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Hexestrol

Hexestrol
Clinical data
Trade namesSynestrol, Synoestrol, Estrifar, Estronal
Other namesHexoestrol; Hexanestrol; Hexanoestrol; Dihydrodiethylstilbestrol; Dihydrostilbestrol; 4,4'-(1,2-Diethylethylene)diphenol; NSC-9894
Routes of
administration		By mouth, intramuscular injection (as an ester)
Drug classNonsteroidal estrogen
Identifiers
  • 4-[4-(4-Hydroxyphenyl)hexan-3-yl]phenol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.001.380 Edit this at Wikidata
Chemical and physical data
FormulaC18H22O2
Molar mass270.372 g·mol−1
3D model (JSmol)
  • CCC(C1=CC=C(C=C1)O)C(CC)C2=CC=C(C=C2)O
  • InChI=1S/C18H22O2/c1-3-17(13-5-9-15(19)10-6-13)18(4-2)14-7-11-16(20)12-8-14/h5-12,17-20H,3-4H2,1-2H3
  • Key:PBBGSZCBWVPOOL-UHFFFAOYSA-N

Hexestrol, sold under the brand name Synestrol among others, is a nonsteroidal estrogen which was previously used for estrogen replacement therapy and in the treatment of certain hormone-dependent cancers as well as gynecological disorders but is mostly no longer marketed.[1][2][3][4] It has also been used in the form of esters such as hexestrol diacetate (brand name Sintestrol) and hexestrol dipropionate (brand name Hexanoestrol).[1][5] Hexestrol and its esters are taken by mouth, held under the tongue, or via injection into muscle.[5][6][7]

Medical uses

Hexestrol has been used in estrogen replacement therapy, for the treatment of breast cancer in women and prostate cancer in men, and for the treatment of certain gynecological disorders.[2]

Estrogen dosages for prostate cancer
Route/form Estrogen Dosage
Oral Estradiol 1–2 mg 3x/day
Conjugated estrogens 1.25–2.5 mg 3x/day
Ethinylestradiol 0.15–3 mg/day
Ethinylestradiol sulfonate 1–2 mg 1x/week
Diethylstilbestrol 1–3 mg/day
Dienestrol 5 mg/day
Hexestrol 5 mg/day
Fosfestrol 100–480 mg 1–3x/day
Chlorotrianisene 12–48 mg/day
Quadrosilan 900 mg/day
Estramustine phosphate 140–1400 mg/day
Transdermal patch Estradiol 2–6x 100 μg/day
Scrotal: 1x 100 μg/day
IMTooltip Intramuscular or SC injection Estradiol benzoate 1.66 mg 3x/week
Estradiol dipropionate 5 mg 1x/week
Estradiol valerate 10–40 mg 1x/1–2 weeks
Estradiol undecylate 100 mg 1x/4 weeks
Polyestradiol phosphate Alone: 160–320 mg 1x/4 weeks
With oral EE: 40–80 mg 1x/4 weeks
Estrone 2–4 mg 2–3x/week
IV injection Fosfestrol 300–1200 mg 1–7x/week
Estramustine phosphate 240–450 mg/day
Note: Dosages are not necessarily equivalent. Sources: See template.

Pharmacology

Pharmacodynamics

Hexestrol has approximately 302% and 234% of the affinity of estradiol for the estrogen receptors (ERs) ERα and ERβ, respectively.[8] The affinity of hexestrol for the ERs is said to be similar to or slightly higher than that of estradiol.[9] Along with diethylstilbestrol, hexestrol has been said to be one of the most potent estrogens known.[10] The total endometrial proliferation dose per cycle of different forms of hexestrol are 70 to 100 mg for oral hexestrol, 45 mg for sublingual hexestrol diacetate, and 25 mg for hexestrol dipropionate by intramuscular injection.[5] These doses are fairly similar to those of estradiol and its esters.[5] Hexestrol induces mammary gland development in rodents similarly to other estrogens.[11]

Nonsteroidal estrogens like diethylstilbestrol, which is closely related structurally to hexestrol, are known to have dramatically disproportionate estrogenic effects in the liver and on liver protein synthesis.[12]

Parenteral potencies and durations of nonsteroidal estrogens
Estrogen Form Major brand name(s) EPD (14 days) Duration
Diethylstilbestrol (DES) Oil solution Metestrol 20 mg 1 mg ≈ 2–3 days; 3 mg ≈ 3 days
Diethylstilbestrol dipropionate Oil solution Cyren B 12.5–15 mg 2.5 mg ≈ 5 days
Aqueous suspension ? 5 mg ? mg = 21–28 days
Dimestrol (DES dimethyl ether) Oil solution Depot-Cyren, Depot-Oestromon, Retalon Retard 20–40 mg ?
Fosfestrol (DES diphosphate)a Aqueous solution Honvan ? <1 day
Dienestrol diacetate Aqueous suspension Farmacyrol-Kristallsuspension 50 mg ?
Hexestrol dipropionate Oil solution Hormoestrol, Retalon Oleosum 25 mg ?
Hexestrol diphosphatea Aqueous solution Cytostesin, Pharmestrin, Retalon Aquosum ? Very short
Note: All by intramuscular injection unless otherwise noted. Footnotes: a = By intravenous injection. Sources: See template.

