Various types of adenomyosis and endometriosis: in search of optimal management

Currently, hormonal drugs are the mainstay for treating endometriosis or adenomyosis. Aside from staying within the "therapeutic window" and cutting off the hormonal support to the ectopic endometrium, none of these treatments were developed with a previously identified target. The current lack of innovation is humbling, especially considering that among >34,000 PubMed-indexed publications on endometriosis or adenomyosis, approximately 65% of them were published in the last 2 decades, many of them presumably with all the benefits of omics and molecular biology. One major reason for so many doomed research and development (R&D) projects on nonhormonal drugs is the failure to understand the natural history of the ectopic endometrium. Other reasons include, but are not limited to, the number of side effects that these nonhormonal drug candidates presented, which the developers were either unaware of or simply had ignored when pursuing a too narrowly minded development-a common cognitive trap known as invisible gorillas. Unless we have a clear global picture with a good grasp of the natural history of ectopic endometrium, "potholes" and "blind alleys" in drug R&D are difficult to avoid. This review shall explore some new concepts in the progression of ectopic endometrium and explain how these new perspectives offer insights for devising better therapeutic options, explain why some drug R&D projects for endometriosis or adenomyosis have failed, provide a critical analysis of some issues encountered in everyday practice, expose knowledge gaps in need of further research, and, finally, offer possible ways to circumvent hurdles and potholes and avoid cul-de-sacs in nonhormonal drug R&D.