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Wu C, Chen D, Stout MB, Wu M, Wang S. Hallmarks of ovarian aging. Trends Endocrinol Metab 2025; 36:418-439. [PMID: 40000274 DOI: 10.1016/j.tem.2025.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025]
Abstract
Ovarian aging is considered to be the pacemaker of female aging, and is linked to various comorbidities such as osteoporosis, cardiovascular diseases, and cognitive decline. Many efforts have been made to determine the mechanisms underlying ovarian aging, but their potential to act as hallmarks to predict and intervene in this process currently remains unclear. In this review we propose nine hallmarks as common features of ovarian aging: genomic instability, telomere attrition, epigenetic alterations, impaired autophagy, cellular senescence, deregulated nutrient-sensing, mitochondrial dysfunction, oxidative stress, and chronic inflammation. Understanding the interaction between these hallmarks poses a significant challenge but may also pave the way to the identification of pharmaceutical targets that can attenuate ovarian aging.
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Affiliation(s)
- Chuqing Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, 430030 Wuhan, Hubei, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, 430030 Wuhan, Hubei, China
| | - Dan Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, 430030 Wuhan, Hubei, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, 430030 Wuhan, Hubei, China
| | - Michael B Stout
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK, USA
| | - Meng Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, 430030 Wuhan, Hubei, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, 430030 Wuhan, Hubei, China.
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, 430030 Wuhan, Hubei, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, 430030 Wuhan, Hubei, China.
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Arslan NP, Azad F, Orak T, Budak-Savas A, Ortucu S, Dawar P, Baltaci MO, Ozkan H, Esim N, Taskin M. A review on bacteria-derived antioxidant metabolites: their production, purification, characterization, potential applications, and limitations. Arch Pharm Res 2025; 48:253-292. [PMID: 40208553 PMCID: PMC12058845 DOI: 10.1007/s12272-025-01541-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 04/02/2025] [Indexed: 04/11/2025]
Abstract
Antioxidants are organic molecules that scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS), thereby maintaining cellular redox balance in living organisms. The human body synthesizes endogenous antioxidants, whereas humans obtain exogenous antioxidants from other organisms such as plants, animals, fungi, and bacteria. This review primarily focuses on the antioxidant potential of natural metabolites and extracts from five major bacterial phyla, including the well-studied Actinobacteria and Cyanobacteria, as well as less-studied Bacteroides, Firmicutes, and Proteobacteria. The literature survey revealed that the metabolites and the extracts with antioxidant activity can be obtained from bacterial cells and their culture supernatants. The metabolites with antioxidant activity include pigments, phycobiliproteins, polysaccharides, mycosporins-like amino acids, peptides, phenolic compounds, and alkaloids. Both metabolites and extracts demonstrate in vitro antioxidant capacity through radical-scavenging, metal-reducing, and metal-chelating activity assays. In in vivo models, they can scavenge ROS and RNS directly and/or indirectly eliminate them by enhancing the activities of antioxidant enzymes, such as catalase, superoxide dismutase, and glutathione peroxidase. Due to their antioxidant activities, they may find applications in the cosmetic industry as anti-aging agents for the skin and in medicine as drugs or supplements for combating oxidative stress-related disorders, such as neurodegenerative diseases and diabetes. The literature survey also elucidated that some metabolites and extracts with antioxidant activity also exhibited strong antimicrobial properties. Therefore, we consider that they may have future applications in the treatment of infectious diseases, the preparation of pathogen-free healthy foods, and the extension of food shelf life.
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Affiliation(s)
| | - Fakhrul Azad
- Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University, Boston, MA, USA
| | - Tugba Orak
- Department of Molecular Biology and Genetics, Science Faculty, Ataturk University, 25240, Erzurum, Turkey
| | - Aysenur Budak-Savas
- Department of Medical Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Serkan Ortucu
- Department of Molecular Biology and Genetics, Science Faculty, Erzurum Technical University, Erzurum, Turkey
| | - Pranav Dawar
- Environmental Molecular Sciences Laboratory (EMSL), Pacific Northwest National Laboratory (PNNL), Richland, WA, USA
| | - Mustafa Ozkan Baltaci
- Department of Molecular Biology and Genetics, Science Faculty, Ataturk University, 25240, Erzurum, Turkey
| | - Hakan Ozkan
- Department of Molecular Biology and Genetics, Science Faculty, Ataturk University, 25240, Erzurum, Turkey
| | - Nevzat Esim
- Department of Molecular Biology and Genetics, Science and Art Faculty, Bingol University, Bingol, Turkey
| | - Mesut Taskin
- Department of Molecular Biology and Genetics, Science Faculty, Ataturk University, 25240, Erzurum, Turkey.
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Kircali-Haznedar N, Mumusoglu S, Bilgic P. How phytochemicals influence reproductive outcomes in women receiving assisted reproductive techniques: a systematic review. Nutr Rev 2025; 83:e304-e316. [PMID: 38641329 DOI: 10.1093/nutrit/nuae037] [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] [Indexed: 04/21/2024] Open
Abstract
CONTEXT Over the past few years, there has been an increasing amount of scholarly literature suggesting a connection between the nutritional status of pregnant mothers and early fetal development, as well as the long-term health consequences of their offspring. Multiple studies have documented that alterations in dietary patterns prior to conception have the potential to affect the initial stages of embryonic development. OBJECTIVES The aim of this study was to perform a comprehensive review of the research pertaining to the correlation between phytochemicals ( specifically, polyphenols, carotenoids and phytoestrogens) and assisted reproductive technology (ART). DATA SOURCES PubMed, Scopus, Web of Science, and Clinical Trials databases were searched from January 1978 to March 2023. STUDY SELECTION This study comprised observational, randomized controlled, and cohort studies that examined the effects of phytochemicals on ART results. The study's outcomes encompass live birth rate, clinical pregnancy, and ongoing pregnancy. DATA EXTRACTION The assessment of study quality was conducted by 2 researchers, independently, using the Quality Criteria Checklist for Primary Research. RESULTS A total of 13 studies were included, of which there were 5 randomized controlled studies, 1 nonrandomized controlled study, 6 prospective cohort studies, and 1 retrospective cohort study. CONCLUSION This research focused on investigating the impact of phytochemicals on ART and has highlighted a dearth of articles addressing that topic. Collaboration among patients, physicians, and nutritionists is crucial for doing novel research. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration no. CRD42023426332.
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Affiliation(s)
- Nagihan Kircali-Haznedar
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Selcuk University, Selcuklu, Konya, Türkiye
| | - Sezcan Mumusoglu
- Department of Obstetrics and Gynecology, Hacettepe University School of Medicine, Sihhiye, Ankara, Türkiye
| | - Pelin Bilgic
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Hacettepe University, Altindag, Ankara, Türkiye
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Tang X, Zhu Y, Cao Z, Wang X, Cai X, Tang Y, Zhou J, Wu M, Zhen X, Ding L, Yan G, Wang H, Sun H, Jiang R. CDC42 deficiency leads to endometrial stromal cell senescence in recurrent implantation failure. Hum Reprod 2024; 39:2768-2784. [PMID: 39487595 PMCID: PMC11630066 DOI: 10.1093/humrep/deae246] [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: 05/20/2024] [Revised: 09/22/2024] [Indexed: 11/04/2024] Open
Abstract
STUDY QUESTION Does the downregulation of cell division cycle 42 (CDC42) protein in endometrial stroma lead to endometrial senescence in patients with recurrent implantation failure (RIF), and what is the potential mechanism? SUMMARY ANSWER CDC42 deficiency causes endometrial stromal senescence and decidualization defects, impairing uterine receptivity of RIF patients, via activation of Wnt signaling pathway. WHAT IS KNOWN ALREADY Uterine aging is unique due to the cyclic remodeling and decidualization of endometrial tissue. Several transcriptomic studies have reported increased senescence in the endometrium in young patients with RIF. Our previous transcriptomic sequencing study discovered that endometrium from women with RIF showed downregulation of CDC42, which is an essential molecule affected by various senescence-related diseases. STUDY DESIGN, SIZE, DURATION The endometrial samples of a total of 71 fertile control patients and 37 RIF patients were collected to verify the association between CDC42 expression and endometrial senescence of RIF patients. Primary endometrial stromal cells (EnSCs) were isolated from endometrial biopsies taken from patients without any endometrial complications and planning to undergo IVF, then subjected to adenovirus-mediated CDC42 knockdown and decidualization induction to explore the detailed mechanism by which CDC42 governs stromal senescence and decidualization. Wnt inhibitor XAV-939 was used to correct the endometrial senescence and decidualization defect. PARTICIPANTS/MATERIALS, SETTING, METHODS Senescence was determined by cell cycle arrest markers (e.g. P16, P21, and P53), SASP molecules (e.g. IL6 and CXCL8), and SA-β-gal staining. Masson's staining and Sirius Red staining were used to detect the endometrial fibrosis. Decidualization was evaluated by the mRNA expression and protein secretion of PRL and IGFBP1, F-actin immunostaining, and the BeWo spheroids 'in vitro implantation' model. Methods used to assess cell function included adenovirus transduction, RNA-sequencing, bioinformatic analysis, western blotting, RT-qPCR, ELISA, and immunofluorescence. MAIN RESULTS AND THE ROLE OF CHANCE Here, we observed remarkably increased levels of stromal senescence and fibrosis, along with stromal CDC42 deficiency, in the endometrium of patients with RIF (P < 0.001). Knockdown of CDC42 effectively induced premature senescence in EnSCs, leading to aberrant accumulation of senescent EnSCs and collagen deposition during decidualization. CDC42 deficiency in EnSCs restrained the decidualization differentiation and receptivity to trophoblast cells. Transcriptomic analysis revealed Wnt signaling activation as a critical downstream alteration in CDC42-deficient EnSCs. Mechanistically, CDC42 interacted with AKT competitively to impede the binding of GSK3β to AKT. Knockdown of CDC42 increased AKT-mediated phosphorylation of GSK3β to inactivate the Axin-GSK3β destruction complex, leading to accumulation and nuclear translocation of β-catenin. Importantly, Wnt signaling inhibitors partially corrected the endometrial senescence caused by CDC42 deficiency, and improved both decidualization and trophoblast invasion. LARGE SCALE DATA RNA-seq data sets generated in this study have been deposited at the NCBI database with BioProject accession number PRJNA1102745. LIMITATIONS, REASONS FOR CAUTION The present study was based on in vitro cell cultures. Further studies involving CDC42-regulated endometrial senescence are needed in knockout mice model and human endometrial assembloids. WIDER IMPLICATIONS OF THE FINDINGS In addition to uncovering endometrial senescence in RIF, our findings underscore the significance of CDC42 in modulating EnSC senescence to maintain the decidualization function, and suggest Wnt signaling inhibitors as potential therapeutic agents for alleviating endometrial senescence. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Natural Science Foundation of China [82271698 (R.J.), 82030040 (H.S.), 82288102 (H.W.), and 82371680 (G.Y.)]; the Natural Science Foundation of Jiangsu Province [BK20231117 (R.J.)]; and the Medical Science and Technology Development Foundation of Nanjing Department of Health [YKK23097 (Y.Z.)]. The authors declare no potential conflicts of interest.
