Clomifene

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Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome.<ref name=AHFS2016/> It is taken by mouth.<ref name=AHFS2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Common side effects include pelvic pain and hot flashes.<ref name=AHFS2016/> Other side effects can include changes in vision, vomiting, trouble sleeping, ovarian cancer, and seizures.<ref name=AHFS2016/><ref name=WHO2008/> It is not recommended in people with liver disease or abnormal vaginal bleeding of unknown cause or who are pregnant.<ref name=WHO2008>Template:Cite book</ref><ref name=FDAlabel/> Clomifene is in the selective estrogen receptor modulator (SERM) family of medication and is a nonsteroidal medication.<ref name=FDAlabel/><ref>Template:Cite book</ref> It works by causing the release of GnRH by the hypothalamus, and subsequently gonadotropin from the anterior pituitary.<ref name=WHO2008/>

Clomifene was approved for medical use in the United States in 1967.<ref name=AHFS2016/> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref> Its introduction began the era of assisted reproductive technology.<ref name=Hist>Template:Cite journal</ref>

Clomifene (particularly the purified enclomiphene isomer) has also been found to have a powerful ability to boost or restore testosterone levels in hypogonadal men.<ref name="Enclomiphene citrate for the treatm">Template:Cite journal</ref> It can be used to enhance performance in sports and is banned by the World Anti-Doping Agency. Template:TOC limit

Medical uses

Reproductive medicine

Clomifene is one of several alternatives for inducing ovulation in those who are infertile due to anovulation or oligoovulation.<ref name="Committee2013"/> Evidence is lacking for the use of clomifene in those who are infertile without a known reason.<ref name=Hugh2010>Template:Cite journal</ref> In such cases, studies have observed a clinical pregnancy rate 5.6% per cycle with clomifene treatment vs. 1.3%–4.2% per cycle without treatment.<ref name=Committee2013>Template:Cite journal</ref> Clomifene has also been used with other assisted reproductive technology to increase success rates of these other modalities.<ref name="Induction"/>

Clomifene has been effectively used to restore spermatogenesis in trans women looking to have biological children.<ref>Template:Cite journal</ref> The effect of feminizing hormone therapy on fertility is not clear, but it is known that it can prevent sperm production.<ref>Template:Cite journal</ref>

Testosterone replacement therapy

Clomifene is sometimes used in the treatment of male hypogonadism as an alternative to testosterone replacement therapy.<ref name="BachNajari2016">Template:Cite journal</ref>Template:Secondary source needed It has been found to increase testosterone levels by 2–2.5 times in hypogonadal men at such dosages.<ref name="BachNajari2016" /><ref name="TrostKhera2014" /> Despite the use of questionnaires in testosterone replacement comparator trials being called into question, clomifene's lower cost, therapeutic benefits, and greater value towards hypogonadism improvement have been noted.<ref>Template:Cite journal</ref>Template:Secondary source needed

Clomifene consists of two stereoisomers in equal proportion: enclomifene and zuclomifene. Zuclomifene has pro-estrogenic properties, whereas enclomifene is pro-androgenic, i.e. it promotes testosterone production through stimulation of the HPG axis. For this reason, purified enclomifene isomer has been found to be twice as effective in boosting testosterone compared to the standard mix of both isomers.<ref name="Enclomiphene citrate for the treatm"/> Additionally, enclomifene has a half-life of just ten hours,<ref name="singledosekinetics">Template:Cite journal</ref> but zuclomifene has a half-life on the order of several days to a week, so if the goal is to boost testosterone, taking regular clomifene may produce far longer-lasting pro-estrogenic effects than pro-androgenic effects.<ref>Template:Cite journal</ref>

Gynecomastia

Clomifene has been used in the treatment of gynecomastia.<ref name="Becker2001">Template:Cite book</ref> It has been found to be useful in the treatment of some cases of gynecomastia but it is not as effective as tamoxifen or raloxifene for this indication.<ref name="AgrawalGanie2017">Template:Cite book</ref> It has shown variable results for gynecomastia (probably because the zuclomifene isomer is estrogenic), and hence is not recommended for treatment of the condition.<ref name="pmid18622190">Template:Cite journal</ref> Pure enclomifene isomer is likely to be more effective than clomifene at treating gynecomastia, because of the lack of the zuclomifene isomer (as noted above).Template:Medcn

Due to its long half-life, zuclomifene can be detected in urine for at least 261 days after discontinuation<ref>Template:Cite journal</ref> (261 days after discontinuation with a half-life of 30 days, there is still 0.24% of the peak level of zuclomifene being excreted, whereas with a half-life of ten hours, enclomifene reaches the same 0.24% level in less than four daysTemplate:Medcn).

