Onset Of Premature Ovarian Insufficiency Research Articles

Puberty progression in girls with Turner syndrome after ovarian tissue cryopreservation

To study the impact of unilateral ovariectomy for ovarian tissue cryopreservation (OTC) on the function of the remaining ovary in girls with Turner syndrome. A prospective cohort study as a follow-up of OTC in a research setting (the TurnerFertility trial, NCT03381300). University Hospital. A total of 28 girls with Turner syndrome with follicles in their cryopreserved ovarian cortex tissue, aged 5-19 years. Of the 28 girls, 21 had a 45,X/46,XX mosaic karyotype; 5 had structural aberrations of the X chromosome; 1 had a 45,X monosomy; and 1 had a 45,X/47,XXX karyotype. Girls were monitored annually after OTC for pubertal development and levels of antimüllerian hormone (AMH), follicle-stimulating hormone, luteinizing hormone, estradiol, and inhibin B. Thelarche, menarche, and onset of premature ovarian insufficiency. The girls were monitored for a median duration of 3.4 years (maximum 6.6 years). The pubertal development of five prepubertal girls is still unknown; all were aged <10 years and had low gonadotropin and estradiol levels at the end of the follow-up. Seven of the eight girls of approximately pubertal age (10-12 years) experienced spontaneous thelarche, although one received medication to induce puberty. Eleven of the 14 girls between the ages of 14-17 years experienced spontaneous menarche; three other girls with thelarche still had ongoing puberty at the end of follow-up with normal gonadotropins and AMH levels above the detection limit. Approximately 6-12 months after OTC, a decline in AMH concentration was observed in 57% (16/28) of girls, followed by an increase in AMH concentration in the following years. Six of the total 28 girls started hormone replacement therapy because of symptoms of premature ovarian insufficiency, and all had AMH levels <0.50 μg/L before OTC. Pubertal development progressed after unilateral ovariectomy for OTC in most girls with Turner syndrome. Hormone replacement therapy was required within a few years for girls with unfavorable parameters before OTC, such as AMH levels <0.50 μg/L. Decisions regarding OTC should be personalized, considering the girl's preferences and specific characteristics. NCT03381300-Preservation of ovarian cortex tissue in girls with Turner syndrome-Full Text View-ClinicalTrials.gov. Registered on: December 21, 2017. The first patient was recruited on January 1,2018.

Single-nucleus and spatial transcriptomics of paediatric ovary: Molecular insights into the dysregulated signalling pathways underlying premature ovarian insufficiency in classic galactosemia.

Classic galactosemia (CG) is an inborn error of galactose metabolism caused by mutations in the GALT gene. Premature ovarian insufficiency (POI) is a later complication that affects 80% of women with CG due to a significant decline in ovarian reserve (primordial follicle pool). The definite mechanisms underlying the early onset of POI in CG patients are not fully understood. In this study, we performed single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics on ovary tissue biopsies from prepubertal girls diagnosed with CG to investigate dynamic changes in gene expression and altered signalling pathways in granulosa cells, oocytes, and stromal cells. We generated single-nucleus and spatial transcriptomics atlas of human ovaries from prepubertal girls diagnosed with and without CG. snRNA-seq profiling of the paediatric ovary revealed a diverse ovarian microenvironment with seven distinct major cell types. Our transcriptomic analysis revealed an increase in the expression of several endoplasmic reticulum stress and oxidative stress associated genes, which can promote apoptosis of granulosa cells in CG. PTEN/PI3K/AKT signalling, which is crucial for primordial follicle activation and survival was dysregulated as supported by upregulated PTEN transcripts and a significant reduction in phospho-AKT levels in the granulosa cells and oocytes. We also found a marked increase in expression of phospho-H2A.X, LC3A/B and CASP9 in the primordial follicles of CG ovaries suggesting DNA damage, autophagy, and accelerated follicular atresia. Furthermore, we noticed genes participating in extracellular matrix organisation, integrin and gap junction signalling, essential for structural support of the ovarian stroma were profoundly altered. Our findings provide molecular insights into the dysregulated cellular signalling pathways essential for primordial follicle growth and survival that can explain the etiology of POI in CG patients. This study has implications in the development of future therapeutic interventions to preserve ovarian function and promote femalereproductive health. Created a comprehensive single-nucleus transcriptomic atlas and spatial landscape of paediatric ovary tissue from prepubertal girls diagnosed with classic galactosemia (CG). Our transcriptomic analysis revealed activation of genes associated with ER-stress signalling, oxidative stress response and ATM signalling/DNA damage response as shown by significant increase in expression of p-EIF2A, p-H2A.X and LC3A/B in the primordial follicles of CG ovary. PTEN/PI3K/AKT signalling pathways was dysregulated evidenced by a significant reduction in phospho-AKT expression in the primordial follicles of CG ovary, suggesting impaired follicle activation and survival.

