clomifene

{{Further|Ovulation induction|Feminizing hormone therapy#Fertility}}

Clomifene is one of several alternatives for inducing ovulation in those who are infertile due to anovulation or oligoovulation. Evidence is lacking for the use of clomifene in those who are infertile without a known reason.{{cite journal | vauthors = Hughes E, Brown J, Collins JJ, Vanderkerchove P | title = Clomiphene citrate for unexplained subfertility in women | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD000057 | date = January 2010 | volume = 2010 | pmid = 20091498 | pmc = 7052733 | doi = 10.1002/14651858.CD000057.pub2 }} 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.{{cite journal | title = Use of clomiphene citrate in infertile women: a committee opinion | journal = Fertility and Sterility | volume = 100 | issue = 2 | pages = 341–8 | date = August 2013 | pmid = 23809505 | doi = 10.1016/j.fertnstert.2013.05.033 | author1 = Practice Committee of the American Society for Reproductive Medicine | doi-access = free | title-link = doi }} Clomifene has also been used with other assisted reproductive technology to increase success rates of these other modalities.

Clomifene has been effectively used to restore spermatogenesis in trans women looking to have biological children.{{cite journal | vauthors = Powers WJ, Costescu D, Massarella C, Gale J, Singh SS | title = A Gender-Affirming Approach to Fertility Care for Transgender and Gender-Diverse Patients. | journal = O&G Open | date = March 2024 | volume = 1 | issue = 1 | page = e002 | doi = 10.1097/og9.0000000000000002 | url = https://journals.lww.com/ogopen/Documents/OGO-24-5-clean_Powers.pdf |access-date=July 8, 2024 }} The effect of feminizing hormone therapy on fertility is not clear, but it is known that it can prevent sperm production.{{cite journal | vauthors = Schneider F, Neuhaus N, Wistuba J, Zitzmann M, Heß J, Mahler D, van Ahlen H, Schlatt S, Kliesch S | title = Testicular Functions and Clinical Characterization of Patients with Gender Dysphoria (GD) Undergoing Sex Reassignment Surgery (SRS) | journal = The Journal of Sexual Medicine | volume = 12 | issue = 11 | pages = 2190–2200 | date = November 2015 | pmid = 26559385 | doi = 10.1111/jsm.13022 }}

Clomifene is sometimes used in the treatment of male hypogonadism as an alternative to testosterone replacement therapy.{{cite journal| vauthors = Bach PV, Najari BB, Kashanian JA |title=Adjunct Management of Male Hypogonadism|journal=Current Sexual Health Reports|volume=8|issue=4|pages=231–239|year=2016|issn=1548-3584|doi=10.1007/s11930-016-0089-7|s2cid=79220716}}{{Secondary source needed|date=August 2023}} It has been found to increase testosterone levels by 2–2.5 times in hypogonadal men at such dosages. 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.{{cite journal | vauthors = DiGiorgio L, Sadeghi-Nejad H | title = Off label therapies for testosterone replacement | journal = Translational Andrology and Urology | volume = 5 | issue = 6 | pages = 844–849 | date = December 2016 | pmid = 28078215 | pmc = 5182219 | doi = 10.21037/tau.2016.08.15 | doi-access = free | title-link = doi }}{{Secondary source needed|date=August 2023}}

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. Additionally, enclomifene has a half-life of just ten hours,{{cite journal | vauthors = Mikkelson TJ, Kroboth PD, Cameron WJ, Dittert LW, Chungi V, Manberg PJ | title = Single-dose pharmacokinetics of clomiphene citrate in normal volunteers | journal = Fertility and Sterility | volume = 46 | issue = 3 | pages = 392–396 | date = September 1986 | pmid = 3091405 | doi = 10.1016/S0015-0282(16)49574-9 }} 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.{{cite journal | vauthors = Helo S, Mahon J, Ellen J, Wiehle R, Fontenot G, Hsu K, Feustel P, Welliver C, McCullough A | title = Serum levels of enclomiphene and zuclomiphene in men with hypogonadism on long-term clomiphene citrate treatment | journal = BJU International | volume = 119 | issue = 1 | pages = 171–176 | date = January 2017 | pmid = 27511863 | doi = 10.1111/bju.13625 | s2cid = 5538782 }}

