Physiology of the Endometrium and Regulation of Menstruation

The physiological functions of the uterine endometrium (uterine lining) are preparation for implantation, maintenance of pregnancy if implantation occurs, and menstruation in the absence of pregnancy. The endometrium thus plays a pivotal role in reproduction and continuation of our species. Menstruation is a steroid-regulated event, and there are alternatives for a progesterone-primed endometrium, i.e., pregnancy or menstruation. Progesterone withdrawal is the trigger for menstruation. The menstruating endometrium is a physiological example of an injured or “wounded” surface that is required to rapidly repair each month. The physiological events of menstruation and endometrial repair provide an accessible in vivo human model of inflammation and tissue repair. Progress in our understanding of endometrial pathophysiology has been facilitated by modern cellular and molecular discovery tools, along with animal models of simulated menses. Abnormal uterine bleeding (AUB), including heavy menstrual bleeding (HMB), imposes a massive burden on society, affecting one in four women of reproductive age. Understanding structural and nonstructural causes underpinning AUB is essential to optimize and provide precision in patient management. This is facilitated by careful classification of causes of bleeding. We highlight the crucial need for understanding mechanisms underpinning menstruation and its aberrations. The endometrium is a prime target tissue for selective progesterone receptor modulators (SPRMs). This class of compounds has therapeutic potential for the clinical unmet need of HMB. SPRMs reduce menstrual bleeding by mechanisms still largely unknown. Human menstruation remains a taboo topic, and many questions concerning endometrial physiology that pertain to menstrual bleeding are yet to be answered.

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Click Activated Protodrugs Against Cancer Increase the Therapeutic Potential of Chemotherapy through Local Capture and Activation

10.26434/chemrxiv.13087715 ◽

2020 ◽

Author(s):

Kui Wu ◽

Nathan Yee ◽

Sangeetha Srinivasan ◽

Amir Mahmoodi ◽

Michael Zakharian ◽

...

Keyword(s):

Therapeutic Potential ◽

Unmet Need ◽

Sodium Hyaluronate ◽

Maximum Tolerated Dose ◽

The Body ◽

In Vivo Studies ◽

Tumor Biomarker ◽

Tumor Site

<div> <div> <div> <p>A desired goal of targeted cancer treatments is to achieve high tumor specificity with minimal side effects. Despite recent advances, this remains difficult to achieve in practice as most approaches rely on biomarkers or physiological differences between malignant and healthy tissue, and thus benefit only a subset of patients in need of treatment. To address this unmet need, we introduced a Click Activated Protodrugs Against Cancer (CAPAC) platform that enables targeted activation of drugs at a specific site in the body, i.e., a tumor. In contrast to antibodies (mAbs, ADCs) and other targeted approaches, the mechanism of action is based on in vivo click chemistry, and is thus independent of tumor biomarker expression or factors such as enzymatic activity, pH, or oxygen levels. The platform consists of a tetrazine-modified sodium hyaluronate-based biopolymer injected at a tumor site, followed by one or more doses of a trans-cyclooctene (TCO)- modified cytotoxic protodrug with attenuated activity administered systemically. The protodrug is captured locally by the biopolymer through an inverse electron-demand Diels-Alder reaction between tetrazine and TCO, followed by conversion to the active drug directly at the tumor site, thereby overcoming the systemic limitations of conventional chemotherapy or the need for specific biomarkers of traditional targeted therapy. Here, TCO-modified protodrugs of four prominent cytotoxics (doxorubicin, paclitaxel, etoposide and gemcitabine) are used, highlighting the modularity of the CAPAC platform. In vitro evaluation of cytotoxicity, solubility, stability and activation rendered the protodrug of doxorubicin, SQP33, as the most promising candidate for in vivo studies. Studies in rodents show that a single injection of the tetrazine-modified biopolymer, SQL70, efficiently captures SQP33 protodrug doses given at 10.8-times the maximum tolerated dose of conventional doxorubicin with greatly reduced systemic toxicity. </p> </div> </div> </div>

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FTY720 Abrogates the Therapeutic Potential of Adoptively Transferred Treg Via Inhibition of IL-2 Induced in Vivo Expansion

Blood ◽

10.1182/blood.v112.11.2584.2584 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2584-2584

Author(s):

Anna Maria Wolf ◽

Kathrin Hochegger ◽

Robert Zeiser ◽

Christoph Duerr ◽

Michael Sixt ◽

...

