BACKGROUND As cancer survival rates improve, understanding and preventing the adverse off-target and long-term impacts of cancer treatments, including impacts on fertility, have become increasingly important. Cancer therapy-mediated damage to the ovary and depletion of the primordial follicle reserve are well characterised. However, our knowledge of the full extent of damage to the rest of the female reproductive tract, in particular the uterus, is limited. OBJECTIVE AND RATIONALE Improving our understanding of the off-target effects of cancer therapies on the entire female reproductive tract is a critical step towards developing truly effective strategies to protect the fertility of cancer survivors. The objective of this narrative review was to critically evaluate the available literature regarding the capacity for the uterus to sustain a healthy pregnancy following exposure to radiotherapy or chemotherapy. SEARCH METHODS The authors performed PubMed (Medline) searches using the following key words: uterus, cancer survivors, radiotherapy, chemotherapy, pregnancy outcome, fertility preservation, infertility. There were no limits placed on time of publication. OUTCOMES Overall, there were major limitations to the current available literature, meaning that interpretations should be taken with caution. Despite these drawbacks, data suggest that the uterus may sustain off-target damage, with the extent of damage dependent on the type of cancer treatment and patient age. Specifically, uterine growth is stunted and resistant to hormone replacement therapy in prepubertal girls receiving abdominal, pelvic or whole-body radiotherapy. In contrast, females treated with radiotherapy post-puberty can benefit from hormone replacement therapy, as demonstrated by increased uterine volume and function. No live births have been reported in women previously exposed to radiotherapy after transplantation of cryopreserved ovarian tissue, even when menstruation returns. However, this technique has proven to be a successful fertility preservation method for women previously treated with chemotherapy. Obstetricians commonly report that women who maintain sufficient ovarian function can achieve pregnancy naturally following radiotherapy, but they have thin and/or fibrotic myometrium at delivery, compromising safe delivery and subsequent pregnancy. Furthermore, women exposed to either radiotherapy or chemotherapy have a higher prevalence of preterm birth and low birth weight infants, even in those with normal ovarian function or when oocyte donation is utilised. The mechanisms of potential uterine damage are poorly understood. While the myometrium, vasculature and endometrial progenitor cells are possibly targets, further studies are clearly required and well-controlled animal models could provide the best avenue for these types of future investigations. WIDER IMPLICATIONS Female cancer survivors experience greater rates of early pregnancy loss and complications, suggesting that cancer therapy-induced damage to the uterus contributes to infertility. Despite clinical reports dating back to 1989, we highlight a surprising lack of detail in the literature regarding the precise nature and extent of off-target damage inflicted to the uterus in response to cancer therapies. Young women requiring cancer treatment, and the clinicians treating them, must be equipped with accurate information to aid informed decision-making regarding cancer treatment regimens as well as the development and use of effective fertility preservation measures. As the current literature on the impacts of cancer treatments is limited, we hope that our narrative review on this subject will stimulate more research in this important field.
The endometrium is a highly complex tissue that is vulnerable to subtle gene expression changes and is the first point of contact for an implanting blastocyst. Successful blastocyst implantation can only occur when the endometrium is receptive during a short window with each menstrual cycle. microRNAs are small, non-coding RNAs that negatively regulate their gene targets. miR-29c has previously been identified to be differentially regulated across the fertile menstrual cycle, however it has not been investigated in association with infertility. We hypothesised that miR-29c dysregulation in the infertile endometrium would negatively influence endometrial adhesion and blastocyst implantation outcomes during the mid-secretory, receptive phase. miR-29c expression was elevated in early and mid-secretory phase infertile endometrium and localised to the epithelial compartments of endometrial tissue. Overexpression of miR-29c in vitro impaired endometrial epithelial adhesion, and reduced collagen type IV alpha 1 (COL4A1) mRNA expression. COL4A1 was immunolocalised to the luminal and glandular epithelial basement membranes in early and mid-secretory phase fertile and infertile endometrium for the first time. Knockdown of COL4A1 impaired endometrial epithelial adhesion suggesting a role in endometrial receptivity and implantation. Our data suggests miR-29c overexpression with infertility may impair the adhesive capacity of the endometrium, potentially contributing to implantation failure and infertility.
