Guizhi Fuling Capsule ameliorates endometrial hyperplasia through promoting p62-Keap1-NRF2-mediated ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Guizhi Fuling Capsule (GFC) is a classical traditional Chinese medicine officially recorded in Synopsis of the Golden Chamber and has long been used to treat gynecological diseases in China. However, scientific evidence for the anti-endometrial hyperplasia potential of GFC used in traditional medicine is lacking. AIM OF THE STUDY: This study evaluated whether GFC protects against endometrial hyperplasia and its potential mechanism in mice. METHODS AND MATERIALS: We used estrogen (estradiol) to induce endometrial hyperplasia in mice. C57BL/6 mice were treated with estradiol subcutaneously for 21 days, and GFC (75 mg/kg and 150 mg/kg) was given intragastric administration from the first day of the modeling. H&E staining is used to evaluate endometrial tissue structure change. Malondialdehyde was measured to explore lipid peroxidation. Western blot, immunohistochemistry and immunofluorescence were performed to observe the expressions of GPX4, p62, Keap1 and NRF2. RESULTS: The degree of ferroptosis in endometrial tissue of patients with endometrial hyperplasia was lower than normal endometrial tissue. In addition, ferroptosis inducer imidazole ketone erastin could improve endometrial hyperplasia in mice. Interestingly, GFC significantly alleviated endometrial hyperplasia through triggering ferroptosis. Furthermore, GFC inhibited p62-Keap1-NRF2 pathway in estradiol-induced endometrial hyperplasia model. CONCLUSIONS: GFC may attenuate estrogen-induced endometrial hyperplasia in mice through triggering ferroptosis via inhibiting p62-Keap1-NRF2 pathway. These findings suggest that GFC might act as a promising traditional Chinese medicine to treat endometrial hyperplasia.

Treatment with metformin and sorafenib alleviates endometrial hyperplasia in polycystic ovary syndrome by promoting apoptosis via synergically regulating autophagy.

This study aimed to investigate the molecular mechanisms underlying the roles of metformin (MET) and Sorafenib (SOR) in the treatment of endometrial hyperplasia (EH) in polycystic ovary syndrome (PCOS). Effects of MET and SOR on the area of endometrium and myometrium were detected. Western blot analysis and immunohistochemistry assays were carried out to detect the levels of mammalian target of rapamycin complex 1 (mTORC1), mTORC2, LC3-II, P62, and Caspase-3 in rats and cultured cells. Furthermore, cell counting kit-8 assay and flow cytometry analysis was carried out to determine the apoptotic profiles of treated cells. MET and SOR could apparently decrease the areas of endometrium and myometrium in PCOS. MET notably enhanced the expression of LC3-II and Caspase-3 in PCOS while substantially reducing the level of mTORC1 and P62. Similarly, SOR also enhanced the expression of LC3-II and Caspase-3 in PCOS while substantially reducing the level of mTORC2 and P62. Treatment with MET and SOR significantly inhibited the proliferation of HCC-94 and HEC-1-A cells while promoting their apoptosis by upregulating the expression of Caspase-3. In cells treated with MET, the expression of mTORC1 and LC3-II was upregulated while the expression of P62 was downregulated. Similarly, in cells treated with SOR, the expression of mTORC2 and LC3-II was also upregulated while the expression of P62 was also downregulated. Furthermore, MET showed no effect on mTORC2 expression, while SOR showed no effect on mTORC1 expression. In this study, we suggested that MET and SOR alleviated the risk of EH in PCOS via the mTORC1/autophagy/apoptosis axis and mTORC2/autophagy/apoptosis axis, respectively.

Clinical and Metabolic Response to Vitamin D Supplementation in Endometrial Hyperplasia: a Randomized, Double-Blind, Placebo-Controlled Trial.

There was inconsistent evidence showing that vitamin D intake may be associated with reduced cancer risk due to optimized metabolic profile and reduced oxidative stress. However, we are not aware of any study evaluating the effects of vitamin D supplementation on clinical response and metabolic status of patients with endometrial hyperplasia (EH). This research was done to evaluate the effects of vitamin D supplementation on clinical response and metabolic status of patients with EH. This randomized, double-blind, placebo-controlled trial was conducted among 60 women diagnosed with EH. EH diagnosis was made based on specific diagnostic procedures of biopsy. Participants were randomly assigned into two groups to intake either 50,000 IU vitamin D3 supplements (n = 30) or placebo (n = 30) every 2 weeks for 12 weeks. After the 12-week intervention, compared with the placebo, vitamin D supplementation increased serum-25(OH) vitamin D levels (+12.0 ± 10.4 vs. +1.9 ± 7.1 ng/mL, P < 0.001). In addition, vitamin D administration was associated with significant decreases in fasting plasma glucose (FPG) (-1.6 ± 7.0 vs. +2.1 ± 6.1 mg/dL, P = 0.03), serum insulin levels (-0.8 ± 1.9 vs. +1.1 ± 3.5 µIU/mL, P = 0.01), homeostasis model of assessment-insulin resistance (HOMA-IR) (-0.2 ± 0.6 vs. +0.3 ± 0.8, P = 0.01), and a significant increase in the quantitative insulin sensitivity check index (QUICKI) (+0.003 ± 0.01 vs. -0.01 ± 0.02, P = 0.02) compared with the placebo. Additionally, a significant decrease in serum high-sensitivity C-reactive protein (hs-CRP) (-1.9 ± 2.8 vs. -0.003 ± 2.0 µg/mL, P = 0.003) and a significant rise in plasma total antioxidant capacity (TAC) values (+62.5 ± 53.5 vs. +7.5 ± 34.1 mmol/L, P < 0.001) were observed following supplementation with vitamin D compared with the placebo. In conclusion, vitamin D3 supplementation for 12 weeks among women with EH had beneficial effects on glucose metabolism, serum hs-CRP, and plasma TAC concentrations. In addition, vitamin D may have played an indirect role in reducing complications of EH due to its effect on improved glycemic control, hs-CRP, and TAC concentrations.

