Pregnancy is associated with reduced progression of symptomatic adenomyosis: a retrospective pilot study.

BACKGROUND: Adenomyosis is a common gynecological disease in women of reproductive age and causes various symptoms such as dysmenorrhea and heavy menstrual bleeding. However, the influence of pregnancy on the progression of adenomyosis remains unclear. The insight into whether the size of adenomyosis is increased, decreased, or unchanged during pregnancy is also undetermined. The current study aimed to evaluate the influence of pregnancy in patients with symptomatic adenomyosis. METHODS: This study retrospectively enrolled patients diagnosed with adenomyosis by magnetic resonance imaging between 2015 and 2022 at The University of Tokyo Hospital. Uterine size changes were evaluated by two imaging examinations. In the pregnancy group, the patients did not receive any hormonal and surgical treatments, except cesarean section, but experienced pregnancy and delivery between the first and second imaging examinations. In the control group (nonpregnancy group), the patients experienced neither hormonal and surgical treatments nor pregnancy from at least 1 year before the first imaging to the second imaging. The enlargement rate of the uterine size per year (percentage) was calculated by the uterine volume changes (cm3) divided by the interval (years) between two imaging examinations. The enlargement rate of the uterine size per year was compared between the pregnancy group and the control group. RESULTS: Thirteen and 11 patients with symptomatic adenomyosis were included in the pregnancy group and in the control group, respectively. The pregnancy group had a lower enlargement rate per year than the control group (mean ± SE: -7.4% ± 3.6% vs. 48.0% ± 18.5%, P < 0.001), indicating that the size of the uterus with adenomyosis did not change in the pregnancy group. CONCLUSIONS: Pregnancy is associated with reduced progression of symptomatic adenomyosis.

Heterogeneous treatment effects of adjuvant therapy for patients with cervical cancer in the intermediate-risk group.

BACKGROUND: The efficacy of adjuvant therapy for patients with cervical cancer with intermediate risk (CC-IR) remains controversial. We examined the impact of adjuvant therapy on survival outcomes in patients with CC-IR and evaluated the heterogeneous treatment effects (HTEs) of adjuvant therapies based on clinicopathologic characteristics. METHODS: We retrospectively analyzed a previous Japanese nationwide cohort of 6192 patients with stage IB-IIB cervical cancer who underwent radical hysterectomy. We created two pairs of propensity score-matched treatment/control groups to investigate the treatment effects of adjuvant therapies: (1) adjuvant therapy versus non-adjuvant therapy; (2) chemotherapy versus radiotherapy conditional on adjuvant therapy. Multivariate analyses with treatment interactions were performed to evaluate the HTEs. RESULTS: Among the 1613 patients with CC-IR, 619 and 994 were in the non-treatment and treatment groups, respectively. Survival outcomes did not differ between the two groups: 3-year progression-free survival (PFS) rates were 88.1% and 90.3% in the non-treatment and treatment groups, respectively (p = 0.199). Of the patients in the treatment group, 654 and 340 received radiotherapy and chemotherapy, respectively. Patients who received chemotherapy had better PFS than those who received radiotherapy (3-year PFS, 90.9% vs. 82.9%, p = 0.010). Tumor size was a significant factor that affected the treatment effects of chemotherapy; patients with large tumors gained better therapeutic effects from chemotherapy than those with small tumors. CONCLUSION: Adjuvant therapy is optional for some patients with CC-IR; however, chemotherapy can be recommended as adjuvant therapy, particularly for patients with large tumors.

The EZH2-PRC2-H3K27me3 axis governs the endometrial cell cycle and differentiation for blastocyst invasion.

Infertility occurs in 15% of couples worldwide. Recurrent implantation failure (RIF) is one of the major problems in in vitro fertilization and embryo transfer (IVF-ET) programs, and how to manage patients with RIF to achieve successful pregnancy outcomes remains unresolved. Here, a uterine polycomb repressive complex 2 (PRC2)-regulated gene network was found to control embryo implantation. Our RNA-seq analyses of the human peri-implantation endometrium obtained from patients with RIF and fertile controls revealed that PRC2 components, including its core enzyme enhancer of zeste homolog 2 (EZH2)-catalyzing H3K27 trimethylation (H3K27me3) and their target genes are dysregulated in the RIF group. Although fertility of uterine epithelium-specific knockout mice of Ezh2 (eKO mice) was normal, Ezh2-deleted mice in the uterine epithelium and stroma (uKO mice) exhibited severe subfertility, suggesting that stromal Ezh2 plays a key role in female fertility. The RNA-seq and ChIP-seq analyses revealed that H3K27me3-related dynamic gene silencing is canceled, and the gene expression of cell-cycle regulators is dysregulated in Ezh2-deleted uteri, causing severe epithelial and stromal differentiation defects and failed embryo invasion. Thus, our findings indicate that the EZH2-PRC2-H3K27me3 axis is critical to preparing the endometrium for the blastocyst invasion into the stroma in mice and humans.

