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| Trade names | Clomid, Serophene, others[1] |
| Other names | Clomiphene; Chloramifene; Chloramiphene; MRL-41; MRL/41; NSC-35770 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682704 |
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| Routes of administration | By mouth |
| Drug class | Selective estrogen receptor modulator;Progonadotropin |
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| Pharmacokinetic data | |
| Bioavailability | High (>90%) |
| Metabolism | LiverCYP2D6 (withenterohepatic circulation)[2] |
| Metabolites | 4-Hydroxyclomiphene (4-OH-CLO), 4-Hydroxy-N-desethylclomiphene (4-OH-DE-CLO) |
| Eliminationhalf-life | 4–7 days[2][3][4] active metabolites: |
| Excretion | Mainlyfeces, some inurine |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.011.826 |
| Chemical and physical data | |
| Formula | C26H28ClNO |
| Molar mass | 405.97 g·mol−1 |
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Clomifene, also known asclomiphene, is a medication used to treatinfertility in women whodo not ovulate, including those withpolycystic ovary syndrome.[5] It is takenby mouth.[5]
Common side effects includepelvic pain andhot flashes.[5] Other side effects can include changes in vision, vomiting, trouble sleeping,ovarian cancer, andseizures.[5][6] It is not recommended in people withliver disease orabnormal vaginal bleeding of unknown cause or who arepregnant.[6][7] Clomifene is in theselective estrogen receptor modulator (SERM) family of medication and is a nonsteroidal medication.[7][8] It works by causing the release ofGnRH by thehypothalamus, and subsequentlygonadotropin from theanterior pituitary.[6]
Clomifene was approved for medical use in the United States in 1967.[5] It is on theWorld Health Organization's List of Essential Medicines.[9] Its introduction began the era ofassisted reproductive technology.[10]
Clomifene (particularly the purified enclomiphene isomer) has also been found to have a powerful ability to boost or restore testosterone levels inhypogonadal men.[11] It can be used to enhance performance in sports and is banned by theWorld Anti-Doping Agency.
Clomifene is one of several alternatives for inducingovulation in those who are infertile due toanovulation oroligoovulation.[12] Evidence is lacking for the use of clomifene in those who are infertile without a known reason.[13] 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.[12] Clomifene has also been used with otherassisted reproductive technology to increase success rates of these other modalities.[14]
Clomifene has been effectively used to restorespermatogenesis in trans women looking to have biological children.[15] The effect of feminizing hormone therapy on fertility is not clear, but it is known that it can prevent sperm production.[16]
Clomifene is sometimes used in the treatment of malehypogonadism as an alternative totestosterone replacement therapy.[17][non-primary source needed] It has been found to increase testosterone levels by 2–2.5 times in hypogonadal men at such dosages.[17][18] 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.[19][non-primary source needed]
Clomifene consists of twostereoisomers in equal proportion:enclomifene andzuclomifene. Zuclomifene has pro-estrogenic properties, whereas enclomifene is pro-androgenic, i.e. it promotes testosterone production through stimulation of theHPG 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.[11] Additionally, enclomifene has ahalf-life of just ten hours,[4] 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.[20]
Clomifene has been used in the treatment ofgynecomastia.[21] It has been found to be useful in the treatment of some cases of gynecomastia but it is not as effective astamoxifen orraloxifene for this indication.[22] It has shown variable results for gynecomastia (probably because the zuclomifene isomer is estrogenic), and hence is not recommended for treatment of the condition.[23] 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).[medical citation needed]
Due to its long half-life, zuclomifene can be detected in urine for at least 261 days after discontinuation[24] (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[medical citation needed]).
