Ovarian damage from chemotherapy and current approaches to its protection

BACKGROUND: Anti-cancer therapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicle reserve is extremely sensitive to the effects of chemotherapy and radiotherapy. While oocyte, embryo and ovarian cortex cryopreservation can help some women with cancer-induced infertility achieve pregnancy, the development of effective methods to protect ovarian function during chemotherapy would be a significant advantage.OBJECTIVE AND RATIONALE: This paper critically discusses the different damaging effects of the most common chemotherapeutic compounds on the ovary, in particular, the ovarian follicles and the molecular pathways that lead to that damage. The mechanisms through which fertility-protective agents might prevent chemotherapy drug-induced follicle loss are then reviewed.SEARCH METHODS: Articles published in English were searched on PubMed up to March 2019 using the following terms: ovary, fertility preservation, chemotherapy, follicle death, adjuvant therapy, cyclophosphamide, cisplatin, doxorubicin. Inclusion and exclusion criteria were applied to the analysis of the protective agents.OUTCOMES: Recent studies reveal how chemotherapeutic drugs can affect the different cellular components of the ovary, causing rapid depletion of the ovarian follicular reserve. The three most commonly used drugs, cyclophosphamide, cisplatin and doxorubicin, cause premature ovarian insufficiency by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. They also cause an increase in damage to blood vessels and the stromal compartment and increment inflammation. In the past 20 years, many compounds have been investigated as potential protective agents to counteract these adverse effects. The interactions of recently described fertility-protective agents with these damage pathways are discussed.WIDER IMPLICATIONS: Understanding the mechanisms underlying the action of chemotherapy compounds on the various components of the ovary is essential for the development of efficient and targeted pharmacological therapies that could protect and prolong female fertility. While there are increasing preclinical investigations of potential fertility preserving adjuvants, there remains a lack of approaches that are being developed and tested clinically

Defining low prognosis patients undergoing assisted reproductive technology: POSEIDON criteria-the why

Women with impaired ovarian reserve or poor ovarian response (POR) to exogenous gonadotropin stimulation present a challenge for reproductive specialists. The primary reasons relate to the still limited knowledge about the POR pathophysiology and the lack of practical solutions for the management of these conditions. Indeed, clinical trials using the current standards to define POR failed to show evidence in favor of a particular treatment modality. Furthermore, critical factors for reproductive success, such as the age-dependent embryo aneuploidy rates and the intrinsic ovarian resistance to gonadotropin stimulation, are not taken into consideration by the current POR criteria. As a result, the accepted definitions for POR have been criticized for their inadequacy concerning the proper patient characterization and for not providing clinicians a guide for therapeutic management. A novel system to classify infertility patients with "expected" or "unexpected" inappropriate ovarian response to exogenous gonadotropins-the POSEIDON criteria-was developed to provide a more nuanced picture of POR and to guide physicians in the management of such patients. The new standards are provoking as they challenge the current terminology of POR in favor of the newly defined concept of "low prognosis." This article provides readers a critical appraisal of the existing criteria that standardize the definition of POR and explains the primary reasons for the development of the POSEIDON criteria

Ovarian transplantation with robotic surgery and a neovascularizing human extracellular matrix scaffold: a case series in comparison to meta-analytic data

Objective: To report our experience with robot-assisted (RA) autologous cryopreserved ovarian tissue transplantation (ACOTT) with the use of a neovascularizing extracellular matrix scaffold. Design: Case series with meta-analytic update. Setting: Academic. Patient(s): Seven recipients of RA-ACOTT. Intervention(s): Before or shortly after initiating chemotherapy, ovarian tissue was cryopreserved from 7 women, who then underwent RA-ACOTT 9.9 ± 1.8 years (range, 7–12 years) later. Perioperatively, they received transdermal estrogen and low-dose aspirin to enhance graft vascularization. Ovarian cortical pieces were thawed and sutured on an extracellular matrix scaffold, which was then robotically anastomosed to the bivalved remaining ovary in 6 cases and retroperitoneally (heterotopic) to the lower abdomen in 1 case. Main Outcome Measure(s): Ovarian function return, the number of oocytes/embryos, aneuploidy %, live births, and neonatal outcomes were recorded. Graft longevity was compared with the mean from the meta-analytic data. Result(s): Ovarian function returned 13.9 ± 2.7 weeks (11–16.2 weeks) after ACOTT, and oocytes were retrieved in all cases with 12.3 ± 6.9 embryos generated. In contrast to orthotopic, the heterotopic ACOTT demonstrated low embryo quality and an 80% aneuploidy rate. A recipient did not attempt to conceive and 2 needed a surrogate, whereas 4 of 4 delivered 6 healthy children, compared with 115 of 460 (25% pregnancy rate) from the meta-analytic data (n = 79). The mean graft longevity (43.2 ± 23.6/47.4 ± 22.8 months with/without sensitivity analysis) trended longer than the meta-analytic mean (29.4 ± 22.7), even after matching age at cryopreservation. Conclusion(s): In this series, RA-ACOTT resulted in extended graft longevity, with ovarian functions restored in all cases, even when the tissues were cryopreserved after chemotherapy exposure