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. 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 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. 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 and is banned by the World Anti-Doping Agency.
Medical uses
Reproductive medicine
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. 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. 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. The effect of feminizing hormone therapy on fertility is not clear, but it is known that it can prevent sperm production.
Testosterone replacement therapy
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. 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 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.
Gynecomastia
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, 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.Due to its long half-life, zuclomifene can be detected in urine for at least 261 days after discontinuation.
Prohibited use in sports
The World Anti-Doping Agency 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.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.
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 is reversible ovarian enlargement.Less common effects include visual symptoms, headaches, vasomotor flushes, light sensitivity and pupil constriction, abnormal uterine bleeding and/or abdominal discomfort.
Rare adverse events 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.
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
Pharmacodynamics
Selective estrogen receptor modulator activity
Clomifene is a nonsteroidal triphenylethylene derivative that acts as a selective estrogen receptor modulator. It consists of a non-racemic mixture of zuclomifene and enclomifene, each of which has unique pharmacologic properties. It is a mixed agonist and antagonist of the estrogen receptor. 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 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. 4-Hydroxyclomifene, a major active metabolite of clomifene, and afimoxifene, 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 -4-hydroxyclomifene and 16% for -4-hydroxyclomifene relative to estradiol. 4-Hydroxy-N-desethylclomiphene 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-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 pulse frequency and circulating concentrations of follicle-stimulating hormone and luteinizing hormone.
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. 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 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. 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. 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, 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 were observed, although total cholesterol levels decreased significantly.