Efficacy and safety of follitropin delta versus follitropin alpha/beta in infertility treatment: A systematic review and meta-analysis.

Background: Follitropin δ may be an alternative to conventional follitropin α/ß for controlled ovarian stimulation (COS) within assisted reproductive treatment (ART), but its efficacy and safety remain unknown. We performed a random-effects meta-analysis to compare the efficacy and safety of follitropin δ and follitropin α/ß. Methods: We searched randomized controlled trials comparing follitropin δ and follitropin α/ß using MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and WHO-ITCRP on December 14, 2022. The primary outcomes were the live birth rate and the incidence of moderate or severe ovarian hyperstimulation syndrome (OHSS). The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation approach. The protocol was registered on the Open Science Framework. Results: Three studies involving 2682 participants were included in our meta-analysis. The results indicated that follitropin δ may result in little to no difference in live birth rates (risk ratio [RR], 1.12; 95% confidence interval [CI], 0.91-1.38; low certainty) and the incidence of moderate or severe OHSS (RR, 0.78; 95% CI, 0.48-1.26; low certainty) compared with follitropin α/ß. Conclusion: Follitropin δ may result in little to no difference in COS compared with follitropin α/ß, especially in terms of live births and safety.

The novel oral gonadotropin-releasing hormone receptor antagonist relugolix is a new option for controlled ovarian stimulation cycles.

Purpose: Relugolix is an oral gonadotropin-releasing hormone antagonist (GnRHant), which was first introduced in 2019. This study investigated the effects of the conventional injectable GnRHant formulation and this new oral GnRHant formulation on controlled ovarian stimulation (COS) cycles. Methods: Relugolix was administered in 126 cycles and conventional GnRHant injection was administered in 658 cycles (controls). The follicle stimulation was performed by an antagonist method, and for final oocyte maturation, recombinant human chorionic gonadotropin (rHCG), or gonadotropin-releasing hormone agonist (GnRHa), or both (dual trigger) were selected. The number of retrieved oocytes was counted and then they were evaluated for subsequent development up to cleavage stage. Results: The number of retrieved oocytes which was the primary outcome of this research was affected by the combination of GnRHant type and the final oocyte maturation agent. The combination of relugolix and a GnRHa trigger showed a significantly lower number of retrieved oocytes (p < 0.001) than the other combinations. Conclusions: Relugolix is a new option for COS cycles, but should be carefully combined with the final maturation agent. Clinical trial approval: This study was conducted after approval by the Medical Corporation Sankeikai Institutional Ethics Committee (approval number: 2019-34).

Full-length 16S rRNA gene amplicon analysis of human gut microbiota using MinION™ nanopore sequencing confers species-level resolution.

BACKGROUND: Species-level genetic characterization of complex bacterial communities has important clinical applications in both diagnosis and treatment. Amplicon sequencing of the 16S ribosomal RNA (rRNA) gene has proven to be a powerful strategy for the taxonomic classification of bacteria. This study aims to improve the method for full-length 16S rRNA gene analysis using the nanopore long-read sequencer MinION™. We compared it to the conventional short-read sequencing method in both a mock bacterial community and human fecal samples. RESULTS: We modified our existing protocol for full-length 16S rRNA gene amplicon sequencing by MinION™. A new strategy for library construction with an optimized primer set overcame PCR-associated bias and enabled taxonomic classification across a broad range of bacterial species. We compared the performance of full-length and short-read 16S rRNA gene amplicon sequencing for the characterization of human gut microbiota with a complex bacterial composition. The relative abundance of dominant bacterial genera was highly similar between full-length and short-read sequencing. At the species level, MinION™ long-read sequencing had better resolution for discriminating between members of particular taxa such as Bifidobacterium, allowing an accurate representation of the sample bacterial composition. CONCLUSIONS: Our present microbiome study, comparing the discriminatory power of full-length and short-read sequencing, clearly illustrated the analytical advantage of sequencing the full-length 16S rRNA gene.

Characterizing the gut microbiota in females with infertility and preliminary results of a water-soluble dietary fiber intervention study.

