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Baker KM, FernandezCriado R, Eaton JL, Mensah VA. The Clinical Utility of Measures of Ovarian Reserve. Obstet Gynecol Surv 2025; 80:121-133. [PMID: 39924338 DOI: 10.1097/ogx.0000000000001362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
Abstract
Importance Measures of ovarian reserve, particularly anti-Müllerian hormone, have been increasingly and inaccurately utilized as "fertility tests." It is important to understand the available measures of ovarian reserve and how to appropriately interpret and integrate their use into clinical practice. Objectives The objectives of this article are to review the process of reproductive aging, define ovarian reserve, describe the available measures of ovarian reserve, and discuss the clinical utility of these measures. Evidence Acquisition A literature search was performed using the electronic database PubMed. Relevant guidelines, systematic reviews, and original research articles investigating ovarian reserve parameters and their clinical utility were reviewed. Results The fecundity of women gradually declines with increasing reproductive age as oocyte quantity and quality decline. Ovarian reserve is defined as the quantity of oocytes remaining in the ovary. Ovarian reserve can be measured indirectly with the use of serum blood tests or ultrasound imaging. Measures of ovarian reserve are clinically useful in several circumstances, particularly for use during fertility treatment and cycles of assisted reproductive technology. However, measures of ovarian reserve are poor predictors of reproductive potential and should not be used as "fertility tests." Conclusions and Relevance Measures of ovarian reserve are poor predictors of reproductive potential and should not be used as "fertility tests." Age remains a stronger predictor of reproductive success than measures of ovarian reserve.
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Affiliation(s)
- Katherine M Baker
- Fellow, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Women and Infants Hospital and Warren Alpert Medical School of Brown University, Providence, RI
| | - Rodolfo FernandezCriado
- Resident, Department of Obstetrics and Gynecology, Women and Infants Hospital and Warren Alpert Medical School of Brown University, Providence, RI
| | - Jennifer L Eaton
- Division Director/Fellowship Director and Associate Professor, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Women and Infants Hospital and Warren Alpert Medical School of Brown University, Providence, RI
| | - Virginia A Mensah
- Assistant Professor/Clinician Educator, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Women and Infants Hospital and Warren Alpert Medical School of Brown University, Providence, RI
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Loubersac S, Chaillot M, Reignier A, Lefebvre T, Dezellus A, Colombel A, Barriere P, Masson D, Freour T. Serum androgen dynamics in young women aged 18-40 treated with chemotherapy for breast cancer: an observational, multicentric, prospective study in France. HUM FERTIL 2024; 27:2350758. [PMID: 38957151 DOI: 10.1080/14647273.2024.2350758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 04/24/2024] [Indexed: 07/04/2024]
Abstract
Although the deleterious impact of chemotherapy regimen used to treat women of reproductive age with breast cancer on ovarian reserve has been extensively studied, hardly anything has been reported on the effect of these protocols on theca cell function and ovarian androgen secretion. The aim of this prospective multicentric cohort study was to describe serum levels of total testosterone and androstenedione during chemotherapy and 24-month follow-up in 250 patients <40 years treated for breast cancer. Mean basal levels of androstenedione and total testosterone at diagnosis were 1.68 ng/mL and 0.20 ng/mL respectively. No correlation with age was found. Serum levels of androstenedione and total testosterone rapidly decreased after chemotherapy completion, before slowly increasing and almost returning to basal levels in all patients during 2-year follow-up. In conclusion our study demonstrates a chemotherapy-induced alteration of ovarian thecal function, resulting in a significant decrease in serum androgen levels. This alteration of theca cell function adds to the well-known alteration of granulosa cell function, resulting in a global, but partly transient, ovarian failure in young women treated for breast cancer. These data bring new insight into ovarian physiology and emphasize the need for pre and post-treatment ovarian follow-up. Trial registration: ClinicalTrial.gov identifier NCT01114464.
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Affiliation(s)
- S Loubersac
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, Bd Jean Monnet, Nantes, France
| | - M Chaillot
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, Bd Jean Monnet, Nantes, France
- Faculté de médecine, Université de Nantes, Nantes, France
| | - A Reignier
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, Bd Jean Monnet, Nantes, France
- Faculté de médecine, Université de Nantes, Nantes, France
- Centre de Recherche en Transplantation et Immunologie (ou CRTI), Inserm, Université de Nantes, Nantes, France
| | - T Lefebvre
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, Bd Jean Monnet, Nantes, France
- Faculté de médecine, Université de Nantes, Nantes, France
| | - A Dezellus
- Service d'oncologie, Institut de Cancérologie de l'Ouest, Saint Herblain, France
| | - A Colombel
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, Bd Jean Monnet, Nantes, France
| | - P Barriere
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, Bd Jean Monnet, Nantes, France
- Faculté de médecine, Université de Nantes, Nantes, France
- Centre de Recherche en Transplantation et Immunologie (ou CRTI), Inserm, Université de Nantes, Nantes, France
| | - D Masson
- Faculté de médecine, Université de Nantes, Nantes, France
- Laboratoire de biochimie, CHU de Nantes, place Alexis-Ricordeau, Nantes, France
- INSERM UMR 913, rue Gaston Veil, Nantes, France
| | - T Freour
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, Bd Jean Monnet, Nantes, France
- Faculté de médecine, Université de Nantes, Nantes, France
- Centre de Recherche en Transplantation et Immunologie (ou CRTI), Inserm, Université de Nantes, Nantes, France
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Massarotti C, Cimadomo D, Spadoni V, Conforti A, Zacà C, Carosso AR, Vaiarelli A, Venturella R, Vitagliano A, Busnelli A, Cozzolino M, Borini A. Female fertility preservation for family planning: a position statement of the Italian Society of Fertility and Sterility and Reproductive Medicine (SIFES-MR). J Assist Reprod Genet 2024; 41:2521-2535. [PMID: 39030346 PMCID: PMC11405660 DOI: 10.1007/s10815-024-03197-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 07/03/2024] [Indexed: 07/21/2024] Open
Abstract
PURPOSE This position statement by the Italian Society of Fertility and Sterility and Reproductive Medicine (SIFES-MR) aims to establish an optimal framework for fertility preservation outside the standard before oncological therapies. Key topics include the role of fertility units in comprehensive fertility assessment, factors impacting ovarian potential, available preservation methods, and appropriate criteria for offering such interventions. METHODS The SIFES-MR writing group comprises Italian reproductive physicians, embryologists, and scientists. The consensus emerged after a six-month period of meetings, including extensive literature review, dialogue among authors and input from society members. Final approval was granted by the SIFES-MR governing council. RESULTS Fertility counselling transitions from urgent to long-term care, emphasizing family planning. Age, along with ovarian reserve markers, is the primary predictor of female fertility. Various factors, including gynecological conditions, autoimmune disorders, and prior gonadotoxic therapies, may impact ovarian reserve. Oocyte cryopreservation should be the preferred method. Women 30-34 years old and 35-39 years old, without known pathologies impacting the ovarian reserve, should cryopreserve at least 12-13 and 15-20 oocytes to achieve the same chance of a spontaneous live birth they would have if they tried to conceive at the age of cryopreservation (63% and 52%, respectively in the two age groups). CONCLUSIONS Optimal fertility counselling necessitates a long-term approach, that nurtures an understanding of fertility, facilitates timely evaluation of factors that may affect fertility, and explores fertility preservation choices at opportune intervals.
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Affiliation(s)
- Claudia Massarotti
- Physiopathology of Human Reproduction, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi, 10, 16132, Genova, Italy.
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI Department), University of Genova, Genova, Italy.
| | - Danilo Cimadomo
- IVIRMA Global Reseach Alliance, Genera, Clinica Valle Giulia, Rome, Italy
| | | | - Alessandro Conforti
- Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy
| | - Carlotta Zacà
- IVIRMA Global Research Alliance, 9.Baby, Bologna, Italy
| | - Andrea Roberto Carosso
- Obstetrics and Gynecology 1U, Physiopathology of Reproduction and IVF Unit, Department of Surgical Sciences, Sant'Anna Hospital Città della Salute e della Scienza di Torino, University of Torino, Turin, Italy
| | - Alberto Vaiarelli
- IVIRMA Global Reseach Alliance, Genera, Clinica Valle Giulia, Rome, Italy
| | - Roberta Venturella
- Unit of Obstetrics and Gynecology, University of Catanzaro "Magna Grecia", Catanzaro, Italy
| | - Amerigo Vitagliano
- First Unit of Obstetrics and Gynecology, Department of Interdisciplinary Medicine (DIM), University of Bari, Bari, Italy
| | - Andrea Busnelli
- Department of Obstetrics and Gynecology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Mauro Cozzolino
- IVIRMA Global Research Alliance, IVI Roma, Rome, Italy
- IVIRMA Global Research Alliance, Fundación IVI-IIS la Fe, Valencia, Spain
| | - Andrea Borini
- IVIRMA Global Research Alliance, 9.Baby, Bologna, Italy
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Rooda I, Hassan J, Hao J, Wagner M, Moussaud-Lamodière E, Jääger K, Otala M, Knuus K, Lindskog C, Papaikonomou K, Gidlöf S, Langenskiöld C, Vogt H, Frisk P, Malmros J, Tuuri T, Salumets A, Jahnukainen K, Velthut-Meikas A, Damdimopoulou P. In-depth analysis of transcriptomes in ovarian cortical follicles from children and adults reveals interfollicular heterogeneity. Nat Commun 2024; 15:6989. [PMID: 39168975 PMCID: PMC11339373 DOI: 10.1038/s41467-024-51185-0] [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] [Scholar Register] [Received: 11/16/2023] [Accepted: 08/01/2024] [Indexed: 08/23/2024] Open
Abstract
The ovarian cortical reserve of follicles is vital for fertility. Some medical treatments are toxic to follicles, leading to premature ovarian insufficiency. Ovarian tissue cryopreservation is an established method to preserve fertility in adults and even applied in prepuberty despite unproven efficacy. Here, we analyze transcriptomes of 120 cortical follicles from children and adults for detailed comparison. We discover heterogeneity with two main types of follicles in both age groups: one with expected oocyte-granulosa profiles and another with predicted role in signaling. Transcriptional changes during growth to the secondary stage are similar overall in children and adults, but variations related to extracellular matrix, theca cells, and miRNA profiles are found. Notably, cyclophosphamide dose correlates with interferon signaling in child follicles. Additionally, morphology alone is insufficient for follicle categorization suggesting a need for additional markers. Marker genes for early follicle activation are determined. These findings will help refine follicular classification and fertility preservation techniques across critical ages.
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Affiliation(s)
- Ilmatar Rooda
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Stockholm, Sweden.
- Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden.
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia.
| | - Jasmin Hassan
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Stockholm, Sweden
- Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Jie Hao
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Stockholm, Sweden
- Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden
- Department of Reproductive Medicine, Xiangya Hospital, Central South University, Changsha, PR China
| | - Magdalena Wagner
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Stockholm, Sweden
- Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Elisabeth Moussaud-Lamodière
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Stockholm, Sweden
- Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Kersti Jääger
- Institute of Computer Science, University of Tartu, Tartu, Estonia
- Competence Centre on Health Technologies, Tartu, Estonia
| | - Marjut Otala
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Katri Knuus
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Cecilia Lindskog
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Kiriaki Papaikonomou
- Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Sebastian Gidlöf
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Stockholm, Sweden
- Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Cecilia Langenskiöld
- Department of Pediatric Oncology, Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Hartmut Vogt
- Crown Princess Victoria Children's Hospital, and Division of Children's and Women's Health, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Per Frisk
- Department of Women's and Children's Health, Uppsala University Children's Hospital, Uppsala, Sweden
| | - Johan Malmros
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Timo Tuuri
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Andres Salumets
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Stockholm, Sweden
- Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden
- Competence Centre on Health Technologies, Tartu, Estonia
- Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
| | - Kirsi Jahnukainen
- Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Women's and Children's Health, NORDFERTIL Research Lab Stockholm, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Agne Velthut-Meikas
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Pauliina Damdimopoulou
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Stockholm, Sweden.
- Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden.
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Markowska A, Antoszczak M, Markowska J, Huczyński A. Gynotoxic Effects of Chemotherapy and Potential Protective Mechanisms. Cancers (Basel) 2024; 16:2288. [PMID: 38927992 PMCID: PMC11202309 DOI: 10.3390/cancers16122288] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/16/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024] Open
Abstract
Chemotherapy is one of the leading cancer treatments. Unfortunately, its use can contribute to several side effects, including gynotoxic effects in women. Ovarian reserve suppression and estrogen deficiency result in reduced quality of life for cancer patients and are frequently the cause of infertility and early menopause. Classic alkylating cytostatics are among the most toxic chemotherapeutics in this regard. They cause DNA damage in ovarian follicles and the cells they contain, and they can also induce oxidative stress or affect numerous signaling pathways. In vitro tests, animal models, and a few studies among women have investigated the effects of various agents on the protection of the ovarian reserve during classic chemotherapy. In this review article, we focused on the possible beneficial effects of selected hormones (anti-Müllerian hormone, ghrelin, luteinizing hormone, melatonin), agents affecting the activity of apoptotic pathways and modulating gene expression (C1P, S1P, microRNA), and several natural (quercetin, rapamycin, resveratrol) and synthetic compounds (bortezomib, dexrazoxane, goserelin, gonadoliberin analogs, imatinib, metformin, tamoxifen) in preventing gynotoxic effects induced by commonly used cytostatics. The presented line of research appears to provide a promising strategy for protecting and/or improving the ovarian reserve in the studied group of cancer patients. However, well-designed clinical trials are needed to unequivocally assess the effects of these agents on improving hormonal function and fertility in women treated with ovotoxic anticancer drugs.
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Affiliation(s)
- Anna Markowska
- Department of Perinatology and Women’s Health, Poznań University of Medical Sciences, 60-535 Poznań, Poland
| | - Michał Antoszczak
- Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, 61-614 Poznań, Poland
| | - Janina Markowska
- Gynecological Oncology Center, Poznańska 58A, 60-850 Poznań, Poland;
| | - Adam Huczyński
- Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, 61-614 Poznań, Poland
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Roberts JE, Benoit J, Foong S, Saumet J, Korkidakis A, Marr K, McQuillan S, Todd N. Fertility preservation in patients undergoing gonadotoxic treatments: a Canadian Fertility and Andrology Society clinical practice guideline. Reprod Biomed Online 2024; 48:103767. [PMID: 38458057 DOI: 10.1016/j.rbmo.2023.103767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 10/22/2023] [Accepted: 10/23/2023] [Indexed: 03/10/2024]
Abstract
The management of young patients with cancer presents several unique challenges. In general, these patients are ill prepared for the diagnosis and the impact on their fertility. With the improved survival for all tumour types and stages, the need for adequate fertility counselling and a multidisciplinary approach in the reproductive care of these patients is paramount. Recent advances in cryopreservation techniques allow for the banking of spermatozoa, oocytes, embryos and ovarian tissue without compromising survival. This Canadian Fertility and Andrology Society (CFAS) guideline outlines the current understanding of social and medical issues associated with oncofertility, and the medical and surgical technologies available to optimize future fertility.
