Towards non-invasive fertility preservation: an investigation of the effect of chemotherapy on primordial follicles

Advances in cancer treatments have led to improved cancer survival rates, particularly among children and young people. Cancer treatments can have long-term damaging effects on female reproductive health, as radiation and some chemotherapeutic agents can destroy ovarian follicles, which contain developing eggs. Non-growing (primordial follicles) are the largest follicle population within the ovary and represent the ovarian reserve. Chemotherapy drugs cause a loss of these primordial follicles leading to premature ovarian insufficiency (POI), infertility and early menopause. POI and early menopause in turn have wide-ranging effects including increased risk of cardiovascular disease, neurological disease, psychiatric diseases, osteoporosis and mortality. These effects are not limited to adult women, young girls who undergo chemotherapy may suffer a loss in ovarian reserve which may not be felt for years or even decades.

There are currently several methods available to young women who wish to preserve their fertility, including the cryopreservation of eggs, embryos and ovarian tissue, however for pre-pubertal girls who are not yet ovulating, ovarian tissue cryopreservation remains their only option. These methods are invasive, costly and can delay cancer treatment. In recent years there has been growing interest in developing novel methods of non-invasive female fertility preservation. This would involve the administration of a fertoprotective drug alongside the chemotherapy treatment, which would protect the ovaries from the damaging effects of chemotherapy. However, despite ongoing research, the exact mechanisms of chemotherapy-induced follicle damage remain poorly understood. In particular, there is conflicting evidence as to whether primordial follicles are damaged directly, or whether only growing follicles are affected and there is a subsequent indirect loss of primordial follicles. In order to develop protective measures, these mechanisms must be better understood.

The aim of my DPhil is primarily to elucidate the mechanisms of chemotherapy-induced follicle damage to determine whether or not primordial follicles are directly affected by chemotherapeutic agents. Based on these results I will then identify suitable candidate fertoprotective agents and determine whether they are able to prevent or protect follicles from undergoing damage due to chemotherapeutic agents.

This project will utilise in vitro culture of human ovarian tissue which will be treated with chemotherapeutic agents and/or candidate fertoprotective agents. I will develop a novel analysis method involving immunohistochemistry of thick tissue sections and confocal microscopy to assess DNA damage within each follicle. Markers will be used to determine the activation status of follicles, to enable us to assess damage only in quiescent primordial follicles - this is of particular importance when distinguishing between follicles which are quiescent and non-growing and those who have undergone activation and may be more susceptible to chemotherapeutic agents.

Understanding of the mechanisms of chemotherapy-induced follicle damage is critical for the development of novel non-invasive methods of female fertility preservation. Once non-invasive fertoprotective treatments are developed, this will allow patients to retain their normal ovarian function following cancer treatment, thereby prevent premature menopause and infertility and greatly improving quality of life.