Keyword(s):

T Cells ◽

Adoptive Transfer ◽

Chemokine Receptors ◽

Therapeutic Potential ◽

Ex Vivo ◽

Effective Means ◽

Effector T Cells ◽

Target Tissue

Abstract CD4+CD25+ T cells (Treg) entry into secondary lymphoid organs (SLO) and local expansion after activation is at least in part responsible for their immunosuppressive action. Thus we hypothesized that trapping of adoptively transferred Treg in SLO would be an effective means to tip the balance towards a more immunosuppressive milieu within the LN microenvironment. Systemic application of the sphingosine-phosphate receptor agonist FTY720 has been proven to trap harmful effector T cells in SLO, thereby inhibiting their migration and destruction of target tissue. Here we provide first evidence that selective entrapment of adoptively transferred Treg in inflammatory LN can be achieved by blockade of SP-receptors upon ex vivo exposure of Treg to FTY720 before adoptive transfer. FTY720 exposure did not interfere with proper Treg localization within the T-cell areas of SLO as determined by immunofluorescent microscopy after co-transfer of either FTY720- or solvent exposed and subsequently differentially labelled Treg. However, despite the fact that the in vitro phenotype (including expression of adhesion and chemokine receptors), function (including anergy and suppressive activity) and survival (determined by Annexin/PI staining) of Treg remained unaltered by FTY720, it abrogated their protective effect after adoptive transfer in a murine model of acute experimental glomerulonephritis (determined by quantification of proteinuria and histological analysis) as well as in an acute GvHD model (determined by survival analysis and quantification of the in vivo expansion of luciferase-transgenic effector T cells by bioluminiscence technology). Notably, adoptive transfer of CFSE-labelled Treg revealed a markedly impaired proliferation of Treg in inflammatory SLO when pre-exposed to FTY720 ex vivo. Accordingly, FTY720 blocked Treg-proliferation induced by TCR-stimulation in combination with IL-2 in vitro. In line with this observation, FTY720 completely abolishes IL-2 induced phosphorylation of STAT-5. Thus, SP-1P receptors induce Treg trapping in inflammatory SLO but abrogate their in vivo immunosuppressive potential by inhibition of local Treg expansion.

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Correlation between ultrasonographic, hysteroscopic and histopathological findings in patients with abnormal uterine bleeding

International Journal of Reproduction Contraception Obstetrics and Gynecology ◽

10.18203/2320-1770.ijrcog20183326 ◽

2018 ◽

Vol 7 (8) ◽

pp. 3250

Author(s):

Binti R. Bhatiyani ◽

Shrikant Dhumale ◽

Pandeeswari . ◽

Dolly Bashani

Keyword(s):

