Chlorotrianisene

CTA has been used in the treatment of menopausal symptoms and estrogen deficiency in women and prostate cancer in men, among other indications. It has been used to suppress lactation in women.{{Cite book |url=https://books.google.com/books?id=wYxirvD2X2IC&pg=PA203 |title=The Breast: Morphology, Physiology, and Lactation |vauthors=Vorherr H |date=2 December 2012 |publisher=Elsevier Science |isbn=978-0-323-15726-1 |pages=203–}} CTA has been used in the treatment of acne as well.{{Cite book |title=Therapie der Haut- und Geschlechtskrankheiten |vauthors=Schirren C |year=1961 |isbn=978-3-642-94851-0 |pages=470–549 |chapter=Die Sexualhormone |doi=10.1007/978-3-642-94850-3_6}}{{Cite journal |vauthors=Kile RL |date=August 1953 |title=The treatment of acne with TACE |journal=J Invest Dermatol |volume=21 |issue=2 |pages=79–81 |doi=10.1038/jid.1953.73 |pmid=13084969 |doi-access=free}}{{Cite journal |vauthors=Welsh AL |date=April 1954 |title=Use of synthetic estrogenic substance chlorotrianisene (TACE) in treatment of acne |journal=AMA Arch Dermatol Syphilol |volume=69 |issue=4 |pages=418–27 |doi=10.1001/archderm.1954.01540160020004 |pmid=13147544}}

{{Estrogen dosages for breast and prostate cancer}}

{{See also|Estrogen (medication)#Side effects}}

In men, CTA can produce gynecomastia as a side effect.{{Cite book |title=Antineoplastic and Immunosuppressive Agents |vauthors=Dao TL |year=1975 |isbn=978-3-642-65806-8 |veditors=Sartorelli AC, Johns DG |pages=170–192 |chapter=Pharmacology and Clinical Utility of Hormones in Hormone Related Neoplasms |doi=10.1007/978-3-642-65806-8_11 |chapter-url=https://books.google.com/books?id=aU_oCAAAQBAJ&pg=PA170}} Conversely, it does not appear to lower testosterone levels in men, and hence does not seem to have a risk of hypogonadism and associated side effects in men.

File:Testosterone levels with different estrogen therapies in men with prostate cancer.png (RIA). Source was Shearer et al. (1973).]]

CTA is a relatively weak estrogen, with about one-eighth the potency of DES. However, it is highly lipophilic and is stored in fat tissue for prolonged periods of time, with its slow release from fat resulting in a very long duration of action. CTA itself is inactive; it behaves as a prodrug to desmethylchlorotrianisene (DMCTA), a weak estrogen that is formed as a metabolite via mono-O-demethylation of CTA in the liver.{{Cite book |url=https://books.google.com/books?id=fmfSBwAAQBAJ&pg=PA249 |title=Pharmacology |vauthors=Hadden J |date=9 November 2013 |publisher=Springer Science & Business Media |isbn=978-1-4615-9406-2 |pages=249–}} As such, the potency of CTA is reduced if it is given parenterally instead of orally.

Although it is referred to as a weak estrogen and was used solely as an estrogen in clinical practice, CTA is a high-efficacy partial agonist of the estrogen receptor. As such, it is a selective estrogen receptor modulator (SERM), with predominantly estrogenic effects but also with antiestrogenic effects, and was arguably the first SERM to ever be introduced.{{Cite book |url=https://books.google.com/books?id=BP2Bo11gTOMC&pg=SA5-PA56 |title=Analogue-based Drug Discovery III |vauthors=Fischer J, Ganellin CR, Rotella DP |date=15 October 2012 |publisher=John Wiley & Sons |isbn=978-3-527-65110-8 |pages=5–}} CTA can antagonize estradiol at the level of the hypothalamus, resulting in disinhibition of the hypothalamic–pituitary–gonadal axis and an increase in estrogen levels. Clomifene and tamoxifen were both derived from CTA via structural modification, and are much lower-efficacy partial agonists than CTA and hence much more antiestrogenic in comparison. As an example, chlorotrianisene produces gynecomastia in men,{{Cite book |url=https://books.google.com/books?id=-GPl1PA5EgMC&pg=PA34 |title=Triumph of the Heart: The Story of Statins |vauthors=Li JJ |date=3 April 2009 |publisher=Oxford University Press, USA |isbn=978-0-19-532357-3 |pages=34–}} albeit reportedly to a lesser extent than other estrogens,{{Cite book |url=https://books.google.com/books?id=5ZbLRONHoDoC&pg=PA387 |title=Vitamins and Hormones |date=18 May 1976 |publisher=Academic Press |isbn=978-0-08-086630-7 |pages=387–}} while clomifene and tamoxifen do not and can be used to treat gynecomastia.{{Cite journal |vauthors=Khan HN, Blamey RW |date=August 2003 |title=Endocrine treatment of physiological gynaecomastia |journal=BMJ |volume=327 |issue=7410 |pages=301–2 |doi=10.1136/bmj.327.7410.301 |pmc=1126712 |pmid=12907471}}

