What is the recommended dosage and treatment protocol for Clomid (clomiphene citrate) in women with infertility due to ovulation disorders?

Clomiphene Citrate (Clomid) for Ovulation Induction

Recommended Dosage Protocol

Start with 50 mg daily for 5 days beginning on cycle day 5, and increase to 100 mg daily for 5 days only if ovulation does not occur after the first course. 1

Initial Treatment Course

• Starting dose: 50 mg daily for 5 days 1
• Timing: Begin on or about the 5th day of the cycle (either after progestin-induced bleeding or spontaneous uterine bleeding) 1
• If no recent bleeding: May start at any time after excluding pregnancy 1

Dose Escalation Strategy

• If no ovulation after first course: Increase to 100 mg daily (two 50 mg tablets as single daily dose) for 5 days 1
• Earliest repeat: 30 days after previous course, after excluding pregnancy 1
• Maximum recommended dose: 100 mg/day for 5 days—do not exceed this dosage or duration 1

Treatment Duration Limits

• If no ovulation after 3 courses: Discontinue clomiphene and reevaluate the patient 1
• If 3 ovulatory responses occur without pregnancy: Further treatment is not recommended 1
• Maximum total cycles: Approximately 6 cycles total (including 3 ovulatory cycles) 1, 2

Patient Selection Criteria

Ideal Candidates

• Primary indication: Anovulatory infertility in normally estrogenized women (WHO group II anovulation), particularly polycystic ovary syndrome (PCOS) 3, 1, 2
• Expected outcomes: Approximately 80% will ovulate, and about 50% of those who ovulate will conceive 3

Required Pre-Treatment Evaluation

• Exclude pregnancy 1
• Pelvic examination: Mandatory before first and each subsequent course to exclude ovarian cysts or enlargement (except in PCOS) 1
• Adequate endogenous estrogen: Confirmed by vaginal smears, endometrial biopsy, urinary estrogen assay, or bleeding response to progesterone 1
• Normal liver function: Required before initiating therapy 1
• Exclude abnormal vaginal bleeding: Evaluate for neoplastic lesions if present 1
• Rule out other causes: Thyroid disorders, adrenal disorders, hyperprolactinemia, male factor infertility 1

Absolute Contraindications

• Pregnancy 1
• Liver disease, especially decompensated cirrhosis 4, 3
• Ovarian cysts or enlargement (except PCOS) 1
• Insufficient endogenous estrogen levels (e.g., functional hypothalamic amenorrhea without recovery) 5, 4

Special Populations and Considerations

Functional Hypothalamic Amenorrhea (FHA)

• Clomiphene is NOT recommended as first-line treatment for FHA 5, 6
• If used: Only consider in women with sufficient endogenous estrogen levels (recovered FHA), though success rates remain uncertain 5
• BMI requirement: Achieve BMI ≥18.5 kg/m² before any ovulation induction 5, 6
• Preferred alternatives: Pulsatile GnRH therapy is more effective than clomiphene in FHA, particularly with polycystic ovarian morphology 6

PCOS Patients

• Lower doses preferred: Use minimal effective dose to reduce risk of multiple follicular development and ovarian hyperstimulation syndrome 4
• Weight loss first: Even 5% body weight reduction improves ovulation and pregnancy rates 3
• Increased body mass index: Consistently associated with decreased response to clomiphene 2

Monitoring Requirements

• Ultrasound monitoring: Important to minimize risks of hyperstimulation and multiple pregnancy by adjusting doses in subsequent cycles 2
• Timing of intercourse: Should coincide with expected ovulation (typically 5-10 days after completing clomiphene course) 1
• Ovulation confirmation: Use basal body temperature charts or other appropriate tests 1

Critical Safety Warnings

Ovarian Hyperstimulation Syndrome

• Risk factors: Multifollicular development, especially in PCOS patients 4, 3
• Prevention: Use lower doses and ultrasound monitoring 4, 2

Multiple Pregnancy Risk

• Incidence: Increased with clomiphene therapy 7, 2
• Mitigation: Lower doses (50 mg) minimize risk while maintaining similar efficacy to 100 mg 7

Other Adverse Effects

• Cervical mucus impairment: May paradoxically reduce fertility despite inducing ovulation 7
• Endometrial dysfunction: Can occur with clomiphene use 7
• Lipid profile alterations: Monitor in at-risk patients 4, 3
• Uterine fibroids: Exercise caution due to potential for further enlargement 1

When Clomiphene Fails

Clomiphene-Resistant Patients

• Definition: No ovulation after 3 courses at maximum dose (100 mg for 5 days) 1
• Alternative strategies:
  • Extended 10-day course (100 mg for 10 days): 47% ovulation rate, 17% pregnancy rate in resistant cases 8
  • Low-dose gonadotropin therapy to induce monofollicular development 3
  • Combined clomiphene-HMG regimen (though not universally standardized) 1, 9

Important Pitfall

Do not continue clomiphene beyond 6 total cycles or 12 cycles maximum, as prolonged use may be associated with increased risk of borderline or invasive ovarian tumors 2