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Gomez A, Parodis I, Saleh M, Simard JF, Sjöwall C, Arkema EV. Development and evaluation of a Register-Based Organ Damage Index in systemic lupus erythematosus: a nationwide, population-based study from Sweden. Lupus Sci Med 2025; 12:e001403. [PMID: 40011068 PMCID: PMC11865802 DOI: 10.1136/lupus-2024-001403] [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: 09/29/2024] [Accepted: 02/11/2025] [Indexed: 02/28/2025]
Abstract
OBJECTIVE To develop a Register-Based Organ Damage Index (RBODI) in SLE, and evaluate its accuracy in estimating Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI) scores. Additionally, to describe organ damage accrual and associations with mortality in a Swedish population-based nationwide cohort. METHODS SDI items were translated into diagnosis, treatment and procedural codes retrieved from Swedish health registers. RBODI was calculated using the same rules as the SDI and its accuracy was evaluated using SDI data from the Clinical Lupus Register in North-Eastern Gothia cohort as the gold standard. Among newly diagnosed patients with SLE from Sweden (2005-2021), we estimated 5-year risks of organ damage, and adjusted HRs of first RBODI-based organ damage accrual associated with patient characteristics. Lastly, we estimated the association between RBODI-based organ damage within 5 years of diagnosis and mortality. RESULTS The evaluation cohort included 271 prevalent cases (65.3% developed organ damage). RBODI had a positive predictive value of 90%, sensitivity 80% and specificity 83%. Among 4441 newly diagnosed patients with SLE, 40% developed organ damage within 5 years. Males had a 30% higher risk of developing damage compared with females (HR 1.3) and older individuals (>45 years old compared with younger) had more than threefold higher risk (HR 3.3). Early development of organ damage was associated with a 2.1-fold higher risk of mortality. CONCLUSION Our novel RBODI accurately estimates SDI scores and describes long-term trends in damage accrual in the largest cohort of incident SLE to date. The strong association between early damage accrual and mortality highlights the need for efficient prevention strategies.
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Affiliation(s)
- Alvaro Gomez
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Ioannis Parodis
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Department of Rheumatology, Faculty of Medicine and Health, Örebro universitet, Örebro, Sweden
| | - Muna Saleh
- Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköpings universitet, Linköping, Sweden
| | - Julia F Simard
- Department of Epidemiology and Population Health; Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Christopher Sjöwall
- Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköpings universitet, Linköping, Sweden
| | - Elizabeth V Arkema
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
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Cozette C, Pujalte M, Celton N, Bosquet D, Copin H, Cabry R, Garçon L, Benkhalifa M, Scheffler F, Jedraszak G. Genetics Investigation of Idiopathic Premature Ovarian Insufficiency: Contribution of Array-CGH and Next-Generation Sequencing. Genes (Basel) 2025; 16:251. [PMID: 40149403 PMCID: PMC11942377 DOI: 10.3390/genes16030251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 02/14/2025] [Accepted: 02/15/2025] [Indexed: 03/29/2025] Open
Abstract
Objective(s): Premature ovarian insufficiency (POI), affecting 1% of women, is characterized by the loss of ovarian activity with amenorrhea or oligomenorrhea and increased gonadotropins occurring before the age of 40 years. Iatrogenic, autoimmune, and genetic causes are known to be involved in POI, but nearly 70% of all forms remain unexplained. Recent and new genetic analyses promote the identification of new candidate genes. The aim of this study was to evaluate the contribution of array-CGH and next-generation sequencing (NGS) in the diagnosis of POI. Study design: Twenty-eight idiopathic POI patients with primary or secondary amenorrhea underwent genetic screening by array-CGH and NGS using a custom capture design of 163 genes known or suspected to be involved in ovarian function. The clinical, biological, and ultrasound characteristics of the patients were also recorded. Results: Four of the twenty-eight patients had primary amenorrhea (14.3%), and twenty-four (85.7%) had secondary amenorrhea, with an average age at diagnosis of 27.7. Eleven patients (39.3%) had a family history of POI. Our study identified a genetic anomaly in 16 of 28 patients (57.1%): one patient carried a causal copy number variation (CNV), eight patients carried a causal single nucleotide variation (SNV)/indel variation (28.6%), and seven other patients carried variants of uncertain significance. Conclusions: Our study was the first to combine genetic analyses by using both array-CGH and NGS in the same patients. It confirmed the usefulness of both analyses in the identification of pathogenic variations responsible for idiopathic POI. Early genetic diagnosis plays a major role in the management of complications and the screening of relatives.
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Affiliation(s)
- Claire Cozette
- Reproductive Medicine and Biology Department, CECOS of Picardy, Amiens University Hospital, 80000 Amiens, France; (C.C.); (D.B.); (H.C.); (R.C.); (M.B.)
| | - Mathilde Pujalte
- Department of Constitutional Genetics, Amiens University Hospital, 80000 Amiens, France; (M.P.); (N.C.); (L.G.); (G.J.)
| | - Noémie Celton
- Department of Constitutional Genetics, Amiens University Hospital, 80000 Amiens, France; (M.P.); (N.C.); (L.G.); (G.J.)
| | - Dorian Bosquet
- Reproductive Medicine and Biology Department, CECOS of Picardy, Amiens University Hospital, 80000 Amiens, France; (C.C.); (D.B.); (H.C.); (R.C.); (M.B.)
| | - Henri Copin
- Reproductive Medicine and Biology Department, CECOS of Picardy, Amiens University Hospital, 80000 Amiens, France; (C.C.); (D.B.); (H.C.); (R.C.); (M.B.)
| | - Rosalie Cabry
- Reproductive Medicine and Biology Department, CECOS of Picardy, Amiens University Hospital, 80000 Amiens, France; (C.C.); (D.B.); (H.C.); (R.C.); (M.B.)
- Peritox UMR_I 01, CURS, Jules Verne University of Picardy, 80000 Amiens, France
| | - Loic Garçon
- Department of Constitutional Genetics, Amiens University Hospital, 80000 Amiens, France; (M.P.); (N.C.); (L.G.); (G.J.)
- HEMATIM UR4666, CURS, Jules Verne University of Picardy, 80000 Amiens, France
| | - Moncef Benkhalifa
- Reproductive Medicine and Biology Department, CECOS of Picardy, Amiens University Hospital, 80000 Amiens, France; (C.C.); (D.B.); (H.C.); (R.C.); (M.B.)
- Peritox UMR_I 01, CURS, Jules Verne University of Picardy, 80000 Amiens, France
| | - Florence Scheffler
- Reproductive Medicine and Biology Department, CECOS of Picardy, Amiens University Hospital, 80000 Amiens, France; (C.C.); (D.B.); (H.C.); (R.C.); (M.B.)
- Peritox UMR_I 01, CURS, Jules Verne University of Picardy, 80000 Amiens, France
| | - Guillaume Jedraszak
- Department of Constitutional Genetics, Amiens University Hospital, 80000 Amiens, France; (M.P.); (N.C.); (L.G.); (G.J.)
- HEMATIM UR4666, CURS, Jules Verne University of Picardy, 80000 Amiens, France
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Huang Y, Zhang Q, Shen D, Bao X. Mechanisms of He Shi Yu Lin formula in treating premature ovarian insufficiency: insights from network pharmacology and animal experiments. J Ovarian Res 2024; 17:254. [PMID: 39731132 DOI: 10.1186/s13048-024-01575-1] [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: 09/19/2024] [Accepted: 12/08/2024] [Indexed: 12/29/2024] Open
Abstract
OBJECTIVE He Shi Yu Lin Formula (HSYLF) is a clinically proven prescription for treating premature ovarian insufficiency (POI), and has shown a good curative effect. However, its molecular mechanisms are unclear. This study aimed to investigate the molecular mechanisms of HSYLF and clarify how network pharmacology analysis guides the design of animal experiments, including the selection of effective treatment doses and key targets, to ensure the relevance of the experimental results. METHODS Network pharmacology, molecular docking, and animal experiments were utilized to investigate the effects of HSYLF. Key targets were identified by intersecting herb and disease targets to construct protein-protein interaction and "active components-intersection targets-disease" networks. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed using the clusterProfiler package in R. A total of 50 specific pathogen-free female mice of reproductive age were included in the animal experiments. They were divided into five groups: the positive control group, the high-dose HSYLF group, the low-dose HSYLF group, the model blank group, and the normal control group, to evaluate the serum anti-müllerian hormone levels, mitochondrial morphology in oocytes, the levels of reactive oxygen species (ROS), and mitochondrial membrane potential. RESULTS Network pharmacology identified 204 active components connecting 219 key therapeutic targets for POI. Gene Ontology enrichment analysis indicated that the anti-POI targets of HSYLF mainly regulated response to xenobiotic stimulus, cellular response to chemical stress, and response to oxidative stress; and the Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested the primary pathways, including lipid and atherosclerosis, advanced glycation end product-receptor for advanced glycation end product signaling pathway in diabetic complications, bladder cancer, tumor necrosis factor signaling pathway, and interleukin-17 signaling pathway. The low-dose (33 g/kg/d) HSYLF and high-dose (66 g/kg/d) HSYLF groups exhibited a marked elevation in serum anti-müllerian hormone levels (low-dose group: 2657.63 ± 354.82 PG/ml; high-dose group: 2823.73 ± 316.04 PG/ml) and mitochondrial membrane potential compared to the model blank group (P < 0.05 or P < 0.01), along with a significant decline in fluorescence intensity of 2',7'-dichlorofluorescein for the levels of ROS in oocytes (P < 0.05 or P < 0.01). Additionally, both groups showed varying degrees of improvement in the morphology, quantity, and distribution of mitochondria. CONCLUSION This study provides definite evidence for the molecular mechanism by which HSYLF treats POI by decreasing mitochondrial ROS, increasing membrane potential, and improving mitochondrial function. The results from active components of HSYLF and their related key targets also confirmed the characteristics of its multi-component, multi-target, multi-pathway, and overall regulatory effects on POI. Further research regarding the mechanisms is required to generalize these results, and the deeper clinical value of HSYLF also needs to be investigated in the future.
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Affiliation(s)
- Yun Huang
- TCM Gynecology Department, Hangzhou Hospital of Traditional Chinese Medicine, NO.453 Ti Yuchang Road, Hangzhou, 310007, Zhejiang, China.
- Geriatric Department, Hangzhou Hospital of Traditional Chinese Medicine, NO.453 Ti Yuchang Road, Hangzhou, 310007, Zhejiang, China.
| | - Qin Zhang
- TCM Gynecology Department, Hangzhou Hospital of Traditional Chinese Medicine, NO.453 Ti Yuchang Road, Hangzhou, 310007, Zhejiang, China
| | - Dan Shen
- TCM Gynecology Department, Hangzhou Hospital of Traditional Chinese Medicine, NO.453 Ti Yuchang Road, Hangzhou, 310007, Zhejiang, China
| | - Xi Bao
- TCM Gynecology Department, Hangzhou Hospital of Traditional Chinese Medicine, NO.453 Ti Yuchang Road, Hangzhou, 310007, Zhejiang, China.
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Du Y, Hu Y, Sheng Y, Zhu T, Liu S, Ding H, Guan Y. Primary ovarian insufficiency consequence of autoimmune diseases: a bidirectional two-sample Mendelian randomization study. Front Endocrinol (Lausanne) 2024; 15:1417896. [PMID: 39717103 PMCID: PMC11663653 DOI: 10.3389/fendo.2024.1417896] [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: 04/15/2024] [Accepted: 11/20/2024] [Indexed: 12/25/2024] Open
Abstract
Background Observational studies suggest the risk of primary ovarian insufficiency (POI) is increased in autoimmune disorders (AIDs), but it is unclear whether there is a causal relationship. Therefore, we aimed to investigate the bidirectional causality between 20 AIDs and POI using Mendelian randomization (MR) analysis. Methods A bidirectional two-sample MR investigation was designed by using publicly accessible summary-level data from genome-wide association studies (GWAS). The inverse variance weighted (IVW) method was performed as the main analysis, supplemented by several sensitivity analyses. Cochran Q test was used to evaluate SNP estimate heterogeneity. MR-Egger and MR-PRESSO methods were utilized to detect horizontal pleiotropy. Results The MR analyses revealed that genetically determined coeliac disease (CeD) (OR = 1.124, 95% CI 1.033-1.224, P = 0.007), vitiligo (OR = 1.092, 95% CI 1.003-1.188; P = 0.042), systemic lupus erythematosus (SLE) (OR = 1.122, 95% CI 1.030-1.223, P = 0.008), and selective immunoglobulin A deficiency (SIgAD) (OR = 0.866, 95% CI: 0.776-0.967, P = 0.011) exhibited significant causal relationships with POI. We also found suggestive evidence of positive effect of Addison's disease (AD) towards POI (OR5e-6 = 1.076, 95% CI 1.002-1.154, P = 0.043). Conclusion This comprehensive MR analysis indicated that SLE, CeD, vitiligo, and AD caused an increased risk of POI, SIgAD was associated with a decreased risk of POI. These insights carry profound clinical implications, particularly emphasizing the early intervention for women with AIDs/POI who wish to preserve their reproductive potential or plan for future pregnancies.
