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Current medical therapies for fibroids have major limitations due to their hypoestrogenic side effects. Based on our previous work showing the activation of NF-kB in fibroids, we hypothesized that inhibiting NF-kB in vivo would result in the shrinkage of tumors and reduced inflammation. Fibroid xenografts were implanted in SCID mice and treated daily with Bay 11-7082 (Bay) or vehicle for two months. Bay treatment led to a 50% reduction in tumor weight. RNAseq revealed decreased expression of genes related to cell proliferation, inflammation, extracellular matrix (ECM) composition, and growth factor expression. Validation through qRT-PCR, Western blotting, ELISA, and immunohistochemistry (IHC) confirmed these findings. Bay treatment reduced mRNA expression of cell cycle regulators (CCND1, E2F1, and CKS2), inflammatory markers (SPARC, TDO2, MYD88, TLR3, TLR6, IL6, TNFα, TNFRSF11A, and IL1β), ECM remodelers (COL3A1, FN1, LOX, and TGFβ3), growth factors (PRL, PDGFA, and VEGFC), progesterone receptor, and miR-29c and miR-200c. Collagen levels were reduced in Bay-treated xenografts. Western blotting and IHC showed decreased protein abundance in certain ECM components and inflammatory markers, but not cleaved caspase three. Ki67, CCND1, and E2F1 expression decreased with Bay treatment. This preclinical study suggests NF-kB inhibition as an effective fibroid treatment, suppressing genes involved in proliferation, inflammation, and ECM remodeling.

OBJECTIVE: Fibroids are characterized by marked overexpression of tryptophan 2,3 dioxygenase (TDO2). The objective of this study was to determine the effectiveness of in vivo administration of an inhibitor of TDO2 (680C91) on fibroid size and gene expression.
METHODS: Animal and ex vivo human study.
METHODS: Academic Research Institution.
METHODS: Severe combined immunodeficiency mice bearing human fibroid xenografts treated with vehicle and TDO2 inhibitor.
METHODS: Daily intraperitoneal administration of 680C91 or vehicle for 2 months and in vitro studies with fibroid explants.
METHODS: Tumor weight and gene expression profile of xenografts and in vitro mechanistic experiments using fibroid explants.
RESULTS: Compound 680C91 was well-tolerated with no effects on blood chemistry and body weight. Treatment of mice with 680C91 resulted in 30% reduction in the weight of fibroid xenografts after 2 months of treatment and as expected lower levels of kynurenine, the byproduct of tryptophan degradation and an endogenous ligand of aryl hydrocarbon receptor (AhR) in the xenografts. The expression of cytochrome P450 family 1 subfamily B member 1 (CYP1B1), transforming growth factor β3 (TGF-β3), fibronectin (FN1), cyclin-dependent kinase 2 (CDK2), E2F transcription factor 1 (E2F1), interleukin 8 (IL-8) and secreted protein acidic and cysteine rich (SPARC) mRNA were lower in the xenografts of mice treated with 680C91 compared with vehicle controls. Similarly, the protein abundance of collagen, FN1, CYP1B1, and SPARC were lower in the xenografts of 680C9- treated mice compared with vehicle controls. Immunohistochemical analysis of xenografts indicated decreased expression of collagen, Ki67 and E2F1 but no significant changes in cleaved caspase 3 expression in mice treated with 680C91. The levels of kynurenine in the xenografts showed a direct correlation with the tumor weight and FN1 levels. In vitro studies with fibroid explants showed a significant induction of CYP1B1, TGF-β3, FN1, CDK2, E2F1, IL8, and SPARC mRNA by tryptophan, which could be blocked by cotreatment with 680C91 and the AhR antagonist CH-223191.
CONCLUSIONS: The results indicate that correction of aberrant tryptophan catabolism in fibroids could be an effective treatment through its effect to reduce cell proliferation and extracellular matrix accumulation.

OBJECTIVE: Uterine leiomyoma is a common gynecological condition that negatively affects women\'s quality of life. Vitamin D plays an important role in tumor development and progression. However, clinical studies comparing serum vitamin D levels between women with and without uterine leiomyomas are limited and inconclusive. This study aimed to compare serum vitamin D levels in women with and without uterine leiomyomas.
METHODS: This hospital-based case-control study included 150 women who visited a gynecological clinic. The cases included 75 women with uterine leiomyoma, whereas the controls included 75 age-and parity-matched participants without uterine leiomyoma. Serum vitamin D levels were measured in each participant and volumes of the uterine leiomyomas were determined using the water displacement method following myomectomy. The statistical significance was inferred at P<0.05.
RESULTS: The mean serum vitamin D level was 15.26±4.96 ng/mL and 22.45±6.93 ng/mL for the case and control groups, respectively. The difference was statistically significant (t-value -7.302 and P<0.001). Within the fibroid group, nine (12.0%), 49 (65.33%), and 17 (22.67%) participants had vitamin D deficiency, insufficiency, and sufficiency, respectively; and in the control group, two (2.67%), 24 (45.33%), and 39 (52.0%) participants had vitamin D deficiency, insufficiency, and sufficiency, respectively. There was significant negative correlation between the fibroid volume and the serum vitamin D level (r=-0.591, P<0.001).
CONCLUSIONS: Women with uterine leiomyoma had lower vitamin D levels than women in the control group. Lower vitamin D levels were associated with larger fibroid masses. Therefore, vitamin D supplementation may reduce fibroid growth and development.

