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Du T, Su H, Cao D, Meng Q, Zhang M, Liu Z, Li H. Mitochondria-targeted antioxidant mitoquinone mitigates vitrification-induced damage in mouse ovarian tissue by maintaining mitochondrial homeostasis via the p38 MAPK pathway. Eur J Med Res 2024; 29:593. [PMID: 39696534 DOI: 10.1186/s40001-024-02181-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/12/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024] Open
Abstract
OBJECTIVE Ovarian tissue cryopreservation has become a promising alternative for fertility preservation in cancer patients, allowing ovarian tissue to be stored for future autotransplantation. Oxidative stress damage occurring during the cryopreservation process may impact tissue quality and function. This study aims to investigate the protective effects and potential mechanisms of Mitoquinone (MitoQ), a mitochondria-targeted derivative of the antioxidant ubiquinone, during the vitrification of ovarian tissue in mice. METHODS KGN cells were treated with various concentrations (0.1, 1, 10, and 50 μM) of MitoQ to determine the optimal concentration. Female ICR mice were divided into three groups: control, conventional vitrification, and MitoQ-supplemented vitrification. Ovarian samples were cryopreserved, thawed, and assessed for tissue morphology using Hematoxylin and Eosin (H&E) staining, and mitochondrial changes using immunofluorescence, transmission electron microscopy, and Western blot analysis. RNA sequencing (RNA-seq) was employed to explore potential protective mechanisms. Autotransplantation experiments were conducted, and the long-term effects of MitoQ on ovarian function were evaluated by counting follicle numbers through H&E staining and measuring serum estradiol and AMH levels using ELISA. RESULTS MitoQ at 1 μM was found to be the optimal concentration for maintaining follicular morphology after vitrification. It effectively reduced mitochondrial oxidative damage, preserved mitochondrial morphology, and regulated the expression of mitochondrial dynamics proteins (Drp1 and Mfn2). RNA-seq and Western blot analyses revealed that MitoQ inhibited the p38 MAPK pathway, thereby reducing apoptosis. Additionally, autotransplantation experiments showed that MitoQ treatment significantly increased follicle counts, estradiol (E2), and anti-Müllerian hormone (AMH) levels compared to conventional vitrification. CONCLUSIONS MitoQ effectively mitigates vitrification-induced oxidative damage, maintains mitochondrial homeostasis, and preserves both follicular reserve and endocrine function. These findings suggest that MitoQ is a valuable adjunct in ovarian tissue cryopreservation and could significantly improve fertility preservation outcomes for cancer patients.
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Affiliation(s)
- Tianqi Du
- Center for Human Reproduction and Genetics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhouing, China
| | - Han Su
- Key Laboratory of Reproductive Medicine and Offspring Health, Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing Medical University, Suzhouing, China
- Obstetrics and Gynecology Department, BENQ Medical Center, Nanjing, China
| | - Dan Cao
- Department of Pathology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhouing, China
| | - Qingxia Meng
- Center for Human Reproduction and Genetics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhouing, China
| | - Ming Zhang
- Center for Human Reproduction and Genetics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhouing, China
- Key Laboratory of Reproductive Medicine and Offspring Health, Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing Medical University, Suzhouing, China
| | - Zhenxing Liu
- Center for Human Reproduction and Genetics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhouing, China
| | - Hong Li
- Center for Human Reproduction and Genetics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhouing, China.
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2
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Swigonska S, Nynca A, Molcan T, Petroff BK, Ciereszko RE. The Role of lncRNAs in the Protective Action of Tamoxifen on the Ovaries of Tumor-Bearing Rats Receiving Cyclophosphamide. Int J Mol Sci 2024; 25:12538. [PMID: 39684249 DOI: 10.3390/ijms252312538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/29/2024] [Revised: 11/14/2024] [Accepted: 11/17/2024] [Indexed: 12/18/2024] Open
Abstract
Infertility due to ovarian toxicity is a common side effect of cancer treatment in premenopausal women. Tamoxifen (TAM) is a selective estrogen receptor modulator that prevented radiation- and chemotherapy-induced ovarian failure in preclinical studies. In the current study, we examined the potential regulatory role of long noncoding RNAs (lncRNAs) in the mechanism of action of TAM in the ovaries of tumor-bearing rats receiving cyclophosphamide (CPA) as cancer therapy. We identified 166 lncRNAs, among which 49 were demonstrated to be differentially expressed (DELs) in the ovaries of rats receiving TAM and CPA compared to those receiving only CPA. A total of 24 DELs were upregulated and 25 downregulated by tamoxifen. The identified DELs shared the characteristics of noncoding RNAs described in other reproductive tissues. Eleven of the identified DELs displayed divergent modes of action, regulating target transcripts via both cis- and trans-acting pathways. Functional enrichment analysis revealed that, among target genes ascribed to the identified DELs, the majority were involved in apoptosis, cell adhesion, immune response, and ovarian aging. The presented data suggest that the molecular mechanisms behind tamoxifen's protective effects in the ovaries may involve lncRNA-dependent regulation of critical signaling pathways related to inhibition of follicular transition and ovarian aging, along with the suppression of apoptosis and regulation of cell adhesion. Employing a tumor-bearing animal model undergoing chemotherapy, which accurately reflects the conditions of mammary cancer, reinforces the obtained results. Given that tamoxifen remains a key player in the management and prevention of breast cancer, understanding its ovarian-specific actions in cancer patients is crucial and requires detailed functional studies to clarify the underlying molecular mechanisms.
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Affiliation(s)
- Sylwia Swigonska
- Department of Biochemistry, University of Warmia and Mazury in Olsztyn, Prawochenskiego 5, 10-720 Olsztyn, Poland
| | - Anna Nynca
- Department of Animal Anatomy and Physiology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland
| | - Tomasz Molcan
- Molecular Biology Laboratory, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748 Olsztyn, Poland
| | - Brian K Petroff
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824-1314, USA
| | - Renata E Ciereszko
- Department of Animal Anatomy and Physiology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland
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Klangsin S, Matemanosak P, Peeyananjarassri K, Wattanakumtornkul S, Tubtawee T, Trongnit S, Geater AF. Effect of radiation on serum anti-Müllerian hormone during hysterosalpingography in female infertility. Reprod Biomed Online 2024; 48:103843. [PMID: 38554680 DOI: 10.1016/j.rbmo.2024.103843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/19/2023] [Revised: 12/17/2023] [Accepted: 01/02/2024] [Indexed: 04/02/2024]
Abstract
RESEARCH QUESTION Does radiation exposure during hysterosalpingography (HSG) negatively affect serum anti-Müllerian hormone (AMH) levels in infertile women? DESIGN Prospective cohort study conducted at Songklanagarind Hospital, Thailand, between April 2021 and May 2023. Thirty-two infertile women and 34 control participants were enrolled. Serum AMH levels were assessed in the infertile group at baseline before the HSG procedure and at 1 and 3 months after the procedure. Control participants, who self-reported no medical conditions, underwent the same AMH level assessments. Changes in serum AMH levels were compared. RESULTS Infertile women had a mean age of 32.4 ± 3.8 years, body mass index of 21.2 ± 2.0 kg/m2 and baseline mean AMH level of 3.66 ng/ml (95% CI 3.00 to 4.32), which did not significantly differ from the control group. One month after HSG, mean AMH level significantly declined (0.33 ng/ml, 95% CI -0.65 to -0.01; P = 0.045) in the infertile group. The change in serum AMH levels between baseline and 1 month was significantly different in the HSG group compared with controls (-0.33 ng/ml, 95% CI -0.65 to -0.01 versus 0.36 ng/ml, 95% CI 0.06 to 0.67; P = 0.002). Changes in serum AMH levels from baseline to 3 months did not differ between the two groups. CONCLUSIONS One month after the HSG, infertile women experienced a significant decrease in serum AMH levels compared with controls. The change in serum AMH levels between baseline and 3 months after HSG did not significantly differ from that of the control group.
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Affiliation(s)
- Satit Klangsin
- Department of Obstetrics and Gynecology, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand..
| | - Phawat Matemanosak
- Department of Obstetrics and Gynecology, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Krantarat Peeyananjarassri
- Department of Obstetrics and Gynecology, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Saranya Wattanakumtornkul
- Department of Obstetrics and Gynecology, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Teeravut Tubtawee
- Department of Radiology, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Sasipong Trongnit
- Department of Pathology, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Alan F Geater
- Epidemiology Unit, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
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4
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Helgadottir H, Matikas A, Fernebro J, Frödin JE, Ekman S, Rodriguez-Wallberg KA. Fertility and reproductive concerns related to the new generation of cancer drugs and the clinical implication for young individuals undergoing treatments for solid tumors. Eur J Cancer 2024; 202:114010. [PMID: 38520926 DOI: 10.1016/j.ejca.2024.114010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/19/2024] [Revised: 03/03/2024] [Accepted: 03/05/2024] [Indexed: 03/25/2024]
Abstract
The treatment landscape of solid tumors has changed markedly in the last years. Molecularly targeted treatments and immunotherapies have been implemented and have, in many cancers, lowered the risk of relapse and prolonged survival. Patients with tumors harboring specific targetable molecular alterations or mutations are often of a younger age, and hence future fertility and family building can be important concerns in this group. However, there are great uncertainties regarding the effect of the new drugs on reproductive functions, including fertility, pregnancy and lactation and how young patients with cancers, both women and men should be advised. The goal with this review is to gather the current knowledge regarding oncofertility and the different novel therapies, including immune checkpoint inhibitors, antibody-drug conjugates, small molecules and monoclonal antibody targeted therapies. The specific circumstances and reproductive concerns in different patient groups where novel treatments have been broadly introduced are also discussed, including those with melanoma, lung, breast, colorectal and gynecological cancers. It is clear, that more awareness is needed regarding potential drug toxicity on reproductive tissues, and it is of essence that individuals are informed based on current expertise and on available fertility preservation methods.
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Affiliation(s)
- Hildur Helgadottir
- Department of Oncology and Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden; Skin Cancer Centrum, Theme Cancer, Karolinska University Hospital, 171 76 Stockholm, Sweden.
| | - Alexios Matikas
- Department of Oncology and Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden; Breast Center, Karolinska Comprehensive Cancer Center and Karolinska University Hospital, Stockholm, Sweden
| | - Josefin Fernebro
- Department of Oncology and Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden; Division of Gynecological Cancer, Department of Pelvic Cancer, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Jan-Erik Frödin
- Department of Oncology and Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden; Division of Gastrointestinal Oncology, Department of Upper abdomen, Karolinska University Hospital, Sweden
| | - Simon Ekman
- Department of Oncology and Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden; Thoracic Oncology Center, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Kenny A Rodriguez-Wallberg
- Department of Oncology and Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Reproductive Medicine, Division of Gynecology and Reproduction Karolinska University Hospital, Stockholm, Sweden
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5
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Najafi A, Asadi E, Benson JD. Ovarian tissue cryopreservation and transplantation: a review on reactive oxygen species generation and antioxidant therapy. Cell Tissue Res 2023; 393:401-423. [PMID: 37328708 DOI: 10.1007/s00441-023-03794-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/30/2022] [Accepted: 05/31/2023] [Indexed: 06/18/2023]
Abstract
Cancer is the leading cause of death worldwide. Fortunately, the survival rate of cancer continues to rise, owing to advances in cancer treatments. However, these treatments are gonadotoxic and cause infertility. Ovarian tissue cryopreservation and transplantation (OTCT) is the most flexible option to preserve fertility in women and children with cancer. However, OTCT is associated with significant follicle loss and an accompanying short lifespan of the grafts. There has been a decade of research in cryopreservation-induced oxidative stress in single cells with significant successes in mitigating this major source of loss of viability. However, despite its success elsewhere and beyond a few promising experiments, little attention has been paid to this key aspect of OTCT-induced damage. As more and more clinical practices adopt OTCT for fertility preservation, it is a critical time to review oxidative stress as a cause of damage and to outline potential ameliorative interventions. Here we give an overview of the application of OTCT for female fertility preservation and existing challenges; clarify the potential contribution of oxidative stress in ovarian follicle loss; and highlight potential ability of antioxidant treatments to mitigate the OTCT-induced injuries that might be of interest to cryobiologists and reproductive clinicians.
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Affiliation(s)
- Atefeh Najafi
- Department of Biology, University of Saskatchewan, S7N 5E2, Saskatoon, SK, Canada
| | - Ebrahim Asadi
- Department of Biology, University of Saskatchewan, S7N 5E2, Saskatoon, SK, Canada
| | - James D Benson
- Department of Biology, University of Saskatchewan, S7N 5E2, Saskatoon, SK, Canada.