Clomifene has been used in the treatment of gynecomastia.{{cite book| vauthors = Becker KL |title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1206|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=1206–}} 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.{{cite book| vauthors = Agrawal S, Ganie MA, Nisar S |title=Basics of Human Andrology|chapter=Gynaecomastia| year=2017|pages=451–458|publisher=Springer |doi=10.1007/978-981-10-3695-8_26|isbn=978-981-10-3694-1}} It has shown variable results for gynecomastia (probably because the zuclomifene isomer is estrogenic), and hence is not recommended for treatment of the condition.{{cite journal | vauthors = Nordt CA, DiVasta AD | title = Gynecomastia in adolescents | journal = Current Opinion in Pediatrics | volume = 20 | issue = 4 | pages = 375–82 | date = August 2008 | pmid = 18622190 | doi = 10.1097/MOP.0b013e328306a07c | s2cid = 205834072 }} 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).{{medcn|date=May 2024}}

Due to its long half-life, zuclomifene can be detected in urine for at least 261 days after discontinuation{{cite journal | vauthors = Miller GD, Moore C, Nair V, Hill B, Willick SE, Rogol AD, Eichner D | title = Hypothalamic-Pituitary-Testicular Axis Effects and Urinary Detection Following Clomiphene Administration in Males | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 104 | issue = 3 | pages = 906–914 | date = March 2019 | pmid = 30295816 | doi = 10.1210/jc.2018-01159 | doi-access = free | title-link = doi }} (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 days{{medcn|date=May 2024}}).

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.{{cite web |title=Substance Profile: What Athletes Need to Know About Clomiphene |url=https://www.usada.org/spirit-of-sport/education/substance-profile-clomiphene/ |website=USADA |date=2 February 2017}}

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.{{cite web |title=Are poultry and eggs a source of minute amounts of clomiphene in doping control samples |url=https://www.wada-ama.org/en/resources/scientific-research/are-poultry-and-eggs-source-minute-amounts-clomiphene-doping-control |website=World Anti Doping Agency }}

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.{{cite web|title=Clomiphene citrate tablets label|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016131s026lbl.pdf|publisher=FDA|access-date=11 September 2016 |url-status=dead|archive-url= https://web.archive.org/web/20160927072841/http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016131s026lbl.pdf|archive-date=27 September 2016}}

The most common adverse drug reaction associated with the use of clomifene (>10% of people) is reversible ovarian enlargement.

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.

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

Rates of birth defects and miscarriages do not appear to change with the use of clomifene for fertility. Clomifene has been associated with liver abnormalities and a couple of cases of hepatotoxicity.{{cite book|url=https://books.google.com/books?id=xZf-CAAAQBAJ&pg=PA565|title=Drug-Induced Hepatotoxicity| vauthors = Cameron R, Feuer G, de la Iglesia F |date=6 December 2012| publisher=Springer Science & Business Media|isbn=978-3-642-61013-4|pages=565–}}

Some studies have suggested that clomifene if used for more than a year may increase the risk of ovarian cancer. This may only be the case in those who have never been and do not become pregnant.{{cite journal | vauthors = Trabert B, Lamb EJ, Scoccia B, Moghissi KS, Westhoff CL, Niwa S, Brinton LA | title = Ovulation-inducing drugs and ovarian cancer risk: results from an extended follow-up of a large United States infertility cohort | journal = Fertility and Sterility | volume = 100 | issue = 6 | pages = 1660–6 | date = December 2013 | pmid = 24011610 | pmc = 3873340 | doi = 10.1016/j.fertnstert.2013.08.008 }} Subsequent studies have failed to support those findings.{{cite journal | vauthors = Gadducci A, Guerrieri ME, Genazzani AR | title = Fertility drug use and risk of ovarian tumors: a debated clinical challenge | journal = Gynecological Endocrinology | volume = 29 | issue = 1 | pages = 30–5 | date = January 2013 | pmid = 22946709 | doi = 10.3109/09513590.2012.705382 | s2cid = 1240526 }}