Prohibited use in sports

The World Anti-Doping Agency (WADA) prohibits clomifene under category S4 of hormone and metabolic modulators. It can be present as an undeclared ingredient in black market products available online to enhance athletic performance. Like other substances with anabolic properties, clomifene leads to increased muscle mass in males.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Because clomifene can enhance egg production in hens, athletes may inadvertently consume the substance through contaminated food. A WADA study found that clomifene given to laying hens migrates into their eggs but was able to develop a method of distinguishing egg ingestion from doping.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Contraindications

Contraindications include an allergy to the medication, pregnancy, prior liver problems, abnormal vaginal bleeding of unclear cause, ovarian cysts other than those due to polycystic ovarian syndrome, unmanaged adrenal or thyroid problems, and pituitary tumors.<ref name=FDAlabel>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Side effects

The most common adverse drug reaction associated with the use of clomifene (>10% of people) is reversible ovarian enlargement.<ref name=FDAlabel/>

Less common effects (1–10% of people) include visual symptoms (blurred vision, double vision, floaters, eye sensitivity to light, scotomata), headaches, vasomotor flushes (or hot flashes), light sensitivity and pupil constriction, abnormal uterine bleeding and/or abdominal discomfort.<ref name=FDAlabel/>

Rare adverse events (<1% of people) include: high blood level of triglycerides, liver inflammation, reversible baldness and/or ovarian hyperstimulation syndrome.<ref name=FDAlabel/>

Rates of birth defects and miscarriages do not appear to change with the use of clomifene for fertility.<ref name="FDAlabel" /> Clomifene has been associated with liver abnormalities and a couple of cases of hepatotoxicity.<ref name="CameronFeuer2012">Template:Cite book</ref>

Cancer risk

Some studies have suggested that clomifene if used for more than a year may increase the risk of ovarian cancer.<ref name=Hugh2010/> This may only be the case in those who have never been and do not become pregnant.<ref name=Trabert>Template:Cite journal</ref> Subsequent studies have failed to support those findings.<ref name="Committee2013"/><ref>Template:Cite journal</ref>

Clomifene has been shown to be associated with an increased risk of malignant melanomas and thyroid cancer.<ref name="pmid29159661"/> Thyroid cancer risk was not associated with the number of pregnancies carried to viability.<ref>Template:Cite journal</ref>

Pharmacology

Pharmacodynamics

Selective estrogen receptor modulator activity

Clomifene is a nonsteroidal triphenylethylene derivative that acts as a selective estrogen receptor modulator (SERM).<ref name="Induction">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It consists of a non-racemic mixture of zuclomifene (~38%) and enclomifene (~62%), each of which has unique pharmacologic properties.<ref name=":1">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is a mixed agonist and antagonist of the estrogen receptor (ER). Clomifene activates the ERα in the setting of low baseline estrogen levels and partially blocks the receptor in the context of high baseline estrogen levels.<ref name="TrostKhera2014" /> Conversely, it is an antagonist of the ERβ.<ref name="TrostKhera2014" /> Clomifene has antiestrogenic effects in the uterus.<ref name="Goldstein2000">Template:Cite journal</ref> There is little clinical research on the influence of clomifene in many target tissues, such as lipids, the cardiovascular system, and the breasts.<ref name="Goldstein2000" /><ref name="Haskell2003">Template:Cite journal</ref> Positive effects of clomifene on bone have been observed.<ref name="TrostKhera2014" /><ref name="Goldstein2000" /><ref name="Haskell2003" /> Clomifene has been found to decrease insulin-like growth factor 1 (IGF-1) levels in women.<ref name="pmid27704479">Template:Cite journal</ref>

