Follicular development during the follicular phase of the menstrual cycle: the enigma of luteinizing hormone receptor function

Background The luteinizing hormone receptor (LHR) plays a pivotal role in regulating human follicular development and steroidogenesis through temporal and cell-specific expression on theca (TCs) and granulosa cells (GCs). Although LH-like activity (i.e., LH and/or human chorionic gonadotropin (hCG)) has long been incorporated into ovarian stimulation (OS) regimens, its precise physiological role in human folliculogenesis remains poorly defined. Recent large randomised clinical trials (RCT) have failed to demonstrate a consistent benefit of exogenous LH-like activity during OS, suggesting incomplete understanding of LHR-mediated actions in normo-gonadotropic women. Objective To provide a new mechanistic interpretation of the published data from the Rainbow RCT (Fernández Sánchez et al., 2022 (9)), which evaluated the effect of increasing doses of recombinant hCG (rhCG) as LH-like activity co-administration during OS, and to formulate a hypothesis that explains its divergent hormonal responses and reproductive outcomes. Outcome of the Rainbow trial In the Rainbow RCT, increasing doses of (rhCG) added to recombinant FSH (rFSH, i.e., rFSH-Δ) resulted in a dose-dependent reduction in the number of good-quality blastocysts and ongoing pregnancy rates, as well as paradoxical endocrine patterns. Androstenedione, 17-OH-progesterone (17OH-P 4 ), testosterone, and oestradiol (E 2 ) increased dose-dependently, whereas progesterone (P 4 ), inhibin-A, and inhibin-B declined. Hypothesis These findings suggest attenuation of GC function exerted by rhCG despite preserved or enhanced TC activity. The divergent hormonal responses observed reflect fundamental differences in LHR expression, density, and downstream signalling between GCs and TCs. During OS, FSH induces LHR expression in GCs, potentially leading to distinct receptor clustering and susceptibility to biased agonism by different LH or hCG isoforms. Constant exposure to rhCG—as opposed to the physiological pulsatile LH pattern—may further alter receptor dynamics, contributing to selective attenuation of GC-function whilst maintaining TC responsiveness. Conclusion The Rainbow RCT may offer the first in vivo evidence supporting a temporal and cell type–specific difference in LHR function in human TCs and GCs. These data call for renewed investigation into LHR regulation, glycosylation, and receptor density in human immature GC and TC under both natural and stimulated conditions. Clarifying these mechanisms will be essential to optimizing gonadotropin combinations for OS and to advancing understanding of ovarian physiology. Clinical Trial Registration https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-003810-13/results , identifier 2017-003810-13.