Clomifene has been shown to be associated with an increased risk of malignant melanomas and thyroid cancer. Thyroid cancer risk was not associated with the number of pregnancies carried to viability.{{cite journal | vauthors = Yu Q, Lv X, Liu K, Ma D, Wu Y, Dai W, Jiang H | title = Fertility Drugs Associated with Thyroid Cancer Risk: A Systematic Review and Meta-Analysis | journal = BioMed Research International | volume = 2018 | pages = 7191704 | date = 2018 | pmid = 29862285 | pmc = 5971354 | doi = 10.1155/2018/7191704 | doi-access = free | title-link = doi }}

Clomifene is a nonsteroidal triphenylethylene derivative that acts as a selective estrogen receptor modulator (SERM).{{Cite web|url= https://www.uptodate.com/contents/ovulation-induction-with-clomiphene-citrate#H2|title=Ovulation induction with clomiphene citrate| vauthors = Seli E, Arici A |website=UpToDate|access-date=30 July 2019}} It consists of a non-racemic mixture of zuclomifene (~38%) and enclomifene (~62%), each of which has unique pharmacologic properties.{{Cite web|url=https://www.drugs.com/ppa/clomiphene.html| title=ClomiPHENE (Professional Patient Advice)|website=Drugs.com|access-date=30 July 2019}} 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. Conversely, it is an antagonist of the ERβ. Clomifene has antiestrogenic effects in the uterus.{{cite journal | vauthors = Goldstein SR, Siddhanti S, Ciaccia AV, Plouffe L | title = A pharmacological review of selective oestrogen receptor modulators | journal = Human Reproduction Update | volume = 6 | issue = 3 | pages = 212–24 | year = 2000 | pmid = 10874566 | doi = 10.1093/humupd/6.3.212 | doi-access = free | title-link = doi }} There is little clinical research on the influence of clomifene in many target tissues, such as lipids, the cardiovascular system, and the breasts.{{cite journal | vauthors = Haskell SG | title = Selective estrogen receptor modulators | journal = Southern Medical Journal | volume = 96 | issue = 5 | pages = 469–76 | date = May 2003 | pmid = 12911186 | doi = 10.1097/01.SMJ.0000051146.93190.4A | s2cid = 40607634 }} Positive effects of clomifene on bone have been observed. Clomifene has been found to decrease insulin-like growth factor 1 (IGF-1) levels in women.{{cite journal | vauthors = Duarte FH, Jallad RS, Bronstein MD | title = Estrogens and selective estrogen receptor modulators in acromegaly | journal = Endocrine | volume = 54 | issue = 2 | pages = 306–314 | date = November 2016 | pmid = 27704479 | doi = 10.1007/s12020-016-1118-z | s2cid = 10136018 }}

