Effects of reproductive aging on the success of ovarian tissue reimplantation for infertility treatment of oncologic patients.

• Applicant: Dr. Rebekka Einenkel
• Subject Area: Reproductive Medicine, Urology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545895532

Aging leads to drastic hormonal changes in women. In fertile women, FSH (follicle stimulating hormone) control follicle maturation and thus the secretion of estradiol; whereas women experience a decrease of estradiol due to the exhaustion of the follicular reserve and an increase in FSH entering menopause. Gonadotoxic therapies as conducted to fight oncological diseases lead to early aging processes in terms of hormonal changes. Chemotherapies and radiation can damage ovarian tissue and cause an early exhaustion of the follicular reserve accompanied by premature reproductive aging. Here, the decrease in estradiol causes an increase in FSH as well, which is defined as premature ovarian insufficiency (POI) in women under 40 years old. Besides other options for fertility preservation, the cryopreservation of ovarian tissue provides the reintroduction of the follicular reserve. The reimplantation success depends on the construction of a sufficient blood supply. This takes 7-10 days, in which the reimplanted tissue is undersupplied. This causes the loss of up to 90 % of the follicles. Supporting angiogenesis could prevent the loss. Ovarian tissue spontaneously secretes angiogenic factors. Preliminary data showed that the secretion of angiogenic factors might be impaired by high FSH levels. 50 % of patients, who receive ovarian tissue reimplantation, are already affected by POI, through which the reimplanted tissue is exposed to hormonally prematurely aged conditions. The aim of this application is to gain a deeper insight into the hormonal effects on the secretion of angiogenic, chemotactic and inflammatory factors, which support the development of blood supply. Therefore, human ovarian tissue will be thawed and cultured following already established protocols. The effect of 3 different FSH and estradiol concentrations will be assessed, which cover pre-, peri- and post-menopausal hormone levels. Due to the rarity of the tissue a broad examination is planned. Besides the assessment of 48 angiogenesis-relevant secreted factors, the number of vital follicles as well as the induction of apoptosis will be analyzed. The angiogenic potential will be evaluated by the effect on endothelial cells. It is hypothesized that high FSH levels impair angiogenesis; whereas high estradiol levels may rather support the expression of angiogenic factors. The results will contribute to the discussion, whether patients experiencing early hormonal aging by POI, should reverse the aging process by HRT in order to support the recovery of the reimplanted tissue and minimize the loss of follicles. Moreover, this grant will serve as basis for a DFG full application, in which the underlying mechanisms will be addressed in detail and the prospects of success be evaluated in the clinical context.

• DFG Programme: Research Grants