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For:	Committee Opinion No. 605: Primary Ovarian Insufficiency in Adolescents and Young Women. Obstet Gynecol 2014;124:193-7. [DOI: 10.1097/01.aog.0000451757.51964.98] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]

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Cited by Other Article(s)

Hosseinpour F, Zeinolabedini Hezave A, Talaei-Khozani T, Rastgou-Maeini M, Hassanpour-Dehnavi A. Preparation and characterization of human decellularized ovarian scaffold based on supercritical carbon dioxide protocol. Biomed Eng Online 2025;24:59. [PMID: 40361140 PMCID: PMC12070545 DOI: 10.1186/s12938-025-01392-7] [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: 01/10/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025] Open

Abstract

BACKGROUND

Primary ovarian insufficiency affecting 1-3% of women under 40, causes premature menopause and estrogen deficiency. With increasing life expectancy, a large percentage of women also face estrogen-related symptoms. A bioengineered ovary is one of the strategies to replace or enhance ovarian tissue function. A key advancement in bioengineering is the development of ovarian decellularized extracellular matrix scaffolds that mimic natural ovarian niche. Recent studies indicate that supercritical carbon dioxide (scCo2), with a density comparable to liquids and viscosity and diffusion coefficients properties similar to gases, holds substantial promise for application in engineered scaffolds. Therefore, we established a human decellularized ovarian scaffold based on a scCo2 process, as an optimized protocol.

METHODS

We evaluated two distinct pressure conditions (200 and 300 bar), while maintaining identical thermal (40 °C) and temporal (1.5 h) parameters, during the scCO2 decellularization process. In addition, two modifications were implemented to identify the most optimal protocol for enhancing the decellularization process: the inclusion of 70% ethanol as a co-solvent and the application of 1% sodium dodecyl sulfate (SDS) as a pretreatment for 4 h while utilizing the scCO2 system under the previously established conditions. Cell removal was confirmed by DNA quantification and H&E staining. Extracellular matrix structure evaluated by histological staining and scanning electron microscopy (SEM). Glycosaminoglycans (GAGs) content was quantified using a dimethyl methylene blue assay following extraction with HCL and MTT test was conducted to evaluate scaffold's cytocompatibility.

RESULTS

Application of 1% SDS, while utilizing the scCO2 system at 200 bar and 40 °C for 1.5 h, established an optimal protocol for preserving the essential characteristics of the ovarian ECM. This protocol is able to meet previously established decellularization criteria and histological staining and SEM showed that the ECM architecture was satisfactorily preserved. GAGs quantification indicated adequate preservation of GAGs content. Finally, MTT test presented the scaffolds had suitable cytocompatibility.

CONCLUSIONS

We propose an optimal protocol utilizing 1% SDS as a pretreatment, followed by the scCO2 system. This protocol addresses common challenges associated with traditional decellularization methods and presents a promising avenue for advancing ovarian tissue engineering applications.

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Baker KM, FernandezCriado R, Eaton JL, Mensah VA. The Clinical Utility of Measures of Ovarian Reserve. Obstet Gynecol Surv 2025;80:121-133. [PMID: 39924338 DOI: 10.1097/ogx.0000000000001362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]

Cipres DT, Gordon CM. Primary Ovarian Insufficiency, Bone Health, and Other Outcomes in Adolescents. Obstet Gynecol Clin North Am 2024;51:663-678. [PMID: 39510737 PMCID: PMC11566969 DOI: 10.1016/j.ogc.2024.08.004] [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] [Indexed: 11/15/2024]

Tang S, Guo T, Song C, Wang L, Zhang J, Rajkovic A, Lin X, Chen S, Liu Y, Tian W, Wu B, Wang S, Wang W, Lai Y, Wang A, Xu S, Jin L, Ke H, Zhao S, Li Y, Qin Y, Zhang F, Chen ZJ. MGA loss-of-function variants cause premature ovarian insufficiency. J Clin Invest 2024;134:e183758. [PMID: 39545409 PMCID: PMC11563689 DOI: 10.1172/jci183758] [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: 06/11/2024] [Accepted: 09/20/2024] [Indexed: 11/17/2024] Open

Affiliation(s)

Shuyan Tang Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Institute of Medical Genetics and Genomics, Fudan University, Shanghai, China
Ting Guo State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, China
Chengcheng Song Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Institute of Medical Genetics and Genomics, Fudan University, Shanghai, China
Lingbo Wang Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Institute of Medical Genetics and Genomics, Fudan University, Shanghai, China Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
Jun Zhang Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
Aleksandar Rajkovic Department of Pathology, Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California, USA
Xiaoqi Lin Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Institute of Medical Genetics and Genomics, Fudan University, Shanghai, China
Shiling Chen Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
Yujun Liu Human Phenome Institute, Zhangjiang Fudan International Innovation Center and
Weidong Tian School of Life Sciences, Fudan University, Shanghai, China
Bangguo Wu Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
Shixuan Wang Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Wenwen Wang Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Yunhui Lai Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
Ao Wang Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
Shuhua Xu Human Phenome Institute, Zhangjiang Fudan International Innovation Center and School of Life Sciences, Fudan University, Shanghai, China
Li Jin Human Phenome Institute, Zhangjiang Fudan International Innovation Center and School of Life Sciences, Fudan University, Shanghai, China
Hanni Ke Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Institute of Medical Genetics and Genomics, Fudan University, Shanghai, China State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, China
Shidou Zhao State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, China
Yan Li Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Yingying Qin State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, China
Feng Zhang Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Institute of Medical Genetics and Genomics, Fudan University, Shanghai, China Human Phenome Institute, Zhangjiang Fudan International Innovation Center and Shanghai Key Laboratory of Embryo Original Diseases, Soong Ching Ling Institute of Maternity and Child Health, International Peace Maternity and Child Health Hospital of China Welfare Institute, Shanghai, China
Zi-Jiang Chen State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, China Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (no. 2021RU001), Jinan, China Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China

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Grosu-Bularda A, Lita FF, Hodea FV, Bordeanu-Diaconescu EM, Cretu A, Dumitru CS, Cacior S, Marinescu BM, Lascar I, Hariga CS. Navigating the Complexities of Radiation Injuries: Therapeutic Principles and Reconstructive Strategies. J Pers Med 2024;14:1100. [PMID: 39590592 PMCID: PMC11595796 DOI: 10.3390/jpm14111100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/21/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open

Affiliation(s)

