Estrogen and Androgen Receptor Status in Uterosacral Ligaments of Women with Pelvic Organ Prolapse Stratified by the Pelvic Organ Prolapse Histology Quantification System

Menopause is a significant risk factor for pelvic organ prolapse (POP), suggesting that ovarian sex steroids play a major role in the etiology of the condition. POP results from failure of the uterine-cervix-vagina support structures, including the uterosacral ligament (USL). We previously identified consistent degenerative USL phenotypes that occur in POP and used their characteristics to develop a standardized POP Histologic Quantification System (POP-HQ). In this study, POP and matched control USL tissue was first segregated into the unique POP-HQ phenotypes, and specimens were then compared for estrogen receptor (ER) alpha (ERα), ERbeta (ERβ), the G-protein estrogen receptor (GPER), and androgen receptor (AR) content via immunohistochemical staining. ER and AR expression levels in the control USL tissues were indistinguishable from those observed in the POP-A phenotype, and partially overlapped with those of the POP-I phenotype. However, control-USL steroid receptor expression was statistically distinct from the POP-V phenotype. This difference was driven mainly by the increased expression of GPER and AR in smooth muscle, connective tissue, and endothelial cells, and increased expression of ERα in connective tissue. These findings support a multifactorial etiology for POP involving steroid signaling that contributes to altered smooth muscle, vasculature, and connective tissue content in the USL. Furthermore, these data support the concept that there are consistent and distinct degenerative processes that lead to POP and suggest that personalized approaches are needed that target specific cell and tissues in the pelvic floor to treat or prevent this complex condition. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43032-023-01283-z.