Despite the advances in assisted reproductive technology, approximately 8-12% of the individuals worldwide who are willing to conceive are unable to do so. Fertility depends on a receptive state of the endometrium and hormonal adaptations as well as the immune system. Local and systemic immunities are greatly influenced by the microbiota. The aim of the present study was to compare the gut microbiota in female patients with that in infertility with fertile control subjects and to evaluate the effect of prebiotic partially hydrolyzed guar gum supplementation on gut dysbiosis and the outcome of pregnancy in patients treated with assisted reproductive technology. Dietary fiber can reconstitute the host intestinal microbiota and modify the immune function; however, clinical data regarding the effect of dietary fiber treatment on the success of assisted reproductive technology is lacking. To investigate the gut microbiota in fertile and infertile females, we conducted 16S metagenomic analysis of fecal samples. In total 18 fertile female subjects and 18 patients with infertility matched by age were recruited, and fecal samples were obtained to analyze the gut microbiome using 16S rRNA V3-V4 sequencing. The unweighted and weighted principal coordinate analyses showed a trend indicating microbial structural differences in ß-diversity between these two groups. The abundance of the phylum Verrucomicrobia was higher in patients with infertility. At the genus level, a decrease in the abundance of the genera Stenotrophomonas, Streptococcus, and Roseburia and an increase in the abundance of the genera Unclassified [Barnesiellaceae] and Phascolarctobacterium was observed in patients with infertility. Twelve patients agreed to receive the combined therapy comprising embryo transfer by assisted reproductive technology and oral supplementation with partially hydrolyzed guar gum. The success of pregnancy by this combined therapy was 58.3% (7/12), and the failure was 41.7% (5/12). Predictive factors for pregnancy before treatment were characterized by a decrease in the abundance of Paraprevotella and Blautia and an increase in the abundance of Bifidobacterium. Predictive factors for pregnancy before treatment were characterized by a decrease in the abundance of Paraprevotella and Blautia and an increase tendency in the abundance of Bifidobacterium. In conclusion, the present study showed differences in the abundance of gut microbiota between fertile and infertile groups; moreover, partially hydrolyzed guar gum supplementation helped improve gut dysbiosis and the success of pregnancy in females with infertility.

Lifestyle and fertility-specific quality of life affect reproductive outcomes in couples undergoing in vitro fertilization.

Objective: A Mediterranean dietary pattern, sleeping habits, physical activity, and lifestyle appear to affect reproductive health. There are few reports about whether fertility-specific quality of life (QOL) is linked to infertility treatment outcomes. The aim of this study is to investigate when lifestyle factors and fertility-specific QOL are comprehensively considered, which factors influence assisted reproductive technology (ART) outcomes. Methods: This prospective cohort includes 291 women undergoing a first ART treatment at multiple centers in Japan and was designed to evaluate the influence of diet, physical activity, sleeping pattern, computer use duration, and fertility-specific quality of life tool (FertiQoL) score on ART treatment outcomes using a questionnaire. The primary endpoint was the good-quality blastocyst rate per oocyte retrieval and the secondary endpoints were a positive pregnancy test and gestational sac (GS) detection. Results: The good-quality blastocyst rate per oocyte retrieval tended to be negatively associated with frequent fish consumption. After all embryo transfer (ET) cycles, a positive pregnancy test tended to be positively associated with longer sleep and longer computer use (OR = 1.6, 95% CI = 0.9-2.7 and OR = 1.7, CI = 1.0-2.8, respectively) and negatively associated with a smoking partner (OR = 0.6, CI = 0.3-1.0). GS detection was positively and significantly associated with frequent olive oil intake and longer computer use (OR = 1.7, CI = 1.0-3.0 and OR = 1.7, CI = 1.0-3.0, respectively). After ET cycles with a single blastocyst, a positive pregnancy test was positively and significantly associated with longer computer use (OR = 2.0, CI = 1.1-3.7), while GS detection was significantly more likely in women with longer computer use (OR = 2.1, CI = 1.1-3.8) and tended to be more likely in women with a higher FertiQoL Total scaled treatment score (OR = 1.8, CI = 1.0-3.3). p < 0.05 was considered statistically significant and 0.05 ≤ p <0.01 as tendency. Conclusions: Olive oil may be an important factor in dietary habits. Fertility-specific QOL and smoking cessation guidance for partners are important for infertile couples.

Significance of placental CD200 expression in patients with preeclampsia: Comparison between early­ and late­onset patients.

Preeclampsia, characterized by high blood pressure and proteinuria during pregnancy, causes serious complications in both the mother and the fetus. Although there have been several studies on the causes of preeclampsia, the detailed mechanism of this disease remains unclear. Moreover, a few reports have focused on the causes of preeclampsia in number of weeks at onset. The present study aimed to elucidate the differences between early­ and late­onset preeclampsia. This study enrolled patients with preeclampsia from January 2014 to December 2020. They were classified into early­ (<34 weeks) and late­onset (≥34 weeks) preeclampsia groups. The expression profiles of 770 immune­related genes were studied in the placental tissue from five patients each in the early­ and late­onset groups. The expression of CD200 in the trophoblasts of the placenta of 26 and 27 patients in early­ and late­onset groups, respectively, was also analyzed using immunostaining. Analysis of extracted RNA indicated that CD200 was significantly upregulated in the early­onset group compared with late­onset group and normal control. Immunostaining for CD200 demonstrated a significantly increased expression in the early­onset group compared with the late­onset group. The present study demonstrated that upregulation of CD200, which belongs to the immunoglobulin superfamily and is recognized as a molecule that acts in immune tolerance via inhibition of classical macrophage activation, may be associated with early­onset preeclampsia, although it remains unknown whether upregulation of CD200 expression is a cause or effect of the development of early­onset preeclampsia. Early­onset preeclampsia might have a different mechanism from that of late­onset; thus, further studies are needed to clarify the mechanism of these conditions for adequate treatment.