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Affiliation(s)
- Jeffrey E Roberts
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, B.C., Canada.
| | - Janie Benoit
- Department of Obstetrics and Gynecology, McGill University, Montreal, QC, Canada
| | - Shu Foong
- Department of Obstetrics and Gynecology, University of Calgary, Calgary, AB, Canada
| | - Julio Saumet
- Department of Obstetrics and Gynecology, McGill University, Montreal, QC, Canada
| | - Ann Korkidakis
- Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard University, Boston, MA, USA
| | - Kristin Marr
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, B.C., Canada
| | - Sarah McQuillan
- Department of Obstetrics and Gynecology, University of Calgary, Calgary, AB, Canada
| | - Nicole Todd
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, B.C., Canada
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Gutzeit O, Bachar G, Iluz R, Araaf A, Nebenzahl-Sharona K, Nasatzky M, Weiner Z, Beloosesky R, Fainaru O. Hypoxia Leads to Diminished Ovarian Reserve in an Age-Dependent Manner. Gynecol Obstet Invest 2024; 89:278-283. [PMID: 38569488 DOI: 10.1159/000538315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 03/10/2024] [Indexed: 04/05/2024]
Abstract
OBJECTIVES Perinatal hypoxia causes premature activation and initiation of growth in dormant follicles, leading to diminished ovarian reserve. An indirect mechanism such as the release of stress-related hormones may influence ovarian follicle recruitment under hypoxic conditions. We wanted to determine whether hypoxic ovarian damage results from increased follicle growth and "burnout" or from increased apoptosis and whether this damage is age-dependent. DESIGN Animal study was conducted. PARTICIPANTS/MATERIALS, SETTING, METHODS Using adult 6-week-old (n = 8) and one-day-old newborn (n = 20) ICR (CD-1) female mice, ovarian follicular counts were conducted on H&E-stained sections. METHODS Immunohistochemistry was performed on sections stained with Ki-67, anti-Caspase 3, and anti-FOXO3A. RESULTS Exposure to hypoxia resulted in significantly reduced proportion of primordial follicles versus normoxia in both adult dams and newborn pups (3.17 ± 2.75 vs. 17.89 ± 4.4%; p = 0.004; 40.59 ± 14.88 vs. 81.92 ± 31.56%, p = 0.001, respectively), concomitant with increased growing-primary and secondary follicles, and more pronounced in adult dams versus newborn pups (6-fold vs. 2-fold, respectively). Ki67 staining revealed higher scores of cell proliferation in follicular granulosa cells after exposure to hypoxia than normoxia. However, Caspase 3 and Foxo3A staining did not show any differences in these markers of apoptosis in oocytes, granulosa cells, theca cells, or stromal cells when exposed to hypoxia versus normoxia. LIMITATIONS The current study has several limitations; first, the sample size for each group is relatively small, which could limit the generalizability of the findings. Second, the study used an ex vivo culture system, which may not fully capture the complex interactions that occur in the whole animal. Third, the exposure to hypoxia only lasted for 3 h, which may not be long enough to observe all the potential effects. In addition, the study only analyzed specific markers of apoptosis in a few cell types, and other cell types or apoptotic pathways might be involved. Lastly, the study provides evidence for accelerated follicular activation and decreased ovarian reserve, but the underlying mechanisms are not fully explored. CONCLUSIONS Direct tissue hypoxia led to premature activation and initiation of growth in dormant follicles leading to diminished ovarian reserve. Hypoxic damage is age-dependent, with adult ovaries more susceptible than newborn ovaries. These findings support the possibility of follicular "burn out" as a potential mechanism responsible for hypoxia-induced loss of ovarian reserve.
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Affiliation(s)
- Ola Gutzeit
- IVF Unit, Department of Obstetrics and Gynecology, Rambam Health Care Campus, and Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Gal Bachar
- IVF Unit, Department of Obstetrics and Gynecology, Rambam Health Care Campus, and Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel,
| | - Roee Iluz
- IVF Unit, Department of Obstetrics and Gynecology, Rambam Health Care Campus, and Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Alaa Araaf
- IVF Unit, Department of Obstetrics and Gynecology, Rambam Health Care Campus, and Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Keren Nebenzahl-Sharona
- IVF Unit, Department of Obstetrics and Gynecology, Rambam Health Care Campus, and Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Maya Nasatzky
- IVF Unit, Department of Obstetrics and Gynecology, Rambam Health Care Campus, and Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Zeev Weiner
- IVF Unit, Department of Obstetrics and Gynecology, Rambam Health Care Campus, and Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Ron Beloosesky
- IVF Unit, Department of Obstetrics and Gynecology, Rambam Health Care Campus, and Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Ofer Fainaru
- IVF Unit, Department of Obstetrics and Gynecology, Rambam Health Care Campus, and Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
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Lai THT, Lau LSK, Ngu SF, Chu MYM, Chan KKL, Ng EHY, Ngan HYS, Li RHW, Tse KY. Comparison of the multiples of the median of serum anti-müllerian hormone and pregnancy outcomes in patients with gestational trophoblastic disease: A case-control study. Cancer Med 2024; 13:e7134. [PMID: 38545760 PMCID: PMC10973878 DOI: 10.1002/cam4.7134] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 03/04/2024] [Accepted: 03/09/2024] [Indexed: 04/04/2024] Open
Abstract
INTRODUCTION Chemotherapy is crucial in treating gestational trophoblastic neoplasia (GTN), but its impact on gonadotoxicity is unclear. MATERIALS AND METHODS This case-control study included 57 GTN patients and 19 age-matched patients with molar pregnancies (MP) in 2012-2018. Multiples of the median (MoM) of the serum AMH levels were compared between the two groups, and between patients using single-agent and combination chemotherapy, at baseline, 6, 12, and 24 months after treatment. Their pregnancy outcomes were also compared. RESULTS There was no significant difference in the MoM of serum AMH between GTN and MP groups at all time points. Single-agent chemotherapy did not adversely affect the MoM. However, those receiving combination chemotherapy had lower MoM than those receiving single-agent chemotherapy at all time points. The trend of decline from the baseline was marginally significant in patients with combination chemotherapy, but the drop was only significant at 12 months (Z = -2.69, p = 0.007) but not at 24 months (Z = -1.90; p = 0.058). Multivariable analysis revealed that combination chemotherapy did not affect the MoM. There was no significant difference in the 4-year pregnancy rate and the livebirth rate between the single-agent and combination groups who attempting pregnancy, but it took 1 year longer to achieve the first pregnancy in the combination group compared to the single-agent group (2.88 vs. 1.88 years). CONCLUSION This study showed combination chemotherapy led to a decreasing trend of MoM of serum AMH especially at 12 months after treatment, but the drop became static at 24 months. Although pregnancy is achievable, thorough counseling is still needed in this group especially those wish to achieve pregnancy 1-2 years after treatment or with other risk factors.
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Affiliation(s)
| | - Lesley Suk Kwan Lau
- Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, School of Clinical MedicineHong KongChina
| | - Siew Fei Ngu
- Department of Obstetrics and GynaecologyQueen Mary HospitalHong KongChina
- Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, School of Clinical MedicineHong KongChina
| | - Man Yee Mandy Chu
- Department of Obstetrics and GynaecologyQueen Mary HospitalHong KongChina
- Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, School of Clinical MedicineHong KongChina
| | - Karen Kar Loen Chan
- Department of Obstetrics and GynaecologyQueen Mary HospitalHong KongChina
- Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, School of Clinical MedicineHong KongChina
| | - Ernest Hung Yu Ng
- Department of Obstetrics and GynaecologyQueen Mary HospitalHong KongChina
- Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, School of Clinical MedicineThe University of Hong KongHong KongChina
| | - Hextan Yuen Sheung Ngan
- Department of Obstetrics and GynaecologyQueen Mary HospitalHong KongChina
- Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, School of Clinical MedicineHong KongChina
| | - Raymond Hang Wun Li
- Department of Obstetrics and GynaecologyQueen Mary HospitalHong KongChina
- Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, School of Clinical MedicineThe University of Hong KongHong KongChina
| | - Ka Yu Tse
- Department of Obstetrics and GynaecologyQueen Mary HospitalHong KongChina
- Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, School of Clinical MedicineHong KongChina
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9
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Feng Y, Zhang W, Xu X, Wang W, Xu Y, Wang M, Zhang J, Xu H, Fu F. Protective effect of Luffa cylindrica fermentation liquid on cyclophosphamide-induced premature ovarian failure in female mice by attenuating oxidative stress, inflammation and apoptosis. J Ovarian Res 2024; 17:24. [PMID: 38273341 PMCID: PMC10809788 DOI: 10.1186/s13048-024-01353-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 01/15/2024] [Indexed: 01/27/2024] Open
Abstract
Premature ovarian failure (POF) is a leading cause of women's infertility without effective treatment. The purpose of this study was to investigate the protective effects of Luffa cylindrica fermentation liquid (LF) on cyclophosphamide (CTX) -induced POF in mice and to preliminarily investigate the underlying mechanisms. Thirty-two Balb/c mice were divided into four groups randomly. One group served as the control, while the other three received CTX injections to establish POF models. A 14-day gavage of either 5 or 10 μL/g LF was administered to two LF pretreatment groups. To analyze the effects of LF, the ovarian index, follicle number, the levels of serum sex hormones, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), inflammatory factors, and apoptosis of the ovarian cells were measured. The effects of LF pretreatment on the expression of TLR4/NF-κB and apoptosis pathways were also evaluated. We found that LF pretreatment increased the ovarian index and the number of primordial and antral follicles while decreasing those of atretic follicles. LF pretreatment also increased the serum levels of estradiol (E2) and anti-Müllerian hormone (AMH), while decreasing those of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Furthermore, LF pretreatment increased the levels of SOD and GSH in the ovaries, while decreasing those of MDA, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). LF administration reduced the amount of TUNEL+ ovarian cells and the levels of TLR4 and NF-κB P65 protein expression. In conclusion, LF has antioxidant, anti-inflammatory as well as anti-apoptotic effects against CTX-induced POF, and the inhibition of TLR4/NF-κB and apoptosis pathways may be involved in its mechanisms.
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Affiliation(s)
- Yueying Feng
- The Second Affiliated Hospital of Nanchang University, Nanchang University, No. 1 Mingde Road, Nanchang, 330000, People's Republic of China
- State Key Laboratory of Food Science and Resources, Nanchang University, 235 Nanjing East Road, Nanchang, 330047, People's Republic of China
| | - Wei Zhang
- The Second Affiliated Hospital of Nanchang University, Nanchang University, No. 1 Mingde Road, Nanchang, 330000, People's Republic of China
| | - Xiaowei Xu
- State Key Laboratory of Food Science and Resources, Nanchang University, 235 Nanjing East Road, Nanchang, 330047, People's Republic of China
| | - Wanzhen Wang
- The Second Affiliated Hospital of Nanchang University, Nanchang University, No. 1 Mingde Road, Nanchang, 330000, People's Republic of China
- State Key Laboratory of Food Science and Resources, Nanchang University, 235 Nanjing East Road, Nanchang, 330047, People's Republic of China
| | - Yuanyuan Xu
- The Second Affiliated Hospital of Nanchang University, Nanchang University, No. 1 Mingde Road, Nanchang, 330000, People's Republic of China
| | - Mengqi Wang
- State Key Laboratory of Food Science and Resources, Nanchang University, 235 Nanjing East Road, Nanchang, 330047, People's Republic of China
| | - Jinfeng Zhang
- State Key Laboratory of Food Science and Resources, Nanchang University, 235 Nanjing East Road, Nanchang, 330047, People's Republic of China
| | - Hengyi Xu
- State Key Laboratory of Food Science and Resources, Nanchang University, 235 Nanjing East Road, Nanchang, 330047, People's Republic of China.
| | - Fen Fu
- The Second Affiliated Hospital of Nanchang University, Nanchang University, No. 1 Mingde Road, Nanchang, 330000, People's Republic of China.
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10
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Ortiz E, Peña CJ, Hidalgo JJ, Monllor-Tormos A, Zolfaroli I, Vila MJ, Sánchez-Serrano M, Pellicer A, Cano A. Long-term effect of chemotherapy after ovarian decortication on the ovarian function in women surviving cancer. J Assist Reprod Genet 2023; 40:2827-2834. [PMID: 37755614 PMCID: PMC10656377 DOI: 10.1007/s10815-023-02949-y] [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] [Scholar Register] [Received: 04/03/2023] [Accepted: 09/16/2023] [Indexed: 09/28/2023] Open
Abstract
PURPOSE Ovarian decortication may affect ovarian function. We investigated the status of ovarian reserve after ovarian decortication plus chemotherapy at a stage of presumed stabilized recovery in women surviving cancer. METHODS We searched our database for cancer survivors subjected to ovarian decortication and chemotherapy at least 3 years previously. Ovarian function was explored for levels of anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), and estradiol (E2), and menstrual pattern. RESULTS Forty women (mean age 29.6 (SD, 6.1) years) were assessed at a mean of 4.7 (1.5) years after surgery. The predecortication levels of AMH and FSH changed at post-treatment from 2.2 (1.4) to 0.5 (1.3) ng/mL for AMH (p < 0.001) and from 4.7 (2.1) to 16.7 (21. 6) IU/L for FSH (p < 0.001). Amenorrhea consistent with primary ovarian insufficiency (POI) was diagnosed in 11 women, and normal ovarian reserve (AMH ≥ 1.0 ng/mL) was found in 4 of the 21 women who recovered regular cycles. Logistic regression confirmed AMH as an independent predictor of diminished ovarian reserve (OR = 0.24, 95% CI: 0.04-0.63, p = 0.025) and POI (OR = 0.11, 95% CI: 0.01-0.52, p = 0.027), and age was predictive of POI (OR = 1.36, 95% CI: 1.08-1.96, p = 0.035) and of irregular menstrual cycle (OR = 1.20, 95% CI: 1.03-1.46, p = 0.034). CONCLUSION Ovarian decortication plus chemotherapy had a deleterious effect when assessed at a stage of stabilized ovarian recovery, but whether ovarian decortication had a specific impact cannot be revealed from our data.
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Affiliation(s)
- Ester Ortiz
- Service of Obstetrics and Gynecology, University Hospital Dr Peset, Av Gaspar Aguilar 90, 46017, Valencia, Spain
| | - Carlos J Peña
- Bioinformatics and Biostatistics Unit, INCLIVA, Calle Menéndez Pelayo 4, 46010, Valencia, Spain
| | - Juan-José Hidalgo
- Department of Gynecologic Oncology, La Fe University and Polytechnic Hospital, Av Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Aitana Monllor-Tormos
- Service of Obstetrics and Gynecology, INCLIVA, Av Blasco Ibáñez 19, 46010, Valencia, Spain
| | - Irene Zolfaroli
- Department of Gynecologic Oncology, La Fe University and Polytechnic Hospital, Av Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - María-José Vila
- Service of Obstetrics and Gynecology, University Hospital Dr Peset, Av Gaspar Aguilar 90, 46017, Valencia, Spain
| | - María Sánchez-Serrano
- Service of Obstetrics and Gynecology, INCLIVA, Av Blasco Ibáñez 19, 46010, Valencia, Spain
| | - Antonio Pellicer
- IVI RMA Rome Rome Italy; IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Antonio Cano
- Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, INCLIVA, Av Blasco Ibáñez 15, 46010, Valencia, Spain.
