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Molecular alterations in the fallopian tubes play a pivotal role in the development of cancer and reproductive disorders, yet their molecular landscape at the protein level remains poorly defined. Here, we map key fallopian tube proteins at single-cell resolution utilizing an integrated transcriptomics and proteomics approach. Based on RNA-seq analysis, we identify 310 genes with elevated expression in the fallopian tube, the majority of which are associated with motile cilia function. We spatially characterize 133 of the corresponding proteins in the fallopian tube and other human tissues with motile cilia to subcellular structures of ciliated cells, validating the findings with single-cell RNA-seq and mass-spectrometry data. Eleven proteins previously only studied on the transcript level without information in cilia databases are further analyzed in a hydrosalpinx patient, showing a thinner epithelium, lower density of FOXJ1 expression, and reduced expression of FHAD1, RIIAD1, and C2orf81. Our high-resolution spatial map aids in dissecting the pathways underlying infertility and diseases linked to cilia-specific functions.

Background

Ukraine's total fertility rate was 0.9 in 2022, among the lowest in Europe. Amid the ongoing full-scale invasion, understanding reproductive intentions is important for informing future pronatalist policies. This study assessed fertility intentions and attitudes toward parenthood, with a focus on sex differences, and subjective determinants of reproductive decision-making among undergraduate medical students in wartime Ukraine.

Methods

A cross-sectional, confidential, online survey was conducted among students at Odesa National Medical University in May 2024. The Swedish Fertility Awareness Questionnaire was used, supplemented with a question on contraceptive use. Data were analysed using descriptive statistics, univariable, multivariable and stepwise logistic regression.

Results

The mean age was 20 years among the participants: 655 women and 191 men. Overall, 75% intended to have children, with a preferred family size of two children. Women preferred to have their first child at a younger age than men (26.1 vs. 28.1 years; p < 0.001). No sex differences were observed in the perceived importance of having children. Oral and long-acting reversible contraceptive use was relatively low. Furthermore 62% of participants indicated that they would support a hypothetical pregnancy to birth, mainly for moral or religious reasons. Among those opting for abortion, the most commonly cited reasons were financial constraints and war-related concerns. In the case of infertility, more women than men were willing to consider IVF or adoption (p < 0.001). Key prerequisites for parenthood included adequate housing (93%) and financial stability (92%). Women were more likely to anticipate emotional benefits of parenthood (OR 1.66), whereas men were more likely to anticipate negative impacts on personal time (OR 1.91) and finances (OR 1.72). Intention to have children was associated with psychological readiness, emotional fulfilment, life priorities, and perceived housing adequacy (aOR 3.02), as a key independent predictor of overall readiness for parenthood.

Conclusions

Despite the ongoing war, fertility intentions among medical students remain relatively optimistic, equally for women and men. As adequate housing was an important prerequisite for parenthood, post-war pronatalist policies may benefit from integrating housing support into broader family well-being strategies, while also addressing sexuality education and cultural influences on family formation and parenthood decisions.

Introduction: Endometriosis, affecting up to 10% of women, is a chronic estrogen dependent disorder where ectopic endometrial-like tissue causes pelvic pain and infertility. Endometriosis is challenging to diagnose due to symptom overlap and limited imaging accuracy, often requiring surgical visualization. Positron emission tomography (PET) potentially offers a non-invasive, molecular-based approach for highly specific diagnosis and monitoring of endometriosis. Aromatase, typically low in normal endometrial tissue, is elevated in endometriotic lesions, while neutrophils, which are scarce in normal tissue, are increased in these lesions. Fibrosis, resulting from activated platelet-derived growth factor receptor β(PDGFR-β)-expressing myofibroblasts, has been observed in endometriosis lesions. In this study, three PET tracers; [¹¹C]cetrozole ([¹¹C]CET), [¹¹C]GW457427 ([¹¹C]NES), and [⁶⁸Ga]Ga-ATH001, targeting aromatase, neutrophil elastase (NE), and PDGFR-β, respectively, were tested in endometriosis patient biopsies through autoradiography (ARG) combined with histological examinations. A pilot PET/Magnetic resonance imaging (PET/MR) study was performed in endometriosis patients with [¹¹C]NES.

Methods: Ten biopsies from patients with endometriosis were collected. Frozen tissue was sectioned at 20μm for ARG and 4μm for immunohistochemistry (IHC). Total binding and non-specific binding, with quantification using ImageJ (fmol/mm³) was determined. Specific binding was calculated as total minus non-specific binding and expressed as a percentage. Sections were stained with Hematoxylin and Eosin (H/E) and Cytokeratin7 (CK7) for morphology, Sirius Red (SIR) for fibrosis, antibodies against PDGFR-β and NE. Neutrophil extracellular traps (NETs) were identified by combined staining for NE and Histone H3. Three endometriosis patients were scanned with [¹¹C]NES by PET/MR.

