Hexestrol

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Hexestrol
Hexestrol.svg
Clinical data
Trade names Synestrol, 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 class Nonsteroidal 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 InfoCard 100.001.380 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C18H22O2
Molar mass 270.372 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]

Contents

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/formEstrogenDosage
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
Hexestrol5 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
IM 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
EstrogenFormMajor brand name(s)EPD (14 days)Duration
Diethylstilbestrol (DES)Oil solutionMetestrol20 mg1 mg ≈ 2–3 days; 3 mg ≈ 3 days
Diethylstilbestrol dipropionate Oil solutionCyren B12.5–15 mg2.5 mg ≈ 5 days
Aqueous suspension ?5 mg ? mg = 21–28 days
Dimestrol (DES dimethyl ether) Oil solutionDepot-Cyren, Depot-Oestromon, Retalon Retard20–40 mg ?
Fosfestrol (DES diphosphate) aAqueous solutionHonvan ?<1 day
Dienestrol diacetate Aqueous suspensionFarmacyrol-Kristallsuspension50 mg ?
Hexestrol dipropionate Oil solutionHormoestrol, Retalon Oleosum25 mg ?
Hexestrol diphosphate aAqueous solutionCytostesin, 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. Points are one animal each. With the exception of skeletal muscle, tissues with a radioactivity concentration of less than 15% of that of the endometrium are not shown. Hexestrol is concentrated in target tissues such as the uterus and vagina due to binding to estrogen receptors. Distribution of hexestrol radioactivity after a subcutaneous injection of tritiated hexestrol in oil solution in female goats.png
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. Points are one animal each. With the exception of skeletal muscle, tissues with a radioactivity concentration of less than 15% of that of the endometrium are not shown. Hexestrol is concentrated in target tissues such as the uterus and vagina due to binding to estrogen receptors.

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

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 INN. [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]

Related Research Articles

<span class="mw-page-title-main">Diethylstilbestrol</span> Chemical compound

Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a history of recurrent miscarriage, hormone therapy for menopausal symptoms and estrogen deficiency, treatment of prostate cancer and breast cancer, and other uses. By 2007, it was only used in the treatment of prostate cancer and breast cancer. In 2011, Hoover and colleagues reported on adverse health outcomes linked to DES including infertility, miscarriage, ectopic pregnancy, preeclampsia, preterm birth, stillbirth, infant death, menopause prior to age 45, breast cancer, cervical cancer, and vaginal cancer. While most commonly taken by mouth, DES was available for use by other routes as well, for instance, vaginal, topical, and by injection.

<span class="mw-page-title-main">Stilbestrol</span> Chemical compound

Stilbestrol, or stilboestrol, also known as 4,4'-dihydroxystilbene or 4,4'-stilbenediol, is a stilbenoid nonsteroidal estrogen and the parent compound of a group of more potent nonsteroidal estrogen derivatives that includes, most notably, diethylstilbestrol (DES). The term "stilbestrol" is often used incorrectly to refer to DES, but they are not the same compound.

<span class="mw-page-title-main">Polyestradiol phosphate</span> Chemical compound

Polyestradiol phosphate (PEP), sold under the brand name Estradurin, is an estrogen medication which is used primarily in the treatment of prostate cancer in men. It is also used in women to treat breast cancer, as a component of hormone therapy to treat low estrogen levels and menopausal symptoms, and as a component of feminizing hormone therapy for transgender women. It is given by injection into muscle once every four weeks.

<span class="mw-page-title-main">Estradiol benzoate</span> Chemical compound

Estradiol benzoate (EB), sold under the brand name Progynon-B among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for transgender women, and in the treatment of gynecological disorders. It is also used in the treatment of prostate cancer in men. Estradiol benzoate is used in veterinary medicine as well. When used clinically, the medication is given by injection into muscle usually two to three times per week.

<span class="mw-page-title-main">Estradiol cypionate</span> Chemical compound

Estradiol cypionate (EC), sold under the brand name Depo-Estradiol among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in cis women, in hormone therapy for trans women, and in hormonal birth control for cis women. It is given by injection into muscle once every 1 to 4 weeks.

<span class="mw-page-title-main">Estriol succinate</span> Chemical compound

Estriol succinate, sold under the brand name Synapause among others, is an estrogen medication which is used in the treatment of menopausal symptoms. It is taken by mouth, in through the vagina, and by injection.

