What is the evidence for using clomiphene (clomiphene citrate) in treating secondary hypogonadism in males?

Clomiphene Citrate for Secondary Hypogonadism in Males

Clomiphene citrate is an effective off-label treatment for secondary hypogonadism in men, particularly when fertility preservation is desired, with evidence showing significant increases in testosterone levels and improvement in hypogonadal symptoms while maintaining spermatogenesis. 1, 2

When to Consider Clomiphene Citrate

Clomiphene citrate should be the first-line treatment for men with secondary hypogonadism who desire fertility preservation or wish to maintain testicular function. 3, 1 Unlike testosterone replacement therapy, clomiphene does not suppress the hypothalamic-pituitary-gonadal axis, preserving intratesticular testosterone production and spermatogenesis. 1, 4

Diagnostic Requirements Before Initiating Treatment

• Confirm secondary hypogonadism with two separate morning total testosterone measurements below 300 ng/dL drawn between 8-10 AM. 5, 6
• Measure LH and FSH to confirm secondary (not primary) hypogonadism—characterized by low or inappropriately normal gonadotropins with low testosterone. 5, 6
• Rule out reversible causes including medications affecting the hypothalamic-pituitary axis, acute illness, obesity, and metabolic disorders. 5

Ideal Candidates for Clomiphene

• Men with mean testicular volume ≥14 mL have a 2.2-fold higher likelihood of robust testosterone response. 7
• Baseline LH levels ≤6 IU/mL predict a 3.5-fold higher chance of achieving testosterone elevation ≥200 ng/dL. 7
• Approximately 62% of hypogonadal men meet the responder definition (testosterone increase ≥200 ng/dL). 7

Evidence for Efficacy

Testosterone Elevation

• Meta-analysis demonstrates clomiphene increases total testosterone by 2.60 nmol/L (95% CI 1.82-3.38) during treatment. 2
• In men with secondary hypogonadism previously on testosterone gel, clomiphene citrate (specifically the enclomiphene isomer) raised testosterone from baseline 165 pg/dL to 525 pg/dL at 6 months. 4
• Long-term data shows 88% of men treated for more than 3 years achieve eugonadism. 8

Fertility Preservation

• Enclomiphene citrate elevated sperm counts in 7/7 men at 3 months and 6/6 men at 6 months, with concentrations ranging from 75-334 × 10⁶/mL. 4
• This contrasts sharply with testosterone gel, which failed to raise sperm counts above 20 × 10⁶/mL in all five men at 3 months. 4
• Meta-analysis shows significant improvement in fertility rates in hypogonadal men treated with clomiphene. 1

Symptom Improvement

• Among men treated for more than 3 years, 77% reported improved hypogonadal symptoms. 8
• Studies using the Androgen Deficiency in Aging Males (ADAM) questionnaire show symptom improvement during treatment. 2
• Additional benefits include improvement in erectile function, bone mineral density, and reduction in body mass index. 1

Practical Dosing and Monitoring

Starting Regimen

• Typical dosing is 25-50 mg daily or every other day, though specific dosing protocols vary across studies. 1, 2
• Assess testosterone levels at 4 weeks after commencement, then every 6 months. 7
• Monitor LH, FSH, estradiol, and free testosterone alongside total testosterone. 4, 2

Expected Hormonal Changes

• Clomiphene increases not only testosterone but also LH, FSH, sex hormone-binding globulin, and estradiol. 4, 2
• In responders, mean LH rise is 5.6 ± 3.1 IU/mL. 7
• These concomitant changes in LH and FSH suggest normalization of endogenous testosterone production through the hypothalamic-pituitary-testicular axis. 4

Safety Profile and Side Effects

Clomiphene citrate is generally safe and well-tolerated with few side effects, even with long-term use exceeding 3 years. 1, 8, 2

Reported Adverse Effects

• Side effects occur in less than 10% of patients and include mood changes (5%), blurred vision (3%), and breast tenderness (2%) in long-term users. 8, 2
• Other reported effects include headache, dizziness, gynecomastia, and exacerbation of psychiatric illnesses. 1
• No serious adverse events have been reported in any patient treated with clomiphene citrate. 8

Long-Term Safety Data

• Treatment duration in studies ranges from 1.5 to 84 months, with mean duration of 25.5 months. 8
• Results do not significantly differ between patients treated for more than 3 years versus 3 years or less. 8
• Estradiol elevation is expected and significant following clomiphene treatment. 8

Comparison to Testosterone Replacement Therapy

Key Advantages of Clomiphene

• Preserves spermatogenesis and fertility potential, whereas testosterone causes azoospermia that may take months to years to reverse. 5, 1
• Maintains intratesticular testosterone production and testicular volume. 1, 7
• Avoids the absolute contraindication of testosterone therapy in men seeking fertility. 3, 5

When Testosterone is Preferred

• The European Association of Urology recommends testosterone replacement therapy as first-line for men with secondary hypogonadism who are not seeking fertility. 5, 6
• Testosterone provides more predictable symptom relief, particularly for sexual dysfunction. 5
• For men with severe erectile dysfunction, combining testosterone with PDE5 inhibitors yields optimal results. 6

Critical Clinical Caveats

Limitations of Clomiphene

• The AUA/ASRM guidelines note that benefits of selective estrogen receptor modulators (SERMs) like clomiphene are limited relative to results of assisted reproductive technology in idiopathic infertility. 3
• For men with idiopathic infertility and normal testosterone, the incremental benefit is small and outweighed by advantages of IVF. 3
• Clomiphene is not FDA-approved for use in men, representing off-label therapy. 3, 1

When NOT to Use Clomiphene

• Primary hypogonadism (elevated LH/FSH with low testosterone) will not respond to clomiphene, as the testes cannot respond to increased gonadotropin stimulation. 6
• Men with hypogonadotropic hypogonadism requiring immediate fertility may benefit more from gonadotropin therapy (hCG plus FSH). 3, 5
• Eugonadal men (normal testosterone levels) should never receive clomiphene, even if symptomatic. 5, 6

Treatment Algorithm

1. Confirm diagnosis: Two morning testosterone levels <300 ng/dL with low/normal LH and FSH. 5, 6
2. Assess fertility goals: If fertility desired now or in future, clomiphene is preferred over testosterone. 3, 1
3. Check predictors of response: Testicular volume ≥14 mL and baseline LH ≤6 IU/mL predict better outcomes. 7
4. Initiate clomiphene: Start 25-50 mg daily or every other day. 1
5. Monitor at 4 weeks: Check total testosterone, free testosterone, LH, FSH, estradiol. 7, 4
6. Reassess at 6 months: If testosterone increase ≥200 ng/dL and symptoms improve, continue therapy. 7
7. Long-term monitoring: Check hormones every 6 months; treatment can be safely continued for years. 8

If no response after 6 months or if fertility is not a concern and symptoms persist, transition to testosterone replacement therapy. 5, 6