LH administration as a potential strategy for ovarian protection and female preservation against highly gonadotoxic chemotherapy

• Doctorando: Luis Miguel del Castillo Lima
• Grupo de Medicina Reproductiva - Fundación IVI
• Directores: Antonio Pellicer Martínez y Sonia Herraiz Raya
• Opción a mención internacional
• Programa de doctorado: Biomedicina y Biotecnología (UV)

Abstract

The ovaries harbor a non-renewable pool of follicles that produce a single fertilizable oocyte each menstrual cycle during the female reproductive age (15-49 years) but progressively decreases with age. Hence, factors that negatively affect the follicle endowment will cause a significant reduction in reproductive lifespan in women. Oncologic therapies based on the administration of alkylating chemotherapy are commonly used for treating gynecologic cancers in young patients, but they frequently accelerate follicular depletion and menopause onset. Chemotherapy-associated side effects on fertility, together with the increasing survival rates of cancer patients and the delay of motherhood in our current society, become crucial to developing fertility preservation techniques. Cryopreservation of oocytes, embryos, and ovarian tissue are well-established alternatives to female fertility preservation, albeit they do not prevent chemotherapy-induced damage to follicles. Thus, new strategies aiming at the in situ protection of follicle pool are appealing. To this end, the objectives of this thesis were to evaluate the effectiveness of LH treatment to protect in situ the follicle pool and to preserve the reproductive lifespan against the gonadotoxic effects of chemotherapy with alkylating drugs. To achieve this, short and long-term effects of LH were in vivo assessed on follicles at the primordial stage during cyclophosphamide and busulfan exposure by using an adult mouse model, as well as the short-term effects on the already growing follicular populations during chemotherapy administration by using a natural subfertile mouse strain. On the one hand, our results demonstrated that LH treatment was sufficient to preserve ovarian reserve and follicular growth, avoid atresia, restore ovulation, and meiotic spindle configuration in mature oocytes exposed at the primordial stage. The improvement of follicle development and oocyte quality appeared to be influenced by a crucial role of LH in maintaining the ability of protected follicles to establish a suitable crosstalk between oocytes and granulosa cells over the course of folliculogenesis. As a result, LH also improved the cumulative pregnancy rate and litter size of female animals during six consecutive mating attempts. By investigating the ovarian response to LH, we found that the protective effects seemed to be mediated at least by a significant role of LH in the enhancement of DNA repair mechanisms and anti-apoptotic signals in ovaries a few hours after alkylating agents exposure. On the other hand, our findings also indicated that LH also reversed the chemotherapy-induced actions on the already growing follicles, partially avoiding follicle depletion, oocyte DNA damage, granulosa cells apoptosis, and mature oocyte cohort size and quality. Altogether, this thesis highlights an encouraging and potential use of LH to develop novel strategies for preserving female fertility in young cancer patients.  

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