Abstract Endocrine-disrupting chemicals are substances present in the environment that can interfere with normal hormonal balance and thus exert potentially adverse health effects on the human ...organism. Male reproductive system development and function may be susceptible to the effects of such environmental toxicants. Bisphenol A, phthalates and alkylphenols are important components of multiple products and are thus ubiquitously present in the environment. It has been demonstrated under laboratory conditions that they can exert detrimental effects on the male reproductive system. However, human exposure data are scarce and do not uniformly support toxicity of these substances at environmental concentrations. Despite substantial research efforts, the final answer to the problem of endocrine-disrupting chemicals is not yet in sight. Endocrine-disrupting chemicals are substances present in the environment that can interfere with the action of hormones and thus exert potentially adverse health effects on the human organism. Male reproductive system development and function may be susceptible to the effects of such environmental toxicants. Bisphenol A, phthalates and alkylphenols are important components of multiple consumer products as well as industrial processes and are thus ubiquitously present in the environment. After exposure to these substances, numerous adverse effects on male reproductive system have been demonstrated in animal studies. Thus, developmental genital anomalies as well as lower semen quality have been observed. However, human exposure data are scarce and do not uniformly support toxicity of these substances at concentrations present environmentally. Despite substantial research efforts, the final answer to the problem of endocrine-disrupting chemicals is not yet in sight.
Purpose
To synthesise data from genome-wide studies reporting molecular signature of eutopic endometrium through the phases of the menstrual cycle in endometriosis.
Methods
Extraction of data from ...publications reporting genetic signatures characterising endometrium associated with endometriosis. The nomenclature of extracted differentially expressed transcripts and proteins was adopted according to the HUGO Gene Nomenclature Committee (HGNC). Loci were further sorted according to the different phases of the menstrual cycle, i.e. menstrual (M), proliferative (P), secretory (S), early-secretory (ES), mid-secretory (MS), late-secretory (LS), and not specified (N/S) if the endometrial dating was not available. Enrichment analysis was performed using the DAVID bioinformatics tool.
Results
Altered molecular changes were reported by 21 studies, including 13 performed at the transcriptomic, 6 at proteomic, and 2 at epigenomic level. Extracted data resulted in a catalogue of total 670 genetic causes with available 591 official gene symbols, i.e. M = 3, P = 188, S = 81, ES = 82, MS = 173, LS = 36, and N/S = 28. Enriched pathways included
oestrogen signalling pathway
,
extracellular matrix organization
, and
endothelial cell chemotaxis
. Our study revealed that knowledge of endometrium biology in endometriosis is fragmented due to heterogeneity of published data. However, 15 genes reported as dysregulated by at least two studies within the same phase and 33 significantly enriched GO-BP terms/KEGG pathways associated with different phases of the menstrual cycle were identified.
Conclusions
A multi-omics insight into molecular patterns underlying endometriosis could contribute towards identification of endometrial pathological mechanisms that impact fertility capacities of women with endometriosis.
Objective To evaluate whether urinary bisphenol A (BPA) levels in men adversely influence semen quality and embryo development after medically assisted reproduction. Design Prospective, cohort study. ...Setting University-based tertiary care center. Patient(s) A total of 149 couples undergoing their first or second IVF or intracytoplasmic sperm injection (ICSI) procedure. Intervention(s) None. Main Outcome Measure(s) Semen quality and embryo development parameters until the blastocyst stage after the IVF or ICSI procedure. Result(s) Bisphenol A was detected in 98% (n = 146) of the samples with 0.1 ng/mL limit of detection. The geometric mean BPA concentration was 1.55 ng/mL. After the adjustment for potential confounders using linear regression models, an increase of natural logarithm transformed urinary BPA concentration was associated with lower natural logarithm transformed sperm count (β = −0.241, 95% confidence interval CI −0.470 to −0.012), natural logarithm transformed sperm concentration (β = −0.219, 95% CI −0.436 to −0.003), and sperm vitality (β = −2.660, 95% CI −4.991 to −0.329). The embryo development parameters from oocyte fertilization to the blastocyst formation stage were not affected by BPA exposure. Conclusion(s) Urinary BPA concentrations in male partners of subfertile couples may influence semen quality parameters, but do not affect embryo development up to the blastocyst stage after medically assisted reproduction.