Endometrial Thickness ◽

Age Groups ◽

Abnormal Uterine Bleeding ◽

Reproductive Age ◽

Heavy Menstrual Bleeding ◽

Menstrual Bleeding ◽

Complete Evaluation ◽

Medical Visits ◽

Adnexal Pathology ◽

Rule Out

Background: Menstrual disorders are common indication for medical visits among women of reproductive age and heavy menstrual bleeding affects up to 30% of women throughout their reproductive lifetime. This study aims at evaluating the different causes and, the clinical presentation of AUB and to compare the role of hysteroscopy, ultrasonography and histopathology in patients with AUB.Methods: 100 women above 45 years of age, presenting with abnormal bleeding per vaginum were evaluated. All patients underwent transvaginal scan to note down the endometrial thickness and to rule out uterine and adnexal pathology. All the patients underwent diagnostic hysteroscopy, followed by a biopsy of the endometrium using a curette. The endometrium was sent to the pathologist. Findings of these diagnostic modalities then correlated.Results: Incidence of AUB was present between the age groups of 45-49 years of age (66%). The commonest presenting complaint in this series was menorrhagia or heavy menstrual bleeding (60%). The finding of thickened endometrium as the most common abnormality on USG (44%) and also on hysteroscopy (45%). As per present study the sensitivity of hysteroscopy is 97.78% and specificity was 34.55%, the negative predictive value of the test is 95%.Conclusions: TVS may be the first line of investigation while evaluating the endometrium in a perimenopausal AUB. It helps to triage the patients into high risk or low risk. Endometrial thickness >4mm as per the present study needs further evaluation. Patients with endometrial thickness less than 4 mm can be reassured. Hysteroscopy is the gold standard in the diagnosis of focal pathology like sub mucous fibroid, polyps or anomalies. Histopathology probably is an indispensable tool specially to rule out premalignant and malignant conditions. Thus, all the modalities instead of being competitive to one another, are complimentary to each other. For complete evaluation of patient with AUB all the three modalities should be used together to come at exact diagnosis.

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Dynamics of Internalization and Intracellular Interaction of Tau Antibodies and Human Pathological Tau Protein in a Human Neuron-Like Model

Frontiers in Neurology ◽

10.3389/fneur.2020.602292 ◽

2020 ◽

Vol 11 ◽

Author(s):

Dov B. Shamir ◽

Yan Deng ◽

Qian Wu ◽

Swananda Modak ◽

Erin E. Congdon ◽

...

Keyword(s):

Tau Protein ◽

Therapeutic Potential ◽

Ex Vivo ◽

Human Model ◽

Paired Helical Filament ◽

Isotype Control ◽

Culture Models ◽

Cellular Compartments ◽

Cell Culture Models

We and others have shown in various in vivo, ex vivo and cell culture models that several tau antibodies interact with pathological tau within neurons. To further clarify this interaction in a dynamic human model, we differentiated SH-SY5Y cells with retinoic acid and BDNF to create a neuron-like model. Therein, tau antibodies were primarily taken up by receptor-mediated endocytosis, and prevented toxicity of human brain-derived paired helical filament-enriched tau (PHF). Subsequently, we monitored in real-time the interaction of antibodies and PHF within endocytic cellular compartments. Cells were pre-treated with fluorescently-tagged PHF and then incubated with tau antibodies, 4E6, 6B2, or non-specific isotype control IgG1 labeled with a pH sensitive dye. The uptake and binding of the efficacious antibody, 4E6, to PHF occurred mainly within the soma, whereas the ineffective antibody, 6B2, and ineffective control IgG1, were visualized via the processes and showed limited colocalization with PHF within this period. In summary, we have developed a neuron-like model that clarifies the early intracellular dynamics of the interaction of tau antibodies with pathological tau, and identifies features associated with efficacy. Since the model is entirely human, it is suitable to verify the therapeutic potential of humanized antibodies prior to extensive clinical trials.

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Evaluation of Outcome Measures of Hysteroscopy Polypectomy in Women with Abnormal Uterine Bleeding

JOURNAL FOR CLINICAL AND DIAGNOSTIC RESEARCH ◽

10.7860/jcdr/2020/45743.14279 ◽

2020 ◽

Author(s):

Zahra Tavoli ◽

Melika Agha Mohammad Ali Kermani ◽

Somayeh Moradpanah ◽

Ali Montazeri

Keyword(s):

