Abstract
BACKGROUND
Adenomyosis, characterized by the presence of islands of endometrial tissue surrounded by hypertrophic smooth muscle cells within the myometrium, is one of the most challenging ...uterine disorders in terms of diagnosis and management. Adenomyosis presents with pelvic pain, excessive uterine bleeding, anemia and infertility. The relative contributions of abnormal endometrial tissue and myometrial smooth muscle cells to the development and growth of adenomyosis are not well understood. Moreover, there is continuing debate on the origins of adenomyosis; two competing theories describe the invagination of basal endometrium into the myometrium or the metaplastic differentiation of remnant endometrial stem/progenitor cells within the myometrium.
OBJECTIVE AND RATIONALE
A recent series of next-generation sequencing (NGS) studies have provided the best scientific evidence thus far regarding the cellular origins of adenomyosis and the contributions of new signaling pathways to its pathogenesis, survival, and growth. These seminal studies on endometrium, adenomyosis and endometriosis demonstrate or support the following key points. (i) Mutations of KRAS map to both intracavitary endometrial tissue and proximally located adenomyotic samples, supporting the invagination theory of pathogenesis. Driver mutations found in smooth muscle cells of uterine fibroids are absent in adenomyosis. (ii) KRAS and other less frequent mutations are limited to endometrial-type epithelial cells. They are also observed in endometriosis, indicating that the disease process in adenomyosis is similar to that in endometriosis and distinct from that of uterine fibroids. (iii) Activating mutations of KRAS stimulate specific pathways to increase cell survival and proliferation and are associated with progesterone resistance in adenomyosis. Together, these findings suggest that distinct cell populations in eutopic endometrial tissue play key roles in the etiology of adenomyosis. Dependence on ovarian steroids and ovulatory cycles for disease severity is a unique feature of adenomyosis. In this context, common patterns of aberrant gene expression have been reported both in adenomyosis and endometriosis. These include pathways that favor increased estrogen biosynthesis, decreased estradiol metabolism, a unique estrogen receptor beta (ESR2)-driven inflammatory process, and progesterone resistance due to decreased progesterone receptor expression. Since adenomyosis exhibits a uniquely estrogen-driven inflammatory process and progesterone resistance, we discuss the interactions between these molecular characteristics and signaling pathways induced by the newly discovered KRAS mutations.
SEARCH METHODS
We conducted a comprehensive search using PubMed for human and animal studies published until 2020 in the following areas: adenomyosis, endometriosis, endometrium, NGS, whole-exome sequencing, whole-genome sequencing, RNA sequencing, targeted deep sequencing, epigenetics, driver mutation, KRAS, progesterone resistance, estrogen action and steroid production.
OUTCOMES
Targeted deep sequencing analyses of epithelial cells in adenomyosis and adjacent basalis endometrial glands demonstrated recurring KRAS mutations in both cell types. This finding suggests that adenomyosis originates from basalis endometrium. Epithelial cells of the endometrium, adjacent adenomyosis and co-occurring endometriosis also share identical KRAS mutations. These findings suggest both adenomyosis and endometriosis are oligoclonal tissues that arise from endometrial cell populations carrying a specific driver mutation that most commonly affects the KRAS gene.
WIDER IMPLICATIONS
Adenomyosis usually follows an event such as pregnancy that has disrupted the integrity of the endometrial–myometrial junction followed by repetitious menstrual episodes that increase the likelihood of the entrapment of the basalis endometrium within the myometrium. Glandular epithelial cells carrying KRAS mutations and located within the deep crypts of basalis endometrium may become entrapped and invade myometrial tissue to give rise to adenomyosis. Evidence suggests that KRAS mutations may be responsible, in part, for previously observed phenomena such as prolonged cell survival and progesterone resistance in adenomyosis.
Dysbiosis in the genital tract or gut microbiome can be associated with endometriosis. We sampled vaginal, cervical and gut microbiota from 14 women with histology proven stage 3/4 endometriosis and ...14 healthy controls. The V3 and V4 regions of the 16S rRNA gene were amplified following the 16S Metagenomic Sequencing Library Preparation. Despite overall similar vaginal, cervical and intestinal microbiota composition between stage 3/4 endometriosis group and controls, we observed differences at genus level. The complete absence of Atopobium in the vaginal and cervical microbiota of the stage 3/4 endometriosis group was noteworthy. In the cervical microbiota, Gardnerella, Streptococcus, Escherichia, Shigella, and Ureoplasma, all of which contain potentially pathogenic species, were increased in stage 3/4 endometriosis. More women in the stage 3/4 endometriosis group had Shigella/Escherichia dominant stool microbiome. Further studies can clarify whether the association is causal, and whether dysbiosis leads to endometriosis or endometriosis leads to dysbiosis.