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Affiliation(s)
- Xinyi Tang
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Yingchun Zhu
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Zhiwen Cao
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Xiaoying Wang
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Xinyu Cai
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Yurun Tang
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Jidong Zhou
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Min Wu
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Xin Zhen
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Lijun Ding
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Guijun Yan
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Haibin Wang
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Haixiang Sun
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, China
| | - Ruiwei Jiang
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
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Winstanley YE, Stables JS, Gonzalez MB, Umehara T, Norman RJ, Robker RL. Emerging therapeutic strategies to mitigate female and male reproductive aging. NATURE AGING 2024; 4:1682-1696. [PMID: 39672895 DOI: 10.1038/s43587-024-00771-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 10/29/2024] [Indexed: 12/15/2024]
Abstract
People today are choosing to have children later in life, often in their thirties and forties, when their fertility is in decline. We sought to identify and compile effective methods for improving either male or female fertility in this context of advanced reproductive age. We found few clinical studies with strong evidence for therapeutics that mitigate reproductive aging or extend fertility; however, this Perspective summarizes the range of emerging experimental strategies under development. Preclinical studies, in mouse models of aging, have identified pharmaceutical candidates that improve egg and sperm quality. Further, a diverse array of medically assisted reproduction methodologies, including those that stimulate rare ovarian follicles and rejuvenate egg quality using mitochondria, may have future utility for older patients. Finally, we highlight the many knowledge gaps and possible future directions in the field of therapeutics to extend the age of healthy human reproduction.
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Affiliation(s)
- Yasmyn E Winstanley
- Robinson Research Institute, School of Biomedicine; The University of Adelaide, Adelaide, South Australia, Australia
| | - Jennifer S Stables
- Robinson Research Institute, School of Biomedicine; The University of Adelaide, Adelaide, South Australia, Australia
| | - Macarena B Gonzalez
- Robinson Research Institute, School of Biomedicine; The University of Adelaide, Adelaide, South Australia, Australia
| | - Takashi Umehara
- Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan
| | - Robert J Norman
- Robinson Research Institute, Adelaide Medical School; The University of Adelaide, Adelaide, South Australia, Australia
| | - Rebecca L Robker
- Robinson Research Institute, School of Biomedicine; The University of Adelaide, Adelaide, South Australia, Australia.
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Bertoldo A, Pizzol D, Yon DK, Callegari M, Gobbo V, Cuccurese P, Butler L, Caminada S, Stebbing J, Richardson F, Gawronska J, Smith L. Resveratrol and Female Fertility: A Systematic Review. Int J Mol Sci 2024; 25:12792. [PMID: 39684501 DOI: 10.3390/ijms252312792] [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: 11/08/2024] [Revised: 11/25/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
Resveratrol is a natural polyphenolic compound that may have multiple influences on human health, including antiaging, anti-inflammatory, anti-neoplastic, antioxidant, insulin-sensitizing, cardioprotective and vasodilating activities. Growing evidence also suggests a potential positive effect of resveratrol on female fertility. The aim of the present study was to collate and appraise the scientific literature on the relationship between resveratrol and female fertility. We systematically searched Medline, PubMed, Web of Science and Embase from the databases' inception (1951, 1951, 1947 and 1900, respectively) until 9th May 2024. All in vivo or in vitro retrospective or prospective studies reporting the effects of resveratrol interventions on women's fertility were included. We ultimately incorporated twenty-four studies into a systematic review with a narrative summary of the results; of those studies, nine were performed on women seeking natural or assisted fertility, and fifteen were in vitro studies performed on human cells and tissues in different stages of the reproductive cascade. The current literature, though limited, suggests that resveratrol may play a role in female infertility. Specifically, it may significantly and positively impact reproductive outcomes, owing to its potential therapeutic effects improving ovarian function. Further studies are now needed to better understand resveratrol's effects and define the optimal dosage and periods of intake to maximize beneficial effects, as well as to prevent adverse outcomes on implantation, subsequent pregnancy and the fetus.
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Affiliation(s)
- Alessandro Bertoldo
- U.O.S.D. of Assisted Reproductive Technologies "G. Beltrame", Ospedale di Oderzo, ULSS2, 31046 Treviso, Italy
| | | | - Dong Keon Yon
- Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul 02447, Republic of Korea
| | - Maura Callegari
- U.O.S.D. of Assisted Reproductive Technologies "G. Beltrame", Ospedale di Oderzo, ULSS2, 31046 Treviso, Italy
| | - Valentina Gobbo
- U.O.S.D. of Assisted Reproductive Technologies "G. Beltrame", Ospedale di Oderzo, ULSS2, 31046 Treviso, Italy
| | - Pierluigi Cuccurese
- Department of Obstetrics and Gynecology, Ospedale di Oderzo, ULSS2, 31046 Treviso, Italy
| | - Laurie Butler
- Faculty of Science and Engineering, Anglia Ruskin University, Cambridge CB1 1PT, UK
| | | | - Justin Stebbing
- Department of Life Sciences, Anglia Ruskin University, Cambridge CB1 1PT, UK
| | - Fiona Richardson
- The Queen Elizabeth Hospital King's Lynn NHS Foundation Trust, King's Lynn PE30 4ET, UK
| | - Julia Gawronska
- Centre for Health, Performance and Wellbeing, Anglia Ruskin University, Cambridge CB1 1PT, UK
| | - Lee Smith
- Centre for Health, Performance and Wellbeing, Anglia Ruskin University, Cambridge CB1 1PT, UK
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Yildirim RM, Seli E. Mitochondria as therapeutic targets in assisted reproduction. Hum Reprod 2024; 39:2147-2159. [PMID: 39066614 DOI: 10.1093/humrep/deae170] [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: 03/31/2024] [Revised: 06/22/2024] [Indexed: 07/28/2024] Open
Abstract
Mitochondria are essential organelles with specialized functions, which play crucial roles in energy production, calcium homeostasis, and programmed cell death. In oocytes, mitochondrial populations are inherited maternally and are vital for developmental competence. Dysfunction in mitochondrial quality control mechanisms can lead to reproductive failure. Due to their central role in oocyte and embryo development, mitochondria have been investigated as potential diagnostic and therapeutic targets in assisted reproduction. Pharmacological agents that target mitochondrial function and show promise in improving assisted reproduction outcomes include antioxidant coenzyme Q10 and mitoquinone, mammalian target of rapamycin signaling pathway inhibitor rapamycin, and nicotinamide mononucleotide. Mitochondrial replacement therapies (MRTs) offer solutions for infertility and mitochondrial disorders. Autologous germline mitochondrial energy transfer initially showed promise but failed to demonstrate significant benefits in clinical trials. Maternal spindle transfer (MST) and pronuclear transfer hold potential for preventing mitochondrial disease transmission and improving oocyte quality. Clinical trials of MST have shown promising outcomes, but larger studies are needed to confirm safety and efficacy. However, ethical and legislative challenges complicate the widespread implementation of MRTs.
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Affiliation(s)
- Raziye Melike Yildirim
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Emre Seli
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
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8
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Zarnani K, Zarnani K, Maslehat-Lay N, Zeynali B, Vafaei S, Shokri MR, Vanaki N, Soltanghoraee H, Mirzadegan E, Edalatkhah H, Naderi MM, Sarvari A, Attari F, Jeddi-Tehrani M, Zarnani AH. In-utero transfer of decidualized endometrial stromal cells increases the frequency of regulatory T cells and normalizes the abortion rate in the CBA/J × DBA/2 abortion model. Front Immunol 2024; 15:1440388. [PMID: 39380998 PMCID: PMC11460546 DOI: 10.3389/fimmu.2024.1440388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 08/30/2024] [Indexed: 10/10/2024] Open
Abstract
Introduction Failure to adequate decidualization leads to adverse pregnancy outcomes including pregnancy loss. Although there are plenty of reports underscoring immune dysfunction as the main cause of abortion in CBA/J females mated with DBA/2 males (CBA/J × DBA/2), little is known about the potential role of impaired endometrial decidualization. Methods Endometrial stromal cells (ESCs) from CBA/J mice were in-vitro decidualized, and the proteome profile of the secretome was investigated by membrane-based array. CBA/J mice were perfused In-utero with either decidualized ESCs (C×D/D), undecidualized ESCs (C×D/ND), or PBS (C×D/P) 12 days before mating with DBA/2 males. Control mice were not manipulated and were mated with male DBA/2 (C×D) or Balb/c (C×B) mice. On day 13.5 of pregnancy, reproductive parameters were measured. In-vivo tracking of EdU-labeled ESCs was performed using fluorescence microscopy. The frequency of regulatory T cells (Tregs) in paraaortic/renal and inguinal lymph nodes was measured by flow cytometry. The proliferation of pregnant CBA/J splenocytes in response to stimulation with DBA/2 splenocytes was assessed by 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE) flow cytometry. Results In C×D/D mice, the resorption rate was reduced to match that seen in the C×B group. Intrauterine perfused ESCs appeared in uterine stroma after 2 days, which remained there for at least 12 days. There was no difference in the number of implantation sites and embryo weight across all groups. The frequency of Tregs in the inguinal lymph nodes was similar across all groups, but it increased in the paraaortic/renal lymph nodes of C×D/D mice to the level found in C×B mice. No significant changes were observed in the proliferation of splenocytes from pregnant C×D/D compared to those of the C×D group in response to stimulation with DBA/2 splenocytes. Decidualization of ESCs was associated with a profound alteration in ESC secretome exemplified by alteration in proteins involved in extracellular matrix (ECM) remodeling, response to inflammation, senescence, and immune cell trafficking. Discussion Our results showed that the deficiency of Tregs is not the primary driver of abortion in the CBA/J × DBA/2 model and provided evidence that impaired endometrial decidualization probably triggers endometrial immune dysfunction and abortion in this model.
