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GeneXplore Diagnostics and Research Centre Pvt. Ltd. Ahmedabad, Gujarat, India
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To evaluate the proportion of chromosomal abnormalities in recurrent pregnancy loss (RPL) assisted by array comparative genomic hybridization (aCGH) bright out with higher detection rate, more accuracy, and less sample failure as compared with conventional cytogenetic analysis. In this study, product of conception samples with abnormal ultrasonogram (USG) findings of the fetus and clinical history of RPL were first processed for karyotyping and fluorescence in situ hybridization (FISH) analysis. Normal results given by karyotype and FISH samples with major anomalies detected by ultrasound with RPL were divided into six groups and aCGH was performed to detect the gain or loss and copy number variations (CNVs) of a particular gene present in chromosomal segments. Among a total of 300 products of conception samples, 100 abnormal samples were identified either by karyotype (n = 70) or by FISH (n = 30). From the remaining 200 samples, 5 showed the presence of maternal cell contamination excluded. aCGH analysis revealed (n = 195) that 74 (38%) samples with CNVs and 2 samples with variants of unknown clinical significance were clinically associated with the clinical findings and 121(62%) samples showed no change in CNVs. The most frequent CNVs were loss of chromosome regions at 2q33.1, 7q11.21, 15q11.1, 16p11.2, Xp22.33, and Yp11.32. CNVs at arr[GRCh37]7p22.3,p21.2(830852-15124702)×1,7q34q36.3(141464180-158909738)×3, 14.2Mbp deletion of 7p22.3p21.2 (SUN1 gene) and 17.4Mbp duplication of 7q34q36.3 (KCNH2, CNTNAP2, and SHH genes) were found in one sample, and CNVs at arr[GRCh37]8p22.2q22.3(86326349-105509986)×1 and 2.48Mbp deletion of 8p22.2q22.3 (GRHL1 gene) were found in another sample.
Lay summary
Recurrent pregnancy loss is considered as two or more consecutive pregnancy losses. Fetal birth defects are thoroughly associated with chromosomal (thread-like structures containing packaged genetic material) abnormalities, which are the underlying causes of pregnancy loss. The evaluation of chromosomal abnormalities is required to diagnose pregnancy loss to improve the prognosis of future pregnancies. The largest proportion of chromosomal abnormalities was observed in the fetal tissue that remains in the uterus after pregnancy. We analyzed 300 retained fetal tissue samples and implicated different methods to recognize the structural abnormalities in the chromosomes. Moreover, simultaneously detect the expression of thousands of genes from fetal tissue. A clinical indication and their association of chromosomal abnormalities were obtained in 38% of cases with assorted fetal ultrasound defects in multiple pregnancy losses and two samples with a variety of unknown clinical indications. It revealed that chromosomal alteration in fetal birth defects is responsible for multiple pregnancy losses.
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Graphical abstract
Abstract
Patients with chronic pelvic pain (CPP) may experience pain exacerbations requiring hospital admissions. Due to the effects of backlogged elective surgeries and outpatient gynaecology appointments resulting from the COVID-19 pandemic, we hypothesised that there would be an increased number of women admitted with CPP flares. We conducted a retrospective review of all acute gynaecology admissions at the Royal Infirmary of Edinburgh from July to December 2018 (pre-COVID) and 2021 (post-COVID lockdown). We collected information on the proportion of emergency admissions due to CPP, inpatient investigations and subsequent management. Average total indicative hospital inpatient costs for women with CPP were calculated using NHS National Cost Collection data guidance. There was no significant difference in the number of emergency admissions due to pelvic pain before (153/507) and after (160/461) the COVID-19 pandemic. As high as 33 and 31% had a background history of CPP, respectively. Across both timepoints, investigations in women with CPP had low diagnostic yield: <25% had abnormal imaging findings and 0% had positive vaginal swab cultures. Women with CPP received significantly more inpatient morphine, pain team reviews and were more likely to be discharged with strong opioids. Total yearly inpatient costs were £170,104 and £179,156 in 2018 and 2021, respectively. Overall, emergency admission rates for managing CPP flares was similar before and after the COVID-19 pandemic. Inpatient resource use for women with CPP remains high, investigations have low diagnostic yield and frequent instigation of opiates on discharge may risk dependence. Improved community care of CPP is needed to reduce emergency gynaecology resource utilisation.
