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Class of drugs
Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhibiting or suppressing estrogen production.[1][2] Antiestrogens are one of three types of sex hormone antagonists, the others being antiandrogens and antiprogestogens.[3] Antiestrogens are commonly used to stop steroid hormones, estrogen, from binding to the estrogen receptors leading to the decrease of estrogen levels.[4] Decreased levels of estrogen can lead to complications in sexual development.[5]
Types and examples[edit]Antiestrogens include selective estrogen receptor modulators (SERMs) like tamoxifen, clomifene, and raloxifene, the ER silent antagonist and selective estrogen receptor degrader (SERD) fulvestrant,[6][7] aromatase inhibitors (AIs) like anastrozole, and antigonadotropins including androgens/anabolic steroids, progestogens, and GnRH analogues.
Estrogen receptors (ER) like ERα and ERβ include activation function 1 (AF1) domain and activation function 2 (AF2) domain in which SERMS act as antagonists for the AF2 domain, while “pure” antiestrogens like ICI 182,780 and ICI 164,384 are antagonists for the AF1 and AF2 domains.[8]
Although aromatase inhibitors and antigonadotropins can be considered antiestrogens by some definitions, they are often treated as distinct classes.[9] Aromatase inhibitors and antigonadotropins reduce the production of estrogen, while the term "antiestrogen" is often reserved for agents reducing the response to estrogen.[10]
Antiestrogens are used for:
In women, the side effects of antiestrogens include hot flashes, osteoporosis, breast atrophy, vaginal dryness, and vaginal atrophy. In addition, they may cause depression and reduced libido.
Antiestrogens act as antagonists of the estrogen receptors, ERα and ERβ.
Affinities of estrogen receptor ligands for the ERα and ERβ Ligand Other names Relative binding affinities (RBA, %)a Absolute binding affinities (Ki, nM)a Action ERα ERβ ERα ERβ Estradiol E2; 17β-Estradiol 100 100 0.115 (0.04–0.24) 0.15 (0.10–2.08) Estrogen Estrone E1; 17-Ketoestradiol 16.39 (0.7–60) 6.5 (1.36–52) 0.445 (0.3–1.01) 1.75 (0.35–9.24) Estrogen Estriol E3; 16α-OH-17β-E2 12.65 (4.03–56) 26 (14.0–44.6) 0.45 (0.35–1.4) 0.7 (0.63–0.7) Estrogen Estetrol E4; 15α,16α-Di-OH-17β-E2 4.0 3.0 4.9 19 Estrogen Alfatradiol 17α-Estradiol 20.5 (7–80.1) 8.195 (2–42) 0.2–0.52 0.43–1.2 Metabolite 16-Epiestriol 16β-Hydroxy-17β-estradiol 7.795 (4.94–63) 50 ? ? Metabolite 17-Epiestriol 16α-Hydroxy-17α-estradiol 55.45 (29–103) 79–80 ? ? Metabolite 16,17-Epiestriol 16β-Hydroxy-17α-estradiol 1.0 13 ? ? Metabolite 2-Hydroxyestradiol 2-OH-E2 22 (7–81) 11–35 2.5 1.3 Metabolite 2-Methoxyestradiol 2-MeO-E2 0.0027–2.0 1.0 ? ? Metabolite 4-Hydroxyestradiol 4-OH-E2 13 (8–70) 7–56 1.0 1.9 Metabolite 4-Methoxyestradiol 4-MeO-E2 2.0 1.0 ? ? Metabolite 2-Hydroxyestrone 2-OH-E1 2.0–4.0 0.2–0.4 ? ? Metabolite 2-Methoxyestrone 2-MeO-E1 <0.001–<1 <1 ? ? Metabolite 4-Hydroxyestrone 4-OH-E1 1.0–2.0 1.0 ? ? Metabolite 4-Methoxyestrone 4-MeO-E1 <1 <1 ? ? Metabolite 16α-Hydroxyestrone 16α-OH-E1; 17-Ketoestriol 2.0–6.5 35 ? ? Metabolite 