Folate receptor α expression and significance in endometrioid endometrium carcinoma and endometrial hyperplasia.

Endometrioid-type endometrial carcinoma (EEC) developing on the ground of endometrial hyperplasia (EH) is amongst the most commonly observed type of cancer in the world. Folate receptor α (FRα) is a vitamin molecule that has a role in cell proliferation. The fact that FRα, which is known to be needed extremely by the cells of malignancies that proliferate rapidly, is present in limited amounts in normal tissues while it is overexpressed in malignant cells of the same tissues makes folate a candidate for target molecular therapy. In our study, FRα expression in 214 cases, with 95 diagnosed within EEC and 119 with EH, was studied immunohistochemically. FRα expression in EEC was found significantly high compared to EH and normal endometrium (P<0.01). Similarly, FRα expression in EH cases with complex atypia were significantly high compared to other hyperplasia subgroups (P<0.01). The findings of our results make us think that FRα overexpression may play a role in the EEC carcinogenesis and carcinoma progression from EH. Furthermore, we suggest that it can be helpful in the treatment of EEC and/or transition from hyperplasia stage to EEC as a molecular therapy targeting receptors labeled with antibody-based props containing FRα. Finally, we suggest that FRα may be used, based on the expression intensity, as a supplemental option to determine the patients that shall be directed to radical therapy amongst patients with complex atypical EH.

Effects of genistein in combination with conjugated estrogens on endometrial hyperplasia and metabolic dysfunction in ovariectomized mice.

Tissue-selective estrogen complex (TSEC), which combines a selective estrogen receptor modulator (SERM) with one or more estrogens, is a novel approach to menopausal therapy. It has been demonstrated that the phytoestrogen genistein (GEN) exhibits mixed estrogen receptor agonist and antagonist activity, suggesting that GEN may have potential for use as a natural SERM. We evaluated, for the first time, the effects of GEN, conjugated estrogens (CE), and their pairing effects as a TSEC treatment on estrogen-induced endometrial hyperplasia and metabolic dysfunction in ovariectomized (OVX) mice fed a high-fat diet. CE replacement prevented fat accumulation in the adipose tissue and liver, improved glucose homeostasis, and induced endometrial hyperplasia in OVX mice. GEN at 100 mg/kg showed CE mimetic effects in preventing ovariectomy-induced metabolic dysfunctions without endometrial stimulation. Combination treatments with CE and GEN prevented metabolic dysfunctions more strongly than CE alone, but at both low and high doses, GEN did not reverse CE-induced endometrial hyperplasia. In addition, we found that in a TSEC regimen, a typical SERM raloxifene maintains the metabolic benefits of CE while simultaneously protecting the endometrium in OVX mice. These findings indicate that GEN acts as an estrogen agonist in metabolic regulation, but has no SERM function in the uteri of OVX mice.

[Endometrial hyperplasias immunohistochemical aspects]. / Aspecte imunohistochimice in hiperplazii endometriale.

UNLABELLED: Endometrial hyperplasias are now diagnosed according to the histopathological examination. By using immunohistochemistry, the authors search for supplementary elements for the diagnosis and evaluation of the prognosis of this nosologic framework. MATERIAL AND METHODS: We investigated a number of 138 cases of endometrial hyperplasia, using immunohistochemical research. The avidine-biotin-peroxidase method revealed estrogenic and progesterone receptors, together with EGF, proliferative Ki67 and cyclin D1. RESULTS: The reaction was positive in variable percents for estrogenic receptors, especially for complex atypical hyperplasias. A positive immunoreactivity was also found for progesterone receptors and for Ki67 (in atypical hyperplasias); cyclin D1 revealed only a moderate reaction. CONCLUSIONS: Immunohistochemistry can be useful for the prognosis of the lesion, but it is not indispensable for diagnosis, while the histopathologic examination is absolutely necessary for a complete endometrial hyperplasia diagnosis.

Endometrial hyperplasia: a prospective randomized study of histopathology, tissue steroid receptors and plasma steroids after abrasio, with or without high dose gestagen treatment.

274 patients with spontaneous endometrial hyperplasias were randomized into two groups: one treated with only abrasio, and another with additional 500 mg medroxyprogesterone acetate (MPA) twice weekly for 3 months. Total disappearance of all types of hyperplasias was seen following MPA treatment, whereas with only abrasio about 60% were removed suggesting that MPA does not have to be generally given to eliminate endometrial hyperplasias. Quantitative determinations of tissue steroid receptors and plasma steroids do not seem to be useful for the selection of patients in need of gestagen treatment.