Clomifene is a long-acting ER ligand, with a nuclear retention of greater than 48 hours.{{cite book| vauthors = Runnebaum B, Rabe T |title=Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie|url=https://books.google.com/books?id=mBF9BwAAQBAJ&pg=PA88|date=17 April 2013|publisher=Springer-Verlag|isbn=978-3-662-07635-4|pages=88–}} Clomifene is a prodrug being activated via similar metabolic pathways as the related triphenylethylene SERMs tamoxifen and toremifene.{{cite book| vauthors = Roche V, Zito WS, Lemke T, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=r9SlDwAAQBAJ&pg=PT3010|date=29 July 2019|publisher=Wolters Kluwer Health|isbn=978-1-4963-8587-1|pages=3010–}} 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%).{{cite book | vauthors = Wittliff JL, Kerr II DA, Andres SA | year = 2005 | chapter = Estrogens IV: Estrogen-Like Pharmaceuticals | veditors = Wexler P | title = Encyclopedia of Toxicology, 2nd Edition | volume = Dib-L | pages = 254–258 | publisher = Elsevier | isbn = 9780080548005 | chapter-url = https://books.google.com/books?id=dEnbcGW44RYC&pg=PT3318}}{{cite journal | vauthors = Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL, Tong W, Shi L, Perkins R, Sheehan DM | title = The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands | journal = Toxicological Sciences | volume = 54 | issue = 1 | pages = 138–53 | date = March 2000 | pmid = 10746941 | doi = 10.1093/toxsci/54.1.138 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Fang H, Tong W, Shi LM, Blair R, Perkins R, Branham W, Hass BS, Xie Q, Dial SL, Moland CL, Sheehan DM | title = Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens | journal = Chemical Research in Toxicology | volume = 14 | issue = 3 | pages = 280–94 | date = March 2001 | pmid = 11258977 | doi = 10.1021/tx000208y }} 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.{{cite journal | vauthors = Baumann RJ, Bush TL, Cross-Doersen DE, Cashman EA, Wright PS, Zwolshen JH, Davis GF, Matthews DP, Bender DM, Bitonti AJ | title = Clomiphene analogs with activity in vitro and in vivo against human breast cancer cells | journal = Biochemical Pharmacology | volume = 55 | issue = 6 | pages = 841–51 | date = March 1998 | pmid = 9586957 | doi = 10.1016/s0006-2952(97)00574-1 }}{{cite journal | vauthors = Sutherland RL, Watts CK, Ruenitz PC | title = Definition of two distinct mechanisms of action of antiestrogens on human breast cancer cell proliferation using hydroxytriphenylethylenes with high affinity for the estrogen receptor | journal = Biochemical and Biophysical Research Communications | volume = 140 | issue = 2 | pages = 523–9 | date = October 1986 | pmid = 3778464 | doi = 10.1016/0006-291x(86)90763-1 }} The ER affinities of the isomers of 4-hydroxyclomifene were 285% for (E)-4-hydroxyclomifene and 16% for (Z)-4-hydroxyclomifene relative to estradiol. 4-Hydroxy-N-desethylclomiphene has similar affinity to 4-hydroxyclomifene for the ER.{{cite journal | vauthors = Obach RS | title = Pharmacologically active drug metabolites: impact on drug discovery and pharmacotherapy | journal = Pharmacological Reviews | volume = 65 | issue = 2 | pages = 578–640 | date = April 2013 | pmid = 23406671 | doi = 10.1124/pr.111.005439 | s2cid = 720243 }} 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.

Even though clomifene has some estrogenic effect, the antiestrogenic property is believed to be the primary source for stimulating ovulation. 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).{{medcn|date=May 2024}}

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.{{medcn|date=May 2024}} If fertilization does not occur in the post-ovulation period the corpus luteum disintegrates due to a lack of human chorionic gonadotropin (hCG).{{medcn|date=May 2024}} This would normally be produced by the embryo in the effort of maintaining progesterone and estrogen levels during pregnancy.{{medcn|date=May 2024}}

Therapeutically, clomifene is given early in the menstrual cycle to produce follicles.{{medcn|date=May 2024}} Follicles, in turn, produce the estrogen, which circulates in serum.{{medcn|date=May 2024}} In the presence of clomifene, the body perceives a low level of estrogen, similar to day 22 in the previous cycle.{{medcn|date=May 2024}} 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.{{medcn|date=May 2024}} (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.{{medcn|date=May 2024}}) 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.{{medcn|date=May 2024}}

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. Estradiol levels increased by 62 pg/mL in younger men and by 40 pg/mL in elderly men. These findings suggest that the progonadotropic effects of clomifene are stronger in younger men than in older men. 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. 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.{{cite journal | vauthors = Rambhatla A, Mills JN, Rajfer J | title = The Role of Estrogen Modulators in Male Hypogonadism and Infertility | journal = Reviews in Urology | volume = 18 | issue = 2 | pages = 66–72 | date = 2016 | pmid = 27601965 | pmc = 5010627 | doi = 10.3909/riu0711 | doi-broken-date = 1 November 2024 }} No significant changes in HDL cholesterol, triglycerides, fasting glucose, or prolactin levels were observed, although total cholesterol levels decreased significantly.{{cite journal | vauthors = Trost LW, Khera M | title = Alternative treatment modalities for the hypogonadal patient | journal = Current Urology Reports | volume = 15 | issue = 7 | pages = 417 | date = July 2014 | pmid = 24817260 | doi = 10.1007/s11934-014-0417-2 | s2cid = 20304701 }}{{Tissue-specific estrogenic and antiestrogenic activity of SERMs}}

