The effect of pharmacological cessation and restoration of menstrual cycle on bone metabolism in premenopausal women with endometriosis.

Abstract

GnRH-analogs induce bone loss. We aimed to investigate the effects of goserelin-induced menstrual cessation (MC) and subsequent menstrual restoration (MR) on bone metabolism (BM). In this prospective cohort study, premenopausal women (PMW) with histologically verified endometriosis (n=21) received goserelin monthly for 6months (6m) resulting in MC and were followed up for another 6m after MR (12m). Age- and BMI-matched healthy PMW (n=20) served as controls for bone mineral density (BMD) measurements. The primary endpoint was changes in lumbar spine (LS)-BMD at 6m and 12m; Secondary endpoints were changes in femoral neck (FN)-BMD, bone turnover markers (P1NP and CΤx), sclerostin, and expression of bone-related circulating microRNAs (miRNAs) at 6m and 12m. Goserelin-induced MC reduced LS- and FN-BMD at 6m (both p<0.001). From 6m to 12m, LS-BMD increased (p<0.001) but remained below baseline values (p=0.012), whereas FN-BMD remained stable (p=1.000). CTx and P1NP levels increased at 6m (both p<0.001) and decreased at 12m (p<0.001 and p=0.013, respectively), while CTx (p=1.000) alone and not P1NP (p=0.020) returned to baseline. Sclerostin levels did not change. Relative expression of miRNAs targeting RUNX 2 and beta-catenin was significantly downregulated at 6m compared to baseline (p<0.001), while the expression of miRNAs targeting osteoblast and osteoclast function at both directions demonstrated a robust increase (up to 400fold) at 12m (p<0.001). Six months of goserelin-induced MC lead to significant bone loss associated with increased bone turnover and changes in the expression of bone-related miRNAs, changes that are only partially reversed at 6m after MR.