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Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 25664

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Prof. Dr. Seung-Yup Ku

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Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul National University College of Medicine, 28 Yonkeun-dong, Chongno-gu, Seoul 110-744, Republic of Korea
Interests: RNA; ovarian; uterus
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Special Issue Information

Dear Colleagues,

Reproduction is a very critical scientific phenomenon, tied to the origin of mankind. Successful or failed pregnancy, menstrual dysfunction, and the tumorigenesis of female reproductive organs currently offer numerous challenges for meeting clinically unmet needs, and often require advanced therapeutic strategies.

There has been exciting progress in understanding the molecular pathophysiology of various uterine and ovarian diseases and dysfunction in recent years. Genetic or epigenetic alterations represent novel diagnostic and prognostic molecular markers and therapeutic targets for these diseases and dysfunction. To date, specific biomarkers, as well as genetic or epigenetic alterations, have been identified.

This Special Issue of IJMS is searching for answers to some of the above-mentioned questions, in an attempt to provide reproductive biomedical scientists and clinicians with novel answers that should lead to a better understanding of these prevalent and serious universal diseases and dysfunction. Studies using clinical samples, and animal or cell culture models to investigate the molecular pathophysiology of uterine and ovarian diseases and dysfunction will be published.

IJMS looks forward to receiving excellent contributions from all types of investigators of female reproductive tract dysfunction and diseases.

Prof. Dr. Seung-Yup Ku
Guest Editor

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Keywords

uterine tumor
ovarian tumor
hormonal dysfunction
polycystic ovary syndrome
endometriosis
menopause
infertility
pregnancy
abortion
assisted reproduction
pluripotent stem cell
tissue engineering

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Published Papers (9 papers)

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Research

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18 pages, 3932 KiB

Open AccessArticle

Resveratrol Protects Rat Ovarian Luteinized Granulosa Cells from H₂O₂-Induced Dysfunction by Activating Autophagy

by Minghui Cai, Haijuan Sun, Yujia Huang, Haixu Yao, Chen Zhao, Jiao Wang and Hui Zhu

Int. J. Mol. Sci. 2023, 24(13), 10914; https://doi.org/10.3390/ijms241310914 - 30 Jun 2023

Cited by 3 | Viewed by 1483

Abstract

Resveratrol performs a variety of biological activities, including the potential regulation of autophagy. However, it is unclear whether resveratrol protects against luteal dysfunction and whether autophagy involves the regulation of resveratrol. This study aims to investigate whether resveratrol can regulate autophagy to resist H₂O₂-induced luteinized granulosa cell dysfunction in vitro. Our results showed that resveratrol can enhance cell viability, stimulate the secretion of progesterone and estradiol, and resist cell apoptosis in H₂O₂-induced luteinized granulosa cell dysfunction. Resveratrol can activate autophagy by stimulating the expression of autophagy-related genes at the transcriptional and translational levels and increasing the formation of autophagosomes and autophagolysosomes. Rapamycin, 3-methyladenine, and bafilomycin A1 regulated the levels of autophagy-related genes in H₂O₂-induced luteinized granulosa cell dysfunction and further confirmed the protective role of autophagy activated by resveratrol. In conclusion, resveratrol activates autophagy to resist H₂O₂-induced oxidative dysfunction, which is crucial for stabilizing the secretory function of luteinized granulosa cells and inhibiting apoptosis. This study may contribute to revealing the protective effects of resveratrol on resisting luteal dysfunction from the perspective of regulating autophagy. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 3.0)

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19 pages, 10774 KiB

Open AccessArticle

Microfibril Associated Protein 5 (MFAP5) Is Related to Survival of Ovarian Cancer Patients but Not Useful as a Prognostic Biomarker

by Katarzyna Aleksandra Kujawa, Ewa Zembala-Nożynska, Joanna Patrycja Syrkis, Alexander Jorge Cortez, Jolanta Kupryjańczyk and Katarzyna Marta Lisowska

Int. J. Mol. Sci. 2022, 23(24), 15994; https://doi.org/10.3390/ijms232415994 - 15 Dec 2022