TheWorld 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 withanabolic properties, clomifene leads to increased muscle mass in males.[25]
Because clomifene can enhanceegg production in hens, athletes may inadvertently consume the substance through contaminated food.[26] 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.[27]
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, andpituitary tumors.[7]
The most commonadverse drug reaction associated with the use of clomifene (>10% of people) is reversible ovarian enlargement.[7]
Less common effects (1–10% of people) include visual symptoms (blurred vision,double vision, floaters,eye sensitivity to light,scotomata), headaches, vasomotor flushes (orhot flashes), light sensitivity and pupil constriction, abnormal uterine bleeding and/or abdominal discomfort.[7]
Rare adverse events (<1% of people) include:high blood level of triglycerides,liver inflammation, reversiblebaldness and/orovarian hyperstimulation syndrome.[7]
Rates of birth defects and miscarriages do not appear to change with the use of clomifene for fertility.[7] Clomifene has been associated withliver abnormalities and a couple of cases ofhepatotoxicity.[28]
Some studies have suggested that clomifene if used for more than a year may increase the risk ofovarian cancer.[13] This may only be the case in those who have never been and do not become pregnant.[29] Subsequent studies have failed to support those findings.[12][30]
Clomifene has been shown to be associated with an increased risk of malignantmelanomas andthyroid cancer.[3] Thyroid cancer risk was not associated with the number of pregnancies carried to viability.[31]
Clomifene is anonsteroidaltriphenylethylenederivative that acts as aselective estrogen receptor modulator (SERM).[14] It consists of a non-racemic mixture ofzuclomifene (~38%) andenclomifene (~62%), each of which has uniquepharmacologic properties.[32] It is a mixedagonist andantagonist of theestrogen receptor (ER). Clomifene activates theERα in the setting of low baselineestrogen levels and partially blocks the receptor in the context of high baseline estrogen levels.[18] Conversely, it is anantagonist of theERβ.[18] Clomifene has antiestrogenic effects in theuterus.[33] There is little clinical research on the influence of clomifene in many target tissues, such aslipids, thecardiovascular system, and thebreasts.[33][34] Positive effects of clomifene onbone have been observed.[18][33][34] Clomifene has been found to decreaseinsulin-like growth factor 1 (IGF-1) levels in women.[35]
Clomifene is a long-acting ERligand, with anuclear retention of greater than 48 hours.[36] Clomifene is aprodrug being activated via similarmetabolic pathways as the related triphenylethylene SERMs tamoxifen andtoremifene.[37][38] Theaffinity of clomifene for the ER relative toestradiol ranges from 0.1 to 12% in different studies, which is similar to the range for tamoxifen (0.06–16%).[39][40][41] 4-Hydroxyclomifene, a major active metabolite of clomifene, andafimoxifene (4-hydroxytamoxifen), a major active metabolite of tamoxifen, show 89–251% and 41–246% of the affinity of estradiol for the ER in humanMCF-7breast cancercells, respectively.[42][43] The ER affinities of theisomers of 4-hydroxyclomifene were 285% for (E)-4-hydroxyclomifene and 16% for (Z)-4-hydroxyclomifene relative to estradiol.[42] 4-Hydroxy-N-desethylclomiphene has similar affinity to 4-hydroxyclomifene for the ER.[38] In one study, the affinities of clomifene and its metabolites for theERα were ~100 nM for clomifene, ~2.4 nM for 4-hydroxyclomifene, ~125 nM forN-desethylclomiphene, and ~1.4 nM for 4-hydroxy-N-desethylclomiphene.[38]
Even though clomifene has someestrogenic effect, theantiestrogenic property is believed to be the primary source forstimulating ovulation.[5] Clomifene appears to act mostly in thehypothalamus where it depletes hypothalamic ERs and blocks thenegative feedback effect of circulatingendogenousestradiol, which in turn results in an increase inhypothalamicgonadotropin-releasing hormone (GnRH) pulse frequency and circulating concentrations offollicle-stimulating hormone (FSH) andluteinizing hormone (LH).[medical citation needed]
