selective estrogen receptor modulator selective estrogen receptor modulator selective estrogen receptor modulators (serms), also known as estrogen receptor agonist/antagonists (eraas), are a class of drugs that act on the estrogen receptor (er). a characteristic that distinguishes these substances from pure er agonists and antagonists (that is, full agonists and silent antagonists) is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues. selective estrogen receptor modulatordrug classtamoxifen, a nonsteroidal triphenylethylene antiestrogen and a widely used drug in the treatment of breast cancer.class identifierssynonymsserm; estrogen receptor agonist/antagonist; eraausebreast cancer, infertility, osteoporosis, vaginal atrophy, dyspareunia, contraception, male hypogonadism, gynecomastia, breast pain, othersatc codeg03xcbiological targetestrogen receptorin wikidata medical uses serms are used for various estrogen-related diseases, including treatment of ovulatory dysfunction in the management of infertility, treatment and prevention of postmenopausal osteoporosis, treatment and reduction in risk of breast cancer and treatment of dyspareunia due to menopause. serm is also used in combination with conjugated estrogens indicated for the treatment of estrogen deficiency symptoms, and vasomotor symptoms associated with menopause. serms are used dependent on their pattern of action in various tissues: nolvadex (tamoxifen) 20-milligram tablets (uk) tamoxifen is a first-line hormonal treatment of er-positive metastatic breast cancer. it is used for breast cancer risk reduction in women at high risk, and as adjuvant treatment of axillary node-negative and node-positive, ductal carcinoma in situ. tamoxifen treatment is also useful in the treatment of bone density and blood lipids in postmenopausal women. adverse effects include hot flushes and more serious is two to three times higher relative risk of developing endometrial cancer compared to women of an age-matched population. toremifene, a chlorinated tamoxifen derivative, causes fewer dna adducts in liver than seen with tamoxifen in preclinical studies and was developed to avoid hepatic carcinomas. it is used as endocrine therapy in women with er/pr-positive stage 4 or recurrent metastatic breast cancer and has demonstrated similar efficacy compared to tamoxifen as adjuvant treatment of breast cancer and in the treatment of metastatic breast cancer. raloxifene is used for prevention and treatment of postmenopausal osteoporosis and breast cancer prevention in high-risk postmenopausal women with osteoporosis. preclinical and clinical reports suggest that it is considerably less potent than estrogen for the treatment of osteoporosis. it is associated with an acceptable endometrial profile and has not demonstrated tamoxifen-like effects in the uterus but has been associated with adverse effects such as venous thromboembolism and vasomotor symptoms, including hot flushes. ospemifene is an analogous metabolite of toremifene. unlike tamoxifen, toremifene is not a rat hepatocarcinogen and therefore ospemifene would also be a safer serm than tamoxifen. it is used for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy associated with menopause. clinical data on breast cancer are not available, but both in vitro and in vivo data suggest that ospemifene may have chemopreventive activity in breast tissue. bazedoxifene is used as treatment for osteoporosis in postmenopausal women at increased risk of fracture. it has been shown to be relatively safe and well tolerated. it shows no breast or endometrial stimulation and in the first two years, the small increase is better in