GnRH Agonist Triggers Should NOT Be Used in IUI Cycles
Do not apply GnRH agonists or antagonists in IUI cycles with ovarian stimulation. 1 This is an explicit, evidence-based recommendation from international fertility guidelines that applies regardless of OHSS risk.
Clear Guideline Recommendation Against GnRH Agonist Use in IUI
The Human Reproduction Update systematic review and global recommendations explicitly state that addition of GnRH agonist to gonadotropins in IUI with ovarian stimulation is not recommended because there is no increase in pregnancy rate despite increased multiple pregnancy rates and increased costs. 1
The treatment algorithm for IUI clearly specifies:
- Tamoxifen, clomiphene citrate, or ≤75 IU gonadotropins per day can be used for ovarian stimulation 1
- Do not apply GnRH agonists or antagonists 1
Standard Triggering Protocol for IUI
The appropriate triggering method for IUI cycles is:
- Detect spontaneous LH surge OR trigger with hCG when 1-2 follicles are >15mm and <5 follicles are >10mm 1, 2
- Perform single IUI 24-40 hours after hCG trigger or 1 day after detection of spontaneous LH surge 1, 2, 3
- Standard hCG dose is 5,000 IU administered intramuscularly or subcutaneously 3
Why GnRH Agonists Are Reserved for IVF, Not IUI
GnRH agonist triggering is a strategy developed specifically for IVF cycles using GnRH antagonist protocols to prevent OHSS in high responders. 4, 5 The research evidence on GnRH agonist triggers exclusively addresses IVF/ICSI populations, not IUI. 6, 4, 7, 8, 5
Key distinctions:
- IVF allows freeze-all strategies after GnRH agonist trigger to eliminate luteal phase hCG exposure 6, 7
- IUI requires immediate luteal support and cannot employ freeze-all approaches
- GnRH agonist triggers cause luteal phase deficiency requiring rescue protocols that reintroduce OHSS risk 8
OHSS Prevention in IUI: The Correct Approach
If concerned about OHSS risk in IUI cycles, the evidence-based prevention strategy is:
- Cancel the cycle, aspirate excess follicles, or convert to IVF when >2 follicles >15mm OR >5 follicles >10mm are present 1, 2, 9
- Use low-dose gonadotropins (≤75 IU/day) rather than higher doses 1, 9
- Consider clomiphene citrate or tamoxifen as alternatives with lower multiple pregnancy rates 1, 9
The multiple pregnancy risk increases dramatically with multifollicular development: 6% with 2 dominant follicles, 14% with 3 follicles, and 10% with 4 follicles. 1 Primary prevention through cycle cancellation is the appropriate strategy, not GnRH agonist triggering. 1, 2, 9
Critical Caveat About GnRH Agonist Trigger Limitations
Even in IVF cycles where GnRH agonist triggers are appropriate, severe OHSS can still occur despite this strategy. 6, 8 Research shows that 26% of high-risk patients developed severe OHSS even after GnRH agonist trigger plus 1500 IU hCG luteal rescue. 8 This underscores that GnRH agonist triggering is not a foolproof OHSS prevention method and should not be extrapolated to IUI protocols where it has no established role.