Abstract
Background: Ovaries are sensitive to chemotherapy, which may lead to early depletion of primordial follicle reserve. One strategy for gonadal function preservation is temporary ovarian suppression with Gonadotropin Releasing Hormone agonists (GnRHa) during chemotherapy. To date, GnRHa protective mechanism of action remains not fully elucidated. Methods: We collected 260 immature cumulus cell-oocyte complexes (COC) from 111 women < 38 years old, with a normal ovarian reserve. The COC were randomly assigned to the following groups: (a) control; culture with the addition of (b) GnRHa; (c) cyclophosphamide; (d) cyclophosphamide plus GnRHa. After in vitro treatments, RNA and proteins were extracted from oocytes and cumulus cells (CC), separately. Potential effects of drugs were evaluated on GnRH receptors, apoptosis pathways, ceramide pathway, and glutathione synthesis by quantitative PCR and, whenever possible, by Western blot. Results: Cyclophosphamide triggered activation of the extrinsic pathway of apoptosis mediated by BAX in CC. The co-administration of GnRHa inhibited the apoptosis pathway in CC. According to our model, the GnRHa does not directly act on oocytes, which do not express GnRH receptors. Moreover, glutathione synthesis was decreased after GnRHa treatment both in CC and oocytes. Conclusion: Our data suggest that the protective mechanisms induced by GnRHa is mediated by an anti-apoptotic effect on CC.
Highlights
Young women with cancer or non-malignant diseases requiring treatment with cytotoxic chemotherapy are candidates for fertility preservation
We studied immature cell-oocyte complexes (COC) discarded from in vitro fertilization cycles in healthy women to investigate whether Gonadotropin Releasing Hormone agonists (GnRHa) was able to protect the oocytes from cyclophosphamide toxicity
Chemotherapy started a series of molecular signals to trigger apoptosis through
Summary
Young women with cancer or non-malignant diseases requiring treatment with cytotoxic chemotherapy are candidates for fertility preservation. The ovaries are very sensitive to cytotoxic chemotherapy agents; they can induce apoptotic death of the oocytes and the surrounding granulosa cells (GC), leading to irreversible early depletion of the primordial follicle reserve [2,3,4]. In comparison with cryopreservation strategies, temporary ovarian suppression with GnRHa during chemotherapy has been developed as a technique to protect the ovaries from the gonadotoxic effect of cytotoxic systemic therapy. The majority of the studies showed a positive effect for GnRHa treatment in preventing chemotherapy-induced depletion of primordial follicles [17,18,19,20,21,22,23,24,25]. Chemotherapy damages primordial follicle oocytes, this was the only strategy available to us for treatment of ex vivo human COC, the major anatomic and functional unit of the ovary. Data were collected on both oocytes and cumulus cells (CC) by gene expression analysis
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