Clomifene: Difference between revisions

{{Short description|Infertility treatment for women}}

{{Distinguish|Clonidine}}

{{Use dmy dates|date=May 2024}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

| Watchedfields = changed

| verifiedrevid = 460044105

| width = 250

| alt =

| image2 = Clomifene-based-on-xtal-3D-bs-17.png

| width2 = 250

| alt2 =

| tradename = Clomid, Serophene, others<ref name=Brands/>

| Drugs.com = {{drugs.com|monograph|clomiphene-citrate}}

| pregnancy_AU = B3

| routes_of_administration = [[Oral administration|By mouth]]

| class = [[Selective estrogen receptor modulator]]; [[Progonadotropin]]

| ATC_prefix = G03

| ATC_suffix = GB02

| legal_AU = S4

| legal_UK = POM

| legal_US = Rx-only

| legal_status =

| protein_bound =

| metabolism = [[Liver]] [[CYP2D6]] (with [[enterohepatic circulation]])<ref name="pmid29516347"/>

| metabolites = 4-Hydroxyclomiphene (4-OH-CLO), 4-Hydroxy-N-desethylclomiphene (4-OH-DE-CLO)

| elimination_half-life = 4 – 7 days <ref name="pmid29516347"/><ref name="pmid29159661" >{{cite journal | vauthors = Yilmaz S, Yilmaz Sezer N, Gönenç İM, İlhan SE, Yilmaz E | title = Safety of clomiphene citrate: a literature review | journal = Cytotechnology | volume = 70 | issue = 2 | pages = 489–495 | date = April 2018 | pmid = 29159661 | pmc = 5851961 | doi = 10.1007/s10616-017-0169-1 }}</ref><ref name="singledosekinetics"/> <br>

active metabolites: <br>

4-OH-CLO : 13 - 34 hrs<ref name="pmid29516347"/> <br>

4-OH-DE-CLO : 15 - 37 hrs<ref name="pmid29516347"/>

| excretion = Mainly [[feces]], some in [[urine]]

| IUPHAR_ligand = 4159

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 2355051

| synonyms = Clomiphene; Chloramifene; Chloramiphene; MRL-41; MRL/41; NSC-35770

<!--Chemical data-->

| IUPAC_name = (''E'',''Z'')-2-(4-(2-chloro-1,2-diphenylethenyl)phenoxy)-''N'',''N''-diethylethanamine

| C=26 | H=28 | Cl=1 | N=1 | O=1

| SMILES = ClC(c1ccccc1)=C(c2ccc(OCCN(CC)CC)cc2)c3ccccc3

<!-- Definition and medical uses -->

'''Clomifene''', also known as '''clomiphene''', is a medication used to treat [[infertility]] in women who [[anovulation|do not ovulate]], including those with [[polycystic ovary syndrome]].<ref name=AHFS2016/> It is taken [[by mouth]].<ref name=AHFS2016>{{cite web|title=Clomiphene Citrate|url= https://www.drugs.com/monograph/clomiphene-citrate.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url= https://web.archive.org/web/20170914035548/https://www.drugs.com/monograph/clomiphene-citrate.html|archive-date=14 September 2017}}</ref>

<!-- Side effects and mechanism -->

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>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free | pages= 385–386 }}</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>{{cite book| vauthors = Ghumman S |title =Principles and Practice of Controlled Ovarian Stimulation in ART|date=2015|publisher=Springer|isbn=9788132216865|page=65|url=https://books.google.com/books?id=UxecCgAAQBAJ&pg=PA65|url-status=live|archive-url= https://web.archive.org/web/20161227055405/https://books.google.ca/books?id=UxecCgAAQBAJ&pg=PA65|archive-date=27 December 2016}}</ref> It works by causing the release of [[GnRH]] by the [[hypothalamus]], and subsequently [[gonadotropin]] from the [[anterior pituitary]].<ref name=WHO2008/>

<!-- History, society and culture -->

Clomifene was approved for medical use in the United States in 1967.<ref name=AHFS2016/> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]], under the category "Ovulation inducers" (Complementary List).<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> Its introduction began the era of [[assisted reproductive technology]].<ref name=Hist>{{cite journal | vauthors = Dickey RP, Holtkamp DE | title = Development, pharmacology and clinical experience with clomiphene citrate | journal = Human Reproduction Update | volume = 2 | issue = 6 | pages = 483–506 | date = 1996 | pmid = 9111183 | doi = 10.1093/humupd/2.6.483 | doi-access = free }}</ref>

