Endometriosis is a relatively frequent pathology in gynecological practice. We performed an analysis to demonstrate the molecular changes that occur in endometriosis synthetic progestin-treated patients, hoping to sketch a possible pathophysiological pathway that will help us to better understand and treat this debilitating disease. We conducted a prospective study that included a group of 40 women, evaluated in our hospital between 2020-2021. We evaluated immunohistochemical tissue expression of estrogen receptor (ER), progesterone receptor (PR), B-cell lymphoma 2 (Bcl-2) protein, Ki-67, and serum levels of osteopontin (OPN) and vascular endothelial growth factor (VEGF) in patients with ovarian endometrioma with and without progestin treatment. Our study revealed that Desogestrel treatment increases OPN serum levels, PR and Bcl-2 tissue expression and reduces VEGF serum levels and Ki-67 tissue expression. The results we have obtained are very interesting because the serum levels of OPN seem to be more influenced by progestin treatment, than by endometriosis itself. The study we have conducted gives a molecular complex view of what endometriosis represents and on how Desogestrel treatment works.