Chlorotrianisene (CTA), also known as tri-''p''-anisylchloroethylene (TACE) and sold under the brand name Tace among others, is a

nonsteroidal estrogen A nonsteroidal estrogen is an estrogen with a nonsteroidal chemical structure. The most well-known example is the stilbestrol estrogen diethylstilbestrol (DES). Although nonsteroidal estrogens formerly had an important place in medicine, they ...

related to

diethylstilbestrol 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 ...

(DES) which was previously used in the treatment of

menopausal symptoms Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...

and estrogen deficiency in women and

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that su ...

in men, among other indications, but has since been discontinued and is now no longer available. It is taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

. CTA is an

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal a ...

, or an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the

estrogen receptor Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors ( ERα and ERβ), which are members of th ...

s, the

biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...

of estrogens like

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...

. It is a high- efficacy partial estrogen and shows some properties of a

selective estrogen receptor modulator Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists ...

, with predominantly

ic activity but also some

antiestrogen Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or i ...

ic activity. CTA itself is inactive and is a prodrug in the body. CTA was introduced for medical use in 1952. It has been marketed in the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., federal district, five ma ...

and

Europe Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a subcontinent of Eurasia and it is located enti ...

. However, it has since been discontinued and is no longer available in any country.

Medical uses

CTA has been used in the treatment of

and estrogen deficiency in women and

in men, among other indications. It has been used to suppress

lactation Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The pr ...

in women. CTA has been used in the treatment of

acne Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...

as well.

Side effects

In men, CTA can produce

gynecomastia Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse ...

as a

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

. Conversely, it does not appear to lower

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteris ...

levels in men, and hence does not seem to have a risk of

hypogonadism Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low est ...

and associated side effects in men.

Pharmacology

Testosterone levels with different estrogen therapies in men with prostate cancer

CTA is a relatively weak

, with about one-eighth the potency of DES. However, it is highly

lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves li ...

and is stored in

fat tissue Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...

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 Desmethylchlorotrianisene (DMCTA) is a nonsteroidal estrogen which is thought to be the major active metabolite of chlorotrianisene (CTA; TACE). It is a 1:1 mixture of cis and trans isomers. DMCTA is produced from CTA via mono-''O''- demethyla ...

(DMCTA), a weak estrogen that is formed as a

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...

via mono-''O''-

demethylation Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen ato ...

of CTA in the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

. As such, the potency of CTA is reduced if it is given

parenteral A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance is applied. ...

ly instead of orally. Although it is referred to as a weak

and was used solely as an estrogen in clinical practice, CTA is a high- efficacy

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonist ...

of the

. As such, it is a

(SERM), with predominantly estrogenic effects but also with

ic effects, and was arguably the first SERM to ever be introduced. CTA can antagonize

at the level of the

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...

, resulting in disinhibition of the

hypothalamic–pituitary–gonadal axis The hypothalamic–pituitary–gonadal axis (HPG axis, also known as the hypothalamic–pituitary–ovarian/testicular axis) refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single e ...

and an increase in estrogen levels.

Clomifene Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a course ...

and

tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...

were both derived from CTA via

structural modification Molecular modification is chemical alteration of a known and previously characterized lead compound for the purpose of enhancing its usefulness as a drug. This could mean enhancing its specificity for a particular body target site, increasing its ...

, and are much lower-efficacy partial agonists than CTA and hence much more antiestrogenic in comparison. As an example, chlorotrianisene produces

in men, albeit reportedly to a lesser extent than other estrogens, while clomifene and tamoxifen do not and can be used to treat gynecomastia. CTA at a dosage of 48 mg/day inhibits

ovulation Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilize ...

in almost all women. Conversely, it has been reported that CTA has no measurable effect on circulating levels of

in men. This is in contrast to other estrogens, like

, 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.

Chemistry

Chlorotrianisene, also known as tri-''p''-anisylchloroethylene (TACE) or as tris(''p''-methoxyphenyl)chloroethylene, is a synthetic

nonsteroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents. List of nonsteroidal steroid receptor mo ...

compound of the

triphenylethylene Triphenylethylene (TPE) is a simple aromatic hydrocarbon that possesses weak estrogenic activity. Its estrogenic effects were discovered in 1937. TPE was derived from structural modification of the more potent estrogen diethylstilbestrol, which ...

group. It is structurally related to the nonsteroidal estrogen

and to the SERMs

clomifene Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a course ...

and

History

CTA was introduced for medical use in the

in 1952, and was subsequently introduced for use throughout

. It was the first

ic compound of the triphenylethylene series to be introduced. CTA was derived from estrobin (DBE), a

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...

of the very weakly estrogenic compound

(TPE), which in turn was derived from structural modification of

(DES). The SERMs

and

, as well as the

ethamoxytriphetol Ethamoxytriphetol (developmental code name MER-25) is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed. MER-25 was first reported in 1958, and was the first antiestrogen ...

, were derived from CTA via structural modification.

Society and culture

Generic names

''Chlorotrianisene'' is the generic name of the drug and its , , and . It is also known as ''tri-p-anisylchloroethylene'' (''TACE'').

Brand names

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

Availability

CTA is no longer marketed and hence is no longer available in any country.http://www.micromedexsolutions.com/micromedex2/ It was previously used in the

and

References

{{Estrogen receptor modulators Abandoned drugs Hormonal antineoplastic drugs Organochlorides Phenol ethers Prodrugs Progonadotropins Selective estrogen receptor modulators Synthetic estrogens Triphenylethylenes Bis(4-hydroxyphenyl)methanes