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Clomifene ball-and-stick.png
Systematic (IUPAC) name
Clinical data
AHFS/ Micromedex Detailed Consumer Information
Pregnancy cat. B3 (Au), X (U.S.)
Legal status S4 (Au), POM (UK), ℞-only (U.S.)
Routes per os
Pharmacokinetic data
Bioavailability High (>90%)
Metabolism Hepatic (with enterohepatic circulation)
Half-life 5-7 days
Excretion Mainly renal, some biliary
CAS number 911-45-5 YesY
ATC code G03GB02
PubChem CID 2800
DrugBank DB00882
ChemSpider 2698 YesY
KEGG D07726 YesY
Chemical data
Formula C26H28ClNO 
Mol. mass 406 or 598.10 (with citrate)
 N (what is this?)  (verify)

Clomifene (INN) or clomiphene (USAN) (trademarked as Androxal, Clomid and Omifin) is a selective estrogen receptor modulator (SERM) that has become the most widely prescribed drug to induce ovulation in the treatment of female infertility. This synthetic drug is available as a white to pale yellow odorless tablet.

Medical uses[edit]

Clomifene's is useful in those who are infertile due to not ovulating.[1] Evidence is lacking for the use of clomifene in those who are infertile without a known reason.[2] Clomifene has also been used with other assisted reproductive technology to increase success rates of these other modalities.[3]

Therapy should start on the 5th day of the menstrual cycle. Repeat dosing: This 5-day treatment course can be repeated every 30 days. It is not recommended by the manufacturer to use clomifene for more than 6 cycles[4] Intercourse should coincide with the expected timing of ovulation (typically 5–10 days after a course of clomifene).

Adverse events[edit]

The most common adverse drug reaction associated with the use of clomifene (>10% of people) is reversible ovarian enlargement.[5] Less common effects (1-10% of people) include visual symptoms (blurred vision, diplopia, floaters, photophobia, scotomata), headaches, vasomotor flushes (or hot flashes), abnormal uterine bleeding and/or abdominal discomfort.[5] Rare adverse events (<1% of people) include: hypertriglyceridemia, hepatitis, reversible alopecia and/or ovarian hyperstimulation syndrome.[6]

Clomifene can lead to multiple ovulation, hence increasing the chance of twins (10% of births instead of ~1% in the general population) and triplets.

Clomifene citrate if used for more than a year may increase the risk of ovarian cancer.[2] This may only be the case in those who have never been and do not become pregnant.[7] This however is disputed and some feel there is no significant increase in risk.[8]


The incidence (epidemiology) of fetal and neonatal abnormalities for patients on clomifene for fertility is similar to that seen in the general population. There is no data to suggest a higher rate of congenital anomalies or spontaneous abortions after using this drug.[5][9] Clomifene is classified as a pregnancy category X drug as patients should be

Mechanism of action[edit]

Clomifene inhibits estrogen receptors in hypothalamus, inhibiting negative feedback of estrogen on gonadotropin release, leading to up-regulation of the hypothalamic–pituitary–gonadal axis.[10] Zuclomifene, a more active isomer, stays bound for longer periods of time. Clomifene is not a steroid drug.

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 beta-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 5 days. By that time, FSH level is rising steadily, causing 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 (FSH, LH) release. (It should be noted that more rapid, lower amplitude pulses of GnRH lead to increased LH/FSH secretion, while more irregular, larger amplitude pulses of GnRH leads to a decrease in the ratio of LH/FSH.) Increased FSH level causes growth of more ovarian follicles, and subsequently rupture of follicles resulting in ovulation. Ovulation occurs most often 6–7 days after a course of clomifene.


Clomifene is a mixture of two geometric isomers, enclomifene (E-clomifene) and zuclomifene (Z-clomifene). These two isomers have been found to contribute to the mixed estrogenic and anti-estrogenic properties of clomifene.


Off-label use in the treatment of male hypogonadism[edit]

Clomifene citrate has been found very effective in the treatment of secondary male hypogonadism in many cases.[11] This has shown to be a much more attractive option than testosterone replacement therapy (TRT) in many cases because of the reduced cost and convenience of taking a pill as opposed to testosterone injections or gels.[12] Unlike traditional TRT it also does not shrink the testes and as a result can enhance fertility. Traditional TRT has the risk of inducing a chemical gonadectomy, although with monitoring and low-dose hCG as adjunct, this is usually preventable and reversible.[13] Because clomifene citrate has not been FDA approved for use in males it is prescribed off-label. Due to the fact that Clomifene is now a generic medication in most markets, it is unlikely that a drug company would pursue FDA approval for use in men now because of limited profit incentive, mostly due to the relatively small market potential.[14] However, the single isomer of clomifene, enclomiphene under the brand name Androxal, is currently under phase 3 trials for use in men.[15][16]

Recreational use[edit]

