What is the use and dosage of enclomiphene (clomiphene citrate) in treating male infertility or hypogonadism?

Enclomiphene for Male Infertility and Hypogonadism

Enclomiphene citrate (the trans-isomer of clomiphene) is an effective off-label treatment for secondary hypogonadism and male infertility, increasing testosterone levels while preserving or improving spermatogenesis, making it particularly valuable for men desiring fertility. 1, 2

Mechanism and Clinical Use

Enclomiphene functions as a selective estrogen receptor modulator (SERM) that blocks estrogen receptors at the hypothalamus, stimulating GnRH secretion and increasing pituitary release of LH and FSH, which in turn stimulates endogenous testosterone production and spermatogenesis. 3, 2

Key Advantages Over Clomiphene Citrate

• Enclomiphene demonstrates superior efficacy in raising gonadotropin levels (FSH and LH) compared to standard clomiphene citrate. 1
• Total motile sperm count (TMSC) significantly increases with enclomiphene but not with clomiphene citrate. 1
• Both medications increase serum total testosterone without negatively affecting spermatogenesis, but enclomiphene shows more robust hormonal response. 1

Dosing Recommendations

The optimal dosing regimen is 25 mg daily, administered cyclically for 6-9 months, which produces the greatest improvement in semen parameters. 4

• If no response occurs at 25 mg daily, increase to 50 mg daily. 4
• Treatment duration should be at least 3 months minimum to allow for the 74-day spermatogenic cycle. 1
• Monitor gonadotropin levels and semen parameters periodically during therapy. 4

Patient Selection Criteria

Enclomiphene is most effective in men with secondary (hypogonadotropic) hypogonadism who have an intact hypothalamic-pituitary-gonadal axis. 3, 4

Ideal Candidates:

• Men with low testosterone and low or low-normal LH/FSH levels 3
• Adult-onset idiopathic hypogonadotropic hypogonadism (select patients may respond) 5
• Oligospermic men with hypogonadism, including those with obesity (BMI ≥30 kg/m²) 6
• Men desiring fertility who cannot use exogenous testosterone 2

Poor Candidates:

• Men with primary testicular failure (elevated FSH >7.6 IU/L with testicular atrophy) are less likely to benefit 3
• Patients with Kallmann's syndrome or congenital hypogonadotropic hypogonadism typically require gonadotropin therapy instead 5

Expected Outcomes

Hormonal Response:

• Significant increases in serum total testosterone (from ~194 ng/dL to ~333 ng/dL in hypogonadal obese men) 6
• Statistically significant increases in FSH and LH with enclomiphene 1

Semen Parameter Improvements:

• Sperm concentration increases significantly (from 4.5 to 11.4 × 10⁶/mL in oligospermic obese men) 6
• Sperm motility improves substantially (from 31.5% to 42.6%) 6
• Total motile sperm count increases significantly with enclomiphene 1
• Normal morphology may improve 6

Fertility Outcomes:

• Pregnancy rates achieved in select patients with adult-onset idiopathic hypogonadotropic hypogonadism (2 of 3 men in one series) 5

Critical Contraindications and Warnings

Never prescribe exogenous testosterone to men desiring current or future fertility—it suppresses gonadotropin secretion and can cause azoospermia that may take months to years to recover. 3

Limitations and Context

The benefits of SERM therapy in idiopathic infertility are small and outweighed by the distinct advantages of assisted reproductive technology (IVF/ICSI), which offers higher pregnancy rates and faster time to conception. 3

• SERMs including enclomiphene are not FDA-approved for use in men 3, 4
• The quality of evidence supporting SERM use in idiopathic male infertility is low, with few placebo-controlled trials 3
• For men with total motile sperm count <5 million after processing, IUI success rates are limited and IVF/ICSI should be considered 3

Monitoring Protocol

• Baseline: Total testosterone, LH, FSH, complete semen analysis (at least two samples) 3
• During treatment: Recheck hormones and semen analysis every 3 months 4
• Evaluate for hyperprolactinemia if low/low-normal LH with decreased libido 3
• Screen for reversible causes: thyroid dysfunction, obesity, metabolic disorders 3

Special Populations

Oligospermic Obese Hypogonadal Men:

Enclomiphene is particularly effective in this population, substantially improving both testosterone levels and semen parameters without requiring expensive testosterone replacement therapy. 6

Non-Obstructive Azoospermia:

Limited data support pharmacologic manipulation with SERMs prior to surgical sperm retrieval; case series suggest possible benefits but studies are typically uncontrolled. 3