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Regenerative potential of different extracellular vesicle subpopulations derived from clonal mesenchymal stem cells in a mouse model of chemotherapy-induced premature ovarian failure. Life Sci 2023; 321:121536. [PMID: 36868400 DOI: 10.1016/j.lfs.2023.121536] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 02/16/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023]
Abstract
AIMS Some studies have shown that mesenchymal stem cells (MSCs) and their derived extracellular vesicles (MSC-EVs) can restore ovarian function in premature ovarian failure (POF), however, concerns about their efficacy are attributed to the heterogeneity of the cell populations and EVs. Here, we assessed the therapeutic potential of a homogeneous population of clonal MSCs (cMSCs) and their EVs subpopulations in a mouse model of POF. MAIN METHODS Granulosa cells were treated with cyclophosphamide (Cy) in the absence or presence of cMSCs, or cMSCs-derived EV subpopulations (EV20K and EV110K, isolated by high-speed centrifugation and differential ultracentrifugation, respectively). In addition, POF mice were treated with cMSCs, EV20K and/or EV110K. KEY FINDINGS cMSC and both EV types protected granulosa cells from Cy-induced damage. Calcein-EVs were detected in the ovaries. Moreover, cMSC and both EV subpopulations significantly increased body weight, ovary weight, and the number of follicles, restored FSH, E2, and AMH levels, increased the granulosa cell numbers and restored the fertility of POF mice. cMSC, EV20K, and EV110K alleviated inflammatory-related genes expression (Tnf-α and IL8), and improved angiogenesis via upregulation expression of Vegf and Igf1 at the mRNA level and VEGF and αSMA at the protein level. They also inhibited apoptosis through the PI3K/AKT signaling pathway. SIGNIFICANCE The administration of cMSCs and two cMSC-EVs subpopulations improved ovarian function and restored fertility in a POF model. EV20K is more cost-effective and feasible in terms of isolation, particularly in good manufacturing practice (GMP) facilities for treatment of POF patients in comparison with conventional EVs (EV110K).
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12
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Krouwel EM, Birkhoff EML, Nicolai MPJ, Osanto S, Putter H, Pelger RCM, Elzevier HW. An Educational Need Regarding Treatment-Related Infertility and Fertility Preservation: a National Survey Among Members of the Dutch Society for Medical Oncologists. JOURNAL OF CANCER EDUCATION : THE OFFICIAL JOURNAL OF THE AMERICAN ASSOCIATION FOR CANCER EDUCATION 2023; 38:106-114. [PMID: 34623602 PMCID: PMC9852179 DOI: 10.1007/s13187-021-02084-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/29/2021] [Indexed: 06/13/2023]
Abstract
Cancer diagnosis and treatment may influence reproductive planning and impact fertility in patients of reproductive age. Although guidelines have been established in the past decade, education, practice, and attitudes of medical oncologists regarding fertility preservation remain undecided. A nationwide survey was performed among members of the Dutch Society for Medical Oncology. Demographics, practice, knowledge, and barriers were measured regarding information provision of fertility preservation towards cancer patients of childbearing age. From 392 members, 120 oncologists completed the questionnaire (30.6%). Majority of oncologists was convinced it is their responsibility to discuss impact of cancer treatment to fertility (93.2%), yet 68.3% discussed the subject often or always (n = 82). Oncologists employed in district general hospitals were less likely to discuss fertility (p = 0.033). On average, 44.6% of reproductive men and 28.9% of reproductive women is referred to fertility specialists. Half of the respondents declared to possess sufficient knowledge regarding fertility preservation (n = 57, 47.5%). Poor prognosis (53%), unlikely survival (43.1%), and high chances on fertility recovery (28.7%) were identified as barriers to discussing fertility preservation. Among oncologists, impact of cancer treatment on fertility is a well-accepted responsibility to counsel. Despite, self-reported knowledge regarding fertility preservation is strongly varying. In practice, fertility is discussed to some extent, influenced by several barriers and depending on prognosis and type of hospital. Patients benefit from knowledge improvement among oncology care providers concerning fertility effects of cancer treatment. Education during medical school, residency, and among practicing oncologists may raise awareness, together with enhancement of referral possibilities.
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Affiliation(s)
- E. M. Krouwel
- Department of Urology, Leiden University Medical Centre, Leiden, the Netherlands
- Department of Medical Decision Making, Leiden University Medical Centre, Leiden, the Netherlands
| | - E. M. L. Birkhoff
- Department of Urology, Leiden University Medical Centre, Leiden, the Netherlands
- Department of Medical Decision Making, Leiden University Medical Centre, Leiden, the Netherlands
| | - M. P. J. Nicolai
- Department of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands
| | - S. Osanto
- Department of Oncology, Leiden University Medical Centre, Leiden, the Netherlands
| | - H. Putter
- Department of Medical Statistics, Leiden University Medical Centre, Leiden, the Netherlands
| | - R. C. M. Pelger
- Department of Urology, Leiden University Medical Centre, Leiden, the Netherlands
- Department of Medical Decision Making, Leiden University Medical Centre, Leiden, the Netherlands
| | - H. W. Elzevier
- Department of Urology, Leiden University Medical Centre, Leiden, the Netherlands
- Department of Medical Decision Making, Leiden University Medical Centre, Leiden, the Netherlands
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13
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Lan A, Jin Y, Wang Y, Ding N, Wang Y, Dai Y, Jiang L, Tang Z, Peng Y, Liu S. Association of serum reproductive hormones changes after neoadjuvant chemotherapy with hormone receptors expression alterations and survival outcomes in breast cancer. Front Surg 2022; 9:947218. [PMID: 36117838 PMCID: PMC9470751 DOI: 10.3389/fsurg.2022.947218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 08/15/2022] [Indexed: 11/30/2022] Open
Abstract
Purpose This study aimed to determine the effect of neoadjuvant chemotherapy (NAC) on circulating levels of reproductive hormones and evaluate the correlation of hormone changes after NAC with hormone receptors expression alterations and relapse-free survival (RFS) outcomes in breast cancer. Methods Information from 181 breast cancer patients who received NAC was retrospectively analyzed. For hormones parameters, the median and interquartile range (IQR) were provided at baseline and the end of NAC then was compared by Wilcoxon signed-rank test. Categorical variables were represented as numbers and percentages and were compared via two-sided chi-square and Fisher's tests. The RFS outcomes were compared between patients according to hormone changes using the log-rank test. Univariate and multivariate survival analyses with hazard ratios (HR) and 95% confidence intervals (95% CI) were carried out using Cox regression. Results Sex steroids including estradiol, progesterone, testosterone, and dehydroepiandrosterone sulfate (DHEAS) levels decreased significantly after NAC among both premenopausal and postmenopausal patients (all P < 0.05). Decreased estradiol levels were associated with reduced progesterone receptor (PR) expression (P = 0.030). In multivariate survival analysis, the non-decreased progesterone level was strongly associated with worse RFS (non-decreased vs. decreased, HR = 7.178, 95% CI 2.340–22.019, P = 0.001). Patients with decreased progesterone levels exhibited better 3-year RFS compared with those with non-decreased (87.6% vs. 58.3%, log-rank, P = 0.001). Conclusion Multiple reproductive hormone levels were influenced by NAC. The change in estradiol level had a positive connection with PR expression alteration. Furthermore, an inverse association between the change in progesterone level and RFS outcomes was found. These findings may provide a theoretical basis for pre-operative endocrine therapy combined with NAC in breast cancer patients.
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Uldbjerg CS, Wilson LF, Koch T, Christensen J, Dehlendorff C, Priskorn L, Abildgaard J, Simonsen MK, Lim YH, Jørgensen JT, Andersen ZJ, Juul A, Hickey M, Brauner EV. Oophorectomy and rate of dementia: a prospective cohort study. Menopause 2022; 29:514-522. [PMID: 35102101 DOI: 10.1097/gme.0000000000001943] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
OBJECTIVE Globally, dementia disproportionally affects women, which is not fully explained by higher female longevity. Oophorectomy at any age leads to the permanent loss of ovarian sex steroids, potentially increasing the risk of dementia. We aimed to investigate the association between oophorectomy and dementia and whether this was conditional on age at oophorectomy, hysterectomy or use of hormone therapy (HT). METHODS A prospective study of 24,851 female nurses from the Danish Nurse Cohort. Nurses were followed from age 60 years or entry into the cohort, whichever came last, until date of dementia, death, emigration or end of follow-up (December 31, 2018), whichever came first. Poisson regression models with log-transformed person-years as offset were used to estimate the associations. RESULTS During 334,420 person-years of follow-up, 1,238 (5.0%) nurses developed dementia and 1,969 (7.9%)/ 1,016 (4.1%) contributed person-time after bilateral-/unilateral oophorectomy. In adjusted analyses, an 18% higher rate of dementia was observed following bilateral oophorectomy (aRR 1.18: 95% CI, 0.89-1.56) and 13% lower rate (aRR 0.87: 95% CI, 0.59-1.23) following unilateral oophorectomy compared to nurses who retained their ovaries. Similar effects were detected after stratification according to age at oophorectomy. No statistically significant modifying effects of hysterectomy or HT were detected (Pinteraction≥0.60). CONCLUSIONS Bilateral, but not unilateral, oophorectomy was associated with an increased rate of incident dementia. We were unable to establish whether this association was conditional on hysterectomy or HT use. Although an increase in dementia after bilateral oophorectomy is biologically plausible, limited statistical power hampers the precision of the estimates.
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Affiliation(s)
- Cecilie S Uldbjerg
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Denmark
- The International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Denmark
| | - Louise F Wilson
- The University of Queensland, NHMRC Centre for Research Excellence on Women and Non-communicable Diseases (CREWaND), School of Public Health, Herston Road, Herston, Queensland, Australia
| | - Trine Koch
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Denmark
- The International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Denmark
| | - Jane Christensen
- Statistics and Dataanalysis, Danish Cancer Society, Copenhagen, Denmark
| | | | - Lærke Priskorn
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Denmark
- The International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Denmark
| | - Julie Abildgaard
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Denmark
- The International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Denmark
- Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark
| | - Mette K Simonsen
- Diakonissestiftelsen and Parker Institute, Frederiksberg Hospital, Frederiksberg, Denmark
| | - Youn-Hee Lim
- Section of Environmental Health, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
- Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Jeanette T Jørgensen
- Section of Environmental Health, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Zorana J Andersen
- Section of Environmental Health, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Anders Juul
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Denmark
- The International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Denmark
| | - Martha Hickey
- Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia
| | - Elvira V Brauner
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Denmark
- The International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Denmark
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15
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Anderson RA, Cameron D, Clatot F, Demeestere I, Lambertini M, Nelson SM, Peccatori F. Anti-Müllerian hormone as a marker of ovarian reserve and premature ovarian insufficiency in children and women with cancer: a systematic review. Hum Reprod Update 2022; 28:417-434. [PMID: 35199161 PMCID: PMC9071067 DOI: 10.1093/humupd/dmac004] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 11/18/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND Female patients undergoing anticancer treatment are at elevated risk of adverse ovarian outcomes including infertility and premature ovarian insufficiency (POI), which is associated with short- and long-term health risks. Anti-Müllerian hormone (AMH) is a key biomarker of ovarian reserve, but its role prior to and after cancer treatment is less well understood. OBJECTIVE AND RATIONALE To conduct a systematic review evaluating AMH as a biomarker of ovarian reserve and POI before and after anticancer treatment, which has become a pressing clinical issue in reproductive medicine. There are a large number of observational studies, but differences in patient groups, cancer diagnoses and study design make this a confusing field that will benefit from a thorough and robust review. SEARCH METHODS A systematic literature search for AMH in women with cancer was conducted in PubMed, Embase and Cochrane Central Register of Controlled Trials up to 1 April 2021. Bias review was conducted using the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) protocol along with qualitative assessment of quality. Exploratory subgroups were established based on age, cancer type and length of follow-up. OUTCOMES Ninety-two publications (N = 9183 patients) were included in this analysis after quality and bias review. Reduced/undetectable AMH was consistently identified in 69/75 studies (92%) following chemotherapy or radiotherapy, with reductions ranging from 42% to concentrations below the limit of detection, and many reporting mean or median declines of ≥90%. Where longitudinal data were analysed (42 studies), a majority (33/42 (79%)) of studies reported at least partial recovery of AMH at follow-up, however, effect estimates were highly variable, reflecting that AMH levels were strongly impacted by anticancer treatment (i.e. the chemotherapy regimen used and the number of treatment cycles need), with recovery and its degree determined by treatment regimen, age and pre-treatment AMH level. In 16/31 (52%) publications, oligo/amenorrhoea was associated with lower post-treatment AMH consistent with impending POI, although menstruation and/or pregnancy were reported in patients with low or undetectable AMH. Long-term (>5 years) follow-up of paediatric patients following cancer treatment also found significantly lower AMH compared with control groups in 14/20 (70%) of studies, with very variable effect sizes from complete loss of AMH to full recovery depending on treatment exposure, as in adult patients. WIDER IMPLICATIONS AMH can be used to identify the damaging effect of cancer treatments on ovarian function. This can be applied to individual women, including pre-pubertal and adolescent girls, as well as comparing different treatment regimens, ages and pre-treatment AMH levels in populations of women. While there was evidence for its value in the diagnosis of POI after cancer treatment, further studies across a range of diagnoses/treatment regimens and patient ages are required to clarify this, and to quantify its predictive value. A major limitation for the use of AMH clinically is the very limited data relating post-treatment AMH levels to fertility, duration of reproductive lifespan or time to POI; analysis of these clinically relevant outcomes will be important in further research.
