Clomifene trade names Clomid
Pregnancy category AU: B3
Routes of administration By mouth
Drug class Selective estrogen receptor modulator
Bioavailability High (>90%)
Metabolism Liver CYP2D6 (with enterohepatic circulation)
Elimination half-life 4–7 days
Excretion Mainly feces, some in urine
Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome.
It is taken by mouth.
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.
Its introduction began the era of assisted reproductive technology.
Clomifene has also been found to have a powerful ability to boost or restore testosterone levels in hypogonadal men.
It can be used to enhance performance in sports.
Clomifene is one of several alternatives for inducing ovulation in those who are infertile due to anovulation or oligoovulation.
Studies have observed a clinical pregnancy rate 5.6% per cycle with clomifene treatment vs. 1.3%–4.2% per cycle without treatment.
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.
Is is known that it can prevent sperm production.
Clomifene is sometimes used in the treatment of male hypogonadism as an alternative to testosterone replacement therapy.
It has been found to increase testosterone levels by 2–2.5 times in hypogonadal men at such dosages.
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.
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, 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, but it is not as effective as tamoxifen or raloxifene for this indication.
Pure enclomifene isomer is likely to be more effective than clomifene at treating gynecomastia, because of the lack of the zuclomifene isomer.
Due to its long half-life, zuclomifene can be detected in urine for at least 261 days after discontinuation, whereas with a half-life of ten hours, enclomifene reaches the same 0.24% level in less than four days.
Like other substances with anabolic properties, clomifene leads to increased muscle mass in males.
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.
The most common adverse drug reaction associated with the use of clomifene (>10% of people) is reversible ovarian enlargement.
1–10% of people experience 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.
Clomifene has been shown to be associated with an increased risk of malignant melanomas and thyroid cancer.
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%).
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.
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 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%).
Clomifene has some estrogenic effect, however 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 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.
If fertilization does not occur in the post-ovulation period the corpus luteum disintegrates due to a lack of human chorionic gonadotropin (hCG).
Therapeutically, clomifene is given early in the menstrual cycle to produce 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.
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 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.
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.
No significant changes in HDL cholesterol, triglycerides, fasting glucose, or prolactin levels are observed, although total cholesterol levels are decreased significantly.
Clomifene is an inhibitor of the conversion of desmosterol into cholesterol by the enzyme 24-dehydrocholesterol reductase.
Concerns about possible induction of desmosterolosis associated symptoms such as cataracts and ichthyosis 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.
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.
Due to differences in CYP2D6 genetics, steady state concentrations and individual response to clomifene are highly variable.
Most clomifene metabolism occurs in the liver.
Clomifene 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, and is a mixture of two geometric isomers, the cis enclomifene ((E)-clomifene) form and trans zuclomifene ((Z)-clomifene) form.
Clomifene‘s 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.