Lay summary
Existing treatments for chronic pelvic pain (CPP) and endometriosis focus on surgery or hormone medication, but these are often ineffective or associated with unacceptable side-effects. As a result, women continue to experience chronic pain and often have ‘flares’ of worsening pain that may lead to hospital admission. The COVID-19 pandemic resulted in backlogged gynaecology clinics and surgeries. The aim of this study was to compare the management of emergency pelvic pain admissions for women with CPP before and after COVID-19. We also aimed to better understand their in-hospital management and estimate their hospital length of stay costs. We did not find an increase in CPP patients admitted for pelvic pain flares after the COVID-19 lockdown. Women with CPP often undergo multiple hospital tests and are often prescribed with strong pain medications which can cause long-term problems. Efforts are needed to improve long-term pain management for women with CPP.
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The hypothesis that colony-stimulating factor 2 (CSF2) plays a role in the preimplantation development of the bovine embryo was tested by evaluating consequences of inactivation of CSF2RA (the functional receptor in the embryo) for the development of embryos in utero. CRISPR/Cas9 was used to alter sequences on exon 5 and intron 5 of CSF2RA, Control embryos were injected with Cas9 mRNA only. Embryos > 16 cells at day 5 after insemination were transferred to synchronized recipient females in groups of 7–24. Embryos were flushed from the uterus 2 days later. The proportion of recovered embryos that developed to the blastocyst stage was lower for knockout embryos (39%) than for control embryos (63%). RNA sequencing of individual morulae and blastocysts indicated a total of 27 (morula) or 15 (blastocyst) differentially expressed genes (false discovery rate <0.05). Gene set enrichment analysis indicated that the knockout affected genes playing roles in several functions including cell signaling and glycosylation. It was concluded that signaling through CSF2RA is not obligatory for the development of the bovine preimplantation embryo to the blastocyst stage but that CSF2 signaling does enhance the likelihood that the embryo can become a blastocyst and result in specific changes in gene expression.
Lay summary
Development of the early embryo depends upon regulation by chemical signals produced by the uterus. One of these signals is a protein called colony-stimulating factor 2 (CSF2) that can affect the development of embryos in culture. To test whether CSF2 also regulates the embryo in the uterus, where development ordinarily occurs, we evaluated development in the uterus of embryos in which the receptor for CSF2 was disrupted. Embryos without the receptor gene were less likely to develop to the typical stage of development than control embryos and experienced some differences in the expression of specific genes. We conclude that CSF2 regulates embryonic development in the uterus.
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Growth patterns and associated endocrine profiles were compared between dominant anovulatory (ADF) and ovulatory follicles (OvF) developing from different waves within and between menstrual cycles in women. Follicular mapping profiles of 49 healthy women of reproductive age and blood samples were obtained every 1–3 days during one interovulatory interval. Sixty-three dominant follicles were classified into wave 1 (W1ADF; n = 8) and wave 2 (W2ADF; n = 6) anovulatory follicles and wave 2 (W2OvF; n = 33) and wave 3 (W3OvF; n = 16) ovulatory follicles. Comparisons were made between W1ADF and W2ADF, W2ADF and W2OvF, and W2OvF and W3OvF. The waves were numbered 1, 2, or 3 based on when the waves emerged relative to the preceding ovulation. W1ADF emerged closer to the preceding ovulation, and W2ADF emerged in the late luteal or early follicular phase. The interval from emergence to maximum diameter was shorter for W2ADF than W1ADF and for W3OvF than W2OvF. Selection of W3OvF occurred at a smaller diameter compared to W2OvF. W1ADF regressed at a faster rate than W2ADF. Also, W1ADF were associated with lower mean follicle stimulating hormone (FSH) and higher mean estradiol than W2ADF. In contrast, W3OvF were associated with higher FSH and luteinizing hormone (LH) compared to W2OvF. However, W2OvF were associated with higher progesterone than W3OvF. This study contributes to the understanding of the physiologic mechanisms underlying selection of the dominant follicle, ovulation, and pathophysiology of anovulation in women, as well as optimization of ovarian stimulation protocols for assisted reproduction.
Lay summary
Ovarian follicles (the fluid-filled sacs that contain the eggs) develop within 2 or 3 waves during the human menstrual cycle. Typically, only one follicle in each cycle releases an egg during ovulation. The rest of the follicles grow then regress. In this study, we characterized differences in the growth, regression, and associated hormone production between follicles that ovulated and those that did not, developing from different waves within and between menstrual cycles. Differences regarding follicle growth patterns and hormone concentrations were found when comparing different waves and whether a follicle ovulated. Results from this study improve our understanding of the processes underlying follicular growth and ovulation, which in turn may assist in improving fertility and birth control treatments.