Outcome Measures ◽

Abnormal Uterine Bleeding ◽

Complete Recovery ◽

Cross Sectional Study ◽

Uterine Bleeding ◽

Reproductive Age ◽

Heavy Menstrual Bleeding ◽

Menstrual Bleeding ◽

Partial Recovery ◽

Cross Sectional

Introduction: The most common causes of Abnormal Uterine Bleeding (AUB) in women of reproductive age are uterine polyps. Operative hysteroscopy is the management of choice to remove polyp. However, the certainty of the treatment remains to be examined. Aim: To investigate the outcome of hysteroscopy polypectomy in women with AUB. Materials and Methods: This was a cross-sectional study on the samples of women with AUB who underwent a hysteroscopy polypectomy. Patients were assessed pre and postoperatively and were asked to respond to a number of outcome measures including duration of monthly cycle, menstruation cycle, heavy menstrual bleeding, the number of pads used in day and night and improvement of inter-menstrual bleeding, postcoital bleeding, and limited activity. Pre-and postsurgery data were compared using Wilcoxon and McNemar tests. Results: In all, 83 patients were entered into the study. The mean age of participants was 41.8 (±8.37) years. The most common preoperative complaint was heavy menstrual bleeding (n=63, 76%) followed by intermenstrual bleeding (n=40, 48%). There were significant differences between preoperative and postoperative symptoms (p-values <0.05). Perceived complete recovery (n=54, 65%), partial recovery (n=13, 15.7%) and satisfaction (n=66, 79.5%) were high after hysteroscopy. Conclusion: AUB due to polyp might be improved with hysteroscopy. Further investigations are needed to confirm the results and to study on co-existence of other causes of AUB after hysteroscopy polypectomy.

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90 YEARS OF PROGESTERONE: Selective progesterone receptor modulators in gynaecological therapies

Journal of Molecular Endocrinology ◽

10.1530/jme-19-0238 ◽

2020 ◽

Vol 65 (1) ◽

pp. T15-T33

Author(s):

H O D Critchley ◽

R R Chodankar

Keyword(s):

Progesterone Receptor ◽

Unmet Need ◽

Abnormal Uterine Bleeding ◽

Reproductive Age ◽

Female Reproductive Health ◽

Emergency Contraceptive ◽

Health And Disease ◽

Receptor Modulators ◽

Selective Progesterone Receptor Modulators ◽

Progesterone Receptor Modulators

Abnormal uterine bleeding (AUB) is a chronic, debilitating and common condition affecting one in four women of reproductive age. Current treatments (conservative, medical and surgical) may be unsuitable, poorly tolerated or may result in loss of fertility. Selective progesterone receptor modulators (SPRMs) influence progesterone-regulated pathways, a hormone critical to female reproductive health and disease; therefore, SPRMs hold great potential in fulfilling an unmet need in managing gynaecological disorders. SPRMs in current clinical use include RU486 (mifepristone), which is licensed for pregnancy interruption, and CDB-2914 (ulipristal acetate), licensed for managing AUB in women with leiomyomas and in a higher dose as an emergency contraceptive. In this article, we explore the clinical journey of SPRMs and the need for further interrogation of this class of drugs with the ultimate goal of improving women’s quality of life.

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A chemically unmodified agonistic DNA with growth factor functionality for in vivo therapeutic application

Science Advances ◽

10.1126/sciadv.aay2801 ◽

2020 ◽

Vol 6 (14) ◽

pp. eaay2801 ◽

Cited By ~ 1

Author(s):

Ryosuke Ueki ◽

Satoshi Uchida ◽

Naoto Kanda ◽

Naoki Yamada ◽

Ayaka Ueki ◽

...

Keyword(s):

Growth Factors ◽

Growth Factor ◽

Therapeutic Potential ◽

Growth Factor Receptor ◽

Liver Parenchyma ◽

Therapeutic Effects ◽

Target Tissue ◽

Systemic Injection ◽

High Production Cost

Although growth factors have great therapeutic potential because of their regenerative functions, they often have intrinsic drawbacks, such as low thermal stability and high production cost. Oligonucleotides have recently emerged as promising chemical entities for designing synthetic alternatives to growth factors. However, their applications in vivo have been recognized as a challenge because of their susceptibility to nucleases and limited distribution to a target tissue. Here, we present the first example of oligonucleotide-based growth factor mimetics that exerts therapeutic effects at a target tissue after systemic injection. The aptamer was designed to dimerize a growth factor receptor for its activation and mitigated the progression of Fas-induced fulminant hepatitis in a mouse model. This unprecedented functionality of the aptamer can be reasonably explained by its high nuclease stability and migration to the liver parenchyma. These mechanistic analyses provided insights for the successful application of aptamer-based receptor agonists.