Impaired IL-27 signaling aggravates macrophage senescence and sensitizes premature ovarian insufficiency induction by high-fat diet

Premature ovarian insufficiency (POI) critically affects female reproductive health, with obesity being a significant and recognized risk factor. Interleukin-27 (IL-27), known for its role in immune modulation and inflammation, has garnered attention in metabolic syndrome research. Nonetheless, the role of these immunometabolic factors on the initiation of POI remains to be unraveled. Our investigation delves into the influence of impaired IL-27 signaling on POI induction, particularly under the challenge of a high-fat diet (HFD). We analyzed patients' serum profiles and established a correlation of increased serum triglycerides with decreased IL-27 levels in POI cases. Experiments on C57BL/6 mice lacking the IL-27 receptor alpha (Il27ra−/−) revealed that when subjected to HFD, these mice developed hallmark POI symptoms. This includes escalated lipid deposition in both liver and ovarian tissues, increased ovarian macrophages cellular aging, and diminished follicle count, all pointing to compromised ovarian function. These findings unveil a novel pathway wherein impaired IL-27 signaling potentiates the onset of POI in the presence of HFD. Understanding the intricate interplay between IL-27, metabolic alterations, and immune dysregulation sheds light on potential therapeutic avenues for managing POI, offering hope for improved reproductive health outcomes.

POI-associated EIF4ENIF1 mutations exhibit impaired translation regulation abilities

Various genetic variants have been found to be associated with the clinical onset of premature ovarian insufficiency (POI). However, when measured in vitro, the functional influence of the variants can be difficult to determine. By whole-exome sequencing (WES) of 93 patients with sporadic POI, we found a missense variant c.623G > A;p.R208H in the EIF4ENIF1 gene. In silico prediction of the variant using different algorithms suggested it might be a damaging variant. We compared the property of EIF4ENIF1 R208H and Q842P, a POI-related mutant that we reported previously, with wildtype (WT) protein using 293FT cells in vitro. Surprisingly, a change in subcellular distribution and granule forming ability (Q842P) and nuclear import capacity (R208H) was not observed, despite domain prediction evidences. Since EIF4ENIF1 was reported to inhibit translation, we employed T&T-seq, a translation-transcription dual-omics sequencing method, to profile gene expression upon overexpression of EIF4ENIF1 WT and mutants. EIF4ENIF1 WT overexpression group exhibited significantly (P < 0.0001) lower translation efficiency (TE) than empty vector or GFP overexpression control group. Surprisingly, EIF4ENIF1 Q842P overexpression failed to repress global translation, showing an overall TE significantly higher than WT group. Overexpression R208H significantly (P < 0.0001) lowered the overall TE, whereas exhibiting a reduced translation inhibitory effect on high-TE genes (TE > 2 in GFP control group). Several fertility-associated genes, such as AMH in Q842P group and SERPINE1 and THBS1 in R208H group, was translationally up-regulated in mutant groups versus WT control, suggesting a potential mechanism of mutated EIF4ENIF1 causing POI via impaired translation repression. It is further proposed that T&T-seq can be a sensitive evaluation tool for the measurement of functional alteration by variants in many other translational regulator genes, not only EIF4ENIF1, helping to eliminate misinterpretation of clinical significance of genetic variants.

