Tube Epithelium Research Articles

Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma

The distal region of the uterine (Fallopian) tube is commonly associated with high-grade serous carcinoma (HGSC), the predominant and most aggressive form of ovarian or extra-uterine cancer. Specific cell states and lineage dynamics of the adult tubal epithelium (TE) remain insufficiently understood, hindering efforts to determine the cell of origin for HGSC. Here, we report a comprehensive census of cell types and states of the mouse uterine tube. We show that distal TE cells expressing the stem/progenitor cell marker Slc1a3 can differentiate into both secretory (Ovgp1+) and ciliated (Fam183b+) cells. Inactivation of Trp53 and Rb1, whose pathways are commonly altered in HGSC, leads to elimination of targeted Slc1a3+ cells by apoptosis, thereby preventing their malignant transformation. In contrast, pre-ciliated cells (Krt5+, Prom1+, Trp73+) remain cancer-prone and give rise to serous tubal intraepithelial carcinomas and overt HGSC. These findings identify transitional pre-ciliated cells as a cancer-prone cell state and point to pre-ciliation mechanisms as diagnostic and therapeutic targets.

Mullerianosis of the urinary bladder: A great mimicker

Mullerianosis is a rare benign lesion consisting of an admixture of two or more of the following tissues: endometriosis, endocervicosis, and endosalpingiosis. It most commonly affects the urinary bladder and females of reproductive age group. Müllerianosis of the bladder is an extremely rare entity with fewer than 30 cases reported. Herein we report one such rare case of mullerianosis of the urinary bladder in a 33-year-old female who had undergone cesarian section 2 years back, presented with painless hematuria associated with menstruation. USG revealed a soft tissue lesion measuring 23×11 mm abutting the wall of the urinary bladder and extending into it. These findings were suspicious for endometriosis. The patient was admitted to the hospital for transurethral resection of a bladder lesion (TURBT). Operative findings revealed a solid 2x2 cm mass in the posterior wall of the urinary bladder. Superficial and deep TURBT chips were sent for histopathological examination. On microscopic examination, there were variable-sized glands lined by endometrial, endocervical, or tubal epithelium embedded in the bladder wall. The case was diagnosed as mullerianosis of the urinary bladder. As this rare entity, since it mimics benign and malignant neoplasms clinically and radiologically, pathologists should be aware of this rare entity to avoid misdiagnosis, which has great therapeutic implications for the patient.

The uterine secretome initiates growth of gynecologic tissues in ectopic locations.

Endosalpingiosis (ES) and endometriosis (EM) refer to the growth of tubal and endometrial epithelium respectively, outside of their site of origin. We hypothesize that uterine secretome factors drive ectopic growth. To test this, we developed a mouse model of ES and EM using tdTomato (tdT) transgenic fluorescent mice as donors. To block implantation factors, progesterone knockout (PKO) tdT mice were created. Fluorescent lesions were present after oviduct implantation with and without WT endometrium. Implantation was increased (p<0.05) when tdt oviductal tissue was implanted with endometrium compared to oviductal tissue alone. Implantation was reduced (p<0.0005) in animals implanted with minced tdT oviductal tissue with PKO tdT endometrium compared to WT endometrium. Finally, oviductal tissues was incubated with and without a known implantation factor, leukemia inhibitory factor (LIF) prior to and during implantation. LIF promoted lesion implantation. In conclusion, endometrial derived implantation factors, such as LIF, are necessary to initiate ectopic tissue growth. We have developed an animal model of ectopic growth of gynecologic tissues in a WT mouse which will potentially allow for development of new prevention and treatment modalities.