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Affiliation(s)
- Kayhan Zarnani
- School of Biology, College of Sciences, University of Tehran, Tehran, Iran
- Reproductive Immunology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Kimia Zarnani
- School of Biology, College of Sciences, University of Tehran, Tehran, Iran
- Reproductive Immunology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Nasim Maslehat-Lay
- Reproductive Immunology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Bahman Zeynali
- Developmental Biology Lab., School of Biology, College of Sciences, University of Tehran, Tehran, Iran
| | - Sedigheh Vafaei
- Reproductive Immunology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Mohammad-Reza Shokri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, United States
| | - Negar Vanaki
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Haleh Soltanghoraee
- Reproductive Biotechnology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Ebrahim Mirzadegan
- Nanobiotechnology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Haleh Edalatkhah
- Reproductive Biotechnology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Mohammad-Mehdi Naderi
- Reproductive Biotechnology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Ali Sarvari
- Reproductive Biotechnology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Farnoosh Attari
- Department of Animal Biology, School of Biology, College of Sciences, University of Tehran, Tehran, Iran
| | - Mahmood Jeddi-Tehrani
- Monoclonal Antibody Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Amir-Hassan Zarnani
- Reproductive Immunology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Sampaio OGM, Santos SAAR, Damasceno MDBMV, Joventino LB, Schneider A, Masternak MM, Campos AR, Cavalcante MB. Impact of repeated ovarian hyperstimulation on the reproductive function. J Reprod Immunol 2024; 164:104277. [PMID: 38889661 DOI: 10.1016/j.jri.2024.104277] [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: 10/06/2023] [Revised: 05/31/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024]
Abstract
One of six couples (17.5 % of the adult population) worldwide is affected by infertility during their lifetime. This number represents a substantial increase in the prevalence of this gynecological condition over the last decade. Ovulatory dysfunction and anovulation are the main causes of female infertility. Timed intercourse, intrauterine insemination, and assisted reproductive technology (ART), such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), are the most common interventions for infertile couples. Ovulation induction protocols for IVF/ICSI routinely use supraphysiological doses of gonadotropins to stimulate many preovulatory follicles. Animal and human studies suggested that ovarian hyperstimulation, alone or repeatedly, for ART cycles can induce changes in the immune response and increase the oxidative stress (OS) in the ovarian microenvironment. The consequences of repeated ovarian hyperstimulation on the human ovary remain poorly understood, particularly in relation to the effects of ovarian stimulation on the immune system and the potential for ovarian stimulation to cause OS. Animal studies have observed that repeated cycles of ovarian hyperstimulation can accelerate ovarian aging. Changes in ovarian hormone levels, accelerated loss of ovarian reserve, disorders in ovarian ultrastructure, ovarian senescence, and decreased reproductive performance represent possible long-term effects of repeated ovarian hyperstimulation. The short and long-term impact of the combination of antioxidant agents in ovarian hyperstimulation protocols in women undergoing ART must urgently be better understood. The recent increase in the number of ART and fertility preservation cycles may accelerate ovarian aging in these women, promoting consequences beyond the reproductive function and including health deterioration.
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Affiliation(s)
| | | | | | | | - Augusto Schneider
- Nutrition College, Federal University of Pelotas (UFPel), Pelotas, RS 96010-610, Brazil
| | - Michal M Masternak
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA; Department of Head and Neck Surgery, Poznan University of Medical Sciences, Poznan, Poland
| | - Adriana Rolim Campos
- Graduate Program in Medical Sciences, Universidade de Fortaleza (UNIFOR), Fortaleza, CE 60.811-905, Brazil
| | - Marcelo Borges Cavalcante
- Graduate Program in Medical Sciences, Universidade de Fortaleza (UNIFOR), Fortaleza, CE 60.811-905, Brazil; Medical School, Universidade de Fortaleza (UNIFOR), Fortaleza, CE 60.811-905, Brazil; CONCEPTUS - Reproductive Medicine, Fortaleza, CE 60.170-240, Brazil.
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10
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Ardehjani NA, Agha-Hosseini M, Nashtaei MS, Khodarahmian M, Shabani M, Jabarpour M, Fereidouni F, Rastegar T, Amidi F. Resveratrol ameliorates mitochondrial biogenesis and reproductive outcomes in women with polycystic ovary syndrome undergoing assisted reproduction: a randomized, triple-blind, placebo-controlled clinical trial. J Ovarian Res 2024; 17:143. [PMID: 38987824 PMCID: PMC11234766 DOI: 10.1186/s13048-024-01470-9] [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: 04/07/2024] [Accepted: 07/01/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND This study was designed to examine the effect of resveratrol on mitochondrial biogenesis, oxidative stress (OS), and assisted reproductive technology (ART) outcomes in individuals with polycystic ovary syndrome (PCOS). METHODS Fifty-six patients with PCOS were randomly assigned to receive 800 mg/day of resveratrol or placebo for 60 days. The primary outcome was OS in follicular fluid (FF). The secondary outcome involved assessing gene and protein expression related to mitochondrial biogenesis, mitochondrial DNA (mtDNA) copy number, and adenosine triphosphate (ATP) content in granulosa cells (GCs). ART outcomes were evaluated at the end of the trial. RESULTS Resveratrol significantly reduced the total oxidant status (TOS) and oxidative stress index (OSI) in FF (P = 0.0142 and P = 0.0039, respectively) while increasing the total antioxidant capacity (TAC) (P < 0.0009). Resveratrol consumption also led to significant increases in the expression of critical genes involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor gamma coactivator (PGC-1α) and mitochondrial transcription factor A (TFAM) (P = 0.0032 and P = 0.0003, respectively). However, the effect on nuclear respiratory factor 1 (Nrf-1) expression was not statistically significant (P = 0.0611). Resveratrol significantly affected sirtuin1 (SIRT1) and PGC-1α protein levels (P < 0.0001 and P = 0.0036, respectively). Resveratrol treatment improved the mtDNA copy number (P < 0.0001) and ATP content in GCs (P = 0.0014). Clinically, the resveratrol group exhibited higher rates of oocyte maturity (P = 0.0012) and high-quality embryos (P = 0.0013) than did the placebo group. There were no significant differences between the groups in terms of chemical or clinical pregnancy rates (P > 0.05). CONCLUSIONS These findings indicate that resveratrol may be a promising therapeutic agent for patients with PCOS undergoing assisted reproduction. TRIAL REGISTRATION NUMBER http://www.irct.ir ; IRCT20221106056417N1; 2023 February 09.
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Affiliation(s)
- Negar Ajabi Ardehjani
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Marzieh Agha-Hosseini
- Department of Infertility, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Shabani Nashtaei
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Department of Infertility, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahshad Khodarahmian
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Department of Infertility, Arash Women's Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Shabani
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoome Jabarpour
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Department of Infertility, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzane Fereidouni
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Tayebeh Rastegar
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Fardin Amidi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Department of Infertility, Yas Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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11
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Dai Y, Guo Y, Tang W, Chen D, Xue L, Chen Y, Guo Y, Wei S, Wu M, Dai J, Wang S. Reactive oxygen species-scavenging nanomaterials for the prevention and treatment of age-related diseases. J Nanobiotechnology 2024; 22:252. [PMID: 38750509 PMCID: PMC11097501 DOI: 10.1186/s12951-024-02501-9] [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: 03/01/2024] [Accepted: 04/28/2024] [Indexed: 05/18/2024] Open
Abstract
With increasing proportion of the elderly in the population, age-related diseases (ARD) lead to a considerable healthcare burden to society. Prevention and treatment of ARD can decrease the negative impact of aging and the burden of disease. The aging rate is closely associated with the production of high levels of reactive oxygen species (ROS). ROS-mediated oxidative stress in aging triggers aging-related changes through lipid peroxidation, protein oxidation, and DNA oxidation. Antioxidants can control autoxidation by scavenging free radicals or inhibiting their formation, thereby reducing oxidative stress. Benefiting from significant advances in nanotechnology, a large number of nanomaterials with ROS-scavenging capabilities have been developed. ROS-scavenging nanomaterials can be divided into two categories: nanomaterials as carriers for delivering ROS-scavenging drugs, and nanomaterials themselves with ROS-scavenging activity. This study summarizes the current advances in ROS-scavenging nanomaterials for prevention and treatment of ARD, highlights the potential mechanisms of the nanomaterials used and discusses the challenges and prospects for their applications.
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Affiliation(s)
- Yun Dai
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, Hubei, China
| | - Yifan Guo
- Department of Marine Pharmacy, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, 315800, China
| | - Weicheng Tang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, Hubei, China
| | - Dan Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, Hubei, China
| | - Liru Xue
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, Hubei, China
| | - Ying Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, Hubei, China
| | - Yican Guo
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, Hubei, China
| | - Simin Wei
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, Hubei, China
| | - Meng Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, Hubei, China.
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, Hubei, China.
| | - Jun Dai
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, Hubei, China.
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, Hubei, China.
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, 430030, Hubei, China.
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, 430030, Hubei, China.