Clomifene is commonly used by male users to bind the estrogen receptors in their bodies, thereby blocking the effects of estrogen, such as gynecomastia. It also restores the body's natural production of testosterone.[17] It is included on the World Anti-Doping Agency list of illegal doping agents in sport.[18]


Clomifene has been used since the 1960s.[19] 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.[20]

In April 1989, a patent was awarded to Yale University Medical researchers Dr. Florence Comite and Dr. Pamela Jensen for the use of clomiphene to predict fertility in women. A woman capable of sustaining pregnancy would develop denser bone mass while on clomiphene; the bone mass increase would be predictive of fertility, and the changes could be detected on a CT scanner.[21][22]


  1. ^ Practice Committee of the American Society for Reproductive, Medicine (Aug 2013). "Use of clomiphene citrate in infertile women: a committee opinion.". Fertility and sterility 100 (2): 341–8. PMID 23809505. 
  2. ^ a b Hughes, E; Brown, J; Collins, JJ; Vanderkerchove, P (Jan 20, 2010). "Clomiphene citrate for unexplained subfertility in women.". The Cochrane database of systematic reviews (1): CD000057. PMID 20091498. 
  3. ^ Seli, Emre. "Ovulation induction with clomiphene citrate". UpToDate. Retrieved 21 April 2014. 
  4. ^ Trabert, B.; Lamb, E. J.; Scoccia, B.; Moghissi, K. S.; Westhoff, C. L.; Niwa, S.; Brinton, L. A. (2013). "Ovulation-inducing drugs and ovarian cancer risk: Results from an extended follow-up of a large US infertility cohort". Fertility and Sterility. doi:10.1016/j.fertnstert.2013.08.008.  edit
  5. ^ a b c Clomid. Lexi-Comp Online, Hudson, Ohio: Lexi-Comp, Inc.; Accessed on April 19, 2014
  6. ^ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3[page needed]
  7. ^ Trabert, B; Lamb, EJ; Scoccia, B; Moghissi, KS; Westhoff, CL; Niwa, S; Brinton, LA (Dec 2013). "Ovulation-inducing drugs and ovarian cancer risk: results from an extended follow-up of a large United States infertility cohort.". Fertility and sterility 100 (6): 1660–6. PMID 24011610. 
  8. ^ Gadducci, A; Guerrieri, ME; Genazzani, AR (Jan 2013). "Fertility drug use and risk of ovarian tumors: a debated clinical challenge.". Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 29 (1): 30–5. PMID 22946709. 
  9. ^ Clomid [package insert]. Bridgewater, NJ, Sanofi-aventis. 2013
  10. ^ DrugBank > Clomifene. Updated on April 19, 2011
  11. ^ Ioannidoukadis, Stella; Wright, Pat J.; Neely, R. Dermot; Quinton, Richard (2006). "Complete reversal of adult-onset isolated hypogonadotropic hypogonadism with clomiphene citrate". Fertility and Sterility 86 (5): 1513.e5–9. doi:10.1016/j.fertnstert.2006.03.065. PMID 17070201. 
  12. ^ Taylor, Frederick; Levine, Laurence (2010). "Clomiphene Citrate and Testosterone Gel Replacement Therapy for Male Hypogonadism: Efficacy and Treatment Cost". Journal of Sexual Medicine 7 (1 Pt 1): 269–76. doi:10.1111/j.1743-6109.2009.01454.x. PMID 19694928. 
  13. ^ Kaminetsky, Jed; Hemani, Micah L (2009). "Clomiphene citrate and enclomiphene for the treatment of hypogonadal androgen deficiency". Expert Opinion on Investigational Drugs 18 (12): 1947–55. doi:10.1517/13543780903405608. PMID 19938905. 
  14. ^ How Clomid Works in Men
  15. ^ Androxal website
  16. ^ Hill, S.; Arutchelva, V.; Quinton, R. (2009). "Enclomiphene, an estrogen receptor antagonist for the treatment of testosterone deficiency in men". IDrugs 12 (2): 109–19. PMID 19204885. 
  17. ^ Tan RS, Vasudevan D. Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse. Fertil Steril. 2003 Jan;79(1):203-5 PMID 12524089
  18. ^ The WADA Prohibited List 2012 (keyword clomiphene)
  19. ^ Holtkamp DE, Greslin JG, Root CA, Lerner LJ (October 1960). "Gonadotrophin inhibiting and anti-fecundity effects of chloramiphene". Proc. Soc. Exp. Biol. Med. 105: 197–201. PMID 13715563. 
  20. ^ Hughes E, Collins J, Vandekerckhove P (2000). "Clomiphene citrate for ovulation induction in women with oligo-amenorrhoea". Cochrane Database Syst Rev (2): CD000056. doi:10.1002/14651858.CD000056. PMID 10796477. 
  21. ^ Andrews, Edmund L. (29 April 1989). "Patents; A Method to Determine Fertility in Women". 
  22. ^ "Use of clomiphene to predict fertility in a human female". US PAtent US4820736 A. Google/. Retrieved 4 April 2014. 

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