What is the use of Clomifene (clomiphene) in men with hypogonadism and infertility?

Clomiphene Use in Men with Hypogonadism and Infertility

Clomiphene citrate is an effective off-label treatment option for men with hypogonadism who wish to preserve fertility, acting by increasing endogenous testosterone production without suppressing spermatogenesis. 1

Mechanism of Action and Indications

Clomiphene citrate (CC) works as a selective estrogen receptor modulator (SERM) by:

• Blocking estrogen's negative feedback on the hypothalamus and pituitary
• Stimulating gonadotropin (LH and FSH) secretion
• Increasing endogenous testosterone production
• Improving spermatogenesis without suppressing it 2, 1

Key indications for clomiphene use in men include:

• Hypogonadism with desire to preserve fertility
• Male infertility with low testosterone levels
• Alternative to testosterone replacement therapy (TRT) when fertility preservation is desired 1

Clinical Evidence and Efficacy

For Hypogonadism

• Long-term studies show that approximately 88% of men achieve eugonadism with clomiphene treatment 3
• About 77% of patients report improved hypogonadal symptoms when treated for extended periods 3
• Predictors of good response include:
  • Testicular volume ≥14 mL
  • Baseline LH levels ≤6 IU/mL 4

For Male Infertility

• The benefits of SERM administration for idiopathic infertility are small compared to assisted reproductive technologies 2
• Clomiphene may be more beneficial in men with hypogonadism and infertility rather than those with idiopathic infertility alone 2
• Recent evidence suggests enclomiphene citrate (the trans-isomer of clomiphene) may be more effective than clomiphene at raising gonadotropin levels and total motile sperm count 5

Dosing and Administration

• Typical dosing: 25 mg daily is often effective
• Higher doses (50 mg daily) may be considered for non-responders
• Treatment duration:
  • For infertility: 6-9 months in a cyclic fashion
  • For hypogonadism: Can be used long-term (studies show safety up to 7 years) 6, 3

Advantages Over Testosterone Replacement Therapy

1. Preserves fertility and spermatogenesis
2. Maintains testicular size and function
3. Lower risk of polycythemia compared to TRT
4. No suppression of the hypothalamic-pituitary-gonadal axis 1

Safety Profile and Side Effects

• Generally well-tolerated with few side effects (8% reported side effects in long-term studies)
• Most common side effects:
  • Mood changes
  • Visual disturbances (blurred vision)
  • Breast tenderness
• No significant adverse events reported in long-term studies 3

Clinical Recommendations

1. For men with hypogonadism who desire fertility:

   • Clomiphene is preferred over testosterone replacement therapy 2, 1

2. For men with idiopathic infertility:

   • Clinicians should inform patients that SERMs like clomiphene have limited benefits relative to assisted reproductive technologies 2
   • For couples with mild male factor infertility (TMSC >10 million), IUI with ovarian stimulation may be considered 2
   • For couples with moderate male factor infertility (TMSC <10 million), IUI in natural cycles may be considered 2

3. For men with non-obstructive azoospermia:

   • Limited data supports pharmacologic manipulation with SERMs prior to surgical intervention 2

Important Caveats

• Clomiphene is not FDA-approved for use in men
• Response should be monitored with periodic testosterone, LH, FSH, and semen analysis
• Not all men will respond to clomiphene therapy
• There are no clear, reliable data supporting the use of supplements (vitamins, antioxidants) for male infertility 2, 7

For men with hypogonadism seeking fertility, clomiphene offers a valuable therapeutic option that addresses both hormonal deficiency and reproductive potential, with a favorable long-term safety profile compared to traditional testosterone replacement.