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6
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Parental chest computerized tomography examination before IVF/ICSI has no impact on pregnancy and neonatal outcomes: a cohort study of 2680 fresh transfer cycles. BMC Pregnancy Childbirth 2022; 22:965. [PMID: 36572853 PMCID: PMC9791144 DOI: 10.1186/s12884-022-05297-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/12/2022] [Accepted: 12/08/2022] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Some concern has been expressed regarding the negative effects of low-level ionizing radiation exposure in the context of radiological evaluation prior to IVF/ICSI treatment, but the available evidence is limited and conflicting. The aim of this study is to evaluate pregnancy and neonatal outcomes of couples who did chest computed tomography (CT) prior to IVF/ICSI. METHODS This was a retrospective cohort study of 2680 IVF/ICSI fresh embryo transfer cycles conducted from January 2019 - August 2020. Fertility outcomes were compared between couples that had or had not undergone CT examination within 3 months prior to the date of oocyte retrieval and sperm collection. Miscarriage was the primary study outcome, while secondary outcomes included the number of oocytes collected, oocyte maturation, normal fertilization, number of good quality cleavage stage embryos, blastocyst formation, implantation, clinical pregnancy, ectopic pregnancy, live birth, multiple birth, Cesarean section rates, gestational weeks, maternal obstetric complications, birth weight, newborn sex ratio, and birth defect incidence. Propensity score matching was used to control for potential confounding variables. RESULTS Of the 2680 cycles included in this study, couples underwent CT examination in 731 cycles. After 1:1 propensity score matching, 670 cycles were included in each group. When comparing demographic and fertility-related variables between groups that had and had not undergone CT examination after propensity score matching, we detected no significant differences in miscarriage rates (16.99% vs. 15.77%, OR = 1.10, 95CI% = 0.74 to 1.68). Similarly, both groups exhibited comparable oocyte and embryonic development, implantation rates (41.99% vs. 40.42%, OR = 1.07, 95%CI = 0.87 to 1.31), clinical pregnancy rates (45.67% vs. 44.48%, OR = 1.05, 95%CI = 0.85 to 1.30), ectopic pregnancy rates (2.94% vs. 1.68%, OR = 1.78, 95%CI = 0.59 to 5.36), live birth rates (36.57% vs. 35.67%, OR = 1.04, 95%CI = 0.83 to 1.30), multiple birth rates, Cesarean section rates, gestational weeks, maternal obstetric complication rates, and neonatal outcomes. CONCLUSIONS Chest CT examination before IVF/ICSI has no impact on pregnancy and neonatal outcomes associated with fresh embryo transfer. TRIAL REGISTRATION Not applicable.
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7
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Weng D, Xiong H, Zhu C, Wan X, Chen Y, Wang X, Zhang Y, Jiang J, Zhang X, Gao Q, Chen G, Xing H, Wang C, Li K, Chen Y, Mao Y, Hu D, Pan Z, Chen Q, Cui B, Song K, Yi C, Peng G, Han X, An R, Fan L, Wang W, Xiong T, Chen Y, Tang Z, Li L, Yang X, Cheng X, Lu W, Wang H, Kong B, Xie X, Ma D. Adjuvant chemotherapy versus adjuvant concurrent chemoradiotherapy after radical surgery for early-stage cervical cancer: a randomized, non-inferiority, multicenter trial. Front Med 2022; 17:93-104. [PMID: 36422763 PMCID: PMC9686219 DOI: 10.1007/s11684-021-0892-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/26/2021] [Accepted: 08/24/2021] [Indexed: 11/25/2022]
Abstract
We conducted a prospective study to assess the non-inferiority of adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) as an alternative strategy for patients with early-stage (FIGO 2009 stage IB-IIA) cervical cancer having risk factors after surgery. The condition was assessed in terms of prognosis, adverse effects, and quality of life. This randomized trial involved nine centers across China. Eligible patients were randomized to receive adjuvant chemotherapy or CCRT after surgery. The primary end-point was progression-free survival (PFS). From December 2012 to December 2014, 337 patients were subjected to randomization. Final analysis included 329 patients, including 165 in the adjuvant chemotherapy group and 164 in the adjuvant CCRT group. The median follow-up was 72.1 months. The three-year PFS rates were both 91.9%, and the five-year OS was 90.6% versus 90.0% in adjuvant chemotherapy and CCRT groups, respectively. No significant differences were observed in the PFS or OS between groups. The adjusted HR for PFS was 0.854 (95% confidence interval 0.415-1.757; P = 0.667) favoring adjuvant chemotherapy, excluding the predefined non-inferiority boundary of 1.9. The chemotherapy group showed a tendency toward good quality of life. In comparison with post-operative adjuvant CCRT, adjuvant chemotherapy treatment showed non-inferior efficacy in patients with early-stage cervical cancer having pathological risk factors. Adjuvant chemotherapy alone is a favorable alternative post-operative treatment.
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Affiliation(s)
- Danhui Weng
- grid.33199.310000 0004 0368 7223Department of Obstetrics and Gynecology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Huihua Xiong
- grid.33199.310000 0004 0368 7223Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Changkun Zhu
- grid.13402.340000 0004 1759 700XDepartment of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006 China
| | - Xiaoyun Wan
- grid.13402.340000 0004 1759 700XDepartment of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006 China
| | - Yaxia Chen
- grid.13402.340000 0004 1759 700XDepartment of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006 China
| | - Xinyu Wang
- grid.13402.340000 0004 1759 700XDepartment of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006 China
| | - Youzhong Zhang
- grid.27255.370000 0004 1761 1174Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, 250012 China
| | - Jie Jiang
- grid.27255.370000 0004 1761 1174Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, 250012 China
| | - Xi Zhang
- grid.27255.370000 0004 1761 1174Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, 250012 China
| | - Qinglei Gao
- grid.33199.310000 0004 0368 7223Department of Obstetrics and Gynecology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Gang Chen
- grid.33199.310000 0004 0368 7223Department of Obstetrics and Gynecology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Hui Xing
- grid.412979.00000 0004 1759 225XDepartment of Obstetrics and Gynecology, Xiangyang Central Hospital, Hubei University of Arts and Science, Xiangyang, 441021 China
| | - Changyu Wang
- grid.33199.310000 0004 0368 7223Department of Obstetrics and Gynecology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Kezhen Li
- grid.33199.310000 0004 0368 7223Department of Obstetrics and Gynecology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Yaheng Chen
- grid.33199.310000 0004 0368 7223Department of Obstetrics and Gynecology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Yuyan Mao
- grid.13402.340000 0004 1759 700XDepartment of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006 China
| | - Dongxiao Hu
- grid.13402.340000 0004 1759 700XDepartment of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006 China
| | - Zimin Pan
- grid.13402.340000 0004 1759 700XDepartment of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006 China
| | - Qingqin Chen
- grid.13402.340000 0004 1759 700XDepartment of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006 China
| | - Baoxia Cui
- grid.27255.370000 0004 1761 1174Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, 250012 China
| | - Kun Song
- grid.27255.370000 0004 1761 1174Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, 250012 China
| | - Cunjian Yi
- grid.410654.20000 0000 8880 6009Department of Obstetrics and Gynecology, The First Affiliated Hospital of Yangtze University, Jingmen, 448000 China
| | - Guangcai Peng
- grid.410654.20000 0000 8880 6009Department of Obstetrics and Gynecology, The First Affiliated Hospital of Yangtze University, Jingmen, 448000 China
| | - Xiaobing Han
- grid.452438.c0000 0004 1760 8119Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 China
| | - Ruifang An
- grid.452438.c0000 0004 1760 8119Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 China
| | - Liangsheng Fan
- grid.470124.4Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120 China
| | - Wei Wang
- grid.470124.4Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120 China
| | - Tingchuan Xiong
- grid.13394.3c0000 0004 1799 3993Department of Gynecologic Oncology, Affiliated Tumour Hospital, Xinjiang Medical University, Urumqi, 830000 China
| | - Yile Chen
- grid.410622.30000 0004 1758 2377Department of Gynecologic Oncology, Hunan Province Tumor Hospital, Changsha, 410013 China
| | - Zhenzi Tang
- grid.410622.30000 0004 1758 2377Department of Gynecologic Oncology, Hunan Province Tumor Hospital, Changsha, 410013 China
| | - Lin Li
- grid.412979.00000 0004 1759 225XDepartment of Obstetrics and Gynecology, Xiangyang Central Hospital, Hubei University of Arts and Science, Xiangyang, 441021 China
| | - Xingsheng Yang
- grid.27255.370000 0004 1761 1174Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, 250012 China
| | - Xiaodong Cheng
- grid.13402.340000 0004 1759 700XDepartment of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006 China
| | - Weiguo Lu
- grid.13402.340000 0004 1759 700XDepartment of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006 China
| | - Hui Wang
- grid.33199.310000 0004 0368 7223Department of Obstetrics and Gynecology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China ,grid.13402.340000 0004 1759 700XDepartment of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006 China
| | - Beihua Kong
- grid.27255.370000 0004 1761 1174Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, 250012 China
| | - Xing Xie
- grid.13402.340000 0004 1759 700XDepartment of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006 China
| | - Ding Ma
- grid.33199.310000 0004 0368 7223Department of Obstetrics and Gynecology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
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8
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Rives N, Courbière B, Almont T, Kassab D, Berger C, Grynberg M, Papaxanthos A, Decanter C, Elefant E, Dhedin N, Barraud-Lange V, Béranger MC, Demoor-Goldschmidt C, Frédérique N, Bergère M, Gabrel L, Duperray M, Vermel C, Hoog-Labouret N, Pibarot M, Provansal M, Quéro L, Lejeune H, Methorst C, Saias J, Véronique-Baudin J, Giscard d'Estaing S, Farsi F, Poirot C, Huyghe É. What should be done in terms of fertility preservation for patients with cancer? The French 2021 guidelines. Eur J Cancer 2022; 173:146-166. [PMID: 35932626 DOI: 10.1016/j.ejca.2022.05.013] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/15/2022] [Revised: 05/02/2022] [Accepted: 05/12/2022] [Indexed: 11/03/2022]
Abstract
AIM To provide practice guidelines about fertility preservation (FP) in oncology. METHODS We selected 400 articles after a PubMed review of the literature (1987-2019). RECOMMENDATIONS Any child, adolescent and adult of reproductive age should be informed about the risk of treatment gonadotoxicity. In women, systematically proposed FP counselling between 15 and 38 years of age in case of treatment including bifunctional alkylating agents, above 6 g/m2 cyclophosphamide equivalent dose (CED), and for radiation doses on the ovaries ≥3 Gy. For postmenarchal patients, oocyte cryopreservation after ovarian stimulation is the first-line FP technique. Ovarian tissue cryopreservation should be discussed as a first-line approach in case of treatment with a high gonadotoxic risk, when chemotherapy has already started and in urgent cases. Ovarian transposition is to be discussed prior to pelvic radiotherapy involving a high risk of premature ovarian failure. For prepubertal girls, ovarian tissue cryopreservation should be proposed in the case of treatment with a high gonadotoxic risk. In pubertal males, sperm cryopreservation must be systematically offered to any male who is to undergo cancer treatment, regardless of toxicity. Testicular tissue cryopreservation must be proposed in males unable to cryopreserve sperm who are to undergo a treatment with intermediate or severe risk of gonadotoxicity. In prepubertal boys, testicular tissue preservation is: - recommended for chemotherapy with a CED ≥7500 mg/m2 or radiotherapy ≥3 Gy on both testicles. - proposed for chemotherapy with a CED ≥5.000 mg/m2 or radiotherapy ≥2 Gy. If several possible strategies, the ultimate choice is made by the patient.
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Affiliation(s)
- Nathalie Rives
- Normandie Univ, UNIROUEN, Team "Adrenal and Gonadal Physiopathology" Inserm U1239 Nordic, Rouen University Hospital, Biology of Reproduction-CECOS Laboratory, Rouen, France
| | - Blandine Courbière
- Reproductive Medicine and Biology Department, Assistance Publique Hôpitaux de Marseille, Marseille, Provence-Alpes-Côte d'Azur, France
| | - Thierry Almont
- Cancerology, Urology, Hematology Department, Centre Hospitalier Universitaire de Martinique, Fort-de-France, Martinique, France; General Cancer Registry of Martinique UF1441, Centre Hospitalier Universitaire de Martinique, Fort-de-France, Martinique, France
| | - Diana Kassab
- Methodology Unit, Association Française d'Urologie, Paris, Ile-de-France, France
| | - Claire Berger
- Department of Pediatric Hematology and Oncology, University-Hospital of Saint-Etienne, Hospital, Nord Saint-Etienne cedex 02, France 42055; Childhood Cancer Registry of the Rhône-Alpes Region, University of Saint-Etienne, 15 rue Ambroise Paré, Saint-Etienne cedex 02, France 42023
| | - Michaël Grynberg
- Reproductive Medicine and Fertility Department, Hôpital Antoine-Beclère, Clamart, Île-de-France, France
| | - Aline Papaxanthos
- Reproductive Medicine and Biology Department, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, Aquitaine, France
| | - Christine Decanter
- Medically Assisted Procreation and Fertility Preservation Department, Centre Hospitalier Régional Universitaire de Lille, Lille, Hauts-de-France, France
| | - Elisabeth Elefant
- Reference Center for Teratogenic Agents, Hôpital Armand-Trousseau Centre de Référence sur les Agents Tératogènes, Paris, Île-de-France, France
| | - Nathalie Dhedin
- Adolescents and Young Adults Unit, Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris, France
| | - Virginie Barraud-Lange
- Reproductive Medicine and Biology Department, Hôpital Cochin, Paris, Île-de-France, France
| | | | | | - Nicollet Frédérique
- Information and Promotion Department, Association Laurette Fugain, Paris, France
| | - Marianne Bergère
- Human Reproduction, Embryology and Genetics Directorate, Agence de la biomédecine, La Plaine Saint-Denis, France
| | - Lydie Gabrel
- Good Practices Unit - Guidelines and Medicines Directorate, Institut National du Cancer, Billancourt, Île-de-France, France
| | - Marianne Duperray
- Guidelines and Drug Directorate, Institut National du Cancer, Billancourt, Île-de-France, France
| | - Christine Vermel
- Expertise Quality and Compliance Mission - Communication and Information Directorate, Institut National du Cancer, Billancourt, Île-de-France, France
| | - Natalie Hoog-Labouret
- Research and Innovation, Institut National du Cancer, Billancourt, Île-de-France, France
| | - Michèle Pibarot
- OncoPaca-Corse Regional Cancer Network, Assistance Publique - Hôpitaux de Marseille, Marseille, Provence-Alpes-Côte d'Azur, France
| | - Magali Provansal
- Medical Oncology Department, Institut Paoli-Calmettes, Marseille, Provence-Alpes-Côte d'Azur, France
| | - Laurent Quéro
- Cancerology and Radiotherapy Department, Hôpital Saint Louis, AP-HP, Paris, France
| | - Hervé Lejeune
- Reproductive Medicine and Biology Department, Hospices Civils de Lyon, Lyon, Auvergne-Rhône-Alpes, France
| | - Charlotte Methorst
- Reproductive Medicine and Biology Department, Centre Hospitalier des Quatre Villes - Site de Saint-Cloud, Saint-Cloud, France
| | - Jacqueline Saias
- Reproductive Medicine and Biology Department, Assistance Publique Hôpitaux de Marseille, Marseille, Provence-Alpes-Côte d'Azur, France
| | - Jacqueline Véronique-Baudin
- Cancerology, Urology, Hematology Department, Centre Hospitalier Universitaire de Martinique, Fort-de-France, Martinique, France; General Cancer Registry of Martinique UF1441, Centre Hospitalier Universitaire de Martinique, Fort-de-France, Martinique, France
| | - Sandrine Giscard d'Estaing
- Reproductive Medicine and Biology Department, Hospices Civils de Lyon, Lyon, Auvergne-Rhône-Alpes, France
| | - Fadila Farsi
- Regional Cancer Network, Réseau Espace Santé Cancer, Lyon, Rhône-Alpes, France
| | - Catherine Poirot
- Adolescents and Young Adults Unit, Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris, France
| | - Éric Huyghe
- Urology Department, Centre Hospitalier Universitaire de Toulouse, Toulouse, France; Laboratoire Développement Embryonnaire, Fertilité et Environnement (DEFE) UMR 1203, Université Toulouse 3 Paul Sabatier, Toulouse, France.
