Clomifene

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(Redirected from
Clomiphene
)
Not to be confused with Clonidine.
Clomifene
Clinical data
Trade namesClomid, Serophene, others[1]
Other namesClomiphene; Chloramifene; Chloramiphene; MRL-41; MRL/41; NSC-35770
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth
Drug classSelective estrogen receptor modulator; Progonadotropin
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
BioavailabilityHigh (>90%)
MetabolismLiver CYP2D6 (with enterohepatic circulation)[2]
Metabolites4-Hydroxyclomiphene (4-OH-CLO), 4-Hydroxy-N-desethylclomiphene (4-OH-DE-CLO)
Elimination half-life4 – 7 days [2][3][4]

active metabolites:
4-OH-CLO : 13 - 34 hrs[2]

4-OH-DE-CLO : 15 - 37 hrs[2]
ExcretionMainly feces, some in urine
Identifiers
  • (E,Z)-2-(4-(2-chloro-1,2-diphenylethenyl)phenoxy)-N,N-diethylethanamine
JSmol)
  • ClC(c1ccccc1)=C(c2ccc(OCCN(CC)CC)cc2)c3ccccc3
  • 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 checkY
  • Key:GKIRPKYJQBWNGO-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Clomifene, also known as clomiphene, is a medication used to treat

twins.[5] It is taken by mouth once a day, with a course of treatment that usually lasts for five days.[5]

Common side effects include

GnRH by the hypothalamus, and subsequently gonadotropin from the anterior pituitary.[6]

Clomifene was approved for medical use in the United States in 1967.[5] It is on the World Health Organization's List of Essential Medicines, under the category "Ovulation inducers" (Complementary List).[9] Its introduction began the era of assisted reproductive technology.[10]

Clomifene (particularly the purified enclomiphene isomer) has also been found to have a powerful ability to boost or restore testosterone levels in hypogonadal men.[11]

Medical uses

Ovulation induction

Further information: Ovulation induction

Clomifene is one of several alternatives for

oligoovulation.[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]

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.[7][12][14]

The following procedures may be used to monitor induced cycles:[12]

  • Follicular monitoring with
    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.[12] It is not recommended by the manufacturer to use clomifene for more than 6 cycles.[7][15]

It is no longer recommended to perform an ultrasound examination to exclude any significant residual ovarian enlargement before each new treatment cycle.[12]

Other uses

Clomifene has also been used with other assisted reproductive technology to increase success rates of these other modalities.[16]

Testosterone replacement therapy

Clomifene is sometimes used in the treatment of male

testosterone replacement therapy.[17][non-primary source needed] The medication has been used at a dosage of 20 to 50 mg three times per week to once daily for this indication.[18] It has been found to increase testosterone levels by 2- to 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 two

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.[11] Additionally, enclomifene has a half-life of just 10 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]

Gynecomastia

Clomifene has been used in the treatment of gynecomastia.[21] 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.[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).

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 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

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.[7]

Side effects

The most common adverse 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,

scotomata), headaches, vasomotor flushes (or hot flashes), light sensitivity and pupil constriction, abnormal uterine bleeding and/or abdominal discomfort.[7]

Rare adverse events (<1% of people) include:

baldness and/or ovarian hyperstimulation syndrome.[7]

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.

liver abnormalities and a couple of cases of hepatotoxicity.[25]

Cancer risk

Some studies have suggested that clomifene if used for more than a year may increase the risk of ovarian cancer.[13] This may only be the case in those who have never been and do not become pregnant.[15] Subsequent studies have failed to support those findings.[12][26]

Clomifene has been shown to be associated with an increased risk of malignant melanomas and thyroid cancer.[3] Thyroid cancer risk was not associated with the number of pregnancies carried to viability.[27]

Pharmacology

Pharmacodynamics

Selective estrogen receptor modulator activity

Clomifene is a

cardiovascular system, and the breasts.[29][30] Positive effects of clomifene on bone have been observed.[18][29][30] Clomifene has been found to decrease insulin-like growth factor 1 (IGF-1) levels in women.[31]

Clomifene is a long-acting ER

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.[34]

Even though clomifene has some

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

total cholesterol levels decreased significantly.[18][40]

Tissue-specific estrogenic and antiestrogenic activity of SERMs
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.

Other activities

Clomifene is an

visual disturbances.[43][44]

Pharmacokinetics

Clomifene produces N-desmethylclomifene,

peak 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-desmethylclomifene.[2]

Clomifene has an

elimination half-life about 4 - 7days.[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-desmethylclomifene was 15 hours.[2] Individuals with the CYP2D6*10 allele showed longer half-lives for 4-hydroxyclomifene and 4-hydroxy-N-desmethylclomifene.[2] Primarily due to differences in CYP2D6 genetics, steady state concentrations and individual response to clomifene are highly variable.[46]

Most clomifene metabolism occurs in the

enterohepatic recirculation. Clomifene and its metabolites are excreted primarily through feces (42%), and excretion can occur up to 6 weeks after discontinuation.[28]

Chemistry

Clomifene is a

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.[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]

Enclomifene
Zuclomifene

History

A team at

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.[41][48][49] Short-term use (e.g. days to months) did not raise the same concerns and clomifene continued to be studied for other indications.[42][43]

Comparison of early clinical experience with antiestrogens for advanced breast cancer
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 of cataracts
Nafoxidine 180–240 mg/day 1976 31% Cataracts, ichthyosis, photophobia
Tamoxifen 20–40 mg/day 1971–1973 31% Transient thrombocytopeniaa
Footnotes: a = "The particular advantage of this drug is the low incidence of troublesome side effects (25)." "Side effects were usually trivial (26)." Sources: [48][50]

Clinical studies were conducted under an

Kefauver Harris Amendment to the Federal Food, Drug, and Cosmetic Act that had been passed in response to the thalidomide tragedy.[10] It was approved for marketing in 1967 under the brand name Clomid.[10][51] It was first used to treat cases of oligomenorrhea but was expanded to include treatment of anovulation when women undergoing treatment had higher than expected rates of pregnancy.[52]

The drug is widely considered to have been a revolution in the treatment of female infertility, the beginning of the modern era of

Eli Y. Adashi, was "the onset of the US multiple births epidemic".[10][53]

The company was acquired by

oligoovulation.[59]

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.[1]

Regulation

Clomifene is included on the World Anti-Doping Agency list of illegal doping agents in sport.[60] It is listed because it is an "anti-estrogenic substance".

Research

Clomifene has been used almost exclusively for ovulation induction in

postmenopausal women.[61]

Clomifene was studied for treatment and prevention of

cataracts.[63][64]

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External links

  • "Clomifene". Drug Information Portal. U.S. National Library of Medicine.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Clomifene&oldid=1205244015"