Prevalence of an endogenous LH rise following final GnRH antagonist dose in the IVF antagonist protocol

The GnRH antagonist protocol is widely used in IVF/ICSI treatments. It involves daily injections of a GnRH antagonist starting on stimulation day 5 or later to prevent premature ovulation by suppressing the endogenous gonadotropin surge, continuing until hCG is administered to trigger final follicle maturation. Although the protocol is designed to control the timing of ovulation and prevent spontaneous ovulation, the frequency and impact of an endogenous LH rise occurring between the hCG trigger and oocyte pick-up have not been extensively studied.

This was a prospective, non-blinded, observational study of 100 women conducted at two fertility clinics in Denmark between January 2023 and June 2024. All patients underwent standard IVF/ICSI treatment using the fixed GnRH antagonist protocol, with hCG (Ovitrelle® 250 µg/6500 IU) administered to trigger ovulation. Three blood samples were collected after the final GnRH antagonist dose: 1) on the day of hCG trigger, 2) the day after the trigger, and 3) on the day of oocyte pick-up. Plasma concentrations of LH, FSH, hCG, progesterone, and estradiol were measured. An LH concentration > 10 IU/L was used to define an LH rise. During oocyte pick-up, follicular fluid was aspirated to measure LH concentrations within the follicles. The main outcome was the frequency of cycles with an endogenous LH rise after the last GnRH antagonist administration.

An endogenous LH rise on the day after hCG trigger, when the effect of the GnRH antagonist is expected to be decreasing, was observed in 17% of women treated with the fixed GnRH antagonist protocol. These cycles were characterised by a shorter duration of GnRH antagonist administration, lower progesterone levels from trigger day to oocyte pick-up, and fewer oocytes retrieved, despite similar ovarian reserve markers at baseline. The fertilization rate and the number of day 2 embryos per oocyte retrieved were significantly higher in the group with an endogenous LH rise. As samples were collected only once daily, a true LH surge cannot be confirmed.

Further research powered to look at specific GnRH antagonist regimens are needed to validate these findings and assess whether an endogenous LH rise influences important outcomes such as pregnancy and live birth rates.