Andreea Grosu-Bularda Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.) Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
Flavia-Francesca Lita Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania Clinical Department Plastic Surgery and Reconstructive Microsurgery, Central Military Emergency University Hospital “Dr. Carol Davila”, 010825 Bucharest, Romania
Florin-Vlad Hodea Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.) Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
Eliza-Maria Bordeanu-Diaconescu Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.) Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
Andrei Cretu Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.) Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
Catalina-Stefania Dumitru Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.) Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
Stefan Cacior Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.) Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
Bogdan-Mihai Marinescu Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.) Clinical Department Plastic Surgery and Reconstructive Microsurgery, Central Military Emergency University Hospital “Dr. Carol Davila”, 010825 Bucharest, Romania
Ioan Lascar Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.) Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
Cristian-Sorin Hariga Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.) Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania

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Yang Z, Huang N, Zhuang Z, Jin M, Zhang Z, Song Y, Cui H, Zhang S, Huang T, Liu X, Li N. Earlier Age at Menopause, Plasma Metabolome, and Risk of Premature Mortality. Metabolites 2024;14:571. [PMID: 39590807 PMCID: PMC11596455 DOI: 10.3390/metabo14110571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/17/2024] [Accepted: 10/21/2024] [Indexed: 11/28/2024] Open

Affiliation(s)

Zeping Yang Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing 100191, China; (Z.Y.); (N.H.); (Z.Z.); (M.J.); (Z.Z.); (Y.S.); (T.H.)
Ninghao Huang Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing 100191, China; (Z.Y.); (N.H.); (Z.Z.); (M.J.); (Z.Z.); (Y.S.); (T.H.)
Zhenhuang Zhuang Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing 100191, China; (Z.Y.); (N.H.); (Z.Z.); (M.J.); (Z.Z.); (Y.S.); (T.H.)
Ming Jin Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing 100191, China; (Z.Y.); (N.H.); (Z.Z.); (M.J.); (Z.Z.); (Y.S.); (T.H.)
Ziyi Zhang Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing 100191, China; (Z.Y.); (N.H.); (Z.Z.); (M.J.); (Z.Z.); (Y.S.); (T.H.)
Yimin Song Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing 100191, China; (Z.Y.); (N.H.); (Z.Z.); (M.J.); (Z.Z.); (Y.S.); (T.H.)
Haoliang Cui Department of Global Health, School of Public Health, Peking University, Beijing 100191, China;
Shan Zhang Department of Health Policy and Management, School of Public Health, Peking University, Beijing 100191, China;
Tao Huang Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing 100191, China; (Z.Y.); (N.H.); (Z.Z.); (M.J.); (Z.Z.); (Y.S.); (T.H.) Key Laboratory of Epidemiology of Major Diseases, Peking University, Ministry of Education, Beijing 100191, China Center for Intelligent Public Health, Institute for Artificial Intelligence, Peking University, Beijing 100191, China
Xiaojing Liu Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing 100191, China; (Z.Y.); (N.H.); (Z.Z.); (M.J.); (Z.Z.); (Y.S.); (T.H.)
Nan Li Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing 100191, China; (Z.Y.); (N.H.); (Z.Z.); (M.J.); (Z.Z.); (Y.S.); (T.H.)

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Le DC, Ngo MHT, Kuo YC, Chen SH, Lin CY, Ling TY, Pham QTT, Au HK, Myung J, Huang YH. Secretome from estrogen-responding human placenta-derived mesenchymal stem cells rescues ovarian function and circadian rhythm in mice with cyclophosphamide-induced primary ovarian insufficiency. J Biomed Sci 2024;31:95. [PMID: 39390588 PMCID: PMC11468397 DOI: 10.1186/s12929-024-01085-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 09/11/2024] [Indexed: 10/12/2024] Open

Abstract

BACKGROUND

Primary ovarian insufficiency (POI) is an early decline in ovarian function that leads to ovarian failure. Conventional treatments for POI are inadequate, and treatments based on mesenchymal stem cells (MSCs) have emerged as an option. However, the lack of consideration of the estrogen niche in ovarian tissue significantly reduces the therapeutic efficacy, with an unclear mechanism in the MSCs in POI treatment. Furthermore, the disruption of circadian rhythm associated with POI has not been previously addressed.

METHODS

Conditioned medium (CM) and estradiol-conditioned medium (E2-CM) were generated from estrogen receptor positive MSCs (ER+pcMSCs). Chemotherapy-induced POI models were established using C57BL/6 mice (in vivo) and KGN cells (in vitro) treated with cyclophosphamide (CTX) or 4-hydroperoxycyclophosphamide (4-OOH-CP). Gene/protein expressions were detected using RT-qPCR, Western blotting, and immunohistochemistry assays. Locomotor activity was monitored for behavioral circadian rhythmicity. Cytokine arrays and miRNA analysis were conducted to analyze potential factors within CM/E2-CM.

RESULTS

The secretome of ER+pcMSCs (CM and E2-CM) significantly reduced the CTX-induced defects in ovarian folliculogenesis and circadian rhythm. CM/E2-CM also reduced granulosa cell apoptosis and rescued angiogenesis in POI ovarian tissues. E2-CM had a more favorable effect than the CM. Notably, ER+pcMSC secretome restored CTX-induced circadian rhythm defects, including the gene expressions associated with the ovarian circadian clock (e.g., Rora, E4bp4, Rev-erbα, Per2 and Dbp) and locomotor activity. Additionally, the cytokine array analysis revealed a significant increase in cytokines and growth factors associated with immunomodulation and angiogenesis, including angiogenin. Neutralizing the angiogenin in CM/E2-CM significantly reduced its ability to promote HUVEC tube formation in vitro. Exosomal miRNA analysis revealed the miRNAs involved in targeting the genes associated with POI rescue (PTEN and PDCD4), apoptosis (caspase-3, BIM), estrogen synthesis (CYP19A1), ovarian clock regulation (E4BP4, REV-ERBα) and fibrosis (COL1A1).

CONCLUSION

This study is the first to demonstrate that, in considering the estrogen niche in ovarian tissue, an estrogen-priming ER+pcMSC secretome achieved ovarian regeneration and restored the circadian rhythm in a CTX-induced POI mouse model. The potential factors involved include angiogenin and exosomal miRNAs in the ER+pcMSC secretome. These findings offer insights into potential stem cell therapies for chemotherapy-induced POI and circadian rhythm disruption.

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Affiliation(s)

Duy-Cuong Le International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan Laboratory, Vinmec International Hospital, Minh Khai Street, Hai Ba Trung, Hanoi, Vietnam
Mai-Huong T Ngo Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
Yung-Che Kuo TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
Shu-Hwa Chen TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan
Chung-Yen Lin Institute of Information Science, Academia Sinica, Taipei, 11529, Taiwan Institute of Fishery Sciences, College of Life Science, National Taiwan University, Taipei, 10617, Taiwan Genome and Systems Biology Degree Program, National Taiwan University, Taipei, 10617, Taiwan
Thai-Yen Ling Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan
Quoc Thao Trang Pham International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
Heng-Kien Au International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, 11042, Taiwan. Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11042, Taiwan.
Jihwan Myung Graduate Institute of Mind, Brain and Consciousness, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. Brain and Consciousness Research Centre (BCRC), TMU-Shuang Ho Hospital, New Taipei City, 23561, Taiwan. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Wuxing Street, Taipei, 11031, Taiwan.
Yen-Hua Huang International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11042, Taiwan. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Wuxing Street, Taipei, 11031, Taiwan.