venous thromboembolism, and similar in the long term to other serms. the advantage of bazedoxifene over raloxifene is that it increases endothelial nitric oxide synthase activity and does not antagonize the effect of 17β-estradiol on vasomotor symptoms. the first tissue selective estrogen complex (tsec) combines conjugated estrogens and the serm bazedoxifene to blend their activities. the combination therapy is used in the treatment of moderate to severe vasomotor symptoms associated with menopause, prevention of postmenopausal osteoporosis as well as treatment of estrogen deficiency symptoms in non-hysterectomized postmenopausal women. the combination allows for the benefits of estrogen with regard to relief of vasomotor symptoms without estrogenic stimulation of the endometrium. available forms serms marketed for clinical or veterinary use namebrand nameapproved useslaunchnotes anordrinzi yunemergency contraception1970sonly in china, combined with mifepristone bazedoxifeneduaveeosteoporosis prevention2013combined with conjugated estrogens broparestrolacnestroldermatology; breast cancer treatment1970sdiscontinued clomifeneclomidfemale infertility1967 cyclofenilsexovidfemale infertility; menopausal symptoms1970mostly discontinued lasofoxifenefablynosteoporosis prevention, treatment; vaginal atrophy2009only in lithuania and portugal ormeloxifenesahelihormonal contraception1991only in india ospemifeneosphenadyspareunia due to vaginal atrophy2013 raloxifeneevistaosteoporosis prevention, treatment; breast cancer prevention1997 tamoxifennolvadexbreast cancer treatment1978 toremifenefarestonbreast cancer treatment1997 sources: see individual articles. pharmacology pharmacodynamics serms are competitive partial agonists of the er. different tissues have different degrees of sensitivity to the activity of endogenous estrogens, so serms produce estrogenic or antiestrogenic effects depending on the specific tissue in question as well as the percentage of intrinsic activity (ia) of the serm. an example of a serm with high ia and thus mostly estrogenic effects is chlorotrianisene, while an example of a serm with low ia and thus mostly antiestrogenic effects is ethamoxytriphetol. serms like clomifene and tamoxifen are comparatively more in the middle in their ia and their balance of estrogenic and antiestrogenic activity. raloxifene is a serm that is more antiestrogenic than tamoxifen; both are estrogenic in bone, but raloxifene is antiestrogenic in the uterus while tamoxifen is estrogenic in this part of the body. tissue-specific estrogenic and antiestrogenic activity of serms medicationbreastboneliveruterusvaginabrain lipidscoagulationshbgigf-1hot flashesgonadotropins estradiol++++++++++ "ideal serm"–++±±±–++± bazedoxifene–++++ ?–±– ? clomifene–++ ?++– ?–± lasofoxifene–+++ ? ?±±– ? ospemifene–+++++±±–± raloxifene–+++++±––± tamoxifen–++++++––± toremifene–++++++––± effect: + = estrogenic / agonistic. ± = mixed or neutral. – = antiestrogenic / antagonistic. note: serms generally increase gonadotropin levels in hypogonadal and eugonadal men as well as premenopausal women (antiestrogenic) but decrease gonadotropin levels in postmenopausal women (estrogenic). sources: see template. affinities of estrogen receptor ligands for the erα and erβ ligandother namesrelative binding affinities (rba, %)aabsolute binding affinities (ki, nm)aaction erαerβerαerβ estradiole2; 17β-estradiol1001000.115 (0.04–0.24)0.15 (0.10–2.08)estrogen estronee1; 17-ketoestradiol16.39 (0.7–60)6.5 (1.36–52)0.445 (0.3–1.01)1.75 (0.35–9.24)estrogen estriole3; 16α-oh-17β-e212.65 (4.03–56)26 (14.0–44.6)0.45 (0.35–1.4)0.7 (0.63–0.7)estrogen estetrole4; 