Department of Agricultural Science, School of Agriculture and Vocational Studies, Alvan Ikoku Federal College of Education, Owerri, Imo State, Nigeria
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Preovulatory follicle growth and the luteal transition require intense angiogenesis. This enables progesterone production to increase sufficiently to support a pregnancy. Inadequate follicular or luteal vascularisation can lead to reduced ovarian function and thus compromise fertility. Insulin-like growth factor 1 (IGF1) and IGF2 regulate multiple ovarian processes and are key links between an animal’s reproductive and metabolic status. This study investigated the role that the IGF system plays in regulating luteinising follicular endothelial cell (EC) networks and progesterone production in vitro. Bovine luteinising follicular angiogenesis cultures were treated with (i) LR3-IGF1 (10 or 100 ng/mL) under basal and angiogenic-stimulated conditions or (ii) IGF1 receptor (IGF1R) inhibitor (picropodophyllin (PPP); 1 µM) in the presence or absence of LR3-IGF1, IGF2 or combined LR3-IGF1 + IGF2 (10 ng/mL). EC networks were quantified by von Willebrand factor immunohistochemistry. Progesterone production was analysed by ELISA, and cell proliferation was determined by MTT assay. LR3-IGF1 had limited effects on EC growth parameters, whilst PPP (P < 0.001) markedly reduced EC growth parameters (by 60–70%). Cell proliferation was slightly increased (by 3–5%) by LR3-IGF1 (P < 0.001). LR3-IGF1 had variable effects on progesterone production, whilst PPP reduced progesterone concentration (P < 0.001) with or without LR3-IGF1 or IGF2 alone or in combination. IGF1 was detected in cell-conditioned media and was increased by LH (50 ng/mL) (P < 0.001). In conclusion, exogenous IGF1 and IGF2 had minimal effects on luteinising follicular angiogenesis and progesterone production, but the inhibitory effect of the IGF1R inhibitor (PPP) suggests that IGF1R signalling is critical for the development of EC networks and progesterone production in luteinising follicular cells.
Lay summary
The corpus luteum is a part of the ovary responsible for producing the critical pregnancy hormone, progesterone. To fulfil this function, the corpus luteum requires an extensive blood vessel network. Here, we investigated whether an important growth factor known to act on the ovary, insulin like growth factor (IGF) 1, critically regulates the formation of this blood vessel network and progesterone production. Cells from the corpus luteum were cultured with combinations of IGF1, a closely related hormone IGF2 and a chemical which stops both IGF1 and IGF2 from working. Afterwards, we measured the size and pattern of blood vessel networks, the production of progesterone and whether cells increased in number. We found adding IGF1 had limited effects, however stopping IGF1 from working had a very negative impact on both progesterone and on the formation of the blood vessel network. This suggests that cells from the corpus luteum were producing IGF1 and that IGF1/2 are critical for both blood vessel growth and hormone production.
Jean Hailes for Women’s Health, Melbourne, Victoria, Australia
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Department of Obstetrics and Gynaecology, Royal Women’s Hospital, University of Melbourne, Parkville, Victoria, Australia
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Gynaecological Research and Clinical Evaluation (GRACE) Unit, Royal Hospital for Women, Randwick New South Wales, Australia
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Graphical abstract
Abstract
Endometriosis is a common yet under-recognised chronic inflammatory disease, affecting 176 million women, trans and gender diverse people globally. The National Endometriosis Clinical and Scientific Trials (NECST) Registry is a new clinical registry collecting and tracking diagnostic and treatment data and patient-reported outcomes on people with endometriosis. The registry is a research priority action item from the 2018 National Action Plan for Endometriosis and aims to provide large-scale, national and longitudinal population-based data on endometriosis. Working groups (consisting of patients with endometriosis, clinicians and researchers) developing the NECST Registry data dictionary and data collection platform started in 2019. Our data dictionary was developed based on existing and validated questionnaires, tools, meta-data and data cubes – World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project, endometriosis CORE outcomes set, patient-reported outcome measures, the International Statistical Classification of Diseases-10th Revision Australian Modification diagnosis codes and Australian Government datasets: Australian Institute for Health and Welfare (for sociodemographic data), Medicare Benefits Schedule (for medical procedures) and the Pharmaceutical Benefits Scheme (for medical therapies). The resulting NECST Registry is an online, secure cloud-based database, prospectively collecting minimum core clinical and health data across eight patient and clinician modules and longitudinal data tracking disease life course. The NECST Registry has ethics approval (HREC/62508/MonH-2020) and is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622000987763).