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9
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The effect of hematopoietic stem cell transplantation on fertility and strategies for improvement. Bone Marrow Transplant 2022; 57:1649-1656. [PMID: 36038764 DOI: 10.1038/s41409-022-01792-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/11/2022] [Revised: 07/30/2022] [Accepted: 08/15/2022] [Indexed: 11/09/2022]
Abstract
Ovarian dysfunction is an important consequence of hematopoietic stem cell transplantation (HCT). Premature ovarian failure and infertility can severely impact the quality of life for the increasing number of female long-term survivors of HCT. Here, we review the impact of HCT on ovarian function, post-transplant fertility and birth outcomes, and the contemporaneous strategies to preserve fertility for these patients.
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10
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Oxidative Stress and Human Ovarian Response—From Somatic Ovarian Cells to Oocytes Damage: A Clinical Comprehensive Narrative Review. Antioxidants (Basel) 2022; 11:antiox11071335. [PMID: 35883826 PMCID: PMC9311552 DOI: 10.3390/antiox11071335] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/04/2022] [Revised: 07/03/2022] [Accepted: 07/05/2022] [Indexed: 11/17/2022] Open
Abstract
Basic scientific research on human reproduction and oxidative damage has been extensively performed; however, a more clinical view is still lacking. As a result, exhaustive data on the influence of oxidative stress on human ovarian response and, consequently, on fertility are still lacking. This narrative review aims at summarizing the role of oxidative stress in different conditions associated to female infertility and to list some of the main antioxidant agents. A systematic literature search was performed in May 2022 to retrieve studies regarding the oxidative stress and the human ovarian response from somatic ovarian cells to oocytes damage. Only human studies were included and the authors focused their review, in particular, on clinical implications in order to define a new research perspective on the assessment of any eventual strategy to preserve women’s fertility. Thereby, the authors evaluated the contribution of DNA repair pathways in improving women’s fertility by reducing the DNA damage associated with aging or diseases, such as endometriosis or polycystic ovary syndrome, and eventually, in prolonging the reproductive lifespan after cancer treatment.
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11
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Di Tucci C, Galati G, Mattei G, Chinè A, Fracassi A, Muzii L. Fertility after Cancer: Risks and Successes. Cancers (Basel) 2022; 14:2500. [PMID: 35626104 PMCID: PMC9139810 DOI: 10.3390/cancers14102500] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/29/2022] [Revised: 05/08/2022] [Accepted: 05/16/2022] [Indexed: 12/22/2022] Open
Abstract
The incidence of cancer in reproductive-aged women is 7%, but, despite the increased number of cancer cases, advances in early diagnosis and treatment have raised the survival rate. Furthermore, in the last four decades, there has been a rising trend of delaying childbearing. There has been an increasing number of couples referred to Reproductive Medicine Centers for infertility problems after one partner has been treated for cancer. In these cases, the main cause of reduced fertility derives from treatments. In this review, we describe the effects and the risks of chemotherapy, radiotherapy, and surgery in women with cancer, and we will focus on available fertility preservation techniques and their efficacy in terms of success in pregnancy and live birth rates.
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Affiliation(s)
- Chiara Di Tucci
- Department of Obstetrics and Gynecology, “Sapienza” University, 00185 Rome, Italy; (G.G.); (G.M.); (A.C.); (A.F.); (L.M.)
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12
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Wu J, Lakomy DS, Fellman BM, Salcedo MP, Sood AK, Jhingran A, Klopp AH, Iyer RB, Jimenez C, Colbert LE, Eifel PJ, Schmeler KM, Lin LL. Longitudinal Changes in Bone Mineral Measurements Inside and Outside Radiation Fields Used for Cervical Cancer Treatment. Pract Radiat Oncol 2022; 12:e423-e433. [PMID: 35390531 DOI: 10.1016/j.prro.2022.03.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/05/2022] [Revised: 03/18/2022] [Accepted: 03/31/2022] [Indexed: 11/26/2022]
Abstract
PURPOSE We compared the magnitude of changes in bone mineral density (BMD), within and outside the radiation field, among women who received pelvic radiotherapy (RT) with or without chemotherapy for cervical cancer. PATIENTS & METHODS In this secondary analysis of a prospective study, we analyzed serial CT scans and dual-energy X-ray absorptiometry (DXA) scans from 78 patients who received definitive RT or chemoradiation (CRT) for cervical cancer at a single institution from 2008 to 2015. BMD values at L1, L2, L3 and L4 were measured. We compared changes in BMD within the radiation field (i.e., at L4) with those outside the field (i.e., at L1). Linear mixed models were also used to examine the effect of RT on changes in BMD over time and covariate adjustment. RESULTS The median age of the 78 patients was 45.5 years (range 23-88); all received RT and 76 (97%) received concurrent CRT. Treatment was associated with significant declines in BMD in all 4 lumbar vertebral bodies over time (P<0.05), with nadir at 3 months for L4 and at 1 year for L1. Pairwise comparisons at 3 months and 2 years after treatment indicated that BMD in L4 (within the RT field) had improved (P=0.037), but BMD in L1 (outside the RT field) was no different at 3 months and 2 years. CONCLUSIONS Significant BMD declines were observed in all lumbar vertebral bodies immediately following RT. However, in-field vertebral bodies reached nadir BMD earlier than those located outside the RT field. Our results suggest that treatment and patient-related factors other than RT may contribute to declines in BMD after treatment for cervical cancer. Routine bone density screening and post-RT therapy with hormones may be beneficial for selected patients who receive CRT for cervical cancer.
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Affiliation(s)
- Juliana Wu
- University of Texas Medical Branch, Galveston, TX; Departments of Radiation Oncology, Houston, TX
| | - David S Lakomy
- Departments of Radiation Oncology, Houston, TX; Dartmouth Geisel School of Medicine, Hanover, NH
| | | | - Mila P Salcedo
- Departments of Gynecologic Oncology and Reproductive Medicine, Houston, TX; Obstetrics and Gynecology Department, Federal University of Health Sciences/Irmandade Santa Casa de Misericordia, Porto Alegre, Brazil
| | - Anil K Sood
- Departments of Gynecologic Oncology and Reproductive Medicine, Houston, TX
| | | | - Ann H Klopp
- Departments of Radiation Oncology, Houston, TX
| | | | - Camilo Jimenez
- Departments of Endocrinology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | | | | | - Lilie L Lin
- Departments of Radiation Oncology, Houston, TX.
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13
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Luo S, Ruan X, Mueck AO. The effect of Kuntai capsule on ovarian function in cisplatin-induced premature ovarian insufficiency rats. Front Endocrinol (Lausanne) 2022; 13:1097165. [PMID: 36743924 PMCID: PMC9892898 DOI: 10.3389/fendo.2022.1097165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 11/13/2022] [Accepted: 12/29/2022] [Indexed: 01/20/2023] Open
Abstract
OBJECTIVE This study aims to evaluate the effect of Kuntai capsule on ovarian function in cisplatin-induced premature ovarian insufficiency rats and to explore the mechanism of Kuntai capsule on the ovarian function of rats. METHODS Seventy-four female Sprague-Dawley rats were used for this study. Eight of the rats were randomly assigned to the Control group. The remaining sixty-six rats were utilized to establish the POI model via Cisplatin and then randomly divided into four groups: the model Control group, the Estradiol group, and groups treated with low and high doses of Kuntai capsule. For the 28-day administration, the Control and model Control groups were intragastrically administered with 2.0 mL of 0.9% sodium chloride daily, the Estradiol group with 2.0 mL of Estradiol suspension (0.2mg/kg/d), and the low dose Kuntai capsule group and the high dose Kuntai capsule group with 2.0 mL of Kuntai capsule suspension (0.6g/kg/d, 1.8g/kg/d, respectively). Sex hormone levels, estrous cycle, and ovarian coefficient of the five groups were compared, histological sections analyzed follicle counts, and the protein expressions of growth differentiation factor 9, light chain 3 A-II, and Beclin 1 in the ovarian tissue were detected by Western blotting. RESULTS After the 28-day administration, the serum Estradiol and Follicle-Stimulating Hormone levels of the group treated with low dose of Kuntai capsule were not significantly different from the Control group, the serum anti-Müllerian Hormone level of the group treated with high dose of Kuntai capsule was significantly higher than the Estradiol group. The estrous cycle of the group treated with low dose of Kuntai capsule was significantly lower than the model Control group. Regarding ovarian coefficient, resting and growing follicles, growth differentiation factor 9, light chain 3 A-II, and Beclin 1 expression, both Kuntai capsule groups outperformed the model Control group with the statistical difference (P<0.05). CONCLUSION Kuntai capsule can improve the estrous cycle and ovarian coefficient of rats with premature ovarian insufficiency, maintain the number of resting and growing follicles, and up-regulate the protein expression of growth differentiation factor 9, light chain 3 A-II, and Beclin 1 of rats' ovaries.
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Affiliation(s)
- Suiyu Luo
- Department of Gynecological Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Xiangyan Ruan
- Department of Gynecological Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
- Department for Women’s Health, University Women’s Hospital and Research Center for Women’s Health, University of Tuebingen, Tuebingen, Germany
- *Correspondence: Xiangyan Ruan,
| | - Alfred O. Mueck
- Department of Gynecological Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
- Department for Women’s Health, University Women’s Hospital and Research Center for Women’s Health, University of Tuebingen, Tuebingen, Germany
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14
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Mehedintu C, Frincu F, Carp-Veliscu A, Barac R, Badiu DC, Zgura A, Cirstoiu M, Bratila E, Plotogea M. A Warning Call for Fertility Preservation Methods for Women Undergoing Gonadotoxic Cancer Treatment. Medicina (B Aires) 2021; 57:medicina57121340. [PMID: 34946285 PMCID: PMC8709408 DOI: 10.3390/medicina57121340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/01/2021] [Revised: 11/25/2021] [Accepted: 12/02/2021] [Indexed: 11/30/2022] Open
Abstract
Malignant hematological conditions have recognized an increased incidence and require aggressive treatments. Targeted chemotherapy, accompanied or not by radiotherapy, raises the chance of defeating the disease, yet cancer protocols often associate long-term gonadal consequences, for instance, diminished or damaged ovarian reserve. The negative effect is directly proportional to the types, doses, time of administration of chemotherapy, and irradiation. Additionally, follicle damage depends on characteristics of the disease and patient, such as age, concomitant diseases, previous gynecological conditions, and ovarian reserve. Patients should be adequately informed when proceeding to gonadotoxic therapies; hence, fertility preservation should be eventually regarded as a first-intention procedure. This procedure is most beneficial when performed before the onset of cancer treatment, with the recommendation for embryos or oocytes’ cryopreservation. If not feasible or acceptable, several options can be available during or after the cancer treatment. Although not approved by medical practice, promising results after in vitro studies increase the chances of future patients to protect their fertility. This review aims to emphasize the mechanism of action and impact of chemotherapy, especially the one proven to be gonadotoxic, upon ovarian reserve and future fertility. Reduced fertility or infertility, as long-term consequences of chemotherapy and, particularly, following bone marrow transplantation, is often associated with a negative impact of recovery, social and personal life, as well as highly decreased quality of life.