15α,16α-di-oh-17β-e24.03.04.919estrogen alfatradiol17α-estradiol20.5 (7–80.1)8.195 (2–42)0.2–0.520.43–1.2metabolite 16-epiestriol16β-hydroxy-17β-estradiol7.795 (4.94–63)50 ? ?metabolite 17-epiestriol16α-hydroxy-17α-estradiol55.45 (29–103)79–80 ? ?metabolite 16,17-epiestriol16β-hydroxy-17α-estradiol1.013 ? ?metabolite 2-hydroxyestradiol2-oh-e222 (7–81)11–352.51.3metabolite 2-methoxyestradiol2-meo-e20.0027–2.01.0 ? ?metabolite 4-hydroxyestradiol4-oh-e213 (8–70)7–561.01.9metabolite 4-methoxyestradiol4-meo-e22.01.0 ? ?metabolite 2-hydroxyestrone2-oh-e12.0–4.00.2–0.4 ? ?metabolite 2-methoxyestrone2-meo-e1<0.001–<1<1 ? ?metabolite 4-hydroxyestrone4-oh-e11.0–2.01.0 ? ?metabolite 4-methoxyestrone4-meo-e1<1<1 ? ?metabolite 16α-hydroxyestrone16α-oh-e1; 17-ketoestriol2.0–6.535 ? ?metabolite 2-hydroxyestriol2-oh-e32.01.0 ? ?metabolite 4-methoxyestriol4-meo-e31.01.0 ? ?metabolite estradiol sulfatee2s; estradiol 3-sulfate<1<1 ? ?metabolite estradiol disulfateestradiol 3,17β-disulfate0.0004 ? ? ?metabolite estradiol 3-glucuronidee2-3g0.0079 ? ? ?metabolite estradiol 17β-glucuronidee2-17g0.0015 ? ? ?metabolite estradiol 3-gluc. 17β-sulfatee2-3g-17s0.0001 ? ? ?metabolite estrone sulfatee1s; estrone 3-sulfate<1<1>10>10metabolite estradiol benzoateeb; estradiol 3-benzoate10 ? ? ?estrogen estradiol 17β-benzoatee2-17b11.332.6 ? ?estrogen estrone methyl etherestrone 3-methyl ether0.145 ? ? ?estrogen ent-estradiol1-estradiol1.31–12.349.44–80.07 ? ?estrogen equilin7-dehydroestrone13 (4.0–28.9)13.0–490.790.36estrogen equilenin6,8-didehydroestrone2.0–157.0–200.640.62estrogen 17β-dihydroequilin7-dehydro-17β-estradiol7.9–1137.9–1080.090.17estrogen 17α-dihydroequilin7-dehydro-17α-estradiol18.6 (18–41)14–320.240.57estrogen 17β-dihydroequilenin6,8-didehydro-17β-estradiol35–6890–1000.150.20estrogen 17α-dihydroequilenin6,8-didehydro-17α-estradiol20490.500.37estrogen δ8-estradiol8,9-dehydro-17β-estradiol68720.150.25estrogen δ8-estrone8,9-dehydroestrone19320.520.57estrogen ethinylestradiolee; 17α-ethynyl-17β-e2120.9 (68.8–480)44.4 (2.0–144)0.02–0.050.29–0.81estrogen mestranolee 3-methyl ether ?2.5 ? ?estrogen moxestrolru-2858; 11β-methoxy-ee35–435–200.52.6estrogen methylestradiol17α-methyl-17β-estradiol7044 ? ?estrogen diethylstilbestroldes; stilbestrol129.5 (89.1–468)219.63 (61.2–295)0.040.05estrogen hexestroldihydrodiethylstilbestrol153.6 (31–302)60–2340.060.06estrogen dienestroldehydrostilbestrol37 (20.4–223)56–4040.050.03estrogen benzestrol (b2)–114 ? ? ?estrogen chlorotrianisenetace1.74 ?15.30 ?estrogen triphenylethylenetpe0.074 ? ? ?estrogen triphenylbromoethylenetpbe2.69 ? ? ?estrogen tamoxifenici-46,4743 (0.1–47)3.33 (0.28–6)3.4–9.692.5serm afimoxifene4-hydroxytamoxifen; 4-oht100.1 (1.7–257)10 (0.98–339)2.3 (0.1–3.61)0.04–4.8serm toremifene4-chlorotamoxifen; 4-ct ? ?7.14–20.315.4serm clomifenemrl-4125 (19.2–37.2)120.91.2serm cyclofenilf-6066; sexovid151–152243 ? ?serm nafoxidineu-11,000a30.9–44160.30.8serm raloxifene–41.2 (7.8–69)5.34 (0.54–16)0.188–0.5220.2serm arzoxifenely-353,381 ? ?0.179 ?serm lasofoxifenecp-336,15610.2–16619.00.229 ?serm ormeloxifenecentchroman ? ?0.313 ?serm levormeloxifene6720-cdri; nnc-460,0201.551.88 ? ?serm ospemifenedeaminohydroxytoremifene0.82–2.630.59–1.22 ? ?serm bazedoxifene– ? ?0.053 ?serm etacstilgw-56384.3011.5 ? ?serm ici-164,384–63.5 (3.70–97.7)1660.20.08antiestrogen fulvestrantici-182,78043.5 (9.4–325)21.65 (2.05–40.5)0.421.3antiestrogen propylpyrazoletriolppt49 (10.0–89.1)0.120.4092.8erα agonist 16α-le216α-lactone-17β-estradiol14.6–570.0890.27131erα agonist 16α-iodo-e216α-iodo-17β-estradiol30.22.30 ? ?erα agonist methylpiperidinopyrazolempp110.05 ? ?erα antagonist diarylpropionitriledpn0.12–0.256.6–1832.41.7erβ agonist 8β-ve28β-vinyl-17β-estradiol0.3522.0–8312.90.50erβ agonist prinaberelerb-041; way-202,0410.2767–72 ? ?erβ agonist erb-196way-202,196 ?180 ? ?erβ agonist erteberelserba-1; ly-500,307 ? ?2.680.19erβ agonist serba-2– ? ?14.51.54erβ agonist coumestrol–9.225 (0.0117–94)64.125 (0.41–185)0.14–80.00.07–27.0xenoestrogen genistein–0.445 (0.0012–16)33.42 (0.86–87)2.6–1260.3–12.8xenoestrogen equol–0.2–0.2870.85 (0.10–2.85) ? ?xenoestrogen daidzein–0.07 (0.0018–9.3)0.7865 (0.04–17.1)2.085.3xenoestrogen biochanin a–0.04 (0.022–0.15)0.6225 (0.010–1.2)1748.9xenoestrogen kaempferol–0.07 (0.029–0.10)2.2 (0.002–3.00) ? ?xenoestrogen naringenin–0.0054 (<0.001–0.01)0.15 (0.11–0.33) ? ?xenoestrogen 8-prenylnaringenin8-pn4.4 ? ? ?xenoestrogen quercetin–<0.001–0.010.002–0.040 ? ?xenoestrogen ipriflavone–<0.01<0.01 ? ?xenoestrogen miroestrol–0.39 ? ? ?xenoestrogen deoxymiroestrol–2.0 ? ? ?xenoestrogen β-sitosterol–<0.001–0.0875<0.001–0.016 ? ?xenoestrogen resveratrol–<0.001–0.0032 ? ? ?xenoestrogen α-zearalenol–48 (13–52.5) ? ? ?xenoestrogen β-zearalenol–0.6 (0.032–13) ? ? ?xenoestrogen zeranolα-zearalanol48–111 ? ? ?xenoestrogen taleranolβ-zearalanol16 (13–17.8)140.80.9xenoestrogen zearalenonezen7.68 (2.04–28)9.45 (2.43–31.5) ? ?xenoestrogen zearalanonezan0.51 ? ? ?xenoestrogen bisphenol abpa0.0315 (0.008–1.0)0.135 (0.002–4.23)19535xenoestrogen endosulfaneds<0.001–<0.01<0.01 ? ?xenoestrogen keponechlordecone0.0069–0.2 ? ? ?xenoestrogen o,p'-ddt–0.0073–0.4 ? ? ?xenoestrogen p,p'-ddt–0.03 ? ? ?xenoestrogen methoxychlorp,p'-dimethoxy-ddt0.01 (<0.001–0.02)0.01–0.13 ? ?xenoestrogen hptehydroxychlor; p,p'-oh-ddt1.2–1.7 ? ? ?xenoestrogen testosteronet; 4-androstenolone<0.0001–<0.01<0.002–0.040>5000>5000androgen dihydrotestosteronedht; 5α-androstanolone0.01 (<0.001–0.05)0.0059–0.17221–>500073–1688androgen nandrolone19-nortestosterone; 19-nt0.010.2376553androgen dehydroepiandrosteronedhea; prasterone0.038 (<0.001–0.04)0.019–0.07245–1053163–515androgen 5-androstenediola5; androstenediol6173.60.9androgen 4-androstenediol–0.50.62319androgen 4-androstenedionea4; androstenedione<0.01<0.01>10000>10000androgen 3α-androstanediol3α-adiol0.070.326048androgen 3β-androstanediol3β-adiol3762androgen androstanedione5α-androstanedione<0.01<0.01>10000>10000androgen etiocholanedione5β-androstanedione<0.01<0.01>10000>10000androgen methyltestosterone17α-methyltestosterone<0.0001 ? ? ?androgen ethinyl-3α-androstanediol17α-ethynyl-3α-adiol4.0<0.07 ? ?estrogen ethinyl-3β-androstanediol17α-ethynyl-3β-adiol505.6 ? ?estrogen progesteronep4; 4-pregnenedione<0.001–0.6<0.001–0.010 ? ?progestogen norethisteronenet; 17α-ethynyl-19-nt0.085 (0.0015–<0.1)0.1 (0.01–0.3)1521084progestogen norethynodrel5(10)-norethisterone0.5 (0.3–0.7)<0.1–0.221453progestogen tibolone7α-methylnorethynodrel0.5 (0.45–2.0)0.2–0.076 ? ?progestogen δ4-tibolone7α-methylnorethisterone0.069–<0.10.027–<0.1 ? ?progestogen 3α-hydroxytibolone–2.5 (1.06–5.0)0.6–0.8 ? ?progestogen 3β-hydroxytibolone–1.6 (0.75–1.9)0.070–0.1 ? ?progestogen footnotes: a = (1) binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. the full sets of values within the ranges can be found in the wiki code. (2) binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human erα and erβ proteins (except the erβ values from kuiper et al. (1997), which are rat erβ). sources: see template page. binding site the domain structures of erα and erβ, including some of the known phosphorylation sites involved in ligand-independent regulation. serm act on the estrogen receptor (er), which is an intracellular, ligand-dependent transcriptional activator and belongs to the nuclear receptor family. two different subtypes of er have been