INS and obesity due to melanocortin 4 receptor deficiency: Therefore, we suggest that the primary pathogenetic defects in PCOS could be an intrinsic abnormal insulin responsiveness in the ovary, leading to increased androgen synthesis altogether with reduced estrogen availability; meanwhile, other systemic factors (insulin resistance, deregulation of the hypothalamic-pituitary-axis, and obesity, just to mention a few) can potentiate this mechanism and exacerbate the overall clinical picture.