CTA at a dosage of 48 mg/day inhibits ovulation in almost all women.{{Cite journal |vauthors=Duncan CJ, Kistner RW, Mansell H |date=October 1956 |title=Suppression of ovulation by trip-anisyl chloroethylene (TACE) |url=https://journals.lww.com/greenjournal/citation/1956/10000/suppression_of_ovulation_by_tri_p_anisyl.4.aspx |journal=Obstet Gynecol |volume=8 |issue=4 |pages=399–407 |pmid=13370006}} Conversely, it has been reported that CTA has no measurable effect on circulating levels of testosterone in men.{{Cite book |url=https://books.google.com/books?id=8mkyBwAAQBAJ&pg=PA70 |title=The Endocrinology of Prostate Tumours |vauthors=Ghanadian R |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-94-011-7256-1 |pages=70–}} This is in contrast to other estrogens, like diethylstilbestrol, which can suppress testosterone levels by as much as 96%—or to an equivalent extent as castration. These findings suggest that CTA is not an effective antigonadotropin in men.

Chlorotrianisene, also known as tri-p-anisylchloroethylene (TACE) or as tris(p-methoxyphenyl)chloroethylene, is a synthetic nonsteroidal compound of the triphenylethylene group. It is structurally related to the nonsteroidal estrogen diethylstilbestrol and to the SERMs clomifene and tamoxifen.

CTA was introduced for medical use in the United States in 1952, and was subsequently introduced for use throughout Europe.{{Cite book |last=William Andrew Publishing |url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA980 |title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition |date=22 October 2013 |publisher=Elsevier |isbn=978-0-8155-1856-3 |pages=980–}} It was the first estrogenic compound of the triphenylethylene series to be introduced. CTA was derived from estrobin (DBE), a derivative of the very weakly estrogenic compound triphenylethylene (TPE), which in turn was derived from structural modification of diethylstilbestrol (DES).{{Cite book |url=https://books.google.com/books?id=CA0HCAAAQBAJ&pg=PA486 |title=Endocrine Replacement Therapy in Clinical Practice |vauthors=Meikle AW |date=24 April 2003 |publisher=Springer Science & Business Media |isbn=978-1-59259-375-0 |pages=486–}}{{Cite book |url=https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA198 |title=Drug Discovery: A History |vauthors=Sneader W |date=23 June 2005 |publisher=John Wiley & Sons |isbn=978-0-471-89979-2 |pages=198–}}{{Cite journal |vauthors=Jordan VC, Mittal S, Gosden B, Koch R, Lieberman ME |date=September 1985 |title=Structure-activity relationships of estrogens |journal=Environmental Health Perspectives |volume=61 |pages=97–110 |bibcode=1985EnvHP..61...97J |doi=10.1289/ehp.856197 |pmc=1568776 |pmid=3905383}}{{Cite book |url=https://books.google.com/books?id=VEibBwAAQBAJ&pg=PA87 |title=Medicinal Chemistry of Anticancer Drugs |vauthors=Avendano C, Menendez JC |date=11 June 2015 |publisher=Elsevier Science |isbn=978-0-444-62667-7 |pages=87–}} The SERMs clomifene and tamoxifen, as well as the antiestrogen ethamoxytriphetol, were derived from CTA via structural modification.{{Cite book |url=https://books.google.com/books?id=7DSYBwAAQBAJ&pg=PA286 |title=Endocrinology of Breast Cancer |vauthors=Manni A |date=15 January 1999 |publisher=Springer Science & Business Media |isbn=978-1-59259-699-7 |pages=286–287}}{{Cite book |url=https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA178 |title=The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs |vauthors=Ravina E |date=11 January 2011 |publisher=John Wiley & Sons |isbn=978-3-527-32669-3 |pages=178–}}

Chlorotrianisene is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, and {{abbrlink|BAN|British Approved Name}}. It is also known as tri-p-anisylchloroethylene (TACE).

CTA has been marketed under the brand names Tace, Estregur, Anisene, Clorotrisin, Merbentyl, Merbentul, and Triagen among many others.

CTA is no longer marketed and hence is no longer available in any country.http://www.micromedexsolutions.com/micromedex2/{{Dead link|date=June 2019 |bot=InternetArchiveBot |fix-attempted=yes }} It was previously used in the United States and Europe.

{{Reflist}}

{{Estrogens and antiestrogens}}

{{Estrogen receptor modulators}}

Category:Abandoned drugs

Category:Hormonal antineoplastic drugs

Category:Organochlorides

Category:4-Methoxyphenyl compounds

Category:Prodrugs

Category:Progonadotropins

Category:Selective estrogen receptor modulators

Category:Synthetic estrogens

Category:Triphenylethylenes

Category:Bis(4-hydroxyphenyl)methanes