Non-endometrioid Endometrial Cancer Research Articles

Metformin use and endometrial cancer survival

ObjectiveImpaired glucose tolerance and diabetes are risk factors for the development of uterine cancer. Although greater progression free survival among diabetic patients with ovarian and breast cancers using metformin has been reported, no studies have assessed the association of metformin use with survival in women with endometrial cancer (EC). MethodsWe conducted a single-institution retrospective cohort study of all patients treated for uterine cancer from January 1999 through December 2009. Demographic, medical, social, and survival data were abstracted from medical records and the national death registry. Overall survival (OS) was estimated using Kaplan–Meier methods. Cox models were utilized for multivariate analysis. All statistical tests were two-sided. ResultsOf 985 patients, 114 (12%) had diabetes and were treated with metformin, 136 (14%) were diabetic but did not use metformin, and 735 (74%) had not been diagnosed with diabetes. Greater OS was observed in diabetics with non-endometrioid EC who used metformin than in diabetic cases not using metformin and non-endometrioid EC cases without diabetes (log rank test (p=0.02)). This association remained significant (hazard ratio=0.54, 95% CI: 0.30–0.97, p<0.04) after adjusting for age, clinical stage, grade, chemotherapy treatment, radiation treatment and the presence of hyperlipidemia in multivariate analysis. No association between metformin use and OS in diabetics with endometrioid histology was observed. ConclusionDiabetic EC patients with non-endometrioid tumors who used metformin had lower risk of death than women with EC who did not use metformin. These data suggest that metformin might be useful as adjuvant therapy for non-endometrioid EC.

Efficacy of systematic pelvic lymphadenectomy in patients with non‐endometrioid endometrial cancers: A retrospective, multicenter study in Korea

Non-endometrioid endometrial cancer is a clinically and pathologically distinct subtype of endometrial cancer. The aim of this study was to determine whether systematic pelvic lymphadenectomy improves overall survival compared to no lymphadenectomy in non-endometrioid endometrial cancer. The authors retrospectively reviewed the medical records and pathological findings of 112 patients who underwent surgical staging for non-endometrioid endometrial cancer from 2000 to 2006 in Korea. Systematic pelvic lymphadenectomy was performed in 71 patients. Pelvic lymph node metastases were identified in 31% and 14.6% patients who underwent systematic pelvic lymphadenectomy and no lymphadenectomy, respectively. After adjusting for risk factors, there was no significant difference in overall survival (odds ratio = 0.69; 95% confidence interval, 0.29-1.67) between patients who did or did not undergo systematic pelvic lymphadenectomy. On multivariate analysis, patients with lymph node metastasis had higher risk of death (odds ratio = 3.11; 95% confidence interval, 0.97-10.00) than the patients with no lymph node metastasis. Although systematic pelvic lymphadenectomy did not affect overall survival in patients with the non-endometrioid subtype, it has the potential benefit of providing prognostic information and acting as a guide for further adjuvant treatment.

Controversies in the management of endometrial cancer 2012

Endometrial cancer (EC) is the most frequent cancer of the female genital tract, especially in developed countries and the seventh most common cause of death from cancer in women in Western Europe. Major prognostic factors related to endometrial cancer are stage, grade, and depth of myometrial invasion and the presences of lymho-vascular space invasion. Standard treatment of EC consist of surgical and then adjuvant therapy on the basis of pathological prognostic factors. Standard surgical approach for stage I-II endomerial cancer is total hysterectomy and bilateral salpingo-oophorectomy with or without staging. Without question a comprehensive surgical staging procedure similar to that for ovarian carcinoma should be performed for non-endometrioid EC (uterine papiller serous carcinoma and clear cell adenocarcinoma) due to the aggressive clinical behavior. In contrast, there are some controversial issues in the surgical management-staging of EC and the role of ommentectomy and lymphadenectomy are the issues of current debate.