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Affiliation(s)
- Richard A Anderson
- MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK,Correspondence address. MRC Centre for Reproductive Health, The Queen’s Medical Research Institute, Edinburgh BioQuarter, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. Tel: +44-(0)-131-242-6386; E-mail:https://orcid.org/0000-0002-7495-518X
| | - David Cameron
- Edinburgh University Cancer Centre, IGMM, Edinburgh, UK
| | | | - Isabelle Demeestere
- Fertility clinic, CUB-Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Matteo Lambertini
- Department of Medical Oncology, U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy,Department of Internal Medicine and Medical Sciences (DiMI), School of Medicine, University of Genova, Genova, Italy
| | - Scott M Nelson
- School of Medicine, University of Glasgow, Glasgow, UK,NIHR Bristol Biomedical Research Centre, Bristol, UK,The Fertility Partnership, Oxford, UK
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16
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Furlanetto J, Marmé F, Seiler S, Thode C, Untch M, Schmatloch S, Schneeweiss A, Bassy M, Fasching PA, Strik D, Stickeler E, Schem C, Karn T, Grischke EM, Denkert C, van Mackelenbergh M, Müller V, Nekljudova V, Loibl S. Chemotherapy-induced ovarian failure in young women with early breast cancer: Prospective analysis of four randomised neoadjuvant/adjuvant breast cancer trials. Eur J Cancer 2021; 152:193-203. [PMID: 34116270 DOI: 10.1016/j.ejca.2021.04.038] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/19/2021] [Accepted: 04/22/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Young women receiving chemotherapy for early breast cancer (EBC) have a high probability for ovarian failure, defined by chemotherapy-induced amenorrhea (CIA) as a surrogate. CIA is insufficiently reliable and reproducible. We analysed chemotherapy-induced ovarian failure (CIOF) by assessing hormone parameters, CIA, and antral follicle count (AFC). METHODS Blood samples of women aged ≤45 years treated with anthracycline/taxane-based chemotherapy for EBC from four neoadjuvant/adjuvant trials were collected at baseline, at the end of treatment (EOT), and at 6, 12, 18, and 24 months after EOT. Centrally assessed oestradiol (cutoff <52.2 ng/L) and follicle-stimulating hormone (cutoff >12.4IU/L) were used to define CIOF for patients with baseline premenopausal hormone levels, anti-Müllerian hormone (AMH), and AFC to assess ovarian reserve. Further analyses included CIA, regain of premenopausal hormone levels, and disease-free survival (DFS) also in subgroups. RESULTS Six hundred ninety-six patients aged ≤45 years had premenopausal hormone levels at baseline. Overall, 85.1% (592/696) experienced CIOF at EOT, and 147 of 592 had further hormone measurements after EOT. Of those, 32.7% (48/147) regained premenopausal hormone levels after 6 months, 57.9% (66/114) regained premenopausal hormone levels after 12 months, 83.0% (73/88) regained premenopausal hormone levels after 18 months, and 89.2% (74/83) regained premenopausal hormone levels after 24 months. After 24 months, 72.4% (21/29) of patients without CIOF and 100% (14/14) with CIOF had low AMH levels. Four-year DFS without CIOF versus CIOF was 65.9% versus 84.6% (hazard ratio [HR] = 2.09, 95% confidence interval [CI]: 1.37-3.19; P < 0.001); in hormone receptor positive 61.8% versus 87.5% (HR = 2.69, 95% CI: 1.57-4.60; P < 0.001); in <30 years 68.3% versus 92.6% (HR = 4.87, 95% CI: 1.05-22.63; P = 0.026). CONCLUSION Most premenopausal women experienced CIOF after chemotherapy for EBC. After 2 years, nearly all regain premenopausal hormone levels. CIOF was associated with better DFS, especially in patients with hormone receptor-positive EBC or aged <30 years.
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Affiliation(s)
| | | | | | - Christian Thode
- Amedes MVZ Wagnerstibbe für Laboratoriumsmedizin, Medizinische Mikrobiologie und Immunologie, Göttingen, Germany
| | | | | | | | - Martina Bassy
- Amedes MVZ Wagnerstibbe für Laboratoriumsmedizin, Medizinische Mikrobiologie und Immunologie, Göttingen, Germany
| | | | | | | | | | | | | | - Carsten Denkert
- Institut für Pathologie Philipps-Universität Marburg, Germany
| | - Marion van Mackelenbergh
- Universitätsklinikum Schleswig-Holstein, Klinik für Gynäkologie und Geburtshilfe, Schleswig-Holstein, Germany
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Ahmadi S, Mehranjani MS. Taurine improves follicular survival and function of mice ovarian grafts through increasing CD31 and GDF9 expression and reducing oxidative stress and apoptosis. Eur J Pharmacol 2021; 903:174134. [PMID: 33940031 DOI: 10.1016/j.ejphar.2021.174134] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 04/21/2021] [Accepted: 04/26/2021] [Indexed: 10/21/2022]
Abstract
Ischemia-reperfusion (IR) injury is a major limitation of ovarian transplantation which threatens the follicular and graft survival. Taurine as a potent anti-oxidant, anti-apoptotic and anti-inflammatory agent, can prevent graft damages due to IR. We aimed to investigate the effect of taurine on the follicular survival and function of autotransplanted mouse ovaries. Female mice (4-5 weeks old) were divided into: control, autograft and autograft + taurine (200 mg/kg/day). The level of CD31 expression was evaluated two days (48 h) post transplantation. In addition, on day 7 post transplantation the serum levels of malondialdehyde (MDA) and the total antioxidant capacity (TAC) were assessed. Also, 28 days post transplantation; ovaries were studied stereologically and the percentage of apoptotic follicles, level of GDF9 expression and the serum concentrations of progesterone and estradiol were measured. Data were analyzed using one-way ANOVA and Tukey's test and the means were considered significantly different at P < 0.05. The total volume of the ovary (P < 0.01), volume of the cortex (P < 0.01) and medulla (P < 0.04), total number of different types of follicles, expression of GDF9 and CD31 and also the levels of progesterone, estradiol and TAC increased significantly in the autograft + taurine group compared to the autograft group (P < 0.001). The MDA level and apoptosis rate decreased significantly in the autograft + taurine group compared to the autograft group (P < 0.001). Taurine could significantly improve follicular survival and the function of grafted ovaries by accelerating the angiogenesis and reducing oxidative stress and apoptosis.
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Affiliation(s)
- Sepideh Ahmadi
- Department of Biology, Faculty of Science, Arak University, Arak, 381-5688138, Iran
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18
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Martin HL, Ullah S, Abbas N, Scott-Hoy A, Kichenadasse G, Karapetis CS, Roy A, Sukumaran S, Ross DM, Khattak MA, Koczwara B. Predicting chemotherapy-induced menopause using baseline and post-chemotherapy anti-Müllerian hormone levels: Results of a pilot study. Cancer Rep (Hoboken) 2021; 4:e1342. [PMID: 33660428 PMCID: PMC8222560 DOI: 10.1002/cnr2.1342] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 12/28/2020] [Accepted: 01/04/2021] [Indexed: 11/21/2022] Open
Abstract
Background Chemotherapy can cause premature menopause which may result in adverse effects such as fertility loss, osteoporosis, cardiovascular disease and menopausal symptoms. It is thus very important that women are provided with accurate information regarding their risk of premature menopause as a consequence of proposed chemotherapy. Unfortunately, at present there are no reliable tools which can be applied in clinical practice to estimate the risk of premature menopause in women undergoing chemotherapy, beyond age of the patient and form of chemotherapy utilized. Aim This was a pilot study to determine whether AMH levels pre and during chemotherapy are able to predict for chemotherapy induced menopause, and to assess quality of life and menopausal symptoms. Methods and results Premenopausal women between 18 to 45 who were planned to undergo gonadotoxic chemotherapy with curative intent for either breast cancer or haematologic malignancy were recruited from a single centre. AMH, FSH, LH and oestradiol levels were recorded prior to commencement of therapy, during and following completion of chemotherapy. Menstrual status, menopausal symptoms and quality of life data were collected at baseline and during follow‐up. Twenty two women were recruited. The baseline AMH was higher in women who regained menses post‐chemotherapy (median 23.1 vs 9.9 pM (P = .06). Menopausal symptoms were significantly higher at 1 year post diagnosis than at baseline however quality of life was similar. Conclusion AMH may be useful for predicting chemotherapy induced menopause. Further research is still required to determine the place of such testing for patient counselling and management.
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Affiliation(s)
| | - Shahid Ullah
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Nazim Abbas
- Flinders University, Adelaide, Australia.,Flinders Medical Centre, Adelaide, Australia
| | | | | | | | - Amitesh Roy
- Flinders Medical Centre, Adelaide, Australia
| | | | - David M Ross
- Flinders Medical Centre, Adelaide, Australia.,SA Pathology, Adelaide, Australia.,Royal Adelaide Hospital, Adelaide, Australia
| | - Muhammad Adnan Khattak
- Fiona Stanley Hospital, Perth, Australia.,University of Western Australia, Perth, Australia
| | - Bogda Koczwara
- Flinders University, Adelaide, Australia.,Flinders Medical Centre, Adelaide, Australia
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19
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Modern Concepts of Clinical and Diagnostic Criteria for Premature Ovarian Failure (Literature Review). ACTA BIOMEDICA SCIENTIFICA 2021. [DOI: 10.29413/abs.2020-5.6.5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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20
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Zohni K, Lopez L, Mander P, Szaraz P, Filice M, Wyse BA, Garcia M, Gat I, Glass K, Gauthier-Fisher A, Librach CL. Human umbilical cord perivascular cells maintain regenerative traits following exposure to cyclophosphamide. Cancer Lett 2020; 501:133-146. [PMID: 33387641 DOI: 10.1016/j.canlet.2020.12.035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/15/2020] [Accepted: 12/21/2020] [Indexed: 11/19/2022]
Abstract
Chemotherapies can cause germ cell depletion and gonadal failure. When injected post-chemotherapy, mesenchymal stromal cells (MSCs) from various sources have been shown to have regenerative effects in rodent models of chemotherapy-induced gonadal injury. Here, we evaluated two properties of a novel source of MSC, first trimester (FTM) human umbilical cord perivascular cells (HUCPVCs) (with increased regenerative potential compared to older sources), that may render them a promising candidate for chemotherapeutic gonadal injury prevention. Firstly, their ability to resist the cytotoxic effects of cyclophosphamide (CTX) in vitro, as compared to term HUCPVCs and bone marrow cells (BMSCs); and secondly, whether they prevent gonadal dysfunction if delivered prior to gonadotoxic therapy in vivo. BMSC, FTM HUCPVC, term HUCPVC, and control NTERA2 cells were treated with moderate (150 μmol/L) and high (300 μmol/L) doses of CTX in vitro. Viability, proliferative capacity, mesenchymal cell lineage markers and differentiation capacity, immunogenicity, and paracrine gene expression were assessed. CTX was administered to Wistar rats 2 days following an intra-ovarian injection of FTM HUCPVC. HUCPVC survival and ovarian follicle numbers were assessed using histological methods. We conclude that FTM HUCPVC maintain key regenerative properties following chemotherapy exposure and that pre-treatment with these cells may prevent CTX-induced ovarian damage in vivo. Therefore, HUCPVCs are promising candidates for fertility preservation.
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Affiliation(s)
- Khaled Zohni
- CReATe Fertility Centre, Toronto, Ontario, Canada; Department of Obstetrics & Gynecology, University of Toronto, Toronto, Canada; Department of Obstetrics and Gynecology, University of Manitoba, Winnipeg, Canada; Heartland Fertility and Gynecology Clinic, Winnipeg, Manitoba, Canada
| | - Lianet Lopez
- CReATe Fertility Centre, Toronto, Ontario, Canada
| | | | - Peter Szaraz
- CReATe Fertility Centre, Toronto, Ontario, Canada
| | | | | | | | - Itai Gat
- CReATe Fertility Centre, Toronto, Ontario, Canada; Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel HaShomer, Ramat Gan, Affiliated to Sackler Medical School, University of Tel Aviv, Israel
| | - Karen Glass
- CReATe Fertility Centre, Toronto, Ontario, Canada; Department of Obstetrics & Gynecology, University of Toronto, Toronto, Canada
| | | | - Clifford L Librach
- CReATe Fertility Centre, Toronto, Ontario, Canada; Department of Obstetrics & Gynecology, University of Toronto, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada; Department of Gynecology, Women's College Hospital, Toronto, ON, Canada.
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21
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Berjeb KK, Debbabi L, Braham M, Zemni Z, Chtourou S, Hannachi H, Hamdoun M, Ayadi M, Kacem K, Zhioua F, Fadhlaoui A, Bahri O, Chakroun N. Evaluation of ovarian reserve before and after chemotherapy. J Gynecol Obstet Hum Reprod 2020; 50:102035. [PMID: 33307239 DOI: 10.1016/j.jogoh.2020.102035] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 11/20/2020] [Accepted: 12/03/2020] [Indexed: 11/29/2022]
Abstract
BACKGROUND Progress in oncology has improved patient survival. However, cancer chemotherapy can be gonadotoxic and affect their fertility. Recourse to fertility preservation before starting these treatments is therefore necessary in order to allow a better life quality after survival. The aim of this work was to study the impact of chemotherapy on ovarian reserve by AMH measurement. METHODS This is a descriptive and longitudinal study from 2015 to 2018 carried out at Aziza Othmana hospital ART center in Tunis on patient aged less than 41 years who were candidates for fertility preservation. Patients included had AMH measurement prior to cancer treatment. We called them back to follow up the AMH level after chemotherapy. The AMH assay was performed by electrochemilumiescence technique. At the end, only 66 patients met the inclusion criteria. RESULTS The most frequent pathologies were Hodgkin's lymphoma and breast cancer. The mean age of patients was 26.7 ± 6.8. The most used chemotherapy protocols were BEACOPP, ABVD or the combination of both in lymphoma and FEC + TXT for breast cancer treatment. A significant difference between AMH before and after chemotherapy was found for BEACOPP and FEC + TXT protocols (p < 10 3). The patient's age was correlated with the AMH decrease after chemotherapy (r = 0.577, p < 10 3). CONCLUSION Our results showed that the high risk gonadotoxicity protocols were BEACOPP for lymphoma treatment and FEC + TXT for breast cancer treatment. However, studies with a larger sample and more time extended monitoring are necessary for a better gonadotoxicity understanding of the cancer treatments available today.
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Affiliation(s)
- Khadija Kacem Berjeb
- University of Medicine of Tunis, Laboratory of Reproductive Biology and Cytogenetic Laboratory. Aziza Othmana Hospital, Tunis, Tunisia.
| | - Linda Debbabi
- University of Medicine of Tunis, Laboratory of Reproductive Biology and Cytogenetic Laboratory. Aziza Othmana Hospital, Tunis, Tunisia
| | - Marouen Braham
- University of Medicine of Tunis, Gynecology and Obstetrics Department. Aziza Othmana Hospital, Tunis, Tunisia
| | - Zeineb Zemni
- University of Medicine of Tunis, Gynecology and Obstetrics Department. Aziza Othmana Hospital, Tunis, Tunisia
| | - Sana Chtourou
- University of Medicine of Tunis, Laboratory of Reproductive Biology and Cytogenetic Laboratory. Aziza Othmana Hospital, Tunis, Tunisia
| | - Hela Hannachi
- University of Medicine of Tunis, Biochemistry and Microbiology Laboratory, Aziza Othmana Hospital, Tunis, Tunisia
| | - Manel Hamdoun
- University of Medicine of Tunis, Biochemistry and Microbiology Laboratory, Aziza Othmana Hospital, Tunis, Tunisia
| | - Mouna Ayadi
- University of Medicine of Tunis, Medical Oncology Department. Salah Azaiz Institute, Tunis, Tunisia
| | - Karima Kacem
- University of Medicine of Tunis, Hematology Department. Aziza Othmana Hospital, Tunis, Tunisia
| | - Fethi Zhioua
- University of Medicine of Tunis, Gynecology and Obstetrics Department. Aziza Othmana Hospital, Tunis, Tunisia
| | - Anis Fadhlaoui
- University of Medicine of Tunis, Gynecology and Obstetrics Department. Aziza Othmana Hospital, Tunis, Tunisia
| | - Olfa Bahri
- University of Medicine of Tunis, Biochemistry and Microbiology Laboratory, Aziza Othmana Hospital, Tunis, Tunisia
| | - Nozha Chakroun
- University of Medicine of Tunis, Laboratory of Reproductive Biology and Cytogenetic Laboratory. Aziza Othmana Hospital, Tunis, Tunisia
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22
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Moussaoui D, Bénard J, Yaron M, Bernard F, Adam C, Vulliemoz N, Bouthors T, Andrey V, Ansari M, Girardin C, Gumy-Pause F. Hypergonadotropic hypogonadism after ovarian tissue cryopreservation on a 13-year-old female: A case report and review of the literature. J Gynecol Obstet Hum Reprod 2020; 50:102029. [PMID: 33259962 DOI: 10.1016/j.jogoh.2020.102029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 10/22/2022]
Abstract
Ovarian failure is a major long-term adverse event following gonadotoxic treatment of malignant diseases. Ovarian tissue cryopreservation can be offered in some conditions to preserve fertility. We report the case of a 13-year-old female with a diagnosis of acute myeloid leukemia, who presented with hypergonadotropic hypogonadism after unilateral ovariectomy for fertility preservation and before highly gonadotoxic treatment. Even though damage seemed only partial, this case suggests that the remaining contralateral ovarian function may be compromised after ovarian tissue cryopreservation, leading per se to a hypergonadotropic hypogonadism. Although indication of ovarian cryopreservation is not called into question in situations of highly gonadotoxic therapy, this procedure should only be performed after evaluation by a specialized multidisciplinary team and provided a solid indication.