Effect of pelvic radiotherapy on patients with stage IB­IIA cervical cancer after radical hysterectomy: A single­center retrospective study.

The effects of post-operative adjuvant radiotherapy (RT) on intermediate-risk patients with cervical cancer have not been fully elucidated. Therefore, the present study aimed to investigate the impact of RT on intermediate-risk cervical cancer. The data of 112 patients with stage IB and IIA cervical cancer treated with radical hysterectomy between January 2009 and December 2018 were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS), and the frequency of adverse events were compared between patients with and without adjuvant RT (RT+ and RT-, respectively). Subgroup analyses of PFS based on tumor size, cervical stromal invasion, lymphovascular space invasion and histology [squamous cell carcinoma (SCC) vs. non-SCC] were performed. Among the 112 patients, 41 received adjuvant RT. Although there were no significant differences in OS or PFS between the RT+ and RT- groups, the frequency of adverse events was much higher in the RT+ group. Patients in the RT+ group also had more recurrent risk factors than those in the RT- group. Based on the subgroup analyses, although no significant differences were observed between any of the groups, RT demonstrated a different impact on PFS between SCC and non-SCC: No difference was observed in the SCC group, whereas patients in the RT+ group tended to have poorer prognoses compared to those in the RT- group of the non-SCC group. These results suggest that the impact of post-operative RT on stage IB and IIA cervical cancer is limited and is accompanied by increased adverse events. The eligibility of patients for post-operative RT should be carefully determined based on the therapeutic effect of RT in each subgroup.

Levonorgestrel-Releasing Intrauterine System Improves Menorrhagia-Related Quality of Life in Patients with Symptomatic Adenomyosis.

Levonorgestrel-releasing intrauterine system (LNG-IUS) relieves dysmenorrhea and heavy menstrual bleeding (HMB) in adenomyosis. However, its efficacy on health-related quality of life (HR-QOL) in patients with symptomatic adenomyosis remains unclear. The menorrhagia multi-attribute scale (MMAS), which measures HR-QOL improvement through the treatment of HMB, has never been used for evaluating menorrhagia-specific HR-QOL in patients with symptomatic adenomyosis. Hence, this study aimed to investigate the efficacy of LNG-IUS in improving menorrhagia-specific HR-QOL in these patients using the MMAS. The participants were diagnosed by magnetic resonance imaging. We also assessed the relationships between menorrhagia-specific HR-QOL, blood hemoglobin levels, and the degree of dysmenorrhea before and during LNG-IUS treatment. The LNG-IUS treatment improved the menorrhagia-specific HR-QOL more effectively in incipient type adenomyosis than in advanced type adenomyosis. The efficacy of LNG-IUS treatment on dysmenorrhea evaluated by the visual analog scale score tended to be better in the incipient type than in the advanced type. By the treatment of LNG-IUS, the blood hemoglobin level was not improved in the advanced type but in the incipient type. Furthermore, dysmenorrhea and HMB-related anemia were associated with HR-QOL impairment, and LNG-IUS treatment may improve the HR-QOL by relieving the symptoms. In conclusion, the effectiveness of LNG-IUS on HR-QOL is decreased by advanced adenomyosis. Thus, magnetic resonance imaging use should be reinforced to predict LNG-IUS efficacy in improving the HR-QOL of patients with adenomyosis.

A gene network of uterine luminal epithelium organizes mouse blastocyst implantation.