•Three-dimensional bioprinting is an emerging technique in reproductive medicine.•Reproductive medical research has been accelerated with the addition of bioprinting.•Applications include scaffolding ...and reconstruction of reproductive tissues.
Reproductive failure due to age, genetics and disease necessitates innovative solutions. While reproductive tissue transplantation has advanced, ongoing research seeks superior approaches. Biomaterials, bioengineering and additive manufacturing, such as three-dimensional (3D) bioprinting, are harnessed to restore reproductive function. 3D bioprinting uses materials, cells and growth factors to mimic natural tissues, proving popular for tissue engineering, notably in complex scaffold creation with cell distribution. The versatility which is brought to reproductive medicine by 3D bioprinting allows more accurate and on-site applicability to various problems that are encountered in the field. However, in the literature, there is a lack of studies encompassing the valuable applications of 3D bioprinting in reproductive medicine. This systematic review aims to improve understanding, and focuses on applications in several branches of reproductive medicine. Advancements span the restoration of ovarian function, endometrial regeneration, vaginal reconstruction, and male germ cell bioengineering. 3D bioprinting holds untapped potential in reproductive medicine.
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This study has been carried out to identify the relationship between military expenditures (MILEX), energy consumption (FOSSIL), financial development (FD) and environmental pollution (CAFP) for G7 ...countries. Panel data analysis was conducted using annual data for the 1971–2019 period. The results revealed that military expenditures, financial development and energy consumption are long-term determinants of environmental pollution. The study also found that FD had the greatest long-term impact on CAFP followed by FOSSIL and MILEX in that order, and that this impact was statistically significant and positive for FOSSIL and FD and negative for MILEX. A country-by-country evaluation showed that the country in which financial development and energy consumption have the greatest impact on the amount of carbon released into the environment is the USA, while the country in which the impact of military expenditures on the amount of carbon released into the environment is greatest in Germany.
In this paper, it is aimed to examine the relationship between biomass energy consumption (BEC) and economic growth (EG) in NEXT-11 countries (except for Vietnam). In this context, panel data ...analysis was executed using annual data for the 1970-2017 period. According to the findings, it has been found that BEC and EG act together in the long run. In consequence of the causality tests, concluded that the conservation hypothesis is valid for NEXT-11 countries. In the country-specific evaluations, the conservation hypothesis was found to be valid for Indonesia, Nigeria and Bangladesh; the neutrality hypothesis was found to be valid for Turkey, Egypt, Iran, Korea, Mexico, Pakistan, and the Philippines. The findings show that NEXT-11 countries can only realize such a serious, costly biomass energy investment when they achieve EG. These findings provide valuable signals for policymakers.
While gonadotrophin releasing hormone (GnRH) antagonists have been the standard of pituitary suppression during ovarian stimulation for ART, progestin primed ovarian stimulation (PPOS) has emerged as ...an alternative. Progestins can be started simultaneously with gonadotrophins (fixed PPOS) or later in the cycle depending on follicle growth (flexible PPOS). However, the flexible and fixed PPOS regimens have not been directly compared as of yet. This was a retrospective cohort study including women with diminished ovarian reserve who underwent oocyte cryopreservation. All women underwent ovarian stimulation with a fixed 300 IU daily dose of FSH. The primary outcome was the number of MII oocyte retrieved per cycle. Secondary outcome measures included the incidence of premature LH surge (>10ng/mL) and number of follicles larger than 14mm on the day of maturation trigger. During the screening period 2 out of 97 cycles were cancelled before oocyte retrieval, one in each group yielding an overall cancelation rate of 2%. Among women who had oocyte retrieval, 65 underwent flexible and 30 fixed PPOS. At baseline women on fixed and flexible PPOS had similar age (mean difference: -2.17 years, 95
-4.46 to 0.11) and serum AMH levels (mean difference: 0.10 ng/mL, 95% CI: -0.24 to 0.47). Slight imbalances between the groups were rectified with propensity score matching using age and AMH levels. The incidence of premature LH surge (RR: 1.47, 95% CI: 0.51 - 5.27, p = 0.50), follicle count larger than 14mm on hCG day (RR: 1.14, 95% CI: 0.93 - 1.42, p = 0.22), number of MII oocytes retrieved (RR: 0.95, 95% CI: 0.79 - 1.15, p = 0.61) were similar between flexible and fixed PPOS. The rate of no oocyte retrieval was same between the groups (0.0% both) but no formal estimation was possible. Flexible and fixed PPOS regimens had no appreciable differences regarding MII oocyte yield and the incidence of premature LH surges. Cycles without oocyte retrieval were rare in both groups and ultrasonographic parameters of gonadotropin response were similar. Our study suggests the performances of either progestin regimen are comparable in this group of women.