Pyrroloquinoline quinone promotes human mesenchymal stem cell-derived mitochondria to improve premature ovarian insufficiency in mice through the SIRT1/ATM/p53 pathway

BackgroundDNA damage and oxidative stress induced by chemotherapy are important factors in the onset of premature ovarian insufficiency (POI). Studies have shown that mitochondria derived from mesenchymal stem cells (MSC-Mito) are beneficial for age-related diseases, but their efficacy alone is limited. Pyrroloquinoline quinone (PQQ) is a potent antioxidant with significant antiaging and fertility enhancement effects. This study aimed to investigate the therapeutic effect of MSC-Mito in combination with PQQ on POI and the underlying mechanisms involved.MethodsA POI animal model was established in C57BL/6J mice by cyclophosphamide and busulfan. The effects of MSC-Mito and PQQ administration on the estrous cycle, ovarian pathological damage, sex hormone secretion, and oxidative stress in mice were evaluated using methods such as vaginal smears and ELISAs. Western blotting and immunohistochemistry were used to assess the expression of SIRT1, PGC-1α, and ATM/p53 pathway proteins in ovarian tissues. A cell model was constructed using KGN cells treated with phosphoramide mustard to investigate DNA damage and apoptosis through comet assays and flow cytometry. SIRT1 siRNA was transfected into KGN cells to further explore the role of the SIRT1/ATM/p53 pathway in combination therapy with MSC-Mito and PQQ for POI.ResultsThe combined treatment of MSC-Mito and PQQ significantly restored ovarian function and antioxidant capacity in mice with POI. This treatment also reduced the loss of follicles at various stages, improving the disrupted estrous cycle. In vitro experiments demonstrated that PQQ facilitated the proliferation of MitoTracker-labelled MSC-Mito, synergistically restoring mitochondrial function and inhibiting oxidative stress in combination with MSC-Mito. Both in vivo and in vitro, the combination of MSC-Mito and PQQ increased mitochondrial biogenesis mediated by SIRT1 and PGC-1α while inhibiting the activation of ATM and p53, consequently reducing DNA damage-mediated cell apoptosis. Furthermore, pretreatment of KGN cells with SIRT1 siRNA reversed nearly all the aforementioned changes induced by the combined treatment.ConclusionsOur research findings indicate that PQQ facilitates MSC-Mito proliferation and, in combination with MSC-Mito, ameliorates chemotherapy-induced POI through the SIRT1/ATM/p53 signaling pathway.

Rescue of follicle development after oocyte-induced ovary dysfunction and infertility in a model of POI.

The mechanisms and aetiology underlying the development of premature ovarian insufficiency (POI) are poorly understood. However, the oocyte clearly has a role as demonstrated by the Double Mutant (DM) mouse model where ovarian dysfunction (6weeks) is followed by POI (3months) due to oocyte-specific deletion of complex and hybrid N- and O-glycans. The ovaries of DM mice contain more primary follicles (3a stage) accompanied by fewer developing follicles, indicating a block in follicle development. To investigate this block, we first analysed early follicle development in postnatal (8-day), pre-pubertal (3-week) and post-pubertal (6-week and 3-month) DM (C1galt1 F/F Mgat1 F/F:ZP3Cre) and Control (C1galt1 F/F Mgat1 F/F) mice. Second, we investigated if transplantation of DM ovaries into a "normal" endocrine environment would restore follicle development. Third, we determined if replacing DM ovarian somatic cells would rescue development of DM oocytes. At 3-week, DM primary 3a follicles contain large oocytes accompanied by early development of a secondGC layer and increased GC proliferation. At 6-week, DM primary 3a follicles contain abnormally large oocytes, accompanied with decreased GC proliferation. Transplantation of DM ovaries into a 'normal' endocrine environment did not restore normal follicle development. However, replacing somatic cells by generating reaggregated ovaries (ROs) did enable follicle development to progress and thus highlighted intra-ovarian factors were responsible for the onset of POI in DM females. Thus, these studies demonstrate oocyte-initiated altered communication between GCs and oocytes results in abnormal primary follicles which fail to progress and leads to POI.

Rapid ovarian transcript changes during the onset of premature ovarian insufficiency.

