Genomic alterations in ovarian endometriosis and subsequently diagnosed ovarian carcinoma.

STUDY QUESTION: Can the alleged association between ovarian endometriosis and ovarian carcinoma be substantiated by genetic analysis of endometriosis diagnosed prior to the onset of the carcinoma? SUMMARY ANSWER: The data suggest that ovarian carcinoma does not originate from ovarian endometriosis with a cancer-like genetic profile; however, a common precursor is probable. WHAT IS KNOWN ALREADY: Endometriosis has been implicated as a precursor of ovarian carcinoma based on epidemiologic studies and the discovery of common driver mutations in synchronous disease at the time of surgery. Endometrioid ovarian carcinoma and clear cell ovarian carcinoma are the most common endometriosis-associated ovarian carcinomas (EAOCs). STUDY DESIGN, SIZE, DURATION: The pathology biobanks of two university hospitals in Sweden were scrutinized to identify women with surgically removed endometrioma who subsequently developed ovarian carcinoma (1998-2016). Only 45 archival cases with EAOC and previous endometriosis were identified and after a careful pathology review, 25 cases were excluded due to reclassification into non-EAOC (n = 9) or because ovarian endometriosis could not be confirmed (n = 16). Further cases were excluded due to insufficient endometriosis tissue or poor DNA quality in either the endometriosis, carcinoma, or normal tissue (n = 9). Finally 11 cases had satisfactory DNA from all three locations and were eligible for further analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Epithelial cells were collected from formalin-fixed and paraffin-embedded (FFPE) sections by laser capture microdissection (endometrioma n = 11) or macrodissection (carcinoma n = 11) and DNA was extracted. Normal tissue from FFPE sections (n = 5) or blood samples collected at cancer diagnosis (n = 6) were used as the germline controls for each included patient. Whole-exome sequencing was performed (n = 33 samples). Somatic variants (single-nucleotide variants, indels, and copy number alterations) were characterized, and mutational signatures and kataegis were assessed. Microsatellite instability and mismatch repair status were confirmed with PCR and immunohistochemistry, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: The median age for endometriosis surgery was 42 years, and 54 years for the subsequent ovarian carcinoma diagnosis. The median time between the endometriosis and ovarian carcinoma was 10 (7-30) years. The data showed that all paired samples harbored one or more shared somatic mutations. Non-silent mutations in cancer-associated genes were frequent in endometriosis; however, the same mutations were never observed in subsequent carcinomas. The degree of clonal dominance, demonstrated by variant allele frequency, showed a positive correlation with the time to cancer diagnosis (Spearman's rho 0.853, P < 0.001). Mutations in genes associated with immune escape were the most conserved between paired samples, and regions harboring these genes were frequently affected by copy number alterations in both sample types. Mutational burdens and mutation signatures suggested faulty DNA repair mechanisms in all cases. LARGE SCALE DATA: Datasets are available in the supplementary tables. LIMITATIONS, REASONS FOR CAUTION: Even though we located several thousands of surgically removed endometriomas between 1998 and 2016, only 45 paired samples were identified and even fewer, 11 cases, were eligible for sequencing. The observed high level of intra- and inter-heterogeneity in both groups (endometrioma and carcinoma) argues for further studies of the alleged genetic association. WIDER IMPLICATIONS OF THE FINDINGS: The observation of shared somatic mutations in all paired samples supports a common cellular origin for ovarian endometriosis and ovarian carcinoma. However, contradicting previous conclusions, our data suggest that cancer-associated mutations in endometriosis years prior to the carcinoma were not directly associated with the malignant transformation. Rather, a resilient ovarian endometriosis may delay tumorigenesis. Furthermore, the data indicate that genetic alterations affecting the immune response are early and significant events. STUDY FUNDING/COMPETING INTEREST(S): The present work has been funded by the Sjöberg Foundation (2021-01145 to K.S.; 2022-01-11:4 to A.S.), Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (965552 to K.S.; 40615 to I.H.; 965065 to A.S.), Swedish Cancer Society (21-1848 to K.S.; 21-1684 to I.H.; 22-2080 to A.S.), BioCARE-A Strategic Research Area at Lund University (I.H. and S.W.-F.), Mrs Berta Kamprad's Cancer Foundation (FBKS-2019-28, I.H.), Cancer and Allergy Foundation (10381, I.H.), Region Västra Götaland (A.S.), Sweden's Innovation Agency (2020-04141, A.S.), Swedish Research Council (2021-01008, A.S.), Roche in collaboration with the Swedish Society of Gynecological Oncology (S.W.-F.), Assar Gabrielsson Foundation (FB19-86, C.M.), and the Lena Wäpplings Foundation (C.M.). A.S. declares stock ownership and is also a board member in Tulebovaasta, SiMSen Diagnostics, and Iscaff Pharma. A.S. has also received travel support from EMBL, Precision Medicine Forum, SLAS, and bioMCC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Expression of SMADs in orthotopic human endometrium, ovarian endometriosis, and endometriotic lesions in a murine model.

