Ormeloxifene

The World Health Organization's (WHO) Medical Eligibility Criteria for contraceptive use (MEC) provides recommendations on the safety and efficacy of a range of contraceptive methods for users with various medical conditions. However, there are methods with medical regulatory agency approval that are not included in WHO guidance. Our objectives were to evaluate the evidence on methods that have regulatory approval for use in any member state, but which are not included in the MEC 2015, and to determine whether the evidence should be systematically reviewed to inform possible inclusion in a new WHO guideline.

We conducted a scoping review of experimental studies found through two bibliographic databases (PubMed, Embase) from database inception to December 2023. Two reviewers screened abstracts and full texts to determine eligibility based on a priori inclusion and exclusion criteria; one additional reviewer resolved conflicts. Reviewers extracted data on method safety, efficacy, and acceptability using a standardized tool.

We identified three methods that met our review criteria: ormeloxifene, quinestrol-containing contraception, and mifepristone for emergency contraception (EC). Our initial search strategies yielded 386 total results. Five publications related to ormeloxifene, five to quinestrol-containing contraception, and 10 to mifepristone for EC were included. The data on these methods was highly variable.

Rigorous systematic reviews of the evidence on safety, efficacy and dosage of ormeloxifene, quinestrol-containing contraception, and mifepristone for EC are needed to inform WHO recommendations on these methods. As these methods are already being used, international guidance for practitioners is essential.

Ormeloxifene (ORM) is a nonsteroidal selective estrogen receptor modulator (SERM), developed by the CSIR-Central Drug Research Institute that is approved as an oral contraceptive. However, it has also shown promising anti-cancer activity, especially in breast cancer. Here, we have investigated the anti-cancer effect of ORM on colon cancer cells and show that its antiproliferative activity is mediated through mitochondrial fission and autophagy-associated cell death. We observed that ORM treatment led to an elevation in autophagy markers like LC3II, Beclin1, and Atg7. Autophagy induction and LC3II turnover were monitored by immunofluorescence staining and confocal microscopy. Transmission electron microscopy results confirmed the formation of autophagosomes and autophagolysosomes. Autophagic flux was confirmed by the increased expression of LC3II in cells co-treated with BafilomycinA1(autophagy inhibitor) and ORM. This was further corroborated using tandem mRFP-GFP-LC3 (tfLC3) transfection in DLD-1 cells. Interestingly, we observed that inhibition of autophagy reduced the apoptotic cell population, suggesting pro-death autophagy. ORM treatment caused notable ultrastructural alterations indicative of cellular stress. Notably, ORM triggered the generation of mitochondrial ROS, associated with increased levels of mitochondrial fission and a decrease in mitochondrial fusion proteins. Changes in mitochondrial dynamics were observed under the TEM, which included reduced mitochondrial size and increased mitochondrial number. Inhibition of mitochondrial fission resulted in enhanced cell survival and a concomitant decrease in the autophagic markers, implying that ORM-induced autophagy depends on mitochondrial fission. Taken together, our findings bring to light a novel mechanism where Ormeloxifene targets mitochondrial dynamics to promote autophagy-associated cell death in colon cancer cells.