The comparison of clinicopathological characteristics in primary malignant mixed műllerian tumour with epithelial endometrial carcinoma

We performed an age-matched case-control study to compare the clinical and pathology outcomes between histologically diagnosed primary malignant mixed műllerian tumour (MMMT) of the uterus and endometrial carcinoma. Thirty-two women were treated for primary MMMT at seven tertiary medical centres in Korea from 2000 to 2006. For each woman with MMMT, four women with endometrioid and two with non-endometrioid endometrial carcinoma were selected as age-matched controls for analysis. Medical records were retrospectively reviewed to obtain outcome data. The incidence of MMMT was 2.57% (32/1244). In comparison with women with endometrioid endometrial cancer, those with MMMT were characterised by large tumour size, higher incidence of adnexal involvement and lymph node metastases, leading to advanced disease stage. Despite the frequent use of adjuvant treatment, the 5-year survival rate of women with MMMT was significantly poorer than those with endometrioid endometrial cancer. However, women with MMMT were not significantly different from those with non-endometrioid endometrial cancer in terms of important pathologic variables, apart from larger tumour size. In addition, the 5-year survival rate of women MMMT was poorer than that those with non-endometrioid endometrial cancer, but the difference was not statistically significant. Malignant mixed műllerian tumour is characterised by a high incidence of lymph node metastases and advanced stage at diagnosis, leading to poorer overall survival than other subtypes of endometrial carcinoma. Clinical trials for MMMT are critical for improving treatment strategies.

A Unique Spectrum of Somatic PIK3CA (p110α) Mutations Within Primary Endometrial Carcinomas

The goal of this study was to comprehensively define the incidence of mutations in all exons of PIK3CA in both endometrioid endometrial cancer (EEC) and nonendometrioid endometrial cancer (NEEC). We resequenced all coding exons of PIK3CA and PTEN, and exons 1 and 2 of KRAS, from 108 primary endometrial tumors. Somatic mutations were confirmed by sequencing matched normal DNAs. The biochemical properties of a subset of novel PIK3CA mutations were determined by exogenously expressing wild type and mutant constructs in U2OS cells and measuring levels of AKT(Ser473) phosphorylation. Somatic PIK3CA mutations were detected in 52.4% of 42 EECs and 33.3% of 66 NEECs. Half (29 of 58) of all nonsynonymous PIK3CA mutations were in exons 1-7 and half were in exons 9 and 20. The exons 1-7 mutations localized to the ABD, ABD-RBD linker and C2 domains of p110α. Within these regions, Arg88, Arg93, Gly106, Lys111, Glu365, and Glu453, were recurrently mutated; Arg88, Arg93, and Lys111 formed mutation hotspots. The p110α-R93W, -G106R, -G106V, -K111E, -delP449-L455, and -E453K mutants led to increased levels of phospho-AKT(Ser473) compared to wild-type p110α. Overall, 62% of exons 1-7 PIK3CA mutants and 64% of exons 9-20 PIK3CA mutants were activating; 72% of exon 1-7 mutations have not previously been reported in endometrial cancer. Our study identified a new subgroup of endometrial cancer patients with activating mutations in the amino-terminal domains of p110α; these patients might be appropriate for consideration in clinical trials of targeted therapies directed against the PI3K pathway.

Abstract 1472: Bcl-3 as a carcinogenic factor in non-endometrioid endometrial carcinoma

Abstract Objectives : The aim of the study was to evaluate the Bcl-3 expression in normal endometrium, endometrial hyperplasia, and endometrial cancer. Methods : Retrospectively collected paraffin blocks from 30 cases of normal endometrium, 16 of endometrial hyperplasia, 24 of endometrioid endometrial cancer, and 12 of non-endometrioid endometrial cancer were analyzed. Expression of Bcl-3 was assessed by immunohistochemistry. The staining pattern was correlated with clinicopathological variables. Results : While none was positive in normal endometrium and endometrial hyperplasia and only 2 cases (8.3%) were positive for Bcl-3 in endometrioid endometrial cancer, 5 cases (41.7%) was positive in non-endometrioid endometrial cancer. Positive expression of Bcl-3 significantly correlated with non-endometrioid endometrial carcinoma (p=0.017), advanced stage (p=0.030), and high grade (p=0.001). Moreover, Bcl-3 positivity was associated with aggressive parameters including ovarian invasion (p=0.004), peritoneal cytology (p=0.029), lymphovascular space invasion (p=0.002), and lymph node metastases (p=0.029). In contrast, there was no significant correlation between expression of Bcl-3 and myometrial invasion or cervical invasion. In addition, Bcl-3 expression was not related to recurrence of disease. Conclusion : Bcl-3 is strongly expressed in non-endometrioid endometrial cancer, but less frequently in endometrioid endometrial cancer and hyperplasia. It is suggested that Bcl-3 is related with the carcinogenesis of non-endometrioid endometrial cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1472.