Activin A promotes the development of endometriotic lesions in a murine model of endometriosis, and the immunohistochemical localization of phosphorylated suppressor of mothers against decapentaplegic homolog 2/3 (pSMAD2/3) complex in endometriotic lesions has been reported. Activin may therefore be involved in the development and proliferation of endometriotic cells via the SMAD signaling pathway. However, few detailed reports exist on SMAD7 expression in endometriosis. The purpose of this study was to investigate the expression of pSMAD2/3 or pSMAD3 and SMAD7 in the orthotopic human endometrium, ovarian endometriosis, and endometriotic lesions in a murine model and the effect of activin A on pSMAD2/3 and SMAD7 expression. We established an endometriosis murine model via the intraperitoneal administration of endometrial tissue and blood from donor mice. Activin A was intraperitoneally administered to the activin group. We immunohistochemically evaluated orthotopic endometria, ovarian endometriotic tissues, and endometriotic lesions in the murine model followed by western blotting. We found that pSMAD3 and SMAD7 were expressed in ovarian endometriosis and orthotopic endometria from patients with and without endometriosis. In the murine model, endometriotic lesions expressed pSMAD2/3 and SMAD7 in the activin and control groups, and higher SMAD7 expression was found in the activin group. To the best of our knowledge, this study is the first to show that SMAD7 expression is upregulated in endometriosis. In conclusion, these results suggest that activin A activates the SMAD signaling pathway and promotes the development of endometriotic lesions, thus identifying SMAD7 as a potential therapeutic target for endometriosis.

A comprehensive review of the new FIGO classification of ovulatory disorders.

BACKGROUND: The World Health Organization (WHO) system for the classification of disorders of ovulation was produced 50 years ago and, by international consensus, has been updated by the International Federation of Gynecology and Obstetrics (FIGO). OBJECTIVE AND RATIONALE: This review outlines in detail each component of the FIGO HyPO-P (hypothalamic, pituitary, ovarian, PCOS) classification with a concise description of each cause, and thereby provides a systematic method for diagnosis and management. SEARCH METHODS: We searched the published articles in the PubMed database in the English-language literature until October 2022, containing the keywords ovulatory disorders; ovulatory dysfunction; anovulation, and each subheading in the FIGO HyPO-P classification. We did not include abstracts or conference proceedings because the data are usually difficult to assess. OUTCOMES: We present the most comprehensive review of all disorders of ovulation, published systematically according to the logical FIGO classification. WIDER IMPLICATIONS: Improving the diagnosis of an individual's ovulatory dysfunction will significantly impact clinical practice by enabling healthcare practitioners to make a precise diagnosis and plan appropriate management.

Long-term protective effects of lamotrigine in a rat ovarian ischemia-reperfusion model.

Ovarium torsion is a gynecological emergency that is common in women of reproductive age and requires early diagnosis and intervention. In this study, we aimed to investigate the long-term anatomical, histological and biochemical protective effects of lamotrigine in ovariums in the ischemia - reperfusion (I-R) model created experimentally in rats. A total of 40 female Sprague-Dawley rats, 14 weeks old, weighing 220-270 g were used in the study. The subjects were randomly distributed to form 4 groups named SHAM group, I - R group, I - R + Lamotrigine (LTG) group and R + LTG group. Under general anesthesia, the ovaries of the rats were reached and ischemia was created for 3 h with vascular clamps. 20 mg / kg LTG was administered intraperitoneally (ip.) to group 3 30 min before ischemia and to group 4 30 min before reperfusion. At the third hour of ischemia, the vascular clamps were opened and the abdomen of the rats was closed according to the surgical procedure. The rats were followed up for 28 days postoperatively and the ovarium tissues taken on the 28th day were examined anatomically and histologically. Biochemically, estradiol (E2), follicle stimulating hormone (FSH) and antimullerian hormone (AMH) levels were measured from blood samples taken from their hearts. Granulosa cells with diffuse vaculations were observed in degenerative follicles in group I-R. Again in this group, severe hemorrhage, fibrosis and edematous areas were observed in the ovarium stroma (Ovarian Histopathological Scoring (OHS): 7). In the I - R + LTG group, OHS was statistically significantly lower than the I - R group (OHS: 2; p < 0.000). In the R + LTG group, although the OHS score was calculated to be lower than the I - R group, there was no statistically significant difference (OHS: 6; p > 0.05). The protective effect of LTG against experimentally created ischemia and reperfusion damage was determined anatomically and histologically. No protective effect of LTG was observed in terms of FSH, E2 and AMH values measured from the blood sera of rats. These findings may provide a basis for future studies using LTG to treat ovarian ischemia-reperfusion injury.