Cited by 7 | Viewed by 2833

Abstract

Ovarian cancer (OC) is usually diagnosed late due to its nonspecific symptoms and lack of reliable tools for early diagnostics and screening. OC studies concentrate on the search for new biomarkers and therapeutic targets. This study aimed to validate the MFAP5 gene, and its encoded protein, as a potential prognostic biomarker. In our previous study, we found that patients with high-grade serous OC who had higher MFAP5 mRNA levels had shorter survival, as compared with those with lower levels. Here, we used the Kaplan-Meier Plotter and CSIOVDB online tools to analyze possible associations of MFAP5 expression with survival and other clinico-pathological features. In these analyses, higher MFAP5 mRNA expression was observed in the more advanced FIGO stages and high-grade tumors, and was significantly associated with shorter overall and progression-free survival. Next, we analyzed the expression of the MFAP5 protein by immunohistochemistry (IHC) in 108 OC samples and tissue arrays. Stronger MFAP5 expression was associated with stronger desmoplastic reaction and serous vs. non-serous histology. We found no significant correlation between IHC results and survival, although there was a trend toward shorter survival in patients with the highest IHC scores. We searched for co-expressed genes/proteins using cBioPortal and analyzed potential MFAP5 interaction networks with the STRING tool. MFAP5 was shown to interact with many extracellular matrix proteins, and was connected to the Notch signaling pathway. Therefore, although not suitable as a prognostic biomarker for evaluation with a simple diagnostic tool like IHC, MFAP5 is worth further studies as a possible therapeutic target. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 3.0)

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14 pages, 2755 KiB

Open AccessArticle

Identification of Canine Pyometra-Associated Metabolites Using Untargeted Metabolomics

by Hui-Hua Zheng, Chong-Tao Du, Yu-Zhu Zhang, Chao Yu, Rong-Lei Huang, Xin-Yue Tang and Guang-Hong Xie

Int. J. Mol. Sci. 2022, 23(22), 14161; https://doi.org/10.3390/ijms232214161 - 16 Nov 2022

Cited by 6 | Viewed by 4056

Abstract

Canine pyometra frequently occurs in middle-aged to older intact bitches, which seriously affects the life of dogs and brings an economic loss to their owners. Hence, finding a key metabolite is very important for the diagnosis and development of a new safe and effective therapy for the disease. In this study, dogs with pyometra were identified by blood examinations, laboratory analyses and diagnostic imaging, and fifteen endometrium tissues of sick dogs with pyometra and fifteen controls were collected and their metabolites were identified utilizing a UHPLC-qTOF-MS-based untargeted metabolomics approach. The results indicated that the elevated inflammatory cells were observed in dogs with pyometra, suggesting that sick dogs suffered systemic inflammation. In the untargeted metabolic profile, 705 ion features in the positive polarity mode and 414 ion features in the negative polarity mode were obtained in endometrium tissues of sick dogs with pyometra, with a total of 275 differential metabolites (173 in positive and 102 in negative polarity modes). Moreover, the multivariate statistical analyses such as PCA and PLS-DA also showed that the metabolites were significantly different between the two groups. Then, these differential metabolites were subjected to pathway analysis using Metaboanalyst 4.0, and Galactose metabolism, cAMP signaling pathway and Glycerophospholipid metabolism were enriched, proving some insights into the metabolic changes during pyometra. Moreover, the receiver operating characteristic curves further confirmed kynurenic acid was expected to be a candidate biomarker of canine pyometra. In conclusion, this study provided a new idea for exploring early diagnosis methods and a safe and effective therapy for canine pyometra. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 3.0)

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16 pages, 839 KiB

Open AccessArticle

COVID-19, Vaccination, and Female Fertility in the Czech Republic

by Lucie Kolatorova, Karolina Adamcova, Jana Vitku, Lenka Horackova, Marketa Simkova, Marketa Hornova, Michala Vosatkova, Veronika Vaisova, Antonin Parizek and Michaela Duskova

Int. J. Mol. Sci. 2022, 23(18), 10909; https://doi.org/10.3390/ijms231810909 - 18 Sep 2022

Cited by 7 | Viewed by 3367

Abstract

The fast-track process to approve vaccines against COVID-19 has raised questions about their safety, especially in relation to fertility. Over the last 2 years, studies have appeared monitoring female fertility, especially from assisted reproduction centers or in animal experiments. However, studies monitoring healthy populations are still limited. The aim of our study was to monitor the relevant parameters of female fertility (sex and other steroids, LH, FSH, SHBG, Antimüllerian hormone and antral follicle count) before and then 2–4 months after the third dose of vaccination against COVID-19 in a group of 25 healthy fertile woman. In addition, anti-SARS-CoV-2 and anti-SARS-CoV-2S antibodies were determined. We did not observe significant changes in the measured parameters before and after the third dose of vaccination. By comparing levels of the analytes with antibodies indicating a prior COVID-19 infection, we found that women who had experienced the disease had statistically lower levels of estrone, estradiol, SHBG and 5α-dihydroprogesterone, and conversely, higher levels of androgen active dehydroepiandrosterone and dihydrotestosterone. Our results confirm that vaccination does not affect female fertility, and that what fertile women should be worried about is not vaccination, but rather COVID-19 infection itself. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 3.0)