Mismatch repair status and outcomes after adjuvant therapy in patients with surgically staged endometrial cancer

Objectives To determine whether DNA mismatch repair (MMR) modifies the response to chemotherapy or radiotherapy in patients with endometrial cancer. Methods Immunohistochemistry (IHC) for the DNA MMR proteins MLH1, MSH2, MSH6, and PMS2 was performed on a tissue microarray of specimens of primary endometrial cancer. MMR deficiency was defined as lack of expression of one or more proteins. Expression of all proteins classified a tumor as having an intact MMR system. Recurrence rates were calculated for women treated with platinum-based chemotherapy or pelvic external beam radiation. Comparisons were made using the log-rank test. Multiple comparisons were controlled for by utilizing the Bonferroni correction method. Results Four hundred seventy-seven cases of endometrial cancer were evaluated on a tissue microarray (TMA). One hundred fifty-eight patients (41%) received chemotherapy. Sixty-six patients (17%) received pelvic teletherapy. Overall and progression-free survival were not different between patients whose tumors had intact MMR and those with defective MMR when stratified by adjuvant treatment with radiation or chemotherapy. Subgroup analyses stratified by histology (non-endometrioid versus endometrioid) and stage did show significant survival differences. There was a significant increase in overall ( p = 0.003) and progression-free ( p = 0.004) survival in those with MMR-deficient, non-endometrioid tumors treated with teletherapy compared to those with an intact MMR system. Improved progression-free survival was noted in patients with intact MMR with stage III/IV disease treated with adjuvant chemotherapy ( p = 0.031). Conclusions Subgroups of patients with non-endometrioid endometrial cancer and defective MMR may have improved survival after adjuvant radiotherapy. Patients with advanced stage endometrial cancer and defects in mismatch repair may receive less benefit from adjuvant chemotherapy.

The role of omental biopsy in endometrial cancer staging

Omental biopsy is not part of FIGO staging for endometrial cancer. The few studies that have looked into this matter have had conflicting results. This is the largest study in terms of the number of cases studying the incidence of omental involvement in endometrioid and non-endometrioid endometrial cancer. A retrospective study assessing 248 cases of endometrial cancer with omental biopsy at the time of primary surgical treatment for endometrial cancer at the Gynaecological Oncology Centre, Norfolk and Norwich University Hospital between January 2004 and May 2008. Demographic, clinico-pathologic and surveillance data were collected from hospital records, operative notes and histopathology results. The histology included tumour type, stage, grade and omental biopsy. All histological types were included in the study. Two hundred and forty eight patients had an omental biopsy at the time of primary surgical treatment for endometrial cancer during the study period. Of them, 187 cases were stage I, 27 stage II, 27 stage III and seven stage IV. According to histological type, 202 (81.4%) had endometrioid, 20 (8.0%) serous papillary, 20 (8.0%) malignant mixed Mullerian tumour (MMMT), three (1.2%) clear cell and three (1.2%) sarcoma. Overall, six cases (2.4%) had omental involvement, 4/202 (1.98%) with endometrioid type, 1/20 (5.0%) with serous papillary type and 1/20 (5.0%) MMMT. Eighty four percent of omental metastases (five cases) were macroscopic and noted at operation .The overall risk of omental metastases is 2.4% and in the absence of gross lesions the risk is around 0.4%. Most omental metastases can be diagnosed by careful inspection and palpation of the omentum. The possibility of missing microscopic disease is low. Based on these figures and possible increase in morbidity and operative time, omental biopsy cannot be justified as a standard procedure in endometrial cancer staging.

