been shown to prevent the brain-injury-related downregulation of the anti-apoptotic Bcl-2concomitantly with ERβ expression in the rat [21]. Takentogether, these reports support an estrogen receptordependent role of estradiol as well as non-genomic effectsof estrogens in brain development and regeneration frombrain injury.

There is some evidence that estrogens can positively affectcognitive function: αERKO mice but not βERKO miceshowed impaired activity in cognitive function tests [22].Interestingly, estradiol was able to rescue the impairedcognitive activity in αERKO mice and this estrogeniceffect could not be antagonized by the SERM tamoxifen[22]. This indicates that so-called non-genomic effectsindependent of the estrogen receptor contribute to thebeneficial effects of estradiol in brain function. However,care should be taken in the interpretation of these results,as the SERM tamoxifen may not act as an estrogen receptorantagonist in the brain.

Further studies with single and double ERKO mice willprovide more insights into the roles of ERα and ERβ inbrain development and function. Studies in αERKO andwild-type mice with the potent phytoestrogen coumestrol,an ERα and ERβ agonist in vitro, showed unexpectedanti-estrogen activity of coumestrol in the brain of wild-typebut not αERKO mice. This indicates that the antiestro-genic effects of coumestrol were mediated by ERα [23].

Additional studies with mixed and pure estrogen receptoragonists and antagonists could identify SERMs for the protection of brain function.

Estrogen receptors in bone maintenanceThe risk that a postmenopausal woman will suffer bonefractures is equal to her risk of developing breast, uterineand ovarian cancer, combined. It is established that theonset of osteoporosis, which is defined as a loss in bonemass and strength, is associated with the drop in estrogenlevels during menopause and the risk of osteoporosis isreduced by long-term HRT. In bone, ERβ is predominantlyexpressed in osteoblasts, the bone-remodeling cells, and toa minor extent in osteoclasts, the bone-resorbing cells, andosteocytes of cancellous (spongy) bone. In contrast, ERαshows highest expression in cortical bone (solid bone tissue), predominantly in osteoblasts and osteocytes([24–26]). Data obtained in men and women indicate thatERα expression is low in hormone-deficient patients withosteoporosis and elevated levels of ERα are apparent inpatients with repleted ovarian steroid hormone levels[27,28]. Overall, recent reports have demonstrated theexpression of ERα and ERβ in areas of active bone formation and remodeling, indicating an involvement ofboth receptor subtypes in bone maintenance in rodentsand humans.

The description of an estrogen-insensitive male osteoporosispatient and studies in rodents have supported a direct,estrogen receptor mediated effect of estrogens on bonemaintenance in males and females (reviewed in [3,29]). Ina more recent study, Ogawa and colleagues [30•] generatedtransgenic rats harboring a dominant-negative ERα mutationthat attenuated the activity of ERα and ERβ. In thismodel, bone mineral density was comparable betweenestrogen receptor inactivated and wild-type mice, sug-gesting that ERα and ERβ are not required for themaintenance of bone mineral density in hormone-proficientrats [30•]. In ovariectomized mice, however, estradiolrescued bone-mass loss in wild-type mice but not inestrogen receptor impaired mice. This indicates that ERαand/or ERβ are required for the prevention of bone-massloss due to estrogen depletion [30•]. Studies in bone cellshave revealed a more direct mechanistic association ofERα with bone phenotypic markers and factors regulating

Estrogen receptors and endocrine diseases Mueller and Korach 615

Table 1

Expression of ERαα and ERββ in selected tissues*.

Tissue ERα ERβ

Brain + +

Bone + +

Cardiovascular system + +

Adipose tissue + +

*Data comprise mRNA and protein expression in rodents and humans;taken from references cited in the text.

bone mass [31,32]. Furthermore, SERMs like 4-hydroxyta-moxifen inhibit the bone resorbing factor nuclear factor κB(NF-κB) via ERα but not ERβ, whereas estradiol inhibitsNF-κB activity via ERα and ERβ in transactivation assays[33•,34]. In vivo models have also shown that SERMs areable to prevent bone-mass loss in orchidectomized (testesremoved and therefore estrogen deficient) male rats [35].