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12
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Ju W, Zhao Y, Yu Y, Zhao S, Xiang S, Lian F. Mechanisms of mitochondrial dysfunction in ovarian aging and potential interventions. Front Endocrinol (Lausanne) 2024; 15:1361289. [PMID: 38694941 PMCID: PMC11061492 DOI: 10.3389/fendo.2024.1361289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 03/22/2024] [Indexed: 05/04/2024] Open
Abstract
Mitochondria plays an essential role in regulating cellular metabolic homeostasis, proliferation/differentiation, and cell death. Mitochondrial dysfunction is implicated in many age-related pathologies. Evidence supports that the dysfunction of mitochondria and the decline of mitochondrial DNA copy number negatively affect ovarian aging. However, the mechanism of ovarian aging is still unclear. Treatment methods, including antioxidant applications, mitochondrial transplantation, emerging biomaterials, and advanced technologies, are being used to improve mitochondrial function and restore oocyte quality. This article reviews key evidence and research updates on mitochondrial damage in the pathogenesis of ovarian aging, emphasizing that mitochondrial damage may accelerate and lead to cellular senescence and ovarian aging, as well as exploring potential methods for using mitochondrial mechanisms to slow down aging and improve oocyte quality.
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Affiliation(s)
- Wenhan Ju
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yuewen Zhao
- CReATe Fertility Centre, Toronto, ON, Canada
| | - Yi Yu
- Department of Reproduction and Genetics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shuai Zhao
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shan Xiang
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Fang Lian
- Department of Reproduction and Genetics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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13
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Conforti A, Iorio GG, Di Girolamo R, Rovetto MY, Picarelli S, Cariati F, Gentile R, D'Amato A, Gliozheni O, Fioretti B, Alviggi C. The impact of resveratrol on the outcome of the in vitro fertilization: an exploratory randomized placebo-controlled trial. J Ovarian Res 2024; 17:81. [PMID: 38622741 PMCID: PMC11020196 DOI: 10.1186/s13048-024-01391-7] [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: 01/24/2024] [Accepted: 03/13/2024] [Indexed: 04/17/2024] Open
Abstract
BACKGROUND Resveratrol is a natural polyphenolic compound present in plants and red wine with many potential health benefits. This compound has various anti-inflammatory and anti-tumor properties and can improve cellular mitochondrial activity. This trial was designed to evaluate the effect on the outcome of IVF of Resveratrol supplementation in women > 35 years with good ovarian reserve (AMH > 1.2 ng/ml). Women were randomized to receive or placebo or Resveratrol (150 mg per day) for three months preceding the ovarian stimulation (OS). All patients were stimulated with a starting dose of recombinant FSH ranging between 150 and 300 IU according to age and ovarian reserve. GnRH antagonist flexible protocol was adopted for pituitary suppression. Triggering was performed with urinary hCG (10.000 IU). RESULTS The study was conducted between January 2019 and December 2022 with aa total of 37 cases and 33 controls were recruited. No statistically significant differences in the number of oocytes retrieved, biochemical pregnancy, clinical pregnancy and live birth rates were observed between women treated with resveratrol and control group. A statistically significant increase in the follicle output rate (FORT) and follicle-to oocyte index (FOI) was observed in women treated with resveratrol-based nutraceutical (0.92 versus 0.77 [p = 0.02], and 0.77 versus 0.64 [p = 0.006], respectively). CONCLUSIONS Preliminary results from this study indicate that pre-treatment with resveratrol may improve ovarian sensitivity to exogenous FSH, which in turn may decrease the risk of hypo-response to OS in advanced reproductive age women.
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Affiliation(s)
- A Conforti
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine, University of Naples "Federico II, Naples, Italy, Via Sergio Pansini, 5, 80131
| | - G G Iorio
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine, University of Naples "Federico II, Naples, Italy, Via Sergio Pansini, 5, 80131.
| | - R Di Girolamo
- Department of Public Health. School of Medicine, University of Naples "Federico II, Naples, Italy
| | - M Y Rovetto
- Department of Public Health. School of Medicine, University of Naples "Federico II, Naples, Italy
| | - S Picarelli
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine, University of Naples "Federico II, Naples, Italy, Via Sergio Pansini, 5, 80131
| | - F Cariati
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine, University of Naples "Federico II, Naples, Italy, Via Sergio Pansini, 5, 80131
| | - R Gentile
- Department of Chemistry, Biology and Biotechnologies, University of Perugia, Perugia, Italy
| | - A D'Amato
- Department of Interdisciplinary Medicine, University of Bari, 1St Unit of Obstetrics and Gynecology, Bari, Italy
| | - O Gliozheni
- Head of Department of Obstetrics and Gynecology, University Hospital for Obstetrics & Gynecology, University of Medicine of Tirana, KocoGliozheni", Tirana, Albania
| | - B Fioretti
- Department of Chemistry, Biology and Biotechnologies, University of Perugia, Perugia, Italy
| | - C Alviggi
- Department of Public Health. School of Medicine, University of Naples "Federico II, Naples, Italy
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14
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Podgrajsek R, Ban Frangez H, Stimpfel M. Molecular Mechanism of Resveratrol and Its Therapeutic Potential on Female Infertility. Int J Mol Sci 2024; 25:3613. [PMID: 38612425 PMCID: PMC11011890 DOI: 10.3390/ijms25073613] [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: 02/27/2024] [Revised: 03/19/2024] [Accepted: 03/19/2024] [Indexed: 04/14/2024] Open
Abstract
Resveratrol is a polyphenol present in various plant sources. Studies have reported numerous potential health benefits of resveratrol, exhibiting anti-aging, anti-inflammatory, anti-microbial, and anti-carcinogenic activity. Due to the reported effects, resveratrol is also being tested in reproductive disorders, including female infertility. Numerous cellular, animal, and even human studies were performed with a focus on the effect of resveratrol on female infertility. In this review, we reviewed some of its molecular mechanisms of action and summarized animal and human studies regarding resveratrol and female infertility, with a focus on age-related infertility, polycystic ovary syndrome, and endometriosis.
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Affiliation(s)
- Rebeka Podgrajsek
- Department of Human Reproduction, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (R.P.); (H.B.F.)
| | - Helena Ban Frangez
- Department of Human Reproduction, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (R.P.); (H.B.F.)
- Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Martin Stimpfel
- Department of Human Reproduction, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (R.P.); (H.B.F.)
- Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
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15
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Hart RJ. Nutritional supplements and IVF: an evidence-based approach. Reprod Biomed Online 2024; 48:103770. [PMID: 38184959 DOI: 10.1016/j.rbmo.2023.103770] [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: 08/10/2023] [Revised: 10/24/2023] [Accepted: 11/01/2023] [Indexed: 01/09/2024]
Abstract
Many women undergoing IVF take supplements during treatment. The purpose of this review was to systematically review these nutritional supplements. The therapies studied are dehydroepiandrosterone (DHEA), melatonin, co-enzyme Q10 (CoQ1O), carnitine, selenium, vitamin D, myo-inositol, omega-3, Chinese herbs and dietary interventions. A literature search up to May 2023 was undertaken. The data suggest that a simple nutritional approach would be to adopt a Mediterranean diet. With regards to supplements to treat a potential poor ovarian response to ovarian stimulation, starting DHEA and COQ-10 before cycle commencement is better than control therapies. Furthermore, medication with CoQ10 may have some merit, although it is unclear whether its place is for older women, for those with a poor response to ovarian stimulation or for poor embryonic development. There appears a benefit for some IVF outcomes for the use of melatonin, although it is unclear what group of patients would derive the benefit and the appropriate dosing regimen. For women with polycystic ovary syndrome, there may be a benefit to the use of myo-inositol, although again the dosing regimen is unclear. Furthermore, the place of vitamin D supplementation has yet to be clarified, and supplementation with omega-3 free fatty acids may lead to improvements in clinical and embryological IVF outcomes.
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Affiliation(s)
- Roger J Hart
- Division of Obstetrics and Gynaecology, University of Western Australia, Perth, Western Australia, Australia.; Fertility Specialists of Western Australia and City Fertility Clinic, Claremont, Western Australia, Australia..
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16
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Brown K, Theofanous D, Britton RG, Aburido G, Pepper C, Sri Undru S, Howells L. Resveratrol for the Management of Human Health: How Far Have We Come? A Systematic Review of Resveratrol Clinical Trials to Highlight Gaps and Opportunities. Int J Mol Sci 2024; 25:747. [PMID: 38255828 PMCID: PMC10815776 DOI: 10.3390/ijms25020747] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 01/01/2024] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
Resveratrol has long been proposed as being beneficial to human health across multiple morbidities, yet there is currently no conclusive clinical evidence to advocate its recommendation in any healthcare setting. A large cohort with high-quality clinical data and clearly defined biomarkers or endpoints are required to draw meaningful conclusions. This systematic review compiles every clinical trial conducted using a defined dose of resveratrol in a purified form across multiple morbidities to highlight the current 'state-of-play' and knowledge gaps, informing future trial designs to facilitate the realisation of resveratrol's potential benefits to human health. Over the last 20 years, there have been almost 200 studies evaluating resveratrol across at least 24 indications, including cancer, menopause symptoms, diabetes, metabolic syndrome, and cardiovascular disease. There are currently no consensus treatment regimens for any given condition or endpoint, beyond the fact that resveratrol is generally well-tolerated at a dose of up to 1 g/day. Additionally, resveratrol consistently reduces inflammatory markers and improves aspects of a dysregulated metabolism. In conclusion, over the last 20 years, the increasing weight of clinical evidence suggests resveratrol can benefit human health, but more large, high-quality clinical trials are required to transition this intriguing compound from health food shops to the clinic.