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Affiliation(s)
- Yongming Du
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Yichao Hu
- Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Yuehua Sheng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Tianhong Zhu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Shenping Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Huiqing Ding
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Yutao Guan
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
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Zhang T, Aimuzi R, Lu X, Liu B, Lu H, Luo K, Yan J. Exposure to organophosphate esters and early menopause: A population-based cross-sectional study. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 360:124684. [PMID: 39116924 DOI: 10.1016/j.envpol.2024.124684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/07/2024] [Accepted: 08/04/2024] [Indexed: 08/10/2024]
Abstract
Organophosphate esters (OPEs), increasingly used as new flame retardants and plasticizers in various products, have been found to have reproductive toxicity with overt endocrine disruption potential, yet the relationship between OPEs and early menopause remains unexplored. In the present study, we included 2429 women who participated in the U.S. National Health and Nutrition Examination Survey data (2011-2020) and had data of five urinary OPE metabolite levels and information of menopause characteristics, to investigate the associations of OPEs exposure with premature ovarian insufficiency (POI) and age of menopause. Multivariable adjusted linear and logistic regression were used to assess the associations of urinary OPE metabolites with age of menopause and POI, respectively. Quantile g computation (QGC) models were used to assess the relative contribution of individual metabolites to associations of OPE metabolites mixture. After adjusting for covariates, urinary bis(2-chloroethyl) phosphate (BCEP) concentration was inversely associated with menopause age (β = - 0.21; 95% confidence interval (CI): 0.41, - 0.002). Higher urinary BCEP level (>median) was associated with earlier age at menopause (β = -1.14, 95% CI: 1.83, - 0.46), and elevated odds of having POI (OR = 1.93; 95% CI: 1.02, 3.66). These associations were robust to the further adjustment of cardiometabolic diseases and related traits (e.g., body mass index). Further QGC analyses confirmed that BCEP was the dominant metabolite contributing most to the associations of OPEs mixture with age of menopause (weight = 49.5%) and POI (weight = 75.1%). No significant associations were found for the other four OPE metabolites. In this cross-sectional study, urinary BCEP level was associated with earlier menopause and increased odds of POI, highlighting the potential negative impacts of this chemical and its parent compound tris(2-chloroethyl) phosphate on ovarian function. Further studies are required to validate our findings and reveal potential underlying mechanisms.
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Affiliation(s)
- Ting Zhang
- Reproductive Medicine Center, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruxianguli Aimuzi
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
| | - Xiaowei Lu
- Reproductive Medicine Center, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Liu
- Reproductive Medicine Center, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Han Lu
- Reproductive Medicine Center, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kai Luo
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Junkai Yan
- Shanghai Institute for Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
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La Marca A, Diamanti M. Factors affecting age at menopause and their relationship with ovarian reserve: a comprehensive review. EUR J CONTRACEP REPR 2024; 29:245-255. [PMID: 39007753 DOI: 10.1080/13625187.2024.2375281] [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: 03/26/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024]
Abstract
OBJECTIVE The aim of this article was to discuss all the factors affecting the age at menopause and their correlation with ovarian reserve. MATERIALS AND METHODS A narrative review of original articles was performed using PubMed until December 2023. The following keywords were used to generate the list of citations: 'menopause', 'ovarian reserve' 'oocytes quality and quantity', 'ovarian ageing'. RESULTS Menopause is the final step in the process of ovarian ageing and is influenced by the oocyte pool at birth. Conditions that accelerate follicle depletion during the reproductive lifespan lead to premature ovarian insufficiency (POI) and premature ovarian failure (POF), while a higher ovarian reserve is associated with a delayed time to menopause. Reproductive history, sociodemographic, lifestyle and iatrogenic factors may impact ovarian reserve and the age at menopause. CONCLUSIONS Some factors affecting the age at menopause are modifiable and the risks of early menopause may be preventable. We hypothesise that by addressing these modifiable factors we may also preserve ovarian reserve. However, further interventional studies are needed to evaluate the effects of the described strategies on ovarian reserve.
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Affiliation(s)
- Antonio La Marca
- Obstetrics and Gynecology Unit, Department of Medical and Surgical Sciences for Mother, Child and Adult, University of Modena and Reggio Emilia, Modena, Italy
| | - Marialaura Diamanti
- Obstetrics and Gynecology Unit, Department of Medical and Surgical Sciences for Mother, Child and Adult, University of Modena and Reggio Emilia, Modena, Italy
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Federici S, Rossetti R, Moleri S, Munari EV, Frixou M, Bonomi M, Persani L. Primary ovarian insufficiency: update on clinical and genetic findings. Front Endocrinol (Lausanne) 2024; 15:1464803. [PMID: 39391877 PMCID: PMC11466302 DOI: 10.3389/fendo.2024.1464803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 09/02/2024] [Indexed: 10/12/2024] Open
Abstract
Primary ovarian insufficiency (POI) is a disorder of insufficient ovarian follicle function before the age of 40 years with an estimated prevalence of 3.7% worldwide. Its relevance is emerging due to the increasing number of women desiring conception late or beyond the third decade of their lives. POI clinical presentation is extremely heterogeneous with a possible exordium as primary amenorrhea due to ovarian dysgenesis or with a secondary amenorrhea due to different congenital or acquired abnormalities. POI significantly impacts non only on the fertility prospect of the affected women but also on their general, psychological, sexual quality of life, and, furthermore, on their long-term bone, cardiovascular, and cognitive health. In several cases the underlying cause of POI remains unknown and, thus, these forms are still classified as idiopathic. However, we now know the age of menopause is an inheritable trait and POI has a strong genetic background. This is confirmed by the existence of several candidate genes, experimental and natural models. The most common genetic contributors to POI are the X chromosome-linked defects. Moreover, the variable expressivity of POI defect suggests it can be considered as a multifactorial or oligogenic defect. Here, we present an updated review on clinical findings and on the principal X-linked and autosomal genes involved in syndromic and non-syndromic forms of POI. We also provide current information on the management of the premature hypoestrogenic state as well as on fertility preservation in subjects at risk of POI.
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Affiliation(s)
- Silvia Federici
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Raffaella Rossetti
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Silvia Moleri
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Elisabetta V. Munari
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Maria Frixou
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Marco Bonomi
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Luca Persani
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
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Touraine P, Chabbert-Buffet N, Plu-Bureau G, Duranteau L, Sinclair AH, Tucker EJ. Premature ovarian insufficiency. Nat Rev Dis Primers 2024; 10:63. [PMID: 39266563 DOI: 10.1038/s41572-024-00547-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/31/2024] [Indexed: 09/14/2024]
Abstract
Premature ovarian insufficiency (POI) is a cause of infertility and endocrine dysfunction in women, defined by loss of normal, predictable ovarian activity before the age of 40 years. POI is clinically characterized by amenorrhoea (primary or secondary) with raised circulating levels of follicle-stimulating hormone. This condition can occur due to medical interventions such as ovarian surgery or cytotoxic cancer therapy, metabolic and lysosomal storage diseases, infections, chromosomal anomalies and autoimmune diseases. At least 1 in 100 women is affected by POI, including 1 in 1,000 before the age of 30 years. Substantial evidence suggests a genetic basis to POI. However, the cause of idiopathic POI remains unknown in most patients, indicating that gene variants associated with this condition remain to be discovered. Over the past 10 years, tremendous progress has been made in our knowledge of genes involved in POI. Genetic approaches in diagnosis are important as they enable patients with familial POI to be identified, with the opportunity for oocyte preservation. Moreover, genetic approaches could provide a better understanding of disease mechanisms, which will ultimately aid the development of improved treatments.
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Affiliation(s)
- Philippe Touraine
- Department of Endocrinology and Reproductive Medicine, AP-HP Pitié Salpêtrière Hospital, Sorbonne Université Médecine, Paris, France.
- Inserm U1151 INEM, Necker Hospital, Paris, France.
| | - Nathalie Chabbert-Buffet
- Department of Obstetrics, Gynecology and Reproductive Medicine, Tenon Hospital, AP-HP Sorbonne Université, Paris, France
- INSERM UMR S 938, CDR St Antoine, Paris, France
| | - Genevieve Plu-Bureau
- Department of Medical Gynecology, AP-HP Port Royal-Cochin Hospital, Université Paris Cité, Paris, France
- U1151 EPOPEE Team, Paris, France
| | - Lise Duranteau
- Department of Medical Gynecology, Bicêtre Hospital, AP-HP Université Paris-Saclay, Le Kremlin Bicêtre, France
| | - Andrew H Sinclair
- Murdoch Children's Research Institute, Melbourne, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
| | - Elena J Tucker
- Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
- Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
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Nyström A, Mörse H, Øra I, Henic E, Engellau J, Wieslander E, Tomaszewicz A, Elfving M. Anti-Müllerian hormone and fertility in women after childhood cancer treatment: Association with current infertility risk classifications. PLoS One 2024; 19:e0308827. [PMID: 39133666 PMCID: PMC11318921 DOI: 10.1371/journal.pone.0308827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 07/29/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND To identify childhood cancer survivors (CCSs) at risk of premature ovarian insufficiency (POI) and impaired fertility is important given its impact on quality of life. The aim of this study was to assess ovarian markers and fertility outcomes in adult female CCSs. We used the Swedish and the PanCareLIFE classifications for infertility risk grouping. METHODS 167 CCSs, at median age 34.6 years (19.3-57.8) with a median follow-up time of 25.4 years (11.6-41.3), and 164 healthy matched controls were included in this cross-sectional study. We assessed anti-Müllerian hormone (AMH) levels, antral follicle count (AFC), ovarian volume (OV), and fertility outcomes. Based on gonadotoxic treatments given, CCSs were categorized into infertility risk groups. RESULTS The median levels of AMH, AFC and OV were lower in CCSs (1.9 vs. 2.1 ng/ml, 12.0 vs. 13.0, 6.8 vs. 8.0 cm3) compared with controls, although statistically significant only for OV (p = 0.021). AMH levels in CCSs <40 years were lower for those classified as high-risk (p = 0.034) and very high-risk (p<0.001) for infertility, based on the Swedish risk classification. Similarly, AFC was reduced in the high-risk (p<0.001) and the very high-risk groups (p = 0.003). CCSs of all ages showed a trend towards impaired fertility, especially in the very high-risk group. POI was diagnosed in 22/167 CCSs, of whom 14 were in the high- and very high-risk groups. The results according to the PanCareLIFE classification were similar. CONCLUSION Both the Swedish and the PanCareLIFE infertility risk classifications are reliable tools for identifying those at risk of reduced ovarian markers and fertility, as well as POI. We recommend fertility preservation counselling for patients receiving highly gonadotoxic treatments (i.e., Cyclophosphamide Equivalent Dose ≥6 g/m2, radiotherapy exposure to ovaries or stem cell transplantation) with follow-up at a young reproductive age due to the risk of a shortened reproductive window.
