When Is the Right Time to Trigger?

The Science of Follicle Size, Final Oocyte Maturation, and the Dual Trigger Strategy

Once the developing follicular cohort has reached an appropriate stage, a trigger injection is administered to initiate the final stages of oocyte maturation. This is one of the most precisely timed steps of an IVF cycle, as the trigger promotes resumption of oocyte meiosis and prepares mature oocytes for retrieval.

The trigger may contain human chorionic gonadotropin (hCG), a GnRH agonist, or, in selected patients, a combination of the two, known as a dual trigger. hCG binds to the LH receptor and provides a relatively prolonged LH-like signal that promotes final oocyte maturation. A GnRH agonist trigger, when used in an antagonist cycle, stimulates the pituitary gland to produce a short endogenous surge of both LH and FSH.

A dual trigger therefore combines hCG with a GnRH agonist, with the aim of benefiting from both the endogenous LH/FSH surge produced by the agonist and the more sustained LH-receptor activity provided by hCG. This approach is often considered in selected patients, particularly when a previous cycle has resulted in a lower-than-expected number of mature (MII) oocytes, a relatively low oocyte yield compared with the number of developed follicles, or other evidence of suboptimal final oocyte maturation.

There is clinical evidence supporting this approach in selected patients. A systematic review and meta-analysis of randomized controlled trials by Hu et al. (2021), “GnRH agonist and hCG (dual trigger) versus hCG trigger for follicular maturation,” analyzed 1,048 IVF patients. Compared with hCG alone, dual triggering was associated with approximately 1.5 additional retrieved oocytes, one additional mature oocyte, more fertilized oocytes and usable embryos, as well as a higher live birth rate in the pooled analysis. These findings are encouraging, although they do not mean that a dual trigger is necessary or superior for every patient.

When Do We Trigger?

Follicle size is one of the most important factors used to determine when final oocyte maturation should be triggered, but there is no single follicle diameter that is optimal for every woman.

In a conventional ovarian stimulation cycle, we generally aim for most of the clinically relevant follicles to be approximately 16–21 mm when the trigger is administered. This is broadly consistent with international IVF practice, where triggering commonly occurs once several of the leading follicles are approximately 16–22 mm.

However, the relationship between follicle size and oocyte maturity is more complex than simply assuming that “larger is better.” The optimal timing may be different in women with diminished ovarian reserve, previous poor ovarian response, or more advanced reproductive age, particularly when there is concern about premature luteinization or ovulation.

A 2025 study titled “Determination of the optimal follicle size at the time of trigger in patients with diminished ovarian reserve undergoing ICSI cycle” examined 430 individual follicles from 98 women with diminished ovarian reserve. Follicles measuring 15–17 mm demonstrated an oocyte retrieval rate of 88.1%, an MII maturity rate of 83.3%, a fertilization rate of 97.1%, and a top-quality embryo rate of 65.4%, significantly better overall outcomes than follicles measuring either 11–14 mm or ≥18 mm. Importantly, premature ovulation occurred in 13.3% of the initially scheduled patients, and the mean leading follicle size among those experiencing premature ovulation was 18.6 mm.

The same study found that women who experienced premature ovulation had significantly lower AMH and higher FSH levels, supporting the concept that diminished ovarian reserve may be associated with different follicular behavior and potentially earlier readiness for final maturation. Interestingly, the favorable 15–17 mm range was observed in both younger and older women with diminished ovarian reserve, suggesting that ovarian reserve and follicular behavior may be more important than having a universal size for follicles when determining trigger timing.

Similar findings were reported by Lawrenz et al. (2024) in the study “Do women with severely diminished ovarian reserve undergoing modified natural-cycle in-vitro fertilization benefit from earlier trigger at smaller follicle size?” In women with severely diminished ovarian reserve, triggering at follicle sizes of 15 mm or smaller significantly reduced the risk of premature ovulation and cycle cancellation compared with waiting for larger follicles. Importantly, earlier triggering did not significantly reduce the likelihood of retrieving a mature oocyte. Among cycles in which an oocyte was retrieved, maturity rates were approximately 92% for follicles measuring 13–15 mm and 15–17 mm, compared with approximately 59% when follicles were allowed to grow beyond 17 mm in their sensitivity analysis. The authors concluded that waiting for follicles to exceed 17 mm may actually be disadvantageous in some women with severely diminished ovarian reserve.

