Permissive but not causative: layer-specific LHCGR alterations in ovarian aging

Abstract The ovary is among the earliest organs to show clinically consequential age-related decline. The luteinizing hormone/choriogonadotropin receptor (LHCGR) mediates the trophic actions of LH and human chorionic gonadotropin (hCG) in the ovary, and reduced receptor abundance has sometimes been invoked as a possible explanation for age-related loss of LH responsiveness. Through a focused PubMed-based narrative search we identified five human studies that quantified ovarian LHCGR in relation to age, ovarian reserve, stimulation response or premature luteinization. No study demonstrated a uniform decline in LHCGR across follicle stages or regulatory layers. Available studies tend to report higher transcript or total-protein abundance in granulosa cells from older women and from women with diminished ovarian reserve, whereas one study reported a disrupted stage-dependent profile of cell-surface density, with no decline in the largest post-trigger follicles. These layers were measured in different cohorts on different platforms, and never together in the same samples. We therefore advance a trafficking hypothesis rather than a demonstrated mechanism: a transcriptomic profile compatible with premature luteinization may be superimposed on disordered stage-dependent surface presentation. That dissociation is compatible with altered receptor trafficking, but also with differences in stimulation protocol, sampling time and follicle stage. The hypothesis concerns late follicular competence and LH responsiveness rather than follicle-pool depletion, and it positions LHCGR as permissive for late follicular function rather than causative for ovarian aging. It specifies a decisive experiment: simultaneous transcript and surface-protein measurement at matched follicle stages, with mural granulosa and theca analyzed separately. It motivates prospective evaluation of biomarkers for stratified LH supplementation in assisted reproductive technology rather than any change in current practice.