GNRH agonisti löprolid asetat in vitroda kemoterapi ve radyasyona bağlı over hasarına karşı koruyuculuk sağlamıyor

Recent approaches in anticancer therapy led to increased rate of young cancer survivors; hence it became extremely important to minimize the long-term side effects of cancer treatments. For female cancer patients of childbearing age, the major concern is gonadotoxicity of chemotherapy and radiation which eventually results in premature ovarian failure (POF) and infertility. Premature ovarian failure is also associated with other adverse health-related consequences, including osteoporosis, cardiovascular diseases, sleep disturbance, and sexual dysfunction, which can negatively impact on short- and long-term quality of life. Three fertility preservation strategies are currently available for women prior to cytotoxic chemotherapy/radiation for cancer: cryopreservation of oocyte, embryo and ovarian tissue. But ovarian tissue cryopreservation is considered still experimental due to unknown success rate of this procedure. Even though oocyte or embryo freezing prior to chemotherapy can help women achieve pregnancy, these strategies cannot reverse menopause in the native ovaries. Furthermore, ovarian tissue transplantation carries the risk of re-introducing cancer cells especially in hematological malignancies. Therefore, any drug that preserves ovarian reserve during chemotherapy can potentially sustain normal reproductive life span and obviate the need for gamete freezing prior to chemotherapy. Encouraged by the initial reports of animal studies and non-randomized human trials showing a beneficial effect of GnRH (gonadotropin-releasing hormone) agonists in the preservation of ovarian function during chemotherapy, GnRHas (GnRH agonists) have been proposed as a fourth potential fertility preservation strategy. But randomized controlled trials launched so far to assess the effectiveness of this method have shown contradictory results in cancer patients. Some of these trials demonstrated a protective effect of GnRH agonists in preserving ovarian function after chemotherapy, whereas the others could not. This fact, together with the lack of a proven molecular mechanism of action for ovarian protection with GnRHa places this approach under scrutiny as a fertility preservation strategy. We therefore aimed in this thesis to provide in vitro evidence for-or-against the role of GnRHa in the prevention of chemotherapy induced damage in human ovary. Lack of molecular data in this under-studied issue led us to investigate in this study if GnRH agonist leuprolide acetate decreases DNA damage and follicular apoptosis through either activation of GnRH receptors and upregulation of intragonadal antiapoptotic genes during adjuvant chemotherapy. For this purpose we conducted several specific end-point assays in this study to provide a molecular evidence for-or-against the role of GnRHa in the preservation ovarian function and reserve after chemotherapy. This thesis provides in vitro evidence that the co-administration of GnRH agonist leuprolide acetate with cytotoxic chemotherapy agents does not prevent or ameliorates ovarian damage and follicle loss in vitro. This data can be useful when consulting a young patient who opts to receive GnRH treatment with chemotherapy to protect her ovaries from chemotherapy induced damage. Our findings do not conclusively rule out the possibility that GnRHa may offer protection if any, through some other mechanisms in vivo.