Epitiostanol

Epitiostanol, sold under the brand name Thiodrol, is an injected antiestrogen and anabolic–androgenic steroid (AAS) of the dihydrotestosterone (DHT) group which was described in the literature in 1965 and has been marketed in Japan as an antineoplastic agent for the treatment of breast cancer since 1977.[1][2][3][4][5]

Epitiostanol
Clinical data
Trade namesThiodrol
Other namesEpithiostanol; Epithioandrostanol; 10275-S; 2α,3α-Epithio-5α-androstan-17β-ol; 2α,3α-Epithio-4,5α-dihydrotestosterone; 2α,3α-Epithio-DHT
Routes of
administration		Intramuscular injection
Drug classAndrogen; Anabolic steroid; Antiestrogen
Identifiers
IUPAC name
  • (1S,3AS,3bR,5aS,6aS,7aR,8aS,8bS,10aS)-8a,10a-dimethylhexadecahydro-1H-cyclopenta[7,8]phenanthro[2,3-b]thiiren-1-ol
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC19H30OS
Molar mass306.51 g·mol−1
3D model (JSmol)
SMILES
  • CC12CCC3C(C1CCC2O)CCC4C3(CC5C(C4)S5)C
InChI
  • InChI=InChI=1S/C19H30OS/c1-18-8-7-14-12(13(18)5-6-17(18)20)4-3-11-9-15-16(21-15)10-19(11,14)2/h11-17,20H,3-10H2,1-2H3
  • Key:OBMLHUPNRURLOK-UHFFFAOYSA-N

Medical uses

Epitiostanol is used as an antiestrogen and antineoplastic agent in the treatment of breast cancer.[1][2][3][4][5] It has also been found to be effective in the treatment of gynecomastia.[6][7]

Side effects
See also: Anabolic steroid § Adverse effects

A prodrug of epitiostanol, mepitiostane, which is also marketed for the treatment of breast cancer, is reported to show a high rate of virilizing side effects such as acne, hirsutism, and voice changes in women.[8]

Pharmacology

Pharmacodynamics

Epitiostanol binds directly to the androgen receptor (AR) and estrogen receptor (ER), where it acts as an agonist and antagonist, respectively.[3][5][9][10] It is described as potent in its activity as an antiestrogen and comparatively weak as an AAS.[7] In any case, in terms of AAS potency, epitiostanol has been found to have 11 times the anabolic activity and approximately equal androgenic activity relative to that of the reference AAS methyltestosterone.[11] The mechanism of action of epitiostanol in breast cancer is multimodal; it directly suppresses tumor growth through activation of the AR and inhibition of the ER, and, in premenopausal women, it additionally acts as an antigonadotropin and reducing systemic estrogen levels via AR activation and consequent suppression of the hypothalamic-pituitary-gonadal axis.[5][12] Epitiostanol is unique among AAS in acting as an antagonist of the ER.

Pharmacokinetics

Similarly to the case of testosterone, epitiostanol shows poor bioavailability and weak therapeutic efficacy when taken orally due to extensive first-pass metabolism.[13] As such, it must instead be administered via intramuscular injection.[13]

Chemistry
See also: List of androgens/anabolic steroids

Epitiostanol, also known as 2α,3α-epithio-4,5α-dihydrotestosterone (2α,3α-epithio-DHT) or as 2α,3α-epithio-5α-androstan-17β-ol, is a synthetic androstane steroid and a derivative of DHT.[1][2] Mepitiostane, a derivative of epitiostanol with a C17α methoxycyclopentane ether substitution, is an orally active prodrug of epitiostanol.[14][15] Another derivative, methylepitiostanol (2α,3α-epithio-17α-methyl-5α-androstan-17β-ol), has a methyl group at the C17α position and is similarly an orally active variant of epitiostanol; it has surfaced as a novel designer steroid.[12]

Society and culture

Generic names

Epitiostanol is the generic name of the drug and its INN and JAN.[1][2]

References
  1. J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 492–. ISBN 978-1-4757-2085-3.
  2. Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 394–. ISBN 978-3-88763-075-1.
  3. H. Timmerman (20 November 1995). QSAR and Drug Design: New Developments and Applications. Elsevier. pp. 125, 145. ISBN 978-0-08-054500-4.
  4. William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1455–. ISBN 978-0-8155-1856-3.
  5. Matsuzawa A, Yamamoto T (1977). "Antitumor effect of two oral steroids, mepitiostane and fluoxymesterone, on a pregnancy-dependent mouse mammary tumor (TPDMT-4)". Cancer Res. 37 (12): 4408–15. PMID 922732.
  6. Acta obstetrica et gynecologica japonica. Japanese Obstetrical and Gynecological Society. 1975.
  7. "2α 3α-Epithio-5α-androstan-17β-ol in Treatment of Gynecomastia". Japanese Journal of Clinical Oncology. 1973. doi:10.1093/oxfordjournals.jjco.a039832. ISSN 1465-3621.
  8. Inoue K, Okazaki K, Morimoto T, Hayashi M, Uyama S, Sonoo H, Koshiba Y, Takihara T, Nomura Y, Yamagata J, Kondo H, Kanda K, Takenaka K (1978). "Therapeutic value of mepitiostane in the treatment of advanced breast cancer". Cancer Treat Rep. 62 (5): 743–5. PMID 657160.
  9. INTERNATIONAL REVIEW OF CYTOLOGY. Academic Press. 27 June 1986. pp. 319–. ISBN 978-0-08-058640-3.
  10. Croll, Roger P.; Wang, Chunde (2007). "Possible roles of sex steroids in the control of reproduction in bivalve molluscs". Aquaculture. 272 (1–4): 76–86. doi:10.1016/j.aquaculture.2007.06.031. ISSN 0044-8486.
  11. Brueggemeier, Robert W. (2006). "Sex Hormones (Male): Analogs and Antagonists". Encyclopedia of Molecular Cell Biology and Molecular Medicine. doi:10.1002/3527600906.mcb.200500066. ISBN 3527600906.
  12. Rahnema, C. D.; Crosnoe, L. E.; Kim, E. D. (2015). "Designer steroids - over-the-counter supplements and their androgenic component: review of an increasing problem". Andrology. 3 (2): 150–155. doi:10.1111/andr.307. ISSN 2047-2919. PMID 25684733. S2CID 6999218.
  13. Ichihashi, T.; Kinoshita, H.; Yamada, H. (2009). "Absorption and disposition of epithiosteroids in rats (2): Avoidance of first-pass metabolism of mepitiostane by lymphatic absorption". Xenobiotica. 21 (7): 873–880. doi:10.3109/00498259109039527. ISSN 0049-8254. PMID 1776263.
  14. Ichihashi, Teruhisa; Kinoshita, Haruki; Takagishi, Yasushi; Yamada, Hideo (1991). "Intrinsic Lymphatic Partition Rate of Mepitiostane, Epitiostanol, and Oleic Acid Absorbed from Rat Intestine". Pharmaceutical Research. 08 (10): 1302–1306. doi:10.1023/A:1015864131681. ISSN 0724-8741. PMID 1796049. S2CID 31203405.
  15. Ichihashi, Teruhisa; Takagishi, Yasushi; Yamada, Hideo (1992). "Factors Determining the Intrinsic Lymphatic Partition Rate of Epitiostanol and Mepitiostane". Pharmaceutical Research. 09 (12): 1617–1621. doi:10.1023/A:1015824710957. ISSN 0724-8741. PMID 1488406. S2CID 2881279.


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