scholarly journals Patient-derived endometrial organoids from MRKH patients: Insight in disease causing pathways

2021 ◽  
Author(s):  
Sara Y. Brucker ◽  
Thomas Hentrich ◽  
Julia M. Schulze-Hentrich ◽  
Martin Pietzsch ◽  
Noel Wajngarten ◽  
...  
Keyword(s):  
Reproductive Tract ◽  
Ovarian Function ◽  
Female Reproductive Tract ◽  
Mrkh Syndrome ◽  
Powerful Research Tool ◽  
Healthy Control ◽  
Organoid Cultures ◽  
Holding Back

The uterus is responsible for the nourishment and mechanical protection of the developing embryo and fetus and is an essential part in mammalian reproduction. The Mayer-Rokitansky-Kuester-Hauser (MRKH) syndrome is characterized by agenesis of the uterus and upper part of the vagina in females with normal ovarian function. Although heavily studied, the cause of the disease is still enigmatic. Current research in the field of MRKH mainly focusses on DNA-sequencing efforts and, so far, failed to decipher the nature and heterogeneity of the disease, thereby holding back scientific and clinical progress. Here, we developed long-term expandable organoid cultures from endometrium found in uterine rudiment horns of MRKH patients. Phenotypically, they share great similarity with healthy control organoids and are surprisingly fully hormone responsive. Transcriptome analyses, however, identified an array of dysregulated genes that point at potentially disease-causing pathways altered during the development of the female reproductive tract. We consider the endometrial organoid cultures to be a powerful research tool that promise to enable an array of studies into the pathogenic origins of MRKH syndrome and possible treatment opportunities to improve patient quality of life.

scholarly journals Heparan Sulfate Proteoglycan Sulfation Regulates Uterine Differentiation and Signaling During Embryo Implantation

Endocrinology ◽  
2018 ◽  
Vol 159 (6) ◽  
pp. 2459-2472 ◽  
Author(s):  
Yan Yin ◽  
Adam Wang ◽  
Li Feng ◽  
Yu Wang ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Heparan Sulfate ◽  
Signaling Pathways ◽  
Reproductive Tract ◽  
Ovarian Function ◽  
Embryo Implantation ◽  
Uterine Epithelium ◽  
Female Reproductive Tract ◽  
Uterine Receptivity ◽  
Mouse Uterus

Abstract To prepare for embryo implantation, the uterus must undergo a series of reciprocal interactions between the uterine epithelium and the underlying stroma, which are orchestrated by ovarian hormones. During this process, multiple signaling pathways are activated to direct cell proliferation and differentiation, which render the uterus receptive to the implanting blastocysts. One important modulator of these signaling pathways is the cell surface and extracellular matrix macromolecules, heparan sulfate proteoglycans (HSPGs). HSPGs play crucial roles in signal transduction by regulating morphogen transport and ligand binding. In this study, we examine the role of HSPG sulfation in regulating uterine receptivity by conditionally deleting the N-deacetylase/N-sulfotransferase (NDST) 1 gene (Ndst1) in the mouse uterus using the Pgr-Cre driver, on an Ndst2- and Ndst3-null genetic background. Although development of the female reproductive tract and subsequent ovarian function appear normal in Ndst triple-knockout females, they are infertile due to implantation defects. Embryo attachment appears to occur but the uterine epithelium at the site of implantation persists rather than disintegrates in the mutant. Uterine epithelial cells continued to proliferate past day 4 of pregnancy, accompanied by elevated Fgf2 and Fgf9 expression, whereas uterine stroma failed to undergo decidualization, as evidenced by lack of Bmp2 induction. Despite normal Indian hedgehog expression, transcripts of Ptch1 and Gli1, both components as well as targets of the hedgehog (Hh) pathway, were detected only in the subepithelial stroma, indicating altered Hh signaling in the mutant uterus. Taken together, these data implicate an essential role for HSPGs in modulating signal transduction during mouse implantation.

scholarly journals Mechanisms of fibroblast growth factor signaling in the ovarian follicle

2015 ◽  
Vol 228 (2) ◽  
pp. R31-R43 ◽  
Author(s):  
Christopher A Price
Keyword(s):  
Receptor Binding ◽  
Reproductive Tract ◽  
Ovarian Function ◽  
Ovarian Follicle ◽  
Female Reproductive Tract ◽  
Growth Factor Signaling ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Signaling ◽  
Binding Properties ◽  
Differential Action