Results: All three tracers showed high in vitro binding to endometriotic tissue in ARG. [¹¹C]NES and [⁶⁸Ga]Ga-ATH001 had high degree of specific binding to elastase and PDGFR-β, respectively, whereas no specific binding could be shown for [¹¹C]CET. ARG results were validated by IHC: CK7 confirmed epithelial lesions, NE and Histone H3 verified neutrophils and NETs, and PDGFR-β/SIR indicated fibrosis. However, in vivo, no [¹¹C]NES uptake was detected on the PET/MR scans of the three endometriosis patients.

Conclusion: In ARG on endometriotic tissue samples, [⁶⁸Ga]Ga-ATH001 and [¹¹C]NES showed specific binding to their respective targets. However, tracer delivery potentially forms a challenge in visualizing fibrotic endometriosis lesions in vivo, as seen by [¹¹C]NES PET/MR in patients.

Background

Women treated with cervical loop electrosurgical excision procedure require follow-up to detect residual or recurrent HSIL+, defined as high-grade squamous intraepithelial lesions, adenocarcinoma in situ or cervical cancer. Currently, co-testing with cytology and human papillomavirus (HPV) analysis is usually recommended. This study investigates whether HPV testing alone is comparable to co-testing in detecting HSIL + up to three years after treatment. Recurrence rates of HSIL + are also presented, with follow-up extending up to 18 years.

Methods

This retrospective cohort study included all 3,540 women treated with a cervical excision in Uppsala County between 1 January 2005 and 31 December 2019. Women with cancer identified in the cone biopsy were excluded. The main outcome was HSIL + detected within three years of follow-up. Sensitivity, specificity and negative predictive value were calculated for the 1,938 women who had a co-testing result as part of their test of cure. Thus, the analysis for the main outcome could finally be performed on 1,938 out of the total number of 3,540 women. Additionally, long-term data on recurrence and time to HSIL+, along with a separate analysis of results prior to cervical cancer diagnosis, were collected for the whole cohort of 3,399 women.

Results

The sensitivity and negative predictive value for detecting HSIL + were 69% and 97% for HPV alone, and 74% and 98% for co-testing, respectively. These differences were not statistically significant. Specificity was higher for HPV alone than for co-testing. The negative predictive value of HPV testing for excluding cervical cancer (n = 5) within three years was 100%. Recurrence rate of HSIL + in the three-year follow up was 8%, and the total recurrence rate of HSIL + with a mean follow-up of nine years was 10%. Mean time to recurrence was 28 months. None of 19 cervical cancer cases identified in the long-term follow-up had a co-testing result showing negative HPV but positive cytology.

Conclusions

HPV testing alone, as a single test, is comparable to co-testing in detecting HSIL + up to three years after treatment independently of margin status, and demonstrates a higher specificity. Cytology plays a very limited role in the test of cure analysis and could therefore be omitted.

Alterations in the vaginal microbiota, including both species composition and functional pathways, have been associated with HPV infection and progression of dysplasia to cervical cancer. To further explore this, shotgun metagenomic sequencing was used to taxonomically and functionally characterize the vaginal microbiota of women with and without cervical dysplasia. Women with histologically verified dysplasia (n = 177; low grade dysplasia (LSIL) n = 81, high-grade dysplasia (HSIL) n = 94, cancer n = 2) were compared with healthy controls recruited from the cervical screening programme (n = 177). Women with dysplasia had a higher vaginal microbial diversity, and higher abundances of Gardnerella vaginalis, Aerococcus christensenii, Peptoniphilus lacrimalis and Fannyhessea vaginae, while healthy controls had higher relative abundance of Lactobacillus crispatus. Genes involved in e.g. nucleotide biosynthesis and peptidoglycan biosynthesis were more abundant in women with dysplasia. Healthy controls showed higher abundance of genes important for e.g. amino acid biosynthesis, (especially L-lysine) and sugar degradation. These findings suggest that the microbiota may have a role in creating a pro-oncogenic environment in women with dysplasia. Its role and potential interactions with other components in the microenvironment deserve further exploration.

Objective: To investigate whether an early need of hormonal contraceptive (HC), or a failure to find a suitable method, are warning signs for endometriosis.

Design: A retrospective cohort study.

Setting: Sweden.

Population: The cohort consisted of 720 805 women aged 12-27 years during the period 2005-2017. All women, regardless of whether they received a diagnosis of endometriosis or not (reference group), were included.

Methods: We used data from Swedish national registers. Risks are expressed as crude and adjusted hazard ratios (HRs and aHRs, respectively) with 95% confidence intervals (95% CIs), adjusted for age, education level, civil status, parity, country of birth, and diagnoses of infertility, dysmenorrhea or depression.

Main outcome measures: A diagnosis of endometriosis between 12 and 27 years of age.

