Endometrial Proliferative Lesions Research Articles

Serum Anti-Mullerian Hormone Levels Might Indicate Premenopausal Endometrial Lesions.

Endometrial proliferative lesions (EPL) usually refer to endometrial hyperplasia (EH) and endometrial cancer (EC). Among patients with premenopausal EPL who wish to preserve their fertility, only those with EH and early-stage EC have the possibility to undergo fertility preservation therapy. However, there is currently a lack of specific and reliable screening criteria and models for identifying these patients. This study utilized a retrospective diagnostic study design. The training set included medical record information that met the criteria between August 2017 and October 2022, while the validation set consisted of medical record information that met the criteria from November 2022 to May 2023. The endometrial pathological test served as the gold standard. The serum anti-Mullerian hormone (AMH) level before endometrial sampling and a regression model were employed to predict EPL. The study included a total of 1209 patients with PCOS (1119 in the control group and 90 in the endometrial proliferative lesion group) and 5366 women without PCOS (5249 in the control group and 117 in the proliferative lesion group). In the case of PCOS patients aged 20-39 years, the most effective screening threshold for AMH was found to be a serum AMH level of ≤5.39 ng/mL. The model used for this group was logit(p) = -2.562 - 0.430 × AMH + 0.127 × BMI + 1.512 × hypertension + 0.956 × diabetes -1.145 × regular menstruation. On the other hand, for non-PCOS women aged 20-39 years, the optimal screening threshold for AMH was determined to be a serum AMH value of ≤2.18 ng/mL. The model used for this group was logit(p) = -3.778 - 0.823 × AMH + 0.176 × BMI + 2.660 × diabetes -1.527 × regular menstruation -1.117 × dysmenorrhea. It is important to note that all of these findings have successfully passed internal verification. For PCOS and non-PCOS women aged 20-39 years, the serum AMH test and related multiple regression models were obtained for the warning of EPL.

Evaluation of The Effect of Metformin and Progesterone on The Endometrium in Cases of Peri Menopausal Bleeding

Background: Numerous epidemiologic and experimental studies have suggested that unopposed estrogen may be a major factor in the development of benign, premalignant, and malignant endometrial lesions. Objective: To assess the unique effects of progesterone and metformin on simple endometrial hyperplasia and disorganized proliferative endometrium, and to ascertain if metformin is clinically helpful in this situation. Patients and Methods: The study was conducted between April 2023 and September 2023 at the obstetrics and gynecology department of Damanhur Medical National Institute. The study was a double blinded randomized study. 100 patients were involved in this study who were divided into 2 groups: The 1st one (50 cases) was treated with metformin (Glucophage) 500 mg in the first week then raise the dose to reach 1000 mg in the 4th week, for three months long. The 2nd group (50 cases) was administered medroxy progesterone acetate (Provera) 4mg once per day for 3 months long. Next 3 months all cases in both groups were gone for 2nd time endometrial biopsy for assessment of response of treatment and will have ultrasound examination every three months also. Result: Uterine hemorrhage after treatment and endometrial thickness after treatment did not statistically differ between the two study groups. Additionally, there was no statistically significant difference in patient satisfaction or hysterectomy between the two study groups. There was no discernible difference in the two groups' treatment lengths. While there was a high statistical rise in the incidence of nausea, vomiting, and diarrhea in group 2 compared to group 1, there was a strong statistical increase in the incidence of sore breasts, weakness, and metallic taste in group 1 compared to group 2. Conclusion: Progesterone and metformin may both be useful in treating benign endometrial proliferative lesions. To prevent its problems, endometrial proliferative lesions should be identified and treated properly.

Immunohistochemical study of PTEN and survivin in endometrial proliferative lesions

Immunohistochemical study of PTEN and survivin in endometrial proliferative lesions

Uterine adenofibroma and endometrial stromal sarcoma associated with tamoxifen therapy: MR findings

Tamoxifen therapy may result in a variety of endometrial proliferative lesions, including adenofibroma and endometrial stromal sarcoma (ESS). This report describes the MR findings of adenofibroma and ESS associated with tamoxifen therapy. When MRI demonstrates a uterine mass appearing as a heterogeneous mass in the endometrium or myometrium, adenofibroma and ECC must be considered as rare, but possible, diagnoses.