Ovarian Clear Cell Carcinoma and Rectal Adenocarcinoma Detected by Tubo-Ovarian Abscess: A Case Report.

Most cases of tubo-ovarian abscess (TOA) are due to transvaginal infection, while other internal diseases may also be associated with TOAs. We experienced a case of ovarian clear cell carcinoma and rectal carcinoma that was discovered to be a result of TOA. A 46-year-old woman was diagnosed with TOA and referred to our hospital. Laparoscopic abscess drainage was performed, and pathological findings confirmed the presence of ovarian clear cell carcinoma inside the abscess. The tumor marker carcinoembryonic antigen (CEA) was elevated, and rectal cancer was diagnosed by a gastrointestinal endoscopy. Abdominal computed tomography (CT) showed a left adnexal abscess with an air image inside, and penetration of the abscess wall and rectal cancer were observed. Histopathologically, there was an accumulation of neutrophils around the rectal tumor cells. We concluded that the rectal cancer had penetrated the existing ovarian tumor and formed TOA. Non-gynecological diseases may be associated with TOA. It is necessary to consider the possibility that other clinical diseases may be associated with the trigger of TOA.

The novel peptide PFAP1 promotes primordial follicle activation by binding to MCM5.

Premature ovarian failure (POF) is a complication of ovarian dysfunction resulting from the depletion or dysfunction of primordial follicles (PFs) in the ovaries. However, residual follicles that have the potential to be activated are present in POF or aged women. Little is known about the mechanisms by which the remaining dormant PFs in POF patients are activated. Using mass spectrometry, we screened differentially generated peptides extracted from the ovarian cortical tissue biopsies of patients with or without POF, during which we identified PFAP1, a peptide that significantly promoted the activation of PFs in the ovaries of 3 dpp mice in vitro. PFAP1 reversed age-related fertility damage in vivo to a certain extent, promoted estrogen (E2) and anti-mullerian hormone (AMH) production (p < .05), and decreased the levels of follicle-stimulating hormone (FSH) (p < .05). In newborn mouse ovaries, PFAP1 could bind to the protein minichromosome maintenance protein 5 (MCM5) and inhibit its ubiquitination and degradation. In addition, PFAP1 promoted the proliferation of GCs, probably by regulating the function and production of MCM5. In conclusion, PFAP1 could promote the activation of PFs in the ovaries of newborn mice, partially restore the ovarian function of aged mice, and increase the proliferation of primary granulosa cells (GCs) by regulating the function of MCM5. PFAP1 is a promising novel peptide that may be developed into a new therapeutic agent for POF and other ovarian diseases.

The protective effect of erythropoietin on ischemia- reperfusion injury caused by ovarian torsion-detorsion in the experimental rat model.

Ovarian torsion is one of the most dangerous gynecological emergencies requiring surgery. A total of 50%-90% ovarian torsion cases are caused by physiological cysts, endometriosis, and other benign or malignant ovarian neoplasms. The aim of the study was to investigate the effects of erythropoietin (EPO) treatment on ischemia/reperfusion (IR) injury caused by ovarian torsion/detorsion (T/D) injury. Thirty female Wistar albino rats were divided into five groups as follows: Group I: Control; Group II: Torsion (T); Group III: Torsion/Detorsion(T/D); Group IV: Torsion/Detorsion (T/D) + EPO; Group V: EPO. Sections of the ovaries were evaluated for histopathological changes with hematoxylin and eosin stain, a immunohistochemical assay for caspase 3 expression, and the TUNEL assay for apoptosis. Ovarian sections from torsion/detorsion and torsion groups showed more hemorrhage, vascular congestion, edema, degenerative granulosa, and stromal cells. Fewer histopathological changes were found in EPO and T/D + EPO groups. Caspase 3 and TUNEL positive cells were significantly increased in the torsion/detorsion group as compared with the other groups (p < 0.05). Treatment with erythropoietin decreased the number of caspase 3 and TUNEL positive cells. The results of the study showed that erythropoietin administration is effective for recovery from degenerative changes in the ovary induced by the torsion-detorsion injury.

A comparative study of Mesenchymal Stem Cells transplantation approach to antagonize age-associated ovarian hypofunction with consideration of safety and efficiency.

