What is the recommended dosing for Enclomiphene (clomiphene citrate) in the treatment of hypogonadism in males?

Enclomiphene Dosing for Male Hypogonadism

For men with hypogonadism, the recommended dosing of enclomiphene citrate is 12.5-25 mg daily, with most patients responding well to 25 mg daily to achieve target testosterone levels in the 450-600 ng/dL range. 1, 2

Dosing Protocol

• Starting dose: 12.5 mg daily or 25 mg every other day
• Titration: Can increase to 25 mg daily if needed based on testosterone response
• Maximum dose: 25 mg daily (higher doses have been studied but aren't typically necessary)
• Timing of effect:
  • Initial testosterone increases seen at 3-4 weeks
  • Maximum effect typically achieved by 6-8 weeks 1, 3

Monitoring Protocol

• Initial follow-up: 4-6 weeks after starting therapy
• Subsequent monitoring: Every 3 months during first year, then annually if stable
• Target testosterone levels: 450-600 ng/dL (mid-normal range) 1
• Parameters to monitor:
  • Total testosterone
  • LH and FSH levels
  • Estradiol (to monitor for excessive elevation)
  • Hematocrit/hemoglobin
  • Lipid profile

Clinical Evidence

Enclomiphene citrate, the trans-isomer of clomiphene, has been shown to effectively increase testosterone levels in hypogonadal men. In a randomized, single-blind study, enclomiphene at 25 mg daily increased mean testosterone levels from baseline to 604 ± 160 ng/dL after six weeks of treatment 2. This increase was comparable to transdermal testosterone therapy but with the advantage of maintaining or increasing LH and FSH levels rather than suppressing them.

Multiple studies using clomiphene citrate (which contains both enclomiphene and zuclomiphene isomers) have demonstrated significant testosterone increases:

• Increase from 247.6 to 610.0 ng/dL after 4-6 weeks of treatment with 25 mg daily 4
• Increase from 309 to 642 ng/dL after 3 months of treatment with 25 mg daily 5

Advantages of Enclomiphene vs. Exogenous Testosterone

1. Preservation of fertility: Unlike exogenous testosterone which suppresses spermatogenesis, enclomiphene maintains or improves sperm parameters by stimulating endogenous testosterone production 1

2. Physiologic testosterone levels: Stimulates the body's own testosterone production pathway, potentially leading to more stable levels throughout the day

3. Avoids testicular atrophy: By maintaining LH stimulation of the testes

4. Improved T/E ratio: Helps optimize the testosterone to estrogen ratio, which may be particularly beneficial in overweight men 4

Potential Side Effects

• Nipple tenderness (transient)
• Visual disturbances (rare)
• Potential for excessive estradiol elevation in some patients
• Headache
• Mood changes

Important Considerations

• Enclomiphene is most effective for secondary (hypogonadotropic) hypogonadism with low/normal LH levels
• Less effective in primary testicular failure or in patients with pituitary damage
• Not FDA-approved specifically for hypogonadism (off-label use)
• May be particularly beneficial for younger men who wish to preserve fertility
• May not be effective in all patients - one study showed poor response in patients with treated nonfunctioning pituitary adenomas 6

For patients who fail to respond adequately to enclomiphene therapy or who have primary hypogonadism, alternative treatments such as exogenous testosterone therapy should be considered.