STUDY QUESTION What is the impact of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, alone or in combination with chemotherapy on the ovary in mice? SUMMARY ANSWER Olaparib treatment, when administered alone, depletes primordial follicle oocytes, but olaparib does not exacerbate chemotherapy-mediated ovarian follicle loss in mice. WHAT IS KNOWN ALREADY The ovary contains a finite number of oocytes stored within primordial follicles, which give rise to all mature ovulatory oocytes. Unfortunately, they are highly sensitive to exogenous DNA damaging insults, such as cytotoxic cancer treatments. Members of the PARP family of enzymes are central to the repair of single-strand DNA breaks. PARP inhibitors have shown promising clinical efficacy in reducing tumour burden, by blocking DNA repair capacity. Olaparib is a PARP1/2 inhibitor recently FDA-approved for treatment of BRCA1 and BRCA2 mutation carriers with metastatic breast cancer. It is currently being investigated as an adjunct to standard treatment at an earlier stage, potentially curable, BRCA1- and BRCA2-associated breast cancer which affects reproductive age women. Despite this, there is no preclinical or clinical information regarding the potential impacts of olaparib on the ovary or on female fertility. Unfortunately, it may be many years before clinical data on fertility outcomes for women treated with PARP inhibitors becomes available, highlighting the importance of rigorous preclinical research using animal models to establish the potential for new cancer therapies to affect the ovary in humans. We aimed to comprehensively determine the impact of olaparib alone, or following chemotherapy, on the ovary in mice. STUDY DESIGN, SIZE, DURATION On Day 0, mice (n = 5/treatment group) were administered a single intraperitoneal dose of cyclophosphamide (75 mg/kg/body weight), doxorubicin (10 mg/kg), carboplatin (80 mg/kg), paclitaxel (7.5 mg/kg) or vehicle control. From Days 1 to 28, mice were administered subcutaneous olaparib (50 mg/kg) or vehicle control. This regimen is proven to reduce tumour burden in preclinical mouse studies and is also physiologically relevant for women. PARTICIPANTS/MATERIALS, SETTING, METHODS Adult female wild-type C57BL6/J mice at peak fertility (8 weeks) were administered a single intraperitoneal dose of chemotherapy, or vehicle, then either subcutaneous olaparib or vehicle for 28 days. Vaginal smears were performed on each animal for 14 consecutive days from Days 15 to 28 to monitor oestrous cycling. At 24 h after final treatment, ovaries were harvested for follicle enumeration and immunohistochemical analysis of primordial follicle remnants (FOXL2 expressing granulosa cells), DNA damage (γH2AX) and analysis of apoptosis by TUNEL assay. Serum was collected to measure circulating anti-Müllerian hormone (AMH) concentrations by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE Olaparib significantly depleted primordial follicles by 36% compared to the control (P < 0.05) but had no impact on other follicle classes, serum AMH, corpora lutea number (indicative of ovulation) or oestrous cycling. Primordial follicle remnants were rarely detected in control ovaries but were significantly elevated in ovaries from mice treated with olaparib alone (P < 0.05). Similarly, DNA damage denoted by γH2AX foci was completely undetectable in primordial follicles of control animals but was observed in ∼10% of surviving primordial follicle oocytes in mice treated with olaparib alone. These observations suggest that functional PARPs are essential for primordial follicle oocyte maintenance and survival. Olaparib did not exacerbate chemotherapy-mediated follicle depletion in the wild-type mouse ovary. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION This study was performed in mice, so the findings may not translate to women and further studies utilizing human ovarian tissue and sera samples should be performed in the future. Only one long-term time point was analysed, therefore olaparib-mediated follicle damage should be assessed at more immediate time points in the future to support our mechanistic findings. WIDER IMPLICATIONS OF THE FINDINGS Olaparib dramatically depleted primordial follicles and this could be attributed to loss of intrinsic PARP-mediated DNA repair mechanisms. Importantly, diminished ovarian reserve can result in premature ovarian insufficiency and infertility. Notably, the extent of follicle depletion might be enhanced in BRCA1 and BRCA2 mutation carriers, and this is the subject of current investigations. Together, our data suggest that fertility preservation options should be considered for young women prior to olaparib treatment, and that human studies of this issue should be prioritized. STUDY FUNDING/COMPETING INTEREST(S) This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. This work was supported by funding from the National Health and Medical Research Council (NHMRC); (K.J.H. #1050130) (A.L.W. #1120300). K.A.P. is a National Breast Cancer Foundation Fellow (Australia—PRAC-17-004). K.A.P. is the Breast Cancer Trials (Australia) Study Chair for the OlympiA clinical trial sponsored by AstraZeneca, the manufacturer of olaparib. All other authors declare no competing financial or other interests.
Human blastocysts that fail to implant following IVF secrete elevated levels of miR-661, which is taken up by primary human endometrial epithelial cells (HEECs) and impairs their adhesive capability. MicroRNA miR-661 downregulates mouse double minute homologue 2 (MDM2) and MDM4 in other epithelial cell types to activate p53; however, this has not been examined in the endometrium. In this study MDM2 protein was detected in the luminal epithelium of the endometrium, the site of blastocyst attachment, during the mid secretory receptive phase of the menstrual cycle. The effects of miR-661 on gene expression in and adhesion of endometrial cells was also examined. MiR-661 overexpression consistently downregulated MDM2 but not MDM4 or p53 gene expression in the Ishikawa endometrial epithelial cell line and primary HEEC. Adhesion assays were performed on the real-time monitoring xCELLigence system and by co-culture using Ishikawa cells and HEECs with HTR8/SVneo trophoblast spheroids. Targeted siRNA-mediated knockdown of MDM2 in endometrial epithelial cells reduced Ishikawa cell adhesion (P<0.001) and also reduced HTR8/SVneo trophoblast spheroid adhesion to Ishikawa cells (P<0.05) and HEECs (P<0.05). MDM2 overexpression using recombinant protein treatment resulted in enhanced HTR8/SVneo trophoblast spheroid adhesion to Ishikawa cells (P<0.01) and HEECs (P<0.05). This study highlights a potential new mechanism by which human blastocyst-secreted miR-661 reduces endometrial epithelial cell adhesion; via downregulation of MDM2. These findings suggest that MDM2 contributes to endometrial-blastocyst adhesion, implantation and infertility in women.
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