Clomifene is an inhibitor of the conversion of desmosterol into cholesterol by the enzyme 24-dehydrocholesterol reductase.{{cite book| vauthors = Zhang X |title=Estrogen Receptor and Breast Cancer: Celebrating the 60th Anniversary of the Discovery of ER|url=https://books.google.com/books?id=FMhyDwAAQBAJ&pg=PA153|date=16 October 2018|publisher=Springer|isbn=978-3-319-99350-8|pages=153–}}{{cite book| vauthors = Maximov PY, McDaniel RD, Jordan VC |title=Tamoxifen: Pioneering Medicine in Breast Cancer|url=https://books.google.com/books?id=p-W5BAAAQBAJ&pg=PA34 |date=23 July 2013|publisher=Springer Science & Business Media|isbn=978-3-0348-0664-0|pages=34–}} 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. 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.{{cite book | vauthors = Harper MJ | chapter = Pharmacological Control of Reproduction in Women | veditors = Jucker E |title=Progress in Drug Research / Fortschritte der Arzneimittelforschung / Progrès des recherches pharmaceutiques|chapter-url=https://books.google.com/books?id=Y8HzBwAAQBAJ&pg=PA69|date=21 December 2013|publisher=Birkhäuser|isbn=978-3-0348-7065-8|pages=69–}}{{cite book|title=Hormones and Breast Cancer| url=https://books.google.com/books?id=vBvzF6HQ4-QC&pg=PA13|date=25 June 2013|publisher=Elsevier|isbn=978-0-12-416676-9|pages=13–}}

Clomifene produces N-desethylclomiphene, clomifenoxide (clomifene N-oxide), 4-hydroxyclomifene, and 4-hydroxy-N-desethylclomiphene as metabolites.{{cite journal | vauthors = Kim MJ, Byeon JY, Kim YH, Kim SH, Lee CM, Jung EH, Chae WK, Lee YJ, Jang CG, Lee SY, Choi CI | title = Effect of the CYP2D6*10 allele on the pharmacokinetics of clomiphene and its active metabolites | journal = Archives of Pharmacal Research | volume = 41 | issue = 3 | pages = 347–353 | date = March 2018 | pmid = 29516347 | doi = 10.1007/s12272-018-1005-7 | s2cid = 4034257 }}{{cite book|title=Analytical Profiles of Drug Substances and Excipients |url=https://books.google.com/books?id=kia7bq8EM9IC&pg=PA113|date=20 March 1998|publisher=Academic Press|isbn=978-0-08-086120-3|pages=113–|url-status=live|archive-url= https://web.archive.org/web/20171105200803/https://books.google.com/books?id=kia7bq8EM9IC&pg=PA113|archive-date=5 November 2017}} Clomifene is a prodrug most importantly of 4-hydroxyclomifene and 4-hydroxy-N-desethylclomiphene, which are the most active of its metabolites. 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.

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. 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. Individuals with the CYP2D6*10 allele showed longer half-lives for 4-hydroxyclomifene and 4-hydroxy-N-desethylclomiphene. Primarily due to differences in CYP2D6 genetics, steady state concentrations and individual response to clomifene are highly variable.{{cite journal | vauthors = Rostami-Hodjegan A, Lennard MS, Tucker GT, Ledger WL | title = Monitoring plasma concentrations to individualize treatment with clomiphene citrate | journal = Fertility and Sterility | volume = 81 | issue = 5 | pages = 1187–1193 | date = May 2004 | pmid = 15136073 | doi = 10.1016/j.fertnstert.2003.07.044 | doi-access = free | title-link = doi }}

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.

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. The typical ratio of these isomers after synthesis is 38% zuclomiphene and 62% enclomiphene. The United States Pharmacopeia specifies that clomifene preparations must contain between 30% and 50% zuclomiphene.

{{multiple image

| align = left

| image1 = Enclomifene.svg

| caption1 = Enclomifene

| width1 = 150

| image2 = Zuclomifene.svg

| caption2 = Zuclomifene

| width2 = 200

}}{{-}}

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.{{cite patent | title = Therapeutic composition | inventor = Allen RE, Palopoli FP, Schumann EL, Van Campen Jr MG | assign = William S Merrill Company | url = https://www.google.com/patents/US2914563 | country = US | number = 2,914,563 | gdate = 24 November 1959 }} Scientists at Merrell had previously synthesized chlorotrianisene and ethamoxytriphetol. 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.{{cite book| vauthors = Howell A, Jordan VC |chapter=Adjuvant Antihormone Therapy|year=2013|pages=229–254|doi= 10.1142/9781848169586_0010| veditors = Craig JV |title=Estrogen Action, Selective Estrogen Receptor Modulators And Women's Health: Progress And Promise|publisher=World Scientific|isbn=978-1-84816-959-3|chapter-url=https://books.google.com/books?id=ZM26CgAAQBAJ&pg=PA229}} Short-term use (e.g. days to months) did not raise the same concerns and clomifene continued to be studied for other indications.