<span class="mw-page-title-main">Methallenestril</span> Chemical compound

Methallenestril (INN), also known as methallenoestril (BAN) and as methallenestrol, as well as Horeau's acid, is a synthetic nonsteroidal estrogen and a derivative of allenolic acid and allenestrol that was formerly used to treat menstrual issues but is now no longer marketed. It is a seco-analogue of bisdehydrodoisynolic acid, and although methallenestril is potently estrogenic in rats, in humans it is only weakly so in comparison. Vallestril was a brand of methallenestril issued by G. D. Searle & Company in the 1950s. Methallenestril is taken by mouth. By the oral route, a dose of 25 mg methallenestril is approximately equivalent to 1 mg diethylstilbestrol, 4 mg dienestrol, 20 mg hexestrol, 25 mg estrone, 2.5 mg conjugated estrogens, and 0.05 mg ethinylestradiol.

<span class="mw-page-title-main">Estradiol dipropionate</span> Chemical compound

Estradiol dipropionate (EDP), sold under the brand names Agofollin, Di-Ovocylin, and Progynon DP among others, is an estrogen medication which has been used in hormone therapy for menopausal symptoms and low estrogen levels in women and in the treatment of gynecological disorders. It has also been used in feminizing hormone therapy for transgender women and in the treatment of prostate cancer in men. Although widely used in the past, estradiol dipropionate has largely been discontinued and is mostly no longer available today. It appears to remain in use only in Japan, Macedonia, and Australia. Estradiol dipropionate is given by injection into muscle at intervals ranging from once or twice a week to once every week and a half to two weeks.

An estrogen ester is an ester of an estrogen, most typically of estradiol but also of other estrogens such as estrone, estriol, and even nonsteroidal estrogens like diethylstilbestrol. Esterification renders estradiol into a prodrug of estradiol with increased resistance to first-pass metabolism, slightly improving its oral bioavailability. In addition, estrogen esters have increased lipophilicity, which results in a longer duration when given by intramuscular or subcutaneous injection due to the formation of a long-lasting local depot in muscle and fat. Conversely, this is not the case with intravenous injection or oral administration. Estrogen esters are rapidly hydrolyzed into their parent estrogen by esterases once they have been released from the depot. Because estradiol esters are prodrugs of estradiol, they are considered to be natural and bioidentical forms of estrogen.

<span class="mw-page-title-main">Anol</span> Pair of stereoisomers

Anol, also known as para-hydroxypropenylbenzene, is a simple phenol that was derived via demethylation from anethole, an estrogenic constituent of anise and fennel, by Sir Charles Dodds in 1937. It was reported to possess extremely potent estrogenic activity on par with that of steroidal estrogens like estrone, with a dose of 1 μg inducing estrus in rats. However, subsequent studies with different preparations of anol failed to confirm these findings, and it was found that dimerization of anol into dianol and hexestrol can rapidly occur and that the latter impurity was responsible for the highly potent estrogenic effects. Dodds later synthesized the structurally related and extremely potent estrogen diethylstilbestrol in 1938.

<span class="mw-page-title-main">Methestrol</span> Chemical compound

Methestrol or methoestrol, also known as promethestrol or promethoestrol (BAN) or as dimethylhexestrol, is a synthetic nonsteroidal estrogen of the stilbestrol group related to diethylstilbestrol which is no longer marketed.

<span class="mw-page-title-main">Estradiol hexahydrobenzoate</span> Chemical compound

Estradiol hexahydrobenzoate (EHHB), sold under a number of brand names including Benzo-Ginoestril A.P., BenzoGynoestryl Retard, Ginestryl-15-Depot, Menodin, and Tardoginestryl, is an estrogen medication which was previously used for indications such as menopausal hormone therapy and gynecological disorders. EHHB is given by injection into muscle at regular intervals, for instance once every few weeks.

<span class="mw-page-title-main">Dienestrol diacetate</span> Chemical compound

Dienestrol diacetate is a synthetic nonsteroidal estrogen of the stilbestrol group related to diethylstilbestrol. It is an ester of dienestrol.

