scholarly journals Rare deleterious BUB1B variants induce premature ovarian insufficiency and early menopause

2020 ◽  
Vol 29 (16) ◽  
pp. 2698-2707 ◽  
Author(s):  
Qing Chen ◽  
Hanni Ke ◽  
Xuezhen Luo ◽  
Lingbo Wang ◽  
Yanhua Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spindle Assembly Checkpoint ◽  
Late Onset ◽  
Missense Variant ◽  
Premature Ovarian Insufficiency ◽  
Ovarian Activity ◽  
Loss Of Function ◽  
Early Menopause ◽  
Ovarian Insufficiency ◽  
Natural Menopause

Abstract Losing of ovarian functions prior to natural menopause age causes female infertility and early menopause. Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity before 40 years of age. Known genetic causes account for 25–30% of POI cases, demonstrating the high genetic heterogeneity of POI and the necessity for further genetic explorations. Here we conducted genetic analyses using whole-exome sequencing in a Chinese non-syndromic POI family with the affected mother and at least four affected daughters. Intriguingly, a rare missense variant of BUB1B c.273A>T (p.Gln91His) was shared by all the cases in this family. Furthermore, our replication study using targeted sequencing revealed a novel stop-gain variant of BUB1B c.1509T>A (p.Cys503*) in one of 200 sporadic POI cases. Both heterozygous BUB1B variants were evaluated to be deleterious by multiple in silico tools. BUB1B encodes BUBR1, a crucial spindle assembly checkpoint component involved in cell division. BUBR1 insufficiency may induce vulnerability to oxidative stress. Therefore, we generated a mouse model with a loss-of-function mutant of Bub1b, and also employed D-galactose-induced aging assays for functional investigations. Notably, Bub1b+/− female mice presented late-onset subfertility, and they were more sensitive to oxidative stress than wild-type female controls, mimicking the clinical phenotypes of POI cases affected by deleterious BUB1B variants. Our findings in human cases and mouse models consistently suggest, for the first time, that heterozygous deleterious variants of BUB1B are involved in late-onset POI and related disorders.

Prevalence and Risk Factors of Premature Ovarian Insufficiency/Early Menopause

2021 ◽  
Author(s):  
Rinky Giri ◽  
Amanda J. Vincent
Keyword(s):  
Risk Factors ◽  
Premature Ovarian Insufficiency ◽  
Health Impacts ◽  
Ovarian Activity ◽  
Risk Minimization ◽  
Early Menopause ◽  
Ovarian Insufficiency ◽  
Age At Menopause ◽  
Social Environmental ◽  
Underlying Mechanisms

AbstractPremature ovarian insufficiency (POI) and early menopause, defined as loss of ovarian activity prior to 40 years or menopause between the ages of 40 and 45 years, respectively, is associated with significant adverse health impacts. Recent data indicate that the prevalence of POI and early menopause is greater than was previously thought, affecting more than 10% of women. Biopsychosocial risk factors including genetic, autoimmune, reproductive, lifestyle, early-life, social/environmental, and iatrogenic have been associated with POI/early menopause or earlier age at menopause. However, establishing a causal role and the underlying mechanisms remains elusive. Understanding and clarification of these risk factors will facilitate prevention and risk minimization strategies to optimize women's health.

scholarly journals Premature Ovarian Insufficiency: New Perspectives on Genetic Cause and Phenotypic Spectrum

2016 ◽  
Vol 37 (6) ◽  
pp. 609-635 ◽  
Author(s):  
Elena J. Tucker ◽  
Sonia R. Grover ◽  
Anne Bachelot ◽  
Philippe Touraine ◽  
Andrew H. Sinclair
Keyword(s):  
Mouse Models ◽  
Genetic Basis ◽  
Current Knowledge ◽  
Premature Ovarian Insufficiency ◽  
Ovarian Activity ◽  
Substantial Evidence ◽  
Ovarian Insufficiency ◽  
Phenotypic Spectrum ◽  
Disease Mechanisms

Abstract Premature ovarian insufficiency (POI) is one form of female infertility, defined by loss of ovarian activity before the age of 40 and characterized by amenorrhea (primary or secondary) with raised gonadotropins and low estradiol. POI affects up to one in 100 females, including one in 1000 before the age of 30. Substantial evidence suggests a genetic basis for POI; however, the majority of cases remain unexplained, indicating that genes likely to be associated with this condition are yet to be discovered. This review discusses the current knowledge of the genetic basis of POI. We highlight genes typically known to cause syndromic POI that can be responsible for isolated POI. The role of mouse models in understanding POI pathogenesis is discussed, and a thorough list of candidate POI genes is provided. Identifying a genetic basis for POI has multiple advantages, such as enabling the identification of presymptomatic family members who can be offered counseling and cryopreservation of eggs before depletion, enabling personalized treatment based on the cause of an individual's condition, and providing better understanding of disease mechanisms that ultimately aid the development of improved treatments.

