Can Letrozole (aromatase inhibitor) cause hirsutism?

Letrozole Does Not Cause Hirsutism

Letrozole does not cause hirsutism; in fact, by blocking the conversion of androgens to estrogens, it may theoretically increase circulating androgen levels, but hirsutism is not a recognized adverse effect of this medication. 1

Mechanism of Action and Hormonal Effects

Letrozole is a nonsteroidal aromatase inhibitor that blocks the enzyme responsible for converting androgens (such as androstenedione and testosterone) to estrogens 1. This mechanism has several important implications:

• Letrozole inhibits peripheral aromatase by over 98% and suppresses blood and urinary estrogen levels by over 95% 2
• The drug blocks aromatase-dependent synthesis of estradiol but leaves androgens unconverted, which means androgen levels may actually increase relative to estrogen 3, 4
• Letrozole's action appears selective for aromatase and does not significantly affect other steroid hormones 2

Why Hirsutism Is Not a Recognized Side Effect

The evidence from major clinical trials and guidelines consistently documents the adverse effect profile of letrozole, and hirsutism is notably absent:

Documented Adverse Effects from Clinical Trials

The most common adverse effects of letrozole include: 1

• Hot flashes (38-54% of patients)
• Arthralgia/joint pain (53-69% of patients)
• Myalgia/muscle pain (28-37% of patients)
• Fatigue (36-45% of patients)
• Bone-related events including fractures (14% vs 9% with placebo) and new osteoporosis (11% vs 6% with placebo)

Additional documented side effects include: 5

• Arthritis
• Increased fracture risk
• Cardiovascular events (trend toward increased risk)

Androgenic Effects Are Minimal

While letrozole blocks the conversion of androgens to estrogens, the unconverted androgens do not produce virilizing effects like hirsutism 4. In fact:

• Non-aromatizable androgens like dihydrotestosterone actually inhibit breast cancer cell proliferation when acting through the androgen receptor 4
• The androgenic effects appear to be anti-proliferative rather than virilizing 4

Contrast with Exemestane

It's worth noting that exemestane, a steroidal aromatase inhibitor, has androgenic properties due to its structural similarity to androgens 1. However, even exemestane does not cause hirsutism as a recognized adverse effect, and the NCCN considers all three selective aromatase inhibitors (anastrozole, letrozole, exemestane) to have similar toxicity profiles 1.

Common Pitfalls to Avoid

• Do not confuse the mechanism of blocking androgen-to-estrogen conversion with actual androgenic/virilizing effects—the increased relative androgen levels do not translate to hirsutism 3, 4
• Do not overlook the real adverse effects of letrozole, particularly bone health issues, musculoskeletal symptoms, and cardiovascular risks, which require monitoring 1
• Remember that letrozole only works in postmenopausal women because it cannot adequately suppress ovarian estrogen synthesis in premenopausal women with functioning ovaries 3, 1