Introduction: The transplantation of mesenchymal stem cells (MSCs) in patients with premature ovarian failure (POF) could lead to clinical improvement. The transplantation to the ovaries among other transplantation methods have been reported in various animal models, however, there is little evidence regarding the optimal method, including the clinical safety and the efficiency for the treatment of age associated ovarian hypofunction. Objectives: To establish the most effective transplantation route of MSCs, explore the resistance to therapy, its safety and role in the natural aging process of the ovaries. Methods: Highly purified MSCs were injected intraperitoneally, directly into the ovaries or tail-intravenously in mice animal model. The ovarian function, quantity and quality of oocytes, cell viability/apoptosis, were evaluated, applying chemiluminescence analysis (CLIA), western blotting, immunofluorescence staining, transmission electron microscope (TEM), TdT mediated dUTP Nick End Labeling (TUNEL) assay and other techniques. The organ tumorigenicity was also evaluated by long-term observation and histopathological examination. The efficiency of MSCs was further verified in non-human primates by the most effective transplantation route. Results: The 32nd week was ultimately determined as the time point of MSCs transplantation. Our results showed that the intra-ovarian injection was the best transplantation method with a more conspicuous effect. With deeper investigations, we found that the transplanted MSCs showed an effective influence on the follicular number, promoted follicle maturation and inhibited cell apoptosis, which was further verified in non-human primates. In addition, the long-term observation and the histopathological examinations ruled out neoplasms or obvious prosoplasia after MSCs transplantation. Conclusion: MSCs transplantation by intra-ovarian injection could within a month exert the most conspicuous anti-age-associated ovarian hypofunction effects, which may improve the quantity and quality of oocytes by changing the mitochondrial structure, regulating mitochondrial function and attenuating cell apoptosis to increase the storage of the follicle pool without a remarkable potential of tumorigenicity.

Functional and structural assessment of the possible protective effect of platelet-rich plasma against ischemia/reperfusion-induced ovarian injury in adult rats.

This study aimed to evaluate the possible protective effect of platelet-rich plasma (PRP) on ischemia reperfusion (I/R)-induced ovarian injury in a rat model. Forty adult female albino rats were randomly assigned to four groups: control, ischemia, I/R, and I/R + intraperitoneal PRP. Induction of ischemia was done by bilateral ovarian torsion for 3 h, while reperfusion was done by subsequent detorsion for another 3 h. PRP was injected 30 min before detorsion. Histological assessment and measurement of ovarian anti-Mullerian hormone (AMH) were done to assess the degree of tissue damage and the remaining ovarian reserve. Ovarian malondialdehyde (MDA) and total antioxidant capacity (TAC) levels were measured to evaluate the oxidant-antioxidant balance. Tumor necrosis factor-α (TNF-α) was measured to assess degree of inflammation. Immunohistochemical assessment of ovarian vascular endothelial growth factor-A (VEGF-A) was also done. PRP treated I/R group revealed a significant decrease in MDA (P = 0.007), TNF-α (P = 0.001), and a significant increase in TAC (P = 0.001) and VEGF-A (P = 0.003) in comparison to the untreated I/R group. Furthermore, limited vascular congestion and inflammatory infiltration were observed after PRP treatment. However, no significant difference was detected in AMH after PRP treatment. Our results denoted that PRP may help in preservation of ovarian function and structure during surgical conservative detorsion of the torsioned ovary. These protective effects could be attributed to its ability to reduce oxidative stress, inflammation and also to its high content of growth factors especially VEGF.

The role of trimetazidine in ischemia/reperfusion damage treatment in an ovary torsion model experimentally induced in rats.