Deep learning detects premalignant lesions in the Fallopian tube

Tubo-ovarian high-grade serous carcinoma is believed to originate in the fallopian tubes, arising from precursor lesions like serous tubal intraepithelial carcinoma (STIC) and serous tubal intraepithelial lesion (STIL). Adequate diagnosis of these precursors is important, but can be challenging for pathologists. Here we present a deep-learning algorithm that could assist pathologists in detecting STIC/STIL. A dataset of STIC/STIL (n = 323) and controls (n = 359) was collected and split into three groups; training (n = 169), internal test set (n = 327), and external test set (n = 186). A reference standard was set for the training and internal test sets, by a panel review amongst 15 gynecologic pathologists. The training set was used to train and validate a deep-learning algorithm (U-Net with resnet50 backbone) to differentiate STIC/STIL from benign tubal epithelium. The model’s performance was evaluated on the internal and external test sets by ROC curve analysis, achieving an AUROC of 0.98 (95% CI: 0.96–0.99) on the internal test set, and 0.95 (95% CI: 0.90–0.99) on the external test set. Visual inspection of all cases confirmed the accurate detection of STIC/STIL in relation to the morphology, immunohistochemistry, and the reference standard. This model’s output can aid pathologists in screening for STIC, and can contribute towards a more reliable and reproducible diagnosis.

Abstract 6166: A whole-organ ex vivo optical imaging technique for non-destructive, more precise identification of serous tubal intraepithelial carcinoma (STIC) in fallopian tubes

Abstract Objective With the recent discovery of the fallopian tube (FT) origin of the most common and lethal type of ovarian cancer, high grade serous cancer (HGSC), engineering solutions to overcome the limitations of standard histopathology to more reliably identify incipient HGSCs and their serous tubal intraepithelial carcinoma (STIC) precursors are much needed. This investigation tests the potential of whole-organ ex vivo optical imaging of freshly excised FTs to label and sample abnormal tubal epithelium prior to formalin fixation and paraffin embedding for standard histopathology. Methods This investigation prototyped “OVASEEK”, a whole-organ, near-infrared optical imaging platform for identification of STICs. This prospective biospecimen protocol with annotated clinical data was approved by the IRB. Following salpingectomy at the time of hysterectomy for benign indications, FTs from study participants are longitudinally bivalved. Half of the FT is retained for routine evaluation using the Sectioning and Extensively Examining the Fimbriated end (SEE-FIM) protocol by Johns Hopkins gynecologic pathologists (Gyn Path), while the other half is sent overnight in organ transplant media to MIT for imaging on OVASEEK. Hyperspectral “label free” first pass imaging is performed using a series of band-pass filters. Second pass fluorescence imaging is then performed using nanoparticles tagged with anti-LAMC1 antibodies targeting laminin γ1, a known STIC surface marker. Abnormal signal(s) on OVASEEK imaging of the FT epithelium are tattooed with black ink, the tissue is formalin fixed and returned to Gyn Path for serial sectioning. Research findings are reported in an addendum to the formal pathology report in the electronic medical record and discussed with the patient by the gynecologic oncologist co-investigator. Results OVASEEK enabled non-destructive imaging over a wide field-of-view ~ 12×12 cm, with features of interest in the 1,050-1,550 nm range. In this pilot study, OVASEEK identified histopathologic abnormalities missed by standard SEE-FIM in 20% of FTs (n=2 out of 10). In each case, OVASEEK found microscopic (~200 µm) foci of salpingitis, a lymphoplasmacytic infiltrate consistent with inflammation. Performance of serial sectioning and histopathologic examination of the tattooed epithelium yielded this diagnosis. Conclusion Work is ongoing to improve the resolution, speed and sensitivity of OVASEEK for STIC detection. Identification of µm-sized foci of inflammation using OVASEEK is proof-of-principle that whole-organ ex vivo imaging of freshly excised FTs may be an innovation that improves the diagnostic performance of routine histopathology. Accurate and reproducible diagnosis of STIC and concurrent microscopic HGSC is imperative to the understanding of the early pathogenesis of HGSC in clinically actionable ways. Citation Format: Neelkanth M. Bardhan, Vivek Rastogi, Rebecca L. Stone, Angela M. Belcher. A whole-organ ex vivo optical imaging technique for non-destructive, more precise identification of serous tubal intraepithelial carcinoma (STIC) in fallopian tubes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6166.

The shingled girl: Catherine Janet Hill and her contributions to embryology.

Catherine J. Hill is best remembered for her dedication to cataloguing the comprehensive embryological collection of her father J. P. Hill. Yet, her own research, during the interwar years, is little known. She made a significant contribution to interpreting the autonomic innervation of the gut, work that was presented to The Royal Society and earned her a PhD. Working in her father's laboratory, she then set about solving the sequence of secretions from the tubal epithelium and uterine glands that contributed the two layers of egg albumen and three shell layers of the monotreme egg. She was also the first to understand twinning in the marmoset and how two embryos came to share a single extraembryonic coelom, work that often is credited to J. P. Hill. Here. I explain how that happened and explore the context in which she and other female scientists worked at the time.

