Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. It is taken by mouth.
Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonists/antagonists (ERAAs), are a class of drugs that act on estrogen receptors (ERs). Compared to pure ER agonists–antagonists, SERMs are more tissue-specific, allowing them to selectively inhibit or stimulate estrogen-like action in various tissues.
Fertility medications, also known as fertility drugs, are medications which enhance reproductive fertility. For women, fertility medication is used to stimulate follicle development of the ovary. There are very few fertility medication options available for men.
Chlorotrianisene (CTA), also known as tri-p-anisylchloroethylene (TACE) and sold under the brand name Tace among others, is a nonsteroidal estrogen related to diethylstilbestrol (DES) which was previously used in the treatment of menopausal symptoms and estrogen deficiency in women and prostate cancer in men, among other indications, but has since been discontinued and is now no longer available. It is taken by mouth.
Nafoxidine or nafoxidine hydrochloride is a nonsteroidal selective estrogen receptor modulator (SERM) or partial antiestrogen of the triphenylethylene group that was developed for the treatment of advanced breast cancer by Upjohn in the 1970s but was never marketed. It was developed at around the same time as tamoxifen and clomifene, which are also triphenylethylene derivatives. The drug was originally synthesized by the fertility control program at Upjohn as a postcoital contraceptive, but was subsequently repurposed for the treatment of breast cancer. Nafoxidine was assessed in clinical trials in the treatment of breast cancer and was found to be effective. However, it produced side effects including ichthyosis, partial hair loss, and phototoxicity of the skin in almost all patients, and this resulted in the discontinuation of its development.
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 have gradually fallen out of favor following the discovery of toxicities associated with high-dose DES starting in the early 1970s, and are now almost never used. On the other hand, virtually all selective estrogen receptor modulators (SERMs) are nonsteroidal, with triphenylethylenes like tamoxifen and clomifene having been derived from DES, and these drugs remain widely used in medicine for the treatment of breast cancer among other indications. In addition to pharmaceutical drugs, many xenoestrogens, including phytoestrogens, mycoestrogens, and synthetic endocrine disruptors like bisphenol A, are nonsteroidal substances with estrogenic activity.
Broparestrol, also known as α-bromo-α,β-diphenyl-β-p-ethylphenylethylene (BDPE), is a synthetic, nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that has been used in Europe as a dermatological agent and for the treatment of breast cancer. The drug is described as slightly estrogenic and potently antiestrogenic, and inhibits mammary gland development and suppresses prolactin levels in animals. It is structurally related to clomifene and diethylstilbestrol. Broparestrol is a mixture of E- and Z- isomers, both of which are active, and are similarly antiestrogenic but, unlike broparestrol, were never marketed.
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 is a member of the stilbestrol group of nonsteroidal estrogens.
2,8-Dihydroxyhexahydrochrysene (2,8-DHHHC) is a synthetic, nonsteroidal weak estrogen with approximately 1/2,000th the estrogenic potency of the structurally-related estrogen diethylstilbestrol. It is said to be intermediate in structure between estradiol and hexestrol, but conversely to both of them, it is drastically less potent in comparison.
Estrobin, also known as α,α-di(p-ethoxyphenyl)-β-phenylbromoethylene and commonly abbreviated as DBE, is a synthetic, nonsteroidal estrogen of the triphenylethylene group that was never marketed. Chlorotrianisene, and subsequently clomifene and tamoxifen, were derived from it. Estrobin, similarly to other triphenylethylenes, is very lipophilic and hence very long-lasting in its duration of action. Similarly to chlorotrianisene, estrobin behaves a prodrug to a much more potent estrogen in the body.
Ethamoxytriphetol 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 to be discovered. It has been described as "essentially devoid of estrogenic activity" and as having "very low estrogenic activity in all species tested". However, some estrogenic effects in the uterus have been observed, so it is not a pure antiestrogen but is, instead, technically a selective estrogen receptor modulator (SERM). For all intents and purposes, it is a nearly pure antiestrogen, however.