The aim of this experimental animal study was to investigate the histopathological and biochemical efficacy of trimetazidine (TMZ) in decreasing ovary damage in an ovary ischaemia/reperfusion (I/R) model in the rat. A total of 35 Wistar albino female rats were randomly separated into five groups, n = 7 per group: Group 1: Sham (S) was only given a laparotomy procedure. Group 2: Ischaemia (I) group with 2-hour ischaemia using a vascular sutur. Group 3: Ischaemia/Reperfusion (I/R) group with 2 hour ischaemia and 2-hour reperfusion. Group 4: Sham + 10 mg/kg orally TMZ (S + TMZ). Group 5: I/R + 10 mg/kg oral TMZ (I/R + TMZ) group with 2 hours ischaemia and 2 hours reperfusion after the administration orally 10 mg/kg oral TMZ. Two daily doses of TMZ were orally administered to Group 4 (S + TMZ) and Group 5 (I/R + TMZ) for three days. TMZ significantly decreased vascular congestion, haemorrhage, and polymorphonuclear leukocyte infiltration in group 5 compared to group 3 (p < .05). Despite TMZ decreased the malondialdehyde, total oxidant status, and oxidative stress index values, these decreases were not statistically significant (p > .05). TMZ which is an antioxidant agent can efficiently prevent in I/R damage in rat ovaries but further studies are necessary in order to implement it in the clinical settings.IMPACT STATEMENTWhat is already known on this subject? Adnexial torsion is the most common gynecological emergency and there are no specific clinical, laboratories, or radiological findings for adnexal torsion. Unfortunatelly, the currently accepted treatment is adnexal detorsion. Cytoprotective effects of Trimetazidine (TMZ), an antianginal drug, are well-defined and it has been demonstrated to improve oxidative stress markers and limits membrane damage induced by reactive oxygen species and protects tissues from free radicals with its antioxidant effects. The aim of this study is to investigate the effects of TMZ in experimentally induced adnexal torsion in rats and to investigate possible effects in maintaining ovarian reserve to prevent I/R damage or reperfusion damage.What do the results of this study add? Our study showed that TMZ significantly decreased vascular congestion, haemorrhage, and PMNL infiltration. TMZ decreased the malondialdehyde, total oxidant status, and the oxidative stress index values, but these decreases were not statistically significant.What are the implications of these findings for clinical practice and/or further research? Although various antioxidant drugs and chemicals have been used to protect the ovaries against I/R damage, they have not been demostrated to prevent it completely. TMZ, an antioxidant efficacy agent, has been shown to prevent ovarian I/R damage by suppressing inflammation in terms of histopathological parameters. Further studies involving a greater number of experimental animals are required before using TMZ for the treatment of humans with I/R damage in the clinical setting.

Differential transcriptional profiles of human cumulus granulosa cells in patients with diminished ovarian reserve.

PURPOSE: This study compared the gene expression profiles of cumulus granulosa cells in patients with diminished ovarian reserve and those with normal ovarian reserves to identify genes that may be involved in the pathogenesis of diminished ovarian reserve. METHODS: After retrieval of the cumulus-oocyte complex, the cumulus granulosa cells that surrounded the oocytes of 25 patients with diminished ovarian reserve and 25 patients with normal ovarian reserves were removed by mechanical stripping. Extraction of RNA from the cumulus granulosa cells was for RNA sequencing and analysis. RT-PCR was used to confirm the candidate genes. Statistical analysis was performed using student's t test. RESULTS: A total of 294 upregulated genes and 336 downregulated genes were identified in the POSEIDON patients relative to the normal ovarian reserve group. Bioinformatic analysis showed that the downregulated genes were highly enriched in the Wnt signaling pathway, negative regulation of stress fiber assembly, and cell chemotaxis, while the upregulated genes were highly enriched in functions associated with the regulation of interleukin-5 production and regulation of immune system processes. According to the differential expression levels and their potential functions, IL1RL1, IL33, SFRP4, and S1PR1 were validated by quantitative RT-PCR. The results of RT-PCR were consistent with those of RNA sequencing. CONCLUSION: Expression of IL1RL1, IL33, SFRP4, and S1PR1 in the cumulus granulosa cells may be involved in the pathogenesis of diminished ovarian reserve.

Prevalence of deep and ovarian endometriosis in early pregnancy: ultrasound diagnostic study.

OBJECTIVE: To assess the prevalence and morphological appearance of deep endometriosis and ovarian endometrioma using pelvic ultrasound examination in women attending for an early pregnancy assessment. METHODS: This was a prospective observational study set within a dedicated early pregnancy unit. The study included 1341 consecutive women who attended for an early pregnancy assessment for reassurance or because of suspected early pregnancy complications. All women underwent a transvaginal scan to assess the location and viability of their pregnancy. In addition, a detailed examination of pelvic organs was carried out to detect the presence of endometriosis and other gynecological abnormalities. Data analysis was performed using logistic regression and multivariable analysis. RESULTS: The prevalence of deep endometriosis and/or ovarian endometrioma in women attending our early pregnancy unit was 4.9% (95% CI, 3.8-6.2%). In 33/66 (50.0% (95% CI, 37.9-62.1%)) women with endometriosis, this was a new diagnosis that was made during their early pregnancy scan. On multivariable analysis, the presence of endometriosis was strongly associated with a history of subfertility (odds ratio (OR), 3.15 (95% CI, 1.63-6.07)) and presence of a congenital uterine anomaly (OR, 5.69 (95% CI, 2.17-14.9)) and uterine fibroids (OR, 2.37 (95% CI, 1.31-4.28)). Morphological changes typical of decidualization were seen in 11/33 (33.3% (95% CI, 17.2-49.4%)) women with ovarian endometrioma and 18/57 (31.6% (95% CI, 19.5-43.7%)) women with deep endometriotic nodules. CONCLUSIONS: Deep endometriosis and ovarian endometrioma were present in a significant proportion of women attending for early pregnancy assessment. The prevalence varied depending on a history of subfertility, and therefore is likely to differ significantly among populations, depending on their characteristics. Ultrasound is a useful tool for the detection of endometriosis in early pregnancy and the identification of women who may benefit from specialist antenatal care. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Ovarian Endometrioma Negatively Impacts Oocyte Quality and Quantity But Not Pregnancy Outcomes in Women Undergoing IVF/ICSI Treatment: A Retrospective Cohort Study.

