**3. Biology of progesterone and progestins**

The endometrium is highly sensitive to sex steroid hormones. Estrogens cause endometrial proliferation and progesterone inhibits this growth by converting the endometrium to its secretory stage to prepare the uterus for implantation. In relation to endometrial protection, progesterone is the key inhibitor of carcinogenesis. The balance between the estrogen and progesterone activity during the menstrual cycle must be precisely maintained as an increase in the estrogen activity and/or a reduction in the antagonistic activity by progesterone will stimulate carcinogenesis. Estrogens act upon the endometrium through estrogen receptors (ERs), resulting in the induction of growth factors such as the epidermal growth factor, insulinlike growth factor-1 and growth-enhancing protooncogenes c-fos and c-myc. Besides these genomic effects of estrogens in the endometrium, estrogens exert nongenomic effects via activation of the PI3K/Akt prosurvival signaling pathway. Progesterone acts by binding to progesterone receptors (PRs), thus regulating multiple signaling pathways through PRdependent transcriptional activity. In addition to ligand-mediated regulation, PR activity is also modulated by a variety of factors including microRNAs and epigenetic factors. [38] Despite their high degree of sequence identity, the PR isoforms maintain a number of unique biological functions, including: differences in transcriptional activity, ligand response, gene regulation, and tissue-specific physiological effects. [39] Unbeneficial role of some progestins is highlighted by the finding that medroxyprogesterone acetate, a widely used and quite powerful progestin, stimulates vascular thrombin receptor *in vitro*, thus being capable of triggering thromboembolic events. [40, 41]
