Clomifene

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Clomifene
Clomifene.svg
Clomifene ball-and-stick.png
Systematic (IUPAC) name
(E,Z)-2-(4-(2-chloro-1,2-diphenylethenyl)
phenoxy)-N,N-diethyl-ethanamine
Clinical data
AHFS/Drugs.com 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
Identifiers
CAS number 911-45-5 YesY
ATC code G03GB02
PubChem CID 2800
DrugBank DB00882
ChemSpider 2698 YesY
UNII 1HRS458QU2 YesY
KEGG D07726 YesY
ChEBI CHEBI:3752 YesY
ChEMBL CHEMBL1200667 N
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 increases production of gonadotropins by inhibiting negative feedback on the hypothalamus. This synthetic drug comes supplied as white, round tablets in 50 mg strength only. It has become the most widely prescribed of all fertility drugs. It is used in the form of its citrate to induce ovulation.

Use in female infertility[edit]

It is used mainly in female infertility, in turn mainly as ovulation induction to reverse oligoovulation or anovulation such as in infertility in polycystic ovary syndrome, as well as being used for ovarian hyperstimulation, such as part of an in vitro fertilization procedure. 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.[1][2]

Mode 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.[3] Zuclomifene, a more active isomer, stays bound for longer periods of time. The drug is non-steroidal.

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.

Chemistry[edit]

Clomifene is a mixture of two geometric isomers, enclomifene (E-clomifene) and zuclomifene (Z-clomifene).

Enclomifene
Zuclomifene

Adverse effects[edit]

Common adverse drug reactions associated with the use of clomifene (≥1% of patients) include: vasomotor flushes (or hot flashes), abdominal discomfort, visual blurring (dose-dependent), and/or reversible ovarian enlargement and cyst formation. Infrequent adverse effects (0.1–1% of patients) include: abnormal uterine bleeding, nausea, and/or vomiting. Rare adverse effects (<0.1% of patients) include: reversible alopecia and/or ovarian hyperstimulation syndrome.[4]

In comparison to treatment with purified FSH, the rate of ovarian hyperstimulation syndrome is low when using clomifene.

Clomifene can lead to multiple ovulation, hence increasing the chance of twins (10% of births instead of the normal ~1%) and triplets; some parents-to-be then opt for selective reduction to reduce the number of fetuses.

Overall, clomifene citrate has not been found to cause a significant increase in the risk of ovarian cancer, except in women who remain nulligravid after treatment.[5]

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.[6] 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.[7] 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.[8] 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.[9] However, the single isomer of clomifene, enclomiphene under the brand name Androxal, is currently under phase 3 trials for use in men.[10][11]

Prohibited use in sports and use in bodybuilding[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.[12] It is included on the World Anti-Doping Agency list of illegal doping agents in sport.[13]

History[edit]

Clomifene has been used since the 1960s.[14] It was first used to treat cases of oligomenorrhea. When it was realized that women undergoing treatment had higher than expected pregnancy rates, it was then applied to treatment of anovulation.[15]

References[edit]

  1. ^ Andrews, Edmund L. (29 April 1989). "Patents; A Method to Determine Fertility in Women". http://www.nytimes.com/1989/04/29/business/patents-a-method-to-determine-fertility-in-women.html?smid=pl-share. 
  2. ^ "Use of clomiphene to predict fertility in a human female". US PAtent US4820736 A. Google/. Retrieved 4 April 2014. 
  3. ^ DrugBank > Clomifene. Updated on April 19, 2011
  4. ^ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3[page needed]
  5. ^ 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
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ How Clomid Works in Men
  10. ^ Androxal website
  11. ^ 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. 
  12. ^ 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
  13. ^ The WADA Prohibited List 2012 (keyword clomiphene)
  14. ^ 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. 
  15. ^ 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. 

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