2-Hydroxyestriol 2-OH-E3 2.0 1.0 ? ? Metabolite 4-Methoxyestriol 4-MeO-E3 1.0 1.0 ? ? Metabolite Estradiol sulfate E2S; Estradiol 3-sulfate <1 <1 ? ? Metabolite Estradiol disulfate Estradiol 3,17β-disulfate 0.0004 ? ? ? Metabolite Estradiol 3-glucuronide E2-3G 0.0079 ? ? ? Metabolite Estradiol 17β-glucuronide E2-17G 0.0015 ? ? ? Metabolite Estradiol 3-gluc. 17β-sulfate E2-3G-17S 0.0001 ? ? ? Metabolite Estrone sulfate E1S; Estrone 3-sulfate <1 <1 >10 >10 Metabolite Estradiol benzoate EB; Estradiol 3-benzoate 10 ? ? ? Estrogen Estradiol 17β-benzoate E2-17B 11.3 32.6 ? ? Estrogen Estrone methyl ether Estrone 3-methyl ether 0.145 ? ? ? Estrogen ent-Estradiol 1-Estradiol 1.31–12.34 9.44–80.07 ? ? Estrogen Equilin 7-Dehydroestrone 13 (4.0–28.9) 13.0–49 0.79 0.36 Estrogen Equilenin 6,8-Didehydroestrone 2.0–15 7.0–20 0.64 0.62 Estrogen 17β-Dihydroequilin 7-Dehydro-17β-estradiol 7.9–113 7.9–108 0.09 0.17 Estrogen 17α-Dihydroequilin 7-Dehydro-17α-estradiol 18.6 (18–41) 14–32 0.24 0.57 Estrogen 17β-Dihydroequilenin 6,8-Didehydro-17β-estradiol 35–68 90–100 0.15 0.20 Estrogen 17α-Dihydroequilenin 6,8-Didehydro-17α-estradiol 20 49 0.50 0.37 Estrogen Δ8-Estradiol 8,9-Dehydro-17β-estradiol 68 72 0.15 0.25 Estrogen Δ8-Estrone 8,9-Dehydroestrone 19 32 0.52 0.57 Estrogen Ethinylestradiol EE; 17α-Ethynyl-17β-E2 120.9 (68.8–480) 44.4 (2.0–144) 0.02–0.05 0.29–0.81 Estrogen Mestranol EE 3-methyl ether ? 2.5 ? ? Estrogen Moxestrol RU-2858; 11β-Methoxy-EE 35–43 5–20 0.5 2.6 Estrogen Methylestradiol 17α-Methyl-17β-estradiol 70 44 ? ? Estrogen Diethylstilbestrol DES; Stilbestrol 129.5 (89.1–468) 219.63 (61.2–295) 0.04 0.05 Estrogen Hexestrol Dihydrodiethylstilbestrol 153.6 (31–302) 60–234 0.06 0.06 Estrogen Dienestrol Dehydrostilbestrol 37 (20.4–223) 56–404 0.05 0.03 Estrogen Benzestrol (B2) – 114 ? ? ? Estrogen Chlorotrianisene TACE 1.74 ? 15.30 ? Estrogen Triphenylethylene TPE 0.074 ? ? ? Estrogen Triphenylbromoethylene TPBE 2.69 ? ? ? Estrogen Tamoxifen ICI-46,474 3 (0.1–47) 3.33 (0.28–6) 3.4–9.69 2.5 SERM Afimoxifene 4-Hydroxytamoxifen; 4-OHT 100.1 (1.7–257) 10 (0.98–339) 2.3 (0.1–3.61) 0.04–4.8 SERM Toremifene 4-Chlorotamoxifen; 4-CT ? ? 7.14–20.3 15.4 SERM Clomifene MRL-41 25 (19.2–37.2) 12 0.9 1.2 SERM Cyclofenil F-6066; Sexovid 151–152 243 ? ? SERM Nafoxidine U-11,000A 30.9–44 16 0.3 0.8 SERM Raloxifene – 41.2 (7.8–69) 5.34 (0.54–16) 0.188–0.52 20.2 SERM Arzoxifene LY-353,381 ? ? 0.179 ? SERM Lasofoxifene CP-336,156 10.2–166 19.0 0.229 ? SERM Ormeloxifene Centchroman ? ? 0.313 ? SERM Levormeloxifene 6720-CDRI; NNC-460,020 1.55 1.88 ? ? SERM Ospemifene Deaminohydroxytoremifene 0.82–2.63 0.59–1.22 ? ? SERM Bazedoxifene – ? ? 0.053 ? SERM Etacstil GW-5638 4.30 11.5 ? ? SERM ICI-164,384 – 63.5 (3.70–97.7) 166 0.2 0.08 Antiestrogen Fulvestrant ICI-182,780 43.5 (9.4–325) 21.65 (2.05–40.5) 0.42 1.3 Antiestrogen Propylpyrazoletriol PPT 49 (10.0–89.1) 0.12 0.40 92.8 ERα agonist 16α-LE2 16α-Lactone-17β-estradiol 14.6–57 0.089 0.27 131 ERα agonist 16α-Iodo-E2 16α-Iodo-17β-estradiol 30.2 2.30 ? ? ERα agonist Methylpiperidinopyrazole MPP 11 0.05 ? ? ERα antagonist Diarylpropionitrile DPN 0.12–0.25 6.6–18 32.4 1.7 ERβ agonist 8β-VE2 8β-Vinyl-17β-estradiol 0.35 22.0–83 12.9 0.50 ERβ agonist Prinaberel ERB-041; WAY-202,041 0.27 67–72 ? ? ERβ agonist ERB-196 WAY-202,196 ? 