Clomifene is a long-acting ER ligand, with a nuclear retention of greater than 48 hours.<ref name="RunnebaumRabe2013">Template:Cite book</ref> Clomifene is a prodrug being activated via similar metabolic pathways as the related triphenylethylene SERMs tamoxifen and toremifene.<ref name="RocheZito2019">Template:Cite book</ref><ref name="pmid23406671" /> The affinity of clomifene for the ER relative to estradiol ranges from 0.1 to 12% in different studies, which is similar to the range for tamoxifen (0.06–16%).<ref name="WittliffKerr2005">Template:Cite book</ref><ref name="pmid10746941">Template:Cite journal</ref><ref name="pmid11258977">Template:Cite journal</ref> 4-Hydroxyclomifene, a major active metabolite of clomifene, and afimoxifene (4-hydroxytamoxifen), a major active metabolite of tamoxifen, show 89–251% and 41–246% of the affinity of estradiol for the ER in human MCF-7 breast cancer cells, respectively.<ref name="pmid9586957">Template:Cite journal</ref><ref name="pmid3778464">Template:Cite journal</ref> The ER affinities of the isomers of 4-hydroxyclomifene were 285% for (E)-4-hydroxyclomifene and 16% for (Z)-4-hydroxyclomifene relative to estradiol.<ref name="pmid9586957" /> 4-Hydroxy-N-desethylclomiphene has similar affinity to 4-hydroxyclomifene for the ER.<ref name="pmid23406671">Template:Cite journal</ref> In one study, the affinities of clomifene and its metabolites for the ERα were ~100 nM for clomifene, ~2.4 nM for 4-hydroxyclomifene, ~125 nM for N-desethylclomiphene, and ~1.4 nM for 4-hydroxy-N-desethylclomiphene.<ref name="pmid23406671"/>

Even though clomifene has some estrogenic effect, the antiestrogenic property is believed to be the primary source for stimulating ovulation.<ref name=AHFS2016/> Clomifene appears to act mostly in the hypothalamus where it depletes hypothalamic ERs and blocks the negative feedback effect of circulating endogenous estradiol, which in turn results in an increase in hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency and circulating concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).Template:Medcn

In normal physiologic female hormonal cycling, at seven days past ovulation, high levels of estrogen and progesterone produced from the corpus luteum inhibit GnRH, FSH, and LH at the hypothalamus and anterior pituitary.Template:Medcn If fertilization does not occur in the post-ovulation period the corpus luteum disintegrates due to a lack of human chorionic gonadotropin (hCG).Template:Medcn This would normally be produced by the embryo in the effort of maintaining progesterone and estrogen levels during pregnancy.Template:Medcn

Therapeutically, clomifene is given early in the menstrual cycle to produce follicles.Template:Medcn Follicles, in turn, produce the estrogen, which circulates in serum.Template:Medcn In the presence of clomifene, the body perceives a low level of estrogen, similar to day 22 in the previous cycle.Template:Medcn Since estrogen can no longer effectively exert negative feedback on the hypothalamus, GnRH secretion becomes more rapidly pulsatile, which results in increased pituitary gonadotropin release.Template:Medcn (More rapid, lower amplitude pulses of GnRH lead to increased LH and FSH secretion, while more irregular, larger amplitude pulses of GnRH leads to a decrease in the ratio of LH to FSH.Template:Medcn) Increased FSH levels cause the growth of more ovarian follicles, and subsequently rupture of follicles resulting in ovulation. Ovulation occurs most often 6 to 7 days after a course of clomifene.Template:Medcn

In normal men, 50 mg/day clomifene for eight months has been found to increase testosterone levels by around 870 ng/dL in younger men and by around 490 ng/dL in elderly men.<ref name="TrostKhera2014" /> Estradiol levels increased by 62 pg/mL in younger men and by 40 pg/mL in elderly men.<ref name="TrostKhera2014" /> These findings suggest that the progonadotropic effects of clomifene are stronger in younger men than in older men.<ref name="TrostKhera2014" /> In men with hypogonadism, clomifene has been found to increase testosterone levels by 293 to 362 ng/dL and estradiol levels by 5.5 to 13 pg/mL.<ref name="TrostKhera2014" /> In a large clinical study of men with low testosterone levels (<400 ng/dL), 25 mg/day clomifene increased testosterone levels from 309 ng/dL to 642 ng/dL after three months of therapy.<ref name="pmid27601965">Template:Cite journal</ref> No significant changes in HDL cholesterol, triglycerides, fasting glucose, or prolactin levels were observed, although total cholesterol levels decreased significantly.<ref name="TrostKhera2014">Template:Cite journal</ref><ref name="pmid27601965" />Template:Tissue-specific estrogenic and antiestrogenic activity of SERMs

