Gynotoxic Effects of Chemotherapy and Potential Protective Mechanisms

Abstract

Chemotherapy is one of the leading cancer treatments. Unfortunately, its use can contribute to several side effects, including gynotoxic effects in women. Ovarian reserve suppression and estrogen deficiency result in reduced quality of life for cancer patients and are frequently the cause of infertility and early menopause. Classic alkylating cytostatics are among the most toxic chemotherapeutics in this regard. They cause DNA damage in ovarian follicles and the cells they contain, and they can also induce oxidative stress or affect numerous signaling pathways. In vitro tests, animal models, and a few studies among women have investigated the effects of various agents on the protection of the ovarian reserve during classic chemotherapy. In this review article, we focused on the possible beneficial effects of selected hormones (anti-Müllerian hormone, ghrelin, luteinizing hormone, melatonin), agents affecting the activity of apoptotic pathways and modulating gene expression (C1P, S1P, microRNA), and several natural (quercetin, rapamycin, resveratrol) and synthetic compounds (bortezomib, dexrazoxane, goserelin, gonadoliberin analogs, imatinib, metformin, tamoxifen) in preventing gynotoxic effects induced by commonly used cytostatics. The presented line of research appears to provide a promising strategy for protecting and/or improving the ovarian reserve in the studied group of cancer patients. However, well-designed clinical trials are needed to unequivocally assess the effects of these agents on improving hormonal function and fertility in women treated with ovotoxic anticancer drugs.

Keywords: breast cancer; chemotherapy; gynecological cancers; ovarian function; ovarian reserve; ovotoxicity; protective factors.

Figure 1

(A) Ovarian follicle maturation and (B) adverse effects of chemotherapy on the ovarian reserve. Oncological drugs can directly damage PMFs while also reducing the number of growing follicles, thus promoting the maturation of PMFs, which can indirectly affect the reduction of their reserve. Chemotherapeutics can damage oocytes or follicular somatic cells, which leads to oocyte death in both cases. The figure was created with BioRender.com, accessed on 12 April 2024.

Figure 2

Mechanism of action and structure of selected anticancer drugs with gynotoxic properties from the groups of (A) alkylating cytostatics, (B) antimetabolites, (C) topoisomerase I/II inhibitors, and (D) mitosis inhibitors. 5-FU, 5-fluorouracil; FdUMP, 5-fluorodeoxyuridine monophosphate; dUMP, deoxyuridine monophosphate; dTMP, deoxythymidine monophosphate; TYMS, thymidylate synthase. The figure was created with BioRender.com, accessed on 12 April 2024.

Figure 3

Cyclophosphamide activation pathway.

Figure 4

Structure of busulfan and dacarbazine—examples of other alkylating cytostatic drugs with potential ovotoxic properties.

Figure 5

Structural differences between irinotecan and the active metabolite SN-38.

Figure 6

Structure of selected factors with potential ovarian-protective properties during chemotherapy.

Figure 7

Structure of ADR-925—the hydrolysis product (active metabolite) of dexrazoxane.