UNASSIGNED: Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids.
UNASSIGNED: This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843.
UNASSIGNED: Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26-1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29-22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use.
UNASSIGNED: Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring.
UNASSIGNED: UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

OBJECTIVE: Do small and asymptomatic intramural and subserosal uterine fibroids affect female fertility?
CONCLUSIONS: Small and asymptomatic fibroids that do not encroach the endometrial cavity appear to not markedly affect female fertility.
BACKGROUND: The available evidence on uterine fibroids and fertility is limited. Most information has been obtained in IVF settings by comparing the success in women affected and not affected by fibroids. These studies have shown a detrimental effect of submucosal and possibly intramural fibroids. However, this study design provides information only on embryo implantation, not on female fertility in general.
UNASSIGNED: A retrospective observational case-control study on 200 women whose partner was diagnosed with severe male infertility and 200 women with unexplained infertility was conducted. If the null hypothesis (that fibroids do not affect fertility) is valid, one would expect a similar prevalence of fibroids in the two study groups. Conversely, if fibroids do impact fertility, one would expect a higher prevalence among women with unexplained infertility. The study was carried out at the Infertility Unit of the Fondazione IRCCS Ca\' Granda Ospedale Maggiore Policlinico covering a 5-year period between January 2014 and June 2020.
METHODS: We retrospectively recruited women seeking pregnancy whose partner was repeatedly documented to have a sperm concentration below 1 million/ml and matched them by age and study period to a group of women with unexplained infertility. The latter group of women was considered as a case group (infertile subjects), while the former group of women was considered as a control group (reflecting the general female population). Women with fibroids could be included in both study groups; only those with submucosal lesions were excluded.
RESULTS: Fibroids were diagnosed in 31 women (16%) with unexplained infertility and in 32 women (16%) with severe male factor infertility. The adjusted odds ratio of carrying fibroids in women with unexplained infertility was 0.91 (95% CI: 0.52-1.58). Subgroup analyses according to number, dimension and location of fibroids failed to highlight an increased risk of infertility in any group.
CONCLUSIONS: This is a retrospective study and some inaccuracies in fibroids detection cannot be ruled out. Moreover, the relatively small sample size hampers robust subgroup analyses. Even though we excluded women with patent causes of infertility, some women with specific causes of infertility could have been included among controls (yet are expected to account for <10% of the group).
CONCLUSIONS: This study suggests that small fibroids that do not encroach the endometrial cavity do not markedly affect female fertility. This information is clinically relevant when counseling infertile women with small fibroids and an otherwise unremarkable diagnostic work-up. Surgery may still be considered but only in selected cases.
BACKGROUND: This study was partially funded by Italian Ministry of Health: current research IRCCS. E.S. reports grants from Ferring, grants and personal fees from Merck, and grants and personal fees from Theramex outside the submitted work. All the other authors do not have any competing interest to declare.
BACKGROUND: N/A.

OBJECTIVE: This study aimed to compare the laparoscopic-enclosed electromechanical morcellation (LEM) with vaginal-enclosed scalpel morcellation (VSM) in laparoscopic myomectomy procedures.
METHODS: One hundred eighteen patients who underwent laparoscopic myomectomy were enrolled the prospective randomized interventional clinical study in tertiary university hospital. After myomectomy, tissue removal was accomplished via either LEM using the in-glove morcellation technique or VSM.
RESULTS: The median tissue removal time was longer in the LEM group (25 min [range: 14-55]) than the VSM group (20 min [range: 6-38] [p = 0.001]). Rescue analgesia requirement was significantly higher in the LEM group than the VSM group (mean rank: 56.92 vs. 40.92 doses, respectively; p < 0.001). There was no significant difference between preoperative and postoperative third month total scores of female sexual function index (FSFI) and subdomains in the LEM group. Conversely, all subdomains and total scores of FSFI (26.5 [16.7-34.8] vs. 22.7 [15.2-28.7]) except pain significantly worsened 3 months after operation in the VSM group.
CONCLUSIONS: LEM was associated with a longer tissue removal time and increased postoperative analgesic requirement. On the other hand, VSM was associated with worsened postoperative sexual function from baseline.

