For how long is Clomiphene Citrate (CC) continued in an In Vitro Fertilization (IVF) stimulation protocol along with gonadotropins in a woman of reproductive age with infertility issues?

Duration of Clomiphene Citrate in IVF Stimulation Protocols

Clomiphene citrate in IVF stimulation protocols is traditionally administered for 5 days at the beginning of the cycle (typically days 3-7), though recent evidence supports continuing CC throughout the entire stimulation period until trigger when used as an alternative to GnRH antagonists.

Standard 5-Day Protocol

The conventional approach involves:

• CC is administered for 5 consecutive days, typically starting on cycle day 3,4, or 5, with day 5 initiation showing optimal oocyte recovery in traditional protocols 1
• Gonadotropins are started simultaneously with CC and continued daily until hCG trigger 2, 3
• GnRH antagonist is added when the lead follicle reaches 14mm (typically around day 7-8) to prevent premature ovulation 2
• The standard dose is 50-150 mg daily for the 5-day period 4, 1, 2

Extended "Long CC" Protocol

A newer approach extends CC throughout stimulation:

• CC can be continued throughout the entire stimulation cycle until the day of trigger, eliminating the need for GnRH antagonist 5
• This extended protocol leverages CC's antiestrogenic mechanism to prevent LH surge and premature ovulation throughout the cycle 5
• Premature ovulation rates are significantly lower with extended CC (0.3%) compared to the 5-day CC plus antagonist protocol (3.0%) 5
• Mature oocyte yield remains equivalent between extended CC and standard 5-day CC plus antagonist protocols 5

Clinical Outcomes and Cost Considerations

Both protocols demonstrate comparable efficacy:

• Pregnancy rates are similar between CC-based protocols and standard high-dose gonadotropin protocols, with delivery rates of 3-5% per started cycle in women with diminished ovarian reserve 6
• CC protocols reduce gonadotropin consumption by 28-40%, with mean dose reductions of approximately 240 IU 2
• Cost savings are substantial, particularly in hyper-responders where stimulation costs decrease by 32-41% 2
• OHSS risk is reduced with CC protocols (3%) compared to standard long protocols (10%) 3

Safety Monitoring Requirements

Critical safety thresholds must be observed:

• Cancel the cycle if >2 follicles reach >15mm OR >5 follicles reach >10mm to prevent high-order multiple gestations 4, 7
• Avoid CC in patients with liver disease, especially decompensated cirrhosis, due to hepatotoxicity risk 4
• Trigger with hCG when at least 3 follicles reach >17mm with appropriately rising estradiol levels 7

Practical Algorithm

For standard ovarian reserve patients:

• Use 5-day CC protocol (days 3-7) with simultaneous gonadotropins and GnRH antagonist starting day 7-8 2

For diminished ovarian reserve patients:

• Consider extended CC protocol throughout stimulation to reduce costs and injection burden while maintaining equivalent outcomes 5
• Alternative: Use 5-day CC with high-dose gonadotropins (450 IU daily), which yields similar delivery rates to extended protocols 6

For all protocols:

• Gonadotropin doses of ≤75 IU are preferred for IUI with ovarian stimulation, though IVF protocols typically require higher doses 4
• Perform single insemination 24-40 hours post-hCG trigger 7