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Affiliation(s)
- Anna Nyström
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Lund, Sweden
- Paediatric Cardiology, Skåne University Hospital, Lund, Sweden
| | - Helena Mörse
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Lund, Sweden
- Paediatric Oncology and Haematology, Skåne University Hospital, Lund, Sweden
| | - Ingrid Øra
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Lund, Sweden
| | - Emir Henic
- Department of Translational Medicine, Reproductive Medicine, Lund University, Malmö, Sweden
- Reproductive Medicine, Skåne University Hospital, Malmö, Sweden
| | - Jacob Engellau
- Department of Clinical Sciences Lund, Systemic Radiation Therapy, Lund University, Lund, Sweden
- Haematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
| | - Elinore Wieslander
- Haematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
| | - Andrzej Tomaszewicz
- Haematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
| | - Maria Elfving
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Lund, Sweden
- Paediatric Endocrinology, Skåne University Hospital, Lund, Sweden
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10
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Hao J, Li T, Heinzelmann M, Moussaud-Lamodière E, Lebre F, Krjutškov K, Damdimopoulos A, Arnelo C, Pettersson K, Alfaro-Moreno E, Lindskog C, van Duursen M, Damdimopoulou P. Effects of chemical in vitro activation versus fragmentation on human ovarian tissue and follicle growth in culture. Hum Reprod Open 2024; 2024:hoae028. [PMID: 38803550 PMCID: PMC11128059 DOI: 10.1093/hropen/hoae028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 04/15/2024] [Indexed: 05/29/2024] Open
Abstract
STUDY QUESTION What is the effect of the chemical in vitro activation (cIVA) protocol compared with fragmentation only (Frag, also known as mechanical IVA) on gene expression, follicle activation and growth in human ovarian tissue in vitro? SUMMARY ANSWER Although histological assessment shows that cIVA significantly increases follicle survival and growth compared to Frag, both protocols stimulate extensive and nearly identical transcriptomic changes in cultured tissue compared to freshly collected ovarian tissue, including marked changes in energy metabolism and inflammatory responses. WHAT IS KNOWN ALREADY Treatments based on cIVA of the phosphatase and tensin homolog (PTEN)-phosphatidylinositol 3-kinase (PI3K) pathway in ovarian tissue followed by auto-transplantation have been administered to patients with refractory premature ovarian insufficiency (POI) and resulted in live births. However, comparable effects with mere tissue fragmentation have been shown, questioning the added value of chemical stimulation that could potentially activate oncogenic responses. STUDY DESIGN SIZE DURATION Fifty-nine ovarian cortical biopsies were obtained from consenting women undergoing elective caesarean section (C-section). The samples were fragmented for culture studies. Half of the fragments were exposed to bpV (HOpic)+740Y-P (Frag+cIVA group) during the first 24 h of culture, while the other half were cultured with medium only (Frag group). Subsequently, both groups were cultured with medium only for an additional 6 days. Tissue and media samples were collected for histological, transcriptomic, steroid hormone, and cytokine/chemokine analyses at various time points. PARTICIPANTS/MATERIALS SETTING METHODS Effects on follicles were evaluated by counting and scoring serial sections stained with hematoxylin and eosin before and after the 7-day culture. Follicle function was assessed by quantification of steroids by ultra-performance liquid chromatography tandem-mass spectrometry at different time points. Cytokines and chemokines were measured by multiplex assay. Transcriptomic effects were measured by RNA-sequencing (RNA-seq) of the tissue after the initial 24-h culture. Selected differentially expressed genes (DEGs) were validated by quantitative PCR and immunofluorescence in cultured ovarian tissue as well as in KGN cell (human ovarian granulosa-like tumor cell line) culture experiments. MAIN RESULTS AND THE ROLE OF CHANCE Compared to the Frag group, the Frag+cIVA group exhibited a significantly higher follicle survival rate, increased numbers of secondary follicles, and larger follicle sizes. Additionally, the tissue in the Frag+cIVA group produced less dehydroepiandrosterone compared to Frag. Cytokine measurement showed a strong inflammatory response at the start of the culture in both groups. The RNA-seq data revealed modest differences between the Frag+cIVA and Frag groups, with only 164 DEGs identified using a relaxed cut-off of false discovery rate (FDR) <0.1. Apart from the expected PI3K-protein kinase B (Akt) pathway, cIVA also regulated pathways related to hypoxia, cytokines, and inflammation. In comparison to freshly collected ovarian tissue, gene expression in general was markedly affected in both the Frag+cIVA and Frag groups, with a total of 3119 and 2900 DEGs identified (FDR < 0.001), respectively. The top enriched gene sets in both groups included several pathways known to modulate follicle growth such as mammalian target of rapamycin (mTOR)C1 signaling. Significant changes compared to fresh tissue were also observed in the expression of genes encoding for steroidogenesis enzymes and classical granulosa cell markers in both groups. Intriguingly, we discovered a profound upregulation of genes related to glycolysis and its upstream regulator in both Frag and Frag+cIVA groups, and these changes were further boosted by the cIVA treatment. Cell culture experiments confirmed glycolysis-related genes as direct targets of the cIVA drugs. In conclusion, cIVA enhances follicle growth, as expected, but the mechanisms may be more complex than PI3K-Akt-mTOR alone, and the impact on function and quality of the follicles after the culture period remains an open question. LARGE SCALE DATA Data were deposited in the GEO data base, accession number GSE234765. The code for sequencing analysis can be found in https://github.com/tialiv/IVA_project. LIMITATIONS REASONS FOR CAUTION Similar to the published IVA protocols, the first steps in our study were performed in an in vitro culture model where the ovarian tissue was isolated from the regulation of hypothalamic-pituitary-ovarian axis. Further in vivo experiments will be needed, for example in xeno-transplantation models, to explore the long-term impacts of the discovered effects. The tissue collected from patients undergoing C-section may not be comparable to tissue of patients with POI. WIDER IMPLICATIONS OF THE FINDINGS The general impact of fragmentation and short (24 h) in vitro culture on gene expression in ovarian tissue far exceeded the effects of cIVA. Yet, follicle growth was stimulated by cIVA, which may suggest effects on specific cell populations that may be diluted in bulk RNA-seq. Nevertheless, we confirmed the impact of cIVA on glycolysis using a cell culture model, suggesting impacts on cellular signaling beyond the PI3K pathway. The profound changes in inflammation and glycolysis following fragmentation and culture could contribute to follicle activation and loss in ovarian tissue culture, as well as in clinical applications, such as fertility preservation by ovarian tissue auto-transplantation. STUDY FUNDING/COMPETING INTERESTS This study was funded by research grants from European Union's Horizon 2020 Research and Innovation Programme (Project ERIN No. 952516, FREIA No. 825100), Swedish Research Council VR (2020-02132), StratRegen funding from Karolinska Institutet, KI-China Scholarship Council (CSC) Programme and the Natural Science Foundation of Hunan (2022JJ40782). International Iberian Nanotechnology Laboratory Research was funded by the European Union's H2020 Project Sinfonia (857253) and SbDToolBox (NORTE-01-0145-FEDER-000047), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund. No competing interests are declared.
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Affiliation(s)
- Jie Hao
- Department of Reproductive Medicine, Xiangya Hospital, Central South University, Changsha, P.R. China
- Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Tianyi Li
- Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Manuel Heinzelmann
- Department of Environment and Health, Amsterdam Institute for Life and Environment, Amsterdam, The Netherlands
| | - Elisabeth Moussaud-Lamodière
- Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Filipa Lebre
- Nanosafety Group, International Iberian Nanotechnology Laboratory, Braga, Portugal
| | - Kaarel Krjutškov
- Faculty of Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
- Competence Centre on Health Technologies, Tartu, Estonia
| | | | - Catarina Arnelo
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Karin Pettersson
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | | | - Cecilia Lindskog
- Department of Immunology, Genetics and Pathology, Cancer Precision Medicine Research Program, Uppsala University, Uppsala, Sweden
| | - Majorie van Duursen
- Department of Environment and Health, Amsterdam Institute for Life and Environment, Amsterdam, The Netherlands
| | - Pauliina Damdimopoulou
- Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
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Nash Z, Davies M. Premature ovarian insufficiency. BMJ 2024; 384:e077469. [PMID: 38508679 DOI: 10.1136/bmj-2023-077469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/22/2024]
Affiliation(s)
- Zachary Nash
- University College London Hospitals, London, UK
- EGA Institute for Women's Health, University College London
| | - Melanie Davies
- University College London Hospitals, London, UK
- EGA Institute for Women's Health, University College London
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12
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Mishra GD, Davies MC, Hillman S, Chung HF, Roy S, Maclaran K, Hickey M. Optimising health after early menopause. Lancet 2024; 403:958-968. [PMID: 38458215 DOI: 10.1016/s0140-6736(23)02800-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/09/2023] [Accepted: 12/11/2023] [Indexed: 03/10/2024]
Abstract
The typical age at menopause is 50-51 years in high-income countries. However, early menopause is common, with around 8% of women in high-income countries and 12% of women globally experiencing menopause between the ages of 40 years and 44 years. Menopause before age 40 years (premature ovarian insufficiency) affects an additional 2-4% of women. Both early menopause and premature ovarian insufficiency can herald an increased risk of chronic disease, including osteoporosis and cardiovascular disease. People who enter menopause at younger ages might also experience distress and feel less supported than those who reach menopause at the average age. Clinical practice guidelines are available for the diagnosis and management of premature ovarian insufficiency, but there is a gap in clinical guidance for early menopause. We argue that instead of distinct age thresholds being applied, early menopause should be seen on a spectrum between premature ovarian insufficiency and menopause at the average age. This Series paper presents evidence for the short-term and long-term consequences of early menopause. We offer a practical framework for clinicians to guide diagnosis and management of early menopause, which considers the nature and severity of symptoms, age and medical history, and the individual's wishes and priorities to optimise their quality of life and short-term and long-term health. We conclude with recommendations for future research to address key gaps in the current evidence.
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Affiliation(s)
- Gita D Mishra
- Australian Women and Girls' Health Research Centre, School of Public Health, University of Queensland, Brisbane, QLD, Australia.
| | - Melanie C Davies
- Institute for Women's Health, University College London, London, UK
| | - Sarah Hillman
- Unit of Academic Primary Care, Warwick Medical School, University of Warwick, Coventry, UK
| | - Hsin-Fang Chung
- Australian Women and Girls' Health Research Centre, School of Public Health, University of Queensland, Brisbane, QLD, Australia
| | - Subho Roy
- Department of Anthropology, University of Calcutta, Kolkata, India
| | - Kate Maclaran
- Department of Gynaecology, Chelsea and Westminster Hospital, London, UK
| | - Martha Hickey
- Department of Obstetrics, Gynaecology and Newborn Health, University of Melbourne and the Royal Women's Hospital, Melbourne, VIC, Australia
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Sundell M, Brynhildsen J, Fredrikson M, Hoffmann M, Spetz Holm AC. Insufficient use of menopausal hormone therapy in Swedish women with early or premature menopause caused by bilateral oophorectomy: a register-based study. BJOG 2024; 131:500-507. [PMID: 37667667 DOI: 10.1111/1471-0528.17647] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/14/2023] [Accepted: 08/19/2023] [Indexed: 09/06/2023]
Abstract
OBJECTIVE To investigate the use of menopausal hormone therapy (MHT) in premenopausal women after bilateral oophorectomy. DESIGN Retrospective register-based cohort study. SETTING Sweden. POPULATION Swedish women aged 35-44 years without malignancy who underwent bilateral oophorectomy in 2005-2020 were identified using The Swedish National Quality Register of Gynaecological Surgery (GynOp). METHODS Data from GynOp were cross-linked with data on dispensed drugs extracted from the Swedish Prescribed Drug Register. MAIN OUTCOME MEASURES Proportion of women dispensed MHT at least once within 1 year after surgery. Repeated treatment episodes were defined, and the proportion of 'person time' covered by dispensations was analysed. RESULTS In total, 1231 of all women (n = 1706) were dispensed MHT at some point after surgery, with 1177 women dispensed MHT within 1 year. This proportion increased from 64% in 2005 to 84% in 2019 (p < 0.001). In the total population, 4537 'treatment years' transpired, corresponding to 43% of the mean time covered. In women dispensed MHT within 1 year, the proportion of time covered was 63%. CONCLUSIONS Only 69% of all women without malignancy of any kind who underwent bilateral oophorectomy were dispensed MHT within 1 year after surgery, and the duration of treatment was limited. It is important to study further the reasons behind the low dispensation rate in this group to increase adherence to current treatment guidelines, improve quality of life, and avoid increased morbidity and mortality.
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Affiliation(s)
- Micaela Sundell
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Obstetrics and Gynaecology, Kalmar County Hospital, Kalmar, Sweden
| | - Jan Brynhildsen
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Department of Obstetrics and Gynecology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Mats Fredrikson
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Mikael Hoffmann
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
- The NEPI Foundation, Stockholm, Sweden
| | - Anna-Clara Spetz Holm
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Obstetrics and Gynaecology, Linköping University Hospital, Linköping, Sweden
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14
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Kakinuma K, Kakinuma T. Significance of oxidative stress and antioxidant capacity tests as biomarkers of premature ovarian insufficiency: A case control study. World J Clin Cases 2024; 12:479-487. [PMID: 38322464 PMCID: PMC10841946 DOI: 10.12998/wjcc.v12.i3.479] [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: 08/25/2023] [Revised: 11/27/2023] [Accepted: 01/02/2024] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND Premature ovarian insufficiency (POI) is a condition that causes secondary amenorrhea owing to ovarian hypofunction at an early stage. Early follicular depletion results in intractable infertility, thereby considerably reducing the quality of life of females. Given the continuum in weakened ovarian function, progressing from incipient ovarian failure (IOF) to transitional ovarian failure and further to POI, it is necessary to develop biomarkers for predicting POI. The oxidative stress states in IOF and POI were comprehensively evaluated via oxidative stress [diacron-reactive oxygen metabolites (d-ROMs)] test and antioxidant capacity [biological antioxidant potential (BAP)]. AIM To explore the possibilities of oxidative stress and antioxidant capacity as biomarkers for the early detection of POI. METHODS Females presenting with secondary amenorrhea over 4 mo and a follicle stimulating hormone level of > 40 mIU/mL were categorized into the POI group. Females presenting with a normal menstrual cycle and a follicle stimulating hormone level of > 10.2 mIU/mL were categorized into the IOF group. Healthy females without ovarian hypofunction were categorized into the control group. Among females aged < 40 years who visited our hospital from January 2021 to June 2022, we recruited 11 patients into both POI and IOF groups. For the potential antioxidant capacity, the relative oxidative stress index (BAP/d-ROMs × 100) was calculated, and the oxidative stress defense system was comprehensively evaluated. RESULTS d-ROMs were significantly higher in the POI and IOF groups than in the control group, (478.2 ± 58.7 U.CARR, 434.5 ± 60.6 U.CARR, and 341.1 ± 35.1 U.CARR, respectively) (U.CARR is equivalent to 0.08 mg/dL of hydrogen peroxide). However, no significant difference was found between the POI and IOF groups. Regarding BAP, no significant difference was found between the control, IOF, and POI groups (2078.5 ± 157.4 μmol/L, 2116.2 ± 240.2 μmol/L, and 2029.0 ± 186.4 μmol/L, respectively). The oxidative stress index was significantly higher in the POI and IOF groups than in the control group (23.7 ± 3.3, 20.7 ± 3.6, and 16.5 ± 2.1, respectively). However, no significant difference was found between the POI and IOF groups. CONCLUSION High levels of oxidative stress suggest that evaluating the oxidative stress state may be a useful indicator for the early detection of POI.
