What is the recommended initial dosage and treatment protocol for clomiphene (Clomid) in a patient seeking fertility treatment, possibly with a history of ovulation disorders like PCOS?

Clomiphene Citrate for Ovulation Induction in Anovulatory Infertility

Start with clomiphene citrate 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 cycle. 1

Initial Dosing Protocol

• Begin with 50 mg daily for 5 days starting on or about the 5th day of the menstrual cycle (after progestin-induced bleeding if needed, or spontaneous bleeding). 1
• Therapy may be started at any time in patients without recent uterine bleeding. 1
• Do not start with higher doses—the majority of patients who will ovulate do so after the first course at 50 mg. 1

Dose Escalation Strategy

• If no ovulation occurs after the first 50 mg cycle, increase to 100 mg daily for 5 days in the second cycle, starting as early as 30 days after the previous course (after excluding pregnancy). 1
• Maximum recommended dose is 100 mg daily for 5 days—increasing beyond this is not recommended. 1
• When ovulation occurs at 50 mg, there is no advantage to increasing the dose in subsequent cycles. 1

Special Considerations for PCOS Patients

• Use the lowest dose (50 mg) and shortest duration in PCOS patients due to unusual sensitivity to pituitary gonadotropin and increased risk of ovarian hyperstimulation syndrome. 1
• The American Academy of Family Physicians recommends clomiphene as first-line treatment for WHO group II anovulation (which includes PCOS), with approximately 80% ovulation rates and 50% conception rates among those who ovulate. 2
• Some PCOS patients may be oversensitive and require even lower doses (as low as 12.5 mg has been reported effective in case series). 3

Treatment Duration and Stopping Rules

• Stop after 3 ovulatory cycles without pregnancy—further clomiphene treatment is not recommended. 1
• Stop after 3 cycles if no ovulation occurs—the patient should be reevaluated and alternative treatments considered. 1
• Total treatment should not exceed approximately 6 cycles of long-term cyclic therapy. 1
• If menses does not occur after an ovulatory response, reevaluate to exclude pregnancy. 1

Critical Safety Monitoring

Ovarian Hyperstimulation Syndrome (OHSS)

• Check for ovarian enlargement between each treatment cycle—do not give additional clomiphene until ovaries return to pretreatment size. 1
• Early warning signs include abdominal pain/distention, nausea, vomiting, diarrhea, and weight gain. 1
• OHSS can progress rapidly (within 24 hours to several days) to a serious medical disorder with ascites, pleural effusion, oliguria, and thromboembolism. 1
• Perform abdominal and pelvic examinations very cautiously due to fragility of enlarged ovaries. 1

Visual Symptoms

• Discontinue treatment immediately if any visual symptoms occur (blurring, scotomata, phosphenes) and perform complete ophthalmological evaluation. 1
• Visual symptoms typically resolve after stopping therapy but require prompt evaluation. 1

Contraindications

• Absolutely contraindicated in liver disease, especially decompensated cirrhosis. 4, 2
• Only use when sufficient endogenous estrogen is present—not appropriate for hypogonadotropic hypogonadism or functional hypothalamic amenorrhea without adequate estrogen. 4, 2
• Exclude pregnancy, ovarian enlargement, or ovarian cyst formation before each treatment cycle. 1

Timing of Intercourse and Monitoring

• Ovulation typically occurs 5-10 days after completing the 5-day course. 1
• Time intercourse to coincide with expected ovulation. 1
• Use appropriate ovulation detection tests during this window. 1

Alternative Considerations

While clomiphene remains first-line per ACOG guidelines based on long-established safety, letrozole produces superior pregnancy outcomes with higher pregnancy rates, shorter time to conception, and more monofollicular development in PCOS patients. 5 However, clomiphene's advantages include lower cost and greater convenience. 6

Low-dose FSH may be considered if clomiphene fails after appropriate trials, though it requires more intensive monitoring. 2, 6

Common Pitfalls to Avoid

• Do not increase dose beyond 100 mg daily or extend treatment beyond 5 days per cycle—this does not improve outcomes and increases risks. 1
• Do not continue treatment beyond 3 ovulatory cycles without pregnancy or 6 total cycles—this increases risks without improving outcomes. 1
• Do not overlook the need for dose reduction in PCOS patients—they are at higher risk for hyperstimulation. 1
• Do not ignore ovarian enlargement—wait for regression before continuing treatment. 1