Regarding "Stress management and In Vitro Fertilization (IVF): A pilot randomized controlled trial".

Koumparou et al.1 recently published a randomized controlled trial (RCT) on the effectiveness of psychological interventions (stress management training, SMT) for women planning in vitro fertilization (IVF). They concluded that while the effect of SMT was limited in terms of IVF outcome, it resulted in a significant reduction of stress levels in infertile patients. Since most women undergoing infertility treatment are exposed to high psychological stress,2 this study may be of great value in demonstrating the need for proactive SMT to maintain infertile women's mental health and motivation to continue treatment. However, we are concerned that the reliability of this RCT has been compromised in several ways. First, the registration of the RCT was not clearly stated. According to The CONsolidated Standards of Reporting Trials (CONSORT) 2010 guidelines, a prospective registration of the RCT is required, which prevents unnecessary concerns about the bias of results selection.3,4 Second, the lack of specific figures on the background of the participants in the case and control groups risks distorting the RCT results. The article states that there was no significant difference between the two groups. However, since aging and prolonged infertility treatment increase the psychological burden on infertile patients,5 detailed background information is necessary to interpret the results of an RCT accurately. Selection bias could not be determined, which weakened the validity of this RCT. Furthermore, the absence of any mention of case dropout makes the conclusions of this RCT uncertain; a discussion of cases demonstrating difficulty in completing an 8-week psychological program would clarify whether temporary SMT would show efficacy for patients. Finally, it is essential to note that the details of IVF have not been clarified. Since the timing of the SMT and IVF-ET cycles or details of the IVF-ET protocol were not shown, this RCT could not be used as a reference for IVF facilities to actually operate SMT. There is no doubt that psychological interventions are necessary for infertile patients exposed to high psychological stress, but this RCT has many details that have not been clarified, and the conclusions are attenuated. As details become clearer, this RCT will provide a foundation for the active use of SMT in infertility treatment settings.

MinION, a portable long-read sequencer, enables rapid vaginal microbiota analysis in a clinical setting.

BACKGROUND: It has been suggested that the local microbiota in the reproductive organs is relevant to women's health and may also affect pregnancy outcomes. Analysis of partial 16S ribosomal RNA (rRNA) gene sequences generated by short-read sequencers has been used to identify vaginal and endometrial microbiota, but it requires a long time to obtain the results, making it unsuitable for rapid bacterial identification from a small specimen amount in a clinical context. METHODS: We developed a simple workflow using the nanopore sequencer MinION that allows high-resolution and rapid differentiation of vaginal microbiota. Vaginal samples collected from 18 participants were subjected to DNA extraction and full-length 16S rRNA gene sequencing with MinION. RESULTS: The principal coordinate analysis showed no differences in the bacterial compositions regardless of the sample collection method. The analysis of vaginal microbiota could be completed with a total analysis time of approximately four hours, allowing same-day results. Taxonomic profiling by MinION sequencing revealed relatively low diversity of the vaginal bacterial community, identifying the prevailing Lactobacillus species and several causative agents of bacterial vaginosis. CONCLUSIONS: Full-length 16S rRNA gene sequencing analysis with MinION provides a rapid means for identifying vaginal bacteria with higher resolution. Species-level profiling of human vaginal microbiota by MinION sequencing can allow the analysis of associations with conditions such as genital infections, endometritis, and threatened miscarriage.

Thyroid Hormone Facilitates in vitro Decidualization of Human Endometrial Stromal Cells via Thyroid Hormone Receptors.