Fibroblast growth factors (FGFs) have been shown to alter growth and differentiation of reproductive tissues in a variety of species. Within the female reproductive tract, the effects of FGFs have been focused on the ovary, and the most studied one is FGF2, which stimulates granulosa cell proliferation and decreases differentiation (decreased steroidogenesis). Other FGFs have also been implicated in ovarian function, and this review summarizes the effects of members of two subfamilies on ovarian function; the FGF7 subfamily that also contains FGF10, and the FGF8 subfamily that also contains FGF18. There are data to suggest that FGF8 and FGF18 have distinct actions on granulosa cells, despite their apparent similar receptor binding properties. Studies of non-reproductive developmental biology also indicate that FGF8 is distinct from FGF18, and that FGF7 is also distinct from FGF10 despite similar receptor binding properties. In this review, the potential mechanisms of differential action of FGF7/FGF10 and FGF8/FGF18 during organogenesis will be reviewed and placed in the context of follicle development. A model is proposed in which FGF8 and FGF18 differentially activate receptors depending on the properties of the extracellular matrix in the follicle.

scholarly journals Cryopreserved ovarian tissues can maintain a long-term function after heterotopic autotransplantation in rat

Reproduction ◽  
2009 ◽  
Vol 138 (3) ◽  
pp. 519-525 ◽  
Author(s):  
Xiaohui Deng ◽  
Hua Zheng ◽  
Xuan Yu ◽  
Hongling Yu ◽  
Chengmei Zhang ◽  
...  
Keyword(s):  
Reproductive Tract ◽  
Ovarian Function ◽  
Hormone Secretion ◽  
Endocrine Function ◽  
Heterotopic Transplantation ◽  
Adult Rats ◽  
Primordial Follicles ◽  
Time Points ◽  
Adult Rat

The functional longevity of cryopreserved ovarian grafts is one of the most challenging questions regarding ovarian transplantation at present. This study used a rat ovarian grafting model to investigate whether ovarian tissues from adult rats, which had been cryopreserved by vitrification and followed by heterotopic transplantation, could establish long-term hormone secretion and follicle development. Fresh and cryopreserved ovarian tissues were autologously transplanted under the kidney capsule. One-third of the animals in each group (sham-operated, fresh autografts, cryopreserved autografts, or castrated) were killed 5, 8, or 10 months after transplantation. Vaginal cytology, serum estradiol (E2), progesterone, and the morphology of the reproductive tract were used to assess ovarian function. Both fresh and cryopreserved ovarian grafts survived well in all the animal models with comparable proportion of follicles at each stage of folliculogenesis at all three time points. The serum E2 and progesterone concentrations in the groups with fresh or cryopreserved grafts remained comparable with those in sham-operated controls at all investigated time points. However, a loss of grafts and primordial follicles following heterotopic transplantation was noted. In conclusion, the heterotopic autotransplantation of vitrified ovarian tissues from adult rat without vascular anastomosis can maintain long-term ovarian function and exert endocrine function in target organs, in spite of the reduction in follicle pool.

scholarly journals Measles-based Zika vaccine induces long-term immunity and requires NS1 antibodies to protect the female reproductive tract.

2020 ◽  
Author(s):  
Matthias Schnell ◽  
Drishya Kurup ◽  
Christoph Wirblich
Keyword(s):  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Viral Clearance ◽  
Measles Vaccine ◽  
Fetal Protection ◽  
Cell Responses ◽  
Asian Strain ◽  
African Strain ◽  
The Brain

Abstract Zika virus (ZIKV) can cause devastating effects in the unborn fetus of pregnant women. To develop a candidate vaccine that can protect human fetuses, we generated a panel of live measles vaccine (MV) vectors expressing ZIKV-E and -NS1. Our MV-based ZIKV-E vaccine, MV-E2, protected mice from the non-lethal Zika Asian strain (PRVABC59) and the lethal African strain (MR766) challenge. Despite 100% survival of the MV-E2 mice, however, complete viral clearance was not achieved in the brain and reproductive tract of the lethally challenged mice. We then tested a combination of two MV-based vaccines, the MV-E2 and a vaccine expressing NS1 (MV-NS1[2]), and we observed durable plasma cell responses, complete clearance of ZIKV from the female reproductive tract, and complete fetal protection in the lethal African challenge model. Our findings suggest that NS1 antibodies are required to enhance the protection achieved by ZIKV-E antibodies in the female reproductive tract.