{{Comparison of early clinical experience with antiestrogens for advanced breast cancer}}

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. It was approved for marketing in 1967 under the brand name Clomid.{{cite journal | vauthors = Holtkamp DE, Greslin JG, Root CA, Lerner LJ | title = Gonadotrophin inhibiting and anti-fecundity effects of chloramiphene | journal = Proceedings of the Society for Experimental Biology and Medicine | volume = 105 | pages = 197–201 | date = October 1960 | pmid = 13715563 | doi = 10.3181/00379727-105-26054 | s2cid = 1448466 }} 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.{{cite journal | vauthors = Hughes E, Collins J, Vandekerckhove P | title = Clomiphene citrate for ovulation induction in women with oligo-amenorrhoea | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD000056 | year = 2000 | pmid = 10796477 | doi = 10.1002/14651858.CD000056 }}{{Retracted|intentional=yes |doi=10.1002/14651858.cd000056.pub2}}

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".{{cite journal| vauthors = Adashi EY |title=Iatrogenic Birth Plurality: The Challenge and Its Possible Solution|journal=Harvard Health Policy Review|date=Fall 2014|volume=14|issue=1|pages=9–10|url=http://hhpronline.org/wp-content/uploads/2014/11/Features-Adashi.pdf|url-status=dead|archive-url=https://web.archive.org/web/20161006151300/http://hhpronline.org/wp-content/uploads/2014/11/Features-Adashi.pdf|archive-date=6 October 2016|access-date=12 September 2016}}

The company was acquired by Dow Chemical in 1980,{{cite news| vauthors = Lee P |title=Dow Chemical to Get Control of Marion Labs : $5-Billion-Plus Deal Is an Effort to Diversify|url=https://www.latimes.com/archives/la-xpm-1989-07-18-fi-4000-story.html|work=Los Angeles Times|date=18 July 1989|url-status=live|archive-url=https://web.archive.org/web/20160629071651/http://articles.latimes.com/1989-07-18/business/fi-4000_1_merrell-dow|archive-date=29 June 2016}}{{cite journal| vauthors = Williams W |title=Dow Broadens Product Lines|journal=The New York Times|date=11 February 1981|url=https://www.nytimes.com/1981/02/11/business/dow-broadens-product-lines.html|issn=0362-4331|url-status=live|archive-url=https://web.archive.org/web/20161006175438/http://www.nytimes.com/1981/02/11/business/dow-broadens-product-lines.html|archive-date=6 October 2016}} and in 1989 Dow Chemical acquired 67 percent interest of Marion Laboratories, which was renamed Marion Merrell Dow. In 1995, Hoechst AG acquired the pharmaceutical business of Marion Merrell Dow.{{cite news|title=Hoechst AG to Buy Marion Merrell Dow / Acquisition worth over $7 billion|url=http://www.sfgate.com/business/article/Hoechst-AG-to-Buy-Marion-Merrell-Dow-3035234.php|work=San Francisco Chronicle|agency=Reuters|date=5 May 1995|url-status=live|archive-url=https://web.archive.org/web/20161006125440/http://www.sfgate.com/business/article/Hoechst-AG-to-Buy-Marion-Merrell-Dow-3035234.php|archive-date=6 October 2016}} Hoechst in turn became part of Aventis in 1999,Arturo Bris and Christos Cabolis, [http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.365.5937&rep=rep1&type=pdf Corporate Governance Convergence Through Cross-Border Mergers The Case of Aventis] {{webarchive|url=https://web.archive.org/web/20140421081504/http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.365.5937&rep=rep1&type=pdf |date=21 April 2014 }}, Chapter 4 in [https://books.google.com/books?id=Cfc22UYifJQC 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{{rp|9–11}} and subsequently a part of Sanofi.{{cite news| vauthors = Timmons H, Bennhold K |title=France Helped Broker the Aventis-Sanofi Deal|url=https://www.nytimes.com/2004/04/27/business/france-helped-broker-the-aventis-sanofi-deal.html?_r=0|work=The New York Times|date=27 April 2004|url-status=live|archive-url=https://web.archive.org/web/20171105200804/http://www.nytimes.com/2004/04/27/business/france-helped-broker-the-aventis-sanofi-deal.html?_r=0|archive-date=5 November 2017}} It became the most widely prescribed drug for ovulation induction to reverse anovulation or oligoovulation.{{cite book| vauthors = Strauss JF, Barbieri RL |title=Yen and Jaffe's Reproductive Endocrinology|url=https://books.google.com/books?id=KZ95AAAAQBAJ&pg=PA518|date=13 September 2013|publisher=Elsevier Health Sciences|isbn=978-1-4557-2758-2|pages=518–|url-status=live|archive-url=https://web.archive.org/web/20171105200803/https://books.google.com/books?id=KZ95AAAAQBAJ&pg=PA518|archive-date=5 November 2017}}

