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      The PARP inhibitor, olaparib, depletes the ovarian reserve in mice: implications for fertility preservation

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          Abstract

          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.

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          Most cited references16

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          Poly(ADP-ribose): novel functions for an old molecule.

          The addition to proteins of the negatively charged polymer of ADP-ribose (PAR), which is synthesized by PAR polymerases (PARPs) from NAD(+), is a unique post-translational modification. It regulates not only cell survival and cell-death programmes, but also an increasing number of other biological functions with which novel members of the PARP family have been associated. These functions include transcriptional regulation, telomere cohesion and mitotic spindle formation during cell division, intracellular trafficking and energy metabolism.
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            Is Open Access

            Mouse Estrous Cycle Identification Tool and Images

            The efficiency of producing timed pregnant or pseudopregnant mice can be increased by identifying those in proestrus or estrus. Visual observation of the vagina is the quickest method, requires no special equipment, and is best used when only proestrus or estrus stages need to be identified. Strain to strain differences, especially in coat color can make it difficult to determine the stage of the estrous cycle accurately by visual observation. Presented here are a series of images of the vaginal opening at each stage of the estrous cycle for 3 mouse strains of different coat colors: black (C57BL/6J), agouti (CByB6F1/J) and albino (BALB/cByJ). When all 4 stages (proestrus, estrus, metestrus, and diestrus) need to be identified, vaginal cytology is regarded as the most accurate method. An identification tool is presented to aid the user in determining the stage of estrous when using vaginal cytology. These images and descriptions are an excellent resource for learning how to determine the stage of the estrous cycle by visual observation or vaginal cytology.
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              Cancer incidence and mortality among young adults aged 20–39 years worldwide in 2012: a population-based study

              To date, the burden of cancer among young adults has rarely been studied in depth. Our aim was to describe the scale and profile of cancer incidence and mortality worldwide among 20-39 year-olds, highlighting major patterns by age, sex, development level, and geographical region.
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                Author and article information

                Journal
                Human Reproduction
                Oxford University Press (OUP)
                0268-1161
                1460-2350
                June 30 2020
                June 30 2020
                Affiliations
                [1 ]Ovarian Biology Laboratory, Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Stem Cells and Development Program, Monash University, Clayton, VIC 3800, Australia
                [2 ]Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
                [3 ]Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3000, Australia
                [4 ]Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC 3010, Australia
                Article
                10.1093/humrep/deaa128
                32604417
                3fdd1830-a534-41e8-96a6-47c0cc2194e7
                © 2020

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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