Effects of estrogens and metabolites on endometrial carcinogenesis in young adult mice initiated with N-ethyl- N′-nitro- N-nitrosoguanidine

The present study assessed effects of estrogens and their steroid metabolites on the endometrial carcinogenesis in young adult mice initiated with N-ethyl- N′-nitro- N-nitrosoguanidine (ENNG). A total of 272 female CD-1 (ICR) mice were used and equally divided into 17 groups. Mice were implanted cholesterol pellets to the back subcutis at 9 weeks of age. Pellets contained nothing (control) or one of the experimental agents, three different estrogens and their 13 different steroid metabolites, at a concentration of 0.5% (w/w). At 10 weeks of age, mice were given a single intra-uterine administration of ENNG at a dose of 25 mg/kg body weight. When reaching the 30 weeks of age (20 weeks after the ENNG treatment), mice were sacrificed to assess the development of endometrial proliferative lesions. While endometrial proliferative lesions, including hyperplasias and adenocarcinomas, were observed in all groups, the incidences of hyperplasias in the groups treated with 2-hydroxyestriol, 2-methoxyestradiol, 2-methoxyestriol and 16-epiestriol were significantly higher than that in the control group. On the other hand, adenocarcinomas were significantly developed in the groups treated with estrone, estradiol, estriol, 16β-hydroxyestrone, 16α-hydroxyestrone and 17-epiestriol. These results indicate that, on the endometrial carcinogenesis in mice initiated with ENNG, estrogens and their metabolites belonging to the 16α-hydroxylation pathway and the upstream of the 16β-hydroxylation pathway exert both promoting and progressing effects, whereas, the estrogen metabolites belonging to the 2- and 4-hydroxylation pathways (catechol estrogens) and the downstream of the 16β-hydroxylation pathway exert only promoting or no effects. It is thus suggested that a metabolic profile of estrogens may be crucial for the endometrial carcinogenesis and that the rate of the 16α-hydroxylation may be associated with the increased carcinogenic risks of estrogens on the endometrium.

Promoting Effects of Ethinylestradiol but not Atrazine on <i>N</i>-ethyl-<i>N</i>-nitrosourea-induced Uterine Carcinogenesis in ICR Mice

In order to assess the modifying effects of atrazine (ATR) on uterine endometrial carcinogenesis, female ICR mice received an intra-uterine injection via the vagina of 50 mg/kg body weight of N-ethyl-N-nitrosourea (ENU), followed by no further treatment, by a diet containing 5, 50 or 500 ppm ATR or by a diet containing 2.5 ppm ethinylestradiol (EE) for 26 weeks. In the ENU + EE (positive control) group, depression of body weight gain was seen throughout the treatment period, and the incidence of uterine endometrial proliferative lesions such as adenocarcinomas and atypical hyperplasias, and PCNA positive indices were significantly increased as compared to the ENU alone group. On the other hand, although only slight depression of body weight was seen throughout the study in the ENU + 500 ppm ATR group, but no significant differences in uterine weights, incidence of uterine proliferative lesions with their PCNA positive indices and the immunohistochemical expression of ERα were found in all of the ENU + ATR groups as compared with those of the ENU alone group. The results in the present study indicate that ATR up to 500 ppm in diet has no modifying effects on uterine carcinogenesis in ICR mice initiated with ENU.

Promotion, but not progression, effects of tamoxifen on uterine carcinogenesis in mice initiated with N-ethyl-N'-nitro-N-nitrosoguanidine.

