Paeonol ameliorates endometrial hyperplasia in mice via inhibiting PI3K/AKT pathway-related ferroptosis.

BACKGROUND: Paeonol (Pae) is one of the active ingredients from components of Guizhi Fuling Capsule, a traditional Chinese medicine widely used for the treatment of women's diseases, which exhibits various biological and pharmacological activities. PURPOSE: The objective of this study was to investigate the molecular mechanism underlying the role of Pae in protecting against endometrial hyperplasia (EH). METHODS: CCK-8 assay was performed to detect the effect of Pae on cell proliferation. Hematoxylin and eosin (H&E) staining was performed to evaluate uterine tissue structure. A network pharmacology study was performed to search the disease targets. Single-cell transcriptome analysis was performed with uterine tissues from 3 healthy donors and 3 EH patients on 10X Genomics platform. Changes in lipid peroxidation were detected by the MDA reaction. IHC assay, Western blot, immunofluorescence and RT-qPCR were used to study the effects of estradiol and Pae on the expression levels of GPX4, PI3K, AKT, p-PI3K, p-AKT in mice. RESULTS: Pae treatment resulted in a decrease in cell viability of endometrial epithelial cells. Loss of uterus weight and morphology changes were observed in mice. In addition, Fe iron concentration and MDA levels increased, while the expression of GPX4, p-PI3K and p-AKT diminished. CONCLUSIONS: Pae exhibited obvious alleviative activity in estradiol-induced mice via PI3K/AKT signaling pathway-regulated ferroptosis.

Effects of Isoflavone Supplementation on the Response to Medroxyprogesterone in Premenopausal Women with Nonatypical Endometrial Hyperplasia: A Randomized, Double-Blind, Placebo-Controlled Trial.

Objective: The purpose of this study was to evaluate the impact of isoflavone supplementation compared with placebo on endometrial histology and serum estradiol levels in premenopausal women with nonatypical endometrial hyperplasia. Materials and Methods: The present double-blindplacebo-controlled clinical trial was conducted on 100 women with nonatypical endometrial hyperplasia in the age range of 30 to 45 years. Participants were randomly assigned to receive 50 mg of isoflavone (n = 50) or placebos (n = 50) daily for three months. Both groups received the standard treatment of nonatypical endometrial hyperplasia. Endometrial biopsy and blood samples were taken at the baseline and three months after the intervention. The incidence of drug side effects was assessed as well. Results: After three months, 88.4% of isoflavone-administered subjects had a significant histological improvement compared to 68.9% subjects in the placebo group (P=0.02). There were no significant differences between the two groups in the changes of serum estradiol levels and the incidence of drug side effects. Conclusion: The findings of the present study demonstrated that the coadministration of 50 mg of isoflavones and medroxyprogesterone acetate increases the treatment efficacy in women with nonatypical endometrial hyperplasia. Clinical Trial Registration. This trial was registered on the Iranian website for clinical trial registration (https://www.irct.ir/trial/53553).

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.

The Effects of Folic Acid Supplementation on Recurrence and Metabolic Status in Endometrial Hyperplasia: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Data on the effects of folic acid supplementation on clinical symptoms and metabolic profiles of patients with endometrial hyperplasia (EH) are limited. This investigation was performed to evaluate the effects of folic acid supplementation on clinical symptoms and metabolic status of patients with EH. METHODS: This randomized, double-blind, placebo-controlled trial was conducted among 60 women diagnosed with EH. Diagnosis of EH was made based on biopsy results. Participants were randomly allocated to 2 groups to take 5 mg/d folic acid supplements (n = 30) or placebo (n = 30) for 12 weeks. RESULTS: After the 12-week intervention, folic acid supplementation significantly decreased fasting plasma glucose (ß -3.99 mg/ dL; 95% CI, -7.39, -0.59; P = 0.02), serum insulin levels (ß -2.82 µIU/mL; 95% CI, -4.86, -0.77; P = 0.008), homeostasis model assessment for insulin resistance (ß -0.68; 95% CI, -1.20, -0.17; P = 0.009), triglycerides (ß -16.47 mg/dL; 95% CI, -28.72, -4.22; P = 0.009) and very-low-density lipoprotein (VLDL) cholesterol (ß -3.29 mg/dL; 95% CI, -5.74, -0.84; P = 0.009), and significantly increased the quantitative insulin sensitivity check index (ß 0.01; 95% CI, 0.004, 0.03; P = 0.01) compared with the placebo. Additionally, folic acid intake resulted in a significant reduction in serum high sensitivity C-reactive protein (hs-CRP) (ß -0.36 mg/L; 95% CI, -0.52, -0.21; P < 0.001) compared with the placebo. Folic acid supplementation did not affect other metabolic parameters. CONCLUSION: In conclusion, we found that folic acid administration for 12 weeks to subjects with EH improved glycemic control, triglycerides, VLDL-cholesterol and hs-CRP levels, but did not influence recurrence and other metabolic profiles.