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Affiliation(s)
- Kaoru Kakinuma
- Department of Obstetrics and Gynecology, International University of Health and Welfare Hospital, Tochigi 329-2763, Japan
- Graduate School of Medicine, International University of Health and Welfare, Tokyo 107-8402, Japan
| | - Toshiyuki Kakinuma
- Department of Obstetrics and Gynecology, International University of Health and Welfare Hospital, Tochigi 329-2763, Japan
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15
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Zhang Q, Zhang W, Wu X, Ke H, Qin Y, Zhao S, Guo T. Homozygous missense variant in MEIOSIN causes premature ovarian insufficiency. Hum Reprod 2023; 38:ii47-ii56. [PMID: 37982418 DOI: 10.1093/humrep/dead084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 03/30/2023] [Indexed: 11/21/2023] Open
Abstract
STUDY QUESTION Are variants of genes involved in meiosis initiation responsible for premature ovarian insufficiency (POI)? SUMMARY ANSWER A MEIOSIN variant participates in the pathogenesis of human POI by impairing meiosis due to insufficient transcriptional activation of essential meiotic genes. WHAT IS KNOWN ALREADY Meiosis is the key event for the establishment of the ovarian reserve, and several gene defects impairing meiotic homologous recombination have been found to contribute to the pathogenesis of POI. Although STRA8 and MEIOISN variants have been found to associate with POI in a recent study, the condition of other meiosis initiation genes is unknown and direct evidence of variants participating in the pathogenesis of POI is still lacking. STUDY DESIGN, SIZE, DURATION This was a retrospective genetic study. An in-house whole exome sequencing (WES) database of 1030 idiopathic POI patients was screened for variations of meiosis initiation genes. PARTICIPANTS/MATERIALS, SETTING, METHODS Homozygous or compound heterozygous variations of genes involved in meiosis initiation were screened in the in-house WES database. The pathogenicity of the variation was verified by in vitro experiments, including protein structure prediction and dual-luciferase reporter assay. The effect of the variant on ovarian function and meiosis was demonstrated through histological analyses in a point mutation mouse model. MAIN RESULTS AND THE ROLE OF CHANCE One homozygous variant in MEIOSIN (c.1735C>T, p.R579W) and one in STRA8 (c.258 + 1G>A), which initiates meiosis via the retinoic acid-dependent pathway, were identified in a patient with idiopathic POI respectively. The STRA8 variation has been reported in the recently published work. For the MEIOSIN variation, the dual-luciferase reporter assay revealed that the variant adversely affected the transcriptional function of MEIOSIN in upregulating meiotic genes. Furthermore, knock-in mice with the homologous mutation confirmed that the variation impacted the meiotic prophase I program and accelerated oocyte depletion. Moreover, the variant p.R579W localizing in the high-mobility group (HMG) box domain disrupted the nuclear localization of the MEIOSIN protein but was dispensable for the cell-cycle switch of oocytes, suggesting a unique role of the MEIOSIN HMG box domain in meiosis initiation. LIMITATIONS, REASONS FOR CAUTION Further studies are needed to explore the role of other meiosis initiation genes in the pathogenesis of POI. WIDER IMPLICATIONS OF THE FINDINGS The MEIOSIN variant was verified to cause POI by impaired transcriptional regulation of meiotic genes and was inherited by a recessive mode. The function of HMG box domain in MEIOSIN protein was also expanded by this study. Although causative variations in meiotic initiation genes are rare in POI, our study confirmed the pathogenicity of a MEIOSIN variant and elucidated another mechanism of human infertility. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Key Research & Developmental Program of China (2022YFC2703800, 2022YFC2703000), National Natural Science Foundation for Distinguished Young Scholars (82125014), National Natural Science Foundation of China (32070847, 32170867, 82071609), Basic Science Center Program of NSFC (31988101), Natural Science Foundation of Shandong Province for Grand Basic Projects (ZR2021ZD33), Natural Science Foundation of Shandong Province for Excellent Young Scholars (ZR2022YQ69), Taishan Scholars Program for Young Experts of Shandong Province (tsqn202211371), and Qilu Young Scholars Program of Shandong University. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A.
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Affiliation(s)
- Qian Zhang
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Wenzhe Zhang
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Xinyi Wu
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Hanni Ke
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Yingying Qin
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Shidou Zhao
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Ting Guo
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
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Moustaki M, Kontogeorgi A, Tsangkalova G, Tzoupis H, Makrigiannakis A, Vryonidou A, Kalantaridou SN. Biological therapies for premature ovarian insufficiency: what is the evidence? FRONTIERS IN REPRODUCTIVE HEALTH 2023; 5:1194575. [PMID: 37744287 PMCID: PMC10512839 DOI: 10.3389/frph.2023.1194575] [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] [Received: 03/27/2023] [Accepted: 08/22/2023] [Indexed: 09/26/2023] Open
Abstract
Premature Ovarian Insufficiency (POI) is a multi-factorial disorder that affects women of reproductive age. The condition is characterized by the loss of ovarian function before the age of 40 years and several factors have been identified to be implicated in its pathogenesis. Remarkably though, at least 50% of women have remaining follicles in their ovaries after the development of ovarian insufficiency. Population data show that approximately up to 3.7% of women worldwide suffer from POI and subsequent infertility. Currently, the treatment of POI-related infertility involves oocyte donation. However, many women with POI desire to conceive with their own ova. Therefore, experimental biological therapies, such as Platelet-Rich Plasma (PRP), Exosomes (exos) therapy, In vitro Activation (IVA), Stem Cell therapy, MicroRNAs and Mitochondrial Targeting Therapies are experimental treatment strategies that focus on activating oogenesis and folliculogenesis, by upregulating natural biochemical pathways (neo-folliculogenesis) and improving ovarian microenvironment. This mini-review aims at identifying the main advantages of these approaches and exploring whether they can underpin existing assisted reproductive technologies.
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Affiliation(s)
- Melpomeni Moustaki
- Department of Endocrinology and Diabetes Center, Hellenic Red Cross Hospital, Athens, Greece
| | | | | | | | - Antonis Makrigiannakis
- Department of Obstetrics and Gynecology, University of Crete Medical School, Heraklion, Greece
| | - Andromachi Vryonidou
- Department of Endocrinology and Diabetes Center, Hellenic Red Cross Hospital, Athens, Greece
| | - Sophia N. Kalantaridou
- Serum IVF Fertility Center, Athens, Greece
- 3rd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Medical School, Athens, Greece
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17
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Jambarsang S, Khodayarian M, Sefidkar R, Yoshany N. Prevalence of premature ovarian insufficiency (POI) and its relationship with female reproductive factors in Iranian women: a cross-sectional study from the Persian (Shahedieh) cohort data. BMC Womens Health 2023; 23:467. [PMID: 37658371 PMCID: PMC10474657 DOI: 10.1186/s12905-023-02620-9] [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: 03/19/2023] [Accepted: 08/24/2023] [Indexed: 09/03/2023] Open
Abstract
BACKGROUND In premature ovarian insufficiency, the cessation of menstruation, and cessation of ovarian function occurs before the age of 40, and this phenomenon is associated with many complications and problems for women. Since several factors can affect this situation, this study was conducted to determine the relationship between fertility history, and premature ovarian failure. METHODS This cross-sectional study was conducted on the data of the first phase of cohort study, which was a sample of 10,000 people from an Iranian adult population (age: 35-70 years). 1276 women were included who naturally experienced menopause from this population. They were separated into three groups based on the age of menopause: premature ovarian failure for those who reached menopause before the age of 40, early menopause for those who reached menopause between the ages of 40 and 45, and natural menopause for those who reached menopause at or after the age of 45. The demographic and fertility characteristics of two groups of women, one with premature ovarian failure and the other with early menopause, were compared with a group of women experiencing normal menopause. The comparison was based on frequency and percentage. Moreover, the odds ratio (OR) of these two groups compared to normal group was crudely calculated, and adjusted based on age at the time of the interview using a logistic regression model. SPSS 23 software was used to fit models and calculations. RESULTS The prevalence of premature ovarian failure was 3%. The likelihood of premature ovarian failure decreases as the number of live births rises. The risk is considerably higher for births ranging from zero to three children compared to those with more than four. Increased duration of breastfeeding is associated to a reduced risk of premature ovarian failure compared to the spontaneous occurrence (OR = 0.98, 95% CI (0.97, 0.99)). This relationship is maintained even after adjusting for age (OR = 0.98, 95% CI (0.97, 0.99). CONCLUSION Based on the results of present study, it can be concluded that the factor of the number of births, and the duration of breastfeeding affect reducing the occurrence of POI, therefore, in health and treatment programs and policies, encouragement to have children, which is now part of the policies population of Iran, and the importance, and benefits of breastfeeding for mother and baby should be emphasized more.
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Affiliation(s)
- Sara Jambarsang
- Center for Healthcare Data Modeling, Departments of Biostatistics and Epidemiology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mahsa Khodayarian
- Department of Health Education and Health Promotion, Social Determinants of Health Research Center, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Reyhane Sefidkar
- Center for Healthcare Data Modeling, Departments of Biostatistics and Epidemiology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Nooshin Yoshany
- Department of Health Education and Health Promotion, Social Determinants of Health Research Center, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Wu J, Tan L, Ning Y, Yuan W, Lee Z, Ma F, Wang E, Zhuo Y. Characteristics of retinal image associated with premature ovarian insufficiency: a case- control study. J Ovarian Res 2023; 16:146. [PMID: 37488629 PMCID: PMC10367310 DOI: 10.1186/s13048-023-01231-0] [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: 01/24/2022] [Accepted: 07/07/2023] [Indexed: 07/26/2023] Open
Abstract
PURPOSE To establish an early clinical diagnosis model based on the retinal vascular features associated with POI, supplying a non-invasive way for accurately and early predicted the risk of POI. METHODS A total of 78 women with spontaneous POI and 48 healthy women were recruited from the Affiliated Shenzhen Maternity & Child Healthcare Hospital in the study. Retinal characteristics were analyzed using an automated retinal image analysis system. Binary logistic regression was used to identify POI cases and develop predictive models. RESULTS Compared to the normal group, the POI group had larger central retinal artery equivalent (CRAE) (P = 0.006), central retinal vein equivalent (CRVE) (P = 0.001), index of venules asymmetry (Vasym) (P = 0.000); larger bifurcation angles of arterioles (Aangle) (P = 0.001), bifurcation coefficient of venule (BCV) (P = 0.001) and more obvious arteriovenous nipping (Nipping) (P = 0.005), but lower arteriole-to-venule ratio (AVR) (P = 0.012). In the POI group, the odds ratio (OR) of Vasym was 6.72e-32 (95% C.I. 4.62e-49-9.79e-15, P = 0.000), the OR of BCV was 5.66e-20 (95% C.I. 1.93e-34-.0000, P = 5.66e-20) and the OR of Nipping was 6.65e-06 (95% C.I. 6.33e-10-.0698, P = 0.012). Moreover, the area under the ROC curve for the binary logistic regression with retinal characteristics was 0.8582, and the fitting degree of regression models was 60.48% (Prob > chi-square = 0.6048). CONCLUSION This study demonstrated that retinal image analysis can provide useful information for POI identification and certain characteristics may help with early clinical diagnosis of POI.
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Affiliation(s)
- Jiaman Wu
- Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, 518028, China
| | - Liya Tan
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yan Ning
- Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, 518028, China
| | - Weiqu Yuan
- Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
| | - Zuowei Lee
- Division of Biostatistics, Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China
- Centre for Clinical Trials and Biostatistics Lab, CUHK Shenzhen Research Institute, Shenzhen, China
| | - Fei Ma
- Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, 518028, China
| | - Erfeng Wang
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuanyuan Zhuo
- Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China.
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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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Affiliation(s)
- Kaoru Kakinuma
- Department of Obstetrics and Gynecology, International Health and Welfare Hospital, Nasushiobara 327-2763, Japan
| | - Toshiyuki Kakinuma
- Department of Obstetrics and Gynecology, International Health and Welfare Hospital, Nasushiobara 327-2763, Japan
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Li M, Zhu Y, Wei J, Chen L, Chen S, Lai D. The global prevalence of premature ovarian insufficiency: a systematic review and meta-analysis. Climacteric 2023; 26:95-102. [PMID: 36519275 DOI: 10.1080/13697137.2022.2153033] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE The objective of this review was to answer the global prevalence of premature ovarian insufficiency (POI), and explore the associated factors including etiopathology and regions with POI. METHODS The search was conducted on reports from a total of eight databases that comprised Chinese National Knowledge Infrastructure (CNKI), Wanfang, China BioMedical Literature Database (CBM), PubMed, the Cochrane Library, Embase, Web of Science and Ovid MEDLINE® between 1946 and 2021. To analyze the source of heterogeneity, we performed subgroup analysis based on different etiologies and regions. Meta-analysis was carried out by Stata14.0 software. RESULTS The results showed that the global overall prevalence of POI among women was 3.5%. By subgroup analysis, the prevalence of POI among women with iatrogenic etiology was 11.2%, followed by autoimmunity (10.5%); the prevalence of POI by region was 11.3% at the highest in North America followed by South America (5.4%); and the prevalence of POI was 5.3% in a developing country, higher than 3.1% in a developed country. The trend of prevalence of POI over the past 20 years was on the rise (although p > 0.05). CONCLUSION We recommend that health and medical institutions strengthen public health awareness, achieve health-education goals related to POI and increase women's awareness of and attention to POI.
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Affiliation(s)
- M Li
- Department of Nosocomial Infection, The International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Y Zhu
- Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai, P.R. China
- Department of Scientific Research, Children's Hospital of Fudan University, Shanghai, P.R. China
| | - J Wei
- Department of Pharmacy, Shanghai Chest Hospital, Shanghai, P.R. China
| | - L Chen
- Department of Nosocomial Infection, The International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - S Chen
- Department of Nosocomial Infection, The International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - D Lai
- Department of Nosocomial Infection, The International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Shanghai Key Laboratory of Embryo Original Diseases, The International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
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21
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Sakka R, Abdelhedi F, Sellami H, Pichon B, Lajmi Y, Mnif M, Kebaili S, Derbel R, Kamoun H, Gdoura R, Delbaere A, Desir J, Abramowicz M, Vialard F, Dupont JM, Ammar-Keskes L. An unusual familial Xp22.12 microduplication including EIF1AX: A novel candidate dosage-sensitive gene for premature ovarian insufficiency. Eur J Med Genet 2022; 65:104613. [PMID: 36113757 DOI: 10.1016/j.ejmg.2022.104613] [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: 11/15/2021] [Revised: 07/22/2022] [Accepted: 09/09/2022] [Indexed: 11/19/2022]
Abstract
We report on the results of array-CGH and Whole exome sequencing (WES) studies carried out in a Tunisian family with 46,XX premature ovarian insufficiency (POI). This study has led to the identification of a familial Xp22.12 tandem duplication with a size of 559.4 kb, encompassing only three OMIM genes (RPS6KA3, SH3KBP1and EIF1AX), and a new heterozygous variant in SPIDR gene: NM_001080394.3:c.1845_1853delTATAATTGA (p.Ile616_Asp618del) segregating with POI. Increased mRNA expression levels were detected for SH3KBP1 and EIF1AX, while a normal transcript level for RPS6KA3 was detected in the three affected family members, explaining the absence of intellectual disability (ID). To the best of our knowledge, this is the first duplication involving the Xp22.12 region, reported in a family without ID, but rather with secondary amenorrhea (SA) and female infertility. As EIF1AX is a regulatory gene escaping X-inactivation, which has an extreme dosage sensitivity and highly expressed in the ovary, we suggest that this gene might be a candidate gene for ovarian function. Homozygous nonsense pathogenic variants of SPIDR gene have been reported in familial cases in POI. It has been suggested that chromosomal instability associated with SPIDR molecular defects supports the role of SPIDR protein in double-stranded DNA damage repair in vivo in humans and its causal role in POI. In this family, the variant (p.Ile616_Asp618del), present in a heterozygous state, is located in the domain that interacts with BLM and might disrupt the BLM binding ability of SPIDR protein. These findings strengthen the hypothesis that the additional effect of this variant could lead to POI in this family. Although the work represents the first evidence that EIF1AX duplication might be responsible for POI through its over-expression, further functional studies are needed to clarify and prove EIF1AX involvement in POI phenotype.