Purpose: To determine the impact of ovarian endometrioma per se on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes. Methods: This retrospective study was conducted using two groups. The endometrioma group consisted of 862 women with infertility who had ovarian endometriomas and underwent their first ovarian stimulation for IVF/ICSI treatment between January 2011 to December 2019 at a public university hospital. A non-endometrioma comparison group, comprising 862 women with other infertility factors, was matched according to maternal age, body mass index (BMI), and infertility duration. Ovarian reserve and response and IVF/ICSI and pregnancy outcomes between the two groups were analyzed. Multivariate logistic regression (MLR) analysis was conducted on the basis of clinical covariates assessed for their association with live birth. Results: The results showed that significantly lower antral follicle count (AFC), anti-Müllerian hormone (AMH), ovarian sensitivity index (OSI), oocyte maturation and fertilization rates, blastocyst rate, number of oocytes retrieved, and available embryos were found in women with endometrioma compared with the control, respectively (P < 0.05). The cumulative live birth rate per patient in women with endometrioma was lower than that of women without endometrioma (39.32% vs. 46.87%, P = 0.002). In women with endometrioma, those who underwent surgical intervention prior to IVF/ICSI treatment had higher maturation (86.03% vs. 83.42%, P = 0.003), fertilization (78.16% vs. 74.93%, P = 0.004), and top-quality embryo rates (42.94% vs. 39.93%, P = 0.097) but had fewer oocytes retrieved (8.01 ± 5.70 vs. 9.12 ± 6.69, P = 0.013) than women without surgery. However, live birth rates were comparable between women with endometrioma and women in the control group, regardless of whether they had a prior history of ovarian surgery. MLR analysis showed no correlation between endometrioma per se and live birth after being adjusted for number of top-quality embryos transferred and stage of embryo transfer. Conclusions: The data from this study supported the conclusion that ovarian endometrioma negatively impacts oocyte quality and quantity, but not overall pregnancy outcomes, in women undergoing IVF/ICSI treatment. Endometrioma lowers the cumulative live birth rate by decreasing the number of embryos. Surgical excision of endometrioma prior to IVF/ICSI can partly improve oocyte maturation and fertilization rates but not pregnancy outcomes.

Impact of endometriosis on oocyte morphology in IVF-ICSI: retrospective study of a cohort of more than 6000 mature oocytes.

BACKGROUND: Infertility associated with endometriosis can be explained by several non-exclusive mechanisms. The oocyte plays a crucial role in determining embryonic competence and this is particularly relevant for in vitro fertilization (IVF) outcomes. According to some authors, the morphology of oocytes could also be a non-invasive marker of oocyte quality. The aim of this study was to evaluate the relationship between endometriosis and oocyte morphology after controlled ovarian stimulation for intracytoplasmic sperm injection (ICSI) on a large oocyte cohort. METHODS: Single-center comparative retrospective study in the academic In Vitro Fertilization (IVF) unit of the Lille University Hospital. A total of 596 women treated for IVF-ICSI with ejaculated spermatozoa for sperm alterations were included. They were classified as endometriosis (n = 175) or control groups (n = 401). The morphological evaluation of 2,016 mature oocytes from 348 cycles of patients with endometriosis was compared with that of 4,073 mature oocytes from 576 control cycles. The main outcome measures were Average Oocyte Quality Index (AOQI) and metaphase II oocyte morphological scoring system (MOMS). Comparison of groups was carried out by a mixed linear model and by a generalized estimation equation model with a "patient" random effect to consider that a patient might have several attempts. RESULTS: No difference in AOQI and MOMS scores was found between endometriosis and control women (adjusted p = 0.084 and 0.053, respectively). In case of endometriosis, there were significantly fewer metaphase II oocytes retrieved, embryos obtained, grade 1 embryos and number of cumulative clinical pregnancies compared to controls. In the endometriosis group, endometriosis surgery was associated with a reduced number of mature oocytes retrieved, and the presence of endometrioma(s) was associated with some abnormal oocyte shapes. Nevertheless, no difference concerning the AOQI and MOMS scores was found in these subgroups. CONCLUSION: Endometriosis does not have a negative impact on oocytes' morphology in IVF-ICSI. TRIAL REGISTRATION: On December 16, 2019, the Institutional Review Board of the Lille University Hospital gave unrestricted approval for the anonymous use of all patients' clinical, hormonal and ultrasound records (reference DEC20150715-0002).