Ion nitriding is a glow discharge surface modification technique, which is primarily used to increase the fatigue strength, wear, corrosion resistance and surface hardness of steels. Because of the ...formation of high compressive residual stresses in the case region, increasing surface hardness and case depth cause remarkable improvement in fatigue properties of steels. In this study, the ion nitrided properties of quenched and tempered AISI 4340 low alloy steel were investigated under different process parameters including time and temperature. It has been found that the ion nitriding surface treatment improves the fatigue strength and increases the fatigue limit depending on the case depth. Up to 91% improvement in fatigue strength of the steel has been attained by ion nitriding. It was determined that, the subsurface ‘fish eye’ type formation is the dominant fatigue crack initiation mechanism in ion nitrided AISI 4340 steel in high cycle region and its origin was nonmetallic inclusions.
Aim
To evaluate whether the duration of sexual abstinence has impact on oxidative stress in semen samples.
Methods
Oxidative reaction was tested for different levels of reactive oxygen species (ROS) ...by nitro blue tetrazolium assay in 90 patients with the diagnosis of unexplained or male factor infertility that were grouped into 3 groups as 0–2 (group 1), 3–4 (group 2) and >4 days (group 3) of duration of sexual abstinence. Subsequently, the remaining semen was prepared by gradient method for ovarian stimulation and intrauterine insemination (IUI) cycles to compare pregnancy rates in terms of different levels of ROS and different abstinence periods.
Results
Increased staining pigment intensity was related to higher level of ROS in >4 days' group as compared to groups 0–2 and 3–4 days (70% vs 43.3% and 50%, P = 0.013 and P = 0.014, respectively). Pregnancy rates significantly decrease with prolonged abstinence period (26.7%, 16.7% and 6.7% in groups 1, 2 and 3, respectively, P = 0.039). Progressive motile sperm count after gradient method of sperm preparation for IUI was highest in 3–4 days of abstinence period than shorter and longer abstinence groups.
Conclusion
Longer duration of sexual abstinence causes higher oxidative stress and decreases pregnancy rates in IUI cycles.
Purpose
To determine the predictive value of serum anti-müllerian hormone (AMH) concentrations and antral follicle counts (AFC), on ovarian response and live birth rates after IVF and compare with ...age and basal FSH.
Methods
Basal levels of AMH, FSH and antral follicle count were measured in 192 patients prior to IVF treatment. The predictive value of these parameters were evaluated in terms of retrieved oocyte number and live birth rates.
Results
Poor responders in IVF were older, had lower AFC and AMH but higher basal FSH levels. In multivariate analysis AFC was the best and only independent parameter among other parameters and AMH was better than age and basal FSH to predict poor response to ovarian stimulation. Addition of AMH, basal FSH, age and total gonadotropin dose to AFC did not improve its prognostic reliability. Area under curve (AUC) for each parameter according to ROC analysis also revealed that AFC performed better in poor response prediction compared with AMH, basal FSH and age. The cut-off point for mean AMH and AFC in discriminating the best between poor and normal ovarian response cycles was 0.94 ng/mL (with a sensitivity of 70 % and a specificity of 86 %) and 5.5 (with a sensitivity of 91 % and a specificity of 91 %), respectively. However, age was the only independent predictor of live birth in IVF as compared to hormonal and ultrasound indices of ovarian reserve.
Conclusion
AFC is better than AMH to predict poor ovarian response. Although AMH and AFC could be used to predict ovarian response they had limited value in live birth prediction. The only significant predictor of the probability of achieving a live birth was age.
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