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Let5.0
Letrozole Research
Mostly mechanism / observationalLimited safety
8 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most Letrozole studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from medium-quality meta-analyses and randomised trials published 2003–2022 with a typical study size of 42 participants.
Based on 8 studies · 2 meta-analyses · 5 RCTs · 846 total participants
Confidence
High
By outcome
Women's health
Mostly mechanism / observational8 studies
Testosterone & male hormones
Mostly mechanism / observational5 studies
Ovulation induction & fertility
Mostly mechanism / observational4 studies
Bone & growth
Mostly mechanism / observational3 studies
Cholesterol & lipids
Too few graded studies1 study
Safety profile
Too few graded studies1 study
Steady research
2 studies in the last 5 years · Latest meta-analysis: 2022
200320122022
1RCTn=750 · large study2014
Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007)... letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome.
Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, et al. · N Engl J Med (2014)
Double-blind, multicenter RCT (NCT00719186) of 750 women with PCOS randomized 1:1 to letrozole vs clomiphene for up to five cycles; primary outcome live birth
Letrozole beat clomiphene on cumulative live births (27.5% vs 19.1%, P=0.007) and on ovulation rate (61.7% vs 48.3% of cycles, P<0.001)
Clomiphene caused more hot flushes; the honest counter-evidence in clomiphene's own approved indication — the reason letrozole displaced it as PCOS first-line
Letrozole appears to improve live birth rates and pregnancy rates in infertile women with anovulatory PCOS, compared to SERMs, when used for ovulation induction.
Franik S, Le QK, Kremer JA, Kiesel L, Farquhar C. · Cochrane Database of Systematic Reviews (2022)
Cochrane systematic review of 41 RCTs (6522 women); letrozole was used in all trials
Higher live-birth rates with letrozole vs clomiphene/SERMs (OR 1.72, 95% CI 1.40-2.11; high-certainty evidence; NNTB 10)
High-certainty evidence that OHSS rates are similar (0.5% in both arms) and no difference in miscarriage or multiple-pregnancy rates
Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory polycystic ovary syndrome, compared to clomiphene citrate.
Franik S, Eltrop SM, Kremer JA, Kiesel L, Farquhar C. · Cochrane Database of Systematic Reviews (2018)
Earlier Cochrane systematic review including 42 RCTs (7935 women); letrozole was used in all studies
Higher live-birth rates with letrozole vs clomiphene followed by timed intercourse (OR 1.68, 95% CI 1.42-1.99; moderate-quality evidence)
High-quality evidence that OHSS, miscarriage, and multiple-pregnancy rates were similar between letrozole and clomiphene
Despite a marked rise in serum testosterone, low-dose aromatase inhibition had no somatic or psychological effects in men with obesity-related hypogonadotropic hypotestosteronemia.
Loves S, de Jong J, van Sorge A, Telting D, Tack CJ, Hermus A, Westerterp K, de Boer H. · European journal of endocrinology (2013)
Double-blind, placebo-controlled 6-month RCT of letrozole in 42 obese men (BMI >35) with low testosterone, dose-titrated to a target testosterone
Letrozole halved estradiol (119 to 59 pmol/l) and roughly doubled-plus testosterone (8.6 to 21.5 nmol/l) while raising LH
Despite the marked hormonal change, there were NO significant effects on psychological function, body composition, exercise capacity, or glucose/lipid/bone metabolism
Treatment with the aromatase inhibitor letrozole delays bone maturation and improves predicted adult height in boys with idiopathic short stature.
Hero M, Norjavaara E, Dunkel L. · The Journal of clinical endocrinology and metabolism (2005)
Prospective, double-blind, placebo-controlled RCT of letrozole 2.5 mg/d vs placebo for 2 years in 31 boys (aged 9.0-14.5) with idiopathic short stature
Predicted adult height increased by 5.9 cm (P<0.0001) and height-SD-for-bone-age by 0.7 SD with letrozole, with no change in the placebo group
Areal bone mineral density rose similarly in both groups; no adverse effect on bone mineralization was evident at 2 years
AI therapy during prepuberty or early puberty may predispose to vertebral deformities... If AIs are used in growth indications, follow-up of vertebral morphology is indicated.
Hero M, Toiviainen-Salo S, Wickman S, Mäkitie O, Dunkel L. · Journal of bone and mineral research (2010)
MRI study of vertebral morphology in boys previously randomized to letrozole or placebo for growth indications
Mild vertebral-body deformities were found in 5 of 11 (45%) letrozole-treated boys with idiopathic short stature versus 0% in the placebo group (P=0.01)
The deformities likely reflect impaired vertebral-body growth from estrogen deprivation rather than fragility fractures
1-yr treatment with this new P450 aromatase inhibitor in pubertal boys is unlikely to be associated with any major harmful effect on developing peak bone mass... close follow-up of bone metabolism is still warranted.
Wickman S, Kajantie E, Dunkel L. · The Journal of clinical endocrinology and metabolism (2003)
RCT of 23 boys with constitutional delay of puberty randomized to testosterone plus placebo or testosterone plus letrozole
Letrozole held estradiol at baseline while testosterone rose more than 5-fold higher than in the placebo arm — a clean test of estrogen suppression
No significant difference in bone mineral density between groups at 1 year, but bone-turnover markers shifted and the authors caution that rare/minor effects need larger studies
AIs, especially nonsteroidal letrozole and anastrozole, could significantly inhibit the production of E2 and its negative feedback on the HPG axis, resulting in increased T and FSH production as well as improved semen parameters in infertile men.
Yang C, Li P, Li Z. · Human reproduction update (2021)
Narrative review of aromatase inhibitors (letrozole, anastrozole) for male infertility, covering mechanism, clinical trials, and side effects
AIs lower estradiol and release HPG-axis feedback, raising testosterone and FSH and improving semen parameters, especially when the T:E2 ratio is low (e.g. obesity)
Notes that, owing to the lack of large randomized trials, the efficacy and safety of AIs in male infertility remain controversial