Studies to discriminate the contributions of ERα and ERβ tobone maintenance have been performed in ERKO mice.Initial studies showed shorter bone lengths and reduced bonemineral density in αERKO mice compared with wild-typemice (reviewed in [3]). Subsequent studies comparing malemice deficient in ERα, ERβ or both receptor subtypes, showedthat ERα-deficient and double knockout mice, but not ERβknockout mice, have small but partly significant decreases ofbone maintenance parameters like bone-mineral density, bonediameter and length [36]. Accordingly, male ERβ-null micehave no major bone abnormalities compared with wild-typemice [37]. Female βERKO mice show slightly elevated bone-mineral density in adult but not prepubescent mice, indicatinga possible inhibitory role of ERβ in the regulation of bonegrowth in female adolescent mice [37]. Taken together, thebone phenotype of the estrogen-insensitive patient and resultsobtained with ERKO male mice suggest that ERα is importantfor the prevention of bone-mass loss and is therefore apotential target for the treatment of osteoporosis in males andfemales. More mechanistic studies using single and doubleERKO mice have to be conducted to delineate further thespecific roles of ERα and ERβ during development of theskeletal system as well as in bone maintenance.

Estrogen receptors and cardiovascular diseasesPremenopausal women have a low incidence of cardiovasculardiseases, but the incidence of coronary heart disease

increases significantly in postmenopausal women.Epidemiological data suggests that HRT may reduce therisk of postmenopausal cardiovascular diseases, althoughrecent studies have questioned the benefit of HRT inwomen with coronary diseases (reviewed in [38,39]).Nevertheless, estrogens may have beneficial effects on thecardiovascular system. These effects may be due, in part,to a reduction of total cholesterol, low-density lipoprotein(LDL) cholesterol and triglyceride levels, as is observed inpostmenopausal women and men treated with estrogensand SERMs [40,41].

The epidemiological data and the expression of ERα andERβ in coronary artery, aortic smooth-muscle cells andblood vessels ([3,42]), indicate that estrogens exert theircardiovascular effects via ERα and/or ERβ. Indeed, exper-imental data has shown that estrogens are vasoprotective inrats and inhibit cell proliferation and migration of humanaortic smooth-muscle cells in vitro — effects that are pre-vented by the estrogen receptor antagonist ICI 182,780[43,44]. Moreover, expression of ERβ mRNA was inducedafter injury of the rat carotid artery and vasoprotectiveeffects were observed in the presence of estradiol andthe phytoestrogen genistein [45].

Other studies, however, have shown that estrogens havedirect effects on the vascular wall and these non-genomiceffects occur rapidly and may be mediated by a membrane-bound form of the estrogen receptor. Endothelial nitricoxide synthase (eNOS), which produces the vasodilatornitric oxide (NO), can be rapidly induced by estradiol andmembrane-impermeable conjugated estradiol in humanendothelial cells [46•]. Furthermore, the eNOS inductionis abrogated by estrogen receptor antagonists and thesuspected membrane estrogen receptor is immunoreactive

616 Endocrine and metabolic diseases

Figure 4

Cellular mechanisms of estrogen andestrogen receptor signaling. Four potentialmechanisms of estrogen and estrogenreceptor (R, in red and blue) action are shownschematically for estradiol (E2) — the differentcolors indicate the two subtypes of ER.(a) The classical ligand-dependent estrogenreceptor mediated transactivation of targetgenes (see Figure 1 for more details); (b) theligand-independent pathway, which includesphosphorylation (P) of the estrogen receptorcaused by growth factor (GF) signaling;(c) the ERE-independent pathways, e.g.interaction of the estrogen receptors with Fosand Jun at AP-1 binding sites result inexpression of AP-1-regulated genes; and(d) the estrogen receptor independent, non-genomic pathway that leads to rapid effectswithout involvement of gene transcription. Thislast pathway (d) is shown with a dotted line asthe exact processes that lead to non-genomictissue responses are unclear. Reproduced,with permission, from [8].