scholarly journals Premature Ovarian Insufficiency - an update on recent advances in understanding and management

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2069 ◽  
Author(s):  
Saioa Torrealday ◽  
Pinar Kodaman ◽  
Lubna Pal
Keyword(s):  
Ovarian Function ◽  
Clinical Medicine ◽  
Premature Ovarian Insufficiency ◽  
Clear Understanding ◽  
Timely Manner ◽  
Ovarian Insufficiency ◽  
Ongoing Research ◽  
Health Complications

Premature ovarian insufficiency is a complex and relatively poorly understood entity with a myriad of etiologies and multisystem sequelae that stem from premature deprivation of ovarian sex hormones. Timely diagnosis with a clear understanding of the various comorbidities that can arise from estrogen deficiency is vital to appropriately counsel and treat these patients. Prompt initiation of hormone therapy is critical to control the unsolicited menopausal symptoms that many women experience and to prevent long-term health complications. Despite ongoing efforts at improving our understanding of the mechanisms involved, any advancement in the field in recent decades has been modest at best and researchers remain thwarted by the complexity and heterogeneity of the underpinnings of this entity. In contrast, the practice of clinical medicine has made meaningful strides in providing assurance to the women with premature ovarian insufficiency that their quality of life as well as long-term health can be optimized through timely intervention. Ongoing research is clearly needed to allow pre-emptive identification of the at-risk population and to identify mechanisms that if addressed in a timely manner, can prolong ovarian function and physiology.

Role of new and current methods in semen technology for genetic resource conservation

2004 ◽  
Vol 30 ◽  
pp. 191-205
Author(s):  
W.V. Holt ◽  
P.F. Watson
Keyword(s):  
Reproductive Tract ◽  
Genetic Resource ◽  
Resource Conservation ◽  
Female Reproductive Tract ◽  
Practical Implementation ◽  
New Information ◽  
Frozen Semen ◽  
Genetic Resource Conservation

AbstractThe establishment of repositories of frozen semen, for the conservation of agricultural genetic resources, is not a simple matter of collecting and freezing semen in the hope that one day it will be suitable for use in an artificial insemination procedure. Important genetic issues need to be considered; for example, how many samples should be stored and from how many individuals? Aside from these, many biological and logistic issues must be considered. Cryopreservation technology does not work equally well in all species, often because of anatomical differences in the female reproductive tract leading to significant variability in the number of spermatozoa needed in order to achieve an acceptable conception rate. Moreover, spermatozoa from different species are not equally susceptible to cryoinjury. However, it is also emerging that semen samples from individuals within a species are also of different quality; several studies have revealed that these differences reflect the quality of DNA within the spermatozoon itself and also the efficacy of biochemical functions, including metabolic and signalling systems, within individual cells. As new possibilities to select spermatozoa for insemination arise, especially the use of flowsorting for gender selection, these issues may become more significant. In this article we interpret the way in which some of this new information may impact upon the practical implementation of genetic resource conservation.

Mechanisms of epigenetic remodelling during preimplantation development

2016 ◽  
Vol 28 (2) ◽  
pp. 25 ◽  
Author(s):  
Pablo Juan Ross ◽  
Sebastian Canovas
Keyword(s):  
Information Needs ◽  
Reproductive Tract ◽  
Environmental Changes ◽  
Primordial Germ Cells ◽  
Early Embryo ◽  
Female Reproductive Tract ◽  
Preimplantation Embryos ◽  
Epigenetic Information ◽  
Health And Disease

Epigenetics involves mechanisms independent of modifications in the DNA sequence that result in changes in gene expression and are maintained through cell divisions. Because all cells in the organism contain the same genetic blueprint, epigenetics allows for cells to assume different phenotypes and maintain them upon cell replication. As such, during the life cycle, there are moments in which the epigenetic information needs to be reset for the initiation of a new organism. In mammals, the resetting of epigenetic marks occurs at two different moments, which both happen to be during gestation, and include primordial germ cells (PGCs) and early preimplantation embryos. Because epigenetic information is reversible and sensitive to environmental changes, it is probably no coincidence that both these extensive periods of epigenetic remodelling happen in the female reproductive tract, under a finely controlled maternal environment. It is becoming evident that perturbations during the extensive epigenetic remodelling in PGCs and embryos can lead to permanent and inheritable changes to the epigenome that can result in long-term changes to the offspring derived from them, as indicated by the Developmental Origins of Health and Disease (DOHaD) hypothesis and recent demonstration of inter- and trans-generational epigenetic alterations. In this context, an understanding of the mechanisms of epigenetic remodelling during early embryo development is important to assess the potential for gametic epigenetic mutations to contribute to the offspring and for new epimutations to be established during embryo manipulations that could affect a large number of cells in the offspring. It is of particular interest to understand whether and how epigenetic information can be passed on from the gametes to the embryo or offspring, and whether abnormalities in this process could lead to transgenerationally inheritable phenotypes. The aim of this review is to highlight recent progress made in understanding the nature and mechanisms of epigenetic remodelling that ensue after fertilisation.