Genistein aglycone: a new therapeutic approach to reduce endometrial hyperplasia.

OBJECTIVE: Endometrial hyperplasia without cytological atypia is commonly treated with progestins, but other treatment regimes may be available with equivalent efficacy and low side effects. DESIGN: A randomized double-blind, placebo and progesterone-controlled clinical trial to evaluate the effects of genistein aglycone in reducing endometrial hyperplasia. PATIENTS: A group of 56 premenopausal women with non-atypical endometrial hyperplasia were enrolled and received: genistein aglycone (n=19; 54 mg/day); norethisterone acetate (n=19; 10 mg/day on days 16-25 of the menstrual cycle) or placebo (n=18) for 6 months. MEASUREMENTS: Hysteroscopy was performed with biopsies and symptomology assessed at baseline, 3 and 6 months of administration. The effect on estrogen (ER) and progesterone receptors (PR) expression in uterine biopsies were assessed after 3 and 6 months. For each treatment follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), sex hormone-binding globulin (SHBG) and progesterone (PG) levels were also evaluated. RESULTS: After 6 months, 42% of genistein aglycone-administered subjects had a significant improvement of symptoms (histologically confirmed in the 29%) compared to 47% of norethisterone acetate subjects (histologically confirmed in the 31%), but only 12% in the placebo group with 19% exhibiting worsening symptoms and increased endometrial thickness. No significant differences were noted for hormone levels for any treatment, but immunohistochemical analysis revealed significantly reduced staining for ER-alpha and PR and enhanced ER-beta1 staining in genistein-administered subjects associated with a complete regression of bleeding. CONCLUSIONS: These results suggest that genistein aglycone might be useful for the management of endometrial hyperplasia without atypia in women that cannot be treated with progestin.

Portulaca oleracea L. in the treatment of patients with abnormal uterine bleeding: a pilot clinical trial.

Abnormal uterine bleeding (AUB) is a common cause of referral to the gynecology clinic. Portulaca oleracea L., commonly named purslane, is used in Iranian folk medicine to treat AUB. To verify this use, ten premenopausal women with AUB comprising menorrhagia, metrorrhagia, polymenorrhea and intermenstrual bleeding who had not responded to standard drugs and were candidates for hysterectomy participated in the clinical trial. Endometrial biopsies demonstrated the etiologies of AUB in six (60%) patients, fibroma; one (10%) patient, endometrial hyperplasia and one (10%) patient, endometrial cyst. Endometrial biopsies of two (20%) subjects were normal. The subjects took 5 g of purslane seeds powder in a glass of water every 4 h orally 48 h after the onset of menstruation for 3 days. The participants were requested to report the effects of seeds powder on the volume, duration and pattern of bleeding. Eight (80%) patients reported that the duration and volume of bleeding had reduced and their patterns of periods had normalized. The seeds powder was ineffective in two (20%) patients. One of the patients had endometrial hyperplasia and the other had fibroma. No adverse effects were reported. AUB did not recur in the patients responding to treatment for the duration of a 3 months follow-up. The results suggest that purslane seeds could be effective and safe in the treatment of AUB.

Progestin therapy of complex endometrial hyperplasia with and without atypia.