Clomifene (particularly the purified enclomiphene isomer) has also been found to have a powerful ability to boost or restore testosterone levels in [[hypogonadism|hypogonadal]] men.<ref name="Enclomiphene citrate for the treatm">{{cite journal | vauthors = Rodriguez KM, Pastuszak AW, Lipshultz LI | title = Enclomiphene citrate for the treatment of secondary male hypogonadism | journal = Expert Opinion on Pharmacotherapy | volume = 17 | issue = 11 | pages = 1561–7 | date = August 2016 | pmid = 27337642 | pmc = 5009465 | doi = 10.1080/14656566.2016.1204294 }}</ref>

{{TOC limit|3}}

==Medical uses==

===Ovulation induction===

{{Further|Ovulation induction}}

Clomifene is one of several alternatives for [[ovulation induction]] 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>{{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 }}</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>{{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 }}</ref>

===Other uses===

Clomifene has also been used with other [[assisted reproductive technology]] to increase success rates of these other modalities.<ref name="Induction"/>

==== Testosterone replacement therapy ====

Clomifene is sometimes used in the treatment of male [[hypogonadism]] as an alternative to [[testosterone replacement therapy]].<ref name="BachNajari2016">{{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}}</ref>{{Secondary source needed|date=August 2023}} It has been found to increase testosterone levels by 2- to 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>{{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 }}</ref>{{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.<ref name="Enclomiphene citrate for the treatm"/> Additionally, enclomifene has a [[half-life]] of just 10 hours,<ref name="singledosekinetics">{{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 }}</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>{{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 }}</ref>

==== Gynecomastia ====

Clomifene has been used in the treatment of [[gynecomastia]].<ref name="Becker2001">{{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–}}</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">{{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}}</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">{{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 }}</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).{{medcn|date=May 2024}}

Due to its long half-life, zuclomifene can be detected in urine for at least 261 days after discontinuation<ref>{{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 }}</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 10 hours, enclomifene reaches the same 0.24% level in less than 4 days{{medcn|date=May 2024}}).

Because of its potential for boosting testosterone, clomifene is listed as banned for use by competitive sportsmen, both in and out of competition, by the [[World Anti-Doping Agency]], absent an organic etiology of [[primary hypogonadism]].{{cn|date=May 2024}}

==== Fertility restoration in transgender women ====

{{Further information|Feminizing hormone therapy#Fertility}}

Clomifene has been effectively used to restore [[spermatogenesis]] in transwomen looking to have biological children.<ref>{{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 }}</ref> The effect of feminizing hormone therapy on fertility is not clear, but it is known that it can prevent sperm production.<ref>{{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 }}</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>{{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=live|archive-url= https://web.archive.org/web/20160927072841/http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016131s026lbl.pdf|archive-date=27 September 2016}}</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, [[diplopia|double vision]], floaters, [[photophobia|eye sensitivity to light]], [[scotomata]]), headaches, vasomotor flushes (or [[hot flash]]es), light sensitivity and pupil constriction, abnormal uterine bleeding and/or abdominal discomfort.<ref name=FDAlabel/>

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

Clomifene can lead to multiple ovulation, hence increasing the chance of [[twin]]s (10% of births instead of ~1% in the general population) and [[Multiple birth|triplets]].{{medcn|date=May 2024}}

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">{{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–}}</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>{{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 }}</ref> Subsequent studies have failed to support those findings.<ref name="Committee2013"/><ref>{{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 }}</ref>

Clomifene has been shown to be associated with an increased risk of malignant [[melanoma]]s and [[thyroid cancer]].<ref name="pmid29159661"/> Thyroid cancer risk was not associated with the number of pregnancies carried to viability.<ref>{{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 }}</ref>

==Pharmacology==

===Pharmacodynamics===

====Selective estrogen receptor modulator activity====

Clomifene is a [[nonsteroidal]] [[triphenylethylene]] [[chemical derivative|derivative]] that acts as a [[selective estrogen receptor modulator]] (SERM).<ref name="Induction">{{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}}</ref> It consists of a non-racemic mixture of [[zuclomifene]] (~38%) and [[enclomifene]] (~62%), each of which has unique [[pharmacology|pharmacologic]] properties.<ref name=":1">{{Cite web|url=https://www.drugs.com/ppa/clomiphene.html| title=ClomiPHENE (Professional Patient Advice)|website=Drugs.com|access-date=30 July 2019}}</ref> It is a mixed [[agonist]] and [[receptor antagonist|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 [[receptor antagonist|antagonist]] of the [[ERβ]].<ref name="TrostKhera2014" /> Clomifene has antiestrogenic effects in the [[uterus]].<ref name="Goldstein2000">{{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 }}</ref> There is little clinical research on the influence of clomifene in many target tissues, such as [[lipid]]s, the [[cardiovascular system]], and the [[breast]]s.<ref name="Goldstein2000" /><ref name="Haskell2003">{{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 }}</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">{{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 }}</ref>