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Witham M, Hengel S. The role of RAD51 regulators and variants in primary ovarian insufficiency, endometriosis, and polycystic ovary syndrome. NAR MOLECULAR MEDICINE 2024;1:ugae010. [PMID: 39359934 PMCID: PMC11443433 DOI: 10.1093/narmme/ugae010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 09/09/2024] [Accepted: 09/26/2024] [Indexed: 10/04/2024]

Dilbaz B. Editorial: Fertility preservation. Front Glob Womens Health 2024;5:1452588. [PMID: 39188538 PMCID: PMC11345206 DOI: 10.3389/fgwh.2024.1452588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 07/15/2024] [Indexed: 08/28/2024] Open

Memi E, Pavli P, Papagianni M, Vrachnis N, Mastorakos G. Diagnostic and therapeutic use of oral micronized progesterone in endocrinology. Rev Endocr Metab Disord 2024;25:751-772. [PMID: 38652231 PMCID: PMC11294403 DOI: 10.1007/s11154-024-09882-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/04/2024] [Indexed: 04/25/2024]

Abstract

Progesterone is a natural steroid hormone, while progestins are synthetic molecules. In the female reproductive system, progesterone contributes to the control of luteinizing hormone and follicle-stimulating hormone secretion and their pulsatility, via its receptors on the kisspeptin, neurokinin B, and dynorphin neurons in the hypothalamus. Progesterone together with estradiol controls the cyclic changes of proliferation and decidualization of the endometrium; exerts anti-mitogenic actions on endometrial epithelial cells; regulates normal menstrual bleeding; contributes to fertilization and pregnancy maintenance; participates in the onset of labor. In addition, it exerts numerous effects on other endocrine systems. Micronized progesterone (MP) is natural progesterone with increased bioavailability, due to its pharmacotechnical micronized structure, which makes it an attractive diagnostic and therapeutic tool. This critical literature review aims to summarize and put forward the potential diagnostic and therapeutic uses of MP in the field of endocrinology. During reproductive life, MP is used for diagnostic purposes in the evaluation of primary or secondary amenorrhea as a challenge test. Moreover, it can be prescribed to women presenting with amenorrhea or oligomenorrhea for induction of withdrawal bleeding, in order to time blood-sampling for diagnostic purposes in early follicular phase. Therapeutically, MP, alone or combined with estrogens, is a useful tool in various endocrine disorders including primary amenorrhea, abnormal uterine bleeding due to disordered ovulation, luteal phase deficiency, premenstrual syndrome, polycystic ovary syndrome, secondary amenorrhea [functional hypothalamic amenorrhea, premature ovarian insufficiency], perimenopause and menopause. When administrated per os, acting as a neurosteroid directly or through its metabolites, it exerts beneficial effects on brain function such as alleviation of symptoms of anxiety and depression, asw well as of sleep problems, while it improves working memory in peri- and menopausal women. Micronized progesterone preserves full potential of progesterone activity, without presenting many of the side-effects of progestins. Although it has been associated with more frequent drowsiness and dizziness, it can be well tolerated with nocturnal administration. Because of its better safety profile, especially with regard to metabolic ailments, breast cancer risk and veno-thromboembolism risk, MP is the preferred option for individuals with an increased risk of cardiovascular and metabolic diseases and of all-cause mortality.

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Serota A, D’Erasmo G. Estrogen exposure and skeletal health: Special populations and considerations. JOURNAL OF THE PEDIATRIC ORTHOPAEDIC SOCIETY OF NORTH AMERICA 2024;7:100061. [PMID: 40433279 PMCID: PMC12088159 DOI: 10.1016/j.jposna.2024.100061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 04/03/2024] [Indexed: 05/29/2025]

Benor A, Decherney A. Gonadotropin-Releasing Hormone (GnRH) Agonists Do Not Protect Ovarian Function in Patients Undergoing Stem Cell Transplants. Cureus 2024;16:e58387. [PMID: 38756303 PMCID: PMC11097921 DOI: 10.7759/cureus.58387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/16/2024] [Indexed: 05/18/2024] Open

Abstract

Introduction Medical indications for fertility preservation include any malignancy, chronic illness, or disease that would require gonadotoxic chemotherapy or radiation (conditioning regimens), which would impede a woman's ability to conceive in the future. Thus, any patient who plans to undergo a gonadotoxic regimen is advised to cryopreserve oocytes or embryos, which can be used in the future at the patient's convenience. Attempts have been made to suppress ovarian function with gonadotropin-releasing hormone agonists (GnRH-a) to induce ovarian quiescence and, thereby, theoretically limit the gonadotoxic impact on the follicular pool. We explored the use of leuprolide (a type of GnRH-a) in preventing primary ovarian insufficiency (POI) in a cohort study of patients who underwent hematopoietic stem cell transplants (HSCT) at the National Institutes of Health (NIH); since the conditioning regimens for HSCT include cyclophosphamide and other gonadotoxic therapies, we hypothesized that GnRH-a would be ineffective in preventing POI. Methods We assessed patients who underwent fertility preservation prior to their stem cell transplant, as their follicular-stimulating hormone (FSH) levels were evaluated prior to and post-chemotherapy. Twenty-nine patients who underwent hormonal evaluation prior to and post-chemotherapy were included. The control group did not receive GnRH-a prior to chemotherapy, while the treatment group did receive GnRH-a pre-chemotherapy. Results Our data revealed that 80% of the control group had menopausal levels post-chemotherapy, while 91% of the treatment group still had menopausal levels post-chemotherapy (p=0.33). Conclusions Thus, our hypothesis that GnRH-a is ineffective in reducing the risk of POI in a cohort of patients who receive conditioning regimens for HSCT was confirmed.

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Persico T, Tranquillo ML, Seracchioli R, Zuccarello D, Sorrentino U. PGT-M for Premature Ovarian Failure Related to CGG Repeat Expansion of the FMR1 Gene. Genes (Basel) 2023;15:6. [PMID: 38275588 PMCID: PMC10815814 DOI: 10.3390/genes15010006] [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: 10/25/2023] [Revised: 12/14/2023] [Accepted: 12/15/2023] [Indexed: 01/27/2024] Open

Kim SM, Yoo JY, Hong YH, Lee J, Kim JH, Lee JR. The effect of growth hormone on ovarian function recovery in a mouse model of ovarian insufficiency. Front Endocrinol (Lausanne) 2023;14:1184977. [PMID: 37854196 PMCID: PMC10579899 DOI: 10.3389/fendo.2023.1184977] [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: 03/13/2023] [Accepted: 09/08/2023] [Indexed: 10/20/2023] Open

Abstract

Objectives

To evaluate the effects and mechanisms of action of growth hormone (GH) in the recovery of ovarian function in ovarian insufficiency induced by cyclophosphamide (CP) in a mouse model.