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Markers of human endometrial hypoxia can be detected in vivo and ex vivo during physiological menstruation

Human Reproduction ◽

10.1093/humrep/deaa379 ◽

2021 ◽

Author(s):

J J Reavey ◽

C Walker ◽

M Nicol ◽

A A Murray ◽

H O D Critchley ◽

...

Keyword(s):

Menstrual Cycle ◽

Blood Loss ◽

Ex Vivo ◽

Abnormal Uterine Bleeding ◽

Uterine Bleeding ◽

Menstrual Bleeding ◽

Menstrual Blood ◽

Menstrual Phase ◽

Menstrual Blood Loss

Abstract STUDY QUESTION Can markers of human endometrial hypoxia be detected at menstruation in vivo? SUMMARY ANSWER Our in vivo data support the presence of hypoxia in menstrual endometrium of women during physiological menstruation. WHAT IS KNOWN ALREADY Current evidence from animal models and human in vitro studies suggests endometrial hypoxia is present at menstruation and drives endometrial repair post menses. However, detection of human endometrial hypoxia in vivo remains elusive. STUDY DESIGN, SIZE, DURATION We performed a prospective case study of 16 women with normal menstrual bleeding. PARTICIPANTS/MATERIALS, SETTING, METHODS Reproductively aged female participants with a regular menstrual cycle underwent objective measurement of their menstrual blood loss using the alkaline haematin method to confirm a loss of <80 ml per cycle. Exclusion criteria were exogenous hormone use, an intrauterine device, endometriosis or fibroids >3 cm. Participants attended for two MRI scans; during days 1–3 of menstruation and the early/mid-secretory phase of their cycle. The MRI protocol included dynamic contrast-enhanced MRI and T2* quantification. At each visit, an endometrial sample was also collected and hypoxia-regulated repair factor mRNA levels (ADM, VEGFA, CXCR4) were quantified by RT-qPCR. MAIN RESULTS AND THE ROLE OF CHANCE Women had reduced T2* during menstrual scans versus non-menstrual scans (P = 0.005), consistent with menstrual hypoxia. Plasma flow (Fp) was increased at menstruation compared to the non-menstrual phase (P = 0.0005). Laboratory findings revealed increased ADM, VEGF-A and CXCR4 at menstruation on examination of paired endometrial biopsies from the menstrual and non-menstrual phase (P = 0.008; P = 0.03; P = 0.009). There was a significant correlation between T2* and these ex vivo hypoxic markers (P < 0.05). LIMITATIONS, REASONS FOR CAUTION This study examined the in vivo detection of endometrial hypoxic markers at specific timepoints in the menstrual cycle in women with a menstrual blood loss <80 ml/cycle and without significant uterine structural abnormalities. Further research is required to determine the presence of endometrial hypoxia in those experiencing abnormal uterine bleeding with and without fibroids/adenomyosis. WIDER IMPLICATIONS OF THE FINDINGS Heavy menstrual bleeding (HMB) is a common, debilitating condition. Understanding menstrual physiology may improve therapeutics. To our knowledge, this is the first in vivo data supporting the presence of menstrual hypoxia in the endometrium of women with normal menstrual bleeding. If aberrant in those with HMB, these non-invasive tests may aid diagnosis and facilitate personalized treatments for HMB. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by Wellbeing of Women grant RG1820, Wellcome Trust Fellowship 209589/Z/17/Z and undertaken in the MRC Centre for Reproductive Health, funded by grants G1002033 and MR/N022556/1. H.O.D.C. has clinical research support for laboratory consumables and staff from Bayer AG and provides consultancy advice (but with no personal remuneration) for Bayer AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc; Myovant Sciences GmbH. H.O.D.C. receives royalties from UpToDate for articles on abnormal uterine bleeding. TRIAL REGISTRATION NUMBER N/A.

