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 names	Thiodrol
Other names	Epithiostanol; 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 class	Androgen; 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	2363-58-8 Y
PubChem CID	3243
ChemSpider	391989
UNII	YE7586973L
CompTox Dashboard (EPA)	DTXSID2045367
Chemical and physical data
Formula	C19H30OS
Molar mass	306.51 g·mol−1
3D model (JSmol)	Interactive image
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.^{[citation needed]}

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 INNTooltip International Nonproprietary Name and JANTooltip Japanese Accepted Name.^[1][2]

References

1. Elks J (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. Timmerman H (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 (December 1977). "Antitumor effect of two oral steroids, mepitiostane and fluoxymesterone, on a pregnancy-dependent mouse mammary tumor (TPDMT-4)". Cancer Research. 37 (12): 4408–4415. PMID 922732.
6. Kurachi K, Aono T, Tomoyama J, Matsumoto K, Nakasima A (January 1975). "Effects of 2alpha, 3alpha-epithio-5alpha-androstan-17beta-ol (epitiostanol) on hypothalamo-pituitary-gonadal axis in humans". Acta Obstetrica et Gynaecologica Japonica. 22 (1). Japanese Obstetrical and Gynecological Society: 42–8. PMID 1224948.
7. Abe O, Kumaoka S, Yamamoto H (December 1973). "2α 3α-Epithio-5α-androstan-17β-ol in Treatment of Gynecomastia". Japanese Journal of Clinical Oncology. 3 (2): 99–104. doi:10.1093/oxfordjournals.jjco.a039832. ISSN 1465-3621.
8. Inoue K, Okazaki K, Morimoto T, Hayashi M, Uyama S, Sonoo H, et al. (May 1978). "Therapeutic value of mepitiostane in the treatment of advanced breast cancer". Cancer Treatment Reports. 62 (5): 743–745. PMID 657160.
9. Matsuzawa A (27 June 1986). "Hormone Dependence and Independence in Mammary Tumors in Mice". In Bourne GH, Heon KW, Friedlander M (eds.). International Review of Cytology. Vol. 103. Academic Press. pp. 319–. ISBN 978-0-08-058640-3.
10. Croll RP, Wang C (2007). "Possible roles of sex steroids in the control of reproduction in bivalve molluscs". Aquaculture. 272 (1–4): 76–86. Bibcode:2007Aquac.272...76C. doi:10.1016/j.aquaculture.2007.06.031. ISSN 0044-8486.
11. Brueggemeier RW (2006). "Sex Hormones (Male): Analogs and Antagonists". Encyclopedia of Molecular Cell Biology and Molecular Medicine. Wiley-VCH Verlag GmbH & Co. KGaA. doi:10.1002/3527600906.mcb.200500066. ISBN 3-527-60090-6.
12. Rahnema CD, Crosnoe LE, Kim ED (March 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. PMID 25684733. S2CID 6999218.
13. Ichihashi T, Kinoshita H, Yamada H (July 1991). "Absorption and disposition of epithiosteroids in rats (2): Avoidance of first-pass metabolism of mepitiostane by lymphatic absorption". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 21 (7): 873–880. doi:10.3109/00498259109039527. PMID 1776263.
14. Ichihashi T, Kinoshita H, Takagishi Y, Yamada H (October 1991). "Intrinsic lymphatic partition rate of mepitiostane, epitiostanol, and oleic acid absorbed from rat intestine". Pharmaceutical Research. 8 (10): 1302–1306. doi:10.1023/A:1015864131681. PMID 1796049. S2CID 31203405.
15. Ichihashi T, Takagishi Y, Yamada H (December 1992). "Factors determining the intrinsic lymphatic partition rate of epitiostanol and mepitiostane". Pharmaceutical Research. 9 (12): 1617–1621. doi:10.1023/A:1015824710957. PMID 1488406. S2CID 2881279.