Materials and methods

After inducing ovarian insufficiency by administering 400 mg/kg of CP intraperitoneally to 6-week-old ICR mice, the mice were divided into four groups (control, CP, 1 mg/kg GH, and 2 mg/kg GH) with 10 mice in each group. GH was administered a week later for 7 days. Five mice from each group were sacrificed the next day, and their ovaries were collected for histological examination. The remaining mice were superovulated for in vitro fertilization (IVF). The terminal deoxynucleotidyl transferase dUTP-nick end labeling assay was performed to detect apoptosis. Masson's trichrome staining was used to analyze the degree of fibrosis. To quantify angiogenesis, CD31 immunohistochemistry was performed. Angiogenesis-related gene expression profiles were assessed using quantitative reverse transcription polymerase chain reaction.

Results

CP induced the loss of non-growing (primordial and primary) follicles while GH significantly protected primordial follicles and increased follicular quality. The CP group showed a decrease in fertilization and blastocyst formation rates in IVF. In contrast, the GH treatment group showed dose-dependent enhanced IVF outcomes. Furthermore, GH treatment decreased apoptosis and stromal fibrosis and increased angiogenesis. Many genes involved in angiogenesis, especially Leptin (Lep), platelet endothelial cell adhesion molecule 1 (Pecam-1), and angiogenin (Ang) were up-regulated in the GH treatment groups.

Conclusion

GH treatment may promote the recovery of ovarian function in ovarian insufficiency induced by the administration of CP via decreasing apoptosis and stromal fibrosis and upregulating Lep, Pecam-1, and Ang genes.

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Sütcüoğlu BM, Güler M. Appropriateness of premature ovarian insufficiency recommendations provided by ChatGPT. Menopause 2023;30:1033-1037. [PMID: 37671567 DOI: 10.1097/gme.0000000000002246] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/07/2023]

Nelson LM, Spencer H, Hijane K, Thinuan P, Nelson CW, Vincent AJ, Gordon CM, Plant TM, Fazeli PK. My 28 Days - a global digital women's health initiative for evaluation and management of secondary amenorrhea: case report and literature review. Front Endocrinol (Lausanne) 2023;14:1227253. [PMID: 37772077 PMCID: PMC10523024 DOI: 10.3389/fendo.2023.1227253] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/18/2023] [Indexed: 09/30/2023] Open

Abstract

There is a need to close the gap between knowledge and action in health care. Effective care requires a convenient and reliable distribution process. As global internet and mobile communication increase capacity, innovative approaches to digital health education platforms and care delivery are feasible. We report the case of a young African woman who developed acute secondary amenorrhea at age 18. Subsequently, she experienced a 10-year delay in the diagnosis of the underlying cause. A global digital medical hub focused on women's health and secondary amenorrhea could reduce the chance of such mismanagement. Such a hub would establish more efficient information integration and exchange processes to better serve patients, family caregivers, health care providers, and investigators. Here, we show proof of concept for a global digital medical hub for women's health. First, we describe the physiological control systems that govern the normal menstrual cycle, and review the pathophysiology and management of secondary amenorrhea. The symptom may lead to broad and profound health implications for the patient and extended family members. In specific situations, there may be significant morbidity related to estradiol deficiency: (1) reduced bone mineral density, 2) cardiovascular disease, and 3) cognitive decline. Using primary ovarian insufficiency (POI) as the paradigm condition, the Mary Elizabeth Conover Foundation has been able to address the specific global educational needs of these women. The Foundation did this by creating a professionally managed Facebook group specifically for these women. POI most commonly presents with secondary amenorrhea. Here we demonstrate the feasibility of conducting a natural history study on secondary amenorrhea with international reach to be coordinated by a global digital medical hub. Such an approach takes full advantage of internet and mobile device communication systems. We refer to this global digital women's health initiative as My 28 Days®.

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Hoefgen HR, Benoit J, Chan S, Jayasinghe Y, Lustberg M, Pohl V, Saraf A, Schmidt D, Appiah LC. Female reproductive health in pediatric, adolescent, and young adult cancer survivors. Pediatr Blood Cancer 2023;70 Suppl 5:e29170. [PMID: 37381166 DOI: 10.1002/pbc.29170] [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: 01/10/2021] [Revised: 05/02/2021] [Accepted: 05/11/2021] [Indexed: 06/30/2023]

Kakinuma K, Kakinuma T. Analysis of oxidative stress and antioxidative potential in premature ovarian insufficiency. World J Clin Cases 2023;11:2684-2693. [PMID: 37214574 PMCID: PMC10198121 DOI: 10.12998/wjcc.v11.i12.2684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/20/2023] [Accepted: 03/23/2023] [Indexed: 04/25/2023] Open

Abstract

BACKGROUND

Premature ovarian insufficiency (POI) is characterized by an early decline in ovarian function, inducing secondary amenorrhea. While the cause of POI has not yet been identified, the function of mitochondria in the ovaries and the cytotoxicity associated with reactive oxygen species (ROS) have been implicated in follicle pool depletion and a decline in follicle quality. Recently developed tests have enabled easy measurement of diacron-reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP). The combination of these two tests is used to comprehensively assess oxidative stress in the blood.

AIM

To comprehensively assess the oxidative stress of d-ROMs and BAP in POI.

METHODS

Participants were classified into two groups: A POI group of 11 women aged < 40 years examined between January 2021 and June 2022 with a history of secondary amenorrhea for at least 4 mo in our hospital and an FSH value of ≥ 40 mIU/mL; and a control group of healthy women of the same age with normal ovarian function in our hospital. Plasma d-ROMs and BAP were measured in both these groups underwent. Differences between groups were assessed using the t-test.

RESULTS

The mean age and mean body mass index (BMI) were 35.8 ± 3.0 years and 20.1 ± 1.9 kg/m² in the control group and 35.8 ± 2.7 years and 19.4 ± 2.5 kg/m² in the POI group, respectively. The mean gravidity and parity in control and POI groups were 0.6 ± 0.7 and 0.4 ± 0.5 and 0.6 ± 0.9 and 0.3 ± 0.5, respectively. The two groups did not differ significantly in terms of mean age, BMI, gravidity, or parity. The d-ROMs level was significantly higher in the POI group than in the control group (478.2 ± 58.7 vs 341.1 ± 35.1 U.CARR; P < 0.001); however, the BAP level did not significantly differ between the two groups (2078.5 ± 157.4 vs 2029.0 ± 186.4 μmol/L). The oxidase stress index (d-ROMs/BAP × 100) was significantly higher in the POI group than in the control group (23.7 ± 3.3 vs 16.5 ± 2.1; P < 0.001).