scholarly journals Managing menopausal symptoms in patients with hormone receptor-positive gynecologic cancers

2020 ◽  
Vol 22 (3) ◽  
pp. 154-159
Author(s):  
O. V. Shabalova ◽  
S. V. Yureneva ◽  
S. V. Khokhlova ◽  
Zh. R. Gardanova ◽  
E. I. Ermakova
Keyword(s):  
Quality Of Life ◽  
Reproductive Tract ◽  
Ovarian Function ◽  
Disease Free Survival ◽  
Climacteric Symptoms ◽  
Effective Treatment Option ◽  
Natural Menopause ◽  
First Line Therapy ◽  
Pharmacological Correction

Young women with reproductive tract neoplasms who receive treatment leading to termination of ovarian function often suffer from menopause symptoms that contribute to dramatic drop in quality of life. Climacteric symptoms in women with iatrogenic menopause are more severe than in case of natural menopause, especially in women with reproductive tract neoplasms. They lead to dramatic drop in quality of life and are one of the main reasons to stop applying endocrine therapy in women with hormone-positive tumors, which leads to decrease in disease free survival and to decline the prognosis. The most effective treatment option for climacteric symptoms of moderate to severe degrees is menopause hormone therapy; however, such therapy is not suitable for patients with estrogen-dependent tumors in past medical history due to the likelihood risk of progression of cancer, as well as the risk of venous thrombosis, the frequency of which in cancer patients increases. Non-hormonal pharmacological and non-pharmacological correction methods are used as first-line therapy for menopause disorders in women with estrogen-dependent tumors of the reproductive system. Among non-hormonal non-pharmacological correction methods actively study such methods as acupuncture, yoga, exercise to control weight, and a diet rich in phytoestrogens. The most effective non-hormonal methods of correcting vasomotor symptoms are serotonin and norepinephrine reuptake inhibitors. However, currently in Russia these drugs can be prescribed only by a psychiatrist. The finding of effective and safe non-hormonal methods to correct menopause symptoms in women with hormone-positive reproductive tract tumors is the important task in practice among doctors in different specialties.

scholarly journals Kezdeti tapasztalataink a petefészekszövet-fagyasztás bevezetésével

2016 ◽  
Vol 157 (49) ◽  
pp. 1947-1954
Author(s):  
Péter Fancsovits ◽  
János Urbancsek ◽  
László Fónyad ◽  
Anna Sebestyén ◽  
Gézáné †Csorba ◽  
...  
Keyword(s):  
Histological Analysis ◽  
Ovarian Function ◽  
Ovarian Tissue ◽  
Hormone Production ◽  
Oncological Treatment ◽  
Progesterone Production ◽  
Long Term Storage ◽  
Term Storage

Introduction: The oncological treatment may damage ovarian function. To prevent this, it is possible to cryopreserve the ovarian tissue, and to keep the samples for long-term storage. The frozen-thawed tissue could be retransplanted after chemo- or radiotherapy. Aim: The aim of our study was to examine the effect of cryopreservation on the viability of ovarian tissue. Method: We analyzed the survival of frozen-thawed donated ovarian tissues. The quality of the follicles and hormone production in fresh and frozen-thawed samples were compared. Results: Histological analysis showed that the number of viable follicles was reduced by 23% in the frozen-thawed samples. However, viable follicles still presented in post thawing ovarian tissues. Maximal estradiol production in frozen-thawed tissues was 908 pg/ml and hormone production was similar to the control tissues. The maximal progesterone production was 1.95 ng/ml post thawing, but these values were lower than the progesterone production of fresh tissues. Conclusions: The method of ovarian cryopreservation used in our laboratory was able preserve the viability of follicles in frozen-thawed ovarian tissues. Orv. Hetil., 2016, 157(49), 1947–1954.

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