In recent decades, advancements in cancer therapies have led to increased survival rates worldwide. As a result, an increasing number of cancer patients of reproductive age are surviving the disease. Yet, various sequelae related to the use of cytotoxic chemotherapeutic regimens have been observed in this population, with premature ovarian failure(POF) being a common side effect of such treatments.
Cyclophosphamide is a chemotherapeutic drug that is widely used in the treatment of multiple cancers [Calabresi, P., and Parks, R 1980], including breast cancer [Koyama, H et al. 1977],, Hodgkin’s disease, acute lymphoblastic leukemia[Sirus, E. S. et al. 1976, Himmelstein-Braw et al. R.1978], and Burkitt’s lymphoma[Fosdick, W. M.et al, 1968]. Moreover, it can be used for the treatment of connective tissue disorders and autoimmune diseases. However, cyclophosphamide has detrimental effects on the gonads in male and female patients [Fairley KF et al. 1968, Sobrinho LG et al. 1972]. Thus, patients who need to undergo chemotherapy should be counseled regarding their fertility preservation options.
The gonad protective effects of various agents, including GnRH analogs, recombinant anti-Müllerian hormone (AMH) [Roness H et al. 2019,Sonigo C et al,2019], progesterone [Ozdamar S et al,2019], antioxidants [Unal F et al.2016, Melekoglu R et al, 2018], and antiapoptotic molecules such as sphingomyelin metabolites (e.g., sphingosine-I-phosphate, ceramide-I-phosphate) [Morita Y et al. 2000, Pascuali N et al.2018] have previously been investigated. However, there is no solid evidence concerning the benefits of co-treatment with GnRH analogs and chemotherapy agents [Blumenfeld Z et al. 1996, Imai A et al. 2007] in relation to fertility preservation[Oktay K et al. 2018, Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion,2019, Fertility preservation and reproduction in patients facing gonadotoxic therapies: an Ethics Committee opinion,2018, Elgindy EA et al.2013, Gerber B. et al. 2011, .Munster PN MA et al. 2012, Elgindy E et al. 2015, Bedaiwy MA et al. 2011]. To date, oocyte or embryo cryopreservation options have been considered the most reliable treatments for preserving fertility, although the need for such treatments could delay the start of anti-cancer treatments.
It has been shown that cyclophosphamide could cause ovarian damage by increasing the levels of free oxygen radicals such as tissue malondialdehyde (MDA) and decreasing the levels of anti-oxidant enzymes such as superoxide dismutase (SOD), thereby causing lipid peroxidation and, consequently, cell death [Yener et al. 2013]. In addition, two primary active metabolites of cyclophosphamide, namely phosphoramide mustard and acrolein, are known to be potent cytotoxic molecules that can be eliminated by another anti-oxidant, glutathione (GSH) [ Lopez et al.2004]. In light of this, an agent with antioxidative properties could serve to protect the ovaries from cyclophosphamide-related gonadotoxicity.
Mesna (2-mercaptoethane sodium sulfonate) is an anti-oxidant drug that is used to prevent cyclophosphamide- and ifosfamide-related urotoxicity [Haselberger MB et al. 1995]. It binds the cytotoxic metabolites of cyclophosphamide and exerts protective effects on the bladder and intestinal mucosa [Ypsilantis P et al.2004, Rybak LP et al. 2007]. Mesna has also been shown to protect the ovaries following cisplatin treatment [Yeh J et al 2008, Li X. et al 2013]. Yet, although mesna has been reported to be a protective agent, it has not previously been assessed in relation to cyclophosphamide, despite it being one of the most commonly used chemotherapeutic and cytotoxic agents in women of reproductive age [Haselberger MB, Schwinghammer TL.1995, Ypsilantis P et al. 2004, Rybak LP et al. 2007, Yeh J et al. 2008, Li X et al.2013] .
The present study sought to investigate the protective effect of mesna on the ovarian reserve of women being treated with cyclophosphamide.