CONCLUSION

Oxidative stress was significantly greater in the POI group than in the control group, suggesting oxidative stress as a factor that can serve as a POI biomarker.

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Reynolds AC, McKenzie LJ. Cancer Treatment-Related Ovarian Dysfunction in Women of Childbearing Potential: Management and Fertility Preservation Options. J Clin Oncol 2023;41:2281-2292. [PMID: 36888938 PMCID: PMC10115556 DOI: 10.1200/jco.22.01885] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 12/22/2022] [Accepted: 01/24/2023] [Indexed: 03/10/2023] Open

Patricia Wodi A, Marquez P, Mba-Jonas A, Barash F, Nguon K, Moro PL. Spontaneous reports of primary ovarian insufficiency after vaccination: A review of the vaccine adverse event reporting system (VAERS). Vaccine 2023;41:1616-1622. [PMID: 36732165 DOI: 10.1016/j.vaccine.2022.12.038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 02/03/2023]

Abstract

BACKGROUND

Since 2012, reports of primary ovarian insufficiency (POI) temporally associated with receipt of human papillomavirus (HPV) vaccine have been published leading to questions about a potential causal association. A Vaccine Safety Datalink study did not find an increased risk for POI after vaccination. We reviewed the Vaccine Adverse Event Reporting System (VAERS) to describe POI reports.

METHODS

We searched VAERS, a U.S. passive surveillance system, for domestic POI reports received from 01/01/1990 to 12/31/2017 after any vaccination. The search used both Medical Dictionary for Regulatory Activity Preferred Terms and a text-based search for POI and its symptoms. All reports were reviewed, and the American College of Obstetricians and Gynecologists (ACOG) guidelines for POI diagnosis were applied. Data mining for disproportionate reporting was conducted.

RESULTS

Six hundred fifty-two reports met the search criteria and clinical review identified 19 POI reports. Most reports (n = 16) were received between 2013 and 2017. The median age at vaccination was 14.5 years (range 10-25 years) and the median interval between first dose of vaccination and reporting the event to VAERS was 43 months (range 4-132 months; mean 59.6 months). Four reports met ACOG diagnostic criteria; one with an underlying cause (47XXX chromosomal abnormality) reported. Eleven reports documented menstrual irregularity ≥ 3 months; 5 had ≥ 1 laboratory test result used to diagnose POI. Eighteen of 19 reports described receipt of HPV vaccine with or without other vaccines. Other vaccines reported were meningococcal conjugate vaccine, hepatitis A, varicella and tetanus toxoid, reduced diphtheria toxoid and acellular pertussis. Disproportionate reporting was found for three relevant coding terms after HPV vaccination.

CONCLUSIONS

POI is rarely reported to VAERS. Most reports contained limited diagnostic information and were submitted after published cases of POI following HPV vaccination. Results of our review do not suggest a safety concern.

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Barrera EP, Grimstad FW, Boskey ER. Young Adult Patients with Testosterone Management Concerns after Gender-Affirming Hysterectomy and Bilateral Oophorectomy: A Case Series. J Pediatr Adolesc Gynecol 2023;36:89-91. [PMID: 35850361 DOI: 10.1016/j.jpag.2022.07.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/09/2022] [Accepted: 07/11/2022] [Indexed: 01/18/2023]

Erol Koc EM, Ceyhan M, Yaman S, Neselioglu S, Erel O, Ozaksit MG. Prolidase as a marker of fibrogenesis in idiopathic primary ovarian insufficiency. Eur J Obstet Gynecol Reprod Biol 2023;281:7-11. [PMID: 36521400 DOI: 10.1016/j.ejogrb.2022.12.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 10/30/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022]

Stuenkel CA, Gompel A. Primary Ovarian Insufficiency. N Engl J Med 2023;388:154-163. [PMID: 36630623 DOI: 10.1056/nejmcp2116488] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]

Jang S, Kim MS, Kim PW, Kim S. Korean medicine treatment for premature ovarian failure: Three case reports. Explore (NY) 2023;19:121-126. [PMID: 36085273 DOI: 10.1016/j.explore.2022.08.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 08/22/2022] [Accepted: 08/28/2022] [Indexed: 01/25/2023]

Dural O, Ulusoy HE, Tikiz MA, Gurbanova T, Yasa C, Ugurlucan FG, Akhan SE. Effects of Hormone Replacement Therapy on Low Bone Mineral Density in Adolescents and Young Women with Hypogonadism: Comparison of Oral and Transdermal 17 Beta-Estradiol Administration. J Pediatr Adolesc Gynecol 2022;35:634-637. [PMID: 35644512 DOI: 10.1016/j.jpag.2022.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 05/05/2022] [Accepted: 05/19/2022] [Indexed: 11/16/2022]

Mokhtar R, Hans P, Sinha A. Comparing Non-invasive Prenatal Testing With Invasive Testing for the Detection of Trisomy 21. Cureus 2022;14:e31252. [PMID: 36514620 PMCID: PMC9733793 DOI: 10.7759/cureus.31252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2022] [Indexed: 11/09/2022] Open

Abstract

Background Non-invasive prenatal test (NIPT) is an intermediate step between serum screening and invasive diagnostic testing. It involves analysis of the cell-free fetal DNA (cffDNA) present in the maternal blood sample for determining the likelihood of fetal aneuploidy. Owing to its high sensitivity and specificity, NIPT has quickly gained popularity across the globe since its introduction to clinical practice, making it an attractive alternative to the available screening and diagnostic tests in use. Amniocentesis is currently the gold standard test for obtaining fetal DNA and diagnosing fetal trisomy prenatally, but it is invasive and has procedure-related adverse effects. This study aims to compare NIPT and amniocentesis in pregnancies screened positive for fetal trisomy. Material and methods This is an analytic cross-sectional prospective study conducted in the Department of Obstetrics & Gynecology, Patna Medical College and Hospital, for two and half years from December 2018 to June 2021. A total of 34 pregnant women screened positive for trisomy 21, attending the antenatal care outpatient department, in their second trimester, with their written consent, were enrolled in the study. Results Out of 34 pregnant patients, three refused NIPT and directly opted for amniocentesis. A total of 31 pregnant women have undergone NIPT. A total of 28 cases were positive for trisomy 21 on both NIPT and amniocentesis. The sensitivity of NIPT was 100% with the confidence interval being 87.66% to 100.00%. The specificity of NIPT was 100% with the confidence interval being 29.24% to 100.00%. Conclusion The high performance and effectiveness of NIPT are undeniable. Though the process by which this test has to be integrated into the clinical practice needs more study and should be determined with meticulous assessment.

