ArticleFrontiers in endocrinology2026
Follicular development during the follicular phase of the menstrual cycle: the enigma of luteinizing hormone receptor function.
Article in Frontiers in endocrinology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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 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 Clinical Trial Registration: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-003810-13/results, identifier 2017-003810-13.
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