Hadassa Roness

Cyclophosphamide Triggers Follicle Activation and “Burnout”; AS101 Prevents Follicle Loss and Preserves Fertility

Cyclophosphamide activates dormant follicle growth, leading to depletion of ovarian reserve, and AS101 prevents this activation, rescuing fertility in mice. Of Mice and Women: Protecting Cancer Patients from Treatment-Induced Infertility Cancer, especially in advanced stages, is a multisystem disease that can affect a patient in a myriad ways. Unfortunately, cancer treatments such as chemotherapy can also wreak havoc on the body, and some of their side effects can be felt for the rest of the patient’s lifetime. One notable consequence of chemotherapy is infertility, which is particularly problematic in young cancer patients who receive their treatments before they’ve had an opportunity to have children. Alkylating agents such as cyclophosphamide (Cy) carry a high risk of ovarian toxicity and are among the worst offenders with regard to risk of future infertility. Now, Kalich-Philosoph et al. present findings that show how Cy exerts its toxic effects on ovarian cells, as well as a potential method of protecting the ovaries and preserving fertility. In a mouse model of Cy treatment, the authors demonstrated that this chemotherapy drug attacks the ovaries by a twofold mechanism. It is toxic to dividing cells and kills actively growing ovarian follicles. At the same time, it also activates the quiescent follicles, inducing them to grow and proliferate, which makes them susceptible to the effects of the drug as well. In this way, Cy treatment depletes the ovarian reserve, leading to early ovarian failure and infertility. The authors also showed that an experimental drug called AS101 may provide protection against this adverse effect of cancer treatment. Mice treated with AS101 in conjunction with Cy fared much better than their counterparts receiving chemotherapy alone. Their primordial ovarian follicles remained dormant, did not start proliferating prematurely, and survived through the entire treatment. Subsequently, the mice that received AS101 along with Cy had normal fertility, whereas the ones treated with Cy alone had a lower rate of pregnancy and fewer total offspring. Future experiments will be needed to translate this work from mice into human patients and confirm the effectiveness of AS101 for preserving fertility in the clinical setting. Promisingly, AS101 is already in phase 2 clinical trials and appears to be safe for human use. Moreover, AS101 itself appears to have anticancer effects and may be able to reinforce for the therapeutic action of Cy while counteracting its reproductive toxicity. Premature ovarian failure and infertility are major side effects of chemotherapy treatments in young cancer patients. A more thorough understanding of the mechanism behind chemotherapy-induced follicle loss is necessary to develop new methods to preserve fertility in these patients. We show that the alkylating agent cyclophosphamide (Cy) activates the growth of the quiescent primordial follicle population in mice, resulting in loss of ovarian reserve. Despite the initial massive apoptosis observed in growing, though not in resting, follicles of Cy-treated mice, differential follicle counts demonstrated both a decrease in primordial follicles and an increase in early growing follicles. Immunohistochemistry showed that granulosa cells were undergoing proliferation. Analysis of the phosphatidylinositol 3-kinase signaling pathway demonstrated that Cy increased phosphorylation of proteins that stimulate follicle activation in the oocytes and granulosa cells. Coadministration of an immunomodulator, AS101, reduced follicle activation, thereby increasing follicle reserve and rescuing fertility after Cy, and also increased the efficacy of Cy against breast cancer cell lines. These findings suggest that the mechanism in Cy-induced loss of ovarian reserve is accelerated primordial follicle activation, which results in a “burnout” effect and follicle depletion. By preventing this activation, AS101 shows potential as an ovarian-protective agent, which may be able to preserve fertility in female cancer patients.

