Enclomiphene for Sperm Preservation: Not Recommended as Primary Strategy
Sperm cryopreservation, not enclomiphene, is the standard of care for fertility preservation in men—enclomiphene has no established role in sperm preservation and should not be used for this indication. 1
Primary Recommendation: Sperm Cryopreservation
All men at risk of infertility should be offered sperm cryopreservation before any gonadotoxic treatment (chemotherapy, radiation, or surgery that may impair spermatogenesis). 1
Sperm banking should include at least three samples with 48-hour abstinence intervals between collections. 1
This is the most cost-effective and established method for fertility preservation in men. 2
For men with severe oligospermia or azoospermia, testicular sperm extraction (TESE or microTESE) should be considered. 1
Why Enclomiphene Is Not Used for Sperm Preservation
Medical gonadoprotection with hormonal agents (including GnRH analogs with or without androgens, antiandrogens, or progestins) should NOT be offered for fertility preservation in male cancer patients. 1
Studies in cancer patients demonstrate that hormonal therapy is not successful in preserving fertility when highly sterilizing chemotherapy is given, nor does it speed recovery of spermatogenesis. 1
Small prospective studies evaluating hypothalamic-pituitary-gonadal suppression plus testosterone in men rendered azoospermic after chemotherapy showed no recovery of spermatogenesis after 12 weeks. 1
Enclomiphene's Actual Role: Treatment of Hypogonadism (Not Preservation)
Enclomiphene is used for treating existing hypogonadism in men who desire fertility, not for preserving fertility before gonadotoxic exposure:
Dosing for Hypogonadism Treatment
For idiopathic male infertility with hypogonadism: 25 mg daily for 25 days with a 5-day break, continuing for 3 months. 3
Research studies have used doses ranging from 6.25 mg to 25 mg daily, with 25 mg being most effective at raising testosterone to normal range (mean 604 ± 160 ng/dL). 4, 5
Enclomiphene increases testosterone while preserving or improving sperm counts (75-334 × 10⁶/mL range) by stimulating endogenous LH and FSH production. 4, 6
Important Limitations
Enclomiphene is NOT FDA-approved for use in men—all use is off-label. 3
Benefits are limited compared to assisted reproductive techniques (ART), which offer higher pregnancy rates and shorter time to conception. 3
If no improvement occurs after 3 months, proceed to intrauterine insemination (IUI) with ovarian stimulation (if total motile sperm count >10 million) or IVF/ICSI. 3
Critical Distinction: Hypogonadotropic Hypogonadism
For men with hypogonadotropic hypogonadism (HH) who desire fertility, exogenous gonadotropins or pulsatile GnRH are preferred over clomiphene/enclomiphene. 3
After excluding hypogonadotropic hypogonadism, if sperm are present in semen, proceed directly to sperm cryopreservation. 1
One study combining hCG with clomiphene citrate 25 mg daily in HH patients showed 47.4% had sperm after 12 months, though most were severely abnormal. 7
Safety Considerations
Avoid clomiphene/enclomiphene in patients with liver disease, especially decompensated cirrhosis, due to potential hepatotoxicity. 3
Long-term use (>3 years) shows good safety profile with only 8% reporting side effects (mood changes, blurred vision, breast tenderness). 8
Exogenous testosterone therapy must be avoided in men seeking fertility as it suppresses spermatogenesis. 2
Clinical Algorithm for Fertility Preservation
Identify men at risk of gonadotoxicity from planned cancer treatment or other gonadotoxic therapy. 1
Refer immediately to fertility specialist before treatment initiation. 1
Exclude hypogonadotropic hypogonadism with hormonal evaluation (LH, FSH, testosterone). 1
If able to ejaculate: Proceed directly to sperm cryopreservation (at least 3 samples). 1
If unable to ejaculate or azoospermic: Consider TESE/microTESE. 1
Do NOT use enclomiphene or other hormonal agents for gonadoprotection during cancer treatment. 1