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Roseanne Rosario, Wanyuan Cui, and Richard A Anderson

Unlike traditional chemotherapy agents which are generally cytotoxic to all cells, targeted anti-cancer therapies are designed to specifically target proliferation mechanisms in cancer cells but spare normal cells, resulting in high potency and reduced toxicity. There has therefore been a rapid increase in their development and use in clinical settings, including in curative-intent treatment regimens. However, the targets of some of these drugs including kinases, epigenetic regulatory proteins, DNA damage repair enzymes and proteasomes, have fundamental roles in governing normal ovarian physiology. Inhibiting their action could have significant consequences for ovarian function, with potentially long-lasting adverse effects which persist after cessation of treatment, but there is limited evidence of their effects on reproductive function. In this review, we will use literature that examines these pathways to infer the potential toxicity of targeted anti-cancer drugs on the ovary.

Lay summary

Compared to traditional chemotherapy agents, anti-cancer therapies are thought to be highly effective at targeting cancer cells but sparing normal cells, resulting in reduced drug side effects. However, many of processes within the cells that these drugs affect are also important for the ovary to work normally, so suppressing them in this way could have long-lasting implications for female fertility. This review examines the potential toxicity of anti-cancer therapies on the ovary.

Menghe Liu, Katja Hummitzsch, Nicole A Bastian, Monica D Hartanti, Helen F Irving-Rodgers, Richard A Anderson, and Raymond J Rodgers

Polycystic ovary syndrome (PCOS) is an endocrine metabolic disorder that appears to have a genetic predisposition and a fetal origin. The fetal ovary has two major somatic cell types shown previously to be of different cellular origins and different morphologies and to differentially express 15 genes. In this study, we isolated the somatic gonadal ridge epithelial-like (GREL) cells (n  = 7) and ovarian fetal fibroblasts (n  = 6) by clonal expansion. Using qRT-PCR, we compared the gene expression levels of PCOS candidate genes with previous data on the expression levels in whole fetal ovaries across gestation. We also compared these levels with those in bovine adult ovarian cells including fibroblasts (n  = 4), granulosa cells (n  = 5) and surface epithelial cells (n  = 5). Adult cell types exhibited clear differences in the expression of most genes. In fetal ovarian cells, DENND1A and ERBB3 had significantly higher expression in GREL cells. HMGA2 and TGFB1I1 tended to have higher expression in fetal fibroblasts than GREL cells. The other 19 genes did not exhibit differences between GREL cells and fetal fibroblasts and FBN3, FSHB, LHCGR, FSHR and ZBTB16 were very lowly expressed in GREL cells and fibroblasts. The culture of fetal fibroblasts in EGF-containing medium resulted in lower expression of NEIL2 but higher expression of MAPRE1 compared to culture in the absence of EGF. Thus, the two fetal ovarian somatic cell types mostly lacked differential expression of PCOS candidate genes.

Lay summary

Polycystic ovary syndrome (PCOS) is one of the most common reproductive problems. The cause is not known so there are no specific treatments or prevention strategies. We know it can be linked to issues that occur in the womb and that some people may be more likely to get PCOS due to their genetic makeup. Our recent studies showed that many of the genes linked to PCOS were found to be switched on in the fetal ovary and are likely to be involved in the development of the fetal ovary. In order to improve our understanding of PCOS, we need to identify the type of cells in the fetal ovary where these genes are switched on. In this study, we examined the PCOS genes in two types of cells that mature as the fetal ovary develops and found very little difference between them but bigger differences to their mature adult counterparts.