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Shylasree TS, Singh P, Kazi M, Gupta S, Engineer R, Patil PS, DeSouza A, Saklani A. Laparoscopic ovarian transposition in teenage and young women with locally advanced rectal cancer: Respite amidst cancer chaos. Colorectal Dis 2022;24:697-705. [PMID: 35133696 DOI: 10.1111/codi.16084] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 01/02/2022] [Accepted: 01/12/2022] [Indexed: 02/08/2023]

Nickel RS, Maher JY, Hsieh MH, Davis MF, Hsieh MM, Pecker LH. Fertility after Curative Therapy for Sickle Cell Disease: A Comprehensive Review to Guide Care. J Clin Med 2022;11:2318. [PMID: 35566443 PMCID: PMC9105328 DOI: 10.3390/jcm11092318] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/07/2022] [Accepted: 04/12/2022] [Indexed: 12/30/2022] Open

Gómez-Rojas S, Aristizábal-Duque JE, Muñoz-Fernández LF, Sarmiento-Ramón MP, Pereira-Gómez MDP. Nueva variante del gen STAG3 causante de insuficiencia ovárica prematura. REVISTA COLOMBIANA DE OBSTETRICIA Y GINECOLOGÍA 2022;73:142-148. [PMID: 35503298 PMCID: PMC9097685 DOI: 10.18597/rcog.3806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 04/05/2022] [Indexed: 11/23/2022]

Steinman B, Kilduff S, Del Rio M, Hayde N. Amenorrhea in a pediatric kidney transplant recipient: Answers. Pediatr Nephrol 2022;37:565-567. [PMID: 34731311 DOI: 10.1007/s00467-021-05320-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 09/27/2021] [Indexed: 12/01/2022]

Turkyilmaz A, Alavanda C, Ates EA, Geckinli BB, Polat H, Gokcu M, Karakaya T, Cebi AH, Soylemez MA, Guney Aİ, Ata P, Arman A. Whole-exome sequencing reveals new potential genes and variants in patients with premature ovarian insufficiency. J Assist Reprod Genet 2022;39:695-710. [PMID: 35066699 PMCID: PMC8995228 DOI: 10.1007/s10815-022-02408-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 01/19/2022] [Indexed: 10/19/2022] Open

Kuang X, Tang Y, Xu H, Ji M, Lai D. The Evaluation of Ovarian Function Recovery Following Treatment of Primary Ovarian Insufficiency: A Systematic Review. Front Endocrinol (Lausanne) 2022;13:855992. [PMID: 35573993 PMCID: PMC9095968 DOI: 10.3389/fendo.2022.855992] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 03/28/2022] [Indexed: 11/18/2022] Open

Abstract

BACKGROUND

Primary ovarian insufficiency (POI) is gaining awareness as its prevalence increases and its effect on patients is extremely negative. To date, several therapies have been designed to treat POI, but the conclusions are conflicting, in part, due to inconsistent evaluation methods. Thus, we explore a multi-index of ovarian function assessment methods to evaluate the recovery of ovarian function after various therapies in order to evaluate effectiveness in a more comprehensive manner.

AIM

The purpose of this review is to assess the effectiveness of various therapies to recover ovarian function in patients with POI. The primary outcome measures were anti-Müllerian hormone (AMH) levels, follicle stimulating hormone (FSH) levels, and antral follicle count (AFC). The secondary outcomes included the change of mean ovarian volume, menstruation recovery, and pregnancy rate.

METHODS

Our systematic searching including PubMed, Web of Science, Cochrane, and Embase databases was conducted to find all human clinical trial articles published from January 2000 to April 2021 and related to POI treatment, including the keywords: POI, AFC, and hormones. All prospective and retrospective studies exploring ovarian function recovery that include AFC, AMH levels, and FSH levels evolution throughout treatment were included. All patients included in the studies met the POI criteria described by the European Society for Human Reproductive Embryology (ESHRE) guideline.

RESULTS

Six studies were selected based on the criteria: one randomized controlled trial and five observational studies. Among them, two studies focused on the intraovarian platelet-rich plasma (PRP) infusion treatment, two studies focused on dehydroepiandrosterone (DHEA) supplements, one study focused on hormone replacement therapy (HRT), and one study focused on autologous adipose-derived stromal cells (ADSCs) treatment. There was insufficient scientific evidence that any approach could help ovarian function recovery in patients with POI because the ovarian function markers in each study had inconsistent changes with 26 patients (6.2%) reporting spontaneous pregnancy.

CONCLUSION

Serum AMH levels, FSH levels, and AFC are sensitive indicators and reflect the evolution of ovarian function. Large randomized controlled trials are necessary, and the data on ovarian function should be collected comprehensively to evaluate the effectiveness of a variety of treatments.

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Ovarian Telomerase and Female Fertility. Biomedicines 2021;9:biomedicines9070842. [PMID: 34356906 PMCID: PMC8301802 DOI: 10.3390/biomedicines9070842] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/08/2021] [Accepted: 07/14/2021] [Indexed: 11/16/2022] Open

Verrilli L, Johnstone E, Allen-Brady K, Welt C. Shared genetics between nonobstructive azoospermia and primary ovarian insufficiency. F&S REVIEWS 2021;2:204-213. [PMID: 36177363 PMCID: PMC9518791 DOI: 10.1016/j.xfnr.2021.04.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]

Patel S, Vargo JA, Olson A, Mahajan A. Supportive care for toxicities in children undergoing radiation therapy. Pediatr Blood Cancer 2021;68 Suppl 2:e28597. [PMID: 33818886 DOI: 10.1002/pbc.28597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 06/16/2020] [Accepted: 07/01/2020] [Indexed: 11/08/2022]

Debiec KE, Todd N. Gynecologic Care for Pediatric and Adolescent Patients Undergoing Hematopoietic Stem Cell Transplantation. J Pediatr Adolesc Gynecol 2021;34:112-116. [PMID: 33338627 DOI: 10.1016/j.jpag.2020.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/01/2020] [Accepted: 12/08/2020] [Indexed: 12/20/2022]

Premature ovarian insufficiency: pathogenesis and therapeutic potential of mesenchymal stem cell. J Mol Med (Berl) 2021;99:637-650. [PMID: 33641066 DOI: 10.1007/s00109-021-02055-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 01/29/2021] [Accepted: 02/21/2021] [Indexed: 12/14/2022]

Biswas L, Tyc K, Yakoubi WE, Morgan K, Xing J, Schindler K. Meiosis interrupted: the genetics of female infertility via meiotic failure. Reproduction 2021;161:R13-R35. [PMID: 33170803 PMCID: PMC7855740 DOI: 10.1530/rep-20-0422] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 11/10/2020] [Indexed: 12/14/2022]

La Marca A, Mastellari E. Fertility preservation for genetic diseases leading to premature ovarian insufficiency (POI). J Assist Reprod Genet 2021;38:759-777. [PMID: 33495935 DOI: 10.1007/s10815-021-02067-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 01/07/2021] [Indexed: 12/13/2022] Open

Abstract

PURPOSE

The current review aims to summarize the data available concerning the applicability of fertility preservation techniques to genetic conditions at risk of premature ovarian insufficiency (POI).