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Affiliation(s)
- Claudia Mehedintu
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.M.); (F.F.); (A.C.-V.), (R.B.); (A.Z.); (M.C.); (E.B.)
- Department of Obstetrics and Gynecology, “Nicolae Malaxa” Clinical Hospital, 022441 Bucharest, Romania;
| | - Francesca Frincu
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.M.); (F.F.); (A.C.-V.), (R.B.); (A.Z.); (M.C.); (E.B.)
- Department of Obstetrics and Gynecology, “Nicolae Malaxa” Clinical Hospital, 022441 Bucharest, Romania;
| | - Andreea Carp-Veliscu
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.M.); (F.F.); (A.C.-V.), (R.B.); (A.Z.); (M.C.); (E.B.)
| | - Ramona Barac
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.M.); (F.F.); (A.C.-V.), (R.B.); (A.Z.); (M.C.); (E.B.)
| | - Dumitru-Cristinel Badiu
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.M.); (F.F.); (A.C.-V.), (R.B.); (A.Z.); (M.C.); (E.B.)
- Correspondence: ; Tel.: +40-723226346
| | - Anca Zgura
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.M.); (F.F.); (A.C.-V.), (R.B.); (A.Z.); (M.C.); (E.B.)
| | - Monica Cirstoiu
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.M.); (F.F.); (A.C.-V.), (R.B.); (A.Z.); (M.C.); (E.B.)
| | - Elvira Bratila
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.M.); (F.F.); (A.C.-V.), (R.B.); (A.Z.); (M.C.); (E.B.)
| | - Mihaela Plotogea
- Department of Obstetrics and Gynecology, “Nicolae Malaxa” Clinical Hospital, 022441 Bucharest, Romania;
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15
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Zheng S, Ma M, Chen Y, Li M. Effects of quercetin on ovarian function and regulation of the ovarian PI3K/Akt/FoxO3a signalling pathway and oxidative stress in a rat model of cyclophosphamide-induced premature ovarian failure. Basic Clin Pharmacol Toxicol 2021; 130:240-253. [PMID: 34841658 DOI: 10.1111/bcpt.13696] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/02/2021] [Revised: 10/17/2021] [Accepted: 11/22/2021] [Indexed: 12/28/2022]
Abstract
To investigate the ability of quercetin to improve ovarian function and inhibit ovarian oxidative stress through the PI3K/Akt/FoxO3a signalling pathway in a rat model of premature ovarian failure (POF), we constructed a POF rat model with cyclophosphamide (CTX) and treated it with quercetin. Haematoxylin and eosin staining (H&E staining) was used to observe the morphological changes of the ovaries. The serum levels of AMH, E2, FSH, SOD, GSH-Px and MDA were determined by enzyme-linked immunosorbent assays. The expression of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), forkhead box O3a (FoxO3a) and their phosphorylated forms AMH, FSH and their receptors in the ovary were detected by western blots. The mRNA expression of PI3K, Akt, FOXO3a, AMH, FSH and their receptors was detected by qRT-PCR. Our results showed that quercetin could significantly increase the expression of AMH, E2, SOD and GSH-Px, upregulate the protein expression of AMH, FSH and its receptor and decrease the expression ratio of phosphorylated PI3K, Akt, FOXO3a and the unphosphorylated forms. Moreover, quercetin inhibited the mRNA expression of PI3K, Akt and FOXO3a. These results suggest that quercetin can restore ovarian function and inhibit oxidative stress by regulating the PI3K/Akt/FoxO3a signalling pathway.
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Affiliation(s)
- Shaoyan Zheng
- Pharmacy Department, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
| | - Mingying Ma
- Pharmacy Department, Nanfang Hospital Affiliated to Southern Medical University, Guangzhou, China
| | - Yanxia Chen
- Pharmacy Department, The First Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Miaoxia Li
- Comprehensive Laboratory, Guangdong Huiqun Chinese Traditional Medicine Co., Ltd, Shantou, China
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16
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Kim S, Kim SW, Han SJ, Lee S, Park HT, Song JY, Kim T. Molecular Mechanism and Prevention Strategy of Chemotherapy- and Radiotherapy-Induced Ovarian Damage. Int J Mol Sci 2021; 22:ijms22147484. [PMID: 34299104 PMCID: PMC8305189 DOI: 10.3390/ijms22147484] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/29/2021] [Accepted: 07/12/2021] [Indexed: 12/14/2022] Open
Abstract
Fertility preservation is an emerging discipline, which is of substantial clinical value in the care of young patients with cancer. Chemotherapy and radiation may induce ovarian damage in prepubertal girls and young women. Although many studies have explored the mechanisms implicated in ovarian toxicity during cancer treatment, its molecular pathophysiology is not fully understood. Chemotherapy may accelerate follicular apoptosis and follicle reservoir utilization and damage the ovarian stroma via multiple molecular reactions. Oxidative stress and the radiosensitivity of oocytes are the main causes of gonadal damage after radiation treatment. Fertility preservation options can be differentiated by patient age, desire for conception, treatment regimen, socioeconomic status, and treatment duration. This review will help highlight the importance of multidisciplinary oncofertility strategies for providing high-quality care to young female cancer patients.
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Affiliation(s)
- Seongmin Kim
- Gynecologic Cancer Center, CHA Ilsan Medical Center, CHA University College of Medicine, 1205 Jungang-ro, Ilsandong-gu, Goyang-si 10414, Korea;
| | - Sung-Woo Kim
- Department of Obstetrics and Gynecology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea; (S.-W.K.); (S.-J.H.)
| | - Soo-Jin Han
- Department of Obstetrics and Gynecology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea; (S.-W.K.); (S.-J.H.)
| | - Sanghoon Lee
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea; (H.-T.P.); (J.-Y.S.); (T.K.)
- Correspondence: ; Tel.: +82-2-920-6773
| | - Hyun-Tae Park
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea; (H.-T.P.); (J.-Y.S.); (T.K.)
| | - Jae-Yun Song
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea; (H.-T.P.); (J.-Y.S.); (T.K.)
| | - Tak Kim
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea; (H.-T.P.); (J.-Y.S.); (T.K.)
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17
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Oubiña G, Pascuali N, Scotti L, Bianchi S, May M, Martínez JE, Marchese Ragona C, Higuera J, Abramovich D, Parborell F. Local application of low level laser therapy in mice ameliorates ovarian damage induced by cyclophosphamide. Mol Cell Endocrinol 2021; 531:111318. [PMID: 33989716 DOI: 10.1016/j.mce.2021.111318] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/07/2020] [Revised: 05/05/2021] [Accepted: 05/07/2021] [Indexed: 01/06/2023]
Abstract
The aim of the present study is to assess whether low level laser therapy (LLLT) can protect ovaries from chemotherapy-induced gonadotoxicity using a mice model of premature ovarian failure induced by cyclophosphamide (CTX). LLLT (64 J/cm2) increased the number of antral follicles whilst decreasing the number of atretic follicles compared to CTX alone. LLLT increased the number of primordial follicles compared with those in the CTX group but they did not differ from those in the control group. LLLT treatment increased the number of AMH-positive follicles compared to CTX alone. LLLT application increased ovarian weight, serum progesterone concentration and P450scc protein levels compared to CTX alone. LLLT reduced the apoptosis in antral follicles and the BAX/BCL-2 ratio compared to CTX alone. Vascular morphology, analysed by CD31 and α-SMA immunostaining, was restored in LLLT-treated ovaries compared to CTX alone. In conclusion, application of LLLT prior to CTX might serve as a promising and novel protocol to preserve female fertility in cancer survivors.
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Affiliation(s)
- Gonzalo Oubiña
- Instituto de Biología y Medicina Experimental (IByME) - CONICET, Buenos Aires, Argentina
| | - Natalia Pascuali
- Instituto de Biología y Medicina Experimental (IByME) - CONICET, Buenos Aires, Argentina
| | - Leopoldina Scotti
- Instituto de Biología y Medicina Experimental (IByME) - CONICET, Buenos Aires, Argentina
| | - Silvia Bianchi
- Instituto de Biología y Medicina Experimental (IByME) - CONICET, Buenos Aires, Argentina
| | - María May
- Instituto de Investigaciones Farmacológicas (ININFA-UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | | | | | | | - Dalhia Abramovich
- Instituto de Biología y Medicina Experimental (IByME) - CONICET, Buenos Aires, Argentina
| | - Fernanda Parborell
- Instituto de Biología y Medicina Experimental (IByME) - CONICET, Buenos Aires, Argentina.
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18
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Kauffman RP, Young C, Castracane VD. Perils of prolonged ovarian suppression and hypoestrogenism in the treatment of breast cancer: Is the risk of treatment worse than the risk of recurrence? Mol Cell Endocrinol 2021; 525:111181. [PMID: 33529690 DOI: 10.1016/j.mce.2021.111181] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/01/2020] [Revised: 01/04/2021] [Accepted: 01/21/2021] [Indexed: 01/18/2023]
Abstract
Premenopausal breast cancer is usually estrogen receptor positive, and hence, prolonged ovarian suppression by medical or surgical means to prevent recurrence has become standard of management to improve disease-free survival. Ten-year adjuvant tamoxifen therapy is associated with 3.5% fewer recurrences compared to five years. The SOFT trial demonstrated small but statistically significant incremental improvements in long-term disease-free survival by the addition of gonadotropin-releasing hormone analog treatment (triptorelin) to an aromatase inhibitor (exemestane). Profound hypoestrogenism in the premenopausal age group may not be well tolerated due to a host of bothersome side effects (primarily vasomotor symptoms, musculoskeletal complaints, genitourinary syndrome of menopause, and mood disorders). Prolonged hypoestrogenism in younger women is associated with premature development of cardiovascular disease, bone loss, cognitive decline, and all-cause mortality. This paper explores multi-system consequences of prolonged hypoestrogenism in premenopausal women derived from studies of women with and without breast cancer. Pretreatment counseling in estrogen receptor positive breast cancer should emphasize the benefit of prolonged estrogen suppression on breast cancer recurrence and established risks of lifelong hypoestrogenism on quality of life and all-cause mortality. Future genomic research may help identify the best candidates for extended ovarian suppression to avoid treating many women when only a minority benefit.
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Affiliation(s)
- Robert P Kauffman
- Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, School of Medicine, 1400 S. Coulter Rd, Amarillo, TX, 79106, USA.
| | - Christina Young
- Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, School of Medicine, 1400 S. Coulter Rd, Amarillo, TX, 79106, USA
| | - V Daniel Castracane
- Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, School of Medicine, 1400 S. Coulter Rd, Amarillo, TX, 79106, USA
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19
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Ibrahim MA, Albahlol IA, Wani FA, Abd-Eltawab Tammam A, Kelleni MT, Sayeed MU, Abd El-Fadeal NM, Mohamed AA. Resveratrol protects against cisplatin-induced ovarian and uterine toxicity in female rats by attenuating oxidative stress, inflammation and apoptosis. Chem Biol Interact 2021; 338:109402. [PMID: 33587916 DOI: 10.1016/j.cbi.2021.109402] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/15/2020] [Revised: 01/02/2021] [Accepted: 01/31/2021] [Indexed: 12/20/2022]
Abstract
Cisplatin is an important antineoplastic drug used in multiple chemotherapeutic regimens but unfortunately causes serious toxic effects as ovarian and uterine toxicity. This study aimed to investigate the potential protective effect of resveratrol (RSV) against cisplatin-induced ovarian and uterine toxicity in female rats. Thirty-two female Wistar rats were divided randomly into four groups (n = 8 in each). Control group received oral normal saline for 28 days; RSV group received RSV (10 mg/kg; daily) via oral gavage; CIS group received a single dose of CIS (7 mg/kg; i.p.) on the 21st day; (CIS + RSV) group received both RSV and CIS by the same schedules and doses of RSV and CIS groups, respectively. Results demonstrated a significant decrease in MDA level and a significant increase in both glutathione content and activity of the antioxidant enzymes GPx, SOD, and CAT in the tissues of the ovary and uterus of CIS + RSV group in comparison to that of CIS group (P<0.05), also there are significantly decreased tissue levels of the proinflammatory cytokines and enzymes (NF-κB, IL-1β, IL-6, TNF-α, COX-2, and iNOS), increased estradiol, progesterone, prolactin and decreased FSH serum levels in CIS + RSV group compared to CIS group (P < 0.05). Moreover, there is downregulation of tissues Cleaved Caspase-3, NF-κB and Cox-2 proteins as shown in Western blot analysis, also apoptosis was significantly inhibited, evidenced by downregulation of Bax and upregulation of Bcl-2 proteins, and the ovarian and uterine histological architecture and integrity were maintained in CIS + RSV group compared to CIS group. In conclusion, these findings indicate that RSV has beneficial effects in ameliorating cisplatin-induced oxidative stress, inflammation, and apoptosis in the ovarian and uterine tissues of female rats.