There is also evidence that women with reduced ovarian reserve are more susceptible to a premature LH surge, even when a GnRH antagonist is being used. A study titled “Diminished Ovarian Reserve Predisposes to Premature Luteinizing Hormone Surges in Gonadotropin-Releasing Hormone Antagonist Cycles in In Vitro Fertilization” found that patients experiencing premature LH surges were generally older and had higher baseline FSH, lower AMH and lower antral follicle counts than unaffected patients.

These findings are consistent with what we have observed in our own clinical practice. In selected patients, particularly women with diminished ovarian reserve, previous evidence of early luteinization, or a history suggesting that their oocytes mature at smaller follicular diameters, we will consider triggering somewhat earlier, sometimes when the majority of the clinically relevant follicular cohort is approximately 14–18 mm, rather than waiting for most follicles to reach the conventional larger range.

This does not mean that all older women or all women with diminished ovarian reserve should be triggered early. Trigger timing must remain individualized. Triggering too early can result in a greater proportion of immature oocytes, just as triggering too late may increase the risk of premature luteinization or ovulation in susceptible patients.

For this reason, we do not make the decision according to follicle size alone. We consider the number and distribution of follicle sizes,

patient age,
AMH and antral follicle count,
previous IVF response, duration of stimulation,
previous oocyte maturity rates and,
serum estradiol, LH and progesterone levels.

The objective is not necessarily to produce the largest possible follicles, but to identify the point at which the greatest proportion of the available oocyte cohort is likely to have reached developmental competence without waiting unnecessarily long.

Timing of Egg Retrieval

Once the trigger injection has been administered, timing becomes extremely important. Egg retrieval is usually scheduled approximately 35–36 hours later, providing sufficient time for final oocyte maturation while aiming to retrieve the oocytes before spontaneous follicular rupture and ovulation occur.

For this reason, the trigger injection should be administered at precisely the time instructed by the medical team. Even a well-designed stimulation cycle can be compromised if the trigger is administered substantially earlier or later than scheduled.

The follicle sizes and timing discussed above should therefore be regarded as clinical reference ranges rather than fixed rules. Different patients and sometimes different cycles in the same patient can demonstrate different patterns of follicular growth and oocyte maturation. The final decision regarding trigger type and timing should always be individualized according to the complete clinical picture.

Dr. Ahmet Ozyigit,
MD, MSc, PgDip, FAAMM, ABAARM

Elite Hospital

References:

1. Hu KL, Wang S, Ye X, Zhang D, Hunt S. GnRH agonist and hCG (dual trigger) versus hCG trigger for follicular maturation: a systematic review and meta-analysis of randomized trials. Reproductive Biology and Endocrinology. 2021;19:78. DOI: 10.1186/s12958-021-00766-5.

2. Naghshineh E, Ghasemi Tehrani H, Mehrabian F, Mardanian F, Rezaei M.

Determination of the optimal follicle size at the time of trigger in patients with diminished ovarian reserve undergoing ICSI cycle. Journal of Ovarian Research. 2025;18(1):284. DOI: 10.1186/s13048-025-01873-2.

3. Lawrenz B, Kalafat E, Ata B, Melado L, Del Gallego R, Elkhatib I, Fatemi H.

Do women with severely diminished ovarian reserve undergoing modified natural-cycle in-vitro fertilization benefit from earlier trigger at smaller follicle size? Ultrasound in Obstetrics & Gynecology. 2024;64(2):245–252. DOI: 10.1002/uog.27611.

4. Kochhar PK, Ghosh P. Diminished Ovarian Reserve Predisposes to Premature Luteinizing Hormone Surges in Gonadotropin-Releasing Hormone Antagonist Cycles in In Vitro Fertilization. Journal of Human Reproductive Sciences. 2020;13(3):191–195. DOI: 10.4103/jhrs.JHRS_133_19