Prevention of chemotherapy-induced ovarian damage: possible roles for hormonal and non-hormonal attenuating agents

BACKGROUND Current options for female fertility preservation in the face of cytotoxic treatments include embryo, oocyte and ovarian tissue cryopreservation. However these methods are limited by the patient age, status or available timeframe before treatment and they necessitate invasive procedures. Agents which can prevent or attenuate the ovotoxic effects of treatment would provide significant advantages over the existing fertility preservation techniques, and would allow patients to retain their natural fertility without the necessity for costly, invasive and risky procedures. Recent studies have contributed to our understanding of the mechanisms involved in cytotoxicity-induced ovarian follicle loss and highlight a number of agents that may be able to prevent or reduce this loss. METHODS This paper reviews the relevant literature (research articles published in English up to December 2013) on the mechanisms of cytotoxic-induced ovarian damage and the implications for fertility preservation. We present a comprehensive discussion of the potential agents that have been shown to preserve the ovarian follicle reserve in the face of cytotoxic treatments, including an analysis of their respective advantages and risks, and mechanisms of action. RESULTS Multiple molecular pathways are involved in the cellular response to cytotoxic treatments, and specific cellular reactions depend on variables including the drug class and dose, cell type, and cell stage. A number of agents acting on different elements of these pathways have demonstrated potential for preventing or reducing ovarian follicle loss, although in most cases, the studies are still very preliminary. CONCLUSIONS Advances in our understanding of the mechanisms and pathways involved in both cytotoxic ovarian damage and follicle growth and development have opened up new directions for fertility preservation. In order to bring these agents from the lab to the clinic, it will be vital to accurately evaluate the efficacy of each agent and additionally to demonstrate that co-treatment with these agents will not interfere with the anti-cancer activity of the chemotherapy drugs, or produce genetically comprised embryos.

Prevention of chemotherapy-induced ovarian damage

Recent advances in our understanding of the mechanisms underlying the impact of cytotoxic drugs on the ovary have opened up new directions for the protection of the ovary from chemotherapy-induced damage. These advances have spurred the investigation of pharmacological agents to prevent ovarian damage at the time of treatment. Prevention of ovarian damage and follicle loss would provide significant advantages over existing fertility preservation techniques. This manuscript reviews new methods for the prevention of chemotherapy-induced ovarian damage, including agents that act on the PI3K/PTEN/Akt follicle activation pathway, apoptotic pathways, the vascular system, and other potential methods of reducing chemotherapy-induced ovotoxicity.

Optimizing outcomes from ovarian tissue cryopreservation and transplantation; activation versus preservation

Ovarian tissue cryopreservation and transplantation (OTCP) is gaining increasing traction in the field of fertility preservation as a result of accumulated successes. We now have a decade of experience with the technique, with tens of live births and greater than 90% return of ovarian function in graft recipients. Recently, a novel method of OTCP has been described, termed in vitro activated OTCP which proposes significant changes to the standard protocol. This method aims to stimulate activation of dormant follicles within the grafts prior to transplantation and ensure that mature oocytes can be generated in the immediate short term after transplantation. By contrast, conventional OTCP seeks to maintain dormancy and thus preserve the follicle reserve in the graft with the aim of maximizing graft lifespan. This opinion paper will compare the two methods of OTCP, highlighting their respective advantages and disadvantages, and provide suggestions as to when to apply either one of these methods in a clinical setting.

Preclinical Approaches to the Protection of Ovarian Function

Recent advances in our understanding of the mechanisms underlying the impact of cytotoxic drugs on the ovary have opened up new directions for the protection of ovarian function from chemotherapy-induced damage. There has been parallel effort towards the development of pharmacological agents that may prevent ovarian damage at the time of treatment, which would provide significant advantages over existing fertility-preservation techniques. This chapter will review preclinical developments for the protection of the ovary during ovotoxic treatment, including agents that act on relevant apoptotic pathways, the PI3K/PTEN/Akt follicle activation pathway, the vascular system, and other potential methods of reducing chemotherapy-induced ovotoxicity. These preclinical studies continue to advance our understanding of the mechanisms and pathways involved in cytotoxic ovarian damage, thus bringing us closer to preventing chemotherapy-induced infertility.