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Affiliation(s)
- Mahrous Abdelbasset Ibrahim
- Forensic Medicine and Clinical Toxicology, College of Medicine, Jouf University, Aljouf, Saudi Arabia; Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Suez Canal University (SCU), Ismailia, 41522, Egypt.
| | - Ibrahim Abdelkhalek Albahlol
- Obstetrics and Gynecology Department, College of Medicine, Jouf University, Aljouf, Saudi Arabia; Obstetrics and Gynecology Department, Faculty of Medicine, Mansoura University, Egypt.
| | - Farooq Ahmed Wani
- Pathology Department, College of Medicine, Jouf University, Aljouf, Saudi Arabia.
| | - Ahmed Abd-Eltawab Tammam
- Physiology Department, College of Medicine, Jouf University, Aljouf, Saudi Arabia; Physiology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt.
| | - Mina Thabet Kelleni
- Pharmacology Department, Faculty of Medicine, Minia University, Minia, Egypt.
| | | | - Noha M Abd El-Fadeal
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University (SCU), Ismailia, Egypt.
| | - Alaa Abdelhamid Mohamed
- Medical Biochemistry Division, Pathology Department, College of Medicine, Jouf University, Aljouf, Saudi Arabia; Medical Biochemistry Department, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt.
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20
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Amargant F, Manuel SL, Larmore MJ, Johnson BW, Lawson M, Pritchard MT, Zelinski MB, Duncan FE. Sphingosine-1-phosphate and its mimetic FTY720 do not protect against radiation-induced ovarian fibrosis in the nonhuman primate†. Biol Reprod 2021; 104:1058-1070. [PMID: 33524104 DOI: 10.1093/biolre/ioab012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/08/2020] [Revised: 12/18/2020] [Accepted: 01/29/2021] [Indexed: 12/26/2022] Open
Abstract
Oocytes are highly radiosensitive, so agents that prevent radiation-induced ovarian follicle destruction are important fertility preservation strategies. A previous study in rhesus macaques demonstrated that ovarian treatment with antiapoptotic agents, sphingosine-1-phosphate (S1P) and FTY720, its long-acting mimetic, preserved follicles following a single dose of 15 Gy X-ray radiation, and live offspring were obtained from FTY720-treated animals. However, it is unknown whether these antiapoptotic agents also protected the ovarian stroma from late effects of radiation, including vascular damage and fibrosis. Using ovarian histological sections from this study, we evaluated the vasculature and extracellular matrix in the following cohorts: vehicle + sham irradiation, vehicle + irradiation (OXI), S1P + irradiation (S1P), and FTY720 + irradiation (FTY720). One ovary from each animal was harvested prior to radiation whereas the contralateral ovary was harvested 10 months post-treatment. We assessed vasculature by immunohistochemistry with a PECAM1 antibody, hyaluronan by a hyaluronan binding protein assay, and collagen by picrosirius red and Masson's trichrome staining. Disorganized vessels were observed in the medulla in the OXI and S1P cohorts relative to the sham, but the vasculature in the FTY720 cohort appeared intact, which may partially explain fertoprotection. There were no differences in the hyaluronan matrix among the cohorts, but there was thickening of the tunica albuginea and fibrosis in the OXI cohort relative to the sham, which was not mitigated by either S1P or FTY720 treatment. Thus, the fertoprotective properties of S1P and FTY720 may be limited given their inability to protect the ovarian stroma against the late effects of radiation-induced fibrosis.
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Affiliation(s)
- Farners Amargant
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Sharrón L Manuel
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Megan J Larmore
- Department of Comparative Medicine, University of Washington, Seattle, WA, USA
| | - Brian W Johnson
- Department of Comparative Medicine, University of Washington, Seattle, WA, USA
| | - Maralee Lawson
- Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, OR, USA
| | - Michele T Pritchard
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Mary B Zelinski
- Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, OR, USA.,Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, USA
| | - Francesca E Duncan
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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21
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Michalczyk K, Cymbaluk-Płoska A. Fertility Preservation and Long-Term Monitoring of Gonadotoxicity in Girls, Adolescents and Young Adults Undergoing Cancer Treatment. Cancers (Basel) 2021; 13:E202. [PMID: 33429908 PMCID: PMC7827074 DOI: 10.3390/cancers13020202] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/20/2020] [Revised: 01/03/2021] [Accepted: 01/07/2021] [Indexed: 11/23/2022] Open
Abstract
Chemo- and radio-therapy can often affect reproductive organs impairing hormonal regulation, fertility, and sexual function. As cancer treatments become more effective and many patients have long term survival, concerns related to patient's quality of life and reproductive health become relevant. It is especially important for girls and young females facing cancer therapy who have not yet started family planning. Chemotherapy protocols using alkylating agents and abdominal radiotherapy, which are frequently used in the treatment of childhood and adolescent cancer, can cause gonadal injury. The most common clinical manifests are ovarian hormone insufficiency, premature ovarian insufficiency, early menopause and infertility. In this review we assess current literature and summarize current recommendations on the reproductive function of girls and young females undergoing cancer treatment and their follow-up. Fertility preservation methods are discussed, including psychological and ethical considerations and barriers. Improvement of reproductive health and quality of life of adolescents and young adults (AYA) undergoing cancer treatment is an important issue. Further research should be continued to develop efficient and accessible methods for fertility preservation in young patients. An expert panel including oncologists, radiation oncologists, endocrinologists and gynecologists should always consider fertility preservation in pediatric, adolescent and AYA cancer patients, minding patients' medical condition, cancer staging and potential risk of treatment-related gonadotoxicity.
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Affiliation(s)
- Kaja Michalczyk
- Department of Gynecological Surgery and Oncology of Adults and Adolescents, Pomeranian Medical University, al. Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland;
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22
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Onder GO, Balcioglu E, Baran M, Ceyhan A, Cengiz O, Suna PA, Yıldız OG, Yay A. The different doses of radiation therapy-induced damage to the ovarian environment in rats. Int J Radiat Biol 2021; 97:367-375. [PMID: 33320730 DOI: 10.1080/09553002.2021.1864497] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/30/2022]
Abstract
PURPOSE The sequelae of premature loss of ovarian function can undoubtedly have undesirable effects for a woman although radiotherapy is one of the most relevant treatment modalities for various types of malignancies. The aim of this study was to determine the effect of different doses of radiation on ovarian folliculogenesis, inflammation, and apoptotic markers. MATERIALS AND METHODS For this purpose, 40 healthy Wistar albino female rats divided into four groups: 1) Control group; 2) those that were exposed to total body 1 Gy of gamma rays; 3) those that were exposed to the total body 5 Gy of gamma rays, and 4) those that were exposed to total body 10 Gy of gamma rays. External irradiation to the total body was given with gamma irradiation delivered by the Co60 teletherapy machine. The day after radiation application the rats were sacrificed and the ovaries were removed in all groups. Histopathologic examination, follicle counting, and classification were performed in the ovarian tissues. The expression of AMH, TNF-α, IL1-β, Bax, and Bcl-2 was detected. The stained sections were examined for caspase 3 positive apoptotic cell numbers. RESULTS The recorded results revealed that increased radiation dose induced obvious ovarian injuries that were indicated by histopathological, and immunohistochemical alterations, including elevation of ovarian injury markers. A significantly lower number of total and primordial follicles was detected with increasing radiation dose compared with the control group. According to our immunohistochemical results, 10 Gy of gamma rays group had the lowest AMH expression levels, while had the highest TNF-α, IL1-β expression level compared to the control group. When the groups were evaluated in terms of apoptosis, it was seen that the number of caspase 3 positive cells and Bax immunoreactivity intensity increased with radiation dose. In contrast, Bcl-2 immunoreactivity intensity decreased with increasing radiation dose compared with the control group. CONCLUSIONS We demonstrate here that dose rate plays an important role when estimating the relation between exposure to an increased dose of ionizing radiation and the risk of ovarian disease. According to these results, certain factors have to be optimized before introducing them into clinics.
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Affiliation(s)
- Gozde Ozge Onder
- Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Esra Balcioglu
- Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.,Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey
| | - Munevver Baran
- Department of Pharmaceutical Basic Science, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey
| | - Ayse Ceyhan
- Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Ozge Cengiz
- Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Pinar Alisan Suna
- Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Oguz Galip Yıldız
- Department of Radiation Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Arzu Yay
- Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.,Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey
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23
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Protective effect of edaravone against radiation-induced ovarian injury: a histopathological and immunohistochemical evaluation in an experimental rat model. Arch Gynecol Obstet 2020; 303:1009-1016. [PMID: 33201374 DOI: 10.1007/s00404-020-05888-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/18/2020] [Accepted: 09/25/2020] [Indexed: 10/23/2022]
Abstract
PURPOSE We aimed to evaluate the protective effect of edaravone on radiation-induced ovarian damage in an experimental rat model. METHODS Thirty-two Wistar albino female rats were randomly divided into four groups. Group 1: control, no treatment, and radiation was applied throughout the study; Group 2: sham, only radiation was applied; Group 3: 45 mg/kg edaravone and radiation were applied; Group 4: 450 mg/kg edaravone and radiation were applied. Edaravone was administered intraperitoneally 30 min before radiotherapy (5 Gy). Two days after radiation exposure, the rats were sacrificed and the ovaries were removed. Histologic changes under light microscopy and immunoreactivity for anti-caspase-3 were noted and compared between the four groups. RESULTS There was a statistically significant difference in follicle counts, vascular congestion, edema, cytoplasmic vacuolization, hemorrhage, and interstitial cell degeneration between the groups. Radiation causes deterioration in most histopathological parameters. Administration of edaravone at different doses seems to reverse these alterations and alleviate the injury. Antioxidant defense mechanisms appear to be enhanced by edaravone as shown by histopathologically and decreased apoptosis by reducing the expression of anti-caspase-3 activity as demonstrated immunohistochemically. CONCLUSION This is the first study evaluating the protective effects of edaravone on radiation-induced ovarian damage. Edaravone decreased the follicular apoptosis and attenuates the radiation-induced ovarian damage in rats.
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24
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Rozen G, Rogers P, Chander S, Anderson R, McNally O, Umstad M, Winship A, Hutt K, Teh WT, Dobrotwir A, Hart R, Ledger W, Stern K. Clinical summary guide: reproduction in women with previous abdominopelvic radiotherapy or total body irradiation. Hum Reprod Open 2020; 2020:hoaa045. [PMID: 33134561 PMCID: PMC7585646 DOI: 10.1093/hropen/hoaa045] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/04/2020] [Revised: 08/13/2020] [Indexed: 11/13/2022] Open
Abstract
STUDY QUESTION What is the evidence to guide the management of women who wish to conceive following abdominopelvic radiotherapy (AP RT) or total body irradiation (TBI)? SUMMARY ANSWER Pregnancy is possible, even following higher doses of post-pubertal uterine radiation exposure; however, it is associated with adverse reproductive sequelae and pregnancies must be managed in a high-risk obstetric unit. WHAT IS KNOWN ALREADY In addition to primary ovarian insufficiency, female survivors who are treated with AP RT and TBI are at risk of damage to the uterus. This may impact on its function and manifest as adverse reproductive sequelae. STUDY DESIGN SIZE DURATION A review of the literature was carried out and a multidisciplinary working group provided expert opinion regarding assessment of the uterus and obstetric management. PARTICIPANTS/MATERIALS SETTING METHODS Reproductive outcomes for postpubertal women with uterine radiation exposure in the form of AP RT or TBI were reviewed. This included Pubmed listed peer-reviewed publications from 1990 to 2019, and limited to English language.. MAIN RESULTS AND THE ROLE OF CHANCE The prepubertal uterus is much more vulnerable to the effects of radiation than after puberty. Almost all available information about the impact of radiation on the uterus comes from studies of radiation exposure during childhood or adolescence.An uncomplicated pregnancy is possible, even with doses as high as 54 Gy. Therefore, tumour treatment doses alone cannot at present be used to accurately predict uterine damage. LIMITATIONS REASONS FOR CAUTION Much of the data cannot be readily extrapolated to adult women who have had uterine radiation and the publications concerning adult women treated with AP RT are largely limited to case reports. WIDER IMPLICATIONS OF THE FINDINGS This analysis offers clinical guidance and assists with patient counselling. It is important to include patients who have undergone AP RT or TBI in prospective studies to provide further evidence regarding uterine function, pregnancy outcomes and correlation of imaging with clinical outcomes. STUDY FUNDING/COMPETING INTERESTS This study received no funding and there are no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.
