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Aim: Endometriosis is a complex, multifactorial disease. Recent advances in molecular biology underscore that somatic mutations within the epithelial component of the normal endometrium, alongside aberrant epigenetic alterations within endometrial stromal cells, may serve as stimulators for the proliferation of endometriotic tissue within the peritoneal cavity. Nevertheless, pivotal inquiries persist: the deterministic factors driving endometriosis development in certain women while sparing others, notwithstanding comparable experiences of retrograde menstruation. Within this review, we endeavor to synopsize the current understanding of diverse pathophysiologic mechanisms underlying the initiation and progression of endometriosis and delineate avenues for future research., Methods: A literature search without time restriction was conducted utilizing PubMed and Google Scholar., Results: Given that aberrant clonal expansion stemming from cancer-associated mutations is common in normal endometrial tissue, only endometrial cells harboring mutations imparting proliferative advantages may be selected for survival outside the uterus. Endometriotic cells capable of engendering metabolic plasticity and modulating mitochondrial dynamics, thereby orchestrating responses to hypoxia, oxidative stress, inflammation, hormonal stimuli, and immune surveillance, and adeptly acclimating to their harsh surroundings, stand a chance at viability., Conclusion: The genesis of endometriosis appears to reflect the evolutionary principles of mutation, selection, clonal expansion, and adaptation to the environment., (© 2024 Japan Society of Obstetrics and Gynecology.)

Aim: The refinement of assisted reproductive technology, including the development of cryopreservation techniques (vitrification) and ovarian stimulation protocols, makes frozen embryo transfer (FET) an alternative to fresh ET and has contributed to the success of assisted reproductive technology. Compared with fresh ET cycles, FET cycles were associated with better in vitro fertilization outcomes; however, the occurrence of pregnancy-induced hypertension, preeclampsia, and placenta accreta spectrum (PAS) was higher in FET cycles. PAS has been increasing steadily in incidence as a life-threatening condition along with cesarean rates worldwide. In this review, we summarize the current understanding of the pathogenesis of PAS and discuss future research directions., Methods: A literature search was performed in the PubMed and Google Scholar databases., Results: Risk factors associated with PAS incidence include a primary defect of the decidua basalis or scar dehiscence, aberrant vascular remodeling, and abnormally invasive trophoblasts, or a combination thereof. Freezing, thawing, and hormone replacement manipulations have been shown to affect multiple cellular pathways, including cell proliferation, invasion, epithelial-to-mesenchymal transition (EMT), and mitochondrial function. Molecules involved in abnormal migration and EMT of extravillous trophoblast cells are beginning to be identified in PAS placentas. Many of these molecules were also found to be involved in mitochondrial biogenesis and dynamics., Conclusion: The etiology of PAS may be a multifactorial genesis with intrinsic predisposition (e.g., placental abnormalities) and certain environmental factors (e.g., defective decidua) as triggers for its development. A distinctive feature of this review is its focus on the potential factors linking mitochondrial function to PAS development., (© 2024 Japan Society of Obstetrics and Gynecology.)

Aim: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by menstrual irregularities, androgen excess, and polycystic ovarian morphology, but its pathogenesis remains largely unknown. This review focuses on how androgen excess influences the molecular basis of energy metabolism, mitochondrial function, and mitophagy in granulosa cells and oocytes, summarizes our current understanding of the pathogenesis of PCOS, and discuss perspectives on future research directions., Methods: A search of PubMed and Google Scholar databases were used to identify relevant studies for this narrative literature review., Results: Female offspring born of pregnant animals exposed to androgens recapitulates the PCOS phenotype. Abnormal mitochondrial morphology, altered expression of genes related to glycolysis, mitochondrial biogenesis, fission/fusion dynamics, and mitophagy have been identified in PCOS patients and androgenic animal models. Androgen excess causes uncoupling of the electron transport chain and depletion of the cellular adenosine 5'-triphosphate pool, indicating further impairment of mitochondrial function. A shift toward mitochondrial fission restores mitochondrial quality control mechanisms. However, prolonged mitochondrial fission disrupts autophagy/mitophagy induction due to loss of compensatory reserve for mitochondrial biogenesis. Disruption of compensatory mechanisms that mediate the quality control switch from mitophagy to apoptosis may cause a disease phenotype. Furthermore, genetic predisposition, altered expression of genes related to glycolysis and oxidative phosphorylation, or a combination of these factors may also contribute to the development of PCOS., Conclusion: In conclusion, fetuses exposed to a hyperandrogenemic intrauterine environment may cause the PCOS phenotype possibly through disruption of the compensatory regulation of the mitophagy-apoptosis axis., (© 2024 Japan Society of Obstetrics and Gynecology.)