Heterotopic ovarian hilus cells of the salpinx: a case report and literature review

Ovarian hilus cells (OHCs), a counterpart of testicular Leydig cells, are usually found in the ovarian poles and produce androstenedione. Their origin remains a matter of debate, although OHCs are assumed to come from the adrenogenital primordium. OHCs are rarely observed around the poles of the ovary, including the mesoovarium, stroma (perisalpinx) of the salpinx, and the wall of paratubal cysts. Their clinical and pathological characteristics are not well-known because of their rarity. Herein, we present a case of ectopic OHCs in a 48-year-old woman. The patient underwent total hysterectomy and bilateral salpingectomy for vaginal bleeding due to multiple leiomyomas. We incidentally found OHCs in the stroma of the infundibulum of the salpinx, just beneath the tubal epithelium. Their size was less than 1 mm, and they were composed of large cells with central round nuclei and abundant clear or granular cytoplasm. OHCs share morphological and immunohistochemical profiles with ectopic adrenal glands, and the differential diagnosis is sometimes difficult. They do not exhibit microscopic encapsulation or the normal adrenal cortex zonation pattern. The patient was discharged and did not show any abnormal findings during 19 months of follow-up. Analyzing the characteristics of testicular Leydig cells will help understand how OHCs develop and why heterotopic OHCs occur in and around the salpinges.

Abstract 175: Determining the genetic alterations in initiation and progression of high-grade serous ovarian carcinoma

Abstract High grade serous carcinoma (HGSC) is the most common and deadly form of ovarian cancer. Although HGSC can arise from cells in the ovarian surface epithelium (OSE) or fallopian (oviductal) tubal epithelium (TE), the cell state and genetic alterations for HGSC initiation and progression remains unclear. Previous studies with cell type-specific mouse knockouts found inconsistencies in tumorigenesis and chemoresistance. These data can be explained if specific gene signatures in specific cell types have varied tumorigenic potential and chemoresistance. To determine specific gene combinations necessary for OSE and TE malignant transformation, we designed a CRISPR knock out (KO) mini-library against commonly mutated genes of HGSC. Our previous results revealed efficient gene combinations for ex vivo OSE transformation events and a preference for OSE stem cell transformation. To build on our previous studies, we extended our screening methods into TE cells. Our studies utilize an organoid approach to identify the most cancer-prone cell populations. They also test if cell differentiation state determines a specific set of genetic alterations necessary for HGSC initiation. Our screening platform has the potential to determine whether specific genetic alterations in specific cell types are required for malignant transformation. Additionally, our results may improve on previous models of HGSC initiation and progression. Citation Format: Daryl J. Phuong, Amanda P. Armstrong, Andrea Flesken-Nikitin, Alexander Y. Nikitin, John C. Schimenti. Determining the genetic alterations in initiation and progression of high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 175.

Neurotensin and Its Involvement in Reproductive Functions: An Exhaustive Review of the Literature

Neurotensin (NTS) is a peptide discovered in 1973, which has been studied in many fields and mainly in oncology for its action in tumor growth and proliferation. In this review of the literature, we wanted to focus on its involvement in reproductive functions. NTS participates in an autocrine manner in the mechanisms of ovulation via NTS receptor 3 (NTSR3), present in granulosa cells. Spermatozoa express only its receptors, whereas in the female reproductive system (endometrial and tube epithelia and granulosa cells), we find both NTS secretion and the expression of its receptors. It consistently enhances the acrosome reaction of spermatozoa in mammals in a paracrine manner via its interaction with NTSR1 and NTSR2. Furthermore, previous results on embryonic quality and development are discordant. NTS appears to be involved in the key stages of fertilization and could improve the results of in vitro fertilization, especially through its effect on the acrosomal reaction.