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Affiliation(s)
- G Rozen
- Reproductive Services, Royal Women's Hospital, Parkville, VIC, Australia.,Department of Obstetrics and Gynaecology, Royal Women's Hospital, University of Melbourne and Gynaecology Research Centre, Parkville, VIC, Australia.,Melbourne IVF, East Melbourne, VIC, Australia
| | - P Rogers
- Department of Obstetrics and Gynaecology, Royal Women's Hospital, University of Melbourne and Gynaecology Research Centre, Parkville, VIC, Australia
| | - S Chander
- Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - R Anderson
- University of Edinburgh, MRC Centre for Reproductive Health Queens Medical Research Institute, Edinburgh, UK
| | - O McNally
- Royal Women's Hospital, Gynae-Oncology Unit, Parkville, VIC, Australia
| | - M Umstad
- Department of Maternal Fetal Medicine, Royal Women's Hospital, Parkville, VIC, Australia.,Department of Obstetrics and Gynaecology, University of Melbourne School of BioSciences, Melbourne, VIC, Australia
| | - A Winship
- Development and Stem Cells Program, Monash University Monash Biomedicine Discovery Institute, Clayton, VIC, Australia.,Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
| | - K Hutt
- Development and Stem Cells Program, Monash University Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
| | - W T Teh
- Reproductive Services, Royal Women's Hospital, Parkville, VIC, Australia.,Department of Obstetrics and Gynaecology, Royal Women's Hospital, University of Melbourne and Gynaecology Research Centre, Parkville, VIC, Australia.,Melbourne IVF, East Melbourne, VIC, Australia
| | - A Dobrotwir
- Royal Women's Hospital, Radiology, Parkville, VIC, Australia
| | - R Hart
- University of Western Australia, School of Womens and Infants Health University of Western Australia King Edward Memorial Hospital Subiaco, Perth, WA, Australia
| | - W Ledger
- University of New South Wales, School of Womens and Childrens Health Level 1, Royal Hospital for Women, Sydney, NSW, Australia
| | - K Stern
- Reproductive Services, Royal Women's Hospital, Parkville, VIC, Australia.,Melbourne IVF, East Melbourne, VIC, Australia
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25
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Bahrehbar K, Rezazadeh Valojerdi M, Esfandiari F, Fathi R, Hassani SN, Baharvand H. Human embryonic stem cell-derived mesenchymal stem cells improved premature ovarian failure. World J Stem Cells 2020; 12:857-878. [PMID: 32952863 PMCID: PMC7477659 DOI: 10.4252/wjsc.v12.i8.857] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 02/22/2020] [Revised: 06/01/2020] [Accepted: 07/18/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Premature ovarian failure (POF) affects many adult women less than 40 years of age and leads to infertility. According to previous reports, various tissue-specific stem cells can restore ovarian function and folliculogenesis in mice with chemotherapy-induced POF. Human embryonic stem cells (ES) provide an alternative source for mesenchymal stem cells (MSCs) because of their similarities in phenotype and immunomodulatory and anti-inflammatory characteristics. Embryonic stem cell-derived mesenchymal stem cells (ES-MSCs) are attractive candidates for regenerative medicine because of their high proliferation and lack of barriers for harvesting tissue-specific MSCs. However, possible therapeutic effects and underlying mechanisms of transplanted ES-MSCs on cyclophosphamide and busulfan-induced mouse ovarian damage have not been evaluated. AIM To evaluate ES-MSCs vs bone marrow-derived mesenchymal stem cells (BM-MSCs) in restoring ovarian function in a mouse model of chemotherapy-induced premature ovarian failure. METHODS Female mice received intraperitoneal injections of different doses of cyclophosphamide and busulfan to induce POF. Either human ES-MSCs or BM-MSCs were transplanted into these mice. Ten days after the mice were injected with cyclophosphamide and busulfan and 4 wk after transplantation of the ES-MSCs and/or BM-MSCs, we evaluated body weight, estrous cyclicity, follicle-stimulating hormone and estradiol hormone concentrations and follicle count were used to evaluate the POF model and cell transplantation. Moreover, terminal deoxynucleotidyl transferase mediated 2-deoxyuridine 5-triphosphate nick end labeling, real-time PCR, Western blot analysis and immunohistochemistry and mating was used to evaluate cell transplantation. Enzyme-linked immunosorbent assay was used to analyze vascular endothelial growth factor, insulin-like growth factor 2 and hepatocyte growth factor levels in ES-MSC condition medium in order to investigate the mechanisms that underlie their function. RESULTS The human ES-MSCs significantly restored hormone secretion, survival rate and reproductive function in POF mice, which was similar to the results obtained with BM-MSCs. Gene expression analysis and the terminal deoxynucleotidyl transferase mediated 2-deoxyuridine 5-triphosphate nick end labeling assay results indicated that the ES-MSCs and/or BM-MSCs reduced apoptosis in the follicles. Notably, the transplanted mice generated new offspring. The results of different analyses showed increases in antiapoptotic and trophic proteins and genes. CONCLUSION These results suggested that transplantation of human ES-MSCs were similar to BM-MSCs in that they could restore the structure of the injured ovarian tissue and its function in chemotherapy-induced damaged POF mice and rescue fertility. The possible mechanisms of human ES-MSC were related to promotion of follicular development, ovarian secretion, fertility via a paracrine effect and ovarian cell survival.
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Affiliation(s)
- Khadijeh Bahrehbar
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran 1665659911, Iran
- Department of Developmental Biology, University of Science and Culture, Tehran 1665659911, Iran
| | - Mojtaba Rezazadeh Valojerdi
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Tehran 1665659911, Iran
- Department of Anatomy, Faculty of Medical Science, Tarbiat Modares University, Tehran 1665659911, Iran
| | - Fereshteh Esfandiari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran 1665659911, Iran
| | - Rouhollah Fathi
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Tehran 1665659911, Iran
| | - Seyedeh-Nafiseh Hassani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran 1665659911, Iran
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran 1665659911, Iran
- Department of Developmental Biology, University of Science and Culture, Tehran 1665659911, Iran.
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26
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Quan N, Harris LR, Halder R, Trinidad CV, Johnson BW, Horton S, Kimler BF, Pritchard MT, Duncan FE. Differential sensitivity of inbred mouse strains to ovarian damage in response to low-dose total body irradiation†. Biol Reprod 2020; 102:133-144. [PMID: 31436294 PMCID: PMC7334620 DOI: 10.1093/biolre/ioz164] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/21/2019] [Revised: 07/08/2019] [Accepted: 08/15/2019] [Indexed: 12/15/2022] Open
Abstract
Radiation induces ovarian damage and accelerates reproductive aging. Inbred mouse strains exhibit differential sensitivity to lethality induced by total body irradiation (TBI), with the BALB/cAnNCrl (BALB/c) strain being more sensitive than the 129S2/SvPasCrl (129) strain. However, whether TBI-induced ovarian damage follows a similar pattern of strain sensitivity is unknown. To examine this possibility, female BALB/c and 129 mice were exposed to a single dose of 1 Gy (cesium-137 γ) TBI at 5 weeks of age, and ovarian tissue was harvested for histological and gene expression analyses 2 weeks post exposure. Sham-treated mice served as controls. 1 Gy radiation nearly eradicated the primordial follicles and dramatically decreased the primary follicles in both strains. In contrast, larger growing follicles were less affected in the 129 relative to BALB/c strain. Although this TBI paradigm did not induce detectable ovarian fibrosis in either of the strains, we did observe strain-dependent changes in osteopontin (Spp1) expression, a gene involved in wound healing, inflammation, and fibrosis. Ovaries from BALB/c mice exhibited higher baseline Spp1 expression that underwent a significant decrease in response to radiation relative to ovaries from the 129 strain. A correspondingly greater change in the ovarian matrix, as evidenced by reduced ovarian hyaluronan content, was also observed following TBI in BALB/c mice relative to 129 mice. These early changes in the ovary may predispose BALB/c mice to more pronounced late effects of TBI. Taken together, our results demonstrate that aspects of ovarian damage mirror other organ systems with respect to overall strain-dependent radiation sensitivity.
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Affiliation(s)
- Natalie Quan
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Lacey R Harris
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Ritika Halder
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Camille V Trinidad
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Brian W Johnson
- Department of Comparative Medicine, University of Washington, Seattle, WA, USA
| | - Shulamit Horton
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Bruce F Kimler
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Michele T Pritchard
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Francesca E Duncan
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA
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Sullivan LK, Livingston EW, Lau AG, Rao-Dayton S, Bateman TA. A Mouse Model for Skeletal Structure and Function Changes Caused by Radiation Therapy and Estrogen Deficiency. Calcif Tissue Int 2020; 106:180-193. [PMID: 31583426 DOI: 10.1007/s00223-019-00617-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/12/2019] [Accepted: 09/18/2019] [Indexed: 12/23/2022]
Abstract
Radiation therapy and estrogen deficiency can damage healthy bone and lead to an increased fracture risk. The goal of this study is to develop a mouse model for radiation therapy using a fractionated biologically equivalent dose for cervical cancer treatment in both pre- and postmenopausal women. Thirty-two female C57BL/6 mice 13 weeks of age were divided into four groups: Sham + non-irradiated (SHAM + NR), Sham + irradiated (SHAM + IRR), ovariectomy + non-irradiated (OVX + NR) and ovariectomy + irradiated (OVX + IRR). The irradiated mice received a 6 Gy dose of X-rays to the hindlimbs at Day 2, Day 4 and Day 7 (18 Gy total). Tissues were collected at Day 35. DEXA, microCT analysis and FEA were used to quantify structural and functional changes at the proximal tibia, midshaft femur, proximal femur and L1 vertebra. There was a significant (p < 0.05) decline in proximal tibia trabecular BV/TV from (1) IRR compared to NR mice within Sham (- 46%) and OVX (- 41%); (2) OVX versus Sham within NR mice (- 36%) and IRR mice (- 30%). With homogenous material properties applied to the proximal tibia mesh using FEA, there was (1) an increase in whole bone (trabecular + cortical) structural stiffness from IRR compared to NR mice within Sham (+ 10%) and OVX (+ 15%); (2) a decrease in stiffness from OVX versus Sham within NR mice (- 18%) and IRR mice (- 14%). Fractionated irradiation and ovariectomy both had a negative effect on skeletal microarchitecture. Ovariectomy had a systemic effect, while skeletal radiation damage was largely specific to trabecular bone within the X-ray field.
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Affiliation(s)
- Lindsay K Sullivan
- Department of Biomedical Engineering, University of North Carolina, Chapel Hill, USA.
| | - Eric W Livingston
- Department of Biomedical Engineering, University of North Carolina, Chapel Hill, USA
| | - Anthony G Lau
- Department of Biomedical Engineering, The College of New Jersey, Ewing, USA
| | - Sheila Rao-Dayton
- Department of Biomedical Engineering, University of North Carolina, Chapel Hill, USA
| | - Ted A Bateman
- Department of Biomedical Engineering, University of North Carolina, Chapel Hill, USA
- Department of Radiation Oncology, University of North Carolina, Chapel Hill, USA
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Fontana J, Martínková S, Petr J, Žalmanová T, Trnka J. Metabolic cooperation in the ovarian follicle. Physiol Res 2019; 69:33-48. [PMID: 31854191 DOI: 10.33549/physiolres.934233] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/12/2022] Open
Abstract
Granulosa cells (GCs) are somatic cells essential for establishing and maintaining bi-directional communication with the oocytes. This connection has a profound importance for the delivery of energy substrates, structural components and ions to the maturing oocyte through gap junctions. Cumulus cells, group of closely associated GCs, surround the oocyte and can diminished the effect of harmful environmental insults. Both GCs and oocytes prefer different energy substrates in their cellular metabolism: GCs are more glycolytic, whereas oocytes rely more on oxidative phosphorylation pathway. The interconnection of these cells is emphasized by the fact that GCs supply oocytes with intermediates produced in glycolysis. The number of GCs surrounding the oocyte and their age affect the energy status of oocytes. This review summarises available studies collaboration of cellular types in the ovarian follicle from the point of view of energy metabolism, signaling and protection of toxic insults. A deeper knowledge of the underlying mechanisms is crucial for better methods to prevent and treat infertility and to improve the technology of in vitro fertilization.
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Affiliation(s)
- J Fontana
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
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Carvacrol and Thymol Modulate the Cross-Talk between TNF- α and IGF-1 Signaling in Radiotherapy-Induced Ovarian Failure. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:3173745. [PMID: 31531182 PMCID: PMC6721489 DOI: 10.1155/2019/3173745] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 03/17/2019] [Revised: 07/01/2019] [Accepted: 07/18/2019] [Indexed: 02/08/2023]
Abstract
Premature ovarian failure (POF) is a common cause of infertility in premenopausal women who are unavoidably exposed to cytotoxic therapy. Radiotherapy is one of the most effective cytotoxic treatments. However, the radiosensitivity of ovarian tissues limits its therapeutic outcome and results in the depletion of the primordial follicle and loss of fertility. Therefore, the need for an effective radioprotective therapy is evident especially when none of the current clinically used modalities for radioprotection succeeds efficiently. The present study investigated the potential radioprotective effect of carvacrol (CAR) (80 mg) or thymol (80 mg) on gamma- (γ-) irradiation-induced ovarian damage as well as their role in the cross-talk between IGF-1 and TNF-α signaling and antioxidative activity. In immature female Wister rats, a single dose of whole-body irradiation (3.2 Gy, LD20) produced considerable ovarian damage, which was evident by histopathological findings and hormonal changes. Interestingly, pretreatment with CAR or thymol significantly enhanced the follicular development and restored the anti-Mullerian hormone (AMH), E2, and FSH levels. Both essential oils improved the irradiation-mediated oxidative stress and reduction in proliferating cell nuclear antigen (PCNA) expression. Moreover, irradiated rats exhibited an inverse relationship between IGF-1 and TNF-α levels two days post irradiation, which was further inverted by the pretreatment with CAR and thymol and ought to contribute in their radioprotective mechanisms. In conclusion, CAR and thymol showed a radioprotective effect and rescued the ovarian reserve mainly through counteracting oxidative stress and the dysregulated cross-talk between IGF-1 and TNF-α.
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Prasad SK, Bose A, Bhattacharjee A, Banerjee O, Singh S, Mukherjee S, Pal S. Radioprotective effect of ethanolic extract of Alocasia indica on γ-irradiation-induced reproductive alterations in ovary and uterus. Int J Radiat Biol 2019; 95:1529-1542. [DOI: 10.1080/09553002.2019.1642545] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/26/2022]
Affiliation(s)
| | - Ananya Bose
- Department of Physiology, Serampore College, Hooghly, India
| | | | - Oly Banerjee
- Department of Physiology, Serampore College, Hooghly, India
| | | | | | - Swagata Pal
- Department of Physiology, Raja Peary Mohan College, Hooghly, India
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Abstract
PURPOSE OF REVIEW There are competing risks and benefits of cancer therapies and fertility preservation in young women with breast cancer. Here we discuss the impact of therapy on fertility, fertility preservation options, and emerging information in fertility issues for the breast cancer patient. RECENT FINDINGS All systemic forms of breast cancer treatment can impact future fertility. Pre-therapy fertility preservation may offer the best opportunity for future fertility. Shared decision making with the individual patient and clinical scenario is important. Early referral to a fertility specialist should be offered to young patients. We find that fertility preservation options for young women diagnosed with breast cancer are currently available, but potentially under-utilized. We conclude that a multidisciplinary approach is necessary, with discussion of potential risks and benefits of fertility preservation options in the context of the patient's clinical disease.