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Affiliation(s)
- Dehlia Moussaoui
- Division of General Pediatrics, Department of Woman, Child and Adolescent Medicine, Geneva University Hospitals, Geneva, Switzerland.
| | - Julie Bénard
- Division of Gynecology, Department of Woman, Child and Adolescent Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - Michal Yaron
- Division of Gynecology, Department of Woman, Child and Adolescent Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - Fanette Bernard
- Pediatric Onco-Hematology Unit, Department of Woman, Child and Adolescent Medicine, Geneva University Hospitals, Geneva, Switzerland; CANSEARCH Research Laboratory, Department of Woman, Child and Adolescent Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Cécile Adam
- Division of Pediatrics, Oncology and Hematology Unit, Woman-Mother-Child Department, Lausanne University Hospital, Lausanne, Switzerland
| | - Nicolas Vulliemoz
- Fertility Medicine and Gynecologic Endocrinology Unit, Woman-Mother-Child Department, Lausanne University Hospital, Lausanne, Switzerland
| | - Thérèse Bouthors
- Division of Pediatrics, Pediatric Endocrinology and Diabetology Unit, Woman-Mother-Child Department, Lausanne University Hospital, Lausanne, Switzerland
| | - Véronique Andrey
- Division of Pediatric Surgery, Woman-Mother-Child Department, Lausanne University Hospital, Lausanne, Switzerland
| | - Marc Ansari
- Pediatric Onco-Hematology Unit, Department of Woman, Child and Adolescent Medicine, Geneva University Hospitals, Geneva, Switzerland; CANSEARCH Research Laboratory, Department of Woman, Child and Adolescent Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Céline Girardin
- Pediatric Endocrine and Diabetes Unit, Department of Woman, Child and Adolescent Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - Fabienne Gumy-Pause
- Pediatric Onco-Hematology Unit, Department of Woman, Child and Adolescent Medicine, Geneva University Hospitals, Geneva, Switzerland; CANSEARCH Research Laboratory, Department of Woman, Child and Adolescent Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
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23
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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: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar 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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24
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Shin W, Park SY, Kang S, Lim MC, Seo SS. The survival effect of ovary preservation in early stage endometrial cancer: a single institution retrospective analysis. J Ovarian Res 2020; 13:97. [PMID: 32828125 PMCID: PMC7443286 DOI: 10.1186/s13048-020-00698-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 08/03/2020] [Indexed: 12/11/2022] Open
Abstract
PURPOSE We investigated the effect of ovary preserving surgery in early International Federation of Obstetrics and Gynecology (FIGO) stage endometrial cancer patients. METHODS Medical records were retrospectively reviewed for 539 patients who were diagnosed with early stage endometrial cancer between Jan 2006 and Dec 2017. Patients were categorized into ovary preservation and ovary removal groups. Demographics, recurrence free survival (RFS), and five-year overall survival (OS) rate were compared, and the clinical factors affecting survival were evaluated by univariate and multivariate analysis. RESULTS The median follow-up period was 85 months (range, 6-142 months), and the median age was 52.7 years. The mean age was higher in the ovary removal group than in the ovary preservation group (54.4 vs 40.94 years; P < 0.001). The ovary preservation group showed an earlier FIGO stage than the ovary removal group (P = 0.0264). There was a greater incidence of adjuvant chemotherapy administration in the removal group. There were no statistical differences in other baseline characteristics. When comparing the RFS and OS rates, there were no statistical differences between the preservation and removal groups. (recurrence free rate 98.5% vs 92.7%, p = 0.4360, and 5-year survival rate 98.6% vs 93.0%, p = 0.0892, respectively). Endometrioid histology (p = 0.006) and post-operative adjuvant chemotherapy (p = 0.0062) were related to OS, and adjuvant chemotherapy (p < 0.001) and radiotherapy (p = 0.005) were related to RFS. CONCLUSIONS Ovary preservation in early stage endometrial cancer is worth considering, as it does not affect survival in early stage endometrial cancer patients.
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Affiliation(s)
- Wonkyo Shin
- Center for Gynecologic Cancer, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
| | - Sang-Yoon Park
- Center for Gynecologic Cancer, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.,Common Cancer Branch, Research Institute Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea
| | - Sokbom Kang
- Center for Gynecologic Cancer, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.,Precision Medicine Branch, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.,Department of Cancer Control & Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea
| | - Myong Cheol Lim
- Center for Gynecologic Cancer, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.,Department of Cancer Control & Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.,Center for Clinical Trials, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.,Cancer Healthcare Research Branch, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea
| | - Sang-Soo Seo
- Center for Gynecologic Cancer, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.
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25
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Ashizawa M, Kanda Y. Preservation of fertility in patients with hematological malignancies. Jpn J Clin Oncol 2020; 50:729-742. [PMID: 32419028 DOI: 10.1093/jjco/hyaa043] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/06/2020] [Accepted: 03/19/2020] [Indexed: 11/13/2022] Open
Abstract
Oncofertility is the medical field that bridges oncology and reproduction that seeks to give healthcare providers and patients the opportunity to optimize residual fertility. The treatment for hematological malignancies carries gonadal toxicity, so that the preservation of fertility should be considered in all patients in childhood, adolescence and young adulthood. Most patients who receive only chemotherapy remain fertile, whereas those who receive regimens consisting of high-dose alkylating agents or total body irradiation can develop permanent infertility. In postpubertal patients, there are established methods for preserving fertility, such as the cryopreservation of sperm, oocytes and embryos. Although ideally performed before the initiation of gonadotoxic treatment, these procedures for fertility preservation can be performed any time prior to the loss of gonadal function. In contrast, a standard option is not available in prepubertal patients, and the preservation of fertility must be sought through experimental methods. Future advances in reproductive medicine may overcome this limitation. Gonadal tissue cryopreservation might be performed in the hope that sperm or mature oocytes could later be extracted from cryopreserved tissue. Healthcare providers, including hematologists, reproductive endocrinologists, nurses, clinical psychotherapists and embryologists, need to optimize the patient's fertility through shared decision-making while always remaining aware of the rapidly progressing developments in reproductive medicine.
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Affiliation(s)
- Masahiro Ashizawa
- Division of Hematology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan, and
| | - Yoshinobu Kanda
- Division of Hematology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan, and.,Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
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26
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Xie Y, Li S, Zhou L, Lin H, Jiao X, Qiu Q, Liang Y, Zhang Q. Rapamycin preserves the primordial follicle pool during cisplatin treatment in vitro and in vivo. Mol Reprod Dev 2020; 87:442-453. [PMID: 32112509 DOI: 10.1002/mrd.23330] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 01/16/2020] [Indexed: 12/22/2022]
Abstract
Rapamycin has been proven to effectively inhibit the activation of primordial follicles while cisplatin-induced the loss of primordial follicles due to the over-activation of the primordial follicle stockpile. Whether rapamycin could inhibit the loss of primordial follicles induced by cisplatin is still unknown. The ovaries of neonatal Sprague Dawley rats were cultured in vitro in different doses of rapamycin (0.08, 0.16, and 0.32 μg/ml) and cisplatin (0.1, 0.4, and 0.8 μg/ml). The immature BALB/c mice were administered cisplatin with or without rapamycin by intraperitoneal injection. Ovaries were collected to analyze the histomorphology, the messenger RNA (mRNA) expression of anti-Mullerian hormone (AMH), growth differentiation factor 9 (GDF9), and bone morphogenetic protein 15 (BMP15) and the expression of key proteins of mammalian target of rapamycin (mTOR) pathway. Growing follicle counts of ovaries cultured in vitro in the R0.16 and R0.32 groups were decreased and the ratio of growing to primordial follicles was also decreased in a dose-dependent manner. In the C0.8 group, growing follicles were decreased compared with the other groups while the ratio was substantially increased in the C0.4 and C0.8 group. Co-treatment attenuated primordial follicle loss and reduced the upregulated ratio induced by cisplatin. Ovarian follicle dynamics in vivo was consistent with the in vitro results. Primordial follicles counts were statistically increased and the ratio was reduced in the rapamycin group compared with the control group. Primordial follicle counts were dramatically reduced in the cisplatin group whereas co-treatment with rapamycin slightly recovered its counts. There was no obvious difference in the number of growing follicles between the cisplatin group and other groups. The ratio was significantly increased in cisplatin-treated mice whereas decreased in the co-treatment group. The apoptosis rate of antral follicles in cisplatin-treated mice was higher than the other groups while the apoptosis rate was decreased in the co-treatment group in vivo. Compared with the control and rapamycin group, the mRNA expression of AMH, GDF9, and BMP15 were downregulated in the cisplatin group. The co-treatment group recovered the mRNA expression of BMP15. In addition, the expression of key protein of mTOR pathway rpS6 and its phosphorylated forms were increased in the cisplatin-treated group while co-treatment decreased their expression. Rapamycin attenuated the loss of primordial follicles induced by cisplatin through the inhibitory effect of rapamycin on the mTOR pathway. These results suggest that rapamycin may be an effective drug for the protection of ovarian function during chemotherapy.
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Affiliation(s)
- Yanqiu Xie
- Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Gongdong, China.,Department of Obstetrics and Gynecology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Gongdong, China
| | - Song Li
- Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Gongdong, China
| | - Linyan Zhou
- Department of Reproductive Medicine Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Gongdong, China
| | - Haiyan Lin
- Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Gongdong, China
| | - Xuedan Jiao
- Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Gongdong, China
| | - Qi Qiu
- Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Gongdong, China
| | - Yihua Liang
- Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Gongdong, China
| | - Qingxue Zhang
- Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Gongdong, China
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Ter Welle-Butalid MEE, Vriens IJHI, Derhaag JGJ, Leter EME, de Die-Smulders CEC, Smidt MM, van Golde RJTR, Tjan-Heijnen VCGV. Counseling young women with early breast cancer on fertility preservation. J Assist Reprod Genet 2019; 36:2593-2604. [PMID: 31760547 PMCID: PMC6910894 DOI: 10.1007/s10815-019-01615-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 10/18/2019] [Indexed: 02/07/2023] Open
Abstract
PURPOSE Women with early-stage breast cancer may still have a future child wish, while chemotherapy may impair fertility. To pursue on fertility preservation shortly after breast cancer diagnosis is complex. This review holds a critical reflection on all topics that need to be counseled to give them the opportunity to make a well-informed decision before starting any oncological treatment. METHODS A comprehensive literature review was performed on papers published in English language on breast cancer in young women, risk of chemotherapy-induced infertility, fertility preservation techniques, impact of possible mutation carriership, and future pregnancy outcome. RESULTS Below 40 years of age, the risk of permanent chemotherapy-induced ovarian function failure is approximately 20%, where taxanes do not significantly add to this risk. Overall, 23% of reported women who performed fertility preservation by cryopreserving oocytes or embryos returned for embryo transfer. Of these, 40% gave live birth. Both fertility preservation in women diagnosed with breast cancer and pregnancy after treatment seem safe with respect to breast cancer survival. Women who have a genetic predisposition for breast cancer like BRCA gene mutation should also be informed about the possibility of pre-implantation genetic diagnosis. CONCLUSIONS Women with an early stage of breast cancer and a possible future child wish should be referred to an expertise center in breast cancer, fertility preservation, and genetics in this complex decision-making process, shortly after diagnosis.
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Affiliation(s)
- M E Elena Ter Welle-Butalid
- Department of Obstetrics and Gynaecology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
| | - I J H Ingeborg Vriens
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
- Department of Internal Medicine, division of Medical Oncology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
| | - J G Josien Derhaag
- Department of Obstetrics and Gynaecology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
| | - E M Edward Leter
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
- Department of Clinical Genetics, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, the Netherlands
| | - C E Christine de Die-Smulders
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
- Department of Clinical Genetics, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, the Netherlands
| | - M Marjolein Smidt
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, the Netherlands
| | - R J T Ron van Golde
- Department of Obstetrics and Gynaecology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
| | - V C G Vivianne Tjan-Heijnen
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands.
- Department of Internal Medicine, division of Medical Oncology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands.
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Hoekman EJ, Louwe LA, Rooijers M, van der Westerlaken LAJ, Klijn NF, Pilgram GSK, de Kroon CD, Hilders CGJM. Ovarian tissue cryopreservation: Low usage rates and high live-birth rate after transplantation. Acta Obstet Gynecol Scand 2019; 99:213-221. [PMID: 31538662 PMCID: PMC7003842 DOI: 10.1111/aogs.13735] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 08/17/2019] [Accepted: 09/04/2019] [Indexed: 11/26/2022]
Abstract
Introduction The likelihood of survival after cancer treatment among young women with cancer has increased considerably, quality of life after treatment has drawn more attention. However, in young fertile women, fertility preservation is an important issue with regard to quality of life. One of the options of fertility preservation is ovarian tissue cryopreservation. The purpose of this follow‐up study is to present our clinical experiences and evaluate the long‐term follow up of ovarian cryopreservation to improve future patient selection. Material and methods From July 2002 to December 2015 at the Leiden University Hospital, the Netherlands, 69 young women underwent ovarian tissue cryopreservation when they were at risk of iatrogenic premature ovarian insufficiency. Follow‐up data with regard to ovarian function were obtained until October 2018, from medical records and questionnaires. Results Of the 69 women in whom ovarian tissue cryopreservation was performed, 12 died (15.9%), 57 were approached to participate, of which 6 were lost to follow up. The indications for ovarian tissue cryopreservation were malignant (81.1%) and benign (18.9%) diseases in which gonadotoxic treatment was scheduled. In total, twenty women (39.2%) are known to have premature ovarian insufficiency due to gonadotoxic treatment. Fifteen women conceived spontaneously, and delivered 25 babies. In this cohort, the usage rate of autotransplantation is 8.7% (7/69). In total, nine autotransplantations of cryopreserved ovarian tissue were performed in seven patients (of which 1 ovarian tissue cryopreservation was performed in another hospital) after which 6 babies were born to four women, giving a live‐birth rate of 57%. Conclusions Ovarian tissue cryopreservation followed by autotransplantation is an effective method to restore fertility (live‐birth rate of 57%). The usage rate of 8.7% (6/69) indicates that more knowledge about the risk of premature ovarian insufficiency after gonadotoxic treatment is needed to be able to offer ovarian tissue cryopreservation more selectively.