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Affiliation(s)
- Rim Sakka
- Human Molecular Genetics Laboratory, Faculty of Medicine of Sfax, University of Sfax, Tunisia; Center of Medical Genetics, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Fatma Abdelhedi
- Human Molecular Genetics Laboratory, Faculty of Medicine of Sfax, University of Sfax, Tunisia; Medical Genetics Department, Hedi Chaker Hospital, Sfax, Tunisia.
| | - Hanen Sellami
- Water Researches and Technologies Center (CERTE), University of Carthage, Tourist Road Soliman, Nabeul, Tunisia; Toxicology, Environmental Microbiology and Health Research Laboratory (LR17ES06), Faculty of Sciences of Sfax, University of Sfax, Tunisia
| | - Bruno Pichon
- Center of Medical Genetics, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Yosra Lajmi
- Cytogenetics Department, Cochin Hospital, Assistance Publique des Hôpitaux de Paris, Sorbonne Paris Cité, Paris Descartes University, Medical School, Paris, France
| | - Mouna Mnif
- Department of Endocrinology, Hedi Chaker Hospital, Sfax, Tunisia
| | - Sahbi Kebaili
- Department of Gynecology, HediChaker Hospital, Sfax, Tunisia
| | - Rihab Derbel
- Human Molecular Genetics Laboratory, Faculty of Medicine of Sfax, University of Sfax, Tunisia
| | - Hassen Kamoun
- Medical Genetics Department, Hedi Chaker Hospital, Sfax, Tunisia
| | - Radhouane Gdoura
- Toxicology, Environmental Microbiology and Health Research Laboratory (LR17ES06), Faculty of Sciences of Sfax, University of Sfax, Tunisia
| | - Anne Delbaere
- Fertility Clinic, Department of Gynecology and Obstetrics, Erasme Hospital, UniversitéLibre de Bruxelles, Brussels, Belgium
| | - Julie Desir
- Center of Medical Genetics, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Marc Abramowicz
- Center of Medical Genetics, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - François Vialard
- Genetics Department, CHI Poissy St Germain-en-Laye, F-78300, Poissy, France; RHuMA Team, UMR-BREED, INRAE-UVSQ-ENVA, UFR-SVS, F-78180, Montigny le Bretonneux, France
| | - Jean-Michel Dupont
- Cytogenetics Department, Cochin Hospital, Assistance Publique des Hôpitaux de Paris, Sorbonne Paris Cité, Paris Descartes University, Medical School, Paris, France
| | - Leila Ammar-Keskes
- Human Molecular Genetics Laboratory, Faculty of Medicine of Sfax, University of Sfax, Tunisia
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Zhang Q, Tao C, Gao S, Li S, Xu B, Ke H, Wang Y, Zhang F, Qin Y, Zhang L, Guo T. Homozygous Variant in KASH5 Causes Premature Ovarian Insufficiency by Disordered Meiotic Homologous Pairing. J Clin Endocrinol Metab 2022; 107:2589-2597. [PMID: 35708642 DOI: 10.1210/clinem/dgac368] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Indexed: 11/19/2022]
Abstract
CONTEXT Premature ovarian insufficiency (POI) affects 1% to 3.7% of women at reproductive age, and its etiology is heterogeneous. The linker of nucleoskeleton and cytoskeleton (LINC) complex, consisting of KASH5 and SUN1, plays an indispensable role in meiotic homolog pairing, determining the ovarian reserve. However, their roles in the pathogenesis of POI are unknown. OBJECTIVE To investigate the role of KASH5 variation in the pathogenesis of POI. DESIGN Whole-exome sequencing was performed in a pedigree with 2 POI patients. The pathogenicity of identified variant was illustrated by in vitro functional studies, and its effect on ovarian function and meiosis was confirmed by histological analysis and oocyte spreads with Kash5 C-terminal deleted mice model. RESULTS A homozygous splicing site variant in KASH5 (c.747G > A) was identified. In vitro studies found the variant disturbed the nuclear membrane localization of KASH5 and its binding with SUN1. Moreover, the Kash5 C-terminal deleted mice revealed defective meiotic homolog pairing and accelerated depletion of oocytes. CONCLUSIONS The splicing site variant in KASH5 is responsible for POI due to defective meiotic homolog pairing and accelerated depletion of oocytes. Our study is the first to report disorganized LINC complex participating in POI pathogenesis, potentially suggesting the essential roles of meiotic telomere attachment and dynein-driven proteins for chromosome movement in ovarian function maintenance.
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Affiliation(s)
- Qian Zhang
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Chengqiu Tao
- Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
| | - Shuchang Gao
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Shan Li
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Bingying Xu
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Hanni Ke
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Yiyang Wang
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Feng Zhang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Institute of Reproduction and Development, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Yingying Qin
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Ling Zhang
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Institute of Reproduction and Development, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Ting Guo
- Center for Reproductive Medicine, Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
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Therapeutic Effect of Melatonin in Premature Ovarian Insufficiency: Hippo Pathway Is Involved. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3425877. [PMID: 36017238 PMCID: PMC9398856 DOI: 10.1155/2022/3425877] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 07/20/2022] [Accepted: 08/01/2022] [Indexed: 11/23/2022]
Abstract
Objective Premature ovarian insufficiency (POI) is a female reproductive disorder of unknown etiology with no definite pathogenesis. Melatonin (MT) is an endogenous hormone synthesized mainly by pineal cells and has strong endogenous effects in regulating ovarian function. To systematically explore the pharmacological mechanism of MT on POI therapy, a literature review approach was conducted at the signaling pathways level. Methods Relevant literatures were searched and downloaded from databases, including PubMed and China National Knowledge Infrastructure, using the keywords “premature ovarian insufficiency,” “Hippo signaling pathways,” and “melatonin.” The search criteria were from 2010 to 2022. Text mining was also performed. Results MT is involved in the regulation of Hippo signaling pathway in a variety of modes and has been correlated with ovarian function. Conclusions The purpose of this review is to summarize the research progress of Hippo signaling pathways and significance of MT in POI, the potential crosstalk between MT and Hippo signaling pathways, and the prospective therapy.
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Silvén H, Savukoski SM, Pesonen P, Pukkala E, Gissler M, Suvanto E, Niinimäki M. Incidence and familial risk of premature ovarian insufficiency in the Finnish female population. Hum Reprod 2022; 37:1030-1036. [PMID: 35134918 PMCID: PMC9071220 DOI: 10.1093/humrep/deac014] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 12/21/2021] [Indexed: 11/13/2022] Open
Abstract
STUDY QUESTION What is the incidence of premature ovarian insufficiency (POI), has the incidence of POI changed over time, and what is the risk of POI among relatives of POI women? SUMMARY ANSWER The incidence of POI increased among females aged 15-19 years from 2007 onwards and decreased in older age groups, and among relatives of women with POI the risk of POI is significantly increased. WHAT IS KNOWN ALREADY So far, there has been no good quality, nationwide studies of the incidence of POI. Early menopause has been associated with the elevated risk of early menopause among relatives, but the knowledge of the familial risk of POI is scarce. Lower socioeconomic status has been associated with lower age at natural menopause. STUDY DESIGN, SIZE, DURATION Population-based study with 5011 women diagnosed with POI in 1988-2017. The data were collected from national registries and covers POI subjects in entire Finland. PARTICIPANTS/MATERIALS, SETTING, METHODS Women with hormone replacement therapy reimbursement for POI were identified from Social Insurance Institution (SII). We calculated POI incidence in different age groups and studied the changes in the incidence rate over time in 5-year segments. Four population-based controls were selected from the Digital and Population Data Services Agency (DVV) for each POI woman. Family members of the POI cases and controls were identified from the DVV and linked to SII reimbursement data to identify POI diagnoses among them. The familial risk of POI was estimated with a logistical regression model. MAIN RESULTS AND THE ROLE OF CHANCE The incidence was highest in the 35-39 age group, ranging from 73.8/100 000 women-years in 1993-1997 to 39.9/100 000 women-years in 2013-2017. From 2007, the incidence among 15- to 19-year-olds rose from 7.0 to 10.0/100 000 women-years in 2015-2017. Cumulative incidence of POI for women under 40 years in 1988-2017 was 478/100 000 women. The relative risk of POI among relatives of women with POI was 4.6 (95% CI 3.3-6.5) compared to relatives of women without POI. POI women tended to have slightly lower socioeconomic status and level of education compared to controls. LIMITATIONS, REASONS FOR CAUTION For some women with POI, diagnosis or reimbursement may be lacking. However, we presume that these women represent a minority due to the nature of the disease and the economic benefits of reimbursement. Some changes in the incidence of POI can reflect changes in clinical practice and changing treatments and reimbursement criteria. WIDER IMPLICATIONS OF THE FINDINGS The risk of developing POI is significantly higher in women who have first-degree relatives diagnosed with POI. Raising awareness of the increased risk might lead to earlier diagnosis and initiation of hormonal replacement therapy, possibly preventing adverse effects of low oestrogen levels, such as osteoporosis. STUDY FUNDING/COMPETING INTEREST(S) This work was financially supported by the Oulu University Hospital. H.S. received a grant from Finnish Menopause Society. S.M.S. received a grant from the Finnish Menopause Society, the Finnish Medical Foundation and the Juho Vainio Foundation. The authors do not have any competing interests to declare. TRIAL REGISTRATION NUMBER N/A.
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Affiliation(s)
- H Silvén
- Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland
- PEDEGO Research Unit, University of Oulu, Oulu, Finland
- Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - S M Savukoski
- Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland
- PEDEGO Research Unit, University of Oulu, Oulu, Finland
- Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - P Pesonen
- Northern Finland Birth Cohorts, Arctic Biobank, Infrastructure for Population Studies, Faculty of Medicine, University of Oulu, Oulu, Finland
| | - E Pukkala
- Faculty of Social Sciences, Tampere University, Tampere, Finland
- Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland
| | - M Gissler
- Information Services Department, THL Finnish Institute for Health and Welfare, Helsinki, Finland
- Academic Primary Health Care Centre, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, 171 76, Karolinska Institute, Stockholm, Sweden
| | - E Suvanto
- Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland
- PEDEGO Research Unit, University of Oulu, Oulu, Finland
- Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - M Niinimäki
- Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland
- PEDEGO Research Unit, University of Oulu, Oulu, Finland
- Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
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Nash Z, Al-Wattar BH, Davies M. Bone and heart health in menopause. Best Pract Res Clin Obstet Gynaecol 2022; 81:61-68. [PMID: 35400590 DOI: 10.1016/j.bpobgyn.2022.03.002] [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: 03/06/2022] [Accepted: 03/07/2022] [Indexed: 11/02/2022]
Abstract
Age at menopause has been shown to have an impact on bone and heart health, with younger menopause age consistently associated with a higher risk of cardiovascular disease, osteoporosis, and fracture. These risks are particularly high increased among women who encountering menopause at an early age, including women with premature ovarian insufficiency (POI) and early menopause, due to a prolonged period of oestrogen deprivation. Several interventions are suggested to optimise the bone and cardiovascular health of women with menopause including lifestyle modification, dietary supplements, hormonal, and non-hormonal therapies. Hormone therapy (HT) is indicated for women with POI. For women with early menopause, there is a paucity of evidence for the management of bone and cardiovascular health. For women beyond the average age of menopause, HT is not indicated solely for bone protection and cardiovascular health. In this group, screening for bone and heart disease, as well as primary and secondary prevention, should be undertaken in line with national and international guidelines.
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Affiliation(s)
- Zachary Nash
- EGA Institute for Women's Health, University College London, London, UK; University College London Hospitals, London, UK.
| | - Bassel H Al-Wattar
- EGA Institute for Women's Health, University College London, London, UK; University College London Hospitals, London, UK
| | - Melanie Davies
- EGA Institute for Women's Health, University College London, London, UK; University College London Hospitals, London, UK
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Does the Value of FSH Predict Severity of Metabolic Complications in Females with POI? J Clin Med 2022; 11:jcm11072024. [PMID: 35407635 PMCID: PMC8999648 DOI: 10.3390/jcm11072024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 03/29/2022] [Accepted: 04/01/2022] [Indexed: 01/22/2023] Open
Abstract
Premature ovarian insufficiency (POI) is defined as a cessation of ovarian function before the age of 40. Such early deprivation of estrogens in women may be associated with several adverse cardiovascular and metabolic consequences. The aim of this retrospective study was to investigate whether women with POI and a serum follicle-stimulating hormone (FSH) level of 25−40 I/U (Group A) have the same metabolic profile as women with POI and a serum FSH level of >40 I/U (Group B). One hundred twenty-three women were included in the study group (Group A; n = 41; Group B; n = 82). The control group comprised 77 healthy women with regular menstruation. In the age- and BMI-adjusted model, no differences were found between the groups with respect to total cholesterol, high-density lipoproteins, triglycerides, HOMA-IR, glucose, and insulin. The only significant difference was found in terms of low-density lipoprotein cholesterol (LDL-C). The highest serum concentration was found in Group B, the second highest was found in Group A, and the lowest was in the controls. In conclusion, changing the threshold of FSH required to establish a POI diagnosis may have an impact on the level of serum LDL-C.
