Emerging evidence regarding statins use as novel endometriosis targeted treatment: real "magic pills" or "trendy" drugs? Some considerations.

Dear Editors, We read with great interest the recent review by Gibran et al. concerning the evidence of pleiotropic effects of statins in conservative treatment of endometriosis disease [1]. The authors performed an exhaustive review of the literature investigating all the possible molecular mechanisms through which statins may interfere with cellular and tissue pathways involved in development, establishment and progression of endometriosis. To date, several drugs have been proposed and administered with the intention of treating endometriosis conservatively but many of these drugs are affected by time-limited administration and several side effects, with the result that they are frequently useful only for symptom reduction with little benefit on disease severity and/or on restoration of fertility [2]. Unexpectedly, from 2006 to the present, encouraging results derived from in vitro human-cell studies and in vivo murine studies seem to strongly nominate statins as “magic pills” for long term conservative treatment of endometriosis, due to their low cost, safe pharmacological profile and apparent neutrality on the hormonal profile of women of childbearing age [1]. This is new exciting evidence, especially because it was collected during research on conservative treatment for a disease whose etiopathological mechanisms are not well understood and to date without any curative treatment, but it may erroneously result in a “reassuring and optimistic message” for both scientists and clinicians. Much of the data demonstrating the dose-dependent effective reduction in number and volume of endometriotic lesions after administration of statins was collected in murine models or in vitro studies. To date only one study, by Almassinokiani et al. [3], has reported data from the in vivo human model, and the endpoint was focused on post-surgical pain reduction. The authors observed that, after adequate surgical treatment, therapy with atorvastatin (20 mg/day) was comparable to gonadotropin-releasing hormone agonists (3.75 mg/IM/month) in reducing post-surgical pain due to endometriosis. Though encouraging, however, this study was affected by several biases such as small sample size (60 patients), short term follow-up (16 weeks), and absence of an untreated control group (making it impossible to prove whether the observed benefits were due to surgical treatment or to post-operative medical therapy). In addition, Almassinokiani et al. administered statins to women who were trying to conceive, apparently underestimating the possible risks associated with the administration of therapy in the pre-conceptional and early pregnancy period. Besides the lack of evidence about possible teratogenic effects, the impact that this class of drugs may have on female fertility considering both germ line cells and somatic cells is not clearly defined. Only one in vivo study has investigated the potential adverse effect on human female gonadal function using as outcome the reduction of luteal-phase length [4]. It reported that 4 months of simvastatin administration did not result in ovarian hormonal function impairment. Contradictory data collected by an in vitro study demonstrating a pro-apoptotic effect of statins on human ovarian periovulatory granulosa cells [5] underline the not-underestimable bias of the above-mentioned in vivo study regarding the methodology used to achieve its reassuring conclusions. Further studies aimed at clarifying the safety profile of statin administration in fertile women should consider a longer time-exposure to really quantify the in vivo biological effects on ovarian reserve. Moreover, further in vitro studies will better clarify the cause–effect relationship between pleiotropic effects of statins and the pathways involved in humans. Overcoming these potential limitations may be useful for evaluating the real effectiveness of statins in reducing both “organic” and “functional” damage caused by endometriosis onset, establishment and progression. In our opinion, while awaiting further evidence regarding the innocuousness of statins on female gonadal function and fertility, it would be appropriate to test these molecules on fertile women affected by endometriosis who do not desire pregnancy or have already completed their reproductive program.