Endometrial stromal cells differentiate into decidual cells through the process of decidualization. This differentiation is critical for embryo implantation and the successful establishment of pregnancy. Recent epidemiological studies have suggested that thyroid hormone is important in the endometrium during implantation, and it is commonly believed that thyroid hormone is essential for proper development, differentiation, growth, and metabolism. This study aimed to investigate the impact of thyroid hormone on decidualization in human endometrial stromal cells (hESCs) and define its physiological roles in vitro by gene targeting. To identify the expression patterns of thyroid hormone, we performed gene expression profiling of hESCs during decidualization after treating them with the thyroid hormone levothyroxine (LT4). A major increase in decidual response was observed after combined treatment with ovarian steroid hormones and thyroid hormone. Moreover, LT4 treatment also affected the regulation of many transcription factors important for decidualization. We found that type 3 deiodinase, which is particularly important in fetal and placental tissues, was upregulated during decidualization in the presence of thyroid hormone. Further, it was observed that progesterone receptor, an ovarian steroid hormone receptor, was involved in thyroid hormone-induced decidualization. In the absence of thyroid hormone receptor (TR), due to the simultaneous silencing of TRα and TRß, thyroid hormone expression was unchanged during decidualization. In summary, we demonstrated that thyroid hormone is essential for decidualization in the endometrium. This is the first in vitro study to find impaired decidualization as a possible cause of infertility in subclinical hypothyroidism (SCH) patients.

Glucose transporter 1 is important for the glycolytic metabolism of human endometrial stromal cells in hypoxic environment.

AIM: The study aimed to elucidate the glycolytic metabolism of human endometrial stromal cells (hESCs) in hypoxic environment. MAIN METHODS: The hESCs were cultured in hypoxic environment, and their metabolic pathways were analyzed using metabolomics. We assessed glucose uptake using 2-deoxyglucose (2-DG) assay. The expression of glucose transporters (GLUTs) required for glucose uptake was determined using real-time quantitative polymerase chain reaction (qPCR) and western blotting. Furthermore, we knocked down GLUT1 and examined the uptake of 2-DG. KEY FINDINGS: Under hypoxia, glucose-6-phosphate, fructose-6-phosphate, and fructose-1,6-diphosphate were significantly elevated in hESCs (P < 0.05). This finding indicated enhancement in glycolysis. The volume of glucose uptake increased significantly under hypoxia (P < 0.05). Hypoxia simultaneously induced the expression of GLUT1 and GLUT3 mRNA (P < 0.05) and attenuated the expression of GLUT8 (P < 0.05). Glucose uptake was significantly inhibited upon knockdown of GLUT1 (P < 0.0001). SIGNIFICANCE: These results demonstrated a very important role of glucose transport under hypoxia. Also, hESCs utilize glycolysis to adapt to hypoxic conditions that could occur in menstrual and implantation period. These findings pave the way to study implantation failure and tumors originating from the endometrium.

Rare Primary Adenocarcinoma of the Broad Ligament: Report of Two Cases and a Literature Review.

Malignant primary tumors arising in the uterine broad ligament are extremely rare, and only 26 cases have been reported to date. We describe 2 new cases of primary adenocarcinoma of the broad ligament, and we review the previous literature on such rare tumors. In Case 1, a 71-year-old woman presented with a 2-month history of increased yellow vaginal discharge and lower abdominal pain during bowel movement. Transvaginal sonography revealed a 6.5 cm mass located on the dorsum of the uterus and a 7.0 cm mass (with cystic and solid parts) near the right adnexa. We postoperatively diagnosed the mass as a high-grade serous carcinoma of the broad ligament (pT3cNXM0). The patient is currently receiving adjuvant chemotherapy with paclitaxel and carboplatin. In Case 2, during a complete medical checkup a 43-year-old woman was found to have a pelvic mass indicative of leiomyoma. Transvaginal sonography revealed a 3.8 cm mass located on the dorsum of the uterus. Following surgery, we diagnosed the mass as a clear cell adenocarcinoma of the broad ligament (pT2bN1M0). This patient is also now receiving adjuvant chemotherapy with paclitaxel and carboplatin.

Etiology of Ascites and Pleural Effusion Associated with Ovarian Tumors: Literature Review and Case Reports of Three Ovarian Tumors Presenting with Massive Ascites, but without Peritoneal Dissemination.

Borderline ovarian tumors are benign but relatively large tumors that are often initially mistaken as ovarian cancers. We report three cases of stage I borderline ovarian tumors having massive ascites that we (preoperatively) suspected of being advanced ovarian cancer. The three patients (35, 47, and 73 years old) reported feeling fullness of the abdomen before consulting their gynecologist. By CT scan, they were diagnosed with a pelvic tumor accompanied by massive ascites, the diameters of which were 11, 20, and 11 cm, respectively. Postsurgical pathology showed all were stage I borderline ovarian tumors without dissemination; two were mucinous and one was serous. The amount of ascites was 6,300, 2,600, and 3,600 mL, respectively, and was serous in all. Cytodiagnosis of the ascites found that one was positive for tumor cells and two were negative. After resection of the mass, the ascites disappeared in all three cases. No pleural effusion was present at any time. The literature is reviewed concerning ascites and pleural effusions linked to ovarian tumors, and a supposition is forwarded of why pleural effusion presents sporadically in these cases.