scholarly journals Heterozygous FMN2 Missense Variant Found in A Family Case of Premature Ovarian Insufficiency

2021 ◽  
Author(s):  
Jie Li ◽  
Tianliu Peng ◽  
Le Wang ◽  
Panpan Long ◽  
Ruping Quan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Low Frequency ◽  
Missense Variant ◽  
Sporadic Case ◽  
Premature Ovarian Insufficiency ◽  
Chinese Family ◽  
Ovarian Insufficiency ◽  
Mutant Type ◽  
Pathogenic Genes ◽  
Whole Exome

Abstract Background Premature Ovarian Insufficiency plagues 1% of women under 40, while quite a few remain an unknown cause. The development of sequencing has helped find pathogenic genes and reveal the relationship between DNA repair and ovarian reserve. Through the exome sequencing, our study targets screening out the possible POI pathogenic gene and variants in a Chinese family and 20 sporadic POI patients, preliminarily exploring the functional impact and finding out potential linkages between the gene and POI. Results The whole exome sequencing suggested a novel FMN2 heterozygous variant c.1949C > T (p.Ser650Leu) carried by all three patients in a Chinese family and another c.1967G > A(p.Arg656His) variant in a sporadic case. Since no FMN2 missense mutation is reported for causing human POI, we preliminarily assessed p.Ser650Leu variant via cross-species alignment and 3D modeling and found it possibly deleterious. A series of functional evidence was consistent with our hypothesis. We proved the expression of FMN2 in different stages of oocytes and observed a statistical difference of chromosomal breakages between the POI patient carrying p.Arg656His variant and the health control (p = 0.0013). Western Blot also suggested a decrease in FMN2 and P21 in the mutant type and an associated increase in H2AX. The p.Arg656His variant with an extremely low frequency also indicated that the gene FMN2 might play an essential role in the genetic etiology of POI. To the best of our knowledge, this is the first POI report on missense variants of FMN2. Conclusion This finding indicates a novel gene possibly related to POI and sheds lights on the study of FMN2.

scholarly journals Age at menopause and the correlates of natural menopause among urban and rural women in the southern Nigeria

2021 ◽  
Vol 10 (4) ◽  
pp. 1266
Author(s):  
Eugene M. Ikeanyi ◽  
Ebenezer H. Ikobho
Keyword(s):  
Rural Women ◽  
Late Onset ◽  
Preventive Health Care ◽  
Ovarian Activity ◽  
Menopausal Woman ◽  
Chronic Hypertension ◽  
Cross Sectional Survey ◽  
Natural Menopause ◽  
Cross Sectional ◽  
Age At Menopause

Background: Menopause, the point in a woman’s life when permanent cessation of cyclical menstruation occurs for a period of 12 months due to the loss of ovarian activity marking the end of reproductive lifespan and potential. Natural menopause is a physiological event, universal women phenomenon and irreversible part of the entire normal aging process. It brings the menopausal woman for preventive health care services due to its associated health implications. This study sought to investigate the age at menopause and its correlates in southern Nigerian women.Methods: A cross-sectional survey of datasets of women from two different communities attending annual religious conference was conducted using tested semi-structured researcher-administered questionnaire in 2019.Results: Data was analyzed on 152 participants from an urban and a rural communities. Mean chronological age was 58.8±8.8 years and parity was 6.4±2.2. Mean age at menopause was 50.0±4.6 years, median (IQR) 50.0 (47-53) and 49.2±4.7 versus 50.5±4.5 and median (IQR) 49.5 (46-51) and 50.5 (47-54) for urban and rural participants respectively.  1.3%, 9.2%, 69.7% and 19.7% were premature, early, normal and late onset menopause respectively. Risk of early onset menopause was insignificantly increased by higher education, social class, lower BMI and low parity. Forgetfulness (20.3%), irritability (19.5%), hot flushes (17.3%) and insomnia (16.5%) were the leading symptoms. Main complications were chronic hypertension 62 (40.8%), diabetes mellitus 12 (7.9%) and 4 (2.6%) recent fractures.Conclusions: Age at menopause was moderate, early menopause was rather high, programmed preventive healthcare services should address modifiable risk factors. Cancer screening services for late onset women is equally crucial.

scholarly journals Early menopause and premature ovarian insufficiency are associated with increased risk of type 2 diabetes: a systematic review and meta-analysis

2019 ◽  
Vol 180 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Panagiotis Anagnostis ◽  
Konstantinos Christou ◽  
Aikaterini-Maria Artzouchaltzi ◽  
Nifon K Gkekas ◽  
Nikoletta Kosmidou ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Meta Analysis ◽  
Premature Ovarian Insufficiency ◽  
Early Menopause ◽  
Ovarian Insufficiency ◽  
Pubmed Central ◽  
Age At Menopause ◽  
Increased Risk ◽  
Comprehensive Search