Gestational choriocarcinoma of the ovary is an exceptionally rare and highly aggressive tumor. Preoperative diagnosis of extrauterine choriocarcinoma is difficult due to nonspecific clinical ...presentation and its resemblance to ectopic pregnancy. Without molecular genetic analysis, it is not possible to reliably differentiate gestational from non-gestational choriocarcinoma. Here, we present a case of a 44-year-old woman who presented to our emergency department with complaints of pelvic pain, vaginal bleeding, and amenorrhea. Because of a recent history of conservatively managed ectopic pregnancy, the patient underwent emergency laparoscopy. Right-sided salpingo-oophorectomy was performed due to intraoperatively suspected ovarian ectopic pregnancy. Histopathology results revealed the diagnosis of ovarian choriocarcinoma of possible gestational origin. It was classified as FIGO stage IV and WHO ultra-high-risk, and she underwent multi-agent chemotherapy without major complications. She has remained in complete remission after a 12-month follow-up. Considering the rarity of this diagnosis, we conducted a literature review including all published cases of suspected gestational choriocarcinomas of the ovary. We conclude that due to the rarity of this entity, preoperative differentiating between ovarian ectopic pregnancy and ovarian choriocarcinoma is extremely challenging, and without molecular genetic analysis, it is not possible to identify the genetic origin of the tumor.
The overall survival of women with endometrial cancer is excellent after management. Different management strategies are associated with variable patient-reported outcomes (PROs). Evaluating PROs in ...the follow-up period can aid in better counseling and intervention for PRO improvement. This study aimed to evaluate the properties of the Slovenian translation of the EORTC QLQ-EN24 assessment scale. Women treated at the University Medical Centre Maribor, Slovenia, between January 2016 and December 2019 were invited to report their symptoms using the EORTC QLQ-EN24 questionnaire. Data were correlated with treatment modalities and clinical characteristics. The median age of participants in our study was 61 years old. PROs were not specific to therapy or clinical characteristics. Overall, women who more frequently reported gastrointestinal symptoms, muscular pain, or back pain also had statistically more frequently decreased levels of PROs in other assessed areas. Women who reported sexual or vaginal problems more often reported significantly poorer body images. Sexual activity within 4 weeks prior to completing the scale was reported by 39% of women. Sexual functioning assessments also showed important correlations between sexual interest, enjoyment, and activity. Individualized follow-ups addressing PROs should be offered to better address concerns and improve long-term outcomes in women with endometrial cancer.
Endometrial cancer is the most common gynecological cancer in developed countries. The disease is diagnosed with increasing frequency in younger women, commonly also in their reproductive age. The ...standard treatment of endometrial cancer is surgical in the form of hysterectomy and bilateral salpingo-oophorectomy, and this precludes future fertility in younger women. The current challenge is to identify the group of women with endometrial cancer and low-risk features that would benefit from more conservative treatment options. More focus in management needs to be aimed towards the preservation of quality of life, without jeopardizing oncological outcomes. In this review, we analyze the current approaches to identification of women for conservative management and evaluate the success of different medical options for treatment and surgical techniques that are fertility sparing. We also elaborate on the future perspectives, focusing on the incorporation of molecular characterization of endometrial cancer to fertility preservation algorithms. Future studies should focus specifically on identifying reliable clinical and molecular predictive markers in this group of young women. With improved knowledge and better risk assessment, the precision medicine is the path towards improved understanding of the disease and possibly widening the group of women that could benefit from treatment methods preserving their fertility.
Gestational trophoblastic disease (GTD) is a heterogeneous group of rare tumours characterised by abnormal proliferation of trophoblastic tissue. It consists of benign or premalignant conditions, ...such as complete and partial molar pregnancy and variants of malignant diseases. The malignant tumours specifically are commonly referred to as gestational trophoblastic neoplasia (GTN). They consist of invasive mole, choriocarcinoma, placental-site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT).
Patients with GTD are often asymptomatic, although vaginal bleeding is a common presenting symptom. With the advances in ultrasound imaging in early pregnancy, the diagnosis of molar pregnancy is most commonly made in the first trimester of pregnancy. Sometimes, additional imaging such as chest X-ray, CT or MRI can help detect metastatic disease. Most women can be cured, and their reproductive function can be preserved. In this review, we focus on the advances in management strategies for gestational trophoblastic disease as well as possible future research directions.
