Antiestrogen

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]

Antiestrogen
Drug class
Fulvestrant, a steroidal antiestrogen and a drug used in the treatment of breast cancer.
Class identifiers
SynonymsEstrogen antagonists; Estrogen blockers; Estradiol antagonists
UseBreast cancer; Infertility; Male hypogonadism; Gynecomastia; transgender men
ATC codeL02BA
Biological targetEstrogen receptor
Chemical classSteroidal; Nonsteroidal (triphenylethylene, others)
External links
MeSHD020847
In Wikidata

Types and examples

Antiestrogens include selective estrogen receptor modulators (SERMs) like tamoxifen, clomifene, and raloxifene, the ER silent antagonist and selective estrogen receptor degrader (SERD) fulvestrant,[4][5] aromatase inhibitors (AIs) like anastrozole, and antigonadotropins including androgens/anabolic steroids, progestogens, and GnRH analogues.

Although aromatase inhibitors and antigonadotropins can be considered antiestrogens by some definitions, they are often treated as distinct classes.[6] Aromatase inhibitors and antigonadotropins reduce the production of estrogen, while the term "antiestrogen" is often reserved for agents reducing the response to estrogen.[7]

Medical uses

Antiestrogens are used for:

Side effects

Side effects of antiestrogens include hot flashes, osteoporosis, breast atrophy, vaginal dryness, and vaginal atrophy. In addition, they may cause depression and reduced libido.

Pharmacology

Antiestrogens act as antagonists of the estrogen receptors, ERα and ERβ.

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
OspemifeneDeaminohydroxytoremifene2.631.22??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
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
Nandrolone19-Nortestosterone; 19-NT0.010.2376553Androgen
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.

History

Ethamoxytriphetol (MER-25) was the first antagonist of the ER to be discovered,[8] followed by clomifene and tamoxifen.[9][10]

References
  1. "Definition of antiestrogen - NCI Dictionary of Cancer Terms, Definition of antiestrogen - NCI Dictionary of Cancer Terms".,
  2. "antiestrogen" at Dorland's Medical Dictionary
  3. Judi Lindsley Nath (2006). Using Medical Terminology: A Practical Approach. Lippincott Williams & Wilkins. pp. 977–. ISBN 978-0-7817-4868-1.
  4. Eckhard Ottow; Hilmar Weinmann (8 September 2008). Nuclear Receptors as Drug Targets. John Wiley & Sons. pp. 164–165. ISBN 978-3-527-62330-3.
  5. Bruce A. Chabner; Dan L. Longo (8 November 2010). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams & Wilkins. pp. 660–. ISBN 978-1-60547-431-1.
  6. Riggins RB, Bouton AH, Liu MC, Clarke R (2005). "Antiestrogens, aromatase inhibitors, and apoptosis in breast cancer". Vitam. Horm. Vitamins & Hormones. 71: 201–37. doi:10.1016/S0083-6729(05)71007-4. ISBN 9780127098715. PMID 16112269.
  7. Thiantanawat, Apinya; Long, Brian; Brodie, Angela (2003-11-15). "Signaling Pathways of Apoptosis Activated by Aromatase Inhibitors and Antiestrogens". The Journal of Cancer Research. Retrieved 2015-04-13.
  8. Philipp Y. Maximov; Russell E. McDaniel; V. Craig Jordan (23 July 2013). Tamoxifen: Pioneering Medicine in Breast Cancer. Springer Science & Business Media. pp. 7–. ISBN 978-3-0348-0664-0.
  9. V Craig Jordan (27 May 2013). Estrogen Action, Selective Estrogen Receptor Modulators and Women's Health: Progress and Promise. World Scientific. pp. 7, 112. ISBN 978-1-84816-959-3.
  10. Walter Sneader (23 June 2005). Drug Discovery: A History. John Wiley & Sons. pp. 198–199. ISBN 978-0-471-89979-2.

 This article incorporates public domain material from the U.S. National Cancer Institute document: "Dictionary of Cancer Terms".


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