In normal physiologic female hormonal cycling, at seven days pastovulation, high levels of estrogen andprogesterone produced from the corpus luteum inhibit GnRH, FSH, and LH at the hypothalamus and anterior pituitary.[medical citation needed] If fertilization does not occur in the post-ovulation period thecorpus luteum disintegrates due to a lack ofhuman chorionic gonadotropin (hCG).[medical citation needed] This would normally be produced by the embryo in the effort of maintaining progesterone and estrogen levels during pregnancy.[medical citation needed]
Therapeutically, clomifene is given early in themenstrual cycle to produce follicles.[medical citation needed] Follicles, in turn, produce the estrogen, which circulates in serum.[medical citation needed] In the presence of clomifene, the body perceives a low level of estrogen, similar to day 22 in the previous cycle.[medical citation needed] 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.[medical citation needed] (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.[medical citation needed]) 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.[medical citation needed]
In normal men, 50 mg/day clomifene for eight months has been found to increasetestosterone levels by around 870 ng/dL in younger men and by around 490 ng/dL in elderly men.[18]Estradiol levels increased by 62 pg/mL in younger men and by 40 pg/mL in elderly men.[18] These findings suggest that theprogonadotropic effects of clomifene are stronger in younger men than in older men.[18] In men withhypogonadism, clomifene has been found to increase testosterone levels by 293 to 362 ng/dL and estradiol levels by 5.5 to 13 pg/mL.[18] 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.[44] No significant changes inHDL cholesterol,triglycerides, fastingglucose, orprolactin levels were observed, althoughtotal cholesterol levels decreased significantly.[18][44]
| Medication | Breast | Bone | Liver | Uterus | Vagina | Brain | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Lipids | Coagulation | SHBGTooltip Sex hormone-binding globulin | IGF-1Tooltip Insulin-like growth factor 1 | Hot flashes | Gonadotropins | |||||||||
| Estradiol | + | + | + | + | + | + | + | + | + | + | ||||
| "Ideal SERM" | – | + | + | ± | ± | ± | – | + | + | ± | ||||
| Bazedoxifene | – | + | + | + | + | ? | – | ± | – | ? | ||||
| Clomifene | – | + | + | ? | + | + | – | ? | – | ± | ||||
| Lasofoxifene | – | + | + | + | ? | ? | ± | ± | – | ? | ||||
| Ospemifene | – | + | + | + | + | + | ± | ± | – | ± | ||||
| Raloxifene | – | + | + | + | + | + | ± | – | – | ± | ||||
| Tamoxifen | – | + | + | + | + | + | + | – | – | ± | ||||
| Toremifene | – | + | + | + | + | + | + | – | – | ± | ||||
| Effect:+ =Estrogenic /agonistic.± = Mixed or neutral.– =Antiestrogenic /antagonistic.Note: SERMs generally increase gonadotropin levels in hypogonadal and eugonadal men as well as premenopausal women (antiestrogenic) but decrease gonadotropin levels in postmenopausal women (estrogenic).Sources: See template. | ||||||||||||||
Clomifene is aninhibitor of the conversion ofdesmosterol intocholesterol by theenzyme24-dehydrocholesterol reductase.[45][46] Concerns about possible induction ofdesmosterolosis and associated symptoms such ascataracts andichthyosis with extended exposure precluded the use of clomifene in the treatment of breast cancer.[45][46] 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 producevisual disturbances.[47][48] In 2025, clomifene, along with the structurally related moleculestamoxifen andtoremifene, was reported to interact withtubulin and inhibit its polymerization.[49]
Clomifene producesN-desethylclomiphene,clomifenoxide (clomifeneN-oxide), 4-hydroxyclomifene, and 4-hydroxy-N-desethylclomiphene asmetabolites.[2][50] Clomifene is aprodrug most importantly of 4-hydroxyclomifene and 4-hydroxy-N-desethylclomiphene, which are the most active of its metabolites.[37][38] In one study, thepeak 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.[2]