Lay summary
The National Endometriosis Clinical and Scientific Trials (NECST) Registry is part of a national collaborative project by Australian clinicians, researchers and patient advocates – the NECST Network, an Australian Government initiative. The NECST Registry will be a national resource of participant data, facilitating high-quality research aiming to understand the causes of endometriosis and to improve diagnosis and treatment outcomes and may eventually reduce the burden of disease. Currently, there is limited long-term clinical data about endometriosis and a delay of 7–12 years before a diagnosis of endometriosis is made for some people. In addition, clear care management plans, that are based on high-quality and strong clinical trial studies, are not yet available (despite the available guidelines) due to the lack of understanding of how endometriosis develops or changes during a woman’s lifetime. The NECST Registry will collect and securely store demographic and health-related information from consenting participants, who experience and/or seek management for endometriosis and/or endometriosis-related symptoms or conditions (e.g. adenomyosis).
Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing, China
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Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing, China
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Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing, China
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Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing, China
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Graphical Abstract
Abstract
The transition of maternal to zygotic gene expression regulation is critical for human preimplantation embryo development. In recent years, single-cell RNA sequencing (scRNA-seq) had been applied to detect the factors that regulate human oocyte maturation and early embryo development. Here, the evaluation of transcriptomes in single blastomere from the embryo collected from patients by scRNA-seq was performed. There were 20 blastomeres biopsied from 8-cell embryos of seven patients who received more than two ART cycles due to low embryo competence. Meanwhile, ten cells were collected from 8-cell embryos of four patients who received ART treatment due to male or tubal factors. The blastomeres were then evaluated using the previously established scRNA-seq method to determine the associations between their gene expression and developmental competence. The total number of genes detected in 8-cell embryos that failed to form blastocyst including maternal and zygotic mRNAs was reduced. There were 324 differently expressed genes detected among the 8-cell embryos including 65 genes that were significantly suppressed in the 8-cell embryos that failed to form blastocyst. Further analysis found these 8-cell embryos arrested at the cleavage stage due to the dysfunction of the cell cycle, DNA transcription activity, histone methylation, and cell division-related genes such as SMCO-1, ZNF271P,ZNF679, ASF1b, BEX3, DPPA2, and ORC4. The alterations of gene expression detected in human 8-cell embryos are tightly associated with its developmental competence and could be used as targets to enhance embryo development or parameters to predict the embryo’s development outcomes.
Lay summary
Many females are suffering infertility due to the failure of embryonic development at early stages due to unknown causes. At the very beginning of human embryo development, the embryos start to express its own genes, which should be achieved at 8-cell stage. In current research, we isolated one cell from 8-cell embryos and detected the gene expression at single-cell level. Then the remaining cells of these embryos were cultured to form blastocyst. Meanwhile, the data was analyzed according to the outcomes of embryo development. We detected 324 differently expressed genes between the 8-cell embryos that succeeded and failed to form blastocyst. Our research showed the association between the gene expression and the developmental competence of 8-cell embryos. The findings could be used to predict the embryo quality and potential therapy target to improve the efficiency of assisted reproductive techniques.
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Paediatric Integrated Cancer Service, VIC, Australia
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Cytotoxic chemotherapies have been a mainstay of cancer treatment but are associated with numerous systemic adverse effects, including impacts on fertility and endocrine health. Irreversible ovarian damage and follicle depletion are the side effects of chemotherapy that can lead to infertility and premature menopause, both being major concerns of young cancer patients. Notably, many women will proceed with fertility preservation, but unfortunately existing strategies do not entirely solve the problem. Most significantly, oocyte and embryo freezing do not prevent cancer treatment-induced ovarian damage from occurring, which may result in the impairment of long-term hormone production. Unfortunately, loss of endogenous endocrine function is not fully restored by hormone replacement therapy. Additionally, while GnRH agonists are standard care for patients receiving alkylating chemotherapy to lessen the risk of premature menopause, their efficacy is incomplete. The lack of more broadly effective options stems, in part, from our poor understanding of how different treatments damage the ovary. Here, we summarise the impacts of two commonly utilised chemotherapies – cyclophosphamide and cis-diamminedichloroplatinum(II) (cisplatin) – on ovarian function and fertility and discuss the mechanisms underpinning this damage. Additionally, we critically analyse current research avenues in the development of novel fertility preservation strategies, with a focus on ferto-protective agents.
Lay summary
Over the past few decades, advances in the detection and treatment of cancer have dramatically improved survival rates in young women. This means that ensuring patients have a high quality of life after cancer treatment has become a new priority. Therefore, it is important to understand and prevent any long-term negative side effects of cancer treatments, with infertility and early-onset menopause being major concerns for women receiving chemotherapy. The current fertility preservation options available to young women have significant limitations. Therefore, the identification of new approaches to protect fertility has been an intense topic of research in recent years. In this review, we provide information on the negative side effects of two commonly used chemotherapy drugs – cyclophosphamide and cis-diamminedichloroplatinum(II) (cisplatin) – on fertility, and discuss how they cause damage to the ovaries. We also critically analyse recent preclinical studies related to the development of new fertility preservation techniques.