A perplexing papillary proliferation: the endosalpingosis enigma

Introduction: Endosalpingiosis is the presence of tubal epithelium outside the fallopian tube. Usually presenting as gland-like lesions on peritonealised surfaces, papillary endosalpingiosis can mimic serous borderline tumour. Awareness of papillary endosalpingiosis and the diagnostic dilemma it provides, can prevent misdiagnosis.

Microbiota of female genital tract – functional overview of microbial flora from vagina to uterine tubes and placenta

Microorganisms and eukaryotic human cells coexist in synergistic relationships in nearly every niche of the human body. The female genital tract consisting of the vagina, uterus with its cervix and endometrium, uterine tubes and ovaries - harbors its own typical microbiota, which accounts for 9 % of the total bacterial population in females. To this organ system, we also assigned the microbiome of the placenta, which has not been studied much until now. Among the spectrum of microbial species, the female genital tract is mainly dominated by Lactobacillus species, which are considered to be one of the simplest yet most important microbial communities. However, this relationship between macro- and micro-organisms seems to have a number of physiological functions, e.g., the vaginal and cervical microbiota have unique impact on reproductive health. The aim of this review was to provide current view on female genital tract microbiota and its role in reproductive health. We describe in detail the association of vaginal or tubal epithelium with microbiota or the role of microbiota in normal placental function.

From a Passive Conduit to Highly Dynamic Organ. What are the Roles of Uterine Tube Epithelium in Reproduction?

It is well known that the mammalian uterine tube (UT) plays a crucial role in female fertility, where the most important events leading to successful fertilization and pre-implantation embryo development occur. The known functions of these small intra-abdominal organs are: an uptake and transport of oocytes; storage, transportation, and capacitation of spermatozoa, and finally fertilization and transport of the fertilized ovum and early embryo through the isthmus towards the uterotubal junction. The success of all these events depends on the interaction between the uterine tube epithelium (UTE) and gametes/embryo. Besides that, contemporary research revealed that the tubal epithelium provides essential nutritional support and the most suitable environment for early embryo development. Moreover, recent discoveries in molecular biology help understand the role of the epithelium at the cellular and molecular levels, highlighting the factors involved in regulating the UT signaling, that affects different steps in the fertilization process. According to the latest research, the extracellular vesicles, as a major component of tubal secretion, mediate the interaction between gametes/embryo and epithelium. This review aims to provide up-to-date knowledge on various aspects concerning tubal epithelium activity and its cross-talk with spermatozoa, oocytes and preimplantation embryo and how these interactions affect fertilization and early embryo development.

SCANNING ELECTRONIC MICROSCOPY OF MUCOUS MEMBRANE OF THE UTERINE TUBE UNDER THE CONDITIONS OF PHYSIOLOGICAL NORM AND SIX-WEEK ADMINISTRATION OF OPIOID

The toxic effects of opioids on the female reproductive system are important for theoretical and practical medicine, because excessive use of narcotic drugs causes pathological changes in organs and tissues and can predict the negative effects of "nalbuphine" on the female genitals. The excessive use of narcotic drugs, the prevalence of drug addiction, the use of opioids by modern medicine for therapeutic purposes, creates the need to carefully study the effects of opioids on the body of women, primarily the organs of the reproductive system, because despite the successes achieved in diagnosis and treatment, female infertility is an urgent problem.&#x0D; Aim of the research: to establish and describe the features of the structural organization of the mucous membrane of the uterine tube of a female laboratory rat in normal and under conditions of prolonged exposure to «nalbuphine» according to the results of scanning electron microscopy.&#x0D; Materials and methods. The material of the research was the mucous membrane of the uterine tubes of 20 mature white female rats, aged 4.5–6.0 months with body weight 180–220, which were kept in standard conditions at the vivarium of the Danylo Halytskyi Lviv National Medical University. The structural organization of the mucous membrane of the uterine tubes was normally studied in 5 animals. Experimental animals were divided into 2 groups. The first group of experimental animals (10 rats) was administered «nalbuphine» intramuscularly once daily, in one period of time for 6 weeks. The second group - control animals - 5 white female rats, which were injected with saline. The method of scanning electron microscopy of the mucous membrane of the uterine tube of the rat was used in the research.&#x0D; Results. Lesions of the reproductive system damage is an integral part of clinic both opiate addiction and intoxication of pharmaceutical remedies in particular the group of opioids. The connection between duration of «nalbuphine» administration and depth of changes of structural organization of mucous membrane of the uterine tube was established in the experiment. The obtained data show that the six-week administration of «nalbuphine» causes destructive changes in the mucous membrane of the uterine tube wall similar to long-term inflammatory processes, in particular, an increase in the lumen of the uterine tube, a decrease or absence of folds in certain areas of the uterine tube, a decrease in the number of microvilli of tubal exocrinocytes, and the occurrence of adenomatous proliferation of the tubal epithelium.&#x0D; The damage that has occurred indicates the ability of the opioid to cause irreversible changes with prolonged use.&#x0D; Conclusions. The connection between duration of «nalbuphine» administration and depth of changes of structural organization of the mucous membrane of the uterine tube was established in the experiment. Prolonged administration of opioids causes irreversible destructive changes in the mucous membrane of the uterine tube of the female rat, which is manifested by the phenomena of disorganization of both endothelial cells. The damage that has occurred proves the ability of opioid in long-term use to cause irreversible changes and structure and function damages on all levels starting with structural. The results of the work can serve as a basis for the further search for optimal methods of correcting changes in the structure of organs caused by the long-term use of opioids.

