Clomifene, also known as clomiphene, is a medication used to treat infertility in women who anovulation, 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.][
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Clomifene was approved for medical use in the United States in 1967.[ It is on the World Health Organization's List of Essential Medicines.]
Clomifene (particularly the purified enclomiphene isomer) has also been found to have a powerful ability to boost or restore testosterone levels in hypogonadism men.
Medical uses
Reproductive medicine
Clomifene is one of several alternatives for inducing ovulation in those who are infertile due to anovulation or oligoovulation.
Clomifene has been effectively used to restore spermatogenesis in trans women looking to have biological children.
Testosterone replacement therapy
Clomifene is sometimes used in the treatment of male hypogonadism as an alternative to testosterone replacement therapy.
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.
Gynecomastia
Clomifene has been used in the treatment of gynecomastia.
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 (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 with anabolic steroid 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 (>10% of people) is reversible ovarian enlargement.[
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Less common effects (1–10% of people) include visual symptoms (blurred vision, diplopia, floaters, photophobia, scotomata), headaches, vasomotor flushes (or ), light sensitivity and pupil constriction, abnormal uterine bleeding and/or abdominal discomfort.[
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Rare adverse events (<1% of people) include: high blood level of triglycerides, hepatitis, reversible alopecia and/or ovarian hyperstimulation syndrome.[
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Rates of birth defects and miscarriages do not appear to change with the use of clomifene for fertility.
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.]
Clomifene has been shown to be associated with an increased risk of malignant and thyroid cancer.
Pharmacology
Pharmacodynamics
Selective estrogen receptor modulator activity
Clomifene is a nonsteroidal triphenylethylene derivative that acts as a selective estrogen receptor modulator (SERM).
Clomifene is a long-acting ER ligand, with a nuclear retention of greater than 48 hours.
Even though clomifene has some estrogenic effect, the 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 hypothalamus gonadotropin-releasing hormone (GnRH) pulse frequency and circulating concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
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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). 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. (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 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.
Other activities
Clomifene is an enzyme inhibitor of the conversion of desmosterol into cholesterol by the enzyme 24-dehydrocholesterol reductase.
Pharmacokinetics
Clomifene produces N-desethylclomiphene, clomifenoxide (clomifene N-oxide), 4-hydroxyclomifene, and 4-hydroxy- N-desethylclomiphene as .
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.
Most clomifene metabolism occurs in the liver, where it undergoes enterohepatic recirculation. Clomifene and its metabolites are excretion primarily through feces (42%), and excretion can occur up to 6 weeks after discontinuation.
Chemistry
Clomifene is a triphenylethylene derivative. It is a mixture of two 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.[ The typical ratio of these isomers after synthesis is 38% zuclomiphene and 62% enclomiphene.]
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.[ 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.]
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.[ It was approved for marketing in 1967 under the brand name Clomid.]
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".
The company was acquired by Dow Chemical in 1980,[Arturo Bris and Christos Cabolis, Corporate Governance Convergence Through Cross-Border Mergers The Case of Aventis , Chapter 4 in 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] and subsequently a part of Sanofi.
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.
Regulation
Clomifene is included on the World Anti-Doping Agency list of illegal doping agents in sport.
Research
Clomifene has been used almost exclusively for ovulation induction in premenopausal women, and has been studied very limitedly in postmenopausal women.
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.