Other activities

Clomifene is an inhibitor of the conversion of desmosterol into cholesterol by the enzyme 24-dehydrocholesterol reductase.<ref name="Zhang2018">Template:Cite book</ref><ref name="MaximovMcDaniel2013a">Template:Cite book</ref> Concerns about possible induction of desmosterolosis and associated symptoms such as cataracts and ichthyosis with extended exposure precluded the use of clomifene in the treatment of breast cancer.<ref name="Zhang2018" /><ref name="MaximovMcDaniel2013a" /> Continuous use of clomifene has been found to increase desmosterol levels by 10% and continuous high doses of clomifene (200 mg/day) have been reported to produce visual disturbances.<ref name="Jucker2013">Template:Cite book</ref><ref>Template:Cite book</ref>

Pharmacokinetics

Clomifene produces N-desethylclomiphene, clomifenoxide (clomifene N-oxide), 4-hydroxyclomifene, and 4-hydroxy-N-desethylclomiphene as metabolites.<ref name="pmid29516347">Template:Cite journal</ref><ref name="AcademicPress1998">Template:Cite book</ref> Clomifene is a prodrug most importantly of 4-hydroxyclomifene and 4-hydroxy-N-desethylclomiphene, which are the most active of its metabolites.<ref name="RocheZito2019" /><ref name="pmid23406671" /> In one study, the peak levels after a single 50 mg dose of clomifene were 20.37 nmol/L for clomifene, 0.95 nmol/L for 4-hydroxyclomifene, and 1.15 nmol/L for 4-hydroxy-N-desethylclomiphene.<ref name="pmid29516347" />

Clomifene has an onset of action of five to ten days following course of treatment and an elimination half-life about four to seven days.<ref name="pmid29516347"/><ref name="singledosekinetics"/> In one study, after a single 50 mg dose of clomifene, the half-life of clomifene was 128 hours (5.3 days), of 4-hydroxyclomifene was 13 hours, and of 4-hydroxy-N-desethylclomiphenewas 15 hours.<ref name="pmid29516347" /> Individuals with the CYP2D6*10 allele showed longer half-lives for 4-hydroxyclomifene and 4-hydroxy-N-desethylclomiphene.<ref name="pmid29516347" /> Primarily due to differences in CYP2D6 genetics, steady state concentrations and individual response to clomifene are highly variable.<ref>Template:Cite journal</ref>

Most clomifene metabolism occurs in the liver, where it undergoes enterohepatic recirculation. Clomifene and its metabolites are excreted primarily through feces (42%), and excretion can occur up to 6 weeks after discontinuation.<ref name=":1" />

Chemistry

Clomifene is a triphenylethylene derivative. It is a mixture of two geometric isomers, the cis enclomifene ((E)-clomifene) form and trans zuclomifene ((Z)-clomifene) form. These two isomers contribute to the mixed estrogenic and antiestrogenic properties of clomifene.<ref name=Hist/> The typical ratio of these isomers after synthesis is 38% zuclomiphene and 62% enclomiphene.<ref name="singledosekinetics"/> The United States Pharmacopeia specifies that clomifene preparations must contain between 30% and 50% zuclomiphene.<ref name="singledosekinetics"/>

History

A team at William S. Merrell Chemical Company led by Frank Palopoli synthesized clomifene in 1956; after its biological activity was confirmed a patent was filed and issued in November 1959.<ref name=Hist/><ref>Template:Cite patent</ref> Scientists at Merrell had previously synthesized chlorotrianisene and ethamoxytriphetol.<ref name=Hist/> Clomifene was studied in the treatment of advanced breast cancer during the period of 1964 to 1974 and was found to be effective but was abandoned due to concerns about desmosterolosis with extended use.<ref name="Zhang2018"/><ref name="pmid12796359"/><ref name="HowellJordan2013B">Template:Cite book</ref> Short-term use (e.g. days to months) did not raise the same concerns and clomifene continued to be studied for other indications.<ref name="MaximovMcDaniel2013a" /><ref name="Jucker2013" />

