The estrogen contained in combined oral contraceptives (OCs) could theoretically stimulate endometriosis growth, but some new in vitro data have postulated the opposite: ethinilestradiol (EE) could not significantly stimulate the growth and helps the progestogen action in the endometriotic tissue which is progesterone resistant. The balance between the stimulating and indirectly inhibiting effects of estrogen is critical to the clinical outcome of OCs-based treatment of endometriosis. Dienogest (DNG) is the best progestogen treatment for endometriosis, but what happens if is combined with EE? Only randomized clinical data can confirm it as beneficial o detrimental. While waiting, prescribers must rely on in vitro data and the theoretical considerations hereby reviewed.

Endometriotic tissue self-produces estradiol, while the EE/DNG pill maintains stably low E2 levels, which could not significantly stimulate endometriosis growth. Endometriotic tissue is progesterone resistant. The EE in OCs may support the beneficial action of progestins, like DNG, up-regulating progesterone receptors and thereby enhancing responsiveness to progestin. There is a long lasting experience with OCs to suppress endometriosis, reduce recurrence and control endometriotic pain. The link between OCs use and endometriosis, found by some studies, is not a causal one, but it could be better explained by the preferential OCs use by endometriosis symptomatic patients. Therefore there should be no reason to avoid OCs in these patients and, as endometriosis increases the risk of endometriosis-associated ovarian cancer, OCs could reduce this risk better than DNG only. While waiting for adequate clinical data, the effect of EE/DNG versus DNG alone in endometriosis patients will remain controversial. If endometriosis suppression is the only need DNG is still the first choice. When the aim of the treatment is ovarian cancer prevention and estrogen mediated benefits, like contraception and non contraceptive OCs benefits, the EE plus DNG pill seems better than DNG alone or at least not contraindicated in endometriosis patients.