Abstract
Advances in cancer therapy have focused attention on the quality of life of cancer survivors. Since infertility is a major concern following chemotherapy, it is important to characterize the drug-specific damage to the reproductive system to help find appropriate protective strategies. This study investigates the damage on neonatal mouse ovary maintained in vitro for 6 days, and exposed for 24 h (on Day 2) to clinically relevant doses of Docetaxel (DOC; low: 0.1 µM, mid: 1 µM, high: 10 µM). Furthermore, the study explores the putative protective action exerted by Tri-iodothyronine (T3; 10−7 M). At the end of culture, morphological analyses and follicle counts showed that DOC negatively impacts on early growing follicles, decreasing primary follicle number and severely affecting health at the transitional and primary stages. Poor follicle health was mainly due to effects on granulosa cells, indicating that the effects of DOC on oocytes were likely to be secondary to granulosa cell damage. DOC damages growing follicles specifically, with no direct effect on the primordial follicle reserve. Immunostaining and western blotting showed that DOC induces activation of intrinsic, type II apoptosis in ovarian somatic cells; increasing the levels of cleaved caspase 3, cleaved caspase 8, Bax and cleaved poly(ADP-ribose) polymerase, while also inducing movement of cytochrome C from mitochondria into the cytosol. T3 did not prevent the damage induced by the low dose of DOC. These results demonstrated that DOC induces a gonadotoxic effect on the mouse ovary through induction of somatic cell apoptosis, with no evidence of direct effects on the oocyte, and that the damaging effect is not mitigated by T3.
Highlights
As a consequence of advances in modern cancer care, an increasing number of women are long-term survivors following treatment
Docetaxel primarily affects granulosa cells (GCs) of early growing follicles In order to analyse which follicle cell type was the principal target of DOC damage, the percentage of follicles with unhealthy oocyte only, GCs only or both oocyte and GCs (OO+GCs) was determined (Fig.2)
The percentage of follicles categorised as unhealthy due to unhealthy oocytes and GCs (OO+GCs) was significantly greater in the MID- and HIGH-DOC groups compared with CONTROL (Fig.2A-iii).When each stage of follicle development was analysed separately, primordial follicles showed no signs of damage in response to drug treatment over that seen in CONTROL primordial follicles (Fig. 2B-i, B-ii, B-iii)
Summary
As a consequence of advances in modern cancer care, an increasing number of women are long-term survivors following treatment. It is well recognised that some anticancer drugs are gonadotoxic, with infertility representing a major concern for women undergoing cancer treatments, so for younger patients (Meirow et al, 2010). The key basis for the adverse effects on the ovary is the limited supply of oocytes contained within the ovarian follicles, which are formed before birth. This population of primordial follicles represents a female’s ovarian reserve. Insults and pathological circumstances affecting the ovary can precociously deplete this reserve, leading to premature ovarian insufficiency (POI) with loss of fertility and the consequences of estrogen deficiency
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