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Stuenkel CA, Gompel A, Davis SR, Pinkerton JV, Lumsden MA, Santen RJ. Approach to the Patient With New-Onset Secondary Amenorrhea: Is This Primary Ovarian Insufficiency? J Clin Endocrinol Metab 2022; 107:825-835. [PMID: 34693971 DOI: 10.1210/clinem/dgab766] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Indexed: 11/19/2022]
Abstract
Menstrual cyclicity is a marker of health for reproductively mature women. Absent menses, or amenorrhea, is often the initial sign of pregnancy-an indication that the system is functioning appropriately and capable of generating the intended evolutionary outcome. Perturbations of menstrual regularity in the absence of pregnancy provide a marker for physiological or pathological disruption of this well-orchestrated process. New-onset amenorrhea with duration of 3 to 6 months should be promptly evaluated. Secondary amenorrhea can reflect structural or functional disturbances occurring from higher centers in the hypothalamus to the pituitary, the ovary, and finally, the uterus. Amenorrhea can also be a manifestation of systemic disorders resulting in compensatory inhibition of reproduction. Identifying the point of the breakdown is essential to restoring reproductive homeostasis to maintain future fertility and reestablish reproductive hormonal integrity. Among the most challenging disorders contributing to secondary amenorrhea is primary ovarian insufficiency (POI). This diagnosis stems from a number of possible etiologies, including autoimmune, genetic, metabolic, toxic, iatrogenic, and idiopathic, each with associated conditions and attendant medical concerns. The dual assaults of unanticipated compromised fertility concurrently with depletion of the normal reproductive hormonal milieu yield multiple management challenges. Fertility restoration is an area of active research, while optimal management of estrogen deficiency symptoms and the anticipated preventive benefits of hormone replacement for bone, cardiovascular, and neurocognitive health remain understudied. The state of the evidence for an optimal, individualized, clinical management approach to women with POI is discussed along with priorities for additional research in this population.
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Affiliation(s)
- Cynthia A Stuenkel
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Anne Gompel
- Unite de Gynecologie Medicale, l'Universite de Paris Descartes, 75015 Paris, France
| | - Susan R Davis
- Women's Health Research Program, School of Public Health and Preventive Medicine, Monash University, 3004 Melbourne, Australia
| | - JoAnn V Pinkerton
- Division Director of Midlife Health, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Mary Ann Lumsden
- University of Glasgow School of Medicine, CEO, International Federation of Obstetrics and Gynecology, Glasgow G31 2ER, UK
| | - Richard J Santen
- Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
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Huang QY, Chen SR, Chen JM, Shi QY, Lin S. Therapeutic options for premature ovarian insufficiency: an updated review. Reprod Biol Endocrinol 2022; 20:28. [PMID: 35120535 PMCID: PMC8815154 DOI: 10.1186/s12958-022-00892-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 01/15/2022] [Indexed: 11/16/2022] Open
Abstract
Primary ovarian insufficiency (POI) is a rare gynecological condition. This disease causes menstrual disturbances, infertility, and various health problems. Historically, hormone replacement therapy is the first-line treatment for this disorder. Women diagnosed with POI are left with limited therapeutic options. In order to remedy this situation, a new generation of therapeutic approaches, such as in vitro activation, mitochondrial activation technique, stem cell and exosomes therapy, biomaterials strategies, and platelet-rich plasma intra-ovarian infusion, is being developed. However, these emerging therapies are yet in the experimental stage and require precise design components to accelerate their conversion into clinical treatments. Thus, each medical practitioner bears responsibility for selecting suitable therapies for individual patients. In this article, we provide a timely analysis of the therapeutic strategies that are available for POI patients and discuss the prospects of POI therapy.
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Affiliation(s)
- Qiao-Yi Huang
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, No.34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Shao-Rong Chen
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, No.34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Jia-Ming Chen
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, No.34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Qi-Yang Shi
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, No.34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China.
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, No.34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China.
- Diabetes and Metabolism Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia.
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Hershko Klement A, Oron G, Bentov Y. Editorial: The Expansion of Female Fertility. FRONTIERS IN REPRODUCTIVE HEALTH 2022; 3:781019. [DOI: 10.3389/frph.2021.781019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/08/2021] [Indexed: 11/13/2022] Open
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Sabouni R, Tarrab R, Kalaji D, Abbassi H. A new approach of using platelet-rich autologous plasma to increase the ovarian reservoir in a Syrian patient with ovarian insufficiency: A case report. Ann Med Surg (Lond) 2022; 73:103149. [PMID: 34976384 PMCID: PMC8683667 DOI: 10.1016/j.amsu.2021.103149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/03/2022] Open
Abstract
Introduction The prevalence of Primary ovarian insufficiency (POI) is estimated to be 1–2%, resulting from many causes, including, iatrogenic causes which are becoming more common. There is no precise treatment to restore fertility in POI patients. However, new treatments -such as ovarian rejuvenation using platelet-rich autologous plasma (PRP)- are being tested and have shown promising results. We report using a new PRP injection protocol to manage a Syrian patient with ovarian insufficiency. Case presentation A 35-year-old woman with five years of primary infertility presented with decreased anti-mullerian hormone (AMH) after she underwent a laparoscopy one year ago. Where the AMH dropped from 1.07 to 0.39 ng/mL after it. She underwent an ovarian rejuvenation using PRP. Half mL of PRP was injected into every ovary, 2 mL were injected into the cervix, 7 mL intra-uterus, and 7 mL were injected intramuscularly to the patient's legs. Fifteen days following the operation, the patient's new AMH level was 0.94 ng/mL. The patient was placed on ovarian stimulation, and five days later the ultrasonography showed the development of six follicles in each ovary. Discussion Managing POI using ovarian rejuvenation is the best alternative treatment; When the donor eggs programs are not acceptable. The use of PRP in ovarian rejuvenation has been reported to be effective. Conclusion The use of PRP was beneficial in restoring fertility in a Syrian patient with ovarian insufficiency. Furthermore, the new PRP injection protocol was successful. However, more studies are needed to confirm this result.
Primary ovarian insufficiency effect 1–2% of all women. It is a major problem in countries where donor eggs programs are not acceptable. Ovarian rejuvenation using platelet-rich plasma showed promising results. The combination of generalized and localized effects may enhance the outcomes.
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Affiliation(s)
- Rami Sabouni
- Faculty of Medicine, Damascus University, Damascus, Syria
| | - Rand Tarrab
- Faculty of Medicine, Damascus University, Damascus, Syria
| | - Dania Kalaji
- Department of Radiology, Faculty of Medicine, Damascus University, Damascus, Syria
| | - Haitham Abbassi
- Department of Obstetrics and Gynecology, Faculty of Medicine, Damascus University, Syria
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Christin-Maitre S, Givony M, Albarel F, Bachelot A, Bidet M, Blanc JV, Bouvattier C, Brac de la Perrière A, Catteau-Jonard S, Chevalier N, Carel JC, Coutant R, Donadille B, Duranteau L, El-Khattabi L, Hugon-Rodin J, Houang M, Grynberg M, Kerlan V, Leger J, Misrahi M, Pienkowski C, Plu-Bureau G, Polak M, Reynaud R, Siffroi JP, Sonigo C, Touraine P, Zenaty D. Position statement on the diagnosis and management of premature/primary ovarian insufficiency (except Turner Syndrome). ANNALES D'ENDOCRINOLOGIE 2021; 82:555-571. [PMID: 34508691 DOI: 10.1016/j.ando.2021.09.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Premature ovarian insufficiency (POI) is a rare pathology affecting 1-2% of under-40 year-old women, 1 in 1000 under-30 year-olds and 1 in 10,000 under-20 year-olds. There are multiple etiologies, which can be classified as primary (chromosomal, genetic, auto-immune) and secondary or iatrogenic (surgical, or secondary to chemotherapy and/or radiotherapy). Despite important progress in genetics, more than 60% of cases of primary POI still have no identifiable etiology; these cases are known as idiopathic POI. POI is defined by the association of 1 clinical and 1 biological criterion: primary or secondary amenorrhea or spaniomenorrhea of>4 months with onset before 40 year of age, and elevated follicle-stimulating hormone (FSH)>25IU/L on 2 assays at>4 weeks' interval. Estradiol level is low, and anti-Müllerian hormone (AMH) levels have usually collapsed. Initial etiological work-up comprises auto-immune assessment, karyotype, FMR1 premutation screening and gene-panel study. If all of these are normal, the patient and parents may be offered genome-wide analysis under the "France Génomique" project. The term ovarian insufficiency suggests that the dysfunction is not necessarily definitive. In some cases, ovarian function may fluctuate, and spontaneous pregnancy is possible in around 6% of cases. In confirmed POI, hormone replacement therapy is to be recommended at least up to the physiological menopause age of 51 years. Management in a rare diseases center may be proposed.
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Affiliation(s)
- Sophie Christin-Maitre
- Sorbonne University, Hôpital St Antoine, Assistance Publique- Hôpitaux de Paris (AP-HP), Paris, France.
| | - Maria Givony
- French National Healthcare Network for Rare Endocrine Diseases (FIRENDO), AP-HP, Paris, France
| | - Frédérique Albarel
- Conception University Hospital, Assistance Publique-Hôpitaux de Marseille (AP-HM), Marseille, France
| | - Anne Bachelot
- Sorbonne University, Hôpital de la Pitié-Salpétrière, AP-HP, Paris, France
| | - Maud Bidet
- Clinique mutualiste La Sagesse, Rennes, France
| | - Jean Victor Blanc
- Sorbonne University, Hôpital St Antoine, Assistance Publique- Hôpitaux de Paris (AP-HP), Paris, France
| | | | | | | | | | | | | | - Bruno Donadille
- Sorbonne University, Hôpital St Antoine, Assistance Publique- Hôpitaux de Paris (AP-HP), Paris, France
| | - Lise Duranteau
- Saclay University, Hôpital du Kremlin-Bicêtre, AP-HP, Paris, France
| | - Laïla El-Khattabi
- Paris-Centre University, Hôpital Cochin Port-Royal, AP-HP, Paris, France
| | | | - Muriel Houang
- Sorbonne University, Hôpital Trousseau, AP-HP, Paris, France
| | - Michaël Grynberg
- Saclay University, Hôpital Antoine Béclère, AP-HP, Clamart, France
| | - Véronique Kerlan
- University of Brest, Centre Hospitalier Régional Universitaire, Brest, France
| | - Juliane Leger
- Paris-Centre University, Hôpital Robert Debré, AP-HP, Paris, France
| | | | | | | | - Michel Polak
- Paris Centre University, Hôpital Necker, AP-HP, Paris, France
| | | | | | - Charlotte Sonigo
- Saclay University, Hôpital Antoine Béclère, AP-HP, Clamart, France
| | - Phillipe Touraine
- Sorbonne University, Hôpital de la Pitié-Salpétrière, AP-HP, Paris, France
| | - Delphine Zenaty
- Paris-Centre University, Hôpital Robert Debré, AP-HP, Paris, France
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Vo KCT, Kawamura K. Ovarian Fragmentation and AKT Stimulation for Expansion of Fertile Lifespan. FRONTIERS IN REPRODUCTIVE HEALTH 2021; 3:636771. [PMID: 36304045 PMCID: PMC9580792 DOI: 10.3389/frph.2021.636771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 01/22/2021] [Indexed: 11/13/2022] Open
Abstract
Since the first baby was born after in vitro fertilization, the female infertility treatment has been well-developed, yielding successful outcomes. However, successful pregnancies for patients with premature ovarian insufficiency and diminished ovarian reserve are still difficult and diverse therapies have been suggested to improve the chances to have their genetically linked offspring. Recent studies demonstrated that the activation Akt pathway by using a phosphatase and tensin homolog enzyme inhibitor and a phosphatidylinositol-3 kinase stimulator can activate dormant primordial follicles in both mice and human ovaries. Subsequent researches suggested that the disruption of Hippo signaling pathway by ovarian fragmentation increased the expression of downstream growth factors and secondary follicle growth. Based on the combination of ovarian fragmentation and Akt stimulation, the in vitro activation (IVA) approach has resulted in successful follicle growth and live births in premature ovarian insufficiency patients. The approach with disruption of Hippo signaling only was also shown to be effective for treating poor ovarian responders with diminishing ovarian reserve, including advanced age women and cancer patients undergoing sterilizing treatments. This review aims to summarize the effectiveness of ovarian fragmentation and Akt stimulation on follicle growth and the potential of IVA in extending female fertile lifespan.