Clomifene is a long-acting ER [[ligand (biochemistry)|ligand]], with a [[nuclear retention]] of greater than 48&nbsp;hours.<ref name="RunnebaumRabe2013">{{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–}}</ref> Clomifene is a [[prodrug]] being activated via similar [[metabolic pathway]]s as the related triphenylethylene SERMs tamoxifen and [[toremifene]].<ref name="RocheZito2019">{{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–}}</ref><ref name="pmid23406671" /> The [[affinity (pharmacology)|affinity]] of clomifene for the ER relative to [[estradiol (medication)|estradiol]] ranges from 0.1 to 12% in different studies, which is similar to the range for tamoxifen (0.06–16%).<ref name="WittliffKerr2005">{{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}}</ref><ref name="pmid10746941">{{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 }}</ref><ref name="pmid11258977">{{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 }}</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]] [[cell (biology)|cell]]s, respectively.<ref name="pmid9586957">{{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 }}</ref><ref name="pmid3778464">{{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 }}</ref> The ER affinities of the [[isomer]]s of 4-hydroxyclomifene were 285% for (''E'')-4-hydroxyclomifene and 16% for (''Z'')-4-hydroxyclomifene relative to estradiol.<ref name="pmid9586957" /> 4-Hydroxy-''N''-desmethylclomifene has similar affinity to 4-hydroxyclomifene for the ER.<ref name="pmid23406671">{{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 }}</ref> In one study, the affinities of clomifene and its metabolites for the [[ERα]] were ~100&nbsp;nM for clomifene, ~2.4&nbsp;nM for 4-hydroxyclomifene, ~125&nbsp;nM for ''N''-desmethylclomifene, and ~1.4&nbsp;nM for 4-hydroxy-''N''-desmethylclomifene.<ref name="pmid23406671"/>

Even though clomifene has some [[estrogen (medication)|estrogenic]] effect, the [[antiestrogen]]ic property is believed to be the primary source for [[ovulation induction|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 [[hypothalamus|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&nbsp;mg/day clomifene for 8&nbsp;months has been found to increase [[testosterone]] levels by around 870&nbsp;ng/dL in younger men and by around 490&nbsp;ng/dL in elderly men.<ref name="TrostKhera2014" /> [[Estradiol]] levels increased by 62&nbsp;pg/mL in younger men and by 40&nbsp;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&nbsp;ng/dL and estradiol levels by 5.5 to 13&nbsp;pg/mL.<ref name="TrostKhera2014" /> In a large clinical study of men with low testosterone levels (<400&nbsp;ng/dL), 25&nbsp;mg/day clomifene increased testosterone levels from 309&nbsp;ng/dL to 642&nbsp;ng/dL after 3&nbsp;months of therapy.<ref name="pmid27601965">{{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 = 31 January 2024 }}</ref> No significant changes in [[HDL cholesterol]], [[triglyceride]]s, fasting [[glucose]], or [[prolactin]] levels were observed, although [[total cholesterol]] levels decreased significantly.<ref name="TrostKhera2014">{{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 }}</ref><ref name="pmid27601965" />{{Tissue-specific estrogenic and antiestrogenic activity of SERMs}}

====Other activities====

Clomifene is an [[enzyme inhibitor|inhibitor]] of the conversion of [[desmosterol]] into [[cholesterol]] by the [[enzyme]] [[24-dehydrocholesterol reductase]].<ref name="Zhang2018">{{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–}}</ref><ref name="MaximovMcDaniel2013a">{{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–}}</ref> Concerns about possible induction of [[desmosterolosis]] and associated symptoms such as [[cataract]]s 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&nbsp;mg/day) have been reported to produce [[visual disturbance]]s.<ref name="Jucker2013">{{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–}}</ref><ref>{{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–}}</ref>