METHODS

A literature review through the PubMed Database was carried out.

RESULTS

About 10% of cases of POI is related to genetic diseases. The most frequent conditions associated with POI are Turner syndrome and fragile X pre-mutation; mutation of BRCA 1-2 genes and several other mutations and genetic syndromes have recently been highlighted, although they rarely occur. If a diagnosis is issued before POI onset, counseling on currently available fertility preservation techniques is advisable. In case of spontaneous menarche (this can occur variably depending on the mutation) established techniques like embryo or oocyte cryopreservation can be proposed, even if, in some cases, their effectiveness may be reduced by ovarian alterations connected to the mutation. Ovarian tissue cryopreservation has recently been defined as an established medical procedure for fertility preservation in young cancer patients and may be an option for prepubertal patients. However, it is still experimental in special populations with genetic diseases causing POI. New innovative experimental techniques, like in vitro maturation of immature oocytes (IVM) and vitro activation (IVA) of immature follicles on ovarian tissue, have shown limited but encouraging data and they will be probably available in the near future. For a correct risk-benefit evaluation, the following aspects should be considered: actual knowledge about the pathology-specific efficacy of the various techniques, the average age of onset of POI, the possible risks associated with the procedure in relation to the underlying pathology, the probability of spontaneous conception, as well as the health implications of a possible future pregnancy..

CONCLUSIONS

Fertility preservation techniques represent a crucial opportunity for patients with genetic risk of POI. Early diagnosis increases the chances to apply these techniques. No specific recommendations concerning fertility preservation for each genetic pathology are available, and clinicians should first counsel the patient and her relatives about known risks and benefits of the available techniques, both those established and those considered as experimental.

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Mastellari E, La Marca A. Genetic conditions impairing female fertility. Panminerva Med 2020;62:260-267. [PMID: 33185415 DOI: 10.23736/s0031-0808.20.04208-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]

Davis SM, Soares K, Howell S, Cree-Green M, Buyers E, Johnson J, Tartaglia NR. Diminished Ovarian Reserve in Girls and Adolescents with Trisomy X Syndrome. Reprod Sci 2020;27:1985-1991. [PMID: 32578162 PMCID: PMC7529937 DOI: 10.1007/s43032-020-00216-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 05/06/2020] [Indexed: 10/24/2022]

Genetics of Primary Ovarian Insufficiency. Clin Obstet Gynecol 2020;63:687-705. [PMID: 33074977 DOI: 10.1097/grf.0000000000000575] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]

Lin D, Quan H, Chen K, Lin L, Lin L, Ji Q. An adolescent girl with premature ovarian failure, Graves' disease, and chronic urticaria: a case report. J Med Case Rep 2020;14:184. [PMID: 33038927 PMCID: PMC7548041 DOI: 10.1186/s13256-020-02491-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/07/2020] [Indexed: 01/03/2023] Open

Wesevich V, Kellen AN, Pal L. Recent advances in understanding primary ovarian insufficiency. F1000Res 2020;9. [PMID: 32934798 PMCID: PMC7477642 DOI: 10.12688/f1000research.26423.1] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/27/2020] [Indexed: 12/12/2022] Open

Fattet AJ, Toupance S, Thornton SN, Monnin N, Guéant JL, Benetos A, Koscinski I. Telomere length in granulosa cells and leukocytes: a potential marker of female fertility? A systematic review of the literature. J Ovarian Res 2020;13:96. [PMID: 32825843 PMCID: PMC7442985 DOI: 10.1186/s13048-020-00702-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 08/04/2020] [Indexed: 12/17/2022] Open

Abstract

In the context of a continuously increased delay of motherhood and of an increase of the incidence of premature ovarian failure, it is of the greatest interest to dispose of a predictive marker of the duration of the fertility window. Unfortunately, current available markers of women's fertility (hormonal rates or echography count of small follicles) have a poor predictive value of premature ovarian failure. In the last ten years, some studies have suggested that telomere length may be correlated with premature ovarian failure, but the results of these studies are contradictory.In accordance with guidelines from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), this systematic review of the literature selected studies evaluating telomere length or telomerase activity in granulosa cells and/or in leukocytes as a premature ovarian failure marker.Five publications (252 premature ovarian failure patients) were included in this review of experimental evidence. Two of them studied telomere length and/or telomerase activity in granulosa cells and 4 in leukocytes in women with premature ovarian failure. For each study, authors determined if there was a positive or a negative correlation between telomeric parameters and premature ovarian failure.3 studies (178 premature ovarian failure patients) found shorter telomere length in granulosa cells and/or leukocytes and/or lower telomerase activity in premature ovarian failure patients. 2 studies (74 premature ovarian failure patients) presented contradictory results about the correlation of leucocyte telomere length with premature ovarian failure.Shorter telomeres and diminished telomerase activity in granulosa cells appear to be associated with ovarian insufficiency. However, the number of studies and of subjects within are low and the methodology questionable. The confirmation of these results is essential with more subjects, better defined populations and more adapted methodology, in order to consider telomere length in granulosa cells and/or in leucocytes as an early and reliable marker for the decline of ovarian function.

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Tang R, Yu Q. Novel variants in women with premature ovarian function decline identified via whole-exome sequencing. J Assist Reprod Genet 2020;37:2487-2502. [PMID: 32789750 DOI: 10.1007/s10815-020-01919-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 08/06/2020] [Indexed: 12/14/2022] Open

Benetti-Pinto CL, Soares Júnior JM, Maciel GA, Nácul AP, Yela DA, Silva ACJSRE. Premature ovarian insufficiency: A hormonal treatment approach. REVISTA BRASILEIRA DE GINECOLOGIA E OBSTETRÍCIA 2020;42:511-518. [PMID: 32898916 PMCID: PMC10309232 DOI: 10.1055/s-0040-1716929] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open

Cattoni A, Parissone F, Porcari I, Molinari S, Masera N, Franchi M, Cesaro S, Gaudino R, Passoni P, Balduzzi A. Hormonal replacement therapy in adolescents and young women with chemo- or radio-induced premature ovarian insufficiency: Practical recommendations. Blood Rev 2020;45:100730. [PMID: 32654893 DOI: 10.1016/j.blre.2020.100730] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/10/2020] [Accepted: 06/23/2020] [Indexed: 12/27/2022]