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.{{cite web|title=International brands of clomifene -|url=https://www.drugs.com/international/clomifene.html|publisher=Drugs.com|access-date=11 September 2016|url-status=live|archive-url=https://web.archive.org/web/20160920215822/https://www.drugs.com/international/clomifene.html|archive-date=20 September 2016}}

Clomifene is included on the World Anti-Doping Agency list of illegal doping agents in sport.{{Cite web |url=https://wada-main-prod.s3.amazonaws.com/resources/files/wada-2016-prohibited-list-en.pdf |archiveurl=https://web.archive.org/web/20160306124802/https://wada-main-prod.s3.amazonaws.com/resources/files/wada-2016-prohibited-list-en.pdf |url-status=dead |title=World Anti Doping Agency | wada-2016-prohibited-list-en.pdf |archivedate=6 March 2016 |website=wada-main-prod.s3.amazonaws.com}} It is listed because it is an "anti-estrogenic substance".{{cn|date=May 2024}}

Clomifene has been used almost exclusively for ovulation induction in premenopausal women, and has been studied very limitedly in postmenopausal women.{{cite journal | vauthors = Palacios S | title = The future of the new selective estrogen receptor modulators | journal = Menopause International | volume = 13 | issue = 1 | pages = 27–34 | date = March 2007 | pmid = 17448265 | doi = 10.1258/175404507780456791 | s2cid = 29053109 }}

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.{{cite journal | vauthors = Maximov PY, Lee TM, Jordan VC | title = The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice | journal = Current Clinical Pharmacology | volume = 8 | issue = 2 | pages = 135–55 | date = May 2013 | pmid = 23062036 | pmc = 3624793 | doi = 10.2174/1574884711308020006 }} 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.{{cite book|title=Hormones and Breast Cancer|url=https://books.google.com/books?id=vBvzF6HQ4-QC&pg=PA13|date=25 June 2013|publisher=Elsevier|isbn=978-0-12-416676-9|pages=13–|url-status=live|archive-url=https://web.archive.org/web/20171105200803/https://books.google.com/books?id=vBvzF6HQ4-QC&pg=PA13|archive-date=5 November 2017}}{{cite book| vauthors = Maximov PY, McDaniel RE, Jordan VC |title=Tamoxifen |chapter=Tamoxifen Goes Forward Alone |series=Milestones in Drug Therapy |year=2013|pages=31–46|publisher=Springer |issn=2296-6064|doi=10.1007/978-3-0348-0664-0_2|isbn=978-3-0348-0663-3}}

{{Reflist}}

{{Estrogens and antiestrogens}}

{{Assisted reproductive technology}}

{{Estrogen receptor modulators}}

{{Portal bar | Medicine}}

{{Authority control}}

Category:2-Phenoxyethanamines

Category:24-Dehydrocholesterol reductase inhibitors

Category:Diethylamino compounds

Category:Drugs developed by Merck

Category:Hepatotoxins

Category:Organochlorides

Category:Prodrugs

Category:Progonadotropins

Category:Selective estrogen receptor modulators

Category:Triphenylethylenes

Category:Wikipedia medicine articles ready to translate

Category:World Health Organization essential medicines