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In laboratory mice, sperm quality is usually assessed in spermatozoa collected from the cauda epididymidis of freshly sacrificed males. Percutaneous epididymal sperm aspiration (PESA) is a non-terminal alternative that would allow repeated sperm collection for sperm quality assessment in living males. To test whether PESA is a suitable method to assess sperm quality, we compared sperm traits between samples collected by PESA vs the commonly applied terminal cauda epididymidis dissection. The collected sperm samples were analyzed using computer-assisted sperm analysis and various parameters, including sperm motility, swimming velocity and morphology, were determined. We were able to retrieve motile sperm from all mice using PESA and the terminal cauda epididymidis dissection. Based on computer-assisted sperm analysis, however, sperm motility and swimming velocity were significantly lower after PESA compared to samples obtained by cauda epididymidis dissection. In addition, we found significantly more morphological abnormalities in PESA samples, probably induced as a side effect of the sampling technique. Although sperm samples collected by PESA are successfully used for in vitro fertilization, we cannot recommend PESA as a suitable method to assess sperm quality in mice, since the procedure seems to impair various sperm traits.
Lay summary
In mice, sperm quality is usually assessed in sperm collected from the epididymis (organ where ripe sperm is stored) of euthanized males. However, there is one non-terminal and minimal invasive alternative to collect sperm, called percutaneous epididymal sperm aspiration (PESA), which allows repeated sample collections from the same individual. Given that individual sperm quality is variable and can change according to various factors, PESA could allow to track sperm quality over time and would be highly appreciated in different research fields. Here, we tested the suitability of PESA to determine sperm quality by comparing sperm samples collected by PESA vs the commonly applied terminal epididymis dissection. We used computer-assisted sperm analysis to determine various sperm quality traits. Surprisingly, we found that sperm collected by PESA showed significantly reduced motility, swimming velocity and more morphological abnormalities compared to sperm samples collected by epididymis dissection. Thus, we cannot recommend PESA as a suitable method to determine sperm quality traits as the procedure itself seems to affect collected sperm cells.
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Females are born with a finite number of oocytes, collectively termed the ovarian reserve, established within the developing fetal ovary. Consequently, maternal exposure to reproductive toxicants can have harmful effects on the future fertility of her unborn female fetus. The chemical benzo[a]pyrene (B[a]P) is a prominent component of cigarette smoke. Despite it being a known ovotoxicant, around 8% of women in Europe smoke during pregnancy.
The purpose of this research was to examine the effect of B[a]P on the developing ovary, using the mouse as a model and with experiments carried out in vitro. B[a]P-exposure to the fetal ovary prior to follicle formation reduced the number of germ cells and subsequently, the number of healthy primordial follicles, by up to 76%; however, while proliferation of germ cells was not affected, the germ cells contained higher levels of DNA double-strand breaks. Exposure to B[a]P also affected the proportion of oocytes progressing through prophase I of meiosis. B[a]P exposure to neonatal mouse ovaries, after follicle formation, resulted in an 85% reduction in the number of healthy follicles, with a corresponding increase in apoptotic cell death and reduction in somatic cell proliferation. Although there was a trend towards a higher level of oxidative stress in B[a]P-exposed ovaries, this was not statistically significant; likewise, the antioxidant melatonin failed to protect against the B[a]P-induced ovarian damage. Together, the results here demonstrate that B[a]P-exposure damages the developing ovary, both before and shortly after follicle formation, an effect that could lead to a subsequent decrease in fertility.
Lay summary
Cigarette smoking during pregnancy can affect the fertility of the offspring, yet in Europe around 1 in 12 children born have been exposed to cigarette smoke before birth due to their mother smoking. Benzo[a]pyrene (B[a]P), one of the main chemicals found in cigarette smoke, can have damaging effects on the ovary as it develops in the fetus during the time that the population of future eggs, known as ovarian germ cells also develop. In this research, ovaries from mouse fetuses at stages of development, equivalent to the second and third trimesters of a human pregnancy, were cultured with or without B[a]P. Fetal mouse ovaries exposed to B[a]P had fewer germ cells and larger numbers of cells did not survive. Overall, the results suggest that development of the ovary of a fetus could be affected if the mother is exposed to B[a]P, whether that is through cigarette smoke, or other types of exposure.