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23 pages, 4677 KiB

Open AccessArticle

Lower Plasmatic Levels of Saturated Fatty Acids and a Characteristic Fatty Acid Composition in the Ovary Could Contribute to the High-Fertility Phenotype in Dummerstorf Superfertile Mice

by Michela Calanni-Pileri, Joachim M. Weitzel, Dirk Dannenberger, Martina Langhammer and Marten Michaelis

Int. J. Mol. Sci. 2022, 23(18), 10245; https://doi.org/10.3390/ijms231810245 - 6 Sep 2022

Cited by 3 | Viewed by 2031

Abstract

In recent decades, fertility traits in humans as well as in farm animals have decreased worldwide. As such, it is imperative to know more about the genetics and physiology of increased or high fertility. However, most of the current animal models with reproductive phenotypes describe lower fertility or even infertility (around 99%). The “Dummerstorf high-fertility lines” (FL1 and FL2) are two unique mouse lines selected for higher reproductive performances, more specifically for higher number of pups per litter. We recently described how those superfertile mice managed to increase their reproductive phenotype by doubling the ovulation rate and consequently the litter size compared to the unselected mice of the same founder population. FLs show an unusual estrous cycle length and atypical levels of hormones that link reproduction and metabolism, such as insulin in FL1 and leptin in FL2. Moreover, we described that their higher ovulation rate is mostly due to a higher quality of their oocytes rather than their sheer quantity, as they are characterized by a higher quantity of high-quality oocytes in antral follicles, but the quantity of follicles per ovary is not dissimilar compared to the control. In the present study, we aimed to analyze the lipid composition of the fertility lines from plasma to the gonads, as they can connect the higher reproductive performances with their metabolic atypicalities. As such, we analyzed the fat content of FLs and fatty acid composition in plasma, liver, fat, oocytes of different quality, and granulosa cells. We demonstrated that those mice show higher body weight and increased body fat content, but at the same time, they manage to decrease the lipid content in the ovarian fat compared to the abdominal fat, which could contribute to explaining their ovarian quality. In addition, we illustrate the differences in fatty acid composition in those tissues, especially a lower level of saturated fatty acids in plasma and a different lipid microenvironment of the ovary. Our ongoing and future research may be informative for farm animal biology as well as human reproductive medicine, mostly with cases that present characteristics of lower fertility that could be reversed following the way-of-managing of Dummerstorf high-fertility lines. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 3.0)

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14 pages, 2934 KiB

Open AccessArticle

Oviductal Oxygen Homeostasis in Patients with Uterine Myoma: Correlation between Hypoxia and Telocytes

by Anna Wrona, Veronika Aleksandrovych, Tomasz Bereza, Paweł Basta, Anna Gil, Magdalena Ulatowska-Białas, Małgorzata Mazur-Laskowska, Kazimierz Pityński and Krzysztof Gil

Int. J. Mol. Sci. 2022, 23(11), 6155; https://doi.org/10.3390/ijms23116155 - 31 May 2022

Cited by 6 | Viewed by 2154

Abstract

Oxygen balance is crucial for angiogenesis, immunity, and tissue repair. The human oviduct is essential for reproductive function, and any imbalance in homeostasis leads to fertility disturbances and might be a reason for ectopic pregnancy development. Uterine myoma is a widespread benign tumour, which is often accompanied by infertility. Telocytes have been discussed in the contexts of motility, fibrosis development, and angiogenesis. We observed the oviducts from patients with and without uterine myoma, comparing the expression of HIF-1, HO, VEGF and its receptor, NOS, oestrogen, and progesterone receptors by immunolabeling. The myometrial and oviductal telocytes were also compared in both groups. Biochemical analyses were conducted for FSH, LH, AMH, sFlt, oestrogen, and progesterone in blood samples. Patients with uterine myoma have different expressions of sex steroid receptors and an increased number of telocytes. The decreasing VEFG expression was compensated by the rise in the HIF-1 and NOS expression. Blood biochemical analyses revealed a higher progesterone level and lower AMH in patients with uterine myoma. No differences in sFlt, FSH, and LF were observed. Uterine myoma impacts oviduct oxygen homeostasis and might cause fertility disturbances (uterine and oviductal infertility factors). Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 3.0)

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Review

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14 pages, 502 KiB

Open AccessReview

Prolactin in Pregnancies Affected by Pre-Existing Maternal Metabolic Conditions: A Systematic Review

by Kate Rassie, Rinky Giri, Anju E. Joham, Helena Teede and Aya Mousa

Int. J. Mol. Sci. 2023, 24(3), 2840; https://doi.org/10.3390/ijms24032840 - 2 Feb 2023