Affiliation(s)

A Cattoni Department of Pediatrics, Università degli Studi di Milano Bicocca, Fondazione Monza e Brianza per il Bambino e la sua Mamma, Azienda Ospedaliera San Gerardo, Via Pergolesi 33, 20900 Monza, Italy.
F Parissone Department of Obstetrics and Gynecology, Azienda Ospedaliera Universitaria Integrata di Verona, Università di Verona, Piazzale Aristide Stefani 1, 37126 Verona, Italy
I Porcari Department of Obstetrics and Gynecology, Azienda Ospedaliera Universitaria Integrata di Verona, Università di Verona, Piazzale Aristide Stefani 1, 37126 Verona, Italy
S Molinari Department of Pediatrics, Università degli Studi di Milano Bicocca, Fondazione Monza e Brianza per il Bambino e la sua Mamma, Azienda Ospedaliera San Gerardo, Via Pergolesi 33, 20900 Monza, Italy.
N Masera Department of Pediatrics, Università degli Studi di Milano Bicocca, Fondazione Monza e Brianza per il Bambino e la sua Mamma, Azienda Ospedaliera San Gerardo, Via Pergolesi 33, 20900 Monza, Italy
M Franchi Department of Obstetrics and Gynecology, Azienda Ospedaliera Universitaria Integrata di Verona, Università di Verona, Piazzale Aristide Stefani 1, 37126 Verona, Italy.
S Cesaro Pediatric Hematology Oncology, Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata di Verona, Università di Verona, Piazzale Aristide Stefani 1, 37126 Verona, Italy.
R Gaudino Pediatric Endocrinology, Azienda Ospedaliera Universitaria Integrata di Verona, Università di Verona, Piazzale Aristide Stefani 1, 37126 Verona, Italy.
P Passoni Department of Obstetrics and Gynecology, Azienda Ospedaliera San Gerardo, Via Pergolesi 33, 20900 Monza, Italy
A Balduzzi Department of Pediatrics, Università degli Studi di Milano Bicocca, Fondazione Monza e Brianza per il Bambino e la sua Mamma, Azienda Ospedaliera San Gerardo, Via Pergolesi 33, 20900 Monza, Italy.

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McGowan MC, Doyle EA, Boulware SD. Primary Ovarian Insufficiency in the Prepubertal Adolescent: A Case Report. J Pediatr Health Care 2020;34:256-263. [PMID: 32334747 DOI: 10.1016/j.pedhc.2019.12.007] [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: 09/07/2019] [Revised: 12/06/2019] [Accepted: 12/11/2019] [Indexed: 11/29/2022]

Gruber N, Kugler S, de Vries L, Brener A, Zung A, Eyal O, Rachmiel M, Koren I, Tenenbaum-Rakover Y, Hershkovitz E, Landau Z, Oren M, Eliakim A, Zangen D, German A, Majdoub H, Mazor-Aronovitch K, Modan-Moses D, Yeshayahu Y, Naugolni L, Levy-Shraga Y, Ben-Ami M, Brill G, Zuckerman-Levin N, Levy-Khademi F, Avnon-Ziv C, Tiosano D, Harel S, Kedem E, Segev-Becker A, Shoenfeld Y, Pinhas-Hamiel O. Primary Ovarian Insufficiency Nationwide Incidence Rate and Etiology Among Israeli Adolescents. J Adolesc Health 2020;66:603-609. [PMID: 31987720 DOI: 10.1016/j.jadohealth.2019.11.315] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 11/13/2019] [Accepted: 11/27/2019] [Indexed: 02/08/2023]

Affiliation(s)

Noah Gruber Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
Shir Kugler Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
Liat de Vries Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel; The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
Avivit Brener Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel; The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
Amnon Zung Pediatric Endocrinology Unit, Kaplan Medical Center, Rehovot, Israel; The School of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
Ori Eyal Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel; Pediatric Endocrinology and Diabetes Unit, Dana-Dwek Children Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Marianna Rachmiel Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel; Pediatric Endocrinology Unit, Assaf Haroffeh Medical Center, Zerifin, Israel
Ilana Koren Pediatric Clinic, Armon Child Center, Clalit Health Services, Haifa, Israel
Yardena Tenenbaum-Rakover Pediatric Endocrine Unit, Ha'Emek Medical Center, Affula, Israel; The Rappaport Endocrinology Faculty of Medicine, Technion, Haifa, Israel
Eli Hershkovitz Pediatric Endocrinology and Metabolic Unit, Soroka University Medical Center, Israel and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
Zohar Landau Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel; Pediatric Endocrine and Diabetes Unit, E. Wolfson Medical Center, Holon, Israel
Meirav Oren Paediatric Endocrine Unit, Rambam Health Care Campus, Haifa, Israel
Alon Eliakim Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel; Pediatric Department, Meir Medical Center, Kfar Saba, Israel
David Zangen The School of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel; Division of Pediatric Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem, Israel
Alina German Pediatric Department, Bnei Zion Medical Center, Haifa, Israel
Hussein Majdoub Pediatric Clinic, Armon Child Center, Clalit Health Services, Haifa, Israel
Kineret Mazor-Aronovitch Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
Dalit Modan-Moses Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
Yonatan Yeshayahu Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
Larisa Naugolni Pediatric Endocrinology Unit, Assaf Haroffeh Medical Center, Zerifin, Israel
Yael Levy-Shraga Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
Michal Ben-Ami Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
Gherta Brill Migdal Hamea Health Services, Clalit Health Services, Tel Aviv, Israel
Nehama Zuckerman-Levin The Rappaport Endocrinology Faculty of Medicine, Technion, Haifa, Israel; Institute of Diabetes, Endocrinology and Metabolism, Rambam Medical Center, Haifa, Israel
Floris Levy-Khademi The School of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel; Division of Pediatric Endocrinology, Shaare Zedek Medical Center, Jerusalem, Israel
Carmit Avnon-Ziv The School of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel; Division of Pediatric Endocrinology, Shaare Zedek Medical Center, Jerusalem, Israel
Dov Tiosano The Rappaport Endocrinology Faculty of Medicine, Technion, Haifa, Israel; Paediatric Endocrine Unit, Rambam Health Care Campus, Haifa, Israel
Shira Harel Maccabi Health Services, Central District, Tel Aviv, Israel
Einat Kedem Pediatric Endocrine and Diabetes Unit, E. Wolfson Medical Center, Holon, Israel
Anat Segev-Becker Pediatric Endocrinology and Diabetes Unit, Dana-Dwek Children Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Yehuda Shoenfeld Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel; Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
Orit Pinhas-Hamiel Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel

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