Premature ovarian insufficiency (POI) affects 1-3% of women under 40 years of age. The identified causes are highly heterogeneous, and 70% of the cases are idiopathic. The ovarian manifestation varies from a variable population of follicles that fail to develop (follicular POI) to the absence of follicles (afollicular POI) with a transition from one to the other over time. Previously, we have described a mouse model of POI that results from an oocyte-specific deletion of N- and O-glycans; Double Mutant (DM). DM females produce only one litter before undergoing POI due to ovarian dysfunction. In this study, we have characterised the gene expression profile of prepuberal (3 weeks), fertile (6 weeks) and infertile (9 weeks) DM ovaries. Up-regulation of cathepsin K (Ctsk, with unknown ovarian function) seems to trigger transcriptional changes in DM ovaries. Significant transcriptional changes then occur rapidly, associated with morphophysiological changes displayed by DM mice throughout the onset of POI. We identified genetic pathways such as extracellular matrix and immune response as candidates for the onset of POI in DM females. Remarkably, DM mice and POI women share a set of differentially expressed genes, including a functionally and co-expressed network of Mcm (minichromosome maintenance proteins) family members. The transcriptomic profile of the DM mouse model provides novel insight into the aetiology of POI.Lay summaryProblems in ovary function lead to reduced fertility or infertility. One such condition is premature ovarian insufficiency (POI) which affects 1% of women under 40 years of age, and in over 70% of these, the cause of POI is unknown. To investigate POI, we have developed a mouse model. These mice are initially fertile but develop POI by 3 months of age. In this study, we investigated the changes in genes activated in the ovaries during the transition from fertility to POI, and we did this by comparing them to normal mice; gene activation leads to molecule production. A molecule known as cathepsin K seems to trigger changes during the onset of POI, followed by others related to structure and immune response pathways. In addition, some genes were identified that are similar between the POI mice and POI women.

Fertility preservation for genetic diseases leading to premature ovarian insufficiency (POI).

The current review aims to summarize the data available concerning the applicability of fertility preservation techniques to genetic conditions at risk of premature ovarian insufficiency (POI). A literature review through the PubMed Database was carried out. About 10% of cases of POI is related to genetic diseases. The most frequent conditions associated with POI are Turner syndrome and fragile X pre-mutation; mutation of BRCA 1-2 genes and several other mutations and genetic syndromes have recently been highlighted, although they rarely occur. If a diagnosis is issued before POI onset, counseling on currently available fertility preservation techniques is advisable. In case of spontaneous menarche (this can occur variably depending on the mutation) established techniques like embryo or oocyte cryopreservation can be proposed, even if, in some cases, their effectiveness may be reduced by ovarian alterations connected to the mutation. Ovarian tissue cryopreservation has recently been defined as an established medical procedure for fertility preservation in young cancer patients and may be an option for prepubertal patients. However, it is still experimental in special populations with genetic diseases causing POI. New innovative experimental techniques, like in vitro maturation of immature oocytes (IVM) and vitro activation (IVA) of immature follicles on ovarian tissue, have shown limited but encouraging data and they will be probably available in the near future. For a correct risk-benefit evaluation, the following aspects should be considered: actual knowledge about the pathology-specific efficacy of the various techniques, the average age of onset of POI, the possible risks associated with the procedure in relation to the underlying pathology, the probability of spontaneous conception, as well as the health implications of a possible future pregnancy.. Fertility preservation techniques represent a crucial opportunity for patients with genetic risk of POI. Early diagnosis increases the chances to apply these techniques. No specific recommendations concerning fertility preservation for each genetic pathology are available, and clinicians should first counsel the patient and her relatives about known risks and benefits of the available techniques, both those established and those considered as experimental.

AMH assessment five or more years after an initially low AMH level

PurposeAnti-Müllerian hormone (AMH) is a biomarker reflecting ovarian reserve. A low AMH level before 39 years may be associated with a risk of menopause between 40 and 45 years. The risk of onset of premature ovarian insufficiency (POI) is, however, poorly documented. The objective of the study was to determine the prevalence of POI 5–10 years after an AMH assay below 8 pmol/L. MethodsWe included women aged younger than 36 years who underwent a complete workup for infertility between January 2008 and December 2013 at the University Hospital and had an AMH level less than 8 pmol/L. In 2018, 47 of these women were assessed clinically, and 21 of them agreed to undergo an ovarian reserve test. ResultsThe prevalence of POI after at least 5 years was 8/47, or 17 % [8 %–31 %]. The median time to diagnosis was 5.1 years [2.9–7.3]. There was a significant difference at T0 in the regularity of cycles between the two groups (p = 0.024) and in their baseline serum AMH level: 6.0 pmol/L in the non-POI group vs 4.2 pmol/L in the POI group (p = 0.002). ConclusionSerum AMH < 8 pmol/L before the age of 36 years appears to be a risk factor for POI. These women require regular follow-up, especially if their cycles are irregular.