Non-Endometrioid Adenocarcinoma of the Uterine Corpus: A Review of Selected Histological Subtypes

Understanding the etiology, presentation, evaluation, and management of selected non-endometrioid endometrial adenocarcinomas of the uterine corpus is needed to define optimal treatment regimens. The pathology and treatment of selected non-endometrioid endometrial adenocarcinomas of the uterus are reviewed and summarized. The most common non-endometrioid histology is papillary serous (10%), followed by clear cell (2% to 4%), mucinous (0.6% to 5%), and squamous cell (0.1% to 0.5%). Some non-endometrioid endometrial carcinomas behave more aggressively than the endometrioid cancers such that even women with clinical stage I disease often have extrauterine metastasis at the time of surgical evaluation. Therefore, when technically and medically feasible, comprehensive surgical staging is helpful for women with non-endometrioid endometrial cancer histology. Comprehensive surgical staging includes hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and cytological evaluation of the abdominal cavity. While whole abdominal radiotherapy has a limited role in early-stage uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC), there may be a role for postoperative chemotherapy and volume-directed radiotherapy in both early-stage UPSC and CC. In the setting of optimally debulked advanced-stage disease, a combination of radiation and chemotherapy may be indicated. In the setting of recurrent disease or in women with residual disease after surgery, a platinum-based regimen or enrollment in a clinical trial is recommended. UPSC and CC are managed similarly since sufficient data to separate treatment recommendations are lacking. Because both histologies are associated with a high rate of recurrence, adjuvant therapy is recommended even in women with early-stage disease. The remaining cell types should be treated similar to endometrioid or other low-grade histologies.

HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer

Type II endometrial cancers (uterine serous papillary and clear cell histologies) represent rare but highly aggressive variants of endometrial cancer (EC). HER2 and EGFR may be differentially expressed in type II EC. Here, we evaluate the clinical role of HER2 and EGFR in a large cohort of surgically staged patients with type II (nonendometrioid) EC and compare the findings with those seen in a representative cohort of type I (endometrioid) EC. In this study HER2 gene amplification was studied by fluorescence in situ hybridisation (FISH) and EGFR expression by immunohistochemistry. Tissue microarrays were constructed from 279 patients with EC (145 patients with type I and 134 patients with type II EC). All patients were completely surgically staged and long-term clinical follow up was available for 258 patients. The rate of HER2 gene amplification was significantly higher in type II EC compared with type I EC (17 vs 1%, P<0.001). HER2 gene amplification was detected in 17 and 16% of the cases with uterine serous papillary and clear cell type histology, respectively. In contrast, EGFR expression was significantly lower in type II compared with type I EC (34 vs 46%, P=0.041). EGFR expression but not HER2 gene amplification was significantly associated with poor overall survival in patients with type II EC, (EGFR, median survival 20 vs 33 months, P=0.028; HER2, median survival 18 vs 29 months, P=0.113) and EGFR expression retained prognostic independence when adjusting for histology, stage, grade, and age (EGFR, P=0.0197; HER2, P=0.7855). We conclude that assessment of HER2 gene amplification and/or EGFR expression may help to select type II EC patients who could benefit from therapeutic strategies targeting both HER2 and EGFR.

Combined treatment and prognostic factors for stage III and IV endometrial carcinoma

To evaluate prognostic factors and treatment of patients with advanced stage endometrial cancer. One hundred and eighteen patients with advanced stage endometrial cancer were treated in our hospital between January 1996 and December 2006. The treatment and prognosis were retrospectively analyzed. The mean follow-up time was 26 months. During the follow-up, 33 cases (28.0%) died and 25 patients (21.2%) had disease progression. The 3-year overall survival for patients with stage III and stage IV was 78.3% and 39.4%, and for endometrioid and nonendometrioid endometrial carcinoma was 69.3% and 42.0%, respectively. Four patients with positive cytology only were followed closely after surgery and were free of disease up to the report time. Patients with late stages, deep myometrial invasion, nonendometrioid endometrial cancer, poor differentiation, without lymphadenectomy and without radiochemotherapy after surgery were associated with a worse prognosis by univariate analysis (P < 0.05), while in a multivariate analysis only late stages and deep myometrial invasion were associated with a poor prognosis (P < 0.05). The patients who received lymphadenectomy and whose residual disease after the surgery was less than 1 cm had better prognoses than those otherwise (P < 0.05). The patients who received postoperative radiochemotherapy had better prognoses than those who did not (P < 0.05). Pathological stage and myometrial invasion are independent prognostic factors for late stage endometrial cancer. Satisfactory cytoreduction surgery and lymphadenectomy, followed by postoperative radiochemotherapy, except for stage IIIa patients with positive cytology only, are recommended in order to improve prognosis.

