Gonadotropin-Releasing Hormone Protocols in Assisted Reproductive Technologies

Gonadotropin-releasing hormone (GnRH) protocols are central to controlled ovarian stimulation in assisted reproductive technologies. Two principal approaches exist: GnRH agonist regimens that induce an initial pituitary flare followed by down-regulation, and GnRH antagonist regimens that provide rapid suppression of luteinising hormone (LH) surges. Agonist long protocols have long been used to synchronise follicular recruitment and reduce the risk of premature ovulation, but they entail extended treatment duration and increased gonadotrophin requirements. Antagonist protocols offer a shorter, more cost-effective stimulation with a lower incidence of ovarian hyperstimulation syndrome and fewer injections, at the expense of altered follicular kinetics and potential effects on endometrial receptivity. Recent advances include flexible dosing strategies, individualised antagonist initiation based on follicle size or hormonal thresholds, and half-dose antagonist regimens aimed at reducing endometrial exposure. Optimisation of protocol choice according to ovarian reserve, patient age and clinical priority has improved live birth rates while minimising complications.

Research from Nature Portfolio

Recent studies have delved into the molecular impact of antagonist protocols on endometrial receptivity. Analysis of endometrial gene expression during the implantation window revealed that antagonist use upregulates genes linked to natural killer cell-mediated cytotoxicity. Elevated uterine natural killer cell numbers and increased perforin expression were noted in antagonist cycles, suggesting a dose-dependent modulation of the local immune environment. These findings provide mechanistic insight into the subtle alterations in endometrial function associated with antagonist use and may inform future strategies to balance ovarian suppression with optimal endometrial preparation.

Gonadotropin-Releasing Hormone Protocols in Assisted Reproductive Technologies publication trend

The graph below shows the total number of articles in gonadotropin-releasing hormone protocols in assisted reproductive technologies across all publications each year (not limited to Nature Index journals).

Technical terms

Gonadotropin-releasing hormone (GnRH): A hypothalamic decapeptide that regulates pituitary secretion of follicle-stimulating hormone and luteinising hormone.

GnRH agonist protocol: A stimulation regimen using GnRH analogues to initially stimulate, then down-regulate pituitary gonadotrophins over several weeks.

GnRH antagonist protocol: A regimen employing competitive GnRH analogues to rapidly inhibit LH surges during late follicular development.

Controlled ovarian stimulation (COS): The use of exogenous gonadotrophins, often with GnRH analogues, to recruit multiple follicles for oocyte retrieval.

Premature luteinising hormone (LH) surge: An early, endogenous peak of LH before intended ovulation trigger, potentially leading to cycle cancellation.

Endometrial receptivity: The capacity of the uterine lining to allow embryo attachment and implantation during a defined ‘window of implantation’.

References

1. Effect of Flexible Half-Dose Gonadotropin-Releasing Hormone Antagonist Protocol on in vitro Fertilization Outcome in Predicted Normal Responder: A Study Protocol for a Multicentered, Randomized, Non-Inferiority, Parallel Controlled Trial. Drug Design Development and Therapy (2023).
2. Optimal timing of GnRH antagonist initiation in IVF-ET: a retrospective cohort study on advanced maternal age women. Frontiers in Endocrinology (2024).
3. A premature luteinizing hormone surge without elevated progesterone levels has no adverse effect on cumulative live birth rate in patient undergoing a flexible GnRH antagonist protocol: a retrospective study. Journal of Ovarian Research (2023).
4. Increased Uterine NK cell numbers and perforin expression during the implantation phase in IVF Cycles with GnRH Antagonist Protocol. Scientific Reports (2017).