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Molecular and Clinical Aspects of Endometriosis Pathophysiology

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Dear Colleagues,

Endometriosis is a disease that affects the quality of life and fertility of up to 10% of women worldwide. It is a heterogeneous, estrogen-dependent inflammatory disease that is characterized by the growth of endometrial-like lesions outside of the uterus and is associated with chronic cyclic pain and reduced fertility. Resolving open questions in the pathophysiology of endometriosis may guide better diagnosis and treatment of the disease. Hence, we are pleased to invite submissions of original research articles and reviews on the topic of our Special Issue entitled “Molecular and Clinical Aspects of Endometriosis Pathophysiology”. We look forward to receiving your contributions that address the pathology of endometriosis and relate findings to the potential for improving clinical practice.

Dr. Quanah J. Hudson
Dr. Iveta Yotova
Guest Editors

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Published Papers (3 papers)

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16 pages, 16488 KiB

Open AccessArticle

Peritoneal Endometriosis Impairs Ovarian Reserve and Increases Atresia in a Rat Model

by Analía Ricci, Tatiana Bengochea, Carla Olivares, Sofía del Valle, Julieta Simone, Kristina Gemzell-Danielsson, Rosa Inés Barañao, Gabriela Meresman and Mariela Bilotas

Biomedicines 2025, 13(2), 348; https://doi.org/10.3390/biomedicines13020348 - 3 Feb 2025

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Abstract

Background/Objectives: Endometriosis has a marked impact on fertility, although the mechanisms behind this relationship remain poorly understood, particularly in cases without significant anatomical distortions or in the context of ovarian endometriomas. This study aimed to investigate the effect of peritoneal endometriosis on ovarian function by assessing ovarian reserve and apoptosis. Methods: Peritoneal endometriosis was surgically induced in Sprague Dawley rats through the autotransplantation of uterine fragments onto the bowel mesothelium. One month post-surgery, ovarian structures were counted, follicle and corpora lutea apoptosis was evaluated by TUNEL, and apoptotic-related protein expression in ovaries was assessed by Western blot. Additionally, a co-culture system using 12Z endometriotic and KGN granulosa cell lines was utilized to evaluate gene expression by RT-qPCR. Results: Rats with peritoneal endometriosis exhibited a significant reduction in ovarian structures characterized by a low number of total follicles, particularly primordial, primary, preantral, and late-antral follicles. Consistently, AMH protein expression was decreased in ovaries in the presence of endometriosis. In addition, this disease led to a significant increase in late-antral follicles that were TUNEL-positive and in the number of apoptotic cells in corpora lutea, indicating higher apoptosis in endometriosis ovaries. Concomitantly, the altered expression of apoptosis-related proteins was observed, with increased procaspase 3 and decreased BCL-2 expression. In addition, KGN granulosa cells co-cultured with 12Z endometriotic cells displayed reduced KITLG mRNA expression and increased AMHR2 mRNA expression. Conclusions: Peritoneal endometriosis significantly impairs ovarian health by disrupting folliculogenesis, reducing ovarian reserve, and increasing apoptosis, potentially accelerating ovarian aging and contributing to infertility. These results underscore the need for further research to identify the molecular pathways involved and to develop targeted therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular and Clinical Aspects of Endometriosis Pathophysiology)