Objective/Design Menopausal transition has been associated with a derangement of glucose metabolism. However, it is not known if early menopause (EM, defined as age at menopause <45 years) or premature ovarian insufficiency (POI, defined as age at menopause <40 years) are associated with increased risk of type 2 diabetes mellitus (T2DM). To systematically investigate and meta-analyze the best evidence regarding the association of age at menopause with the risk of T2DM. Methods A comprehensive search was conducted in PubMed, CENTRAL and Scopus, up to January 31, 2018. Data are expressed as odds ratio (OR) with 95% confidence intervals (CI). The I 2 index was employed for heterogeneity. Results Thirteen studies were included in the qualitative and quantitative analysis (191 762 postmenopausal women, 21 664 cases with T2DM). Both women with EM and POI were at higher risk of T2DM compared with those of age at menopause of 45–55 years (OR: 1.15, 95% CI: 1.04–1.26, P = 0.003; I 2: 61%, P < 0.002 and OR: 1.50, 95% CI: 1.03–2.19, P = 0.033; I 2: 75.2%, P < 0.003), respectively). Similar associations emerged when women with EM and POI were compared with those of age at menopause >45 years (OR: 1.12, 95% CI: 1.01–1.20, P < 0.02; I 2: 78%, P < 0.001 and OR: 1.53, 95% CI: 1.03–2.27, P = 0.035; I 2: 78%, P < 0.001), respectively). Conclusions Both EM and POI are associated with increased risk of T2DM.

scholarly journals Prevalence of premature ovarian insufficiency and its determinants in Iranian populations: Tehran lipid and glucose study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Marzieh Rostami Dovom ◽  
Razieh ‌Bidhendi-Yarandi ◽  
Kazem Mohammad ◽  
Maryam Farahmand ◽  
Fereidoun Azizi ◽  
...  
Keyword(s):  
Failure Time ◽  
Population Based ◽  
Normal Weight ◽  
Influential Factors ◽  
Reproductive Age ◽  
Premature Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Natural Menopause ◽  
Age At Menopause ◽  
Aft Model

Abstract Background Premature ovarian insufficiency (POI) considered as a concerning health issue for women of reproductive age. In this study we aim to estimate the prevalence of POI and assessing the influential factors. Methods Data was obtained from Tehran lipid and glucose study (TLGS). All eligible post-menarcheal female participants of the TLGS, ages 20–65, were recruited (n = 6521). Participants were followed for the event of menopause, and age at menopause was recorded. Kaplan Meier analysis was applied to estimate mean and median for age at menopause. Weibull accelerated failure time survival regression model (AFT), was applied to assess influential determinants of POI. Conditional probability approach was used to provide estimation for prevalence of POI. Results In this population-based study, the prevalence of POI (menopause age < 40 years) and early menopause (menopause age < 45 years) were estimated 3.5% and 24.6%, respectively. AFT model showed that in comparison to normal weight women, time to menopause was decreased by − 0.09 year (95% CI − 0.27, − 0.01, p = 0.023) and − 0.03 year (95% CI − 0.05, − 0.02, p = 0.000) in underweight and overweight women, respectively. Moreover, time to natural menopause was increased by 0.12 year (95% CI 0.07 to 0.17, p = 0.000) in women used oral contraceptives for > 6 months. Conclusion About one quartile of Iranian women experienced menopause at an age less than 45, especially the non-normal weight ones; this high prevalence is a critical public health concerns that needs to be addressed by health policy makers.

Premature and Early Menopause in Relation to Cardiovascular Disease

2021 ◽  
Author(s):  
Izaäk Schipper ◽  
Yvonne V. Louwers
Keyword(s):  
Cardiovascular Disease ◽  
Postmenopausal Women ◽  
Cardiovascular Events ◽  
Premature Ovarian Insufficiency ◽  
Premature Menopause ◽  
Bilateral Oophorectomy ◽  
Early Menopause ◽  
Ovarian Insufficiency ◽  
Age At Menopause ◽  
Increased Risk

AbstractPostmenopausal women have an increased risk for cardiovascular diseases. It has been postulated that the loss of ovarian function and subsequent deficiency of endogenous estrogens after menopause contributes to this elevated risk of cardiovascular disease in postmenopausal women. Compared with woman entering menopause at the mean age of 51 years, in women with early menopause or premature ovarian insufficiency the risk for cardiovascular disease is even greater. These women lack the cardioprotective effect of endogenous estrogens for many more years than do women entering natural menopause. The majority of data assessing the risk of cardiovascular disease in relation to age at menopause and specifically premature menopause are derived from large epidemiological cohort studies. In addition, observations in women undergoing bilateral oophorectomy at an early age provide convincing evidence regarding association between early menopause or POI and the development of cardiovascular events and mortality. Moreover, genetic variants associated with earlier age at menopause have also been found to increase the risk of cardiovascular events in women. It has been substantiated that hormone replacement therapy (HRT) decreases the risk for ischemic heart disease and eliminates the increased cardiovascular disease mortality. It is therefore crucial to start HRT as soon as possible, particularly in women with premature ovarian insufficiency.

Sign in / Sign up

Export Citation Format

Share Document