Carcinomas With Concurrent Involvement of the Endometrium and Uterine Adnexa—Implications for Pathological Diagnosis and Clinical Management in Current Practice

Abstract A proportion of endometrial and adnexal carcinomas have concurrent involvement of the other site. In the case of high-grade serous carcinomas involving the tubal epithelium as well as endometrium, distinction of tubo-ovarian high-grade serous from endometrial serous carcinoma can have implications for surgical as well as nonsurgical treatment approaches, including targeted therapies and referral to clinical genetics services. The other situation is involvement of the endometrium and ovary by low-grade endometrioid carcinoma; here separation of high-stage endometrial carcinoma from 2 low-stage, low-grade tumors determines adjuvant treatment decisions. These challenging scenarios are illustrated with case presentations and criteria for pathological reporting while acknowledging uncertainty where this is warranted. It is accepted that these are areas in transition, and any criteria offered are likely to change in the light of new information.

Single-cell analysis of the tubal transcriptome in germline BRCA1 mutation carriers: Exploring early events in carcinogenesis (123)

<b>Objectives:</b> Loss of ciliated cells in the fallopian tube has been proposed to be a primary step in tumor initiation in high-grade serous ovarian cancer (HGSOC). Our objective was to identify single-cell transcriptional networks related to ciliated cell function in the fallopian tubes of women with germline <i>BRCA1</i> mutations who are at high risk of developing HGSOC. <b>Methods:</b> Four women aged 38-44 years with pathogenic germline <i>BRCA1</i> mutations underwent risk-reducing surgery at an urban, academic tertiary care center. Under the supervision of a pathologist, fallopian tube ampullae were collected, digested and primary cells were reconstituted in a single-cell suspension. Single-cell RNA-sequencing libraries were prepared using the Chromium Next GEM Single Cell 3' kit with a cell recovery target of 2000-8000 cells. Libraries were sequenced on an Illumina NovaSeq 6000. Seurat v3 and Harmony were used for data dimensionality reduction, cell cluster identification, and classification. Ancestry-based cluster analysis and pseudo-time trajectory analysis were performed using Harmony and Monocle 3. <b>Results:</b> Integrated analysis of 6015 cells from four <i>BRCA1</i> tubal epithelia samples identified ten cell clusters with unique transcriptional profiles. Of these, clusters 4 and 10 had features of ciliated cells. Cluster 4 cells expressed <i>PAX8, RFX2, RFX3,</i> and <i>FOXJ1</i> associated with an intermediate phase ciliated and secretory cell phenotype. Gene ontology analysis showed upregulation of cilia-related genes and stemness pathways, including an upregulation of the gene, <i>SNAI2,</i> belonging to stem-cell development pathway (Enrichment score [ES]: 6.30, p=1.83 x 10^-3). Cluster 10 cells expressed <i>RFX2</i> and <i>RFX3</i> associated with early progenitor ciliated cells, and gene ontology analysis showed upregulation of stemness pathways, with <i>SOX17, SOX18,</i> and <i>NOTCH1</i> regulating stem-cell proliferation (ES: 7.45, p=5.79 x10^-4). Trajectory analysis identified an early progenitor ciliated cell population and a late-stage ciliated cell population with stem-cell populations intermediate to the two populations. Cells belonging to Cluster 4 showed transitionary features and are identified at all branch points along the trajectory. <b>Conclusions:</b> Single-cell RNA sequencing analysis of the tubal epithelia from <i>BRCA1</i> mutation carriers identified select clusters having progenitor and stem-like transcriptional profiles of secretory and ciliated cells, with the <i>SOX18, PAX8, RFX2,</i> and <i>RFX3</i> genes defining these cell populations. Trajectory analysis indicated the differential potential of the ciliated cells to be involved in malignant transformation. The implications of these findings will be further explored by comparison to wild-type and HGSOC transcriptomes.

