Can adding Clomiphene Citrate (CC) 100mg to Gonadotropins (Gn) reduce the dose of Gn required for adequate ovarian stimulation in a woman of reproductive age undergoing an In Vitro Fertilization (IVF) cycle?

Adding Clomiphene Citrate 100mg to Gonadotropins in IVF: Dose Reduction Potential

Adding clomiphene citrate 100mg to gonadotropins in IVF cycles can reduce the total gonadotropin dose required, but this approach is NOT recommended for standard IVF protocols and should be reserved only for poor responders who have failed previous conventional stimulation cycles. 1

Evidence Against Routine Use in Standard IVF

The available guideline evidence addresses clomiphene citrate primarily in the context of IUI (intrauterine insemination), not IVF cycles. In IUI protocols, clomiphene citrate (100mg daily for 5 days) is positioned as an alternative to gonadotropins rather than an adjunct, with the explicit trade-off of lower live birth rates despite reduced costs and lower multiple pregnancy rates. 1

Critical distinction: The guidelines do not support combining CC with gonadotropins in standard IVF for the general population. 1

Evidence for Poor Responders Only

Gonadotropin Dose Reduction

• Yes, CC 100mg does reduce gonadotropin requirements in poor responders, but with important caveats. 2, 3, 4
• In poor responders, adding CC 100mg (days 3-7) to gonadotropin protocols resulted in similar oocyte yields while using significantly less gonadotropin medication. 2, 4
• One randomized trial showed that 150 IU gonadotropins plus CC 100mg produced more blastocysts than 450 IU gonadotropins plus CC (1.77 vs 0.83 blastocysts, P=0.006), suggesting better oocyte quality with lower gonadotropin doses when CC is added. 4

Clinical Outcomes Remain Uncertain

• The most recent high-quality evidence (2017 Cochrane review) found no conclusive difference in live birth rates between CC/letrozole protocols combined with gonadotropins versus gonadotropins alone in either general IVF populations or poor responders. 5
• For poor responders specifically: live birth rate showed no significant difference (RR 1.16,95% CI 0.49-2.79), meaning outcomes ranged from 2% to 14% compared to 5% with standard protocols. 5
• Clinical pregnancy rates were also similar (RR 0.85,95% CI 0.64-1.12) in poor responders. 5

Major Drawbacks of CC Addition

Increased Cycle Cancellation

• Significantly higher cycle cancellation rates occur with CC protocols compared to standard gonadotropin protocols in both general populations (RR 1.87,95% CI 1.43-2.45) and poor responders (RR 1.46,95% CI 1.18-1.81). 5
• This represents a 46-87% increase in the likelihood of cycle cancellation, which is clinically significant for patient burden and cost-effectiveness. 5

Reduced Oocyte Yield

• Fewer oocytes are retrieved with CC protocols, though this may be acceptable in poor responders who already have limited ovarian reserve. 5, 6

Endometrial Effects

• Reduced endometrial thickness was observed in groups receiving CC, which could negatively impact implantation. 4
• This anti-estrogenic effect on the endometrium is a well-known limitation of clomiphene citrate. 4

Practical Algorithm for Decision-Making

DO NOT use CC + gonadotropins if:

• Patient is a normal responder to standard IVF stimulation 5
• Patient has adequate ovarian reserve 5
• This is the patient's first IVF cycle 5

CONSIDER CC 100mg + reduced gonadotropins (150 IU) if:

• Patient meets Bologna criteria for poor ovarian response 4
• Patient has failed previous conventional gonadotropin-only IVF cycles 2, 6
• Cost of gonadotropins is a significant barrier 3, 5
• Patient accepts higher cycle cancellation risk in exchange for lower medication costs 5

Specific Protocol When Used:

• CC 100mg daily from cycle day 3-7 2, 4
• Start gonadotropins at 150 IU daily (not 450 IU) for better blastocyst formation 4
• Use GnRH antagonist protocol 2, 4
• Monitor FSH levels: high-dose gonadotropins (450 IU) produce elevated FSH without improving oocyte yield 4
• Plan for fresh transfer in same cycle if possible, as frozen embryo transfer cumulative rates may be lower 3, 5

Critical Caveats

The evidence quality is low to moderate for all outcomes related to CC in IVF, with most studies underpowered to detect differences in live birth rates. 5

Long-term safety data are lacking, particularly regarding fetal abnormalities following CC protocols in IVF. 5

The reduction in OHSS risk seen with CC protocols in IUI (Peto OR 0.21) has not been definitively demonstrated in IVF populations. 5

Bottom line: While CC 100mg can reduce gonadotropin dose requirements, it does not improve—and may worsen—the outcomes that matter most (live birth rate, cycle cancellation rate). Reserve this approach exclusively for poor responders who have exhausted standard options. 5, 4