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Affiliation(s)
- Ellen J Hoekman
- Department of Gynecology and IVF, Leiden University Medical Center, Leiden, The Netherlands
| | - Leoni A Louwe
- Department of Gynecology and IVF, Leiden University Medical Center, Leiden, The Netherlands
| | - Maxime Rooijers
- Department of Gynecology and IVF, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Nicole F Klijn
- Department of Gynecology and IVF, Leiden University Medical Center, Leiden, The Netherlands
| | - Gonneke S K Pilgram
- Department of Gynecology and IVF, Leiden University Medical Center, Leiden, The Netherlands
| | - Cornelis D de Kroon
- Department of Gynecology and IVF, Leiden University Medical Center, Leiden, The Netherlands
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Said RS, Mantawy EM, El-Demerdash E. Mechanistic perspective of protective effects of resveratrol against cisplatin-induced ovarian injury in rats: emphasis on anti-inflammatory and anti-apoptotic effects. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2019; 392:1225-1238. [PMID: 31129703 DOI: 10.1007/s00210-019-01662-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Accepted: 05/02/2019] [Indexed: 12/18/2022]
Abstract
Chemotherapeutic platinum-containing drugs are widely used to treat a variety of cancer types; however, they cause ovarian failure and infertility. The aim of this study is to investigate the molecular mechanism underlying the potential protective effect of resveratrol against cisplatin-induced ovarian damage in a rat model. Female rats were given either cisplatin (6 mg/kg, i.p., once per week for two consecutive weeks) and/or resveratrol (10 mg/kg, orally for 17 days). Follicular development, ovarian function markers, as well as apoptotic and inflammatory markers were assessed 24 h after the last resveratrol dose. Resveratrol ameliorated the marked follicular loss and the significant reduction in anti-Müllerian hormone (AMH) level triggered by cisplatin. Mechanistically, cisplatin elicited a potent inflammatory response in ovarian tissue as evidenced by the elevated expression of tumor necrosis factor, nuclear factor kappa-B, and proinflammatory enzymes. Co-treatment with resveratrol inhibited the elevation in inflammatory mediators induced by cisplatin. Further, cisplatin switched on the apoptotic machinery in ovarian tissues via increasing the expression of both cytochrome c and caspase-3 which was reversed upon resveratrol co-treatment. Resveratrol also counteracts the upregulating poly(ADP-ribose) polymerase expression which could attribute to the inflammatory and apoptotic effects of cisplatin. Resveratrol protects the ovary from cisplatin-induced toxicity through preventing the loss of the AMH-secreting granulosa cells, diminishing PARP-1 expression, and downregulating the inflammatory and apoptotic events implicated in cisplatin toxicity.
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Affiliation(s)
- Riham S Said
- Department of Drug Radiation Research, National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
| | - Eman M Mantawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abasia, Cairo, Egypt
| | - Ebtehal El-Demerdash
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abasia, Cairo, Egypt.
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Gosset A, Cohade C, Grosclaude P, Oumsack E, Dalenc F, Montagut M, Parinaud J, Vaysse C. [Regional state-of-the-art of the access to oncofertility consultation for young women with breast cancer]. ACTA ACUST UNITED AC 2019; 47:732-738. [PMID: 31493561 DOI: 10.1016/j.gofs.2019.08.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Indexed: 11/29/2022]
Abstract
OBJECTIVES According to the 2004 Bioethics Act, oncofertility counselling must be systematically offered to all women of childbearing age before they are exposed to potentially gonadotoxic treatment. The main objective of this study was to evaluate the proportion of women under 40 years of age treated with chemotherapy for breast cancer in Midi-Pyrénées who have received an oncofertility consultation. A secondary objective was to assess practitioners' knowledge on the subject. METHODS A cross-reference was made between the databases of the oncology network in Midi-Pyrénées and the two approved centres for the preservation of fertility in the region. A computerized practitioner questionnaire was sent to all surgeons and oncologists who could manage these patients. RESULTS From 2012 and 2017, 667 women aged≤40 years received (neo)adjuvant chemotherapy treatment: only 156 (23.4%) had access to an oncofertility consultation and 58 (8.7%) received preservation. This rate (23.4%) varied according to the age of the patients, ranging from 56.9% for those aged 25-29 to 13.4% for those aged 35-39 and the managing institution. Of the 85 practitioners surveyed, 45 (55%) responded to the questionnaire, and of these 20 (44%) knew that ovarian stimulation treatment could be used even in hormone-dependent breast cancer situations and 13 (29%) of practitioners believed that the time required to preserve fertility was more than 1 month. CONCLUSION Our study revealed a significant disparity in access to oncofertility consultation. It is essential to set up information and awareness-raising actions on the subject.
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Affiliation(s)
- A Gosset
- Département de médecine de la reproduction, CHU de Toulouse, 330, avenue de Grande Bretagne, TSA 70034, 31059 Toulouse, France
| | - C Cohade
- Département de médecine de la reproduction, CHU de Toulouse, 330, avenue de Grande Bretagne, TSA 70034, 31059 Toulouse, France
| | - P Grosclaude
- Registre des cancers du Tarn, institut Claudius-Regaud, institut universitaire du cancer de Toulouse-Oncopole, 31059 Toulouse, France; Inserm, UMR1027, université de Toulouse, université Paul-Sabatier, 31000 Toulouse, France
| | - E Oumsack
- Registre des cancers du Tarn, institut Claudius-Regaud, institut universitaire du cancer de Toulouse-Oncopole, 31059 Toulouse, France
| | - F Dalenc
- Département d'oncologie médicale, institut Claudius-Regaud, institut universitaire du cancer de Toulouse-Oncopole, 1, avenue Irène-Joliot-Curie, 31059 Toulouse cedex 9, France
| | - M Montagut
- Service d'assistance médicale à la procréation, Clinique Croix du Sud, 20, route de Revel, 31000 Toulouse, France
| | - J Parinaud
- Département de médecine de la reproduction, CHU de Toulouse, 330, avenue de Grande Bretagne, TSA 70034, 31059 Toulouse, France
| | - C Vaysse
- Département de chirurgie gynécologique et oncologique, institut universitaire du cancer de Toulouse-Oncopole, CHU deToulouse, 1, avenue Irène-Joliot-Curie, 31059 Toulouse cedex 9, France.
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Sonigo C, Beau I, Binart N, Grynberg M. Anti-Müllerian Hormone in Fertility Preservation: Clinical and Therapeutic Applications. CLINICAL MEDICINE INSIGHTS. REPRODUCTIVE HEALTH 2019; 13:1179558119854755. [PMID: 31258345 PMCID: PMC6585130 DOI: 10.1177/1179558119854755] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Accepted: 05/13/2019] [Indexed: 12/13/2022]
Abstract
Anti-Müllerian hormone (AMH) is a member of the transforming growth factor
(TGF)-beta family and a key regulator of sexual differentiation and
folliculogenesis. While the serum AMH level has been used in reproductive
medicine as a biomarker of quantitative ovarian reserve for more than 20 years,
new potential therapeutic applications of recombinant AMH are emerging, notably
in the field of oncofertility. Indeed, it is well known that chemotherapy, used
to treat cancer, induces ovarian follicular depletion and subsequent
infertility. Animal models have been used widely to understand the effects of
different cytotoxic agents on ovarian function, and several hypotheses regarding
chemotherapy gonadotoxicity have been proposed, that is, it might have a direct
detrimental effect on the primordial follicles constituting the ovarian reserve
and/or on the pool of growing follicles secreting AMH. Recently, a new mechanism
of chemotherapy-induced follicular depletion, called the “burn-out effect,” has
been proposed. According to this theory, chemotherapeutic agents may lead to a
massive growth of dormant follicles which are then destroyed. As AMH is one of
the factors regulating the recruitment of primordial follicles from the ovarian
reserve, recombinant AMH administration concomitant with chemotherapy might
limit follicular depletion, therefore representing a promising option for
preserving fertility in women suffering from cancer. This review reports on the
potential usefulness of AMH measurement as well as AMH’s role as a therapeutic
agent in the field of female fertility preservation.
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Affiliation(s)
- Charlotte Sonigo
- Department of Reproductive Medicine and Fertility Preservation, Hôpital Antoine Béclère, Hôpitaux Universitaires Paris Sud, Assistance Publique-Hôpitaux de Paris, Clamart, France.,Inserm U1185, Université Paris-Sud, Université Paris Saclay, Le Kremlin Bicêtre, France
| | - Isabelle Beau
- Inserm U1185, Université Paris-Sud, Université Paris Saclay, Le Kremlin Bicêtre, France
| | - Nadine Binart
- Inserm U1185, Université Paris-Sud, Université Paris Saclay, Le Kremlin Bicêtre, France
| | - Michael Grynberg
- Department of Reproductive Medicine and Fertility Preservation, Hôpital Antoine Béclère, Hôpitaux Universitaires Paris Sud, Assistance Publique-Hôpitaux de Paris, Clamart, France.,Université Paris-Sud, Université Paris Saclay, Le Kremlin Bicêtre, France.,Inserm U1133, Université Paris Diderot, Paris, France
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Palinska-Rudzka KE, Ghobara T, Parsons N, Milner J, Lockwood G, Hartshorne GM. Five-year study assessing the clinical utility of anti-Müllerian hormone measurements in reproductive-age women with cancer. Reprod Biomed Online 2019; 39:712-720. [PMID: 31471141 DOI: 10.1016/j.rbmo.2019.06.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 05/03/2019] [Accepted: 06/04/2019] [Indexed: 11/28/2022]
Abstract
RESEARCH QUESTION An important discussion point before chemotherapy is ovarian toxicity, a side-effect that profoundly affects young women with cancer. Their quality of life after successful treatment, including the ability to conceive, is a major concern. We asked whether serum anti-Müllerian hormone (AMH) measurements before chemotherapy for two most common malignancies are predictive of long-term changes in ovarian reserve? DESIGN A prospective cohort study measured serum AMH in 66 young women with lymphoma and breast cancer, before and at 1 year and 5 years after chemotherapy, compared with 124 healthy volunteers of the same age range (18-43 years). Contemporaneously, patients reported their menses and live births during 5-year follow-up. RESULTS After adjustment for age, serum AMH was 1.4 times higher (95% CI 1.1 to 1.9; P < 0.02) in healthy volunteers than in cancer patients before chemotherapy. A strong correlation was observed between baseline and 5-year AMH in the breast cancer group (P < 0.001, regression coefficient = 0.58, 95% CI 0.29 to 0.89). No significant association was found between presence of menses at 5 years and serum AMH at baseline (likelihood ratio test from logistics regression analysis). CONCLUSIONS Reproductive-age women with malignancy have lower serum AMH than healthy controls even before starting chemotherapy. Pre-chemotherapy AMH was significantly associated with long-term ovarian function in women with breast cancer. At key time points, AMH measurements could be used as a reproductive health advisory tool for young women with cancer. Our results highlight the unsuitability of return of menstruation as a clinical indicator of ovarian reserve after chemotherapy.
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Affiliation(s)
- K E Palinska-Rudzka
- Warwick Medical School, University of Warwick Coventry CV4 7AL, UK; University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road Coventry CV2 2DX, UK
| | - T Ghobara
- University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road Coventry CV2 2DX, UK
| | - N Parsons
- Warwick Medical School, University of Warwick Coventry CV4 7AL, UK
| | - J Milner
- CARE Fertility Tamworth House, Ventura Park Road, Tamworth B78 3HL, UK
| | - G Lockwood
- CARE Fertility Tamworth House, Ventura Park Road, Tamworth B78 3HL, UK
| | - G M Hartshorne
- Warwick Medical School, University of Warwick Coventry CV4 7AL, UK; University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road Coventry CV2 2DX, UK.
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Recent Advances in Fertility Preservation and Counseling for Reproductive-Aged Women with Colorectal Cancer: A Systematic Review. Dis Colon Rectum 2019; 62:762-771. [PMID: 30730458 DOI: 10.1097/dcr.0000000000001351] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND The incidence of colorectal cancer among reproductive-aged women is increasing. Concerns regarding future fertility are secondary only to concerns regarding survival and may significantly impact quality of life among reproductive-aged female cancer survivors. Fertility preservation counseling reduces long-term regret and dissatisfaction among cancer survivors. Health care providers counseling patients with colorectal cancer must understand the impact of cancer treatment on future reproductive potential. OBJECTIVE This review aims to examine the effects that colorectal cancer treatments have on female fertility and summarize existing and emerging options for fertility preservation. DATA SOURCES EMBASE, National Library of Medicine (MEDLINE)/PubMed, Cochrane Review Library were the data sources for this review. STUDY SELECTION A systematic literature review was performed using exploded MeSH terms to identify articles examining the effect of surgery, chemotherapy, and radiation, as well as fertility preservation options for colorectal cancer on female fertility. Relevant studies were included. MAIN OUTCOME MEASURES The primary outcome was the effect of colorectal cancer treatment on fertility. RESULTS There are limited data regarding the impact of colorectal surgery on fertility. The gonadotoxic effects of chemotherapy on reproductive capacity depend on age at the time of chemotherapy administration, cumulative chemotherapy, radiation dose, type of agent, and baseline fertility status. Chemotherapy-induced risks for colorectal cancers are considered low to moderate, whereas pelvic radiation with a dose of 45 to 50 Gray induces premature menopause in greater than 90% of patients. Ovarian transposition may reduce but not eliminate the damaging effect of radiation on the ovaries. Embryo and oocyte cryopreservation are considered standard of care for women desiring fertility preservation, with oocyte cryopreservation no longer being considered experimental. Ovarian tissue cryopreservation remains experimental but may be an option for select patients. The use of gonadotropin-releasing hormone agonists remains controversial and has not been definitively shown to preserve fertility. LIMITATIONS The limitations of this review are the lack of randomized controlled trials and high-quality studies, as well as the small sample sizes and the use of surrogate fertility markers. CONCLUSION Reproductive-aged women with colorectal cancer benefit from fertility preservation counseling before the initiation of cancer treatment.
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von Wolff M, Andersen CY, Woodruff TK, Nawroth F. FertiPROTEKT, Oncofertility Consortium and the Danish Fertility-Preservation Networks - What Can We Learn From Their Experiences? CLINICAL MEDICINE INSIGHTS. REPRODUCTIVE HEALTH 2019; 13:1179558119845865. [PMID: 31068758 PMCID: PMC6495450 DOI: 10.1177/1179558119845865] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Accepted: 02/27/2019] [Indexed: 01/18/2023]
Abstract
Fertility preservation is an increasingly important discipline. It requires close coordination between reproductive medicine specialists, reproductive biologists, and oncologists in various disciplines. In addition, it represents a particular health policy challenge, since fertility-protection measures are to be understood as a treatment for side effects of gonadotoxic treatments and would therefore normally have to be reimbursed by health insurance companies. Therefore, it is inevitable that fertility-preservation activities should organise themselves into a network structure both as a medical-logistic network and as a professional medical society. The necessary network structures can differ significantly at regional, national, and international level, as the size of the regions to be integrated and the local cultural and geographical conditions, as well as the political conditions are very different. To address these issues, the current review aims to point out the basic importance and the chances but also the difficulties of fertility-protection networks and give practical guidance for the development of such network structures. We will not only discuss network structures theoretically but also present them based on three established, different sized networks, such as the Danish Network (www.rigshospitalet.dk), representing a centralised network in a small country; the German-Austrian-Swiss network FertiPROTEKT® (www.fertiprotekt.com), representing a centralised as well as decentralised network in a large country; and the Oncofertility® Consortium (www.oncofertility.northwestern.edu), representing a decentralised, internationally oriented network, primarily serving the transfer of knowledge among its members.
