Effects of Enclomiphene on Male Hypogonadism and Fertility
Enclomiphene citrate blocks estrogen receptors at the hypothalamic level, increasing endogenous testosterone production and improving spermatogenesis in men with secondary hypogonadism, making it particularly valuable for men who wish to preserve fertility. 1
Mechanism of Action
Enclomiphene citrate is the trans-isomer of clomiphene citrate and functions as a selective estrogen receptor modulator (SERM). It works by:
- Blocking estrogen receptors at the hypothalamus level, stimulating GnRH secretion
- Increasing pituitary gonadotropin (LH and FSH) release
- Stimulating endogenous testosterone production without suppressing spermatogenesis 1, 2
- Raising testosterone levels while maintaining or improving sperm parameters 2, 3
Effects on Male Hypogonadism
Hormonal Effects
- Significantly increases serum total testosterone levels into the normal range (500-600 ng/dL) 2, 4
- Elevates LH and FSH levels above baseline, indicating restoration of hypothalamic-pituitary-testicular axis function 2, 4
- Effects on testosterone persist for at least one week after discontinuation 4
Clinical Benefits
- Improves hypogonadal symptoms in approximately 77% of men 5
- Maintains efficacy with long-term use (studies show effectiveness for up to 7 years) 5
- Does not cause the fluid retention or erythrocytosis commonly seen with exogenous testosterone 6
Effects on Male Fertility
Spermatogenesis
- Increases sperm counts significantly (studies show ranges of 75-334 million/mL) 2
- Maintains or improves sperm parameters unlike exogenous testosterone therapy 2, 7
- Particularly valuable for men with secondary hypogonadism who wish to preserve fertility 3
Comparison to Testosterone Therapy
- Unlike exogenous testosterone, enclomiphene does not suppress spermatogenesis 2
- Testosterone gel is ineffective in raising sperm counts above 20 million/mL in most men 2
- Exogenous testosterone provides negative feedback to the hypothalamus and pituitary, inhibiting gonadotropin secretion and potentially causing oligospermia or azoospermia 1
Safety Profile
- Generally well-tolerated with few side effects in long-term use 5
- Most common side effects include:
- Mood changes (reported in approximately 5% of long-term users)
- Blurred vision (approximately 3%)
- Breast tenderness (approximately 2%) 5
- No significant adverse events reported in long-term studies 5
Clinical Applications
Appropriate Candidates
- Men with secondary (hypogonadotropic) hypogonadism 6, 7
- Men who desire fertility preservation while treating hypogonadism 3
- Men previously on testosterone therapy who wish to restore fertility 2
Contraindications
- Primary hypogonadism (testicular failure) - less effective 1
- Men with estrogen receptor-positive malignancies 1
Dosing Considerations
- Typical dosing ranges from 6.25mg to 25mg daily 4
- Effects on testosterone levels are typically seen within 2 weeks of starting therapy 4
- Hormonal monitoring should be performed after initiation to ensure adequate response 6
Important Caveats
- Enclomiphene is not FDA-approved for use in men and is prescribed off-label 1
- European Association of Urology guidelines list drug-induced estrogen receptor blockade (including clomiphene) as a potential cause of hypogonadism 1
- Benefits of SERM administration in idiopathic infertility are small compared to assisted reproductive technologies 1
- Quality of evidence for SERMs in idiopathic male infertility is generally low 1
Enclomiphene represents a valuable alternative to testosterone replacement therapy for men with secondary hypogonadism who wish to maintain fertility. By stimulating the body's natural testosterone production pathway, it avoids the fertility-suppressing effects of exogenous testosterone while effectively treating hypogonadal symptoms.