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Affiliation(s)
- Karen Brown
- Leicester Cancer Research Centre, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK; (D.T.); (R.G.B.); (G.A.); (S.S.U.); (L.H.)
| | - Despoina Theofanous
- Leicester Cancer Research Centre, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK; (D.T.); (R.G.B.); (G.A.); (S.S.U.); (L.H.)
| | - Robert G. Britton
- Leicester Cancer Research Centre, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK; (D.T.); (R.G.B.); (G.A.); (S.S.U.); (L.H.)
| | - Grandezza Aburido
- Leicester Cancer Research Centre, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK; (D.T.); (R.G.B.); (G.A.); (S.S.U.); (L.H.)
| | - Coral Pepper
- Odames Library, Victoria Building, Leicester Royal Infirmary, Leicester LE1 5WW, UK
| | - Shanthi Sri Undru
- Leicester Cancer Research Centre, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK; (D.T.); (R.G.B.); (G.A.); (S.S.U.); (L.H.)
| | - Lynne Howells
- Leicester Cancer Research Centre, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK; (D.T.); (R.G.B.); (G.A.); (S.S.U.); (L.H.)
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17
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Chen Y, Yang J, Zhang L. The Impact of Follicular Fluid Oxidative Stress Levels on the Outcomes of Assisted Reproductive Therapy. Antioxidants (Basel) 2023; 12:2117. [PMID: 38136236 PMCID: PMC10740420 DOI: 10.3390/antiox12122117] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/11/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Oocyte quality is a pivotal determinant of assisted reproductive outcomes. The quality of oocytes is intricately linked to their developmental microenvironment, particularly the levels of oxidative stress within the follicular fluid. Oxidative stress levels in follicular fluid may have a substantial influence on oocyte health, thereby impacting the outcomes of ART procedures. This review meticulously explores the intricate relationship between oxidative stress in follicular fluid and ART outcomes. Furthermore, it delves into strategies aimed at ameliorating the oxidative stress status of follicular fluid, with the overarching goal of enhancing the overall efficacy of ART. This research endeavors to establish a robust foundation and provide valuable guidance for clinical treatment approaches, particularly in the context of infertile women, including those of advanced maternal age.
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Affiliation(s)
| | | | - Ling Zhang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, No. 13 Hangkong Road, Wuhan 430030, China; (Y.C.); (J.Y.)
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18
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Elías-López AL, Vázquez-Mena O, Sferruzzi-Perri AN. Mitochondrial dysfunction in the offspring of obese mothers and it's transmission through damaged oocyte mitochondria: Integration of mechanisms. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166802. [PMID: 37414229 DOI: 10.1016/j.bbadis.2023.166802] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/23/2023] [Accepted: 06/29/2023] [Indexed: 07/08/2023]
Abstract
In vivo and in vitro studies demonstrate that mitochondria in the oocyte, are susceptible to damage by suboptimal pre/pregnancy conditions, such as obesity. These suboptimal conditions have been shown to induce mitochondrial dysfunction (MD) in multiple tissues of the offspring, suggesting that mitochondria of oocytes that pass from mother to offspring, can carry information that can programme mitochondrial and metabolic dysfunction of the next generation. They also suggest that transmission of MD could increase the risk of obesity and other metabolic diseases in the population inter- and trans-generationally. In this review, we examined whether MD observed in offspring tissues of high energetic demand, is the result of the transmission of damaged mitochondria from the oocytes of obese mothers to the offspring. The contribution of genome-independent mechanisms (namely mitophagy) in this transmission were also explored. Finally, potential interventions aimed at improving oocyte/embryo health were investigated, to see if they may provide an opportunity to halter the generational effects of MD.
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Affiliation(s)
- A L Elías-López
- Dirección de Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", México.
| | | | - A N Sferruzzi-Perri
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, UK.
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19
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Dong L, Teh DBL, Kennedy BK, Huang Z. Unraveling female reproductive senescence to enhance healthy longevity. Cell Res 2023; 33:11-29. [PMID: 36588114 PMCID: PMC9810745 DOI: 10.1038/s41422-022-00718-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/19/2022] [Indexed: 01/03/2023] Open
Abstract
In a society where women often want successful careers and equal opportunities to men, the early nature of ovarian aging often forces women to make difficult life choices between career and family development. Fertility in women begins to decline after the age of 37 years and it is rare for pregnancies to occur after 45. This reproductive decline in women is inevitable and culminates in menopause, which is a major driver of age-related diseases. In a world where biomedical advances are leading to modifiable biological outcomes, it is time to focus on mitigating female reproductive senescence to maintain fertility and preserve age-related hormonal functions, with the goal of providing increased life choices and enhancing healthspan. To date, reproductive longevity research remains an understudied field. More needs to be done to unravel the biology of the ovarian follicles, which are the functional units of reproductive lifespan and are comprised of cell types including the oocyte (female gamete) and a group of specialized supporting somatic cells. Biological attempts to maintain the quality and quantity of follicles in animal models through manipulating pathways involved in aging can potentially prolong female reproductive lifespan and healthspan. Here, we summarize the molecular events driving ovarian aging and menopause and the interventional strategies to offset these events. Developing solutions to female reproductive senescence will open doors to discover ways to enhance true healthy longevity for both men and women.
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Affiliation(s)
- Lu Dong
- Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore, Singapore
- NUS Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Daniel Boon Loong Teh
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Bia Echo Asia Centre for Reproductive Longevity and Equality, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Brian Keith Kennedy
- Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore, Singapore.
- NUS Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- NUS Bia Echo Asia Centre for Reproductive Longevity and Equality, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Zhongwei Huang
- NUS Bia Echo Asia Centre for Reproductive Longevity and Equality, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore.
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20
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Nacka-Aleksić M, Pirković A, Vilotić A, Bojić-Trbojević Ž, Jovanović Krivokuća M, Giampieri F, Battino M, Dekanski D. The Role of Dietary Polyphenols in Pregnancy and Pregnancy-Related Disorders. Nutrients 2022; 14:nu14245246. [PMID: 36558404 PMCID: PMC9782043 DOI: 10.3390/nu14245246] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/06/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Polyphenols are a group of phytochemicals with extensive biological functions and health-promoting potential. These compounds are present in most foods of plant origin and their increased widespread availability through the intake of nutritional supplements, fortified foods, and beverages, has also led to increased exposure throughout gestation. In this narrative review, we focus on the role of polyphenols in both healthy and pathological pregnancy. General information related to their classification and function is followed by an overview of their known effects in early-pregnancy events, including the current insights into molecular mechanisms involved. Further, we provide an overview of their involvement in some of the most common pregnancy-associated pathological conditions, such as preeclampsia and gestational diabetes mellitus. Additionally, we also discuss the estimated possible risk of polyphenol consumption on pregnancy outcomes. The consumption of dietary polyphenols during pregnancy needs particular attention considering the possible effects of polyphenols on the mechanisms involved in maternal adaptation and fetal development. Further studies are strongly needed to unravel the in vivo effects of polyphenol metabolites during pregnancy, as well as their role on advanced maternal age, prenatal nutrition, and metabolic risk of the offspring.
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Affiliation(s)
- Mirjana Nacka-Aleksić
- Institute for the Application of Nuclear Energy, Department for Biology of Reproduction, University of Belgrade, Banatska 31b, 11080 Belgrade, Serbia
| | - Andrea Pirković
- Institute for the Application of Nuclear Energy, Department for Biology of Reproduction, University of Belgrade, Banatska 31b, 11080 Belgrade, Serbia
| | - Aleksandra Vilotić
- Institute for the Application of Nuclear Energy, Department for Biology of Reproduction, University of Belgrade, Banatska 31b, 11080 Belgrade, Serbia
| | - Žanka Bojić-Trbojević
- Institute for the Application of Nuclear Energy, Department for Biology of Reproduction, University of Belgrade, Banatska 31b, 11080 Belgrade, Serbia
| | - Milica Jovanović Krivokuća
- Institute for the Application of Nuclear Energy, Department for Biology of Reproduction, University of Belgrade, Banatska 31b, 11080 Belgrade, Serbia
| | - Francesca Giampieri
- Research Group on Food, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, 39011 Santander, Spain
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Maurizio Battino
- Research Group on Food, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, 39011 Santander, Spain
- International Joint Research Laboratory of Intelligent Agriculture and Agri-Products Processing, Jiangsu University, Zhenjiang 212013, China
- Dipartimento di Scienze Cliniche Specialistiche, Facoltà di Medicina, Università Politecnica delle Marche, 60131 Ancona, Italy
| | - Dragana Dekanski
- Institute for the Application of Nuclear Energy, Department for Biology of Reproduction, University of Belgrade, Banatska 31b, 11080 Belgrade, Serbia
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21
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The Regulators of Human Endometrial Stromal Cell Decidualization. Biomolecules 2022; 12:biom12091275. [PMID: 36139114 PMCID: PMC9496326 DOI: 10.3390/biom12091275] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/04/2022] [Accepted: 09/07/2022] [Indexed: 11/17/2022] Open
Abstract
Several factors are important for implantation and subsequent placentation in the endometrium, including immunity, angiogenesis, extracellular matrix, glucose metabolism, reactive oxidative stress, and hormones. The involvement or abnormality of these factors can impair canonical decidualization. Unusual decidualization can lead to perinatal complications, such as disruption of trophoblast invasion. Drastic changes in the morphology and function of human endometrial stromal cells (hESCs) are important for decidualization of the human endometrium; hESCs are used to induce optimal morphological and functional decidualization in vitro because they contain estrogen and progesterone receptors. In this review, we will focus on the studies that have been conducted on hESC decidualization, including the results from our laboratory.
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22
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Resveratrol and Reproductive Health. Life (Basel) 2022; 12:life12020294. [PMID: 35207581 PMCID: PMC8875092 DOI: 10.3390/life12020294] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/03/2022] [Accepted: 02/05/2022] [Indexed: 12/16/2022] Open
Abstract
Resveratrol (RSV), a plant-derived polyphenol, demonstrates broad-spectrum health benefits, including anti-proliferative, anti-inflammatory, antidiabetic, anti-ischemic and antioxidant effects. The aim of this review is to give an important heads-up regarding the influence of RSV as a phytoestrogen, RSV effects on most common pregnancy-related complications, as well as its impact on the embryogenesis, spermatogenesis, and women’s reproductive health. Considering the important implications of RSV on human reproductive health, this overview could provide a groundwork, encouraging more detailed research at the clinical level.