===Pharmacokinetics===

Clomifene produces ''N''-desmethylclomifene, [[clomifenoxide]] (clomifene ''N''-oxide), 4-hydroxyclomifene, and 4-hydroxy-''N''-desmethylclomifene as [[metabolite]]s.<ref name="pmid29516347">{{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 }}</ref><ref name="AcademicPress1998">{{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}}</ref> Clomifene is a [[prodrug]] most importantly of 4-hydroxyclomifene and 4-hydroxy-''N''-desmethylclomifene, which are the most active of its metabolites.<ref name="RocheZito2019" /><ref name="pmid23406671" /> In one study, the [[peak levels]] after a single 50&nbsp;mg dose of clomifene were 20.37&nbsp;nmol/L for clomifene, 0.95&nbsp;nmol/L for 4-hydroxyclomifene, and 1.15&nbsp;nmol/L for 4-hydroxy-''N''-desmethylclomifene.<ref name="pmid29516347" />

Clomifene has an [[onset of action]] of 5 to 10&nbsp;days following course of treatment and an [[elimination half-life]] about 4 - 7days.<ref name="pmid29516347"/><ref name="singledosekinetics"/> In one study, after a single 50&nbsp;mg dose of clomifene, the half-life of clomifene was 128&nbsp;hours (5.3&nbsp;days), of 4-hydroxyclomifene was 13&nbsp;hours, and of 4-hydroxy-''N''-desmethylclomifene was 15&nbsp;hours.<ref name="pmid29516347" /> Individuals with the CYP2D6*10 [[allele]] showed longer half-lives for 4-hydroxyclomifene and 4-hydroxy-''N''-desmethylclomifene.<ref name="pmid29516347" /> Primarily due to differences in CYP2D6 genetics, steady state concentrations and individual response to clomifene are highly variable.<ref>{{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 }}</ref>

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

Clomifene is a [[triphenylethylene]] derivative. It is a mixture of two [[geometric isomerism|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"/>

|| [[Image:Enclomifene.png|framed|[[Enclomifene]]]]

|| [[Image:Zuclomifene.png|framed|[[Zuclomifene]]]]

==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>{{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 }}</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">{{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}}</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" />

{{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.<ref name=Hist/> It was approved for marketing in 1967 under the brand name Clomid.<ref name=Hist/><ref>{{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 }}</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>{{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}}</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>{{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}}</ref>

The company was acquired by [[Dow Chemical]] in 1980,<ref name="Los Angeles Times">{{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://articles.latimes.com/1989-07-18/business/fi-4000_1_merrell-dow|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}}</ref><ref>{{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}}</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>{{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}}</ref> Hoechst in turn became part of [[Aventis]] in 1999,<ref name=Bris>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</ref>{{rp|9–11}} and subsequently a part of [[Sanofi]].<ref>{{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}}</ref> It became the most widely prescribed drug for [[ovulation induction]] to reverse [[anovulation]] or [[oligoovulation]].<ref name="StraussBarbieri2013">{{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}}</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">{{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}}</ref>

===Regulation===

Clomifene is included on the [[World Anti-Doping Agency]] list of illegal doping agents in sport.<ref>[https://wada-main-prod.s3.amazonaws.com/resources/files/wada-2016-prohibited-list-en.pdf The WADA Prohibited List 2016 (listed as clomiphene)] {{webarchive|url=https://web.archive.org/web/20160306124802/https://wada-main-prod.s3.amazonaws.com/resources/files/wada-2016-prohibited-list-en.pdf |date=6 March 2016 }}</ref> It is listed because it is an "anti-estrogenic substance".{{cn|date=May 2024}}

==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">{{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 }}</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>{{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 }}</ref> Like the structurally related drug [[triparanol]], clomifene is known to [[enzyme inhibitor|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">{{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}}</ref><ref name="MaximovMcDaniel2013b">{{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}}</ref>

== References ==

{{Reflist}}

{{Estrogens and antiestrogens}}

{{Estrogen receptor modulators}}

{{Portal bar|Medicine}}

[[Category:2-Phenoxyethanamines]]

[[Category:24-Dehydrocholesterol reductase inhibitors]]

[[Category:Diethylamino compounds]]

[[Category:Hepatotoxins]]

[[Category:Drugs developed by Merck]]

[[Category:Prodrugs]]

[[Category:Progonadotropins]]

[[Category:Selective estrogen receptor modulators]]

[[Category:Triphenylethylenes]]

[[Category:World Health Organization essential medicines]]

[[Category:Wikipedia medicine articles ready to translate]]