clomifene clomifene clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. use results in a greater chance of twins. it is taken by mouth once a day, with a course of treatment that usually lasts for five days. not to be confused with clonidine. clomifeneclinical datatrade namesclomid, serophene, othersother namesclomiphene; chloramifene; chloramiphene; mrl-41; mrl/41; nsc-35770ahfs/drugs.commonographpregnancycategory au: b3 routes ofadministrationby mouthdrug classselective estrogen receptor modulator; progonadotropinatc codeg03gb02 (who) legal statuslegal status au: s4 (prescription only) uk: pom (prescription only) us: ℞-only pharmacokinetic databioavailabilityhigh (>90%)metabolismliver cyp2d6 (with enterohepatic circulation)metabolites4-hydroxyclomiphene (4-oh-clo), 4-hydroxy-n-desethylclomiphene (4-oh-de-clo)elimination half-life4 – 7 days active metabolites: 4-oh-clo : 13 - 34 hrs 4-oh-de-clo : 15 - 37 hrsexcretionmainly feces, some in urineidentifiers iupac name (e,z)-2-(4-(2-chloro-1,2-diphenylethenyl)phenoxy)-n,n-diethylethanamine cas number911-45-5 ypubchem cid2800iuphar/bps4159drugbankdb00882 ychemspider2698 yunii1hrs458qu2keggd07726 ychebichebi:3752 ychemblchembl2355051 ycomptox dashboard (epa)dtxsid1022843 echa infocard100.011.826 chemical and physical dataformulac26h28clnomolar mass405.966 g·mol−13d model (jsmol)interactive image smiles clc(c1ccccc1)=c(c2ccc(occn(cc)cc)cc2)c3ccccc3 inchi inchi=1s/c26h28clno/c1-3-28(4-2)19-20-29-24-17-15-22(16-18-24)25(21-11-7-5-8-12-21)26(27)23-13-9-6-10-14-23/h5-18h,3-4,19-20h2,1-2h3 ykey:gkirpkyjqbwngo-uhfffaoysa-n y ny (what is this?) (verify) common side effects include pelvic pain and hot flashes. other side effects can include changes in vision, vomiting, trouble sleeping, ovarian cancer, and seizures. it is not recommended in people with liver disease or abnormal vaginal bleeding of unknown cause or who are pregnant. clomifene is in the selective estrogen receptor modulator (serm) family of medication and is a nonsteroidal medication. it works by causing the release of gnrh by the hypothalamus, and subsequently gonadotropin from the anterior pituitary. clomifene was approved for medical use in the united states in 1967. it is on the world health organization's list of essential medicines, under the category "ovulation inducers" (complementary list). its introduction began the era of assisted reproductive technology. clomifene (particularly the purified enclomiphene isomer) has also been found to have a powerful ability to boost or restore testosterone levels in hypogonadal men. medical uses ovulation induction further information: ovulation induction clomifene is one of several alternatives for ovulation induction 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. 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. proper timing of the drug is important; it should be taken starting on about the fifth day of the cycle, and there should be frequent intercourse. the following procedures may be used to monitor induced cycles: follicular monitoring with vaginal ultrasound, starting 4–6 days after the last pill. serial transvaginal ultrasound can reveal the size and number of developing follicles. it can also provide presumptive evidence of ovulation such as the sudden collapse of the preovulatory follicle, and an increase in fluid volume in the rectouterine pouch. after ovulation, it may reveal signs of luteinization such as loss of clearly defined follicular margins and appearance of internal echoes. serum estradiol levels, starting 4–6 days after the last pill adequacy of lh surge by urine lh surge tests 3 to 4 days after last clomifene pill post-coital test 1–3 days before ovulation to check whether there are at least 5 progressive sperm per hpf mid-luteal progesterone, with at least 10 ng/ml 7–9 days after ovulation being regarded as adequate. repeat dosing: this 5-day treatment course can be repeated every 30 days. the dosage may be increased by 50-mg increments in subsequent cycles until ovulation is achieved. it is not recommended by the manufacturer to use clomifene for more than 6 cycles. it is no longer recommended to perform an ultrasound examination to exclude any significant residual ovarian enlargement before each new treatment cycle. other uses clomifene has also been used with other assisted reproductive technology to increase success rates of these other modalities. clomifene is sometimes used in the treatment of male hypogonadism as an alternative to testosterone replacement therapy. the medication has been used at a dosage of 20 to 50 mg three times per week to once daily for this indication. it has been found to increase testosterone levels by 2- to 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. 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 10 hours, 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. clomifene has been used in the treatment of gynecomastia. 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. it has shown variable results for gynecomastia (probably because the zuclomifene isomer is estrogenic), and hence is not recommended for treatment of the condition. 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). due to its long half-life, zuclomifene can be detected in urine for at least 261 days after discontinuation (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). 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. 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. side effects 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. clomifene can lead to multiple ovulation, hence increasing the chance of twins (10% of births instead of ~1% in the general population) and triplets. 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. cancer risk 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. subsequent studies have failed to support those findings. 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. pharmacology selective estrogen receptor modulator activity clomifene is a nonsteroidal triphenylethylene derivative that acts as a selective estrogen receptor modulator (serm). it consists of a non-racemic mixture of zuclomifene (~38%) and enclomifene (~62%), each of which has unique pharmacologic properties. 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. there is little clinical research on the influence of clomifene in many target tissues, such as lipids, the cardiovascular system, and the breasts. 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. clomifene is a long-acting er ligand, with a nuclear retention of greater than 48 hours. clomifene is a prodrug being activated via similar metabolic pathways as the related triphenylethylene serms tamoxifen and toremifene. 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%). 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. 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-desmethylclomifene has similar affinity to 4-hydroxyclomifene for the er. 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-desmethylclomifene, and ~1.4 nm for 4-hydroxy-n-desmethylclomifene. 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). in normal physiologic female hormonal cycling, at 7 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. if fertilization does not occur in the post-ovulation period the corpus luteum disintegrates due to a lack of human chorionic gonadotropin (hcg). this would normally be produced by the embryo in the effort of maintaining progesterone and estrogen levels during pregnancy. therapeutically, clomifene is given early in the menstrual cycle. it is typically prescribed beginning on day 3 and continuing for five days. by that time, fsh levels are rising steadily, causing the development of a few follicles. follicles, in turn, produce the estrogen, which circulates in serum. in the presence of clomifene, the body perceives a low level of estrogen, similar to day 22 in the previous cycle. 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. (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.) 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. in normal men, 50 mg/day clomifene for 8 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 3 months of therapy. no significant changes in hdl cholesterol, triglycerides, fasting glucose, or prolactin levels were observed, although total cholesterol levels decreased significantly. tissue-specific estrogenic and antiestrogenic activity of serms medicationbreastboneliveruterusvaginabrain lipidscoagulationshbgigf-1hot flashesgonadotropins 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. other activities clomifene is an inhibitor of the conversion of desmosterol into cholesterol