What is the use and dosage of Enclomiphene (clomiphene citrate) in treating infertility?

Enclomiphene (Clomiphene Citrate) for Infertility Treatment

Primary Indication and Patient Selection

Clomiphene citrate is FDA-approved exclusively for treating ovulatory dysfunction in women desiring pregnancy, not for male infertility. 1

Female Infertility - Approved Use

Start with 50 mg daily for 5 days beginning on cycle day 5 for women with documented ovulatory dysfunction. 1

Patient Selection Criteria (Must Meet ALL):

• Confirmed non-pregnant status 1
• No ovarian cysts (exception: polycystic ovary syndrome) 1
• No abnormal vaginal bleeding 1
• Normal liver function 1
• Adequate endogenous estrogen levels 1
• Pelvic examination completed before each treatment cycle 1

Dosing Algorithm:

• Initial dose: 50 mg daily for 5 days starting cycle day 5 1
• If no ovulation after first cycle: Increase to 100 mg daily for 5 days (can start as early as 30 days after previous cycle) 1
• Do not exceed: 100 mg/day for 5 days - higher doses are not recommended 1
• Maximum treatment duration: 6 total cycles (including 3 ovulatory cycles), then discontinue 1

Ovarian Stimulation for IUI:

• For unexplained infertility with Hunault score <30% and total motile sperm count (TMSC) >10 million, clomiphene citrate combined with IUI significantly increases live birth rates (OR 2.07,95% CI: 1.22-3.50) 2
• Use clomiphene citrate or ≤75 IU gonadotropins per day for ovarian stimulation 2
• Cancel cycle if: >2 follicles >15mm OR 1-2 follicles >15mm AND ≥5 follicles >10mm (to prevent high-order multiple pregnancy) 2
• Perform insemination 24-40 hours after hCG trigger 2

Male Infertility - Off-Label Use (Not FDA-Approved)

There are no adequate or well-controlled studies demonstrating effectiveness of clomiphene citrate for male infertility. 1

Despite off-label use for decades, the evidence remains insufficient:

• Only 1 of 9 clinical studies showed statistically significant pregnancy rate improvement 3
• Most studies showed increased sperm concentration but not pregnancy outcomes 3
• A 2023 study in oligospermic obese hypogonadal men showed improved sperm parameters (concentration: 4.5 to 11.4 × 10⁶/mL, p<0.05; motility: 31.5% to 42.6%, p<0.05) and testosterone levels (193.8 to 332.7 ng/dL, p<0.05) 4

Critical Contraindication for Male Use:

Never prescribe clomiphene to men actively using exogenous testosterone. 5

• Exogenous testosterone suppresses LH/FSH via negative feedback, directly blocking clomiphene's mechanism of action 5
• Testosterone must be discontinued first, with recovery potentially taking months to years 5
• For hypogonadal men desiring fertility, use hCG injections (500-2500 IU, 2-3 times weekly) instead 5

Mechanism and Pharmacokinetics

Clomiphene citrate contains two isomers with distinct properties:

• Enclomiphene (trans-isomer): Shorter half-life, primary therapeutic effect 1, 6
• Zuclomiphene (cis-isomer): Longer half-life (persists >1 month), accumulates across consecutive cycles 1, 6
• Zuclomiphene levels plateau after 3 consecutive cycles at approximately 100 nmol/L 6
• Drug may remain in body during early pregnancy in women who conceive during treatment 1

Key Safety Considerations

Ovarian Hyperstimulation Syndrome:

• Use lower doses to minimize multiple follicular development 7
• Particularly high risk in polycystic ovary syndrome patients 7, 1

Contraindications:

• Liver disease, especially decompensated cirrhosis 7
• Pregnancy 1
• Ovarian enlargement (except PCOS) 1

Metabolic Effects:

• Can alter serum lipid profiles 7

Multiple Pregnancy Risk:

• 7.98% incidence in clinical trials (6.9% twins, 0.5% triplets, 0.3% quadruplets) 1
• Monozygotic to dizygotic twin ratio approximately 1:5 1

Congenital Anomalies:

• Overall incidence within range of general population 1
• Various anomalies reported at <1% rate each 1

Treatment Monitoring

• Time coitus 5-10 days after completing 5-day course (expected ovulation window) 1
• Use basal body temperature or other ovulation detection methods 1
• Perform pelvic examination before each treatment cycle 1
• If no ovulation after 3 courses, discontinue and reevaluate 1
• If 3 ovulatory responses occur without pregnancy, discontinue 1