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Affiliation(s)
- Nicole Christian
- Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA
| | - Mary L Gemignani
- Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA.
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McKenzie ND, Kennard JA, Ahmad S. Fertility preserving options for gynecologic malignancies: A review of current understanding and future directions. Crit Rev Oncol Hematol 2018; 132:116-124. [PMID: 30447916 DOI: 10.1016/j.critrevonc.2018.09.020] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/02/2018] [Accepted: 09/29/2018] [Indexed: 02/08/2023] Open
Abstract
Gynecological malignancies affect significant proportion of women in whom fertility preservation is a priority. Advancing reproductive technology and modern surgical techniques are changing the way young women with cancer are counseled regarding their fertility plans at time of cancer diagnosis. This review article provides the reader with fertility preserving updates in gynecologic malignancies as well as those with genetic predisposition for gynecologic malignancies. The different types of gynecologic malignancies including cervical, endometrial, and ovarian cancers and their unique obstacles are addressed separately. New insights into conservative cervical cancer surgery and fertility preserving neoadjuvant chemotherapy followed by fertility preserving surgery for cervical cancer are discussed. Hormonal management of endometrial cancer are highlighted. Additionally, better understanding of ovarian failure with modern chemotherapy/radiation therapy is summarized. Finally, modern reproductive techniques such as ovarian cryopreservation are reviewed as well as those in early stages are development such as artificial ovarian tissue are previewed.
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Affiliation(s)
- Nathalie D McKenzie
- Florida Hospital Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando, FL, 32804, USA.
| | - Jessica A Kennard
- Florida Hospital Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando, FL, 32804, USA
| | - Sarfraz Ahmad
- Florida Hospital Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando, FL, 32804, USA.
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Zingerone ameliorates cisplatin‐induced ovarian and uterine toxicity via suppression of sex hormone imbalances, oxidative stress, inflammation and apoptosis in female wistar rats. Biomed Pharmacother 2018; 102:517-530. [PMID: 29587238 DOI: 10.1016/j.biopha.2018.03.119] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/03/2018] [Revised: 03/20/2018] [Accepted: 03/20/2018] [Indexed: 11/17/2022] Open
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Matsuo K, Machida H, Horowitz MP, Shahzad MMK, Guntupalli SR, Roman LD, Wright JD. Risk of metachronous ovarian cancer after ovarian conservation in young women with stage I cervical cancer. Am J Obstet Gynecol 2017; 217:580.e1-580.e10. [PMID: 28666700 DOI: 10.1016/j.ajog.2017.06.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/31/2017] [Revised: 06/05/2017] [Accepted: 06/20/2017] [Indexed: 11/17/2022]
Abstract
BACKGROUND While there is an increasing trend of ovarian conservation at the time of surgical treatment for young women with stage I cervical cancer, the risk for subsequent ovarian cancer after ovarian conservation has not been well studied. OBJECTIVE We sought to examine the incidence of and risk factors for metachronous ovarian cancer among young women with stage I cervical cancer who had ovarian conservation at the time of hysterectomy. STUDY DESIGN The Surveillance, Epidemiology, and End Results Program was used to identify women aged <50 years who underwent hysterectomy with ovarian conservation for stage I cervical cancer from 1983 through 2013 (n = 4365). Time-dependent analysis was performed for ovarian cancer risk after cervical cancer diagnosis. RESULTS Mean age at cervical cancer diagnosis was 37 years, and the majority of patients had stage IA disease (68.2%) and squamous histology (72.9%). Median follow-up time was 10.8 years, and there were 13 women who developed metachronous ovarian cancer. The 10- and 20-year cumulative incidences of metachronous ovarian cancer were 0.2% (95% confidence interval, 0.1-0.4) and 0.5% (95% confidence interval, 0.2-0.8), respectively. Mean age at the time of diagnosis of metachronous ovarian cancer was 47.5 years, and stage III-IV disease was seen in 55.6%. Age (≥45 vs <45 years, hazard ratio, 4.22; 95% confidence interval, 1.16-15.4; P = .018), ethnicity (non-white vs white, hazard ratio, 4.29; 95% confidence interval, 1.31-14.0; P = .009), cervical cancer histology (adenocarcinoma or adenosquamous vs squamous, hazard ratio, 3.50; 95% confidence interval, 1.17-10.5; P = .028), and adjuvant radiotherapy use (yes vs no, hazard ratio, 3.69; 95% confidence interval, 1.01-13.4; P = .034) were significantly associated with metachronous ovarian cancer risk. The presence of multiple risk factors was associated with a significantly increased risk of metachronous ovarian cancer compared to the no risk factor group: 1 risk factor (hazard ratio range, 2.96-8.43), 2 risk factors (hazard ratio range, 16.6-31.0), and 3-4 risk factors (hazard ratio range, 62.3-109), respectively. CONCLUSION Metachronous ovarian cancer risk after ovarian conservation for women with stage I cervical cancer is <1%. Older age, non-white ethnicity, adenocarcinoma or adenosquamous histology, and adjuvant radiotherapy may be associated with an increased metachronous ovarian cancer risk.
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Affiliation(s)
- Koji Matsuo
- Division of Gynecologic Oncology and Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA.
| | - Hiroko Machida
- Division of Gynecologic Oncology and Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA
| | - Max P Horowitz
- Division of Gynecologic Oncology and Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA
| | - Mian M K Shahzad
- Division of Gynecologic Oncology and Department of Obstetrics and Gynecology, University of South Florida, Tampa, FL
| | - Saketh R Guntupalli
- Division of Gynecologic Oncology and Department of Obstetrics and Gynecology, University of Colorado, Denver, CO
| | - Lynda D Roman
- Division of Gynecologic Oncology and Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA
| | - Jason D Wright
- Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, NY
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Briley SM, Jasti S, McCracken JM, Hornick JE, Fegley B, Pritchard MT, Duncan FE. Reproductive age-associated fibrosis in the stroma of the mammalian ovary. Reproduction 2017; 152:245-260. [PMID: 27491879 DOI: 10.1530/rep-16-0129] [Citation(s) in RCA: 202] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/10/2016] [Accepted: 06/29/2016] [Indexed: 12/13/2022]
Abstract
Under normal physiological conditions, tissue remodeling in response to injury leads to tissue regeneration without permanent damage. However, if homeostasis between synthesis and degradation of extracellular matrix (ECM) components is altered, fibrosis - or the excess accumulation of ECM - can disrupt tissue architecture and function. Several organs, including the heart, lung and kidney, exhibit age-associated fibrosis. Here we investigated whether fibrosis underlies aging in the ovary - an organ that ages chronologically before other organs. We used Picrosirius Red (PSR), a connective tissue stain specific for collagen I and III fibers, to evaluate ovarian fibrosis. Using bright-field, epifluorescence, confocal and polarized light microscopy, we validated the specific staining of highly ordered PSR-stained fibers in the ovary. We next examined ovarian PSR staining in two mouse strains (CD1 and CB6F1) across an aging continuum and found that PSR staining was minimal in ovaries from reproductively young adult animals, increased in distinct foci in animals of mid-to-advanced reproductive age, and was prominent throughout the stroma of the oldest animals. Consistent with fibrosis, there was a reproductive age-associated increase in ovarian hydroxyproline content. We also observed a unique population of multinucleated macrophage giant cells, which are associated with chronic inflammation, within the ovarian stroma exclusively in reproductively old mice. In fact, several genes central to inflammation had significantly higher levels of expression in ovaries from reproductively old mice relative to young mice. These results establish fibrosis as an early hallmark of the aging ovarian stroma, and this altered microenvironment may contribute to the age-associated decline in gamete quality.
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Affiliation(s)
- Shawn M Briley
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160
| | - Susmita Jasti
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160
| | - Jennifer M McCracken
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160
| | - Jessica E Hornick
- Biological Imaging Facility, Northwestern University, Evanston, IL 60208
| | - Barbara Fegley
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160.,Electron Microscopy Research Laboratory, University of Kansas Medical Center, Kansas City, KS 66160
| | - Michele T Pritchard
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160
| | - Francesca E Duncan
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160
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Salama M, Woodruff TK. Anticancer treatments and female fertility: clinical concerns and role of oncologists in oncofertility practice. Expert Rev Anticancer Ther 2017; 17:687-692. [PMID: 28537815 DOI: 10.1080/14737140.2017.1335199] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Anticancer treatments such as aggressive chemotherapy and radiotherapy have deleterious gonadotoxic side effects and are considered the most common causes of pathological and iatrogenic fertility loss in women. Areas covered: In order to preserve fertility of young women and girls with cancer, several established, experimental, and debatable options can be offered in the emerging field of oncofertility. This article reviews the effects of anticancer treatments on female fertility and discusses the current challenges and future directions of fertility preservation options that can be offered to the female patients with cancer. Expert commentary: Although promising, several medical, economic, social and legal barriers face oncofertility practice around the globe especially in underserved areas. To overcome such barriers, more effective solutions should be provided to spread awareness and enhance communication between patients, oncologists and gynecologists. Early referral by oncologists before initiation of chemotherapy and radiotherapy is an important key factor for success in female fertility preservation strategies.
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Affiliation(s)
- Mahmoud Salama
- a Department of Obstetrics and Gynecology, Medical Faculty , University of Cologne , Cologne , Germany
| | - Teresa K Woodruff
- b Department of Obstetrics and Gynecology, Feinberg School of Medicine , Northwestern University , Chicago , Illinois , USA
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Codacci-Pisanelli G, Del Pup L, Del Grande M, Peccatori FA. Mechanisms of chemotherapy-induced ovarian damage in breast cancer patients. Crit Rev Oncol Hematol 2017; 113:90-96. [PMID: 28427528 DOI: 10.1016/j.critrevonc.2017.03.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/11/2016] [Revised: 02/23/2017] [Accepted: 03/08/2017] [Indexed: 01/25/2023] Open
Abstract
Fertility preservation in breast cancer patients is an increasingly relevant topic. In the present paper we review available data on the mechanism of ovarian damage caused by anticancer agents currently used for the treatment of breast cancer. We also describe current methods to preserve fertility including oocytes or ovarian tissue freezing and administration of LH-RHa during chemotherapy. The aim of the paper is to provide clinical oncologists with an adequate knowledge of the subject to enable them to give a correct counselling to young women that must receive chemotherapy and want to increase their possibilities of maintaining fertility.
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Affiliation(s)
- Giovanni Codacci-Pisanelli
- University of Rome "la Sapienza", Department of Medical and Surgical Sciences and Biotechnology, Corso della Repubblica, 79 Latina, 04100, Italy.
| | - Lino Del Pup
- Department of Gynaecological Oncology, National Cancer Institute, Via Franco Gallini, 2, Aviano (Pordenone) 33170 Italy.
| | - Maria Del Grande
- Istituto Oncologico della Svizzera Italiana, Ente Ospedaliero Cantonale, Via Ospedale, Ospedale San Giovanni, 6500 Bellinzona, Switzerland.
| | - Fedro A Peccatori
- Department of Gynaecological Oncology, European Institute of Oncology, Via Ripamonti, 435 Milano 20141, Italy.
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Evaluation of the dose received by ovaries in the treatment of a desmoid tumour presenting in the lower extremity using intensity-modulated radiotherapy tomotherapy. JOURNAL OF RADIOTHERAPY IN PRACTICE 2017. [DOI: 10.1017/s1460396916000613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/07/2022]
Abstract
AbstractBackgroundDesmoid tumour is a rare neoplasm occurring intra- and extra-abdominally.MethodIn this study, a lower extremity desmoid tumour located close to the ovaries was irradiated with tomotherapy after surgery in a 16-year-old female patient. 30 fractions defined for delivery of 54 Gy were administered to the patient.ResultThe planning target volume and organs at risk doses were evaluated and the ovary doses were discussed for fertility.ConclusionThe patient tolerated the radiotherapy well. During radiotherapy, only grade 1 skin toxicity occurred.
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Abstract
Human ovary autotransplantation is a promising option for fertility preservation of young women and girls undergoing gonadotoxic treatments for cancer or some autoimmune diseases. Although experimental, it resulted in at least 42 healthy babies worldwide. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature review was performed for all relevant full-text articles published in English from 1 January 2000 to 01 October 2015 in PubMed to explore the latest clinical and research advances of human ovary autotransplantation. Human ovary autotransplantation involves ovarian tissue extraction, freezing/thawing, and transplantation back into the same patient. Three major forms of human ovary autotransplantation exist including (a) transplantation of cortical ovarian tissue, (b) transplantation of whole ovary, and (c) transplantation of ovarian follicles (artificial ovary). According to the recent guidelines, human ovary autotransplantation is still considered experimental; however, it has unique advantages in comparison to other options of female fertility preservation. Human ovary autotransplantation (i) does not need prior ovarian stimulation, (ii) allows immediate initiation of cancer therapy, (iii) can restore both endocrine and reproductive ovarian functions, and (iv) may be the only fertility preservation option suitable for prepubertal girls or for young women with estrogen-sensitive malignancies. As any other fertility preservation option, human ovary autotransplantation has both advantages and disadvantages and may not be feasible for all cases. The major challenges facing this option are how to avoid the risk of reintroducing malignant cells and how to prolong the lifespan of ovarian transplant as well as how to improve artificial ovary results.
