Letrozole is approved by the United StatesFood 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.
Some studies have shown that letrozole can be used to promote spermatogenesis in male patients suffering from nonobstructive azoospermia.
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.
Estrogens are produced by the conversion of androgens through the activity of the aromatase enzyme. Estrogens then bind to an estrogen receptor, which causes cells to divide.
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.
Letrozole is contraindicated in women having a pre-menopausal hormonal status, during pregnancy and lactation.
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.
In the BIG 1–98 Study, of post-menopausal women with hormonally-responsive breast cancer, letrozole reduced the recurrence of cancer, but did not change survival rate, compared to tamoxifen.
Letrozole can by synthesized from 4-cyanobenzyl bromide, triazole, and 4-fluorobenzonitrile:
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.
^ abDrugs.com: monograph 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 Sterility85 (6): 1761–5. doi:10.1016/j.fertnstert.2006.03.014. PMID16650422.
^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 Reviews30 (4): 343–375. doi:10.1210/er.2008-0016. PMID19389994. edit
^Geneviève Patry, Keith Jarvi, Ethan D. Grober, Kirk C. Lo (August 2009). "Use of the aromatase inhibitor letrozole to treat male infertility". Fertility and Sterility92 (2): 829.e1–829.e2. doi:10.1016/j.fertnstert.2009.05.014.
^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 Biology44 (4–6): 421–8. doi:10.1016/0960-0760(93)90245-R. PMID8476755.