Studies of the mechanistic (mammalian) target of rapamycin inhibitors (mTOR) represent a step towards the targeted treatment of gynecological cancers. It has been shown that women with increased ...levels of mTOR signaling pathway targets have worse prognosis compared to women with normal mTOR levels. Yet, targeting mTOR alone has led to unsatisfactory outcomes in gynecological cancer. The aim of our review was therefore to provide an overview of the most recent clinical results and basic findings on the interplay of mTOR signaling and cold shock proteins in gynecological malignancies. Due to their oncogenic activity, there are promising data showing that mTOR and Y-box-protein 1 (YB-1) dual targeting improves the inhibition of carcinogenic activity. Although several components differentially expressed in patients with ovarian, endometrial, and cervical cancer of the mTOR were identified, there are only a few investigated downstream actors in gynecological cancer connecting them with YB-1. Our analysis shows that YB-1 is an important player impacting AKT as well as the downstream actors interacting with mTOR such as epidermal growth factor receptor (EGFR), Snail or E-cadherin.
Background and Objectives: Gestational trophoblastic disease (GTD) is a group of pregnancy-related malignant and premalignant diseases. The aim of this study was to assess the prognostic value of ...clinical characteristics to predict treatment outcomes in women with GTD. Materials and Methods: In this retrospective study, 34 patients treated for GTD at the Division of Gynaecology and Perinatology, University Medical Centre Maribor, between 2008 and 2022 were identified. Clinical and pathological characteristics were obtained by analysing patient data records. Results: Within the cohort of 34 patients with GTD, 29 patients (85.3%) had a partial hydatidiform mole (HM) and five patients545 (14.7%) had a complete HM. Two patients with a complete HM developed a postmolar gestational trophoblastic neoplasia (GTN), which represents 5.8% of all cases. Conclusions: GTD is a rare disease that is frequently asymptomatic. The subsequent consequences of GTD, which can lead to malignant transformation, as well life-threatening disease complications, warrant training for early recognition of HMs and timely treatment and surveillance.
Women with uterine adenomyosis seeking assisted reproduction have been associated with compromised endometrial receptivity to embryo implantation. To understand the mechanisms involved in this ...process, we aimed to compare endometrial transcriptome profiles during the window of implantation (WOI) between women with and without adenomyosis.
We obtained endometrial biopsies LH-timed to the WOI from women with sonographic features of adenomyosis (n=10) and controls (n=10). Isolated RNA samples were subjected to RNA sequencing (RNA-seq) by the Illumina NovaSeq 6000 platform and endometrial receptivity classification with a molecular tool for menstrual cycle phase dating (beREADY®, CCHT). The program language R and Bioconductor packages were applied to analyse RNA-seq data in the setting of the result of accurate endometrial dating. To suggest robust candidate pathways, the identified differentially expressed genes (DEGs) associated with the adenomyosis group in the receptive phase were further integrated with 151, 173 and 42 extracted genes from published studies that were related to endometrial receptivity in healthy uterus, endometriosis and adenomyosis, respectively. Enrichment analyses were performed using Cytoscape ClueGO and CluePedia apps.
Out of 20 endometrial samples, 2 were dated to the early receptive phase, 13 to the receptive phase and 5 to the late receptive phase. Comparison of the transcriptomics data from all 20 samples provided 909 DEGs (p<0.05; nonsignificant after adjusted p value) in the adenomyosis group but only 4 enriched pathways (Bonferroni p value < 0.05). The analysis of 13 samples only dated to the receptive phase provided suggestive 382 DEGs (p<0.05; nonsignificant after adjusted p value) in the adenomyosis group, leading to 33 enriched pathways (Bonferroni p value < 0.05). These included pathways were already associated with endometrial biology, such as "Expression of interferon (IFN)-induced genes" and "Response to IFN-alpha". Data integration revealed pathways indicating a unique effect of adenomyosis on endometrial molecular organization (e.g., "Expression of IFN-induced genes") and its interference with endometrial receptivity establishment (e.g., "Extracellular matrix organization" and "Tumour necrosis factor production").
Accurate endometrial dating and RNA-seq analysis resulted in the identification of altered response to IFN signalling as the most promising candidate of impaired uterine receptivity in adenomyosis.
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