In an adult male with documented low total testosterone and normal or elevated estradiol who wishes to preserve fertility, is letrozole an appropriate off‑label therapy to raise testosterone levels?

Letrozole for Low Testosterone in Males Desiring Fertility Preservation

Letrozole is an appropriate off-label therapy for adult males with documented low testosterone and elevated estradiol who wish to preserve fertility, particularly when they have low or low-normal LH levels indicating secondary hypogonadism. 1

Mechanism and Rationale

Letrozole works by inhibiting aromatase enzymes (cytochrome P450 isoenzymes 2A6 and 2C19), which blocks the conversion of testosterone to estradiol. 1 This reduction in estradiol removes negative feedback on the hypothalamus, resulting in stronger GnRH pulses that stimulate pituitary FSH and LH production, ultimately increasing endogenous testosterone production and preserving spermatogenesis. 1

Evidence Supporting Use

Hormonal Effects

• Letrozole significantly increases serum testosterone levels in men with low testosterone, with studies showing increases from baseline 5.9 nmol/L to 19.6 nmol/L after 6 weeks of treatment. 2
• The medication effectively suppresses estradiol while raising the testosterone-to-estradiol ratio, which is critical for optimal spermatogenesis. 3
• LH levels increase substantially (from 4.4 to 11.1 U/L), confirming restoration of the hypothalamic-pituitary-gonadal axis. 2

Fertility Preservation

• Letrozole improves sperm parameters including concentration, motility, and forward progression in infertile men. 3
• Even men with normal testosterone-to-estradiol ratios (>10) who have severe oligozoospermia show a 5.5-fold increase in sperm concentration after 4 months of letrozole 2.5 mg daily. 4
• The European Association of Urology guidelines specifically note that aromatase inhibitors increase endogenous testosterone production and improve spermatogenesis in the infertility setting with a safe tolerability profile. 1

Dosing and Monitoring

Initial Dosing

• Start with letrozole 2.5 mg orally once weekly for obese men, as daily dosing may produce supraphysiological free testosterone levels. 2
• For men with severe oligozoospermia or more pronounced hypogonadism, letrozole 2.5 mg daily for 4 months has been studied. 3, 4
• Doses <2.5 mg once weekly may be preferable initially, as 7 out of 12 men developed supraphysiological free testosterone with 2.5 mg weekly dosing. 2

Laboratory Monitoring

• Measure testosterone and estradiol levels at 14 and 28 days after starting treatment or any dose adjustment. 5
• Check LH levels to confirm appropriate hypothalamic-pituitary response. 1
• Target mid-normal testosterone levels (500-600 ng/dL) rather than supraphysiological levels. 5
• Monitor hematocrit periodically and withhold treatment if >54% to prevent erythrocytosis. 5

Advantages Over Testosterone Replacement

The critical advantage of letrozole over exogenous testosterone is preservation of fertility. 1 Testosterone replacement therapy suppresses the hypothalamic-pituitary-gonadal axis, reducing LH and FSH secretion, which impairs spermatogenesis. 1 In contrast, letrozole stimulates endogenous testosterone production while maintaining or improving sperm production. 1

The AUA guidelines explicitly state that testosterone-deficient patients with low or low-normal LH levels are candidates for selective estrogen receptor modulator use (a related class of medications), particularly those wishing to preserve fertility. 1 While this statement refers to SERMs, the same principle applies to aromatase inhibitors like letrozole, which work through a complementary mechanism. 1

Comparison to Alternative Fertility-Preserving Options

Selective Estrogen Receptor Modulators (SERMs)

• SERMs like clomiphene citrate are the traditional first-line alternative for fertility preservation in hypogonadal men. 5
• However, clomiphene may decrease spine bone mineral density, whereas testosterone (and by extension, increased endogenous testosterone from letrozole) improves bone density. 5
• The European Association of Urology notes that both SERMs and aromatase inhibitors significantly improve hormonal and semen parameters, though prospective RCTs are needed to better define efficacy. 1

Human Chorionic Gonadotropin (hCG)

• hCG with or without FSH is well-established for secondary hypogonadism but requires injections and is more expensive. 1
• Letrozole offers an oral alternative that may be more convenient and cost-effective. 3, 4

Adverse Effects and Safety

Letrozole is relatively well-tolerated with no serious adverse effects reported in male fertility studies. 4 Common side effects include:

• Loss of libido (54% in one study, though this may reflect the underlying condition rather than the medication). 4
• Headaches (25%). 4
• Fatigue (21%). 4
• Weakness (13%), hair loss (8%), and dry mouth (8%). 4

A critical caveat is the risk of supraphysiological free testosterone levels, particularly with daily dosing or in certain individuals. 2 This necessitates careful monitoring and dose adjustment.

Clinical Algorithm for Implementation

1. Confirm diagnosis: Document low total testosterone on two separate morning measurements plus symptoms of hypogonadism. 5

2. Measure LH and estradiol: Letrozole is most appropriate when LH is low or low-normal and estradiol is normal or elevated. 1, 6

3. Assess fertility status: Perform testicular exam and measure FSH; consider semen analysis if fertility is a concern. 1

4. Initiate letrozole: Start with 2.5 mg once weekly (or less) for obese men, or 2.5 mg daily for men with severe oligozoospermia. 2, 3

5. Monitor response: Check testosterone, estradiol, and LH at 2 and 4 weeks; adjust dose to achieve mid-normal testosterone without excessive estradiol suppression. 5

6. Assess fertility outcomes: Repeat semen analysis after 4 months of treatment to evaluate improvement in sperm parameters. 3, 4

7. Long-term monitoring: Continue monitoring hematocrit and adjust dose if free testosterone becomes supraphysiological. 5, 2

Important Contraindications

Never use letrozole in men with breast cancer or estrogen receptor-positive malignancies, as the resulting increase in testosterone could worsen outcomes. 6 Additionally, men with hematocrit >54% should not receive treatment until this is addressed. 5

Evidence Quality Considerations

While the European Association of Urology guidelines (2025) provide the most recent and authoritative framework, they acknowledge that prospective RCTs are necessary to better define the efficacy of aromatase inhibitors in male infertility. 1 The available research studies are small and uncontrolled but consistently show hormonal and semen parameter improvements. 3, 4, 2, 7 Given the strong mechanistic rationale, consistent positive findings across multiple studies, favorable safety profile, and explicit guideline support for fertility-preserving hormonal therapies in this population, letrozole represents a reasonable off-label option. 1