HIDDEN PHENOTYPES: A SYSTEMATIC REVIEW OF DIAGNOSTIC DELAYS, PATHOPHYSIOLOGY, AND TARGETED THERAPIES IN LEAN POLYCYSTIC OVARY SYNDROME

Abstract

Polycystic Ovary Syndrome (PCOS)—recently redefined in global consensus statements as Polyendocrine Metabolic Ovarian Syndrome (PMOS)—is typically characterized in clinical literature by its strong association with obesity and insulin resistance. However, a significant subset of patients (20–30%) present with a normal or low body mass index (BMI), defining the "lean PCOS" phenotype. This cohort experiences extensive diagnostic delays, often spanning 5 to 15 years, due to clinical biases that overlook non-obese phenotypes and the diagnostic mimicry of pubertal maturation. Pathophysiologically, lean PCOS is distinctly driven by reproductive neuroendocrine aberrations, primarily a profound acceleration in gonadotropin-releasing hormone (GnRH) pulse frequency and a subsequent increase in pulsatile luteinizing hormone (LH) secretion, operating independently of weight-induced metabolic syndrome. Although insulin resistance exists in lean phenotypes, it remains predominantly tissue-specific or visceral rather than systemic. Standard therapies, such as non-targeted combined oral contraceptive pills (COCPs), frequently mask symptoms while exacerbating subclinical metabolic profiles or inducing hypothalamic-pituitary-ovarian axis suppression. This systematic review synthesizes recent clinical trials and mechanistic insights to delineate the neuroendocrine and metabolic pathways of lean PCOS, quantifies the drivers of clinical diagnostic delays, and provides an evidence-based framework for targeted, phenotype-specific therapeutic interventions.