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Figure 1

Figure 1
Effect of surgically induced endometriosis on folliculogenesis in vivo. (A): The number of follicles, corpora lutea, and total ovarian structures (i.e., follicles + corpora lutea) were assessed in ovarian sections from rats with and without endometriosis (Sham). (B): The number and proportion of each follicular stage were determined. (C): Representative micrographs show histological sections of ovaries from Sham (i,iii) and endometriosis (ii,iv) rats. Ovarian structures are indicated: corpora lutea (*), late-antral follicles (#), preovulatory follicles (&), primordial follicles (white arrows), primary follicles (black arrows), and preantral follicles (black arrowhead). Magnification 20× (i,ii) and 400× (iii,iv). Scale bar indicates 500 µm (ii) or 200 µm (iv). Results are expressed as means ± SEM. Sham: n = 6, endometriosis n = 5: statistical comparisons were performed by Student’s “t” test. * p < 0.05, ** p < 0.01 Sham vs. endometriosis. Full article ">Figure 2
Effect of endometriosis on ovarian apoptosis in vivo. (A): The number of apoptotic cells per follicle and the proportion of follicles with apoptotic cells were determined by TUNEL. Micrographs of histological sections show late-antral follicles from rats with and without endometriosis (Sham). (B): The number of apoptotic cells per corpus luteum area and the proportion of corpora lutea with apoptotic cells were assessed by TUNEL. Micrographs of histological sections show corpora lutea from rats with and without endometriosis (Sham). Arrows indicate TUNEL-positive (TUNEL+) cells. As a negative control, an ovarian section was subjected to treatment without TdT (inset). Magnification 400× and 100×. Scale bar indicates 100 μm. Results are expressed as means ± SEM. Sham: n = 6, endometriosis: n = 6. Statistical comparisons were performed by Student’s “t” test. * p < 0.05, ** p < 0.01 Sham vs. endometriosis. Full article ">Figure 3
Effect of endometriosis on the expression of apoptosis-related proteins in vivo. Protein expression was evaluated by Western blot in ovarian homogenates from rats with and without endometriosis (Sham). (A): Procaspase 3 and caspase 3 p17 and p19 cleaved fragments; (B): Fas and FasL proteins (extrinsic apoptotic pathway); (C): BCL-2 family member proteins (intrinsic apoptotic pathway, upper panel) and proapoptotic to antiapoptotic BCL-2 family member ratios (lower panel). Results are expressed as means ± SEM. Representative blots are presented below each graph. n is expressed in parentheses in each bar. Statistical comparisons were performed by Student’s “t” test. * p < 0.05 Sham vs. endometriosis. Full article ">Figure 4
Effect of endometriosis on the expression of folliculogenesis-related proteins in vivo. Protein expression was assessed by Western blot in ovarian homogenates from rats with and without endometriosis (Sham). (A): AMH; (B): KL; (C): GDF-9. The upper panels show quantification, and the lower panels show representative blots. Results are expressed as means ± SEM. n is expressed in parentheses in each bar. Statistical comparisons were performed by Student’s “t” test. * p < 0.05 Sham vs. endometriosis. Full article ">Figure 5
Effect of endometriotic cells on the expression of folliculogenesis-related genes in granulosa cells in vitro. The AMH (A), AMHR2 (B), KITLG (C), and MTOR (D) mRNA expressions were assessed in KGN granulosa cells by RT-qPCR. KGN cells were cultured alone (KGN) or co-cultured with 12Z endometriotic cells (KGN + 12Z) for 48 h. 18S or RPLP0 were used as housekeeping genes. Results are expressed as means ± SEM. n is expressed in parentheses in each bar. Statistical comparisons were performed by Student’s “t” test. * p < 0.05 KGN vs. KGN + 12Z. Full article ">

Abstract

Background/Objectives: Endometriosis is a painful chronic condition in which the endometrium grows outside the uterus. The epithelial–mesenchymal transition (EMT) is critical to endometriosis progression, where cells lose epithelial traits and gain invasiveness. Methods: This study investigates the effects of phoenixin-14 (PNX-14), a neuropeptide found at reduced levels in endometriosis patients, on the expression of two molecular EMT markers, CDH1 (E-cadherin) and THBS2 (thrombospondin 2), as well as cell viability in the endometriosis-derived 12Z cell line. Cells were treated with physiological (0.2 nM) and endometriosis-relevant (0.05 nM) concentrations of PNX-14. Gene expression was analyzed using RT-qPCR, while protein localization was assessed by immunocytochemistry. Cell viability was measured using an XTT assay. Results: THBS2 gene expression was significantly decreased, and CDH1 remained unchanged in cells stimulated by 0.05 nM PNX-14. Immunolocalization indicates a weaker THBS2 and CDH1 protein immunosignal reaction for 0.05 nM PNX-14. PNX-14 treatment also exhibited a biphasic effect on cell viability. Lower concentration initially decreased viability at 48 h but then significantly increased it at 72 h. This increase coincided with the decrease in THBS2 expression, suggesting a potential link between PNX-14, THBS2, and cell viability. Conclusions: A negative correlation between cell viability and the expression of both EMT markers further highlights their possible involvement in the survival and adaptability of ectopic epithelial cells. Our findings suggest a complex interplay between PNX-14, EMT markers, and cell viability in ectopic epithelial cells. PNX-14’s ability to modulate these factors warrants further investigation to elucidate its role in endometriosis. Full article

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