Differential epithelial and stromal LGR5 expression in ovarian carcinogenesis

Lgr5 has been identified as a marker of the stem/progenitor cells in the murine ovary and oviduct by lineage tracing. However, little is known regarding LGR5 expression or its functional significance in human ovary tissues. Here, using RNA in situ hybridization and/or immunohistochemistry, we thoroughly investigated LGR5 expression in normal human ovaries, fallopian tubes and various ovarian tumors. We discovered that LGR5 expression is negligible in the human ovary surface epithelium, whereas ovarian stromal cells normally express low levels of LGR5. Remarkably, fallopian tube epithelium, inclusion cysts and serous cystadenomas with a Müllerian phenotype expressed high levels of LGR5, and LGR5 expression was restricted to PAX8+/FOXJ1− secretory cells of the tubal epithelium. Strong stromal LGR5 expression without epithelial LGR5 expression was consistently observed in the path from serous cystadenoma to serous borderline tumor to low grade serous carcinoma (LGSC). Unlike LGSC, high grade serous carcinoma (HGSC), clear cell carcinoma, endometrioid carcinomas displayed various epithelial-stromal LGR5 expression. Notably, high levels of LGR5 expression were observed in serous tubal intraepithelial carcinoma, which slightly declined in invasive HGSC. LGR5 expression was significantly associated with improved progression-free survival in HGSC patients. Moreover, in vitro assays demonstrated that LGR5 expression suppressed tumor proliferation and migratory capabilities. Taken together, these findings indicate a tumor-suppressive role for LGR5 in the progression of HGSC.

Drug Eluting Embolization Particles for Permanent Contraception.

Medical technology that blocks the fallopian tubes nonsurgically could increase access to permanent contraception and address current unmet needs in family planning. To achieve total occlusion of the fallopian tube via scar tissue formation, acute trauma to the tubal epithelium must first occur followed by a sustained and ultimately fibrotic inflammatory response. Here, we developed drug-eluting fiber-based microparticles that provide tunable dose and release of potent sclerosing agents. This fabrication strategy demonstrates high encapsulation of physicochemically diverse agents and the potential for scalable manufacturing by utilizing free-surface electrospinning to generate material for fiber micronization. Manipulation of nanofiber formulation such as drug loading, drug hydrophobicity, polymer hydrophobicity, and crystallinity allowed for modulation of the sustained release properties of our fiber microparticles. We assessed various fibrous microparticle formulations in vivo using a newly developed and validated guinea pig model for contraception. We found that fiber microparticles with bolus release doxycycline effectively elicited acute trauma and those formulated with highly loaded phenyl benzoate caused sustained inflammation in the target organs. The demonstrated potency of these electrospun microparticles, as well as their embolic size and shape, suggests potential for proximal agglomeration and inflammatory activity in the fallopian tubes following transcervical delivery.