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23
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24
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Tesarik J. Towards Personalized Antioxidant Use in Female Infertility: Need for More Molecular and Clinical Studies. Biomedicines 2021; 9:1933. [PMID: 34944748 PMCID: PMC8698668 DOI: 10.3390/biomedicines9121933] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/07/2021] [Accepted: 12/16/2021] [Indexed: 12/12/2022] Open
Abstract
Treatment with antioxidants is increasingly used to slow down aging processes in different organs of the human body, including those implicated in female fertility. There is a plethora of different natural, synthetic or semi-synthetic medicines available on the market; most of them can be purchased without medical prescription. Even though the use of antioxidants, even under conditions of auto-medication, was shown to improve many functions related to female infertility related to oxidative stress, the lack of medical control and supervision can lead to an overmedication resulting in an opposite extreme, reductive stress, which can be counterproductive with regard to reproductive function and produce various adverse health effects in general. This paper reviews the current knowledge relative to the effects of different antioxidants on female reproductive function. The persisting gaps in this knowledge are also highlighted, and the need for medical supervision and personalization of antioxidant prescription is underscored.
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Affiliation(s)
- Jan Tesarik
- MARGen Clinic, Camino de Ronda 2, 18006 Granada, Spain
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25
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Gharaei R, Mahdavinezhad F, Samadian E, Asadi J, Ashrafnezhad Z, Kashani L, Amidi F. Antioxidant supplementations ameliorate PCOS complications: a review of RCTs and insights into the underlying mechanisms. J Assist Reprod Genet 2021; 38:2817-2831. [PMID: 34689247 PMCID: PMC8609065 DOI: 10.1007/s10815-021-02342-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is one of the most important gynecological disorders of women in the age of reproduction. Different hormonal and inflammatory cross-talks may play in the appearance of its eventual complications as a leading cause of infertility. Excessive production of reactive oxygen species over the power of the antioxidant system as oxidative stress is known to contribute to a variety of diseases like PCOS. Thus, the utilization of antioxidants can be efficient in preventing or assistant in treating these diseases. In this review, we describe the clinical trial studies that have examined the efficiency of antioxidant strategies against PCOS and the possible underlying mechanisms. The investigations presented here lead us to consider that targeting oxidative stress pathways is probably a powerful promising therapeutic approach towards PCOS. There is preparatory evidence of the effectiveness of antioxidant interventions in ameliorating some of the PCOS complications, including metabolic and hormonal disorders. Due to limited data and relatively few clinical trials, many of these interventions need further investigation before they can be considered effective agents for routine clinical use.
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Affiliation(s)
- Roghaye Gharaei
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Forough Mahdavinezhad
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Esmaeil Samadian
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Jahanbakhsh Asadi
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Zhaleh Ashrafnezhad
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ladan Kashani
- Department of Obstetrics and Gynecology, School of Medicine, Arash Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Fardin Amidi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Department of Infertility, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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26
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Gerli S, Della Morte C, Ceccobelli M, Mariani M, Favilli A, Leonardi L, Lanti A, Iannitti RG, Fioretti B. Biological and clinical effects of a resveratrol-based multivitamin supplement on intracytoplasmic sperm injection cycles: a single-center, randomized controlled trial. J Matern Fetal Neonatal Med 2021; 35:7640-7648. [PMID: 34338114 DOI: 10.1080/14767058.2021.1958313] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Resveratrol display's positive effects on follicle growth and development in preclinical studies while there is scantly information from clinical trials. The aim of this study was to evaluate the biological and clinical impact of a resveratrol-based multivitamin supplement on intracytoplasmatic sperm injection (ICSI) cycles. METHODS A randomized, single-center controlled trial conducted at the University Center of Assisted Reproductive Technologies involving 101 women infertile women undergoing ICSI cycles was conducted. A pretreatment with a daily resveratrol based nutraceutical was administered to the Study Group; Control Group received folic acid. The primary outcomes were the number of developed mature follicles (>16 mm), total oocytes and MII oocytes recovered, the fertilization rate and the number of cleavage embryos/blastocysts obtained. Secondary endpoints were the duration and dosage of gonadotropins, the number of embryos for transfer, implantation, biochemical, clinical pregnancy rates, live birth and miscarriage rates. RESULTS A significantly higher number of oocytes and MII oocytes were retrieved in the Study Group than in Control Group (p = .03 and p = .04, respectively). A higher fertilization rate (p = .004), more cleavage embryos/patient (p = .01), blastocytes/patients (p = .01) and cryopreserved embryos (p = .03) were obtained in the Study Group. No significant differences in biochemical or clinical pregnancy, live birth, and miscarriage rates were revealed, but a trend to a higher live birth rate was revealed in the Study Group. CONCLUSIONS A 3 months period of dietary supplementation with a resveratrol-based multivitamin nutraceutical leads to better biological effects on ICSI cycles. TRIAL REGISTRATION NUMBER ClinicalTrials.gov registration identifier: NCT04386499.
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Affiliation(s)
- Sandro Gerli
- Department of Medicine and Surgery, Centre of Perinatal and Reproductive Medicine, University of Perugia, Perugia, Italy.,Centre of Assisted Reproductive Technologies, S. Maria della Misericordia Hospital, Perugia, Italy
| | - Chiara Della Morte
- Department of Medicine and Surgery, Centre of Perinatal and Reproductive Medicine, University of Perugia, Perugia, Italy.,Centre of Assisted Reproductive Technologies, S. Maria della Misericordia Hospital, Perugia, Italy
| | - Margherita Ceccobelli
- Department of Medicine and Surgery, Centre of Perinatal and Reproductive Medicine, University of Perugia, Perugia, Italy.,Centre of Assisted Reproductive Technologies, S. Maria della Misericordia Hospital, Perugia, Italy
| | - Monica Mariani
- Centre of Assisted Reproductive Technologies, S. Maria della Misericordia Hospital, Perugia, Italy
| | | | - Lucio Leonardi
- Department of R&D, S&R Farmaceutici S.p.A Bastia Umbra, Perugia, Italy
| | - Alessandro Lanti
- Department of R&D, S&R Farmaceutici S.p.A Bastia Umbra, Perugia, Italy
| | | | - Bernard Fioretti
- Centre of Assisted Reproductive Technologies, S. Maria della Misericordia Hospital, Perugia, Italy.,Department of Chemistry, Biology and Biotechnologies, University of Perugia, Perugia, Italy
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27
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Timóteo-Ferreira F, Abreu D, Mendes S, Matos L, Rodrigues A, Almeida H, Silva E. Redox imbalance in age-related ovarian dysfunction and perspectives for its prevention. Ageing Res Rev 2021; 68:101345. [PMID: 33894395 DOI: 10.1016/j.arr.2021.101345] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/07/2021] [Accepted: 04/16/2021] [Indexed: 12/17/2022]
Abstract
The age at which women have their first child is increasing. This change represents a major health problem to society because advanced maternal age is related with a decay in fertility and an increase in the incidence of a variety of pregnancy complications and offspring health issues. The ovary stands as the main contributor for female reproductive ageing because of the progressive age-related decrease in follicle number and oocyte quality. Loss of redox homeostasis and establishment of an ovarian oxidative microenvironment are seen as major underlying causes for such downfall and impairment of ovarian function. Thus, the use of antioxidants to preserve fertility became an important field of research. In this review, new insights on mechanisms underlying the establishment of oxidative stress and its repercussions on ovarian ageing are addressed, along with the current state of knowledge on antioxidant supplementation and its contribution for healthy ageing and extension of ovarian lifespan.
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28
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Iervolino M, Lepore E, Forte G, Laganà AS, Buzzaccarini G, Unfer V. Natural Molecules in the Management of Polycystic Ovary Syndrome (PCOS): An Analytical Review. Nutrients 2021; 13:nu13051677. [PMID: 34063339 PMCID: PMC8156462 DOI: 10.3390/nu13051677] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/12/2021] [Accepted: 05/12/2021] [Indexed: 02/07/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is a heterogenous disorder characterized by chronic ovulation dysfunction and hyperandrogenism. It is considered the most common endocrinological disorder, affecting up to 25% of women of reproductive age, and associated with long-term metabolic abnormalities predisposing to cardiovascular risk, such as insulin resistance (IR), dyslipidemia, endothelial dysfunction, and systemic inflammation. PCOS is also characterized by elevated serum levels of luteinizing hormone (LH), causing a condition of hyperandrogenism and a consequent altered ratio between LH and the follicle stimulating hormone (FSH). Over the years, several different approaches have been proposed to alleviate PCOS symptoms. Supplementation with natural molecules such as inositols, resveratrol, flavonoids and flavones, vitamin C, vitamin E and vitamin D, and omega-3 fatty acids may contribute to overcoming PCOS pathological features, including the presence of immature oocyte, IR, hyperandrogenism, oxidative stress and inflammation. This review provides a comprehensive overview of the current knowledge about the efficacy of natural molecule supplementation in the management of PCOS.