BACKGROUND: Type 3 fibroids are a special subtype of intramural fibroids that are likely to affect the pregnancy outcomes of assisted reproductive techniques. Hysteroscopic resection is a treatment for type 3 fibroids, but there has few study of its efficacy to date. In this study we evaluated the effect of hysteroscopic resection of type 3 fibroids on the pregnancy outcomes in infertile women.
METHODS: This retrospective case-control study was conducted from January 1, 2014 to June 30, 2021. Patients who underwent IVF-ICSI in our unit were divided into a type 3 fibroid group and a hysteroscopic myomectomy group. The inclusion criteria for the type 3 fibroid group and the hysteroscopic myomectomy group were as follows: 1) age ≤ 40 years; 2) fibroid diameter or total fibroid diameter > 2.0 cm. The following exclusion criteria were used: 1) oocyte donor treatment cycles and 2) presence of chromosomal abnormalities; 3) history of other uterine surgery; 4) presence of intracavitary lesions, including submucosal fibroids; 5) single fibroid > 5.0 cm; 6) cervical fibroids; 7) unclear ultrasound description of fibroids; 8) preimplantation genetic testing was performed and 9) congenital or acquired uterine malformations. The control group in our study was selected from patients who were treated with IVF only because of fallopian tube factors. According to the age of the type 3 fibroid group and hysteroscopic myomectomy group, random sampling was carried out in the patients between 25 and 47 years of age to determine a control group. The outcomes measured included the average transfer times to live birth, cumulative clinical pregnancy rate, and cumulative live birth rate.
RESULTS: A total of 302 cycles were enrolled in our study, including 125 cycles with type 3 fibroids, 122 cycles with hysteroscopic myomectomy, and 139 cycles of control patients. The average transfer times to live birth were significantly higher in the type 3 fibroid group than in the other two groups. The frequency of cumulative live births in the type 3 fibroid group was significantly lower than that in the control group. Compared with the control group, the hysteroscopic myomectomy patients had no statistically significant differences in the cumulative clinical pregnancy rate and cumulative live birth rate.
CONCLUSIONS: Type 3 fibroids significantly reduced the cumulative live birth rate of IVF patients. Ultrasound-guided hysteroscopic myomectomy can be used as a treatment for type 3 fibroids and could improve the pregnancy outcomes in infertile women.

Objective: Uterine myoma is the most common benign tumor however with significant distress and reduced quality of life in affected women. Besides, vitamin D deficiency may be a risk factor for uterine myoma. This study aimed to evaluate the effect of vitamin D supplements on the size of myoma in women with vitamin D insufficiency or deficiency. Materials and methods: This clinical trial was conducted in a teaching hospital from 2019 to 2020. According to baseline vitamin D level, participants were assigned into two interventional equal groups (vitamin D deficiency or insufficiency) to receive either 1000 IU daily or 50000 IU weekly vitamin D for 12 weeks. The size and location of the uterine myoma were compared before and after the intervention. Results: Totally, 137 women with uterine myoma were enrolled. Based on baseline vitamin D level, 52 cases had vitamin D insufficiency and 85 cases had vitamin D deficiency. No significant difference was observed in age and BMI in both groups. The location of the subserosal and intramural myoma did not differ, otherwise, the percent of the submucosal myomas were increased significantly (p=0.020) after the intervention. In both groups decreased myoma size otherwise not significant was seen after the intervention (p=0.148 and p=0.664 respectively). Conclusion: Vitamin D supplementation may not be effective in women with vitamin D insufficiency or deficiency in the short term to reduce myoma size.

Uterine leiomyomas are complex tumours with limited medical treatment options. Simvastatin is used to treat hypercholesterolaemia and has shown promising effects as a treatment option for leiomyomas. Previously, our group demonstrated a promising effect of simvastatin treatment in a patient-derived xenograft mouse model. Here, we tested the efficacy of simvastatin liposomal nanoparticles (NPs). After bilateral leiomyoma xenograft implantation, mice (N = 12) were divided into three treatment arms: control, simvastatin and simvastatin-loaded liposome NPs (simvastatin-NPs). Treatment with simvastatin significantly reduced tumour volume and inhibited the Ki67 expression when compared to the control group. There was a trend of reduced tumour volume and Ki67 expression after treatment with simvastatin-NP; however, the results were not significant. Due to low bioavailability and short half-life of simvastatin, liposomal NPs have the potential to enhance drug delivery, however, in this study NP did not provide improvement over simvastatin, but did demonstrate their potential for the delivery of simvastatin.Impact statementWhat is already known on this subject? Simvastatin treatment in a patient-derived xenograft mouse model reduced tumour growth and decreased proliferation.What do the results of this study add? Treatment with simvastatin significantly reduced tumour volume and inhibited the Ki67 expression when compared to the control group. There was a trend of reduced tumour volume and Ki67 expression after treatment with simvastatin-NP, however, it did not improve the efficacy of simvastatin at reducing tumour growth and proliferation.What are the implications of these findings for clinical practice and/or further research? More studies are needed to optimise the formulation of NPs to further enhance the sustainable delivery of simvastatin.