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Profil perdarahan uterus abnormal di RSUP Prof. Dr. R. D. Kandou Manado periode 1 Januari 2013 – 31 Desember 2014

e-CliniC ◽

10.35790/ecl.4.1.2016.12108 ◽

2016 ◽

Vol 4 (1) ◽

Author(s):

Muhammad Rifki ◽

Maria Loho ◽

Frank M.M Wagey

Keyword(s):

Care Center ◽

Abnormal Uterine Bleeding ◽

Reproductive Period ◽

Uterine Bleeding ◽

Reproductive Age ◽

Normal Body Mass Index ◽

Health Care Center ◽

Using Data ◽

Abnormal Vaginal Bleeding

Abstract: Abnormal Uterine Bleeding (AUB) is the most common cause of abnormal vaginal bleeding among women in reproductive age. Approximately 30% of women come to health care center with complaints of AUB during their reproductive period. The causes of AUB include a broad spectrum of diseases. The main classification of AUB according to FIGO has 9 categories of causes that is the acronym as "PALM-COEIN". This was a descriptive retrospective study using data of medical records of patients with abnormal uterine bleeding. The results showed that of: 51 cases with AUB, most were at the age of 41-50 years (24 cases; 47.06%), with the youngest age was 14 years and the oldest age was 55 years. Most of the cases had normal body mass index, multiparity, and housewife. PALM-COEIN classification showed that most were leiomyoma (29 cases; 56.86%) and ovulatory dysfuntion (11 cases; 21.57%). Conclusion: Of the 51 patients with AUB at the Obstetrics and Gynecology Department of Prof. Dr. R. D Kandou Hospital Manado from January 2013 to December 2014, most cases were aged 41-50 years, multiparity, normal BMI, leiomyoma, treatment with D & C, and the pathological tesult was hyperplasia Keywords: abnormal uterine bleeding (AUB) Abstrak: Perdarahan Uterus Abnormal (PUA) merupakan penyebab tersering perdarahan abnormal per vaginam pada masa reproduksi wanita. Sekitar 30% wanita datang ke pusat pelayanan kesehatan dengan keluhan PUA selama masa reproduktif. Penyebab terjadinya PUA mencakup spektrum yang luas dari berbagai penyakit. Klasifikasi utama yang digunakan untuk PUA berdasarkan FIGO terdapat 9 kategori penyebab yaitu akronim dari “PALM-COEIN”. Jenis penelitian ialah deskriptif retrospektif, dengan menggunakan data rekam medik pasien dengan PUA. Hasil penelitian memperlihatkan dari 51 kasus dengan PUA didapatkan paling sering pada usia 41-50 tahun sebanyak 24 kasus (47,06%), dengan usia termuda 14 tahun dan usia tertua 55 tahun. Kasus PUA terbanyak dengan Indeks Massa Tubuh normal, paritas multipara, dan pekerjaan sebagai Ibu Rumah Tangga. Klasifikasi penyebab dengan PALM-COEIN sebagian besar ialah jenis leiomioma sebanyak 29 kasus (56,86%) dan jenis ovulatory dysfuntion sebanyak 11 kasus (21,57%). Simpulan: Dari 51 kasus PUA di Bagian Obstetri dan Ginekologi RSUP Prof. R. D. Kandou Manado kurun waktu Januari 2013 sampai Desember 2014 ditemukan terbanyak pada usia 41-50 tahun, multipara, IMT normal, jenis PUA leiomioma, pengobatan D & C, dengan hasil PA hiperplasia.Kata kunci: perdarahan uterus abnormal (PUA)

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