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Affiliation(s)
- Matteo Iervolino
- R&D Department, Lo.Li. Pharma Srl, 00156 Rome, Italy; (M.I.); (E.L.); (G.F.)
| | - Elisa Lepore
- R&D Department, Lo.Li. Pharma Srl, 00156 Rome, Italy; (M.I.); (E.L.); (G.F.)
| | - Gianpiero Forte
- R&D Department, Lo.Li. Pharma Srl, 00156 Rome, Italy; (M.I.); (E.L.); (G.F.)
| | - Antonio Simone Laganà
- Department of Obstetrics and Gynecology, “Filippo Del Ponte” Hospital, University of Insubria, 2100 Varese, Italy;
- The Experts Group on Inositol in Basic and Clinical Research (EGOI), 00156 Rome, Italy
| | - Giovanni Buzzaccarini
- Unit of Gynecology and Obstetrics, Department of Women and Children’s Health, University of Padua, 35128 Padua, Italy;
| | - Vittorio Unfer
- The Experts Group on Inositol in Basic and Clinical Research (EGOI), 00156 Rome, Italy
- Systems Biology Group Lab, Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
- Correspondence:
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29
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Kuroda K, Nakagawa K, Horikawa T, Moriyama A, Ojiro Y, Takamizawa S, Ochiai A, Matsumura Y, Ikemoto Y, Yamaguchi K, Sugiyama R. Increasing number of implantation failures and pregnancy losses associated with elevated Th1/Th2 cell ratio. Am J Reprod Immunol 2021; 86:e13429. [PMID: 33835626 DOI: 10.1111/aji.13429] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 03/01/2021] [Accepted: 04/06/2021] [Indexed: 12/16/2022] Open
Abstract
PROBLEM We aimed to assess whether an imbalance of T-helper (Th) 1 and Th2 cells contributes to implantation failure and pregnancy loss. METHOD OF STUDY In this cross-sectional study, 197 consecutive patients with a history of repeated implantation failure (RIF) after three or more embryo transfer (ET) cycles and/or recurrent pregnancy loss (RPL) after two or more clinical pregnancy losses underwent Th cell testing. After excluding 42 women aged ≥44 and 9 with vitamin D supplementation, we recruited 146 women including 79 with RIF and 81 with RPL. Fourteen women had a history of both RIF and RPL. We also recruited 45 fertile women and 40 general infertile women without a history of in vitro fertilization treatment. This study was approved by the local ethics committee. RESULTS There was no significant difference in IFN-γ-producing Th1 and IL-4-producing Th2 cell levels between the fertile and general infertile women, but Th1 cell levels and the Th1/Th2 cell ratio were significantly higher in the women with ≥4 ET cycles and ≥2 pregnancy losses than in the fertile and general infertile women. In the general infertile women, the total livebirth rates including natural conception after two ET cycles in the normal and high Th1/Th2 groups (Th1/Th2 <11.8 and ≥11.8, respectively) were 66.7% and 87.5%, respectively (p = .395). CONCLUSIONS A high Th1/Th2 cell ratio was linked to ≥4 implantation failure cycles and ≥2 pregnancy losses but not to general infertility.
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Affiliation(s)
- Keiji Kuroda
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan.,Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Koji Nakagawa
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan
| | - Takashi Horikawa
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan
| | - Azusa Moriyama
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan
| | - Yuko Ojiro
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan
| | - Satoru Takamizawa
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan
| | - Asako Ochiai
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yuko Matsumura
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yuko Ikemoto
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Koushi Yamaguchi
- Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo, Japan
| | - Rikikazu Sugiyama
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan
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30
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Imanaka S, Shigetomi H, Kobayashi H. Reprogramming of glucose metabolism of cumulus cells and oocytes and its therapeutic significance. Reprod Sci 2021; 29:653-667. [PMID: 33675030 DOI: 10.1007/s43032-021-00505-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/21/2021] [Indexed: 12/17/2022]
Abstract
The aim of this review is to summarize our current understanding of the molecular mechanism for the glucose metabolism, especially pyruvate dehydrogenase (PDH), during oocyte maturation, as well as future perspectives of therapeutic strategies for aging focusing on metabolic regulation between aerobic glycolysis and the tricarboxylic acid (TCA) cycle/oxidative phosphorylation (OXPHOS). Each keyword alone or in combination was used to search from PubMed. Glucose metabolism is a dynamic process involving "On" and "Off" switches by the pyruvate dehydrogenase kinase (PDK)-PDH axis, which is crucial for energy metabolism and mitochondrial efficiency in cumulus cell differentiation and oocyte maturation. Activation of PDK suppresses the conversion of pyruvate to acetyl-coenzyme A (acetyl-CoA) through the inactivation of PDH, which allows the cumulus cells to supply sufficient amounts of pyruvate, lactate, and nicotinamide adenine dinucleotide phosphate (NADPH) to the oocytes. On the other hand, inactivation of PDK in oocytes can produce adenosine triphosphate (ATP) through a metabolic shift from aerobic glycolysis to the TCA cycle/OXPHOS. The metabolic balance between aerobic glycolysis and TCA cycle/OXPHOS presents us with a number of enzymes, ligands, receptors, and antioxidants that are potential therapeutic targets, some of which have already been successfully pursued to improve fertility outcomes. However, there are also many reports that question their efficacy. In conclusion, understanding the molecular mechanisms involved in the PDK-PDH axis is a crucial step to advance in novel therapeutic strategies to improve oocyte quality.
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Affiliation(s)
- Shogo Imanaka
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan.,Ms.Clinic MayOne, Kashihara, Japan
| | - Hiroshi Shigetomi
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan.,Aska Ladies Clinic, Nara, Japan
| | - Hiroshi Kobayashi
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan. .,Ms.Clinic MayOne, Kashihara, Japan.
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31
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Zabihi A, Shabankareh HK, Hajarian H, Foroutanifar S. In vitro maturation medium supplementation with resveratrol improves cumulus cell expansion and developmental competence of Sanjabi sheep oocytes. Livest Sci 2021. [DOI: 10.1016/j.livsci.2020.104378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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32
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Palomba S, Piltonen TT, Giudice LC. Endometrial function in women with polycystic ovary syndrome: a comprehensive review. Hum Reprod Update 2020; 27:584-618. [PMID: 33302299 DOI: 10.1093/humupd/dmaa051] [Citation(s) in RCA: 201] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/29/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. An endometrial component has been suggested to contribute to subfertility and poor reproductive outcomes in affected women. OBJECTIVE AND RATIONALE The aim of this review was to determine whether there is sufficient evidence to support that endometrial function is altered in women with PCOS, whether clinical features of PCOS affect the endometrium, and whether there are evidence-based interventions to improve endometrial dysfunction in PCOS women. SEARCH METHODS An extensive literature search was performed from 1970 up to July 2020 using PubMed and Web of Science without language restriction. The search included all titles and abstracts assessing a relationship between PCOS and endometrial function, the role played by clinical and biochemical/hormonal factors related to PCOS and endometrial function, and the potential interventions aimed to improve endometrial function in women with PCOS. All published papers were included if considered relevant. Studies having a specific topic/hypothesis regarding endometrial cancer/hyperplasia in women with PCOS were excluded from the analysis. OUTCOMES Experimental and clinical data suggest that the endometrium differs in women with PCOS when compared to healthy controls. Clinical characteristics related to the syndrome, alone and/or in combination, may contribute to dysregulation of endometrial expression of sex hormone receptors and co-receptors, increase endometrial insulin-resistance with impaired glucose transport and utilization, and result in chronic low-grade inflammation, immune dysfunction, altered uterine vascularity, abnormal endometrial gene expression and cellular abnormalities in women with PCOS. Among several interventions to improve endometrial function in women with PCOS, to date, only lifestyle modification, metformin and bariatric surgery have the highest scientific evidence for clinical benefit. WIDER IMPLICATIONS Endometrial dysfunction and abnormal trophoblast invasion and placentation in PCOS women can predispose to miscarriage and pregnancy complications. Thus, patients and their health care providers should advise about these risks. Although currently no intervention can be universally recommended to reverse endometrial dysfunction in PCOS women, lifestyle modifications and metformin may improve underlying endometrial dysfunction and pregnancy outcomes in obese and/or insulin resistant patients. Bariatric surgery has shown its efficacy in severely obese PCOS patients, but a careful evaluation of the benefit/risk ratio is warranted. Large scale randomized controlled clinical trials should address these possibilities.
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Affiliation(s)
- Stefano Palomba
- Unit of Obstetrics and Gynecology, Grande Ospedale Metropolitano of Reggio Calabria, Reggio Calabria, Italy
| | - Terhi T Piltonen
- Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Linda C Giudice
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA, USA
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Rodríguez-Varela C, Labarta E. Clinical Application of Antioxidants to Improve Human Oocyte Mitochondrial Function: A Review. Antioxidants (Basel) 2020; 9:antiox9121197. [PMID: 33260761 PMCID: PMC7761442 DOI: 10.3390/antiox9121197] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/24/2020] [Accepted: 11/25/2020] [Indexed: 12/11/2022] Open
Abstract
Mitochondria produce adenosine triphosphate (ATP) while also generating high amounts of reactive oxygen species (ROS) derived from oxygen metabolism. ROS are small but highly reactive molecules that can be detrimental if unregulated. While normally functioning mitochondria produce molecules that counteract ROS production, an imbalance between the amount of ROS produced in the mitochondria and the capacity of the cell to counteract them leads to oxidative stress and ultimately to mitochondrial dysfunction. This dysfunction impairs cellular functions through reduced ATP output and/or increased oxidative stress. Mitochondrial dysfunction may also lead to poor oocyte quality and embryo development, ultimately affecting pregnancy outcomes. Improving mitochondrial function through antioxidant supplementation may enhance reproductive performance. Recent studies suggest that antioxidants may treat infertility by restoring mitochondrial function and promoting mitochondrial biogenesis. However, further randomized, controlled trials are needed to determine their clinical efficacy. In this review, we discuss the use of resveratrol, coenzyme-Q10, melatonin, folic acid, and several vitamins as antioxidant treatments to improve human oocyte and embryo quality, focusing on the mitochondria as their main hypothetical target. However, this mechanism of action has not yet been demonstrated in the human oocyte, which highlights the need for further studies in this field.