identified, erα and erβ. erα is considered the main medium where estrogen signals are transduced at the transcriptional level and is the predominant er in the female reproductive tract and mammary glands while erβ is primarily in vascular endothelial cells, bone, and male prostate tissue. erα and erβ concentration are known to be different in tissues during development, aging or disease state. many characteristics are similar between these two types such as size (~600 and 530 amino acids) and structure. erα and erβ share approximately 97% of the amino-acid sequence identity in the dna-binding domain and about 56% in the ligand-binding domain. the main difference of the ligand-binding domains is determined by leu-384 and met-421 in erα, which are replaced by met-336 and ile-373, respectively, in erβ. the variation is greater on the n-terminus between erα and erβ. dna-binding domain consists of two subdomains. one with a proximal box that is involved in dna recognition while the other contains a distal box responsible for dna-dependent, dna-binding domain dimerization. the proximal box sequence is identical between erα and erβ, which indicates similar specificity and affinity between the two subgroups. dna-binding domain's globular proteins contain eight cysteines and allow for a tetrahedral coordination of two zinc ions. this coordination makes the binding of er to estrogen response elements possible. ligand-binding domain is a globular, three-layered structure made of 11 helixes and contains a pocket for the natural or synthetic ligand. influencing factors for binding affinity are mainly the presence of a phenol moiety, molecular size and shape, double bonds and hydrophobicity. the differential positioning of the activating function 2 (af-2) helix 12 in the ligand-binding domain by the bound ligand determines whether the ligand has an agonistic and antagonistic effect. in agonist-bound receptors, helix 12 is positioned adjacent to helices 3 and 5. helices 3, 5, and 12 together form a binding surface for an nr box motif contained in coactivators with the canonical sequence lxxll (where l represents leucine or isoleucine and x is any amino acid). unliganded (apo) receptors or receptors bound to antagonist ligands turn helix 12 away from the lxxll-binding surface that leads to preferential binding of a longer leucine-rich motif, lxxxixxx(i/l), present on the corepressors ncor1 or smrt. in addition, some cofactors bind to er through the terminals, the dna-binding site or other binding sites. thus, one compound can be an er agonist in a tissue rich in coactivators but an er antagonist in tissues rich in corepressors. mechanism of action structural basis for the mechanism of estrogen receptor agonist and antagonist action. the structures shown here are of the ligand binding domain (lbd) of the estrogen receptor (green cartoon diagram) complexed with either the agonist diethylstilbestrol (top, pdb: 3erd​) or antagonist 4-hydroxytamoxifen (bottom, 3ert​). the ligands are depicted as space filling spheres (white = carbon, red = oxygen). when an agonist is bound to a nuclear receptor, the c-terminal alpha helix of the lbd (h12; light blue) is positioned such that a coactivator protein (red) can bind to the surface of the lbd. shown here is just a small part of the coactivator protein, the so-called nr box containing the lxxll amino acid sequence motif. antagonists occupy the same ligand binding cavity of the nuclear receptor. however antagonist ligands in addition have a sidechain extension which sterically displaces h12 to occupy roughly the same position in space as coactivators bind. hence coactivator binding to the lbd is