Idiopathic early ovarian aging: is there a relation with premenopausal accelerated biological aging in young women with diminished response to ART?

PURPOSE: To evaluate whether young women with idiopathic early ovarian aging, as defined by producing fewer oocytes than expected for a given age over multiple in vitro fertilization (IVF) cycles, have changes in telomere length and epigenetic age indicating accelerated biological aging (i.e., increased risk of morbidity and mortality). METHODS: A prospective cohort study was conducted at two Danish public fertility clinics. A total of 55 young women (≤ 37 years) with at least two IVF cycles with ≤ 5 harvested oocytes despite sufficient stimulation with follicle-stimulating hormone (FSH) were included in the early ovarian aging group. As controls, 52 young women (≤ 37 years) with normal ovarian function, defined by at least eight harvested oocytes, were included. Relative telomere length (rTL) and epigenetic age acceleration (AgeAccel) were measured in white blood cells as markers of premenopausal accelerated biological aging. RESULTS: rTL was comparable with a mean of 0.46 (± SD 0.12) in the early ovarian aging group and 0.47 (0.14) in the normal ovarian aging group. The AgeAccel of the early ovarian aging group was, insignificantly, 0.5 years older, but this difference disappeared when adjusting for chronological age. Sub-analysis using Anti-Müllerian hormone (AMH) as selection criterion for the two groups did not change the results. CONCLUSION: We did not find any indications of accelerated aging in whole blood from young women with idiopathic early ovarian aging. Further investigations in a similar cohort of premenopausal women or other tissues are needed to fully elucidate the potential relationship between premenopausal accelerated biological aging and early ovarian aging.

Associations between body mass index and the surgical phenotype and location of endometriotic lesions.

RESEARCH QUESTION: Is there a relationship between body mass index (BMI) and endometriotic lesions, specifically surgical phenotype and lesion location? DESIGN: An observational retrospective cohort study at the Royal Women's Hospital, Melbourne, Australia, including 471 histologically confirmed endometriosis patients. Statistical analyses included multivariate logistic regression and multivariate modelling, correcting for multiple testing. Outcomes were the presence or absence of surgically classified lesion phenotypes, as per revised American Society for Reproductive Medicine criteria including superficial or deep, peritoneal or ovarian, and adhesions (Study I); and lesions at specific anatomical locations (including pelvic side wall, uterosacral ligament, pouch of Douglas, ovarian, uterovesical fold, bladder, and pararectal endometriosis) (Study II). RESULTS: In Study I, patients with higher BMI were more likely to have superficial peritoneal lesions (odds ratio [OR] 1.070, 95% confidence interval [CI] 1.004-1.144; P = 0.044), and less likely to have deep ovarian lesions (OR 0.928, 95% CI 0.864-0.993; P = 0.034). In Study II, patients with higher BMI were less likely to have uterovesical fold lesions (OR 0.927, 95% CI 0.867-0.985; P = 0.021) or anterior compartment lesions (OR 0.940, 95% CI 0.888-0.989; P = 0.023). After correcting for multiple testing, the relationship between BMI and lesion phenotypes did not persist (P > 0.01). CONCLUSIONS: This analysis does not conclusively support an influence of BMI on endometriotic lesion phenotype based on surgical classification or location. Further investigation of the physiological disturbances underlying BMI and the promotion of endometriotic lesion phenotypes and their location is warranted, but any effect is likely to be small.

UHPLC-MS-MS analysis of oxylipins metabolomics components of follicular fluid in infertile individuals with diminished ovarian reserve.