Cited by 3 | Viewed by 2281

Abstract

Women affected by maternal pregestational diabetes mellitus (type 1 or type 2) or by polycystic ovary syndrome experience an increased risk of pregnancy complications, as well as suboptimal lactation outcomes. The hormone prolactin plays important roles in pregnancy and postpartum, both as a metabolic and lactogenic hormone. We aimed to explore, through a systematic review, the relationship between pregestational maternal metabolic conditions and prolactin levels in pregnancy and postpartum. MEDLINE via OVID, CINAHL Plus, and Embase were searched from inception to 9 May 2022. Eligible studies included women who were pregnant or up to 12 months postpartum and had a pre-existing diagnosis of type 1 or type 2 diabetes mellitus or polycystic ovary syndrome; with reporting of at least one endogenous maternal serum prolactin level during this time. Two independent reviewers extracted the data. Eleven studies met the eligibility criteria. The studies were too diverse and heterogeneous to enable meta-analysis. Overall, prolactin levels appeared to be lower in pregnancies affected by type 1 diabetes mellitus. There was little data in polycystic ovary syndrome or type 2 diabetes pregnancy, but prolactin increment across pregnancy in polycystic ovary syndrome emerged as an area for future study. During postpartum, lactation difficulties in women with metabolic disease present before pregnancy are well-described, but the relationship to prolactin remains unclear. Overall, preliminary evidence suggests that pre-existing maternal metabolic disease may alter prolactin dynamics in pregnancy and postpartum. Further well-designed studies in modern cohorts, with standardised collection and serial sampling across pregnancy and postpartum, are required to clarify these associations. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 3.0)

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17 pages, 2044 KiB

Open AccessReview

Ovarian Cancer: A Landscape of Mitochondria with Emphasis on Mitochondrial Dynamics

by Domenico De Rasmo, Antonella Cormio, Gennaro Cormio and Anna Signorile

Int. J. Mol. Sci. 2023, 24(2), 1224; https://doi.org/10.3390/ijms24021224 - 8 Jan 2023

Cited by 13 | Viewed by 3431

Abstract

Ovarian cancer (OC) represents the main cause of death from gynecological malignancies in western countries. Altered cellular and mitochondrial metabolism are considered hallmarks in cancer disease. Several mitochondrial aspects have been found altered in OC, such as the oxidative phosphorylation system, oxidative stress and mitochondrial dynamics. Mitochondrial dynamics includes cristae remodeling, fusion, and fission processes forming a dynamic mitochondrial network. Alteration of mitochondrial dynamics is associated with metabolic change in tumour development and, in particular, the mitochondrial shaping proteins appear also to be responsible for the chemosensitivity and/or chemoresistance in OC. In this review a focus on the mitochondrial dynamics in OC cells is presented. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 3.0)

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28 pages, 1140 KiB

Open AccessReview

Application of Immune Checkpoint Inhibitors in Gynecological Cancers: What Do Gynecologists Need to Know before Using Immune Checkpoint Inhibitors?

by Seon-Mi Lee, Sanghoon Lee, Hyun-Woong Cho, Kyung-Jin Min, Jin-Hwa Hong, Jae-Yun Song, Jae-Kwan Lee and Nak-Woo Lee

Int. J. Mol. Sci. 2023, 24(2), 974; https://doi.org/10.3390/ijms24020974 - 4 Jan 2023

Cited by 11 | Viewed by 3104

Abstract

Standard treatments for gynecological cancers include surgery, chemotherapy, and radiation therapy. However, there are limitations associated with the chemotherapeutic drugs used to treat advanced and recurrent gynecological cancers, and it is difficult to identify additional treatments. Therefore, immune checkpoint inhibitor (ICI) therapy products, including PD-1/PD-L1 inhibitors and CTLA-4 inhibitors, are in the spotlight as alternatives for the treatment of advanced gynecological cancers. Although the ICI monotherapy response rate in gynecological cancers is lower than that in melanoma or non-small cell lung cancer, the response rates are approximately 13–52%, 7–22%, and 4–17% for endometrial, ovarian, and cervical cancers, respectively. Several studies are being conducted to compare the outcomes of combining ICI therapy with chemotherapy, radiation therapy, and antiangiogenesis agents. Therefore, it is critical to determine the mechanism underlying ICI therapy-mediated anti-tumor activity and its application in gynecological cancers. Additionally, understanding the possible immune-related adverse events induced post-immunotherapy, as well as the appropriate management of diagnosis and treatment, are necessary to create a quality environment for immunotherapy in patients with gynecological cancers. Therefore, in this review, we summarize the ICI mechanisms, ICIs applied to gynecological cancers, and appropriate diagnosis and treatment of immune-related side effects to help gynecologists treat gynecological cancers using immunotherapy. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 3.0)

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