Effects of tamoxifen (TAM) on development of uterine endometrial carcinogenesis were studied in intact and ovariectomized (OVX) mice initiated with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG). In experiment I, animals were implanted with cholesterol (ChL, controls) or TAM (5% w/w) and/or 17beta-oestradiol (E(2), 0.5% w/w) pellets s.c. from 9 to 25 weeks of age, until the termination of the experiment, and all received a single intra-uterine administration of ENNG (12.5 mg/kg) at 10 weeks of age. They were divided into four groups: ENNG + ChL (control), ENNG + TAM, ENNG + E(2) and ENNG + TAM + E(2). Endometrial proliferative lesions (hyperplasias and/or carcinomas) were observed in all groups, the incidences in the TAM- and/or E(2)-treated groups being two times higher than in the ChL-treated control animals. High induction (11/20, 55%) of adenocarcinomas was observed in the E(2) group but this was significantly decreased in combination with TAM (2/20, 10%), no carcinomas being found in the TAM group. In experiment II, animals pre-treated with TAM (10 weeks) and receiving E(2) post-treated (4 weeks) developed adenocarcinomas, although no cancers were observed in mice treated by ChL instead of TAM. In animals pre-treated with TAM and post-treated with ChL or TAM, no adenocarcinomas were also developed. In OVX mice (experiment III), proliferative lesions were observed in the TAM- and/or E(2)-treated groups, at incidences significantly higher than in ChL-treated animals, in which these lesions were completely absent. However, no adenocarcinomas were found, only slight hyperplasias being observed in the TAM group, although the incidence of adenocarcinoma was highest in the E(2) alone group, and significantly decreased in combination with TAM, as in experiment I. These results indicate that TAM may itself exert promotion effects, while exhibiting an anti-progression influence on uterine carcinogenesis in adult mice initiated by ENNG and receiving E(2).

Iron lactate induction of pancreatic and endometrial proliferative lesions and a lack of increased tumors in a 104-week carcinogenicity study in F344 rats

Iron lactate has been used as a food additive for iron supplementation. The present study was conducted to determine whether it might have carcinogenic potential. A total of 150 male and 150 female Fischer 344 rats were divided into three groups and fed basal diet containing 0, 1 or 2% of iron lactate for 104 weeks. No iron lactate-induced tumors were observed in any groups, although the incidences of pancreatic acinar cell and endometrial gland hyperplasias were increased in males and females, respectively, in the 2% group. Thus our in vivo animal data indicate that iron lactate lacks carcinogenicity in male and female F344 rats. However, estrogenic effects might be concluded based on the data for endometrial lesions. In a second experiment, an estrogen responsive rat pituitary tumor cell line, MtT/Se, and a human breast cancer cell line, MCF-7, were therefore employed to examine the estrogenic potential of iron lactate with regard to receptor binding affinity and ERE-reporter gene activation. Results in both cases were negative. Further investigations are needed to elucidate the mechanisms of induction of pancreatic and endometrial proliferative lesions by iron lactate.

Rapid induction of uterine endometrial proliferative lesions in transgenic mice carrying a human prototype c-Ha- ras gene (rasH2 mice) given a single intraperitoneal injection of N-ethyl- N-nitrosourea

In our previous study, uterine endometrial stromal sarcomas and atypical hyperplasias of the endometrial glands were induced in heterozygous p53 deficient mice (p53 (+/−) mice) of the CBA strain given a single dose of N-ethyl- N-nitrosourea (ENU). In order to clarify whether uterine tumors can be induced in transgenic mice carrying a human prototype c-Ha- ras gene (rasH2 mice) that are very susceptible to genotoxic carcinogens, rasH2 mice and their wild-type littermates received an intraperitoneal injection of 120 or 0 mg/kg body weight of ENU followed by no further treatment for 22 weeks. Eighteen and 94% of ENU-treated rasH2 mice had uterine endometrial adenocarcinomas and atypical hyperplasias, respectively. Other malignant and benign tumors such as lung alveolar/bronchiolar adenomas and carcinomas, forestomach squamous cell papillomas and carcinomas, splenic hemangiomas/sarcomas, skin papillomas, malignant lymphomas and harderian gland adenomas were also observed in ENU-treated rasH2 mice. The result in the present study suggests that female rasH2 mice are very susceptible to uterine carcinogenesis, providing a useful model for ENU-induced uterine epithelial tumors.

