|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Protein binding||60%, mainly to albumin|
|Metabolism||pharmacologically-inactive carbinol metabolite (4,4΄-methanol-bisbenzonitrile)|
|Molecular mass||285.303 g/mol|
|(what is this?)|
Letrozole is approved by the United States Food and Drug Administration (FDA) for the treatment of local or metastatic breast cancer that is hormone receptor positive or has an unknown receptor status in postmenopausal women.
Letrozole has been used for ovarian stimulation by fertility doctors since 2001 because it has fewer side-effects than clomiphene (Clomid) and less chance of multiple gestation. A Canadian study presented at the American Society of Reproductive Medicine 2005 Conference suggested that letrozole may increase the risk of birth defects. A more detailed ovulation induction follow-up study found that letrozole, compared with a control group of clomiphene, had significantly lower congenital malformations and chromosomal abnormalities at an overall rate of 2.4% (1.2% major malformations) compared with clomiphene 4.8% (3.0% major malformations). Despite this, India banned the usage of letrozole in 2011, citing potential risks to infants. In 2012, an Indian parliamentary committee said that the drug controller office colluded with letrozole's makers to approve the drug for infertility in India and also stated that letrozole's use for infertility was illegal worldwide; however, such off-label uses are legal in many countries such as the US and UK.
The anti-estrogen action of letrozole has been shown to be useful in pretreatment for termination of pregnancy, in combination with misoprostol. It can be used in place of mifepristone, which is expensive and unavailable in many countries.
Letrozole is sometimes used as a treatment for gynecomastia, although it is probably most effective at this if caught in an early stage (such as in users of anabolic steroids).[unreliable source?]
Letrozole has also been shown to delay the fusing of the growth plates in mice. When used in combination with growth hormone, letrozole has been shown effective in one adolescent boy with a short stature.
Mechanism of action
Letrozole prevents the aromatase from producing estrogens by competitive, reversible binding to the heme of its cytochrome P450 unit. The action is specific, and letrozole does not reduce production of mineralo- or corticosteroids.
Generally, side effects include signs and symptoms of hypoestrogenism. There is concern that long term use may lead to osteoporosis, which is in certain patient populations such as post-menopausal women or osteoporotics, bisphosphonates may also be prescribed.
Comparison with tamoxifen
Tamoxifen is also used to treat hormonally-responsive breast cancer, but it does so by interfering with the estrogen receptor. However, letrozole is effective only in post-menopausal women, in whom estrogen is produced predominantly in peripheral tissues (i.e. in adipose tissue, like that of the breast) and a number of sites in the brain. In pre-menopausal women, the main source of estrogen is from the ovaries not the peripheral tissues, and letrozole is ineffective.
See also: (according to art of drug synthesis book)
- Bhatnagar, A. S. (1990). J. Steroid Biochem. Mol. Biol., 37: 1021–1027.
- Bowman, R. M., Steele, R. E., and Browne, L. J. (1990). US 497872 (to Ciba-Gigy).
- Demers, L. M. (1994). J. Steroid Biochem. Mol. Biol., 44: 520.
- Haynes, B. P., Dowsett, M., Miller, W. R., Dixon, J. M., and Bhatnagar, A. S. (2003). J. Steroid Biochem. Mol. Biol., 87: 35–45.
- Lamb, H. M. and Adkins, J. C. (1998). Drugs, 56: 1125–1140.
- Prous, J., Graul, A., and Castan˜er, J. (1994). Drugs Fut., 19: 335–337.
- Sioufi, A., Gauducheau, N., Pineau, V., Marfil, F., Jaouen, A., Cardot, J. M., Godbillon, J., Czendlik, C., Howald, H., Pfister, Ch., and Vreeland, F. (1997). Biopharm. Drug Dispos., 18: 779–789.
- 003330 Letrozole
- Drugs.com: for letrozole. It is also used for ovarian cancer patients after they have completed chemotherapy.
- Tulandi T, Martin J, Al-Fadhli R, et al. (June 2006). "Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate". Fertility and Sterility 85 (6): 1761–5. doi:10.1016/j.fertnstert.2006.03.014. PMID 16650422.
- Sinha, Kounteya (18 October 2011). "Finally, expert panel bans fertility drug Letrozole". The Times of India. Retrieved 14 November 2011.
- "House panel to govt: Punish those guilty of approving Letrozole". The Times of India. 10 April 2007. Retrieved 9 May 2012.
- Chen DT, Wynia MK, Moloney RM, Alexander GC (2009). "Physician knowledge of the FDA-approved indications of commonly prescribed drugs: results of a national survey". Pharmacoepidemiology and Drug Safety 18 (11): 1–7. doi:10.1002/pds.1825. PMID 19697444.
- "GMC | Good practice in prescribing medicines – guidance for doctors". Gmc-uk.org. 16 February 2007. Retrieved 21 November 2011.
- Vivian Chi Yan Lee, Ernest Hung Yu Ng, William Shu Biu Yeung, Pak Chung Ho (2011). "Misoprostol With or Without Letrozole Pretreatment for Termination of Pregnancy". Ob Gyn. 117 (2, Part 1): 317–323. doi:10.1097/AOG.0b013e3182073fbf.
- Santen, R. J.; Brodie, H.; Simpson, E. R.; Siiteri, P. K.; Brodie, A. (2009). "History of Aromatase: Saga of an Important Biological Mediator and Therapeutic Target". Endocrine Reviews 30 (4): 343–375. doi:10.1210/er.2008-0016. PMID 19389994.
- "Gynecomastia and Letrozole". GYNECOMASTIA-GYNO.COM: ...a resource for gynecomastia sufferers... 16 December 2008. Archived from the original on 26 June 2010. Retrieved 26 April 2012.
- Geneviève Patry, Keith Jarvi, Ethan D. Grober, Kirk C. Lo (August 2009). "Use of the aromatase inhibitor letrozole to treat male infertility". Fertility and Sterility 92 (2): 829.e1–829.e2. doi:10.1016/j.fertnstert.2009.05.014.
- R Eshet, G Maor, T Ben Ari, M Ben Eliezer, G Gat-Yablonski, M Phillip (2004). "The aromatase inhibitor letrozole increases epiphyseal growth plate height and tibial length in peripubertal male mice". Journal of Endocrinology 182 (1): 165–172. doi:10.1677/joe.0.1820165. PMID 15225141.
- Ping Zhou MD, Bina Shah MD, Kris Prasad PhD, Raphael David MD (2005). "Letrozole Significantly Improves Growth Potential in a Pubertal Boy With Growth Hormone Deficiency". Journal of the American Academy of Pediatrics 115 (2): 245–248. doi:10.1542/peds.2004-1536. PMID 15653791.
- Endometriosis ESHRE abstract
- Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
- Simpson ER (2003). "Sources of estrogen and their importance". The Journal of Steroid Biochemistry and Molecular Biology 86 (3–5): 225–30. doi:10.1016/S0960-0760(03)00360-1. PMID 14623515.
- Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer, the BIG 1–98 Collaborative Group, N Engl J Med, 361:766, 2009 Aug 20
- 32nd Annual San Antonio Breast Cancer Symposium
- Lang, M; Batzl, C; Furet, P; Bowman, R; Hausler, A; Bhatnagar, A (1993). "Structure-activity relationships and binding model of novel aromatase inhibitors". The Journal of Steroid Biochemistry and Molecular Biology 44 (4–6): 421–8. doi:10.1016/0960-0760(93)90245-R. PMID 8476755.