A New Methodology to Assess Fallopian Tubes Microbiota and Its Impact on Female Fertility

Tubal factor is an important contributor to female infertility, and the current diagnostic approaches cannot correctly identify many subtle causes of tubal dysfunction. While it is known that the most common cause of tubal factor infertility is pelvic inflammatory disease (PID), creating critical alterations of the tubal epithelium, little attention has been devoted to understanding the tubal modifications caused by the resident microbial population and their interaction with the surrounding tubal epithelium. Furthermore, most of these samples are obtained by traumatic procedures such as direct sampling during laparoscopy using a cytobrush. However, as in any other organ of the female genital tract, the microbiota environment of the fallopian tube plays an essential role in maintaining tubal functioning, counteracting the pathogenic effect of acquired microbes. Consequentially, to better analyze the tubal microbiota without causing anatomical and/or functional alteration of the fallopian tube and preserving fertility, the hysteroscopic approach might be the method of choice, guarantying maximal integrity of the uterine cavity and tubal lumen. Here we describe our plan for using atraumatic hysteroscopic sampling methods to investigate the correlation between tubal microbiota and female infertility.

Microscopic anatomical background of unexplained tubal infertility – three new possible causes

Infertility is defined as the inability to conceive within 1 year of unprotected intercourse. The infertility evaluation generally includes an assessment of the ovarian cycle and a semen analysis, but the evaluation of tubal patency is an essential part of the fertility workup. However, in the case of the uterine tube, patency may not be the only cause of tubal infertility. Idiopathic or unexplained infertility is a broad subcategory of infertility defined by the absence of obvious or explainable cause. Based on our previous research, we review and discuss three hypotheses associated with new anatomical and histological knowledge of tubal morphology and transport function and its potential impact on reproductive outcomes in women with unexplained tubal infertility. In 2021, Duffy et al. (Fertility and Sterility) published “Top 10 priorities for future infertility research”, based on their survey among healthcare professionals and patients with fertility problems from 40 countries. No mention of tubal infertility was included in their results. On the other hand, the topic “What causes unexplained infertility?” was one of the most important research priorities for female infertility. In 2018, a neglected structure of the human uterine tube, the lymphatic lacunae of the mucosal folds and fimbriae were described by Varga et al. (Annals of Anatomy). We believe that the lymph and lymphatic lacunae are responsible for the thickening of the fimbriae during ovulation. The fimbriae become enlarged and turgescent, coming into contact with the surface of the ovary, what is important in oocyte pick‐up and the maintenance of the tubal fluid. Hypothetically, disturbed lymph flow, caused by e.g., sedentary work, can cause problems with oocyte pick‐up and subsequent fertilization. In 2019, Varga et al. (Annals of Anatomy) described an important regulatory T‐ cell population in the human tubal epithelium. These intra‐epithelial T‐lymphocytes can be involved in the process of immune tolerance, which could lead to the tolerance of non‐self cells (sperm) and partially non‐self cells (a developing embryo) without the activation of local immune responses. An imbalance between the cells of the intra‐epithelial immune system can hypothetically lead to the immune reaction against sperm and/or embryo during transport through the uterine tube. The recently described cell population of tubal telocytes have many possible functions, but one of the most commonly reported is their ability to “sense” the levels of female sex hormones and thus regulate those processes inside the uterine tubes, which are under hormonal control. As reviewed by Klein et al. (2020, Medicina), telocytes are excessively fragile in the presence of noxious factors. In the uterine tubes, possible mechanisms of unexplained infertility include changes in the structural and functional integrity of the cellular microenvironment, including quantitative reduction and/or functional alteration of telocytes.

Sperm-oviduct interactions: Key factors for sperm survival and maintenance of sperm fertilizing capacity.

BackgroundAlthough millions or even billions of sperm are deposited in the female genital tract, only very few sperm reach the oocyte, and only one single spermatozoon will successfully fertilize. During the journey of the sperm within the female genital tract, the interactions between spermatozoa and fallopian tube are critical for sperm selection, sperm survival, and maintenance of sperm fertilizing capacity.ResultsThis review will provide a comprehensive overview of the latest findings regarding sperm transport and behavior of sperm within the oviduct, sperm selection in the oviduct, the formation of the sperm reservoir, and the release of sperm in the presence of the oocyte. It will primarily focus on recent novel insights on sperm‐oviduct interactions, which have been obtained by cutting‐edge technologies under in vivo or near in vivo conditions.ConclusionsThe comprehensive analysis of the findings to date will elucidate the complex molecular changes in the tubal epithelium, which are induced by the presence of the sperm and will highlight how the epithelial cells of this organ affect transport, behavior, and function of sperm. This knowledge is essential for scientists and clinicians involved in assisted reproductive technologies.