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Affiliation(s)
- Michael von Wolff
- University Women’s Hospital, Division of Gynaecological Endocrinology and Reproductive Medicine, Inselspital, University Hospital, Bern, Switzerland
| | - Claus Yding Andersen
- Laboratory of Reproductive Biology, Faculty of Health Science, The Juliane Marie Centre for Women, Children and Reproduction, University Hospital of Copenhagen, University of Copenhagen, Copenhagen, Denmark
| | - Teresa K Woodruff
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL, USA
| | - Frank Nawroth
- Centre for Infertility, Prenatal Medicine, Endocrinology and Osteology, Amedes group, Hamburg, Germany
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Pascuali N, Scotti L, Di Pietro M, Oubiña G, Bas D, May M, Gómez Muñoz A, Cuasnicú PS, Cohen DJ, Tesone M, Abramovich D, Parborell F. Ceramide-1-phosphate has protective properties against cyclophosphamide-induced ovarian damage in a mice model of premature ovarian failure. Hum Reprod 2019. [PMID: 29534229 DOI: 10.1093/humrep/dey045] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
STUDY QUESTION Is ceramide-1-phosphate (C1P) an ovarian protective agent during alkylating chemotherapy? SUMMARY ANSWER Local administration of C1P drastically reduces ovarian damage induced by cyclophosphamide (Cy) via protection of follicular reserve, restoration of hormone levels, inhibition of apoptosis and improvement of stromal vasculature, while protecting fertility, oocyte quality and uterine morphology. WHAT IS KNOWN ALREADY Cancer-directed therapies cause accelerated loss of ovarian reserve and lead to premature ovarian failure (POF). Previous studies have demonstrated that C1P regulates different cellular processes including cell proliferation, cell migration, angiogenesis and apoptosis. This sphingolipid may be capable of modulating vascular development and apoptosis in ovaries affected by chemotherapy. STUDY DESIGN, SIZE, DURATION The 6-8-week-old mice were weighed and administered either a single intraperitoneal injection of Cy (75 mg/kg) or an equal volume of saline solution only for control mice. Control and Cy mice underwent sham surgery and received an intrabursal injection of saline solution, while Cy + C1P animal groups received 5 μl C1P, either 0.5 or 1 mM, under the bursa of both ovaries 1 h prior to Cy administration. PARTICIPANTS/MATERIALS, SETTING, METHODS Animals were euthanized by cervical dislocation or cardiac puncture 2 weeks after surgery for collection of blood orovary and uterus samples, which were cleaned of adhering tissue in culture medium and used for subsequent assays. Ovaries were used for Western blotting or immunohistochemical and/or histological analyses or steroid extraction, as required (n = 5-8 per group). A set of mice (n = 3/group) was destined for oocyte recovery and IVF. Finally, another set (n = 5-6/group) was separated to study fertility parameters. MAIN RESULTS AND THE ROLE OF CHANCE The number of primordial (P < 0.01), primary (P < 0.05) and preantral follicles (P < 0.05) were decreased in Cy-treated mice compared to control animals, while atretic follicles were increased (P < 0.001). In Cy + C1P mice, the ovaries recovered control numbers of these follicular structures, in both C1P doses studied. Cy affected AMH expression, while it was at least partially recovered when C1P is administered as well. Cy caused an increase in serum FSH concentration (P < 0.01), which was prevented by C1P coadministration (P < 0.01). E2 levels in Cy-treated ovaries decreased significantly compared to control ovaries (P < 0.01), whilst C1P restored E2 levels to those of control ovaries (P < 0.01). Cy increased the expression of BAX (P < 0.01) and decreased the expression of BCLX-L compared to control ovaries (P < 0.01). The ovarian BCLX-L:BAX ratio was also lower in Cy-treated mice (P < 0.05). In the Cy + C1P group, the expression levels of BAX, BCLX-L and BCLX-L:BAX ratio were no different than those in control ovaries. In addition, acid sphingomyelinase (A-SMase) expression was higher in Cy-treated ovaries, whilst remaining similar to the control in the Cy + C1P group. Cy increased the apoptotic index (TUNEL-positive follicles/total follicles) in preantral and early antral stages, compared to control ovaries (P < 0.001 and P < 0.01, respectively). C1P protected follicles from this increase. No primordial or primary follicular cells stained for either cleaved caspase-3 or TUNEL when exposed to Cy, therefore, we have found no evidence for follicular reserve depletion in response to Cy being due to apoptosis. Cy caused evident vascular injury, especially in large cortical stromal vessels, and some neovascularization. In the Cy + C1P group, the disruptions in vascular wall continuity were less evident and the number of healthy stromal blood vessels seemed to be restored. In Cy-treated ovaries α-SMA-positive cells showed a less uniform distribution around blood vessels. C1P coadministration partially prevented this Cy-induced effect, with a higher presence of α-SMA-positive cells surrounding vessels. By H&E staining, Cy-treated mice showed endometrial alterations compared to controls, affecting both epithelial and stromal compartments. However, C1P allowed that the stromal tissue to maintain its loose quality and its glandular branches. Cy-treated animals had significantly lower pregnancy rates and smaller litter sizes compared with control mice (P = 0.013 and P < 0.05, respectively), whereas cotreatment with C1P preserved normal fertility. Furthermore, a higher (P < 0.05) proportion of abnormal oocytes was recovered from Cy-treated mice compared to the control, which was prevented by C1P administration. LARGE SCALE DATA N/A. LIMITATIONS REASONS FOR CAUTION The results of this study were generated from an in-vivo animal experimental model, already used by several authors. Further studies on C1P functions in female reproduction in pathological conditions such as chemotherapy-induced ovarian failure and on the safety of use of this sphingolipid are required. WIDER IMPLICATIONS OF THE FINDINGS The present findings showed that C1P administration prior to Cy might be a promising fertility preservation strategy in female patients who undergo chemotherapy. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants from ANPCyT (PICT 2015-1117), CONICET (PIP 380), Cancer National Institute (INC) and Roemmers Foundation, Argentina. The authors declare no conflicts of interest.
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Affiliation(s)
- Natalia Pascuali
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Leopoldina Scotti
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Mariana Di Pietro
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Gonzalo Oubiña
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Diana Bas
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - María May
- Instituto de Investigaciones Farmacológicas (ININFA-UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Antonio Gómez Muñoz
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Bilbao, Spain
| | - Patricia S Cuasnicú
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Débora J Cohen
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Marta Tesone
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Dalhia Abramovich
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Fernanda Parborell
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
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Kim HA, Choi J, Park CS, Seong MK, Hong SE, Kim JS, Park IC, Lee JK, Noh WC, the ASTRRA trial investigators. Post-chemotherapy serum anti-Müllerian hormone level predicts ovarian function recovery. Endocr Connect 2018; 7:949-956. [PMID: 30300533 PMCID: PMC6144937 DOI: 10.1530/ec-18-0180] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
In the era of precision medicine, the prediction of ovarian function recovery from chemotherapy-induced amenorrhoea using feasible biological markers may be helpful to optimise the treatment strategy for young patients with hormone receptor-positive breast cancer. The purpose of this study was to investigate the accuracy of post-chemotherapy biological markers for predicting the recovery of ovarian function in breast cancer patients of the ASTRRA trial, with chemotherapy-induced amenorrhoea. Using data of 82 participants from a single institution in the ASTRRA trial, the post-chemotherapy serum levels of the anti-Müllerian hormone (AMH), oestradiol, inhibin B and other clinical factors associated with chemotherapy-induced amenorrhoea were evaluated. Recovery of ovarian function was defined by the resumption of menstruation manifested by vaginal bleeding. Fifty-two patients regained menstruation within 55 months after enrolment. In univariate analysis, <40 years of age (P = 0.009), oestradiol ≥37 pg/mL (P = 0.003) or AMH ≥800 pg/mL (P = 0.026) were associated with recovery of menstruation. On multivariate analysis, oestradiol (hazard ratio: 3.171, 95% CI: 1.306–7.699, P = 0.011) and AMH (hazard ratio: 2.853, 95% CI: 1.011–8.046, P = 0.048) remained as significant independent predictors for resumption of menstruation. The diagnostic accuracy of age, oestradiol and AMH in predicting the resumption of menstruation was 38.3, 23.3 and 86.7%, respectively. In conclusion, post-chemotherapy AMH level might be a relatively accurate predictor of the recovery of ovarian function, presented by resumption of menstruation in breast cancer patients with chemotherapy-induced amenorrhoea
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Affiliation(s)
- Hyun-Ah Kim
- Department of SurgeryKorea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Jihye Choi
- Department of SurgeryKorea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Chan Sub Park
- Department of SurgeryKorea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Min-Ki Seong
- Department of SurgeryKorea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Sung-Eun Hong
- Department of Translational ResearchKorea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Jae-Sung Kim
- Division of Basic Radiation BioscienceKorea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - In-Chul Park
- Division of Basic Radiation BioscienceKorea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Jin Kyung Lee
- KIRAMS Radiation BiobankKorea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Woo Chul Noh
- Department of SurgeryKorea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
- Correspondence should be addressed to W C Noh:
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Antral follicle count recovery in women with menses after treatment with and without gonadotropin-releasing hormone agonist use during chemotherapy for breast cancer. J Assist Reprod Genet 2018; 35:1861-1868. [PMID: 30066303 DOI: 10.1007/s10815-018-1203-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 05/01/2018] [Indexed: 10/28/2022] Open
Abstract
PURPOSE After chemotherapy for breast cancer, most women will recover some ovarian function, but the timing and extent of this recovery are poorly understood. We studied post-chemotherapy ovarian recovery in women with and without a history of ovarian suppression during chemotherapy. METHODS Reproductive age breast cancer patients who were seen prior to chemotherapy for fertility preservation consult were consented for follow-up ovarian function assessment (every 3-6 months after chemotherapy) with antral follicle count (AFC) in this prospective cohort study. We restricted our analysis to those with menses present after chemotherapy. Box plots were used to demonstrate the change in follow-up AFC versus time elapsed after chemotherapy. A mixed effects regression model was used to assess differences in AFC. RESULTS Eighty-eight patients with a history of newly diagnosed breast cancer were included. Forty-five patients (51%) had ovarian suppression with GnRH agonist (GnRHa) during chemotherapy. AFC recovery appeared to plateau at 1 year after completing chemotherapy at a median of 40% of pre-chemotherapy AFC. After adjustment for age, initial AFC, cyclophosphamide exposure, combined hormonal contraceptive (CHC) use, and tamoxifen use, AFC recovered faster and to a greater degree for those women who underwent GnRHa therapy for ovarian protection during chemotherapy (P = 0.032). CONCLUSIONS Women with menses after chemotherapy for breast cancer appear to recover their full potential AFC 1 year after their last chemotherapy dose. Treatment with GnRHa during chemotherapy is associated with a higher degree of AFC recovery. The findings of this study can aid in counseling patients prior to chemotherapy about expectations for ovarian recovery and planning post-treatment fertility preservation care to maximize reproductive potential when pre-treatment fertility preservation care is not possible or has limited oocyte yield.
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Jayasinghe YL, Wallace WHB, Anderson RA. Ovarian function, fertility and reproductive lifespan in cancer patients. Expert Rev Endocrinol Metab 2018; 13:125-136. [PMID: 30058903 DOI: 10.1080/17446651.2018.1455498] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 03/19/2018] [Indexed: 12/17/2022]
Abstract
INTRODUCTION The increasing survival of girls and young women after cancer has led to a rapid growth in research into assessment of ovarian function after treatment. AREAS COVERED This aim of this review is to discuss normal ovarian function over time, the impact of cancer treatment on ovarian function, the assessment of ovarian reserve after treatment, and pretreatment predictors of ovarian recovery. EXPERT COMMENTARY Ovarian function damage after chemotherapy and radiotherapy will impact on fertility and reproductive lifespan, but with great variability. Age at menopause has implications for the duration of estrogen deficiency, with its own adverse health consequences. This has led to identification of the key treatment and patient factors at the time of treatment, notably age and ovarian reserve that impact on post-treatment ovarian function. However, most studies have used outcome measures such as ongoing menses, or biomarkers such as anti-mullerian hormone (AMH), with few reporting on fertility or age at menopause.
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Affiliation(s)
- Yasmin L Jayasinghe
- a Department of Obstetrics and Gynaecology , Royal Women's Hospital, University of Melbourne , Melbourne , Australia
| | - W Hamish B Wallace
- b Department of Haematology and Oncology , Royal Hospital for Sick Children , Edinburgh , UK
| | - Richard A Anderson
- c MRC Centre for Reproductive Health, Queens Medical Research Institute , University of Edinburgh , Edinburgh , UK
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Takae S, Tsukada K, Maeda I, Okamoto N, Sato Y, Kondo H, Shinya K, Motani Y, Suzuki N. Preliminary human application of optical coherence tomography for quantification and localization of primordial follicles aimed at effective ovarian tissue transplantation. J Assist Reprod Genet 2018; 35:627-636. [PMID: 29607457 PMCID: PMC5949120 DOI: 10.1007/s10815-018-1166-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 03/15/2018] [Indexed: 11/09/2022] Open
Abstract
Purpose The purpose of this study was to evaluate the possible clinical application of optical coherence tomography for assessing ovarian reserve in individual specimens of human ovarian tissue for fertility preservation. Methods Ovarian tissue examination by optical coherence tomography was performed before ovarian tissue cryopreservation. Three of the four subjects had hematological disease or cancer, and they faced a threat to their fertility due to impending chemotherapy. One patient underwent ovarian tissue extraction for in vitro activation of dormant follicles as fertility treatment. Results The current full-field optical coherence tomography technique can detect primordial follicles in non-fixed and non-embedded human ovarian tissue. These images are well correlated with histological evaluation and the ovarian reserve test, including follicle counts. Conclusion It was demonstrated that optical coherence tomography could assess localization of primordial follicles and ovarian reserve in specimens of non-fixed human ovarian cortex, although optimization for examination of human ovarian tissue is needed for clinical application. Additionally, this technique holds the possibility of assessing the ovarian reserve of patients with unevaluable ovarian reserve. Trial registration number UMIN000023141
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Affiliation(s)
- Seido Takae
- Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216-8511, Japan
| | - Kosuke Tsukada
- Graduate School of Fundamental Science and Technology, Keio University, 3-14-1 Hiyoshi, Kouhoku-ku, Yokohama, Kanagawa, 223-8522, Japan
| | - Ichiro Maeda
- Department of Pathology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216-8511, Japan
| | - Naoki Okamoto
- Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216-8511, Japan
| | - Yorino Sato
- Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216-8511, Japan
| | - Haruhiro Kondo
- Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216-8511, Japan
| | - Kiemi Shinya
- Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216-8511, Japan
| | - Yuki Motani
- Graduate School of Fundamental Science and Technology, Keio University, 3-14-1 Hiyoshi, Kouhoku-ku, Yokohama, Kanagawa, 223-8522, Japan
| | - Nao Suzuki
- Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216-8511, Japan.
