Increasing recombinant hCG doses during ovarian stimulation paradoxically reduced blastocyst quality and pregnancy rates

The Luteinizing Hormone Receptor (LHR) is crucial for regulating human follicular development and steroidogenesis, with temporal and cell-specific expression on theca cells (TCs) and granulosa cells (GCs). While LH-like activity (LH and/or hCG) is a staple in ovarian stimulation (OS) regimens, its precise physiological role in human folliculogenesis remains poorly defined. Recent large randomized clinical trials (RCTs) have shown inconsistent benefits of exogenous LH-like activity, highlighting a significant gap in understanding LHR-mediated actions in normo-gonadotropic women.

This paper provides a new mechanistic interpretation of published data from the Rainbow RCT. The original Rainbow RCT evaluated the effect of increasing doses of recombinant hCG (rhCG) as LH-like activity co-administered with recombinant FSH (rFSH) during ovarian stimulation (OS). The trial assessed reproductive outcomes, specifically the number of good-quality blastocysts and ongoing pregnancy rates, alongside various endocrine patterns. This re-analysis aims to formulate a hypothesis explaining the observed divergent hormonal responses and reproductive outcomes.

The re-interpretation of the Rainbow RCT data revealed significant, dose-dependent effects of rhCG co-administration. Increasing doses of rhCG led to a dose-dependent reduction in both the number of good-quality blastocysts and ongoing pregnancy rates. This was accompanied by paradoxical endocrine patterns. Androstenedione, 17-OH-progesterone (17OH-P4), testosterone, and oestradiol (E2) all increased dose-dependently. Conversely, progesterone (P4), inhibin-A, and inhibin-B declined. > These findings suggest an attenuation of GC function exerted by rhCG, despite preserved or even enhanced TC activity, indicating fundamental differences in LHR expression, density, and downstream signaling between GCs and TCs during OS.