What are the risks and adverse effects of using clomiphene citrate to increase testosterone in men with secondary hypogonadotropic hypogonadism who wish to preserve fertility?

Clomiphene for Testosterone Stimulation in Men: Risks and Adverse Effects

Clomiphene citrate is a safe and effective alternative to testosterone replacement therapy for men with secondary hypogonadism who wish to preserve fertility, with minimal adverse effects reported even with long-term use. 1, 2

Primary Advantages Over Testosterone Replacement

Clomiphene preserves fertility by stimulating endogenous testosterone production without suppressing spermatogenesis, making it the preferred first-line treatment for men actively seeking fertility or wishing to preserve future fertility potential. 1, 3 Unlike exogenous testosterone, which causes azoospermia that may take months to years to reverse, clomiphene maintains or even improves sperm production while normalizing testosterone levels. 1, 4

Additional benefits include:

• No risk of erythrocytosis (compared to 44% risk with injectable testosterone and 15% with transdermal preparations) 1
• Maintenance of testicular volume (testosterone replacement causes testicular atrophy) 1
• Significantly lower cost ($156-200 annually vs. $2,135 for transdermal testosterone) 1
• Oral administration (no injections or daily gel application required) 1

Documented Adverse Effects

Common Side Effects (Reported in Clinical Trials)

The most frequently reported adverse effects in long-term studies include:

• Mood changes (5% of patients treated >3 years) 2
• Blurred vision (3% of patients treated >3 years) 2
• Breast tenderness/gynecomastia (2% of patients treated >3 years) 2
• Headache and dizziness (reported but frequency <1%) 5, 6

Importantly, in a large retrospective study of 400 patients treated for up to 84 months, only 8% reported any side effects, and there were no significant adverse events in any patient. 2

Hormonal Changes

• Estradiol levels increase significantly following clomiphene treatment 2, 7
• However, the testosterone-to-estradiol ratio improves from approximately 8.7 to 14.2, which is clinically favorable 7
• This estradiol elevation is generally well-tolerated and does not require routine intervention 2

Rare or Theoretical Concerns

• Elevated serum desmosterol may occur with prolonged therapy due to direct interference with cholesterol synthesis, though serum sterols remain within normal limits at recommended doses 5
• Visual disturbances including abnormal accommodation, photopsia, and rarely temporary vision loss have been reported post-marketing 5
• Ovarian cancer risk has been noted in female patients with prolonged use; this is not applicable to male patients 5

Clinical Efficacy Data

Testosterone Normalization

Clomiphene rapidly normalizes testosterone levels, with mean values rising from 247.6 ng/dL to 610.0 ng/dL within 4-6 weeks of starting 25 mg daily. 7 In long-term studies, 88% of men treated for more than 3 years achieved eugonadism, and 77% reported improved symptoms. 2

Fertility Outcomes

Enclomiphene (the active isomer) elevated sperm counts in 100% of men at 3 months (7/7) and 6 months (6/6), with concentrations ranging from 75-334 × 10⁶/mL, compared to testosterone gel which was ineffective in raising counts above 20 × 10⁶/mL. 4

Symptom Improvement

Clomiphene produces:

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35, comparable to testosterone replacement) 1, 6
• Improvement in erectile function 6
• Increased bone mineral density 6
• Reduction in body mass index 6

Absolute Contraindications

Men with primary hypogonadism (elevated LH/FSH) are absolutely contraindicated for clomiphene, as they cannot respond to gonadotropin stimulation and require testosterone replacement instead. 1, 3

Dosing and Monitoring

Standard Regimen

The European Association of Urology recommends 25-50 mg orally three times weekly as the standard clomiphene regimen for male hypogonadism. 1 Some studies have used 25 mg daily with excellent results. 7

Monitoring Schedule

• Baseline: Morning total testosterone (×2), LH, FSH, estradiol, free testosterone 1, 3
• 6 weeks: Repeat testosterone, estradiol, LH, FSH to confirm target mid-normal testosterone and avoid excessive estradiol suppression 3
• 3-4 months: Hormonal panel plus semen analysis if fertility is a goal; evaluate libido and erectile function 3
• Ongoing: Every 6-12 months once stable—monitor testosterone, estradiol, and symptom burden 3

Critical Clinical Pitfalls to Avoid

• Never use clomiphene in primary hypogonadism (elevated LH/FSH)—these patients cannot respond to increased gonadotropin stimulation 1, 3
• Do not expect dramatic improvements in energy, mood, or physical function—clomiphene (like testosterone) produces minimal benefit in these domains 1
• Discontinue at 12 months if sexual function has not improved despite achieving target testosterone levels 3
• Do not ignore visual symptoms—any vision changes warrant immediate discontinuation and ophthalmologic evaluation 5

Long-Term Safety Profile

Clomiphene has been demonstrated safe and effective for up to 7 years (84 months) of continuous use, with no significant adverse events reported in large retrospective cohorts. 2 The side effect profile remains stable over time, with no evidence of tolerance, abuse, or dependence. 5, 2

Comparison to Testosterone Replacement Therapy

For men with secondary hypogonadism desiring fertility, clomiphene offers distinct advantages:

• Preserves/improves spermatogenesis vs. causes azoospermia 1, 4
• No erythrocytosis risk vs. 15-44% risk 1
• Maintains testicular volume vs. causes atrophy 1
• Lower cost ($156-200/year vs. $2,135/year) 1
• Oral administration vs. daily gel or bi-weekly injections 1

The primary downside is that clomiphene is ineffective in primary hypogonadism and is not FDA-approved for male use (off-label indication). 1, 3