E2

R

Tissue responses

GF

E2E2

E2

mRNA

Polysomes

Protein

E2

P P PP

ERE(b) Ligand-independent

AP-1

(c) ERE-independent

(a) Classical

(d) Non-genomic

E2

GF R

RE2

R

E2

R

R

RE2

R

E2

R

E2

R

FosJu

n

ERER

Nucleus

to an ERα antibody, indicating the possible existence of amembrane-bound rather than nuclear estrogen receptorform [47•]. In contrast, the SERM raloxifene did not induceeNOS transcriptionally but triggered release of NO,probably by stimulating enzymatic activity of eNOS [48].Intriguingly, estradiol metabolites with no affinity for ERαor ERβ are more potent than estradiol in inhibiting synthesis of the vasoconstrictor endothelin-1 and vascularsmooth-muscle cell growth and these effects are not pre-vented by estrogen receptor antagonists [49]. To summarizethese results, rapid events independent of nuclear estrogenreceptor seem to be responsible predominantly for thevasoprotective effects of estradiol and its metabolites.

Nevertheless, recent studies with ERKO mice havehelped to identify a potential estrogen receptor dependentcardiovascular protective effect of estrogens. Studies withfemale ERα-deficient and ERβ-deficient mice proved thatneither ERα nor ERβ individually are required for thevascular-injury response induced by estrogens (reviewedin [3,50]). The authors speculated that ERα and ERβ haveredundant functions in vasoprotection and the presence ofone receptor subtype can compensate for the lack of theother in single estrogen receptor knockout mice [50]. Incontrast to these studies, analysis of myocardial ischemiaand carotid injury in male mice showed that ERα but notERβ is required for cardioprotection and re-endothelializa-tion [51,52]. Analysis of the lipoprotein profile of ERKOmice indicated that ERα but not ERβ mediates the ben-eficial effects of estrogens in regard to reducing totalcholesterol and LDL cholesterol serum levels [53]. Theseresults were confirmed recently in mice with a disruptionof the apolipoprotein E (ApoE) gene [54]. The reductionof serum cholesterol levels in ApoE knockout mice wascompletely dependent on ERα, whereas the estradiol-induced reduction of atherosclerotic plaques althoughmainly mediated by ERα was also ERα independent [54].

Taken together, reports published to date indicate that non-genomic events account for most of the rapid vasoprotectiveeffects of estrogens but the long-term reduction of cardio-vascular risk factors like serum lipoprotein levels are likelyto be mediated by ERα. The αβERKO mouse should showwhich of the several cardiovascular benefits of estrogens aremediated by ERα or are estrogen receptor independent.

Estrogen receptors and obesityObesity — the incidence of which is rising in the Westernworld — is a heterogeneous disorder that predisposeshumans to a variety of diseases (reviewed in [55]). Men andwomen have differing and distinct distribution of body fat.Ovariectomized female rodents show increased body weightand fat stores, effects that can be prevented by HRT.These experimental and epidemiological data suggest that estrogens are important regulators of adipogenesis.

Although ERα and ERβ are expressed in the adipose tissue (Table 1) and steroid hormones are stored and

synthesized in adipose tissue, the role of ERα and ERβ inadipogenesis is poorly understood [3,56]. A study inadipocytes with forced expression of ERα indicated thatestradiol induced ERα-mediated transcriptional suppres-sion of lipoprotein lipase, an enzyme that catabolizesplasma triglycerides [57]. Estradiol was also found to inhibitfat accumulation in adipocytes expressing ERα [57].Evidence for the involvement of ERα in the suppressionof white adipose tissue accumulation in vivo was providedby analysis of ERKO mice. Mature male ERα-deficientmice and double (ERα/ERβ) knockout mice have increasedbody weights and adipose tissue concomitant with higherlevels of cholesterol and leptin, a sensor of high caloricsupply [53]. Female and male αERKO mice show sig-nificant accumulation of white adipose tissue, which ischaracterized by an increase in adipocyte size and number[58•]. More importantly, this study also showed that the fataccumulation caused by the lack of ERα was accompaniedby impaired glucose tolerance and insulin resistance [58•].In contrast, βERKO mice have normal body weight andadipose tissue, compared with wild-type mice [53].

These studies clearly indicate that ERα but not ERβ is aregulator of white adipose tissue mass and distribution andprovide evidence for a mechanistic linked between ERαsignaling and obesity. Additional studies with ERKO andwild-type mice will prove invaluable to determine whetherERα is a potentially useful molecular target to treat obesity.

