ESTROGEN, PROGESTERONE, AND MOLECULAR SIGNALING PATHWAYS IN THE DEVELOPMENT OF UTERINE LEIOMYOMAS: AN INTEGRATIVE REVIEW OF MECHANISMS, CLINICAL EVIDENCE, REAL-WORLD DATA, AND TRANSLATIONAL PERSPECTIVES

Abstract

Uterine  leiomyomas  are  benign  monoclonal  tumors  whose  development  depends on the integration of ovarian steroid signaling, acquired molecular lesions, fibrotic  extracellular-matrix  remodeling,  and  interactions  between  differentiated  tumor  cells  and  tumor-associated stem or progenitor populations. Estrogen is not merely a direct mitogen:  it  supports  progesterone  receptor  expression  and  alters  the  microenvironment  in  which  progesterone-dependent  growth  signals  operate.  Objective:  To  critically  integrate  the  mechanistic literature on estrogen, progesterone, MED12, HMGA2, WNT/β-catenin, TGF-β/SMAD,  PI3K/AKT/mTOR,  MAPK,  and  mechanotransduction  with  evidence  from  clinical  therapeutics  and  emerging  real-world  analytics.  Methods:  A  structured,  nonsystematic  evidence  synthesis  was  organized  around  landmark  experimental  research,  contemporary clinical reviews, regulator guidance, trial evidence, and digital health policy.