Letrozole belong to a class of compounds known as aromatase inhibitors (AIs). An enzyme known as aromatase is responsible in the human body for producing estrogen by converting androgens into estrogen. Aromatase inhibitors prevent aromatase from fulfilling that role by binding to it and rendering it inactive. AIs fall into two categories: reversible (such as letrozole) and irreversible; irreversible AIs permanently bind to the aromatase complex.
In the United States, letrozole has FDA approval for treatment of local or metastatic hormone receptor positive or unknown-receptor-status breast cancer in postmenopausal women. The most common side-effects are hypoestrogenism-related. The biggest concern with chronic administration is that long term use may lead to osteoporosis. For this reason letrozole is often prescribed with accompanying bisphosphonates or other drugs intended to treat or prevent osteoporosis.
In the BIG 1-98 Study letrozole demonstrated improved recurrence of cancer, but not survival, compared to tamoxifen, in post-menopausal women with hormonally-responsive breast cancer.
In obese men with obesity-related hypogonadism, a single weekly dose of letrozole at 2.5mg normalized total serum testosterone and raised free testosterone to supraphysiological levels in 7 of 12 men. The study continued for six months and levels of testosterone as well as E2 remained stable for the duration of the study.
In a group of female-to-male ovariectomized transexuals who were followed for one year, those receiving 1,000mg testosterone undecanoate with letrozole did not experience any negative changes to insulin resistance, FSH, LH, or body composition. They did however lose bone mineral density averaging 0.9g/cm^2.
In a study by Lapauw et al designed to "assess and compare the effects of short-term aromatase inhibition on glucose metabolism, lipid profile, and adipocytokine levels in young and elderly men," researchers found that:
Short-term aromatase inhibition appears to affect glucose metabolism in young men, and lipid metabolism, including leptin secretion, in young and elderly men. Furthermore, the short period of exposure suggests that these changes might be mediated by direct effects of sex steroids rather than by changes in body composition.
More from Lapauw's findings:
Both in young and elderly men, active treatment significantly increased serum testosterone (+128 and +99%, respectively) and decreased estradiol levels (-41 and -62%, respectively). Fasting glucose and insulin levels decreased in young men after active intervention (-7 and -37%, respectively) compared with placebo. Leptin levels fell markedly in both age groups (-24 and -25%, respectively), while adiponectin levels were not affected by the intervention. Lipid profile was slightly impaired in both groups, with increasing low density lipoprotein-cholesterol levels (+14%) in the younger age group and 10% lower levels of APOA1 in the elderly. A decline in IGF1 levels (-15%) was observed in the younger age group. No changes in weight or body mass index were observed in either young or old men. CONCLUSIONS: Short-term aromatase inhibition appears to affect glucose metabolism in young men, and lipid metabolism, including leptin secretion, in young and elderly men. Furthermore, the short period of exposure suggests that these changes might be mediated by direct effects of sex steroids rather than by changes in body composition.
Patry et al followed the results of a single patient whose infertility due to non obstructive azoospermia was treated with letrozole and reported a successful outcome: "Testis biopsy showed normal spermatogenesis following 4 months of letrozole therapy."
Maurus investigates the potential of letrozole for maximizing growth, presumably vis-a-vis testosterone increase, in short-stature children and concludes:
This class of drugs, if judiciously used for a window of time, offers promise as an adjunct treatment of growth delay in pubertal patients with GH deficiency, idiopathic short stature, testotoxicosis, and other disorders of growth. These evolving uses of aromatase inhibitors, however, represent off-label use of the product, and definitive data on their efficacy are not available for each of the conditions mentioned. Safety issues regarding bone health also require further study.
Tamoxifen and letrozole are often indicated for similar therapeutic uses. Therefore, a number of comparison studies exist measuring various aspects, such as (for example) non-therapeutic effects or side effects. In one such study, Phillips et al analyze data from the BIG 1-98 randomized trial and conclude:
In this sub-study, breast cancer patients taking adjuvant letrozole during the fifth year of treatment had better cognitive function than those taking tamoxifen, suggesting aromatase inhibitors do not adversely impact cognition compared with tamoxifen.
In a novel study on the effects of letrozole used to treat peripubertal boys with short stature, Hero et al found:
Letrozole effectively inhibited the conversion of androgen to oestrogen, as indicated by high serum testosterone and low serum estradiol concentrations in letrozole treated boys who progressed into puberty. In both groups there was a gain in performance during the follow-up period in tests of verbal performance, in most of the tests of visuospatial performance, and in some tests of verbal memory. No significant differences between the letrozole and placebo treated boys in development of cognitive performance were found in any of the tests during the follow-up period. Conclusions: Our results suggest that blockade of oestrogen biosynthesis with an aromatase inhibitor does not influence cognitive performance in prepubertal males.
 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.
 Loves S, Ruinemans-Koerts J, de Boer H. Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism. Eur J Endocrinol. 2008 May;158(5):741-7.
 Meriggiola MC, Armillotta F, Costantino A, Altieri P, Saad F, Kalhorn T, Perrone AM, Ghi T, Pelusi C, Pelusi G. Effects of testosterone undecanoate administered alone or in combination with letrozole or dutasteride in female to male transsexuals. J Sex Med. 2008 Oct;5(10):2442-53.
 Lapauw B, T'Sjoen G, Mahmoud A, Kaufman JM, Ruige JB.. Short-term aromatase inhibition: effects on glucose metabolism and serum leptin levels in young and elderly men. Eur J Endocrinol. 2009 Mar;160(3):397-402.
 Patry G, Jarvi K, Grober ED, Lo KC. Use of the aromatase inhibitor letrozole to treat male infertility.Fertil Steril. 2009 Aug;92(2):829.e1-2.
 Mauras N. Strategies for maximizing growth in puberty in children with short stature. Endocrinol Metab Clin North Am. 2009 Sep;38(3):613-24.
 Phillips KA, Ribi K, Sun Z, Stephens A, Thompson A, Harvey V, Thürlimann B, Cardoso F, Pagani O, Coates AS, Goldhirsch A, Price KN, Gelber RD, Bernhard J. Cognitive function in postmenopausal women receiving adjuvant letrozole or tamoxifen for breast cancer in the BIG 1-98 randomized trial. Breast. 2010 Apr 10.
 Hero M, Maury S, Luotoniemi E, Service E, Dunkel L. Cognitive effects of aromatase inhibitor therapy in peripubertal boys. Eur J Endocrinol. 2010 Apr 26.
*The latter article is intended for educational / informational purposes only. THIS PRODUCT IS INTENDED AS A RESEARCH CHEMICAL ONLY. This designation allows the use of research chemicals strictly for in vitro testing and laboratory experimentation only. Bodily introduction of any kind into humans or animals is strictly forbidden by law.