Clinical studies were conducted under an Investigational New Drug Application; clomifene was third drug for which an IND had been filed under the 1962 Kefauver Harris Amendment to the Federal Food, Drug, and Cosmetic Act that had been passed in response to the thalidomide tragedy.<ref name=Hist/> It was approved for marketing in 1967 under the brand name Clomid.<ref name=Hist/><ref>Template:Cite journal</ref> It was first used to treat cases of oligomenorrhea but was expanded to include treatment of anovulation when women undergoing treatment had higher than expected rates of pregnancy.<ref>Template:Cite journalTemplate:Retracted</ref>

The drug is widely considered to have been a revolution in the treatment of female infertility, the beginning of the modern era of assisted reproductive technology, and the beginning of what in the words of Eli Y. Adashi, was "the onset of the US multiple births epidemic".<ref name=Hist/><ref>Template:Cite journal</ref>

The company was acquired by Dow Chemical in 1980,<ref name="Los Angeles Times">Template:Cite news</ref><ref>Template:Cite journal</ref> and in 1989 Dow Chemical acquired 67 percent interest of Marion Laboratories, which was renamed Marion Merrell Dow.<ref name="Los Angeles Times"/> In 1995, Hoechst AG acquired the pharmaceutical business of Marion Merrell Dow.<ref>Template:Cite news</ref> Hoechst in turn became part of Aventis in 1999,<ref name=Bris>Arturo Bris and Christos Cabolis, Corporate Governance Convergence Through Cross-Border Mergers The Case of Aventis Template:Webarchive, Chapter 4 in Corporate Governance and Regulatory Impact on Mergers and Acquisitions: Research and Analysis on Activity Worldwide Since 1990. Eds Greg N. Gregoriou, Luc Renneboog. Academic Press, 26 July 2007</ref>Template:Rp and subsequently a part of Sanofi.<ref>Template:Cite news</ref> It became the most widely prescribed drug for ovulation induction to reverse anovulation or oligoovulation.<ref name="StraussBarbieri2013">Template:Cite book</ref>

Society and culture

Brand names

Clomifene is marketed under many brand names worldwide, including Beclom, Bemot, Biogen, Blesifen, Chloramiphene, Clofert, Clomene, ClomHEXAL, Clomi, Clomid, Clomidac, Clomifen, Clomifencitrat, Clomifene, Clomifène, Clomifene citrate, Clomifeni citras, Clomifeno, Clomifert, Clomihexal, Clomiphen, Clomiphene, Clomiphene Citrate, Cloninn, Clostil, Clostilbegyt, Clovertil, Clovul, Dipthen, Dufine, Duinum, Fensipros, Fertab, Fertec, Fertex, Ferticlo, Fertil, Fertilan, Fertilphen, Fertin, Fertomid, Ferton, Fertotab, Fertyl, Fetrop, Folistim, Genoclom, Genozym, Hete, I-Clom, Ikaclomin, Klofit, Klomen, Klomifen, Lomifen, MER 41, Milophene, Ofertil, Omifin, Ova-mit, Ovamit, Ovinum, Ovipreg, Ovofar, Ovuclon, Ovulet, Pergotime, Pinfetil, Profertil, Prolifen, Provula, Reomen, Serofene, Serophene, Serpafar, Serpafar, Surole, Tocofeno, and Zimaquin.<ref name="Brands">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Regulation

Clomifene is included on the World Anti-Doping Agency list of illegal doping agents in sport.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is listed because it is an "anti-estrogenic substance".Template:Cn

Research

Clomifene has been used almost exclusively for ovulation induction in premenopausal women, and has been studied very limitedly in postmenopausal women.<ref name="Palacios2007">Template:Cite journal</ref>

Clomifene was studied for treatment and prevention of breast cancer, but issues with toxicity led to abandonment of this indication, as did the discovery of tamoxifen.<ref>Template:Cite journal</ref> Like the structurally related drug triparanol, clomifene is known to inhibit the enzyme 24-dehydrocholesterol reductase and increase circulating desmosterol levels, making it unfavorable for extended use in breast cancer due to risk of side effects like irreversible cataracts.<ref name="Elsevier2013">Template:Cite book</ref><ref name="MaximovMcDaniel2013b">Template:Cite book</ref>