Current Issues in the Management of Endometrial Cancer

Endometrial cancer (EC) remains the most common gynecologic malignancy in the United States. It is expected to become more common as the prevalence of obesity, one of the most common risk factors for EC, increases worldwide. The 2 main histologic subcategories of EC, endometrioid and nonendometrioid EC, show unique molecular aberrations and are responsible for markedly disparate clinical behaviors. The primary treatment of EC is surgery, ie, hysterectomy, removal of the adnexa, and pelvic and para-aortic lymphadenectomy, either via laparotomy or endoscopic techniques. Adjuvant therapy is necessary for patients at high risk of recurrence and consists of vaginal brachytherapy, teletherapy, systemic chemotherapy, or some combination thereof. Multi-institutional trials are in progress in this country and in Europe to better define optimal adjuvant treatment for subsets of patients, as well as the role of surgical staging in reducing both overuse and underuse of radiation therapy. Hormonal therapy is an option for some young women with EC who wish to preserve fertility. This review summarizes the diagnosis and management of EC and discusses current controversies and upcoming investigations pertaining to EC staging and adjuvant treatment.

Novel molecular profiles of endometrial cancer—new light through old windows

Endometrial carcinoma (EC) is the most common gynecological malignancy in the western world. A widely accepted dualistic model, which has been established on a morphological basis, differentiates EC into two broad categories: Type I oestrogen-dependent adenocarcinoma with an endometrioid morphology and Type II non-oestrogen-dependent EC with a serous papillary or clear cell morphology. Molecular genetic evidence indicates that endometrial carcinoma, as described in other malignancies, likely develops as the result of a stepwise accumulation of alterations in cellular regulatory pathways, such as oncogene activation and tumor suppressor gene inactivation, which lead to dysfunctional cell growth. These molecular alterations appear to be specific in Type I and Type II cancers. In type I endometrioid endometrial cancer, PTEN gene silencing in conjunction with defects in DNA mismatch repair genes, as evidenced by the microsatellite instability phenotype, or mutations in the K-ras and/or β-catenin genes, are recognized major alterations, which define the progression of the normal endometrium to hyperplasia, to endometrial intraepithelial neoplasia, and then on to carcinoma. In contrast, Type II cancers show mutations of TP53 and Her-2/neu and seem to arise from a background of atrophic endometrium. Nevertheless, despite the great effort made to establish a molecularly-based histological classification, the following issues must still be clarified: what triggers the tumor cells to invade the myometrium and what causes vascular or lymphatic dissemination, finally culminating in metastasis? RUNX1, a transcription factor, was recently identified as one of the most highly over-expressed genes in a microarray study of invasive endometrial carcinoma. Another candidate gene, which may be associated with an initial switch to myometrial infiltration, is the transcription factor ETV5/ERM. These studies, as well as those conducted for other genes possibly involved in the mitotic checkpoint as a major mechanism of carcinogenesis in non-endometrioid endometrial cancer, could help in understanding the differences in the biology and the clinical outcome among histological types.

Molecular pathology of endometrial carcinoma: transcriptional signature in endometrioid tumors.

A dualistic model, which has been established on a morphological basis and that differentiates type I endometrioid from type II non-endometrioid endometrial cancer, is widely accepted. Molecular genetics have provided us with data supporting the dualistic model of endometrial tumorigenesis and with some clues to speculate about the sequence of the molecular alterations defining the tumorigenesis pathways. In type I endometrioid endometrial cancer, PTEN gene silencing, microsatellite instability associated with defects in DNA mismatch repair genes, or mutations in the K-ras gene are the known major alterations defining the progression from normal endometrium to hyperplasia and then on to carcinoma. Recently, cDNA microarray technology for identifying the differences in gene expression patterns between the histological types of endometrial cancer have permitted the identification of differentially expressed genes that could help us to understand differences in the biology and the clinical outcome between histiotypes. Genes involved in the mitotic checkpoint as a major mechanism of carcinogenesis in non-endometrioid endometrial cancer, or altered genes associated with the initial steps of myometrial infiltration in endometrioid endometrial cancer, represent examples of how useful large genetic screenings can be for understanding the tumorigenesis process and the future directions in the molecular pathogenesis of endometrial cancer.