OBJECTIVE: To assess the likelihood of histologic persistence/progression of complex hyperplasia and atypical hyperplasia among women treated with progestin compared with those not treated, with attention to type, dose, and duration. METHODS: This was a cohort study at an integrated health plan of women, ages 18-85 years, with complex or atypical hyperplasia on independent pathology review with a second endometrial specimen in the 2-6 months after the index diagnosis. Progestin therapy between index diagnosis and follow-up biopsy was determined from the pharmacy database. Medical record abstraction was performed. Relative risks (RRs), adjusted for age and body mass index, were calculated. RESULTS: Among 185 women, average age 55.9 years, follow-up 16.1 weeks, 115 had complex and 70 had atypical hyperplasia. Among women with complex hyperplasia, 28.4% of those treated with progestin and 30.0% of those not treated had persistence/progression (RR 1.20, 95% confidence interval [CI] 0.53-2.72). Among women with atypical hyperplasia, 26.9% of those treated with progestin and 66.7% of those not treated had persistence/progression (RR 0.39, 95% CI 0.21-0.70); there was a suggestion that use of at least a medium dose, or a duration of at least 3 months, was associated with a particularly low probability of persistence/progression. CONCLUSION: Although progestin treatment of women with atypical hyperplasia was associated with a substantial increase in the likelihood of regression of the lesion during the ensuing 2-6 months, persistence/progression was nonetheless present in more than one quarter of treated women. Regression of complex hyperplasia without atypia was common whether progestin had or had not been used.

[Chavanprash in the treatment of hyperplastic processes in the endometrium]. / "Chavanprash" v lechenii giperplasticheskikh protsessov v éndometrii.

Hyperplastic processes in the endometrium are classified as a common gynecological pathology. The drug chavanprash has been shown to improve general bodily resistance, to enhance vital tone of the body. It is endowed with a manifest hepatotropic and antitoxic activity, which fact permits recommending it for use in the combination therapy of hyperplastic processes in the endometrium as well as during the period of rehabilitation in the wake of the course of hormonotherapy.

Hiperplasia endometrial atípica en pacientes infértiles: manejo conservador / Atypical endometrial hyperplasia in infertile patients: conservative management

Se presentan 4 pacientes infértiles portadoras de hiperplasia endometrial con atipías que se manejaron en forma conservadora en nuestro hospital. Tres pacientes recibieron acetato de medroxiprogesterona oral por 6 meses (100 mg día) con demostración histológica de regresión de la lesión e inducción de ovulación subsecuente. Un caso no recibió tratamiento por presentar regresión espontánea de su patología endometrial. Tres pacientes se embarazaron (dos únicos y un gemelar) obsteniéndose un aborto espontáneo y tres recién nacidos de término. Se concluye que el manejo conservador de la hiperplasia endometrial con atipías, empleando acetato de medroxiprogesterona oral en altas dosis, es efectivo. Una vez corregidos los ciclos anovulatorios con inductores de ovulación es posible obtener gestaciones viables

[Effect of thymalin on the immunological indices and morphofunctional structure of the uterus in guinea pigs with endometrial hyperplasia]. / Vliianie timalina na nekotorye immunologicheskie pokazateli i morfofunktsional'nuiu strukturu matki u morskikh svinok s giperplaziei éndometriia.

The efficiency of usage of the preparations of thymalin in hyperplasia of endometrium has been studied in the experiment on 125 female guinea pigs. Indicated pathology was caused by the introduction of oil solution of synestrol during 19 weeks. It is determined that marked hyperplasia of endometrium is developing as a result of prolonged introduction of synestrol in experimental animals and the decrease of the amount of T- and B-lymphocytes takes place. The use of thymalin results in normalization of indexes of immune system and in partial normalization of morphologic structure of endometrium.

[Effect of progestins on the ultrastructure of endometrial cells in pretumorous changes and cancer (an organ-culture study)]. / Vliianie progestinov na ul'trastrukturu kletok éndometriia pri ego predopukholevykh izmeneniiakh i rake (issledovanie organnoi kul'tury).

Morphological and ultrastructural changes of cells in atypical hyperplasia and focal adenomatosis of the endometrium considered to be precancer processes as well as of endometrial adenocarcinoma before and after treatment (in organ culture) with progesterone and norethysterone were studied. In atypical hyperplasia and focal adenomatosis (after 3-day incubation with hormone), early signs of secretory transformation of the glandular epithelium were observed including subnuclear vacuoles containing glycogen, reduction of microvilli, giant mitochondria, crimping of the cellular membrane, complication of the endoplasmic reticulum. In cancer tissue cultures the hormonal effect is manifested at the ultrastructural level only: signs of morphological differentiation of tumor cells were observed. In these pathological conditions, endometrial organ cultures may be used for the determination of hormone sensitivity of the tumor.