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Iwase A, Osuka S, Goto M, Murase T, Nakamura T, Takikawa S, Kikkawa F. Clinical application of serum anti-Müllerian hormone as an ovarian reserve marker: A review of recent studies. J Obstet Gynaecol Res 2018. [PMID: 29517134 DOI: 10.1111/jog.13633] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
It has been more than 15 years since the measurement of serum anti-Müllerian hormone (AMH) first allowed the quantitative assessment of ovarian reserve. Meanwhile, the clinical implication of serum AMH has been expanding. The measurement of serum AMH has been applied in various clinical fields, including assisted reproduction, menopause, reproductive disorders and assessment of ovarian damage/toxicity. Well-known findings about the usefulness of serum AMH revealed by numerous studies executed in the early era include decline with aging, a good correlation with oocyte yield in assisted reproduction, upregulation in polycystic ovarian syndrome and a decrease on ovarian surgery and toxic treatment. More intensive research, including a meta-analysis, cutting-edge clinical trial and advances in AMH assays, has yielded newer findings and firmer clinical interpretations in serum AMH in the past few years. Variations in the AMH decline trajectory in the general population do not support the accurate prediction of menopause. The ability to predict pregnancy in infertility treatment and natural conception is poor, while a nomogram integrating serum AMH as a stimulation protocol is useful for avoiding poor and/or hyper-responses. On the other hand, improvements in measuring very low concentrations of serum AMH may be capable of distinguishing women with poor ovarian function. Age-independent standardization of AMH values may be helpful for comparing ovarian reserves among women at different ages.
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Affiliation(s)
- Akira Iwase
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of Maternal and Perinatal Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Satoko Osuka
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of Maternal and Perinatal Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Maki Goto
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomohiko Murase
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomoko Nakamura
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Sachiko Takikawa
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fumitaka Kikkawa
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Malisic E, Susnjar S, Milovanovic J, Todorovic-Rakovic N, Kesic V. Assessment of ovarian function after chemotherapy in women with early and locally advanced breast cancer from Serbia. Arch Gynecol Obstet 2018; 297:495-503. [PMID: 29101609 DOI: 10.1007/s00404-017-4581-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 10/26/2017] [Indexed: 01/23/2023]
Abstract
PURPOSE Among harmful effects of chemotherapy is the reduction of ovarian function. The aim was to determine the serum levels of FSH, LH, estradiol and AMH after chemotherapy followed by endocrine therapy in breast cancer patients. METHODS The study included 40 premenopausal hormone receptor-positive breast cancer patients aged 33-50 years. Anthracycline-based chemotherapy received 14/40 while anthracycline-taxane combination received 26/40 of patients, followed by tamoxifen (30/40) or tamoxifen plus goserelin (10/40). All of them experienced chemotherapy-induced secondary amenorrhea. Hormone levels were determined by ELISA. Statistics included Spearman's test, Mann-Whitney test and multiple linear regression analysis. RESULTS Undetectable AMH levels were observed in 62.5 and 33.3% of patients with time period < 2 and ≥ 2 years from completion of chemotherapy to sample collection. Median levels of hormones for patients treated with anthracycline-based compared to anthracycline-taxane therapy were: 15.5 vs. 22.3 IU/L for FSH; 10.9 vs. 13.6 IU/L for LH; 55.5 vs. 39.5 pg/mL for estradiol; 0.11 vs. 0.11 ng/mL for AMH. The multiple linear regression showed that: women who received goserelin had significantly lower FSH; those with shorter time from completion of chemotherapy to sample collection had significantly higher LH and lower estradiol; younger women had higher AMH levels. CONCLUSIONS The ovarian function was recovered from chemotherapy-induced secondary amenorrhea with time elapsed since the completion of adjuvant chemotherapy. It may be less disrupted in patients who received anthracycline-based chemotherapy and goserelin plus tamoxifen, as well.
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Affiliation(s)
- Emina Malisic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11 000, Belgrade, Serbia.
| | - Snezana Susnjar
- Department of Medical Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11 000, Belgrade, Serbia
| | - Jelena Milovanovic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11 000, Belgrade, Serbia
| | - Natasa Todorovic-Rakovic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11 000, Belgrade, Serbia
| | - Vesna Kesic
- Department of Obstetrics and Gynecology, Faculty of Medicine, Clinical Center of Serbia, University of Belgrade, Višegradska 26, 11 000, Belgrade, Serbia
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Bi X, Zhang J, Cao D, Sun H, Feng F, Wan X, Xiang Y, Qiu L, Cheng X, Yang J, Shen K. Anti-Müllerian hormone levels in patients with gestational trophoblastic neoplasia treated with different chemotherapy regimens: a prospective cohort study. Oncotarget 2017; 8:113920-113927. [PMID: 29371957 PMCID: PMC5768374 DOI: 10.18632/oncotarget.23027] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 11/13/2017] [Indexed: 11/25/2022] Open
Abstract
Purpose To assess the ovarian reserve of patients with gestational trophoblastic neoplasia (GTN) treated with chemotherapy by evaluating serum anti-Müllerian hormone (AMH) and follicle-stimulating hormone (FSH) levels before, during, and after chemotherapy. Results The basal AMH level (mean: 3.98 ± 3.20 ng/mL) negatively correlated with age, while the basal FSH level (mean: 5.71 ± 9.69 mIU/mL) had no correlation with age. After 3 chemotherapy cycles, serum AMH levels decreased and FSH levels increased. The magnitude of the AMH level decline was significantly greater for combination chemotherapy than for single-agent dactinomycin D therapy (61.80% vs. 27.57%) (p = 0.0004) and was higher in patients whose regimens included etoposide (73.69% vs 40.51%) (p = 0.0359). After chemotherapy completion, AMH levels showed a further decline, and cumulative AMH concentration change was associated with doses of vincristine (p = 0.009) and etoposide (p = 0.032). At the 3-month follow-up, AMH levels significantly increased in the dactinomycin D group (p = 0.0067). Materials and Methods This prospective study included 34 patients with GTN. Serum AMH and FSH levels were measured before chemotherapy, after the 3rd cycle, and at 2 weeks and 3 months after chemotherapy. Cumulative changes of serum AMH levels in patients who received different chemotherapy regimens were analyzed. Conclusions Chemotherapy for GTN affects the ovarian reserve, with substantial differences between chemotherapy protocols. The results improve our understanding of ovarian toxicity and support the use of fertility preservation strategies.
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Affiliation(s)
- Xiaoning Bi
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Jingjing Zhang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Dongyan Cao
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Hengzi Sun
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Fengzhi Feng
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Xirun Wan
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Yang Xiang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Ling Qiu
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Xinqi Cheng
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Jiaxin Yang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Keng Shen
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
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Di Tucci C, Casorelli A, Morrocchi E, Palaia I, Muzii L, Panici PB. Fertility management for malignant ovarian germ cell tumors patients. Crit Rev Oncol Hematol 2017; 120:34-42. [DOI: 10.1016/j.critrevonc.2017.10.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 08/23/2017] [Accepted: 10/11/2017] [Indexed: 01/02/2023] Open
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Pankiewicz K, Szewczyk G, Maciejewski TM, Szukiewicz D. Strategies for overcoming oncological treatment-related ovarian dysfunction - literature review. Gynecol Endocrinol 2017; 33:830-835. [PMID: 28604126 DOI: 10.1080/09513590.2017.1337095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
In the majority of developed countries, it is observed that the time for maternity is being postponed to over the 30th and even 40th year of life. A significant number of cancers are diagnosed during reproductive age, often before the first pregnancy. A fertility preservation is an important issue in oncological treatment, where there is a need for balancing between radicality and the preservation of function of reproductive organs. The authors discuss the problem of ovarian dysfunction after oncological treatment and present the possible strategies for saving the reproductive function of ovaries, including both invasive and pharmacological approaches.
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Affiliation(s)
- Katarzyna Pankiewicz
- a Department of Obstetrics and Gynecology , Institute of Mother and Child , Warsaw , Poland
| | - Grzegorz Szewczyk
- a Department of Obstetrics and Gynecology , Institute of Mother and Child , Warsaw , Poland
- b Department of General and Experimental Pathology , Warsaw Medical University , Warsaw , Poland
| | | | - Dariusz Szukiewicz
- b Department of General and Experimental Pathology , Warsaw Medical University , Warsaw , Poland
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Influence of adjuvant chemotherapy on anti-Müllerian hormone in women below 35 years treated for early breast cancer. Reprod Biomed Online 2017; 35:468-474. [DOI: 10.1016/j.rbmo.2017.06.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 06/02/2017] [Accepted: 06/02/2017] [Indexed: 11/21/2022]
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Rosendahl M, Simonsen MK, Kjer JJ. The influence of unilateral oophorectomy on the age of menopause. Climacteric 2017; 20:540-544. [DOI: 10.1080/13697137.2017.1369512] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- M. Rosendahl
- Department of Gynecology, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark
| | - M. K. Simonsen
- Diakonissestiftelsen & Research Unit, Dietary Studies at the Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark
| | - J. J. Kjer
- Department of Gynecology, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark
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Tal R, Seifer DB. Ovarian reserve testing: a user's guide. Am J Obstet Gynecol 2017; 217:129-140. [PMID: 28235465 DOI: 10.1016/j.ajog.2017.02.027] [Citation(s) in RCA: 273] [Impact Index Per Article: 34.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 02/08/2017] [Accepted: 02/14/2017] [Indexed: 10/20/2022]
Abstract
Ovarian reserve is a complex clinical phenomenon influenced by age, genetics, and environmental variables. Although it is challenging to predict the rate of an individual's ovarian reserve decline, clinicians are often asked for advice about fertility potential and/or recommendations regarding the pursuit of fertility treatment options. The purpose of this review is to summarize the state-of-the-art of ovarian reserve testing, providing a guide for the obstetrician/gynecologist generalist and reproductive endocrinologist. The ideal ovarian reserve test should be convenient, be reproducible, display little if any intracycle and intercycle variability, and demonstrate high specificity to minimize the risk of wrongly diagnosing women as having diminished ovarian reserve and accurately identify those at greatest risk of developing ovarian hyperstimulation prior to fertility treatment. Evaluation of ovarian reserve can help to identify patients who will have poor response or hyperresponse to ovarian stimulation for assisted reproductive technology. Ovarian reserve testing should allow individualization of treatment protocols to achieve optimal response while minimizing safety risks. Ovarian reserve testing may inform patients regarding their reproductive lifespan and menopausal timing as well as aid in the counselling and selection of treatment for female cancer patients of reproductive age who receive gonadotoxic therapy. In addition, it may aid in establishing the diagnosis of polycystic ovary syndrome and provide insight into its severity. While there is currently no perfect ovarian reserve test, both antral follicular count and antimüllerian hormone have good predictive value and are superior to day-3 follicle-stimulating hormone. The convenience of untimed sampling, age-specific values, availability of an automated platform, and potential standardization of antimüllerian hormone assay make this test the preferred biomarker for the evaluation of ovarian reserve in women.
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Anti-Müllerian hormone (AMH) levels in premenopausal breast cancer patients treated with taxane-based adjuvant chemotherapy - A translational research project of the SUCCESS A study. Breast 2017; 35:130-135. [PMID: 28732324 DOI: 10.1016/j.breast.2017.07.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 07/11/2017] [Accepted: 07/12/2017] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Premenopausal women undergoing chemotherapy are at high risk for premature ovarian failure and its long-term consequences. Data on potential markers to evaluate ovarian reserve pre- and posttreatment are limited. Anti-Müllerian hormone (AMH) known for ovarian reserve in reproductive medicine could be a surrogate marker and was assessed in premenopausal breast cancer patients of the SUCCESS A study (EUDRA-CT no. 2005-000490-21). METHODS We identified 170 premenopausal patients, age ≤ 40 years at trial entry, who received FEC-Doc as taxane-anthracylince based chemotherapy. Blood samples were taken at three time points: Before, four weeks after and two years after adjuvant chemotherapy. Serum AMH-levels were evaluated in a central laboratory by a quantitative immunoassay AMH Gen II ELISA (Beckman Coulter, Brea, USA). RESULTS Median age was 36 years (21-40 years). Median serum AMH-level before chemotherapy was 1.37 ng/ml (range < 0.1-11.3 ng/ml). Four weeks after chemotherapy AMH-levels dropped in 98.6% of the patients to <0.1 ng/ml (range < 0.1-0.21 ng/ml). After two years, 73.3% (n = 101) showed no evidence of ovarian function recovery (AMH <0.1 ng/ml, range < 0.1-3.9 ng/ml). Permanent chemotherapy induced amenorrhea occurred only in 50.6% of the patients. CONCLUSIONS In this analysis, premenopausal patients showed a high rate of ovarian impairment reflected by low AMH-levels after chemotherapy.
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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] [Scholar 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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Mörse H, Elfving M, Turkiewicz A, Andersen CY, Øra I. Severe gonadotoxic insult manifests early in young girls treated for Ewing sarcoma. Medicine (Baltimore) 2016; 95:e4512. [PMID: 27537574 PMCID: PMC5370800 DOI: 10.1097/md.0000000000004512] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
We prospectively investigated anti-Müllerian hormone (AMH) as a measure of ovarian insult in young females during and after treatment for Wilms tumor (WT), osteosarcoma (OS), and Ewing sarcoma (ES).Twenty-one female childhood cancer patients, with a mean age of 7.9 years (range 0.6-17), entered the study. Levels of AMH, follicle-stimulating hormone (FSH), and luteinizing hormone were monitored at diagnosis and every 3 to 4 months during, and regularly for a mean of 2.6 years after treatment.A profound decline in AMH was seen in the majority of the 21 study patients 3 to 4 months after the beginning of treatment, the exception being patients with WT, of whom 60% showed no such decline. During the remaining treatment, all patients except those with WT not treated with whole abdominal radiotherapy or stem cell transplantation (SCT) had AMH below detection limit.After completion of treatment, patients with OS and WT (without whole abdominal radiotherapy and SCT) recovered in AMH and had FSH in the normal range. In contrast, ES patients showed no AMH recovery and highly fluctuating FSH in the first years of follow-up, except for the 2 youngest patients, who had a late, slow AMH recovery.In conclusion, young female ES patients already showed signs of severe ovarian dysfunction during the first years after cancer treatment similar to patients treated with SCT and abdominal radiotherapy, in contrast to females with WT and OS. Fertility counseling and information concerning fertility preservation procedures should be considered before starting to treat young females with ES.
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Affiliation(s)
- Helena Mörse
- Department of Pediatrics, Pediatric Oncology and Hematology
- Correspondence: Helena Mörse, Department of Pediatrics, Pediatric Oncology and Hematology, Skane University Hospital, Lund University, Lund, Sweden (e-mail: )
| | | | - Aleksandra Turkiewicz
- Department of Orthopedics, Clinical Epidemiology Unit, Skane University Hospital, Lund University, Lund, Sweden
| | - Claus Yding Andersen
- Laboratory of Reproductive Biology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ingrid Øra
- Department of Pediatrics, Pediatric Oncology and Hematology
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