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.
Triphenylbromoethylene, also known as bromotriphenylethylene or as phenylstilbene bromide, is a synthetic nonsteroidal estrogen of the triphenylethylene group that was marketed in the 1940s similarly to the closely related estrogen triphenylchloroethylene.
Triphenyliodoethylene (TPIE), also known as iodotriphenylethylene or as phenylstilbene iodide, as well as triphenylvinyl iodide, is a synthetic nonsteroidal estrogen of the triphenylethylene group that is related to triphenylchloroethylene and triphenylbromoethylene and was never marketed.
Triphenylmethylethylene, also known as methyltriphenylethylene or as triphenylpropene, is a synthetic nonsteroidal estrogen of the triphenylethylene group that is related to triphenylchloroethylene and was never marketed. Along with diethylstilbestrol and triphenylchoroethylene, triphenylmethylethylene was studied in 1944 by Sir Alexander Haddow for the treatment of breast cancer, and this is historically notable in that it was the first time that high-dose estrogens were found to be effective in the treatment of breast cancer. However, while diethylstilbestrol and triphenylchloroethylene were found to be significantly effective, triphenylmethylethylene was less effective and showed a favorable response in only 1 of 4 treated cases.
Droloxifene, also known as 3-hydroxytamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was developed originally in Germany and later in Japan for the treatment of breast cancer, osteoporosis in men and postmenopausal women, and cardiovascular disorders but was abandoned and never marketed. It reached phase II and phase III clinical trials for these indications before development was discontinued in 2000. The drug was found to be significantly less effective than tamoxifen in the treatment of breast cancer in two phase III clinical trials.
Miproxifene (INN) is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was never marketed. It is a derivative of afimoxifene (4-hydroxytamoxifen) in which an additional 4-isopropyl group is present in the β-phenyl ring. The drug has been found to be 3- to 10-fold more potent than tamoxifen in inhibiting breast cancer cell growth in in vitro models. Miproxifene is the active metabolite of miproxifene phosphate (TAT-59), a phosphate ester and prodrug of miproxifene that was developed to improve its water solubility. Miproxifene phosphate was under development for the treatment of breast cancer and reached phase III clinical trials for this indication but development was discontinued.
Miproxifene phosphate is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was under development in Japan for the treatment of breast cancer but was abandoned and never marketed. It reached phase III clinical trials for this indication before development was discontinued. The drug is a phosphate ester and prodrug of miproxifene (DP-TAT-59) with improved water solubility that was better suited for clinical development. Miproxifene has been found to be 3- to 10-fold as potent as tamoxifen in inhibiting breast cancer cell growth in in vitro models. It is a derivative of afimoxifene (4-hydroxytamoxifen) in which an additional 4-isopropyl group is present in the β-phenyl ring.
Zindoxifene is a nonsteroidal selective estrogen receptor modulator (SERM) that was under development in the 1980s and early 1990s for the treatment of breast cancer but was not marketed. It showed estrogenic-like activity in preclinical studies and failed to demonstrate effectiveness as a treatment for breast cancer in clinical trials. Zindoxifene was the lead compound of the distinct 2-phenylindole class of SERMs, and the marketed SERM bazedoxifene was derived from the major active metabolite of zindoxifene, D-15414. Zindoxifene was first described in 1984.
Nitromifene (INNTooltip International Nonproprietary Name; also as the citrate salt nitromifene citrate (USANTooltip United States Adopted Name), developmental code names CI-628, CN-5518, CN-55945) is a nonsteroidal selective estrogen receptor modulator (SERM) related to triphenylethylenes like tamoxifen that was never marketed. It is a mixture of (E)- and (Z)-isomers that possess similar antiestrogenic activity. The drug was described in 1966. Along with tamoxifen, nafoxidine, and clomifene, it was one of the earliest SERMs.