Purpose: The receptive endometrium is critical for blastocyst implantation. In mice, after blastocysts enter the uterine cavities on day 4 of pregnancy (day 1 = vaginal plug), blastocyst attachment is completed within 24 h, accompanied by dynamic interactions between the uterine luminal epithelium and the blastocysts. Any failures in this process compromise subsequent pregnancy outcomes. Here, we performed comprehensive analyses of gene expression at the luminal epithelium in the peri-implantation period. Methods: RNA-seq combined with laser microdissection (LMD) was used to reveal unique gene expression kinetics in the epithelium. Results: We found that the prereceptive epithelium on day 3 specifically expresses cell cycle-related genes. In addition, days 3 and 4 epithelia express glutathione pathway-related genes, which are protective against oxidative stresses. In contrast, day 5 epithelium expresses genes involved in glycolysis and the regulation of cell proliferation. The genes highly expressed on days 3 and 4 compared to day 5 are related to progesterone receptor signaling, and the genes highly expressed on day 5 compared to days 3 and 4 are associated with the ones regulated by H3K27me3. Conclusions: These results suggest that specific gene expression patterns govern uterine functions during early pregnancy, contributing to implantation success.

Constant Activation of STAT3 Contributes to the Development of Adenomyosis in Females.

Adenomyosis is a benign uterine disease that causes dysmenorrhea, heavy menstrual bleeding, and infertility; however, its pathophysiology remains unclear. Since signal transducer and activator of transcription 3 (STAT3) is crucial for endometrial regeneration, we hypothesized that STAT3 participates in adenomyosis pathophysiology. To investigate the influence of STAT3 on adenomyosis development, this study was performed using a novel mouse model of adenomyosis and human specimens of eutopic endometria and adenomyosis lesions. We established a novel mouse model of adenomyosis by puncturing entire mouse uterine layers with a thin needle. Mouse eutopic and ectopic endometria showed a positive immunoreactivity for phosphorylated STAT3 (pSTAT3), the active form of STAT3. Decreased numbers of adenomyotic lesions and reduced expression of Cxcl1, Icam1, and Spp1, which are associated with immune cell chemotaxis and tissue regeneration, were observed in uterine Stat3-deficient mice compared with the controls. In humans, pSTAT3 was intensely expressed at both the eutopic endometrium and the adenomyotic lesions regardless of the menstrual cycle phases. Conversely, it was limitedly expressed in the eutopic endometrium during the menstrual and proliferative phases in women without adenomyosis. Our findings indicate that continuous STAT3 activation promotes adenomyosis development. STAT3 inhibition can be a promising treatment strategy in patients with adenomyosis.

Uterine Receptivity is Reflected by LIF Expression in the Cervix.

Recurrent implantation failure is a major problem in assisted reproductive technology (ART). Although ART systems have evolved rapidly over the decades, it is still difficult to diagnose uterine conditions suitable for embryo transfer (ET) without the use of invasive endometrial procedures. Previous studies in mice showed that leukemia inhibitory factor (LIF) is a well-known endometrial biomarker for uterine implantation capacity, also known as uterine receptivity. This study focused on LIF in the mouse and human cervix as a possible biomarker of implantation capacity. We found that high expression of LIF in the cervical epithelium is strongly correlated with that of the uterine epithelium during the peri-implantation period in mice. Likewise, human cervical epithelia also exhibit elevated levels of LIF in the peri-implantation period. In addition, cervical LIF is downregulated in mice with defective implantation caused by pharmacological treatments. These results indicated that cervical LIF is a possible biomarker that detected uterine receptivity without invasive endometrial damage.

Prolapse of a pedunculated uterine leiomyoma through the cervix during GnRH antagonist treatment: Case report and literature review.

We here describe a case of the prolapse of pedunculated submucosal leiomyoma through the cervix during the treatment of a gonadotropin-releasing hormone (GnRH) antagonist relugolix. We also present the literature review of the cases of leiomyoma prolapse during GnRH modulators. A 55-year-old woman with atypical vaginal bleeding diagnosed submucosal uterine fibroid 6 cm in diameter, and daily oral administration of relugolix was conducted. On the 35th day of the administration, heavy vaginal bleeding suddenly occurred due to leiomyoma prolapse. Finally, she underwent abdominal hysterectomy to treat heavy bleeding. To date, six cases of leiomyoma prolapse during GnRH modulators have been reported, in which all the previous cases were treated with GnRH agonists. This is the first case report of leiomyoma prolapse during GnRH antagonist treatment. Notably, leiomyoma prolapse is a possible common adverse effect of GnRH modulators for the treatment of submucosal leiomyoma, which is caused by rapid decrease in its volume.