Safety of clomiphene citrate: a literature review

Clomiphene citrate (CC) is a nonsteroidal compound and induces ovulation indirectly. The wide usage of the CC raises a question; is it safe or not? In the light of this question, this review aimed to highlight all researches and insights into the association between the use of CC and risk of genotoxicity, cytotoxicity, embryotoxicity, teratogenicity and risk of different cancer types. We conducted a MEDLINE/PubMed, Scopus, Web of Science, Google Scholar search. After a careful screening process of all authors, 32 of these articles were considered as appropriate, and reviewed. Our evaluations showed that CC has genotoxic, cytotoxic, embryotoxic and teratogenic properties. There is no association between the use of CC and risk of ovarian, breast, uterine, cervix, endometrium, lung, colorectal cancer, and lymphoma. However, risk increased especially after 6 cycles of use and especially in nulligravid women. The use of CC should be restricted to 6 cycles. Moreover, malignant melanoma and thyroid cancer risk was found to be higher among CC treated women in almost all studies. Further works should be conducted especially in animal models to assess its risk features.