Results: During this period, 3268 women were diagnosed with endometriosis (0.45%). Women who started HC at the ages of 12-14 years had a higher risk of receiving the diagnosis (aHR 2.53, 95% CI 2.21-2.90) than those who began at age 17 years or older. Having tried more types of HCs was associated with a twofold increased risk of endometriosis (more that three types of HC, aHR 2.31, 95% CI 1.71-3.12). Using HC for more than 1 year was associated with a decreased risk of endometriosis (>1 year, aHR 0.53, 95% CI 0.48-0.59). Women with endometriosis more commonly had dysmenorrhea, depression or infertility.

Conclusions: The use of HCs at an early age and a failure to find a suitable HC were identified as warning signs of later receiving an endometriosis diagnosis. A longer duration of HC usage reduced the risk of receiving the diagnosis.

Phthalates are endocrine disrupting chemicals (EDCs) found in common consumer products such as soft plastics and cosmetics. Although the knowledge regarding the adverse effects of phthalates on female fertility are accumulating, information on the hormone sensitive endometrium is still scarce. Here, we studied the effects of phthalates on endometrial cell proliferation and gene expression. Human endometrial primary epithelial and stromal cells were isolated from healthy fertile-aged women (n=3), and were compared to endometrial cell lines T-HESC and Ishikawa. Three different epidemiologically relevant phthalate mixtures were used, defined by urine samples in the Midlife Women Health Study (MWHS) cohort. Mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was used as a single phthalate control. Cells were harvested for proliferation testing and transcriptomic analyses after 24 h exposure. Even though all cell models responded differently to the phthalate exposures, many overlapping differentially expressed genes (DEGs, FDR<0.1), related to cell adhesion, cytoskeleton and mitochondria were found in all cell types. The qPCR analysis confirmed that MEHHP significantly affected cell adhesion gene vinculin (VCL) and NADH:ubiquinone oxidoreductase subunit B7 (NDUFB7), important for oxidative phosphorylation. Benchmark dose modelling showed that MEHHP had significant concentrationdependent effects on cytoskeleton gene actin-beta (ACTB). In conclusion, short 24 h phthalate exposures significantly altered gene expression cell-specifically in human endometrial cells, with six shared DEGs. The mixture effects were similar to those of MEHHP, suggesting MEHHP could be the main driver in the mixture. Impact of phthalate exposures on endometrial functions including receptivity should be addressed.

Endometriosis and provoked vestibulodynia (PVD) are prevalent pain conditions among women of reproductive age, significantly impacting their quality of life and psychological well-being. However, comprehensive evidence regarding the lifelong health and socioeconomic outcomes for these individuals remains scarce. Additionally, many prior studies rely on limited and sometimes unrepresentative samples. This study aims to inform on the long-term consequences of these disorders by examining health, fertility, and employment outcomes in a cohort of women diagnosed with endometriosis and/or PVD, tracing their experiences from childhood to their 40s. Leveraging nationwide administrative data from Sweden and employing a matched case-control design, we investigate both similarities and differences between women with these diagnoses and those without. Our findings indicate that women diagnosed with endometriosis and/or PVD demonstrate elevated healthcare utilization patterns, commencing in their early teenage years and progressively increasing over time. Notably, disparities in labor market outcomes emerge in their 20s, showcasing lower labor earnings and a rise in sickness benefit receipt. Moreover, our results show a higher likelihood among these women to experience mental health disorders and concurrent chronic pain diseases, as well as infertility. While the association between endometriosis and infertility is well-documented, this study offers novel insights into a potential similar link between PVD and infertility. Our study informs healthcare professionals and policymakers about the considerable burden of compromised health, adverse psychosocial well-being, and reduced productivity in the labor market faced by young women with these common pain conditions. These findings underscore the urgency of addressing the multifaceted challenges encountered by individuals diagnosed with endometriosis and PVD across their lifespan.

Background: The aim of this study was to examine the natural course of HPV infection in women of 60 years and older who were HPV positive at inclusion, and any association between HPV positivity in historical samples and dysplasia outcome.

Methods: Eighty-nine women aged 60-82 years, who tested positive for HPV between 2012 and 2016 were included. Sampling for cytology and/or histology was also performed. HPV genotyping was carried out on archived material back to 1999.

Results: Of the 89 HPV-positive women 16 had HSIL, 34 had LSIL and 39 were benign at inclusion. Of the women with HSIL, 50.0% had the same HPV type in the archive samples, 12.5% had another type, and 37.5% were HPV negative. Among the 34 women with LSIL, 47.1% had the same HPV type in archive samples, 5.8% had another type, and 47.1% were HPV negative. Of the 39 women without dysplasia at inclusion, 25.6% had the same HPV type in archive samples, 5.1% had another HPV type and 69.2% were HPV negative.

Conclusion: Surprisingly few of the elderly women thus seem to have a history with the same or any HPV infection the years before being diagnosed with an HPV infection and dysplasia. The significance of an HPV infection for dysplasia development in elderly women is still not fully understood.