Aim: Endometriosis is a chronic disease of reproductive age, associated with pelvic pain and infertility. Endometriotic cells adapt to changing environments such as oxidative stress and hypoxia in order to survive. However, the underlying mechanisms remain to be fully elucidated. In this review, we summarize our current understanding of the pathogenesis of endometriosis, focusing primarily on the molecular basis of energy metabolism, redox homeostasis, and mitochondrial function, and discuss perspectives on future research directions., Methods: Papers published up to March 31, 2023 in the PubMed and Google Scholar databases were included in this narrative literature review., Results: Mitochondria serve as a central hub sensing a multitude of physiological processes, including energy production and cellular redox homeostasis. Under hypoxia, endometriotic cells favor glycolysis and actively produce pyruvate, nicotinamide adenine dinucleotide phosphate (NADPH), and other metabolites for cell proliferation. Mitochondrial fission and fusion dynamics may regulate the phenotypic plasticity of cellular energy metabolism, that is, aerobic glycolysis or OXPHOS. Endometriotic cells have been reported to have reduced mitochondrial numbers, increased lamellar cristae, improved energy efficiency, and enhanced cell proliferation and survival. Increased mitochondrial fission and fusion turnover by hypoxic and normoxic conditions suggests an activation of mitochondrial quality control mechanisms. Recently, candidate molecules that influence mitochondrial dynamics have begun to be identified., Conclusion: This review suggests that unique energy metabolism and redox homeostasis driven by mitochondrial dynamics may be linked to the pathophysiology of endometriosis. However, further studies are needed to elucidate the regulatory mechanisms of mitochondrial dynamics in endometriosis., (© 2023 Japan Society of Obstetrics and Gynecology.)

Aim: Tissue factor pathway inhibitor 2 (TFPI2) is a structural homolog of tissue factor pathway inhibitor 1 (TFPI1). Since TFPI2 is a placenta-derived protein, dynamic changes in TFPI2 levels may be related to pregnancy-related diseases. Furthermore, TFPI2 has been reported to be a novel serum biomarker for detecting ovarian cancer, especially clear cell carcinoma (CCC). This review aims to summarize the current knowledge on the biological function of TFPI2, highlight the major challenges that remain to be addressed, and discuss future research directions., Methods: Papers published up to March 31, 2023 in the PubMed and Google Scholar databases were included in this review. We also provide novel complementary information to what is known about the action of TFPI2., Results: Since TFPI2 concentrations in the blood of pregnant women, preeclampsia patients, and cancer patients vary greatly, its pathophysiological functions have attracted attention. Downregulation of TFPI2, a tumor-suppressor gene, by hypermethylation may contribute to the progression of several cancers. On the other hand, TFPI2 overexpressed in CCC is a risk factor for the development of thrombosis, possibly through inhibition of plasmin activity. However, agreement on the biological function of TFPI2 is still lacking and there are many scientific questions to be addressed. In particular, the lack of international standardization for the quantification of TFPI2 concentrations makes it difficult for researchers and clinicians to evaluate, pool, and compare data from different studies across countries., Discussion: This review summarizes current understandings and challenges in TFPI2 research and discusses future perspectives., (© 2023 Japan Society of Obstetrics and Gynecology.)

Aim: Expression of CD44 variant isoforms (CD44v) promotes the synthesis of reduced glutathione and contributes to reactive oxygen species defense through up-regulation of the intracellular antioxidant. The aim of the study was to investigate the expression of CD44v9 and oxidative DNA damage marker, 8-OHdG, in benign ovarian endometrioma (OE) and OE harboring clear cell carcinomas (CCC)., Methods: A retrospective study was performed at the Department of Gynecology, Nara Medical University hospital from January 2006 to December 2012. Patients with histologically confirmed benign OE (n = 27) and OE harboring areas of CCC (n = 8) were selected. Tissue samples were immunohistochemically analyzed for the presence of CD44v9 and 8-OHdG using avidin-biotin complex method., Results: CD44v9 was located on the cell membrane of endometriotic epithelial cells and expressed in 88.9% (24/27) of benign OE tissues. Only 25.0% (2/8) of benign endometriotic lesions adjacent to CCC was found to stain weakly for CD44v9. Percentage of CD44v9 positive cells was 68.5 ± 20.2% (mean ± standard deviation) of benign OE, 16.7 ± 16.5% of CCC endometriotic tissue (P < 0.001). Compared to benign OE, CCC endometriotic tissue showed a significant increase in the proportion of 8-OHdG expression (77.3 ± 22.5% vs 94.9 ± 3.0%, P = 0.049). A significant negative correlation was observed between CD44v9 status and 8-OHdG nuclear expression (r = -0.458, P  =  0.006)., Conclusion: Alterations in CD44v9 and 8-OHdG may be associated with malignant transformation of benign OE., (© 2019 Japan Society of Obstetrics and Gynecology.)