What is the typical dosage and usage of enclomiphene for treating infertility in women with polycystic ovary syndrome (PCOS) and hypogonadism in men?

Enclomiphene for Infertility and Hypogonadism

Enclomiphene is not FDA-approved for either female PCOS-related infertility or male hypogonadism, and current guidelines do not support its use as first-line therapy in either population.

For Women with PCOS

Standard First-Line Treatment

• Clomiphene citrate (not enclomiphene) remains the recommended first-line ovulation induction agent for women with PCOS attempting conception, with approximately 80% achieving ovulation and 50% of those conceiving 1.

• The typical clomiphene citrate dosing for PCOS is 50-100 mg daily for 5 days, starting on cycle day 3-5 1, 2.

Why Enclomiphene Is Not Recommended for Women

• No randomized controlled trials or guideline recommendations support enclomiphene use in women with PCOS 1.

• Clomiphene citrate (the racemic mixture containing both enclomiphene and zuclomiphene isomers) has established efficacy and safety data in women, whereas isolated enclomiphene does not 1.

Critical Pre-Treatment Requirements

• Women should achieve BMI ≥18.5 kg/m² before ovulation induction is offered, per Endocrine Society recommendations 1.

• Weight loss of as little as 5% of initial body weight improves metabolic and reproductive abnormalities in PCOS and should be attempted first 1.

For Men with Hypogonadism

Enclomiphene Dosing in Males (Off-Label)

• Research data suggests enclomiphene 12.5-25 mg daily can increase testosterone levels into the normal range (mean 604 ± 160 ng/dL at 25 mg dose after 6 weeks) while maintaining or improving spermatogenesis 3.

• Treatment duration should be at least 3 months (74 days minimum) to allow sufficient time for spermatogenic response 4, 5.

Patient Selection Criteria for Male Use

• Enclomiphene should only be considered for men with documented low serum testosterone AND infertility concerns, not as first-line therapy for idiopathic infertility with normal testosterone 1, 4.

• Men with elevated FSH (>7.6 IU/L) suggesting testicular dysfunction but with some remaining spermatogenic potential may be appropriate candidates 4.

Comparative Efficacy: Enclomiphene vs. Clomiphene in Men

• Enclomiphene demonstrated superior increases in FSH, LH, and total motile sperm count compared to clomiphene citrate in retrospective analysis 5.

• Both agents significantly increased total testosterone without negatively affecting spermatogenesis, but enclomiphene showed more consistent gonadotropin elevation 5, 3.

Critical Limitations and Warnings

• The benefits of enclomiphene/clomiphene are distinctly limited compared to assisted reproductive technology (ART), which offers higher pregnancy rates and shorter time to conception 1, 4.

• For men with non-obstructive azoospermia, enclomiphene has extremely limited evidence and should not delay surgical sperm retrieval options like micro-TESE 1, 4.

• Female partner age is the most critical factor determining conception success; delaying ART for empiric enclomiphene trials may reduce overall pregnancy chances 4.

Absolute Contraindication

• Never prescribe testosterone monotherapy for males interested in current or future fertility, as it suppresses spermatogenesis through negative feedback on the hypothalamic-pituitary axis 1, 4.

Treatment Algorithm for Male Hypogonadism with Fertility Concerns

1. Confirm low testosterone with morning total testosterone levels on at least two occasions 1.

2. Evaluate for secondary causes: pituitary disorders, medications affecting HPG axis, obesity/metabolic syndrome 1.

3. If hypogonadotropic hypogonadism is confirmed and fertility is desired:

   • First-line: hCG injections (500-2500 IU, 2-3 times weekly) followed by FSH when indicated 1.
   • Alternative: Enclomiphene 12.5-25 mg daily (off-label) if patient prefers oral therapy 5, 3.

4. Monitor response by repeating semen analysis after at least 74 days 4.

5. If inadequate response or time-sensitive fertility: transition directly to IVF/ICSI rather than prolonging medical therapy 4.

Key Pitfalls to Avoid

• Do not use enclomiphene in women—no evidence supports this, and standard clomiphene citrate is the established treatment 1.

• Do not delay ART in couples where female partner is >35 years old, as age-related fertility decline will not be reversed by male hormonal optimization 4.

• Do not prescribe enclomiphene for eugonadal men with idiopathic infertility—it provides minimal benefit compared to ART 1, 4.