Pharmacokinetics

Distribution of hexestrol radioactivity in blood and tissues after a subcutaneous injection of a physiological dose of tritium-labeled hexestrol in oil solution in five juvenile female goats.[13] Points are one animal each.[13] With the exception of skeletal muscle, tissues with a radioactivity concentration of less than 15% of that of the endometrium are not shown.[13] Hexestrol is concentrated in target tissues such as the uterus and vagina due to binding to estrogen receptors.[14]

The pharmacokinetics and distribution of hexestrol have been studied with intravenous injection of aqueous solution in women and with subcutaneous injection of oil solution in female goats and sheep.[15][13]

Chemistry

See also: Stilbestrol § Stilbestrol derivatives, and List of estrogen esters § Hexestrol esters

Hexestrol, also known as dihydrodiethylstilbestrol, is a synthetic nonsteroidal estrogen of the stilbestrol group related to diethylstilbestrol.[1][2] Esters of hexestrol include hexestrol diacetate, hexestrol dicaprylate, hexestrol diphosphate, and hexestrol dipropionate.[1]

History

Hexestrol was first described by Campbell, Dodds, and Lawson in 1938.[16][11][17][18] It was isolated from the demethylation products of anethole.[16][11][17][18]

Society and culture

Generic names

Hexestrol is the generic name of the drug and its INNTooltip International Nonproprietary Name.[1][2]

Brand names

Hexestrol has been marketed under a variety of brand names including Synestrol, Synoestrol, Estrifar, and Estronal, among others.[1][2]

Availability

Hexestrol has mostly been discontinued and remains available in only a handful of countries.[19][4] Esters of hexestrol which have been marketed include hexestrol diacetate, hexestrol dicaprylate, hexestrol diphosphate, and hexestrol dipropionate.[1]

References

  1. ^ a b c d e f g Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 162–. ISBN 978-1-4757-2085-3.
  2. ^ a b c d e Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 140–. ISBN 978-94-011-4439-1.
  3. ^ Thomas JA (12 March 1997). Endocrine Toxicology, Second Edition. CRC Press. pp. 144–. ISBN 978-1-4398-1048-4.
  4. ^ a b "Estradiol: Uses, Dosage & Side Effects".
  5. ^ a b c d Horsky J, Presl J (6 December 2012). Ovarian Function and its Disorders: Diagnosis and Therapy. Springer Science & Business Media. pp. 83, 85, 145, 310. ISBN 978-94-009-8195-9.
  6. ^ Thomas JA, Keenan EJ (6 December 2012). Principles of Endocrine Pharmacology. Springer Science & Business Media. pp. 153–. ISBN 978-1-4684-5036-1.
  7. ^ Barar FS (2012). Textbook of Pharmacology. S. Chand Publishing. pp. 348–. ISBN 978-81-219-4080-1.
  8. ^ Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA (March 1997). "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta". Endocrinology. 138 (3): 863–870. doi:10.1210/endo.138.3.4979. PMID 9048584.
  9. ^ Leclercq G, Heuson JC (December 1979). "Physiological and pharmacological effects of estrogens in breast cancer". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 560 (4): 427–455. doi:10.1016/0304-419x(79)90012-x. PMID 391285.
  10. ^ Solmssen UV (December 1945). "Synthetic estrogens and the relation between their structure and their activity". Chemical Reviews. 37 (3): 481–598. doi:10.1021/cr60118a004. PMID 21013428.
  11. ^ a b c Campbell NR, Dodds EC, Lawson W, Noble RL (1939). "Biological effects of the synthetic œstrogen hexœstrol". The Lancet. 234 (6049): 312–313. doi:10.1016/S0140-6736(00)61997-9. ISSN 0140-6736.
  12. ^ Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID 16112947. S2CID 24616324.
  13. ^ a b c d Glascock RF, Hoekstra WG (August 1959). "Selective accumulation of tritium-labelled hexoestrol by the reproductive organs of immature female goats and sheep". The Biochemical Journal. 72 (4): 673–682. doi:10.1042/bj0720673. PMC 1196992. PMID 13828338.
  14. ^ Jensen EV, DeSombre ER (1972). "Mechanism of action of the female sex hormones". Annual Review of Biochemistry. 41: 203–230. doi:10.1146/annurev.bi.41.070172.001223. PMID 4563437.
  15. ^ Folca PJ, Glascock RF, Irvine WT (October 1961). "Studies with tritium-labelled hexoestrol in advanced breast cancer. Comparison of tissue accumulation of hexoestrol with response to bilateral adrenalectomy and oophorectomy". Lancet. 2 (7206): 796–798. doi:10.1016/s0140-6736(61)91088-1. PMID 13893792.
  16. ^ a b Campbell NR, Dodds EC, Lawson W (1938). "Œstrogenic Activity of Anol; a Highly Active Phenol Isolated from the By-Products". Nature. 142 (3608): 1121. Bibcode:1938Natur.142.1121C. doi:10.1038/1421121a0. ISSN 0028-0836. S2CID 4140616.
  17. ^ a b Medicinal Chemistry. John Wiley & Sons. 1956. p. 40.
  18. ^ a b Campbell NR, Dodds EC, Lawson W (1940). "The nature of the oestrogenic substances produced during the demethylation of anethole". Proceedings of the Royal Society of London. Series B, Biological Sciences. 128 (851): 253–262. Bibcode:1940RSPSB.128..253C. doi:10.1098/rspb.1940.0009. ISSN 2053-9193.
  19. ^ "Micromdex". Merative. Retrieved 10 March 2023.
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