180 ? ? ERβ agonist Erteberel SERBA-1; LY-500,307 ? ? 2.68 0.19 ERβ agonist SERBA-2 – ? ? 14.5 1.54 ERβ agonist Coumestrol – 9.225 (0.0117–94) 64.125 (0.41–185) 0.14–80.0 0.07–27.0 Xenoestrogen Genistein – 0.445 (0.0012–16) 33.42 (0.86–87) 2.6–126 0.3–12.8 Xenoestrogen Equol – 0.2–0.287 0.85 (0.10–2.85) ? ? Xenoestrogen Daidzein – 0.07 (0.0018–9.3) 0.7865 (0.04–17.1) 2.0 85.3 Xenoestrogen Biochanin A – 0.04 (0.022–0.15) 0.6225 (0.010–1.2) 174 8.9 Xenoestrogen 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-Prenylnaringenin 8-PN 4.4 ? ? ? Xenoestrogen Quercetin – <0.001–0.01 0.002–0.040 ? ? 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 Zeranol α-Zearalanol 48–111 ? ? ? Xenoestrogen Taleranol β-Zearalanol 16 (13–17.8) 14 0.8 0.9 Xenoestrogen Zearalenone ZEN 7.68 (2.04–28) 9.45 (2.43–31.5) ? ? Xenoestrogen Zearalanone ZAN 0.51 ? ? ? Xenoestrogen Bisphenol A BPA 0.0315 (0.008–1.0) 0.135 (0.002–4.23) 195 35 Xenoestrogen Endosulfan EDS <0.001–<0.01 <0.01 ? ? Xenoestrogen Kepone Chlordecone 0.0069–0.2 ? ? ? Xenoestrogen o,p'-DDT – 0.0073–0.4 ? ? ? Xenoestrogen p,p'-DDT – 0.03 ? ? ? Xenoestrogen Methoxychlor p,p'-Dimethoxy-DDT 0.01 (<0.001–0.02) 0.01–0.13 ? ? Xenoestrogen HPTE Hydroxychlor; p,p'-OH-DDT 1.2–1.7 ? ? ? Xenoestrogen Testosterone T; 4-Androstenolone <0.0001–<0.01 <0.002–0.040 >5000 >5000 Androgen Dihydrotestosterone DHT; 5α-Androstanolone 0.01 (<0.001–0.05) 0.0059–0.17 221–>5000 73–1688 Androgen Nandrolone 19-Nortestosterone; 19-NT 0.01 0.23 765 53 Androgen Dehydroepiandrosterone DHEA; Prasterone 0.038 (<0.001–0.04) 0.019–0.07 245–1053 163–515 Androgen 5-Androstenediol A5; Androstenediol 6 17 3.6 0.9 Androgen 4-Androstenediol – 0.5 0.6 23 19 Androgen 4-Androstenedione A4; Androstenedione <0.01 <0.01 >10000 >10000 Androgen 3α-Androstanediol 3α-Adiol 0.07 0.3 260 48 Androgen 3β-Androstanediol 3β-Adiol 3 7 6 2 Androgen Androstanedione 5α-Androstanedione <0.01 <0.01 >10000 >10000 Androgen Etiocholanedione 5β-Androstanedione <0.01 <0.01 >10000 >10000 Androgen Methyltestosterone 17α-Methyltestosterone <0.0001 ? ? ? Androgen Ethinyl-3α-androstanediol 17α-Ethynyl-3α-adiol 4.0 <0.07 ? ? Estrogen Ethinyl-3β-androstanediol 17α-Ethynyl-3β-adiol 50 5.6 ? ? Estrogen Progesterone P4; 4-Pregnenedione <0.001–0.6 <0.001–0.010 ? ? Progestogen Norethisterone NET; 17α-Ethynyl-19-NT 0.085 (0.0015–<0.1) 0.1 (0.01–0.3) 152 1084 Progestogen Norethynodrel 5(10)-Norethisterone 0.5 (0.3–0.7) <0.1–0.22 14 53 Progestogen Tibolone 7α-Methylnorethynodrel 0.5 (0.45–2.0) 0.2–0.076 ? ? Progestogen Δ4-Tibolone 7α-Methylnorethisterone 0.069–<0.1 0.027–<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.The first nonsteroidal antiestrogen was discovered by Lerner and coworkers in 1958.[11] Ethamoxytriphetol (MER-25) was the first antagonist of the ER to be discovered,[12] followed by clomifene and tamoxifen.[13][14]
This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute.
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