Speaker George Lianas

The conference video on precise ovulation highlighted the significant challenges faced by couples undergoing fertility treatments. Each failed embryo transfer or stimulation cycle took a heavy emotional and financial toll, causing many to give up. After the first attempt, 10% of couples stopped trying, and by the fourth failed cycle, 62% abandoned their efforts to start a family. Success in IVF (In-vitro Fertilization) was closely linked to the number of oocytes retrieved and follicle size, factors now well-established in reproductive medicine.

Ernesto Boss's recent study reveals that as women age, more mature oocytes are needed to obtain at least one diploid blastocyst. The timing of final oocyte maturation is crucial, affecting outcomes such as the number of cumulus-oocyte complexes retrieved and the fertilization rate. Guidelines vary widely on the optimal follicle size for triggering maturation, leading to retrieval rates ranging from 50% to 90%. Despite ongoing debate, there is no consensus on the best criteria for maximizing oocyte retrieval, highlighting ongoing challenges in clinical practice.

Current triggering criteria for final oocyte maturation, recommended by ESRI (European Society of Reproduction and Embryology), advise triggering when leading follicles measure between 16 and 22 mm. This guideline is based on older studies showing that smaller follicles correlate with lower oocyte recovery, maturity, and fertilization rates, observed from natural cycle data where most follicles rupture at 17 to 25 mm. Early research by Professor Edwards supported this, noting that larger follicles are easier to puncture and yield more mature oocytes, a finding backed by laparoscopic methods in 1989 by Scott's group. They found that follicles under 11 mm were harder to recover, and those under 14 mm were less likely to mature. Recent studies confirm these trends, with smaller follicles showing lower retrieval and maturity rates despite equal fertilization and blastulation rates and the production of high-quality embryos. 

A recent study found that smaller follicles had a 60% retrieval rate and lower maturity but similar fertilization and blastulation rates compared to larger follicles, suggesting they should be punctured. Larger follicles showed slightly reduced retrieval and fertilization rates but produced quality blastocysts. It indicates that cumulus-oocyte complexes (COCs) from smaller follicles are less likely to be retrieved and mature, while very large follicles may exhibit lower fertilization rates. In 2024, the focus on PGD (Preimplantation Genetic Diagnosis) cycles and euploidy prompts questions about the ploidy of oocytes from different follicle sizes. 

A study of 22 donors with 3,330 oocytes from cycles found that follicle size strongly predicts maturity but not blastulation or euploidy. Large and small follicles had equal chances of producing euploid oocytes, emphasizing the importance of retrieving from all sizes to maximize euploid embryo potential. Another study in "Fertility and Sterility" confirmed that euploid blastocysts can develop from follicles above 12 mm, suggesting that follicle size alone should not dictate oocyte retrieval criteria. These findings advocate for adjusting triggering criteria to include follicles over 12 mm to enhance the yield of usable and euploid embryos. 

When a large leading follicle (20 mm) and smaller ones (around 10 mm) are present, delaying the hCG (Human Chorionic Gonadotropin) trigger to let smaller follicles grow can have mixed outcomes. Extending the trigger by one day, after having three follicles at 16 mm, increased mature oocytes without affecting fertilization or pregnancy rates. However, a two-day delay led to more follicles over 11 mm and 17 mm but reduced ongoing pregnancy rates due to endometrial advancement from higher progesterone levels. The solution is the freeze-all approach, freezing embryos for future transfer to avoid these issues.

In 2018, 50% of US cycles were fresh, and 50% were freeze-all. This shift highlights the need to reassess triggering criteria, especially with PGT (Preimplantation Genetic Testing) and oocyte cryopreservation. Accurate 2D ultrasound measurements of follicles are crucial but variable, with more than 20% measurement inconsistency. Follicles grow about 2 mm daily, complicating timing. Although 3D measurements show promise, they haven't proven superior. Future RCTs (Randomized Controlled Trials) should compare volumetric criteria to optimize triggering. AI may aid in determining optimal follicle size for triggering, which is crucial for cumulus-oocyte complex disruption, meiotic maturation, and granulosa cell luteinization. 

Glycoprotein, i.e., HCG, was discovered in 1931 and is known to trigger ovarian hyperstimulation syndrome (OHSS). Lower doses of HCG were tested in an RCT with 80 PCOS (Polycystic Ovary Syndrome) women but showed no significant reduction in OHSS rates. Given the risk, including three maternal deaths per 100,000 IVF cycles, reducing OHSS remains critical. Professor Grisiger noted that having over 18 follicles on triggering day poses a high OHSS risk, suggesting pre-stimulation risk assessments. GnRH (Gonadotropin-Releasing Hormone) agonists, with higher affinity for GnRH receptors, offer a safer alternative to eliminate OHSS. 

The optimal dose of GnRH agonist for triggering oocyte maturation was compared across 0.1, 0.2, and 0.4 mg of triptorelin, showing no differences in outcomes. GnRH agonist triggers had a 0% OHSS incidence in high-risk patients but resulted in lower live birth rates for fresh transfers due to luteal phase issues. Guidelines recommend using GnRH agonist triggers without fresh transfers to avoid OHSS. Dual triggers (hCG + GnRH agonist) increased live birth rates but also the risk of OHSS, which can be as high as 10%. To avoid OHSS, luteal phase rescue is suggested, though insufficient LH exposure can affect oocyte recovery and maturation. The HCG levels after triggering should be between 48 and 249 to be considered normal. Levels below this indicate an insufficient trigger.

Similarly, after a GnRH agonist trigger, LH levels should be above 15. Levels below this can lead to poor outcomes, including lower retrieval rates. Retrospective studies have explored dual triggers (HCG + GnRH agonist) to improve maturation, recovery, and fertilization rates, with some showing beneficial effects. 

Empty follicle syndrome (EFS) has an incidence ranging from 0.005% to 3.5% in the literature. It is often attributed to genuine EFS, where HCG or GnRH agonist levels are evaluated. Only 43 case reports, primarily from observational studies, suggest EFS might not exist. Dual trigger cannot be recommended according to stimulation guidelines until RCT data on efficacy and safety are available.

The optimal interval between the trigger signal and oocyte retrieval has been investigated. No significant difference was found between 36 and 38 hours for HCG, indicating the retrieval time within this range does not impact oocyte retrieval rates. For GnRH agonist triggers, 36 hours was found to be inappropriate, with significantly lower numbers of collected and mature oocytes, suggesting the need for further evaluation of the timing in antagonist cycles.

The conclusion states that the timing of triggering final site maturation is largely empirical; future RCTs should investigate the optimal timing for different interventions. Aiming for follicles greater than 12 mm appears to contribute to the number of COCs, MII, and euploid embryos. GnRH agonist for triggering final oocyte maturation is equally effective as HCG with regards to embryological parameters eliminates the risk of loss and appears to be the golden trigger in high-risk patients, dual trigger after GnRH agonist triggering rescue luteal phase but re-introduces OHSS. 

European Society of Human Reproduction and Embryology, July 7-10, Amsterdam, The Netherland