Time-dependent promotion activity of 17β-estradiol on uterine carcinogenesis in mice initiated with N-ethyl- N-nitrosourea

The time-dependent promotion activity of 17β-estradiol (E 2) by initiation with N-ethyl- N-nitrosourea (ENU) on induction of mouse uterine endometrial proliferative lesions was examined. Illumination-induced persistent estrous female CD-1 mice were divided into five groups at 9 weeks of age. At 10 weeks of age, mice in all groups ( n=25) were given a single intra-uterine administration of ENU (50 mg/kg), dissolved in polyethylene glycol. Animals in Groups 2 to 5 were then implanted s.c. with an E 2 pellet at 9, 11, 14 and 17 weeks of age. The implants were left in place for 8 weeks and then taken out. At the termination of the experiment (week 15 after the ENU-treatment), all surviving mice were killed and the development of uterine proliferative lesions were assessed. All groups demonstrated endometrial hyperplasias and adenocarcinomas and the incidences of the latter in ENU plus E 2 treated animals (Groups 2 to 5; 36, 48, 35 and 36%, respectively) were significantly higher compared to 8% for Group 1, without any variation with the age at E 2 treatment. However, the incidences of adenocarcinomas plus severe hyperplasias increased from Groups 1 to 5 (28, 40, 56; P<0.05, 61; P<0.05 and 80%; P<0.01, respectively), indicating that promotion effects of E 2 on induction of uterine proliferative lesions in the uterine endometrium become more pronounced with the interval after ENU initiation.

Uterine carcinosarcomas in patients receiving tamoxifen. A report of 19 cases.

Uterine carcinosarcomas are highly aggressive neoplasms with a tendency to early extrauterine spread, high stage at diagnosis, and a poor prognosis. Tamoxifen is widely used as adjuvant therapy in the treatment of breast cancer and is known to cause endometrial proliferative lesions, including adenocarcinoma. In recent years, there have been occasional reports of uterine carcinosarcoma in patients taking tamoxifen. The aim of this study is to describe the clinicopathologic profile in 19 women taking tamoxifen who subsequently developed uterine carcinosarcoma. Nineteen patients were identified from cases of uterine carcinosarcoma diagnosed at three institutions. The case notes were examined and the pathology reviewed. The age at diagnosis of carcinosarcoma ranged from 47 to 91 years (mean 71 years). All patients were postmenopausal and received 20 mg tamoxifen daily; the duration of treatment ranged from 1 to 15 years (mean 7.1 years). The cumulative dose of tamoxifen ranged from 7.3 to 109.5 g. Ten tumors were stage I, one stage II, seven stage III, and one stage IV. Ten of the carcinosarcomas were homologous, and nine contained heterologous elements in the form of rhabdomyoblasts (six cases) or malignant cartilage (three cases). The overall prognosis was extremely poor. Fifteen patients died within 35 months of the diagnosis of carcinosarcoma (mean 12 months). Two patients are alive with very short follow-up periods, and two were lost to follow-up. The reported data support an association between tamoxifen therapy and the development of uterine carcinosarcoma. The risk is likely to be highest in those patients who have been taking tamoxifen for a prolonged period. A majority of tumors in the present study were stage I, and this suggests that uterine carcinosarcomas in patients taking tamoxifen may be diagnosed at an earlier stage than those arising de novo. However, the prognosis was still poor even with low-stage disease. Properly controlled epidemiological studies are necessary to confirm an association between tamoxifen and uterine carcinosarcoma.

High Yield Selective Induction of Uterine Endometrial Adenocarcinomas in CD-1 Mice by N-Ethyl-N'-nitro-N-nitrosoguanidine Combined with 17.BETA.-Estradiol.