Clomifene has anonset of action of five to ten days following course of treatment and anelimination half-life about four to seven days.[2][4] 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.[2] Individuals with the CYP2D6*10allele showed longer half-lives for 4-hydroxyclomifene and 4-hydroxy-N-desethylclomiphene.[2] Primarily due to differences in CYP2D6 genetics, steady state concentrations and individual response to clomifene are highly variable.[51]
Most clomifene metabolism occurs in theliver, where it undergoesenterohepatic recirculation. Clomifene and its metabolites areexcreted primarily throughfeces (42%), and excretion can occur up to 6 weeks after discontinuation.[32]
Clomifene is atriphenylethylene derivative. It is a mixture of twogeometric isomers, the cisenclomifene ((E)-clomifene) form and transzuclomifene ((Z)-clomifene) form. These two isomers contribute to the mixed estrogenic and antiestrogenic properties of clomifene.[10] The typical ratio of these isomers after synthesis is 38% zuclomiphene and 62% enclomiphene.[4] The United States Pharmacopeia specifies that clomifene preparations must contain between 30% and 50% zuclomiphene.[4]
A team atWilliam 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.[10][52] Scientists at Merrell had previously synthesizedchlorotrianisene andethamoxytriphetol.[10] Clomifene was studied in the treatment ofadvanced breast cancer during the period of 1964 to 1974 and was found to be effective but was abandoned due to concerns aboutdesmosterolosis with extended use.[45][53][54] Short-term use (e.g. days to months) did not raise the same concerns and clomifene continued to be studied for other indications.[46][47]
| Antiestrogen | Dosage | Year(s) | Response rate | Adverse effects |
|---|---|---|---|---|
| Ethamoxytriphetol | 500–4,500 mg/day | 1960 | 25% | Acute psychotic episodes |
| Clomifene | 100–300 mg/day | 1964–1974 | 34% | Risks ofcataracts |
| Nafoxidine | 180–240 mg/day | 1976 | 31% | Cataracts,ichthyosis,photophobia |
| Tamoxifen | 20–40 mg/day | 1971–1973 | 31% | Transientthrombocytopeniaa |
| Footnotes:a = "The particular advantage of this drug is the low incidence of troublesome side effects (25)." "Side effects were usually trivial (26)."Sources:[53][55] | ||||
Clinical studies were conducted under anInvestigational New Drug Application; clomifene was third drug for which an IND had been filed under the 1962Kefauver Harris Amendment to theFederal Food, Drug, and Cosmetic Act that had been passed in response to thethalidomide tragedy.[10] It was approved for marketing in 1967 under the brand name Clomid.[10][56] It was first used to treat cases ofoligomenorrhea but was expanded to include treatment ofanovulation when women undergoing treatment had higher than expected rates of pregnancy.[57]
The drug is widely considered to have been a revolution in the treatment of female infertility, the beginning of the modern era ofassisted reproductive technology, and the beginning of what in the words ofEli Y. Adashi, was "the onset of the US multiple births epidemic".[10][58]
The company was acquired byDow Chemical in 1980,[59][60] and in 1989 Dow Chemical acquired 67 percent interest of Marion Laboratories, which was renamed Marion Merrell Dow.[59] In 1995, Hoechst AG acquired the pharmaceutical business of Marion Merrell Dow.[61] Hoechst in turn became part ofAventis in 1999,[62]: 9–11 and subsequently a part ofSanofi.[63] It became the most widely prescribed drug forovulation induction to reverseanovulation oroligoovulation.[64]
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.[1]
Clomifene has been used almost exclusively for ovulation induction inpremenopausal women, and has been studied very limitedly inpostmenopausal women.[65]
Clomifene was studied for treatment and prevention ofbreast cancer, but issues with toxicity led to abandonment of this indication, as did the discovery oftamoxifen.[66] Like the structurally related drugtriparanol, clomifene is known toinhibit theenzyme24-dehydrocholesterol reductase and increase circulatingdesmosterol levels, making it unfavorable for extended use in breast cancer due to risk of side effects like irreversiblecataracts.[67][68]
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