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33
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The association between primary ovarian insufficiency and osteoporosis in the Canadian Longitudinal Study on Aging. ACTA ACUST UNITED AC 2021; 28:693-698. [PMID: 33651742 DOI: 10.1097/gme.0000000000001756] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE The objective of this study is to describe the association of premature ovarian insufficiency (POI) and early menopause on bone mineral density (BMD) and osteoporosis in a large cohort of women living in Canada. METHODS Cross-sectional baseline data from a deeply characterized cohort (female participants) of the Canadian Longitudinal Study on Aging was used. Additional bio-psycho-social characteristics that may influence bone health and the development of osteoporosis were explored. RESULTS The mean age of women at the time of baseline assessment was 65 years (N = 12,339). When comparing women with POI to those with early and normal age of menopause, there was no difference in hip BMD between groups, but women in the POI group were more likely to have a higher rate of self-reported osteoporosis (21.9% vs 16.7%) and have used osteoporosis drugs (11.39% vs 7.63%). After adjustment, POI was found to increase the odds of osteoporosis, as diagnosed using BMD. Current cigarette smoking was found to influence this association. Protective factors included obesity and current hormone therapy use, but not the duration of hormone therapy use. Women in the POI group were more likely to be obese, have decreased physical activity, and were more likely to be current smokers. CONCLUSION These results confirm findings from smaller cohorts illustrating that POI is associated with osteoporosis. Increasing understanding of the sequelae associated with an earlier loss of ovarian function will aid in targeting earlier screening and intervention strategies for women in Canada and abroad.
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Moukhah S, Ghorbani B, Behboodi-Moghadam Z, Zafardoust S. Perceptions and experiences of women with premature ovarian insufficiency about sexual health and reproductive health. BMC Womens Health 2021; 21:54. [PMID: 33557799 PMCID: PMC7869211 DOI: 10.1186/s12905-021-01197-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 01/05/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Premature ovarian insufficiency (POI) is a condition with impaired ovarian function that occurred in women before the age of 40. Considering that women with POI are in reproductive age and their fertility and sexual life are afflicted by this disorder directly, the present study aimed to investigate perception and experience of women with POI of sexual and reproductive health (SRH). METHODS This is a qualitative that was implemented based on the conventional content analysis approach. The data were collected using semi-structured in-depth interviews with 16 women having POI, based on purposeful sampling and continued until data saturation. The participants were women with POI that referred to the three infertility center in Tehran, Iran. The audio recorded data were transcribed verbatim and then analyzed using conventional content analysis based on the method proposed by Zhang and Wildmouth. RESULTS After content analysis of the interviews with a focus on the perception and experience of women with POI of SRH, four main categories emerged i.e. endangerment of women's health, psychological agitation, disruption of social life and disturbance in sexual life. CONCLUSION POI affects different aspects of women SRH (women physical, psychological, social and sexual heath). Therefore, knowledge of patients' concerns by health professionals is helpful to improve service delivery and increasing the effectiveness of treatment interventions by a comprehensive health care attitude.
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Affiliation(s)
- Somayeh Moukhah
- Department of Reproductive Health, School of Nursing and Midwifery, Tehran University of Medical Sciences, Tehran, Iran
| | - Behzad Ghorbani
- Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Zahra Behboodi-Moghadam
- Department of Reproductive Health, School of Nursing and Midwifery, Tehran University of Medical Sciences, Tehran, Iran.
| | - Simin Zafardoust
- Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
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Lersten I, Clain E, Santoro N. Use of Hormone Therapy in Women with Early Menopause and Premature Ovarian Insufficiency. Semin Reprod Med 2021; 38:302-308. [PMID: 33540459 DOI: 10.1055/s-0040-1721719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Women with early menopause or primary ovarian insufficiency (POI) experience a menopausal state a decade or more earlier than their peers. The health consequences for POI are vast and varied with detrimental effects seen on neurological, psychological, bone, and cardiovascular systems. The risk profile of POI patients requires special attention, as they differ from a typical menopausal population. This review will explore the health risks associated with POI and examine the various treatment options and also the risks associated with hormone therapy. Given the risks and benefits, POI patients should be strongly encouraged to start hormone therapy until the median age of menopause.
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Affiliation(s)
- Ivy Lersten
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado
| | - Elizabeth Clain
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado
| | - Nanette Santoro
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado
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Tassanakijpanich N, Hagerman RJ, Worachotekamjorn J. Fragile X premutation and associated health conditions: A review. Clin Genet 2021; 99:751-760. [PMID: 33443313 DOI: 10.1111/cge.13924] [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] [Received: 11/01/2020] [Revised: 01/10/2021] [Accepted: 01/11/2021] [Indexed: 12/17/2022]
Abstract
Fragile X syndrome (FXS) is the most common single gene disorder, which causes autism and intellectual disability. The fragile X mental retardation 1 (FMR1) gene is silenced when cytosine-guanine-guanine (CGG) triplet repeats exceed 200, which is the full mutation that causes FXS. Carriers of FXS have a CGG repeat between 55 and 200, which is defined as a premutation and transcription of the gene is overactive with high levels of the FMR1 mRNA. Most carriers of the premutation have normal levels of fragile X mental retardation protein (FMRP) and a normal intelligence, but in the upper range of the premutation (120-200) the FMRP level may be lower than normal. The clinical problems associated with the premutation are caused by the RNA toxicity associated with increased FMR1 mRNA levels, although for some mildly lowered FMRP can cause problems associated with FXS. The RNA toxicity causes various health problems in the carriers including but not limited to fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X-associated neuropsychiatric disorders. Since some individuals with neuropsychiatric problems do not meet the severity for a diagnosis of a "disorder" then the condition can be labeled as fragile X premutation associated condition (FXPAC). Physicians must be able to recognize these health problems in the carriers and provide appropriate management.
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Affiliation(s)
| | - Randi J Hagerman
- UC Davis MIND Institute, UC Davis Health, Sacramento, California, USA.,Department of Pediatrics, University of California, Davis, School of Medicine, Sacramento, California, USA
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Abstract
Advanced maternal age is associated with the natural oocyte depletion, leading to low oocyte yield, high infertility treatment cancellation rates, and eventual decreases in pregnancy rates. Various innovative interventions have been introduced to improve the outcome of infertility treatment for aging patients. Numerous published data demonstrated that early follicle development was regulated by intraovarian growth factors through autocrine or paracrine mechanisms. Platelet-rich plasma (PRP), a plasma fraction of peripheral blood with a high concentration of platelets, has been implemented in regenerative medicine in the last decade. The plasma contains a variety of growth factors that were suggested to be able to enhance angiogenesis regeneration and the cell proliferation process. The initial report showed that an intraovarian injection of PRP improved the hormonal profile and increased the number of retrieved oocytes in patients with diminished ovarian reserve. Subsequently, several studies with larger sample sizes have reported that this approach resulted in several healthy live births with no apparent complications. However, the use of ovarian PRP treatment needs to be fully investigated, because no randomized controlled trial has yet been performed to confirm its efficacy.
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Ishizuka B, Furuya M, Kimura M, Kamioka E, Kawamura K. Live Birth Rate in Patients With Premature Ovarian Insufficiency During Long-Term Follow-Up Under Hormone Replacement With or Without Ovarian Stimulation. Front Endocrinol (Lausanne) 2021; 12:795724. [PMID: 34975766 PMCID: PMC8719621 DOI: 10.3389/fendo.2021.795724] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/01/2021] [Indexed: 11/23/2022] Open
Abstract
We analyzed data from 466 patients with premature ovarian insufficiency (POI) who wished to have a biological child and were followed up while undergoing hormone replacement (HR) therapy with or without ovarian stimulation (OS) between April 2014 and December 2020. OS was conducted in 6891 cycles in 429 patients (Group OS), whereas only HR (Group HR) was conducted in 1117 cycles in 37 patients. The follicle growth rate was 48.3% (207/429) per patient in Group OS and 5.4% (2/37) in Group HR (p<0.01). There were 51 live births (LBs) in 50 patients during follow-up. In Group OS, the LB rate was 5.8% (47/807) in cycles where in vitro fertilization (IVF) and embryo transfer were attempted (Group IVF), and 1.3% (3/236) in cycles where intrauterine insemination/timed intercourse was attempted (p<0.01). No pregnancies occurred in Group HR. Among the patients in Group IVF, the LB rate was significantly higher in patients aged <35 years at the initiation of follow-up than in patients who started at later ages (p<0.01). Among the cases who achieved an LB, 39 were patients with idiopathic POI (Group IVF-1, n=297) and seven were patients who had undergone surgical treatment for benign ovarian tumors (Group IVF-2, n=50); however, no LBs occurred in patients who had undergone treatment for malignancy (n=17), and only one in patients with chromosomal abnormalities (n=22). The LB rate per case in the patients in Group IVF-1 and those aged <35 years at the start of follow-up (Group IVF-1-a) was 24.1% (26/108), which was higher than those of the other age groups. The LB rate per case in the patients in Group IVF-1-a with <4 years of amenorrhea was 37.3% (19/51), and that in the patients in Group IVF-2 with <4 years of amenorrhea was 21.2% (7/33). These results suggest that infertility treatment is possible in some patients with POI, especially those that can be classified in Group IVF-1-a and Group IVF-2 with <4 years of amenorrhea. Therefore, OS combined with HR therapy should be considered for such patients before attempts at oocyte donation.
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Affiliation(s)
- Bunpei Ishizuka
- Rose Ladies Clinic, Tokyo, Japan
- Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kanagawa, Japan
- *Correspondence: Bunpei Ishizuka,
| | | | | | | | - Kazuhiro Kawamura
- Department of Obstetrics and Gynecology, Advanced Reproductive Medicine Research Center, International University of Health and Welfare School of Medicine, Chiba, Japan
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Ishizuka B. Current Understanding of the Etiology, Symptomatology, and Treatment Options in Premature Ovarian Insufficiency (POI). Front Endocrinol (Lausanne) 2021; 12:626924. [PMID: 33716979 PMCID: PMC7949002 DOI: 10.3389/fendo.2021.626924] [Citation(s) in RCA: 132] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 01/20/2021] [Indexed: 12/16/2022] Open
Abstract
Premature ovarian insufficiency (POI) occurs in at least 1% of all women and causes life-long health problems and psychological stress. Infertility caused by POI used to be considered absolute, with infertility treatment having little or no value. Generally, it has been thought that medicine can provide little service to these patients. The etiology of POI has been found to be genetic, chromosomal, and autoimmune. In addition, the increasing numbers of cancer survivors are candidates for iatrogenic POI, along with patients who have undergone ovarian surgery, especially laparoscopic surgery. Over 50 genes are known to be causally related to POI, and the disease course of some cases has been clarified, but in most cases, the genetic background remains unexplained, suggesting that more genes associated with the etiology of POI need to be discovered. Thus, in most cases, the genetic background of POI has not been clarified. Monosomy X is well known to manifest as Turner's syndrome and is associated with primary amenorrhea, but recent studies have shown that some women with numerical abnormalities of the X chromosome can have spontaneous menstruation up to their twenties and thirties, and some even conceive. Hormone replacement therapy (HRT) is recommended for women with POI from many perspectives. It alleviates vasomotor and genitourinary symptoms and prevents bone loss and cardiovascular disease. POI has been reported to reduce quality of life and life expectancy, and HRT may help improve both. Most of the problems that may occur with HRT in postmenopausal women do not apply to women with POI; thus, in POI, HRT should be considered physiological replacement of estrogen (+progesterone). This review describes some new approaches to infertility treatment in POI patients that may lead to new treatments for POI, along with the development of more sensitive markers of secondary/preantral follicles and genetic diagnosis.
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Affiliation(s)
- Bunpei Ishizuka
- Rose Ladies Clinic, Tokyo, Japan
- Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kanagawa, Japan
- *Correspondence: Bunpei Ishizuka,
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Affiliation(s)
- David Hawkes
- Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC 300, Australia
- Molecular Microbiology, VCS Foundation, Carlton, Victoria, Australia
- Pathology, University of Malaya, Kuala Lumpur, Malaysia
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41
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Li Y, Xia G, Tan Y, Shuai J. Acupoint stimulation and Chinese herbal medicines for the treatment of premature ovarian insufficiency: A systematic review and meta-analysis. Complement Ther Clin Pract 2020; 41:101244. [PMID: 33039750 DOI: 10.1016/j.ctcp.2020.101244] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 08/04/2020] [Accepted: 09/25/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND AND PURPOSE Acupoint stimulation and Chinese herbal medicines (CHM) are widely used in the treatment of premature ovarian insufficiency (POI), but the efficacy and safety remain controversial. This systematic review aims to evaluate the efficacy and safety of acupoint stimulation and CHM for POI. METHODS Seven databases were searched and collected studies comparing acupoint stimulation and CHM with hormone replacement therapy (HRT) from inception to July 31, 2019. The methodological quality of the included trials was assessed in line with the criteria of the Cochrane risk of bias assessment tool. RESULTS Meta-analysis was performed in 14 trials, which contained a total of 1030 women with POI. The acupoint stimulation and CHM presented advantages in normalizing of menstrual cycle (RR 2.06, 95% CI 1.62 to 2.61, P < 0.00001) and improving perimenopausal symptoms (RR 2.00, 95% CI 1.56 to 2.56, P < 0.00001) when compared with HRT. After treatment, compared with HRT, acupoint stimulation and CHM effectively decreased the level of follicle stimulating hormone (MD -2.88, 95% CI -5.00 to -0.76, P = 0.008) and increased the level of estradiol (SMD 0.88, 95% CI 0.06 to 1.71, P = 0.04). By contrast, there were no significant between-group differences in the level of luteinizing hormone (MD -3.24, 95% CI -6.77 to 0.29, P = 0.07) and adverse effects (RR 0.31, 95% CI 0.04 to 2.54, P = 0.28). CONCLUSION This meta-analysis suggested that acupoint stimulation and CHM can serve as complementary therapies to alleviate menstrual disorders, perimenopausal symptoms, and serum sex hormone levels in POI females.