In order to assess a combined carcinogen and hormone protocol for selective induction of uterine adenocarcinomas in mice, 79 illumination-induced persistent estrous CD-1 mice, divided into four groups, were treated with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) and/or 17β-estradiol (E2). Groups 1 and 3 were given a single intra-uterine administration of polyethylene glycol (PEG) at 10 weeks of age, while Groups 2 and 4 received ENNG (12.5 mg/kg), dissolved in PEG. Mice of Groups 3 and 4 were also implanted with E2 pellets s.c. one week earlier and the pellets were once renewed after 8 weeks. At 15 weeks after the ENNG treatment, the mice were killed for histopathological and endocrinological examination. All groups demonstrated endometrial proliferative lesions, although no severe hyperplasias or adenocarcinomas were found in the control group (Group 1). The incidences of adenocarcinomas in Groups 2, 3, and 4 were 6 (1/19), 25 (5/20), and 55% (11/20), respectively, those for Groups 3 and 4 being significant as compared to the lack in Group 1. The E2: progesterone (E2: P) ratios in Groups 3 and 4 were also significantly increased. These results indicate that an increased E2: P ratio is important for endometrial adenocarcinoma development in CD-1 mice, acting with or without chemical carcinogen initiation to cause uterine cancer development. The relatively short duration, and specifically high yield mean that the present protocol has advantages for two-stage uterine carcinogenicity studies in mice.

High-yield induction of uterine endometrial adenocarcinomas in Donryu rats by a single intra-uterine administration of N-ethyl-N'-nitro-N-nitrosoguanidine via the vagina.

A total of 130 female Donryu rats (10‐week‐old) were divided into two groups; 80 animals in the experimental group were given a single intra‐uterine administration of 20 mg/kg N‐ethyl‐N‐nitro‐N‐nitrosoguanidine (ENNG) dissolved in polyethylene glycol (PEG) via the vagina without laparotomy, and 50 animals in the control group received PEG alone in the same manner. Small numbers of animals in both groups were killed at 3, 6, 9 and 12 months after ENNG treatment for sequential histological and endocrinological examination, and at 12.5 experimental months (15 months of age) all survivors were killed. At the termination, endometrial adenocarcinomas were present in 49% of the experimental group, compared to 0% in the control group. Severe endometrial hyperplasias were also found only in the experimental group and sequential histological examination showed first appearance of hyperplasia at 6 months and adenocarcinoma at 9 months. No tumors other than uterine carcinomas were induced by ENNG and the carcinogen treatment did not affect the endocrine environment of rats, persistent estrus appearing at 6 months after the start and increasing with age in both groups. The estradio‐17β:progesterone (E:P) ratio was also increased after 6 months, with further elevation at 12 months to about 8 times higher than the level at 6 months. These results indicate that an increased E:P ratio might act as a promoter of development of endometrial proliferative lesions initiated by ENNG in this rat strain. The study indicates that the present simple method using Donryu rats provides a good animal model for endometrial adenocarcinoma development in women.

細胞「配列」の定量化と子宮内膜増殖性病変の解析

細胞診における悪性の判定では, 細胞個々の示す異型だけでなく, 核間距離の不均一や核の重積といった細胞の「配列」異常を把握することも大切である.私どもは細胞「配列」の異常を定量する計測方法を開発し, さらに子宮内膜細胞診への応用を試みた.標本平面に分布する細胞 (核) の「配列」はDP (distribution pattern) index (=rn0) によって定量的に表すことができる.ここでn0は核の密度, rはすべての核からそれぞれ最も近くにある核までの重心間距離の平均である.このDP indexは核が正六角形格子の交点の配列を示せば0.877, 等間隔規則性を失ったランダムな配列を示せば0.5, 完全に1点に重なれば0となり, 配列状態に従ってこれらの値の間を連続的に変化する.子宮内膜から採取された細胞集団についてDP indexを求めると, 正常 (22例) で0.826±0.029, 内膜増殖症 (16例) で0.735±0.019, 高分化型腺癌 (19例) で0.641±0.046となり, 3群間で明らかな有意差が認められた (p<0.01).子宮内膜の増殖性病変では細胞「配列」に異常が生じ, 本来の規則性が失われている.これらの変化を定量的に把握することは, とくに内膜増殖症と高分化型腺癌の鑑別に有用な一助となる.