Prevalence of Stress Urinary Incontinence in Women with Premature Ovarian Insufficiency.

Background: To determine the prevalence of stress urinary incontinence (SUI) and associated factors in women with premature ovarian insufficiency (POI). Materials and Methods: The study included 149 patients with POI and 303 control women without POI. Age, body mass index (BMI), gestational history, time since onset of POI, and status of hormone therapy (HT) for POI were recorded. Results: There was no statistical difference in the mean age, BMI, and parity between the two groups. The prevalence of SUI in the POI group tended to be higher than that in the control group (20.9%, 30/149 vs. 16.2%, 49/303), although not significantly (p = 0.297). About 41.6% (62/149) of patients with POI received HT. Patients with POI and SUI were older (p = 0.018) and had higher BMI (p = 0.007) than women with POI without SUI (p = 0.007). Compared to nulliparas, primiparas were more likely to have SUI (p = 0.046). However, SUI developed irrespective of time since onset of oligomenorrhea/amenorrhea or HT use. Furthermore, regression analysis showed that the prevalence of SUI was higher in women 30-39 years of age (odds ratio [OR] = 3.27, p = 0.002) and older than 40 years (OR = 7.78, p = 0.001). Primiparas (OR = 2.89, p = 0.001) and vaginal delivery (OR = 2.58, p = 0.023) were associated with SUI. Conclusions: The prevalence of SUI was fairly high among patients with POI, and age, parity, and vaginal delivery were the main risk factors. However, duration of POI and HT use had no effect on SUI. Increasing awareness of the importance of urinary system health in this population will improve the quality of life for these women.

Analysis of in vitro follicle development during the onset of premature ovarian insufficiency in a mouse model.

Premature ovarian insufficiency (POI) occurs in 1% of women under 40 years of age and is predominantly idiopathic. In a transgenic mouse model of follicular POI, the Double Mutant (DM), female mice are fertile at 6 weeks of age, become infertile by 9 weeks and exhibit POI by 3 months. DM female mice generate oocytes lacking mucin O-glycans and complex N-glycans due to deletion of core 1 synthase, glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1 (C1galt1) and mannoside acetylglucosaminyltransferase 1 (Mgat1) respectively (DM, C1galt1F/FMgat1F/F:ZP3Cre; Control, C1galt1F/FMgat1F/F). To determine whether DM follicle development could be improved in a controlled environment, follicles from DM and Control mice were cultured individually and follicle growth, morphology, survival and antrum formation were evaluated. DM ovaries were more rigid than Control ovaries at 3, 6 and 9 weeks, which was exacerbated with age, resulting in a failure to isolate follicles from 9 week-old DM females. DM follicles had decreased survival compared with Control follicles from females at 3 and 6 weeks of age. Furthermore, survival rate of DM follicles decreased with age between 3 and 6 weeks. DM follicles at both 3 and 6 weeks had accelerated follicle growth and altered antrum formation during the first few days of culture but, after 6 days, follicles were equivalent in size to the Controls. In conclusion, a population of DM follicles retain the potential to develop in vitro, and therefore follicle culture offers a reliable method to generate antral follicles from preantral follicles after the onset of POI in these female mice.

Premature ovarian insufficiency: from pathogenesis to clinical management.

Premature ovarian insufficiency (POI) represents a condition characterized by the absence of normal ovarian function due to an incipient (by 3-10 years) ovarian aging. In most of the women affected there are no signs or symptoms that precede the interruption of menstruation and the onset of POI and the majority of women have a normal history of menarche, regular menstrual cycles and normal fertility. The possible genetic role in the development of POI has been largely demonstrated and many genes have been involved; on the other hand, ovary is not protected immunologically and the detection of autoantibodies directed against various ovarian targets strongly support the hypothesis of an autoimmune etiology. In approximately 5-10% of women with a diagnosis of POI with a normal karyotype, a spontaneous pregnancy could occur even if the recovery of ovarian function is temporary and poorly predictable. Embryo donation and adoption are other alternatives that should be considered. POI and subsequent loss of reproductive capacity is a devastating condition and a difficult diagnosis for women to accept so it requires an individualized and a multidisciplinary approach. Hormonal replacement therapy (HRT) should be commenced as soon as possible to prevent and to contrast the onset of the symptoms related to hypoestrogenism and to improve the quality of life for these women.