ConclusionsResearch in recent years has provided strong support forthe involvement of ERα and ERβ in the adverse andbeneficial effects of estrogens on human health. Thegeneration of mice with targeted disruption of a singleestrogen receptor subtype as well as double ERα and ERβknockout mice have allowed us to study and dissect theroles of ERα and ERβ in endocrine diseases. The estrogenreceptor has proven to be crucial in so-called non-classicaltarget tissues such as brain, bone, the cardiovascular systemand adipose tissue and ERKO studies have shown thatERα mediates the regulation of adipose tissue distribution,fat accumulation and bone maintenance. The beneficialeffects of estrogens on brain function and protection andon the cardiovascular system are mediated both by ERαand through non-genomic events that appear to beindependent of nuclear estrogen receptors. Nevertheless,more detailed studies with ERKO mice have to beconducted to support a mechanistic link between estrogeneffects and estrogen receptors and to discriminate furtherthe role of ERα from ERβ in endocrine diseases.

Informative work with ERKO mice has been published inrecent years by several laboratories but more is still tocome. The recent description of an estrogen reporter mouse[59••] will allow for the in vivo analysis of the specificactivity of the estrogen receptors in the tissue of interest.Generation of a transgenic estrogen reporter/ERKO mousewill prove invaluable to identify and test SERMs for their

Estrogen receptors and endocrine diseases Mueller and Korach 617

estrogen receptor subtype and tissue specificity andshould accelerate the selection of SERMs with clinicalpotential in endocrine diseases.

AcknowledgementsThe authors thank Wendy N Jefferson and Harriet K Kinyamu for editing themanuscript and the Deutsche Forschungsgemeinschaft (DFG) for providingStefan O Mueller with a research grant (Mu 1490) for the past two years.

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• of special interest••of outstanding interest

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41. Saitta A, Morabito N, Frisina N, Cucinotte D, Corrado F, D’Anna R,Altavilla D, Squadrito G, Minutoli L, Arcoraci V et al.: Cardiovascular effects of raloxifene hydrochloride. Cardiovasc Drug Rev 2001, 19:57-74.

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46. Haynes MP, Sinha D, Russell KS, Collinge M, Fulton D, Morales• Ruiz M, Sessa WC, Bender JR: Membrane estrogen receptor

engagement activates endothelial nitric oxide synthase via thePI3-kinase-Akt pathway in human endothelial cells. Circ Res2000, 87:677-682.

This report presents convincing data for a membrane-bound receptor forestrogens that may mediate release of NO, thereby supporting the anti-atherosclerotic activity of estrogens.

47. Russell KS, Haynes MP, Sinha D, Clerisme E, Bender JR: Human• vascular endothelial cells contain membrane binding sites for

estradiol, which mediate rapid intracellular signaling. Proc NatlAcad Sci USA 2000, 97:5930-5935.

This paper complements Haynes et al. [46•] by providing further support for amembrane-bound estrogen receptor that is detectable with an ERα antibodyand that mediates rapid activation of mitogen-activated protein kinase signaling.

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57. Homma H, Kurachi H, Nishio Y, Takeda T, Yamamoto T, Adachi K,Morishige K, Ohmichi M, Matsuzawa Y, Murata Y: Estrogensuppresses transcription of lipoprotein lipase gene. Existence ofa unique estrogen response element on the lipoprotein lipasepromoter. J Biol Chem 2000, 275:11404-11411.

58. Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS: Increased• adipose tissue in male and female estrogen receptor-alpha

knockout mice. Proc Natl Acad Sci USA 2000, 97:12729-12734.Heine et al. provide strong evidence for the involvement of ERα in insulinresistance and impaired glucose tolerance and link fat accumulation due toERα deficiency with obesity-related diseases.

59. Ciana P, Di Luccio G, Belcredito S, Pollio G, Vegeto E, Tatangelo L,•• Tiveron C, Maggi A: Engineering of a mouse for the in vivo profiling

of estrogen receptor activity. Mol Endocrinol 2001, 15:1104-1113.The authors describe the generation of an estrogen receptor reportermouse. In vivo and in primary cell cultures from these transgenic mice, activ-ity of luciferase (the reporter) is induced by estrogen receptor agonists. Thismouse will be a hallmark in the analysis of tissue-specific activity of estrogenreceptor ligands and in the search for novel synthetic SERMs.

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