BACKGROUND: Diminished ovarian reserve (DOR) refers to a decrease in the number and quality of oocytes in the ovary, which results in a lack of sex hormones and a decline of fertility in women. DOR can potentially progress to premature ovarian failure (POF), which has a negative impact on women's quality of life and is a major cause of female infertility. Oxidative stress is a major contributor to fertility decrease in DOR patients, affecting the follicular microenvironment, oocyte maturation, fertilization, and embryo development. Understanding intracellular signal transduction can be achieved by defining specific oxidized lipid components in follicular fluid (FF) of DOR infertile patients. METHODS: The oxylipins metabolic signatures in the FF of DOR patients and females with normal ovarian reserve (NOR) enrolled for the in vitro fertilization (IVF) cycle were analyzed using UHPLC-MS-MS technology. Principal component analysis (PCA) and orthogonal projections to latent structure discriminant analysis (OPLS-DA) were used to analyze the derived metabolomic profiles. Pathway enrichment analysis was carried out using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and MetaboAnalyst databases. Furthermore, the Spearman rank correlation coefficient was used to determine the correlation between age, FSH, AMH, AFC, oocytes retrieved, MII oocytes, fertilization, high-quality embryos, and the concentration of differential oxidized lipid metabolites in FF. RESULTS: Fifteen oxylipins metabolites were found to be lower in the FF of DOR patients than those in the NOR group, including ±20-HDoHE, ±5-iso PGF2α-VI, 12S-HHTrE, 15-deoxy-Δ12,14-PGJ2, 1a,1b-dihomo PGE2, 1a,1b-dihomo PGF2α, 20-COOH-AA, 20-HETE, 8S,15S-DiHETE, PGA2, PGD2, PGE1, PGF1α, PGF2α, and PGJ2. The pathway enrichment analysis revealed that the 15 differentially oxidized lipid metabolites were closely related to the arachidonic acid metabolic pathway. Correlation analysis revealed that the concentration of 8 different oxidized lipid metabolites in FF was negatively correlated to FSH and positively correlated with AFC. AMH, the number of oocytes retrieved, MII oocytes and fertilization, were all positively correlated with 9 different oxidized lipid metabolites, but only one metabolite was positively correlated with the number of high-quality embryos. CONCLUSIONS: Metabolomic analysis of FF revealed that oxylipins metabolism disorders were closely related to ovarian reserve function. Among these oxylipins metabolites, arachidonic acid metabolism undergoes significant changes that may be related to oocyte development, resulting in decreased fertility in DOR patients. TRIAL REGISTRATION: ChiCTR, ChiCTR2000038182 , Registered 12 September 2020-Retrospectively registered.

PI3K/PTEN/AKT Signaling Pathways in Germ Cell Development and Their Involvement in Germ Cell Tumors and Ovarian Dysfunctions.

Several studies indicate that the PI3K/PTEN/AKT signaling pathways are critical regulators of ovarian function including the formation of the germ cell precursors, termed primordial germ cells, and the follicular pool maintenance. This article reviews the current state of knowledge of the functional role of the PI3K/PTEN/AKT pathways during primordial germ cell development and the dynamics of the ovarian primordial follicle reserve and how dysregulation of these signaling pathways may contribute to the development of some types of germ cell tumors and ovarian dysfunctions.

Ovarian inguinal hernia - a possibility in MURCS syndrome.

BACKGROUND: Inguinal hernia containing ovary and fallopian tube can be found in paediatric population and is a rare finding in women of reproductive age group. Most of the cases are associated with congenital abnormalities of the female genital tract. CASE PRESENTATION: A 20 year old female presented with right reducible inguinal hernia, primary amenorrhea and normal secondary sexual characteristics. Clinical examination revealed scoliosis with convexity towards left side, prominence of left rib cage with Sprengel deformity and right sided heart sounds. Ultrasound of the inguinal swelling revealed right ovary within the hernial sac, Chest X-ray revealed right lung collapse and dextrocardia. Further Magnetic resonance imaging (MRI) of pelvis revealed inguinal hernia with right ovary as its content, normal left ovary and absent uterus. Computed tomography (CT) revealed complete collapse of right lung with compensatory left lung hyperinflation and absent right kidney. Karyotyping of the patient was normal, 46XX. A diagnosis of MURCS syndrome with right ovarian hernia was made. The hernia was surgically managed with repositioning of ovary and fallopian tube into the pelvis. DISCUSSION: Ovary in inguinal hernia is rare in women of reproductive age group. MRKH syndrome, a mullerian duct anomaly, is the congenital aplasia of uterus and upper two-thirds of vagina in a female with normal ovaries, fallopian tube, secondary sexual characteristics and 46XX karyotype. MURCS is a subtype of MRKH type 2 having mullerian duct agenesis with renal, cardiac, muscular & vertebral defects. General physical examination and primary investigations if yields abnormal findings; the patient must undergo an array of investigations to rule out MRKH/MURCS, or other congenital abnormality. Early diagnosis is essential to prevent its incarceration or torsion. The primary treatment of ovary in inguinal hernia is repositioning the ovary and fallopian tube back to pelvis to preserve fertility and repair of inguinal hernia. A multidisciplinary team is required to deal with various abnormalities present in a patient with MURCS.