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Affiliation(s)
- Mahmoud Salama
- Department of Gynecology and Obstetrics, Medical Faculty, University of Cologne, Cologne, Germany
| | - Teresa K Woodruff
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, 303 East Superior Street, Room 10-119, Chicago, IL 60611, USA
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Chen XY, Xia HX, Guan HY, Li B, Zhang W. Follicle Loss and Apoptosis in Cyclophosphamide-Treated Mice: What's the Matter? Int J Mol Sci 2016; 17:E836. [PMID: 27248997 PMCID: PMC4926370 DOI: 10.3390/ijms17060836] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/13/2016] [Revised: 05/14/2016] [Accepted: 05/24/2016] [Indexed: 12/21/2022] Open
Abstract
With increasing numbers of young female cancer survivors following chemotherapy, chemotherapy-induced fertility loss must be considered. Menstrual disorder and infertility are of particular concern in female cancer patients. We showed that treatment with the alkylating agent cyclophosphamide (CTX) could cause severe primordial follicle loss and growing follicle apoptosis, resulting in loss of ovarian reserve. SPF C57BL/6 female mice were treated with a single dose of 120 mg/kg of CTX or saline as a control, and both sides of ovaries were collected three or seven days after injection. Following CTX treatment, the ovaries were mostly composed of collapsed oocytes and presented marked cortical fibrosis and a reduced number of follicles, especially primordial follicles. The loss of primordial follicles was confirmed by primordial follicle counting, immunohistochemistry and Western blot detection of DDx4/MVH. Follicle apoptosis was tested by a TUNEL assay and the number of TUNEL-positive follicle cells increased, as expected, in CTX-treated mice. Furthermore, expression of APAF-1 and cleaved caspase-3 was also increased after CTX treatment. Analysis of the PI3K/Akt/mTOR signaling pathway showed that CTX increased phosphorylation of Akt, mTOR and downstream proteins without affecting total levels. These results demonstrated that the CTX treatment led to the hyperactivation of the PI3K/Akt/mTOR signaling pathway in ovaries which may be related to primordial follicle loss and growing follicle apoptosis.
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Affiliation(s)
- Xiu-Ying Chen
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.
- Department of Obstetrics and Gynecology of Shanghai Medical College, Fudan University, Shanghai 200011, China.
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
| | - He-Xia Xia
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.
| | - Hai-Yun Guan
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.
- Department of Obstetrics and Gynecology of Shanghai Medical College, Fudan University, Shanghai 200011, China.
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
| | - Bin Li
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.
| | - Wei Zhang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.
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Walker AJ, Benrubi ID, Ward KK. Care of survivors of gynecologic cancers. World J Obstet Gynecol 2016; 5:140-149. [DOI: 10.5317/wjog.v5.i2.140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/29/2015] [Revised: 11/16/2015] [Accepted: 02/24/2016] [Indexed: 02/05/2023] Open
Abstract
The number of cancer survivors is increasing and most healthcare providers will manage patients who have completed therapy for malignancy at some point. The care of survivors of gynecologic malignancies may seem daunting in a busy general gynecology practice. This paper intends to review the literature and suggest management of these women for the general gynecologist.
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Duncan FE, Kimler BF, Briley SM. Combating radiation therapy-induced damage to the ovarian environment. Future Oncol 2016; 12:1687-90. [PMID: 27117319 DOI: 10.2217/fon-2016-0121] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Francesca E Duncan
- Department of Anatomy & Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Bruce F Kimler
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Shawn M Briley
- Department of Anatomy & Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Lavery SA, Islam R, Hunt J, Carby A, Anderson RA. The medical and ethical challenges of fertility preservation in teenage girls: a case series of sickle cell anaemia patients prior to bone marrow transplant. Hum Reprod 2016; 31:1501-7. [DOI: 10.1093/humrep/dew084] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/23/2015] [Accepted: 03/23/2016] [Indexed: 11/13/2022] Open
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Dehghan T, Mozdarani H, Khoradmehr A, Kalantar SM. Effects of gamma radiation on fetal development in mice. Int J Reprod Biomed 2016. [DOI: 10.29252/ijrm.14.4.247] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/31/2022] Open
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Abstract
BACKGROUND Loss of fertility is one of the many potential late effects of cancer treatment. For young men and women who have not yet started or completed building their families, this can be a source of considerable emotional distress. Advances in reproductive technology can enable many of these patients to preserve their fertility; however, discussions must be initiated early enough during treatment planning to enable them to take advantage of these options. OBJECTIVES The purpose of this article is to provide oncology nurses with information, strategies, and resources to discuss fertility with men and women starting cancer treatment. METHODS This article summarizes the literature on treatment-related fertility risks and fertility preservation options, and provides a systematic framework for nurses to integrate these discussions into practice. FINDINGS Oncology nurses can effectively collaborate with other members of the healthcare team to ensure that young men and women starting cancer treatment are informed of the potential risks to fertility from their planned treatment, understand options to preserve fertility before treatment, and, if interested, are referred to appropriate reproductive specialists.
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D'Avila ÂM, Biolchi V, Capp E, Corleta HVE. Age, anti-müllerian hormone, antral follicles count to predict amenorrhea or oligomenorrhea after chemotherapy with cyclophosphamide. J Ovarian Res 2015; 8:82. [PMID: 26667243 PMCID: PMC4678664 DOI: 10.1186/s13048-015-0209-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/22/2015] [Accepted: 12/09/2015] [Indexed: 11/14/2022] Open
Abstract
Background A cohort study was performed to identify ovarian reserve markers (ORM) that predicts amenorrhea or oligomenorrhea 6 months after cyclophosphamide CTX in women with breast cancer. Methods 52 eumenorrheic patients with breast cancer were enrolled. FSH, anti-Müllerian hormone (AMH), antral follicles count (AFC) were measured before and 6 months after CTX. A logistic regression for independent samples and determination of the ROC curve were performed. Results The age of 32 years presented 96 % of sensitivity and 39 % of specificity to predict amenorrhea or oligomenorrhea with ROC area under the curve (AUC) of 0.77. ovarian reserve marker (ORM) with power to predict amenorrhea or oligomenorrhea in women after CTX were AMH <3.32 ng/mL (sensitivity of 85 %, specificity of 75 % and AUC 0.87), AFC <13 follicles (sensitivity 81 %, specificity 62 %, AUC 0.81). AMH cutoff to predict amenorrhea was 1.87 ng/mL (sensitivity 82 %, specificity 83 %, AUC 0.84) and AFC cutoff was 9 follicles (sensitivity 71 %, specificity 78 %, AUC 0.73). Conclusions ≥32-years-old women, AMH <3.32 ng/mL and AFC <13 follicles determined significantly higher risk of amenorrhea or oligomenorrhea after CTX with cyclophosphamide. The ORM age (≥32 years) analyzed together with AMH or AFC increases sensitivity and specificity in predicting amenorrhea or oligomenorrhea.
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Affiliation(s)
- Ângela Marcon D'Avila
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul School of Medicine, Bento Gonçalves, RS, Brazil.
| | - Vanderlei Biolchi
- Graduate Program in Biological Sciences: Physiology, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Lajeado, RS, Brazil.
| | - Edison Capp
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul School of Medicine, Bento Gonçalves, RS, Brazil. .,Graduate Program in Biological Sciences: Physiology, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Lajeado, RS, Brazil. .,Department of Obstetrics and Gynecology, Hospital de Clínicas de Porto Alegre, Sul School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. .,Department of Gynecological Endocrinology and Reproductive Medicine, University Hospital Heidelberg, Heidelberg, Germany. .,Serviço de Ginecologia e Obstetrícia - Hospital de Clínicas de Porto Alegre Rua Ramiro Barcelos, 2350/11° andar, Porto Alegre, CEP 90035-903, RS, Brazil.
| | - Helena von Eye Corleta
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul School of Medicine, Bento Gonçalves, RS, Brazil. .,Department of Obstetrics and Gynecology, Hospital de Clínicas de Porto Alegre, Sul School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. .,GENERAR, Porto Alegre, RS, Brazil.
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Growth Hormone Ameliorates the Radiotherapy-Induced Ovarian Follicular Loss in Rats: Impact on Oxidative Stress, Apoptosis and IGF-1/IGF-1R Axis. PLoS One 2015; 10:e0140055. [PMID: 26465611 PMCID: PMC4605641 DOI: 10.1371/journal.pone.0140055] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/01/2015] [Accepted: 09/21/2015] [Indexed: 01/25/2023] Open
Abstract
Radiotherapy is one of the standard cytotoxic therapies for cancer. However, it has a profound impact on ovarian function leading to premature ovarian failure and infertility. Since none of the currently available methods for fertility preservation guarantees future fertility, the need for an effective radioprotective agent is highly intensified. The present study investigated the mechanisms of the potential radioprotective effect of growth hormone (GH) on γ irradiation-induced ovarian failure and the impact of the insulin like growth factor 1 (IGF-1) in the underlying protection. Immature female Sprague-Dawley rats were either exposed to single whole body irradiation (3.2 Gy) and/or treated with GH (1 mg/kg s.c). Experimental γ-irradiation produced an array of ovarian dysfunction that was evident by assessment of hormonal changes, follicular development, proliferation marker (PCNA), oxidative stress as well as apoptotic markers. In addition, IGF-1/IGF-1R axis expression was assessed using real-time PCR and immunolocalization techniques. Furthermore, after full maturity, fertility assessment was performed. GH significantly enhanced follicular development and restored anti-Mullerian hormone serum level as compared with the irradiated group. In addition, GH significantly ameliorated the deleterious effects of irradiation on oxidative status, PCNA and apoptosis. Interestingly, GH was shown to enhance the ovarian IGF-1 at transcription and translation levels, a property that contributes significantly to its radioprotective effect. Finally, GH regained the fertility that was lost following irradiation. In conclusion, GH showed a radioprotective effect and rescued the ovarian reserve through increasing local IGF-1 level and counteracting the oxidative stress-mediated apoptosis.
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Simi G, Obino MER, Casarosa E, Litta P, Artini PG, Cela V. Different stimulation protocols for oocyte cryropreservation in oncological patients: a retrospective analysis of single university centre. Gynecol Endocrinol 2015; 31:966-70. [PMID: 26370262 DOI: 10.3109/09513590.2015.1080237] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE To analyze the results obtain in cancer patients who receive the same controlled ovarian stimulation protocol, started in two different moments of the menstrual cycle, follicular or luteal phase. The stimulation is performed before cancer treatment in order to preserve fertility through oocytes cryopreservation. STUDY DESIGN The study is a retrospective analysis about 25 cancer patients at our centre, Department of Reproductive Medicine of University of Pisa, in order to preserve their fertility before cancer treatment. Patients are divided into two groups depending on the menstrual cycle phase, follicular or luteal phase, at the moment of first examination. Standard stimulation protocol with gonadotropins is administered in the follicular group, whereas in the second group we use GnRH (gonadotropin-releasing hormone) antagonist before gonadotropins administration in order to have a rapid luteolysis. The outcome measures are the number of days needed before starting procedure, duration of stimulation, cumulative dosage of gonadotropins number of oocyte retrieved and percentage of mature oocytes. RESULTS Any difference showed between two groups based on days of stimulation, total amount of gonadotropins administered and the number of good mature quality oocytes was retrieved. The real difference is the number of days needed to start the procedure, lesser in the luteal group. CONCLUSIONS This study suggests that oocytes can be obtained before cancer treatment, irrespective of menstrual cycle phase without compromising the efficacy of procedure. Moreover, starting ovarian stimulation anytime during menstrual cycle allows the patients to not postpone the beginning of cancer treatment. Different stimulation protocols, according to different kinds of disease, are available in order to obtain the maximum results without any complication for patients.
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Affiliation(s)
- Giovanna Simi
- a Department of Clinical and Experimental Medicine , Division of Obstetrics and Gynecology Oncology, University of Pisa , Pisa , Italy and
| | - Maria Elena Rosa Obino
- a Department of Clinical and Experimental Medicine , Division of Obstetrics and Gynecology Oncology, University of Pisa , Pisa , Italy and
| | - Elena Casarosa
- a Department of Clinical and Experimental Medicine , Division of Obstetrics and Gynecology Oncology, University of Pisa , Pisa , Italy and
| | - Pietro Litta
- b Division of Obstetrics and Gynecology Oncology , University of Padova , Pisa , Italy
| | - Paolo Giovanni Artini
- a Department of Clinical and Experimental Medicine , Division of Obstetrics and Gynecology Oncology, University of Pisa , Pisa , Italy and
| | - Vito Cela
- a Department of Clinical and Experimental Medicine , Division of Obstetrics and Gynecology Oncology, University of Pisa , Pisa , Italy and
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Brisbois MD. An Interpretive Description of Chemotherapy-Induced Premature Menopause Among Latinas With Breast Cancer. Oncol Nurs Forum 2014; 41:E282-9. [DOI: 10.1188/14.onf.e282-e289] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/17/2022]
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