Ovarian stromal hyperplasia and ovarian vein steroid levels in relation to endometrioid endometrial cancer

To study the relationship between the presence of endometrioid endometrial cancer, the degree of ovarian stromal hyperplasia and ovarian steroid production in postmenopausal women. Retrospective and prospective study, respectively. Medical Centre Leeuwarden and the University Hospital Groningen, The Netherlands. Postmenopausal women with or without endometrial cancer, undergoing a hysterectomy with bilateral salpingo-oophorectomy. In 112 women with endometrioid endometrial cancer, 47 women with a benign gynaecological condition and 10 women with non-endometrioid endometrial cancer, the degree of ovarian stromal hyperplasia was scored retrospectively on a semi-quantitative scale (atrophy, slight, marked). All women were postmenopausal and had undergone a hysterectomy with bilateral salpingo-oophorectomy. Prospectively, blood sampling from the ovarian veins was performed in a further 60 women. Steroid levels (oestrone, oestradiol, androstenedione, testosterone) were determined and related to the degree of ovarian stromal hyperplasia and the presence (n = 52) or absence (n = 8) of endometrioid endometrial cancer. Degree of ovarian stromal hyperplasia and steroid levels in the utero-ovarian circulation. In the retrospective study, the degree of ovarian stromal hyperplasia was higher in the presence of endometrioid endometrial cancer (P = 0.0001). The prospective study showed that an increasing degree of ovarian stromal hyperplasia was related to higher ovarian levels of both testosterone and androstenedione (P < 0.05 and P < 0.005, respectively), but not to oestrone or oestradiol. A non-significant increase in mean ovarian vein levels of both testosterone and androstenedione was seen in patients with endometrial cancer as compared with patients with benign conditions. In endometrioid endometrial cancer, higher degrees of ovarian stromal hyperplasia were found and with increasing degrees of ovarian stromal hyperplasia, levels of ovarian vein androgens were higher. A causal relationship in the origin of hormone-dependent endometrial pathology may exist between ovarian stromal hyperplasia, ovarian vein androgen levels and endometrioid endometrial carcinoma.

Ovarian stromal hyperplasia and ovarian vein steroid levels in relation to endometrioid endometrial cancer

Objective To study the relationship between the presence of endometrioid endometrial cancer, the degree of ovarian stromal hyperplasia and ovarian steroid production in postmenopausal women. Design Retrospective and prospective study, respectively. Setting Medical Centre Leeuwarden and the University Hospital Groningen, The Netherlands. Population Postmenopausal women with or without endometrial cancer, undergoing a hysterectomy with bilateral salpingo-oophorectomy. Methods In 112 women with endometrioid endometrial cancer, 47 women with a benign gynaecological condition and 10 women with non-endometrioid endometrial cancer, the degree of ovarian stromal hyperplasia was scored retrospectively on a semi-quantitative scale (atrophy, slight, marked). All women were postmenopausal and had undergone a hysterectomy with bilateral salpingo-oophorectomy. Prospectively, blood sampling from the ovarian veins was performed in a further 60 women. Steroid levels (oestrone, oestradiol, androstenedione, testosterone) were determined and related to the degree of ovarian stromal hyperplasia and the presence ( n = 52) or absence ( n = 8) of endometrioid endometrial cancer. Main outcome measures Degree of ovarian stromal hyperplasia and steroid levels in the utero-ovarian circulation. Results In the retrospective study, the degree of ovarian stromal hyperplasia was higher in the presence of endometrioid endometrial cancer ( P = 0.0001). The prospective study showed that an increasing degree of ovarian stromal hyperplasia was related to higher ovarian levels of both testosterone and androstenedione ( P < 0.05 and P < 0.005, respectively), but not to oestrone or oestradiol. A non-significant increase in mean ovarian vein levels of both testosterone and androstenedione was seen in patients with endometrial cancer as compared with patients with benign conditions. Conclusion In endometrioid endometrial cancer, higher degrees of ovarian stromal hyperplasia were found and with increasing degrees of ovarian stromal hyperplasia, levels of ovarian vein androgens were higher. A causal relationship in the origin of hormone-dependent endometrial pathology may exist between ovarian stromal hyperplasia, ovarian vein androgen levels and endometrioid endometrial carcinoma.