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Affiliation(s)
- Yuling Li
- Nanjing University of Chinese Medicine, 210029, China
| | - Guicheng Xia
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China.
| | - Yong Tan
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Jiaqi Shuai
- Masaryk University, Brno 62500, Czech Republic
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Panay N, Anderson RA, Nappi RE, Vincent AJ, Vujovic S, Webber L, Wolfman W. Premature ovarian insufficiency: an International Menopause Society White Paper. Climacteric 2020; 23:426-446. [PMID: 32896176 DOI: 10.1080/13697137.2020.1804547] [Citation(s) in RCA: 134] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The aim of this International Menopause Society White Paper on premature ovarian insufficiency (POI) is to provide the latest information regarding this distressing condition. The impact of POI has far-reaching consequences due to its impact on general, psychological, and sexual quality of life, fertility prospects, and long-term bone, cardiovascular, and cognitive health. Progress in fully understanding the etiology, diagnosis, and optimal management options has been slow thus far due to the complexity of the condition and fragmented research. Recent advances in epidemiological and genetic research have improved our understanding of this condition and randomized prospective trials are being planned to determine the intervention strategies, which will optimize quality of life and long-term well-being. The International Menopause Society has commissioned a number of experts at the forefront of their specialty to define the state of the art in the understanding of this condition, to advise on practical management strategies, and to propose future research strategies. It is hoped that a global task force will subsequently be convened in order to formulate a consensus statement across key societies, to accelerate date collection and analysis of a global POI registry, and to facilitate progress in the key defined areas of research.
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Affiliation(s)
- N Panay
- Queen Charlotte's & Chelsea and Chelsea & Westminster Hospitals, Imperial College, London, UK
| | - R A Anderson
- MRC Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - R E Nappi
- Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, Obstetrics and Gynecology Unit, IRCCS S. Matteo Foundation, Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - A J Vincent
- Department of Endocrinology, Monash Health, Clayton, VIC, Australia.,Monash Centre for Health Research and Implementation, School of Public Health and Preventative Medicine, Monash University, Clayton, VIC, Australia
| | - S Vujovic
- Faculty of Medicine, Clinic of Endocrinology, Diabetes and Diseases of Metabolism, Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia
| | - L Webber
- St. Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - W Wolfman
- Department of Obstetrics and Gynaecology, Mt. Sinai Hospital, University of Toronto, Toronto, ON, Canada
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Sydsjö G, Bladh M, Rindeborn K, Hammar M, Rodriguez-Martinez H, Nedstrand E. Being born preterm or with low weight implies a risk of infertility and premature loss of ovarian function; a national register study. Ups J Med Sci 2020; 125:235-239. [PMID: 32532178 PMCID: PMC7720967 DOI: 10.1080/03009734.2020.1770380] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Background: Being born with non-optimal birth characteristics has several long-term consequences on health in general but also for the individual's reproductive pattern. In premature ovarian insufficiency (POI) the follicles are depleted or dysfunctional. This results in menopause before the age of 40, and for most of the affected women, it causes infertility. The objective of this study was to evaluate the potential effects of being born with non-optimal birth characteristics on the risk of developing POI.Methods: This population-based cohort register study included all women born in Sweden between 1973 and 1993 who were followed until the end of 2012 (age at the end of follow-up ranged between 39 and 59). Women diagnosed with POI were compared with women without this diagnosis with respect to being born small for gestational age, preterm, or with low birth weight. Data on birth characteristics and diagnosis of POI were collected from national registers.Results: A total of 1,033,878 women were included. Being born small for gestational age was associated with a slightly increased odds ratio of POI with 10%. Preterm birth and low birth weight were associated with somewhat increased ORs of POI after exclusion of those born small for gestational age. Similarly, being born preterm or with a low birth weight was also found to be associated with POI to the same extent.Conclusions: Being born with non-optimal birth characteristics may increase the risk of premature ovarian insufficiency.
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Affiliation(s)
- Gunilla Sydsjö
- Faculty of Medicine and Health Sciences, Division of Obstetrics and Gynaecology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- CONTACT Gunilla Sydsjö Division of Obstetrics and Gynaecology, Department of Biomedical and Clinical Sciences, Linköping University, SE-581 85Linköping, Sweden
| | - Marie Bladh
- Faculty of Medicine and Health Sciences, Division of Obstetrics and Gynaecology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Katarina Rindeborn
- Faculty of Medicine and Health Sciences, Division of Obstetrics and Gynaecology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Mats Hammar
- Faculty of Medicine and Health Sciences, Division of Obstetrics and Gynaecology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Heriberto Rodriguez-Martinez
- Faculty of Medicine and Health Sciences, Division of Obstetrics and Gynaecology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Elizabeth Nedstrand
- Faculty of Medicine and Health Sciences, Division of Obstetrics and Gynaecology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals. Arch Toxicol 2020; 94:3359-3379. [PMID: 32638039 PMCID: PMC7502037 DOI: 10.1007/s00204-020-02834-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/30/2020] [Indexed: 12/12/2022]
Abstract
Modern living challenges female reproductive health. We are witnessing a rise in reproductive disorders and drop in birth rates across the world. The reasons for these manifestations are multifaceted and most likely include continuous exposure to an ever-increasing number of chemicals. The cause–effect relationships between chemical exposure and female reproductive disorders, however, have proven problematic to determine. This has made it difficult to assess the risks chemical exposures pose to a woman’s reproductive development and function. To address this challenge, this review uses the adverse outcome pathway (AOP) concept to summarize current knowledge about how chemical exposure can affect female reproductive health. We have a special focus on effects on the ovaries, since they are essential for lifelong reproductive health in women, being the source of both oocytes and several reproductive hormones, including sex steroids. The AOP framework is widely accepted as a new tool for toxicological safety assessment that enables better use of mechanistic knowledge for regulatory purposes. AOPs equip assessors and regulators with a pragmatic network of linear cause–effect relationships, enabling the use of a wider range of test method data in chemical risk assessment and regulation. Based on current knowledge, we propose ten putative AOPs relevant for female reproductive disorders that can be further elaborated and potentially be included in the AOPwiki. This effort is an important step towards better safeguarding the reproductive health of all girls and women.
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45
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França MM, Mendonca BB. Genetics of Primary Ovarian Insufficiency in the Next-Generation Sequencing Era. J Endocr Soc 2020; 4:bvz037. [PMID: 32099950 PMCID: PMC7033037 DOI: 10.1210/jendso/bvz037] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Accepted: 12/17/2019] [Indexed: 01/12/2023] Open
Abstract
Primary ovarian insufficiency (POI) is characterized by amenorrhea, increased follicle-stimulating hormone (FSH) levels, and hypoestrogenism, leading to infertility before the age of 40 years. Elucidating the cause of POI is a key point for diagnosing and treating affected women. Here, we review the genetic etiology of POI, highlighting new genes identified in the last few years using next-generation sequencing (NGS) approaches. We searched the MEDLINE/PubMed, Cochrane, and Web of Science databases for articles published in or translated to English. Several genes were found to be associated with POI genetic etiology in humans and animal models (SPIDR, BMPR2, MSH4, MSH5, GJA4, FANCM, POLR2C, MRPS22, KHDRBS1, BNC1, WDR62, ATG7/ATG9, BRCA2, NOTCH2, POLR3H, and TP63). The heterogeneity of POI etiology has been revealed to be remarkable in the NGS era, and discoveries have indicated that meiosis and DNA repair play key roles in POI development.
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Affiliation(s)
- Monica Malheiros França
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
| | - Berenice Bilharinho Mendonca
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
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Hsu CC, Hsu L, Hsu I, Chiu YJ, Dorjee S. Live Birth in Woman With Premature Ovarian Insufficiency Receiving Ovarian Administration of Platelet-Rich Plasma (PRP) in Combination With Gonadotropin: A Case Report. Front Endocrinol (Lausanne) 2020; 11:50. [PMID: 32140135 PMCID: PMC7043014 DOI: 10.3389/fendo.2020.00050] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 01/27/2020] [Indexed: 11/15/2022] Open
Abstract
The conception rates among women with premature ovarian insufficiency (POI) remain extremely low. To achieve a successful pregnancy, most of these women have to receive donor oocytes through IVF treatment. Ovarian administration of platelet-rich plasma (PRP) has been recently applied to enhance the ovulatory function in women with poor ovarian response. However, no live birth has been reported for this application in patients with POI. In this study, we present a 37-year-old woman with POI who had secondary amenorrhea for 6 months. The clinical manifestations and evaluation of this women with a diminished ovarian function were an undetectable serum level of AMH (<0.02 ng/mL) and an elevated serum level of FSH (63.65 mIU/mL). A single dose of autologous PRP (extracted from 40 mL of peripheral blood) in combination with gonadotropin (150IU rFSH/75 IU rLH) was directly injected into the stroma of bilateral ovaries via vaginal sonographic guidance. Following the treatment, this patient received controlled ovarian stimulation and IVF during the successive months. Following embryo culture, three cleavage-stage embryos were transferred, leading to a successful pregnancy, which later resulted in the live birth of twins. This case report provides one example of alternative therapy that allows POI patients to use autologous oocytes in IVF treatment.
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Affiliation(s)
- Chao-Chin Hsu
- Taiwan United Birth-Promoting Experts (TUBE) Fertility Clinic, Tainan, Taiwan
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
- *Correspondence: Chao-Chin Hsu
| | | | - Isabel Hsu
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Jen Chiu
- Taiwan United Birth-Promoting Experts (TUBE) Fertility Clinic, Tainan, Taiwan
| | - Sonam Dorjee
- Taiwan United Birth-Promoting Experts (TUBE) Fertility Clinic, Tainan, Taiwan
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Li XT, Li PY, Liu Y, Yang HS, He LY, Fang YG, Liu J, Liu BY, Chaplin JE. Health-related quality-of-life among patients with premature ovarian insufficiency: a systematic review and meta-analysis. Qual Life Res 2019; 29:19-36. [PMID: 31620985 PMCID: PMC6962283 DOI: 10.1007/s11136-019-02326-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/01/2019] [Indexed: 12/31/2022]
Abstract
PURPOSE To systematically review studies investigating health-related quality-of-life (HrQoL) in patients with premature ovarian insufficiency (POI), to examine questionnaires used and to conduct a meta-analysis of control studies with normal ovarian function. METHODS Data sources: PubMed, Embase, Web of science, CNKI, and CQVIP, searched from inception until June 2018. The search strategy was a combination of medical (e.g. POI), subjective (e.g. well-being) and methodological (e.g. questionnaires) keywords. PRISMA guidelines were used to assess outcome data quality/validity by one reviewer, verified by a second reviewer. Risk of bias within studies was evaluated. A meta-analysis compared HrQoL in patients and non-patients. Due to measurement differences in the studies, the effect size was calculated as standard mean difference. RESULTS We identified 6869 HrQoL studies. Nineteen geographically diverse studies met inclusion criteria, dated from 2006, using 23 questionnaires. The meta-analysis included six studies with 645 POI participants (age 33.3 ± 5.47) and 492 normal-ovarian control subjects (age 32.87 ± 5.61). Medium effect sizes were found for lower overall HrQoL (pooled SMD = - 0.73, 95% CI - 0.94, - 0.51; I2 = 54%) and physical function (pooled SMD = - 0.54, 95% CI - 0.69, - 0.39; I2 = 55%). Heterogeneity was investigated. Effect sizes varied for sexual function depending on the measure (SMD = - 0.27 to - 0.74), overall HrQoL (SF-36) had the largest effect size (- 0.93) in one study. The effect sizes for psychological and social HrQoL were small. CONCLUSION POI is associated with low-to-medium effect size on HrQoL compared to normal ovarian controls. The greatest effects are found in general HrQoL and most sexual function areas. Condition-specific questionnaires and RCTs are recommended for further investigation.
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Affiliation(s)
- X T Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - P Y Li
- Department of Pediatrics, The Queen Silvia Children's Hospital, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 416 85, Gothenburg, Sweden
| | - Y Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - H S Yang
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - L Y He
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Y G Fang
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - J Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - B Y Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
| | - J E Chaplin
- Department of Pediatrics, The Queen Silvia Children's Hospital, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 416 85, Gothenburg, Sweden
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Huang L, Chen Y, Luo M, Tang Y, Wei S. Acupuncture for patients with premature ovarian insufficiency: A systematic review protocol. Medicine (Baltimore) 2019; 98:e15444. [PMID: 31045813 PMCID: PMC6504249 DOI: 10.1097/md.0000000000015444] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 04/05/2019] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Premature ovarian insufficiency (POI) is a difficult-to-treat gynecological disorder with complex etiologies. Although acupuncture has gained increased popularity for the management of POI, evidence regarding its efficacy is lacking. This systematic review protocol aims to describe a meta-analysis to assess the effectiveness and safety of acupuncture for patients with POI. METHODS The following 10 databases will be searched from the publishment to July 2019: PubMed, Embase, the Web of Science, the Cochrane Central Register of Controlled Trials, 4 Chinese databases (China National Knowledge Infrastructure, Wanfang Digital Periodicals, Chinese Biomedical Literature Database, Chinese Scientific Journal Database database), 1 Korean medical database (KoreaMed), 1 Japanese medical database (National Institute of Informatics). The primary outcomes will be the resumption of menstruation and the serum FSH levels, and the secondary outcomes include the serum Estradiol levels, anti-Mullerian hormone levels, antral follicle count, follicular growth, endometrial thickness, and adverse events. We will use RevMan V.5.3 to conduct the meta-analysis, if possible. If it is not allowed, a descriptive analysis or a subgroup analysis will be conducted. Risk ratio for dichotomous data and mean differences or standardized mean differences for continuous data will be calculated with 95% confidence intervals using a random effects model or a fixed effects model. RESULTS This study will provide the latest analysis of the currently available evidence for the efficacy of acupuncture in treating POI. PROSPERO REGISTRATION NUMBER CRD42019125996.
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Affiliation(s)
- Li Huang
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine
| | - Yu Chen
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine
| | - Mei Luo
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine
| | - Yancai Tang
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine
| | - Shaobin Wei
- Department of Gynecology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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