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Affiliation(s)
- Cristina Rodríguez-Varela
- IVI Foundation—IIS La Fe, Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026 Valencia, Spain;
- Correspondence:
| | - Elena Labarta
- IVI Foundation—IIS La Fe, Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026 Valencia, Spain;
- IVIRMA Valencia, Plaza de la Policía Local 3, 46015 Valencia, Spain
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Kuroda K, Horikawa T, Moriyama A, Nakao K, Juen H, Takamizawa S, Ojiro Y, Nakagawa K, Sugiyama R. Impact of chronic endometritis on endometrial receptivity analysis results and pregnancy outcomes. IMMUNITY INFLAMMATION AND DISEASE 2020; 8:650-658. [PMID: 32969185 PMCID: PMC7654412 DOI: 10.1002/iid3.354] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/08/2020] [Accepted: 09/13/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND The aim of this study is to evaluate the relationship between chronic endometritis (CE) and a personalized window of implantation (WOI), identified by results of endometrial receptivity analysis (ERA), and pregnancy outcomes following embryo transfer (ET) based on the ERA outcomes. METHODS The single-center, cross-sectional study was designed. The study population consisted of 101 infertile women who underwent endometrial sampling between June 2018 and February 2020. We recruited 88 patients who underwent ERA testing and immunohistochemistry of the plasma cell marker CD138 to diagnose CE within 3 months of testing. Subjects were divided into three groups as follows: 33 without CE (non-CE group); 19 with untreated CE at ERA testing (CE group); and 36 successfully treated for CE before ERA testing (cured-CE group). CE diagnosis was defined as ≥5 CD138-positive plasma cells per 10 random stromal areas at ×400 magnification. RESULTS In non-CE, CE, and cured-CE groups, the numbers of CD138-positive cells were 0.7 ± 1.0, 28.5 ± 30.4, and 1.3 ± 1.3, respectively (p < .001). The rates of "receptive" endometrium in non-CE and cured-CE groups were 57.6% (19 women) and 50.0% (18 women), respectively; however, in the CE group, this rate was significantly lower than the other two groups (p = .009) at only 15.8% (3 women). After CE were treated prior or posterior to the ERA test in cured-CE or CE groups, the clinical pregnancy rates at the first ET in non-CE, CE, and cured-CE groups were 77.8% (21/27 cycles), 22.2% (4/18 cycles), and 51.7% (15/29 cycles), respectively (p < 0.001). CONCLUSION CE had detrimental effects on the individual WOI, leading to embryo-endometrial asynchrony; therefore, diagnosis and treatment of CE should be done before ERA testing.
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Affiliation(s)
- Keiji Kuroda
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan.,Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Takashi Horikawa
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan
| | - Azusa Moriyama
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan
| | - Kazuki Nakao
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan
| | - Hiroyasu Juen
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan
| | - Satoru Takamizawa
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan
| | - Yuko Ojiro
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan
| | - Koji Nakagawa
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan
| | - Rikikazu Sugiyama
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan
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Kuroda K, Ochiai A, Brosens JJ. The actions of resveratrol in decidualizing endometrium: acceleration or inhibition?†. Biol Reprod 2020; 103:1152-1156. [PMID: 33029621 DOI: 10.1093/biolre/ioaa172] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/09/2020] [Accepted: 09/17/2020] [Indexed: 12/20/2022] Open
Abstract
Resveratrol, a natural polyphenolic compound, is widely studied for its anti-inflammatory and antisenescent properties. Recently, two studies reported seemingly conflicting findings on the actions of resveratrol on decidualization of human endometrial stromal cells (HESCs). One study by Ochiai et al. demonstrated that resveratrol inhibits decidual transformation of primary cultured HESCs. The other study by Mestre Citrinovitz et al., showed that resveratrol enhances decidualization of HESCs in culture. At a glance, the reason for these opposing observations seems puzzling. However, recent studies demonstrated that decidualization is a multistep process, which starts with an acute proinflammatory stress response that lasts for several days and is followed by the emergence of stress-resistant decidual cells as well as senescent decidual cells. The balance between these decidual subpopulations may determine if the cycling endometrium can successfully transition into the decidua of pregnancy upon embryo implantation. Here, we explore the importance of timing of drugs aimed at modulating the decidual response. We posit that resveratrol treatment during the initial proinflammatory decidual phase, i.e., coinciding with the implantation window in vivo, inhibits decidual transformation of the endometrium. However, when given after the initial phase, resveratrol may promote decidualization by inhibiting decidual senescence. Further, if restricted to the proliferative phase, resveratrol may promote ovarian function without adversely impacting on embryo implantation or decidualization. Thus, failure to align drug interventions with the correct phase of the menstrual cycle may negate beneficial clinical effects and results in adverse reproductive outcomes.
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Affiliation(s)
- Keiji Kuroda
- Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan.,Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Asako Ochiai
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Jan J Brosens
- The Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, Coventry, UK.,Tommy's National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire, Coventry, UK
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Effects of Supplementation with Natural Antioxidants on Oocytes and Preimplantation Embryos. Antioxidants (Basel) 2020; 9:antiox9070612. [PMID: 32664650 PMCID: PMC7402117 DOI: 10.3390/antiox9070612] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 07/03/2020] [Accepted: 07/04/2020] [Indexed: 12/12/2022] Open
Abstract
For most infertile couples, in vitro fertilization (IVF) represents the only chance to conceive. Given the limited success of IVF procedures, novel approaches are continuously tested with the aim of improving IVF outcomes. Growing attention is devoted today to the potential benefit of natural antioxidants in the optimization of infertility treatments. This review summarizes current data in this context, focusing on both experimental studies on oocytes/embryos and clinical trials on antioxidants supplementation. Based on information gained from experimental studies, antioxidant supplementation may have beneficial effects on IVF outcomes in terms of quality and cryotolerance of in vitro produced embryos, together with positive effects on in vitro maturation oocytes and on early embryonic development. Unfortunately, from the clinical side, there is a paucity of evidence favoring the protective qualities of antioxidants. Among the antioxidants considered, coenzyme Q10 may be regarded as one of the most promising for its positive role in rescuing the oxidative stress-induced damages, but further data are needed. It is concluded that further trials are necessary to characterize the potential clinical value of antioxidants in IVF treatments.
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Ochiai A, Kuroda K. Preconception resveratrol intake against infertility: Friend or foe? Reprod Med Biol 2020; 19:107-113. [PMID: 32273814 PMCID: PMC7138940 DOI: 10.1002/rmb2.12303] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 09/20/2019] [Accepted: 09/25/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Resveratrol is an antiaging, antioxidant, anti-inflammatory, and insulin-sensitizing natural polyphenolic compound. Growing evidence indicates that resveratrol has potential therapeutic effects in infertile women with diminished ovarian function, polycystic ovary syndrome (PCOS), or endometriosis. However, only one clinical trial in women undergoing in vitro fertilization (IVF) cycles using resveratrol has ever been reported. This review focuses on the potential therapeutic effects of resveratrol on pregnancy and on its advantages and disadvantages in pregnancy outcomes during infertility treatment. METHODS We performed a literature review to describe the known impacts of resveratrol on the ovary and endometrium. RESULTS Resveratrol upregulates sirtuin (SIRT)1 expression in ovaries, which is associated with protection against oxidative stress. It leads to the activation of telomerase activity and mitochondrial function, improving ovarian function. In the endometrium, resveratrol downregulates the CRABP2-RAR pathway leading to suppressing decidual and senescent changes of endometrial cells, which is essential for embryo implantation and placentation. Moreover, resveratrol may also induce deacetylation of important decidual-related genes. CONCLUSIONS Resveratrol has potential therapeutic effects for improving ovarian function; however, it also has anti-deciduogenic actions in uterine endometrium. In addition, its teratogenicity has not yet been ruled out; thus, resveratrol should be avoided during the luteal phase and pregnancy.
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Affiliation(s)
- Asako Ochiai
- Department of Obstetrics and GynecologyFaculty of MedicineJuntendo UniversityTokyoJapan
| | - Keiji Kuroda
- Department of Obstetrics and GynecologyFaculty of MedicineJuntendo UniversityTokyoJapan
- Center for Reproductive Medicine and Implantation ResearchSugiyama Clinic ShinjukuTokyoJapan
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Deryabin P, Griukova A, Nikolsky N, Borodkina A. The link between endometrial stromal cell senescence and decidualization in female fertility: the art of balance. Cell Mol Life Sci 2020; 77:1357-1370. [PMID: 31728580 PMCID: PMC11104872 DOI: 10.1007/s00018-019-03374-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 12/21/2022]
Abstract
Cell senescence seems to be an ambivalent biological phenomenon in many aspects. At the cellular level it is considered as an irreversible cell-cycle arrest commonly caused by the DNA damage. Senescent cells harbor a lot of impairments in various intracellular systems. Presence of senescent cells within tissues should ultimately lead to their malfunctioning. However, the interlink between cellular senescence and tissue/organismal functioning is far from always being unidirectional. The entangled and complex relationship between senescence and tissue-specific decidual differentiation of endometrial stromal cells (ESCs) is the excellent example reflecting dualism of cellular senescence. ESCs decidualization conditions endometrium responsiveness to embryonic signals and plays a critical role in embryo biosensoring, selection and implantation. Based on the analysis of the existing literary data, here we will try (1) to puzzle out how cellular senescence simultaneously may be an integral part of normal decidualization and may be involved in the progression of repeated implantation failures and recurrent pregnancy losses; (2) to suppose the sequence of cellular events reflecting the role of ESCs' senescence during normal and impaired decidualization. Together, the deep scan of the interlink between ESCs' senescence and decidualization will allow to suggest the preferable application scheme for senolytics targeting senescent cells as a possible approach to restore impaired endometrial receptivity and thus to increase the effectiveness of in vitro fertilization cycles.
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Affiliation(s)
- Pavel Deryabin
- Department of Intracellular Signaling and Transport, Institute of Cytology of the Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064, St-Petersburg, Russia
| | - Anastasiia Griukova
- Department of Intracellular Signaling and Transport, Institute of Cytology of the Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064, St-Petersburg, Russia
| | - Nikolay Nikolsky
- Department of Intracellular Signaling and Transport, Institute of Cytology of the Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064, St-Petersburg, Russia
| | - Aleksandra Borodkina
- Department of Intracellular Signaling and Transport, Institute of Cytology of the Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064, St-Petersburg, Russia.
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Huang J, Kuang Y. Is it too early to deny resveratrol supplementation in embryo transfer cycles? Reprod Biomed Online 2019; 39:177. [PMID: 31078420 DOI: 10.1016/j.rbmo.2019.04.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 04/11/2019] [Indexed: 11/29/2022]
Affiliation(s)
- Jialyu Huang
- Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Yanping Kuang
- Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
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