<span class="mw-page-title-main">Diethylstilbestrol dipropionate</span> Chemical compound

Diethylstilbestrol dipropionate (DESDP), or diethylstilbestrol dipropanoate, also known as stilboestrol dipropionate (BANM), is a synthetic nonsteroidal estrogen of the stilbestrol group that was formerly marketed widely throughout Europe. It is an ester of diethylstilbestrol with propionic acid, and is more slowly absorbed in the body than diethylstilbestrol. The medication has been said to be one of the most potent estrogens known.

<span class="mw-page-title-main">Hexestrol diacetate</span> Chemical compound

Hexestrol diacetate (JAN) is a synthetic, nonsteroidal estrogen of the stilbestrol group related to diethylstilbestrol. It is an ester of hexestrol, and was discovered in 1939.

<span class="mw-page-title-main">Hexestrol dipropionate</span> Chemical compound

Hexestrol dipropionate, or hexestrol dipropanoate, is a synthetic, nonsteroidal estrogen of the stilbestrol group related to diethylstilbestrol. It is an ester of hexestrol, and has been known since at least 1931. The drug has been used in the past to inhibit lactation in women.

<span class="mw-page-title-main">Hexestrol diphosphate</span> Chemical compound

Hexestrol diphosphate is a synthetic, nonsteroidal estrogen of the stilbestrol group related to diethylstilbestrol and used as an estrogen and antineoplastic agent in the treatment of prostate cancer. It is a water-soluble ester of hexestrol. The medication has been known since at least 1956.

<span class="mw-page-title-main">Dianol</span> Chemical compound

Dianol is a synthetic, nonsteroidal estrogen that was never marketed. It is a dimer and impurity of anol, and was, along with hexestrol, involved in erroneous findings of highly potent estrogenic activity with anol. Although a potent estrogen, it requires a dose of 100 μg to show activity, whereas hexestrol shows activity with a mere dose of 0.2 μg.

Hexestrol dicaprylate, or dioctanoylhexestrol, is a synthetic, nonsteroidal estrogen of the stilbestrol group related to diethylstilbestrol that is no longer marketed. It is a long-acting ester of hexestrol.

References

  1. 1 2 3 4 5 6 7 J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 162–. ISBN   978-1-4757-2085-3.
  2. 1 2 3 4 5 I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 140–. ISBN   978-94-011-4439-1.
  3. ↑ John A. Thomas (12 March 1997). Endocrine Toxicology, Second Edition. CRC Press. pp. 144–. ISBN   978-1-4398-1048-4.
  4. 1 2 "Estradiol: Uses, Dosage & Side Effects".
  5. 1 2 3 4 J. Horsky; J. Presl (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. ↑ John A. Thomas; Edward J. Keenan (6 December 2012). Principles of Endocrine Pharmacology. Springer Science & Business Media. pp. 153–. ISBN   978-1-4684-5036-1.
  7. ↑ Barar F.S.K. (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 (1997). "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta". Endocrinology. 138 (3): 863–70. 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". Biochim. Biophys. Acta. 560 (4): 427–55. doi:10.1016/0304-419x(79)90012-x. PMID   391285.
  10. ↑ SOLMSSEN UV (1945). "Synthetic estrogens and the relation between their structure and their activity". Chem. Rev. 37 (3): 481–598. doi:10.1021/cr60118a004. PMID   21013428.
  11. 1 2 3 Campbell, N.R.; Dodds, E.C.; Lawson, W.; Noble, R.L. (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" (PDF). Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID   16112947. S2CID   24616324.
  13. 1 2 3 4 Glascock RF, Hoekstra WG (August 1959). "Selective accumulation of tritium-labelled hexoestrol by the reproductive organs of immature female goats and sheep". Biochem. J. 72 (4): 673–82. doi:10.1042/bj0720673. PMC   1196992 . PMID   13828338.
  14. ↑ Jensen EV, DeSombre ER (1972). "Mechanism of action of the female sex hormones". Annu. Rev. Biochem. 41: 203–30. 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): 796–8. doi:10.1016/s0140-6736(61)91088-1. PMID   13893792.
  16. 1 2 Campbell, N. R.; Dodds, E. C.; 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. 1 2 Medicinal Chemistry. John Wiley & Sons. 1956. p. 40.
  18. 1 2 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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