What is the typical treatment protocol for women with infertility due to ovulation disorders using Clomid (clomiphene citrate)?

Clomiphene Citrate for Ovulation Induction in Infertility

Clomiphene citrate is the first-line treatment for ovulation induction in women with ovulatory dysfunction (WHO Group II anovulation), particularly those with polycystic ovary syndrome, using a starting dose of 50 mg daily for 5 days beginning on cycle day 5. 1, 2

Patient Selection and Prerequisites

Before initiating clomiphene citrate, confirm the following criteria are met:

• Documented ovulatory dysfunction with adequate endogenous estrogen levels (assessed by vaginal smears, endometrial biopsy, or progestin withdrawal bleeding) 2
• Exclusion of pregnancy and absence of ovarian cysts or enlargement (except in PCOS) 2
• Normal liver function (clomiphene is contraindicated in liver disease, especially decompensated cirrhosis) 3, 2
• No abnormal vaginal bleeding (evaluate for neoplastic lesions if present) 2
• Body mass index considerations: Higher BMI consistently predicts decreased response; weight reduction should precede treatment 4
• Exclusion of other infertility factors: thyroid disorders, hyperprolactinemia, male factor, tubal disease 2

Standard Treatment Protocol

Initial Dosing

• Start with 50 mg daily for 5 days, beginning on cycle day 5 (or 5 days after progestin-induced withdrawal bleeding) 2
• Time intercourse to coincide with expected ovulation (typically 5-10 days after completing the medication course) 2
• Monitor ovulation using basal body temperature charts or other appropriate tests 2

Dose Escalation

• If no ovulation occurs after the first cycle: Increase to 100 mg daily for 5 days in the next cycle (starting as early as 30 days after the previous course, after excluding pregnancy) 2
• Do not exceed 100 mg daily for 5 days—increasing dosage or duration beyond this is not recommended 2
• Most patients who will ovulate do so after the first course of therapy 2

Treatment Duration

• Discontinue after 3 ovulatory cycles without pregnancy or after 3 cycles without ovulation 2
• Maximum recommended duration: 6 total cycles (including 3 ovulatory cycles), as prolonged use may increase ovarian tumor risk 2, 4
• However, cumulative conception rates continue to rise through 12 cycles in responsive patients, approaching normal population rates 4

Expected Outcomes

• Ovulation rate: Approximately 80% in women with PCOS 1
• Pregnancy rate: About 50% of those who ovulate will conceive 1
• Per-cycle pregnancy rate: 6-21% depending on patient selection 4, 5
• Pregnancy and miscarriage rates approach those of the normal fertile population in pure anovulatory infertility 4

Monitoring and Risk Mitigation

Ultrasound monitoring is essential to:

• Adjust dosing in subsequent cycles 4
• Minimize risks of ovarian hyperstimulation syndrome 3, 4
• Reduce multiple pregnancy risk (occurs in ~5-10% of pregnancies) 4, 5

Pelvic examination is mandatory before the first and each subsequent treatment cycle 2

Special Populations and Contraindications

When Clomiphene Should NOT Be Used

• Functional hypothalamic amenorrhea (FHA): Clomiphene is not recommended as first-line treatment and should only be considered if sufficient endogenous estrogen is present (though this threshold remains unclear) 1, 3, 6
• Normally ovulatory women: Clomiphene significantly decreases pregnancy rates in women with regular ovulation (22% vs 73% pregnancy rate compared to no treatment) 7
• Decompensated cirrhosis or liver disease 3, 2
• Presence of ovarian cysts (except PCOS) 2
• Uterine fibroids: Use with caution due to potential enlargement 2

Alternative Approaches

• If clomiphene fails after 3 cycles: Consider low-dose gonadotropin therapy (preferred over high-dose to reduce hyperstimulation risk) 1, 6
• For FHA with polycystic ovarian morphology: Pulsatile GnRH therapy is more effective than either clomiphene or gonadotropins 1, 6
• Extended 10-day course (100 mg for 10 days instead of 5) may benefit clomiphene-resistant patients, with 47% ovulation rate and 17% pregnancy rate 8

Critical Pitfalls to Avoid

• Do not use clomiphene in male infertility—it is not effective and has been associated with testicular tumors and gynecomastia 2
• Do not combine with other ovulation-inducing drugs without clear protocols, as there is no universally accepted standard regimen 2
• Do not continue beyond 6-12 cycles due to potential ovarian cancer risk 4
• Do not use in normally ovulating women—it paradoxically decreases fertility 7
• Ensure BMI ≥18.5 kg/m² before starting treatment in women with FHA 1, 6