A dynamic test of hormonal sensitivity of gynecologic malignancy by use of an antiestrogen, tamoxifen

To assess the hormonal sensitivity of tumors, progestin receptor levels in the tumor were monitored before and after tamoxifen, 40 mg/day for 7 days in patients with various gynecologic malignancies. Tamoxifen induced progestin receptors in two of eight-cases of endometrial cancer, four of eight cases of cervical epidermoid cancer, and two of seven cases of cervical adenocarcinoma. Induction of progestin receptors did not occur in one case of uterine mixed müllerian tumor and there were no measured progestin receptors after tamoxifen treatment in three cases of ovarian cancer and in one case of benign ovarian tumor. Because induction of progestin receptors is the best-documented response of estrogen target cells to estrogenic stimuli, this induction of progestin receptor with tamoxifen may be considered to indicate the estrogen sensitivity of a tumor. Further study is warranted to determine whether hormonal sensitivity assessed by the use of tamoxifen might serve to select tumors likely to respond to hormonal therapy.     

子宫内膜非典型增生18例保守治疗结局分析

目的探讨孕激素治疗子宫内膜非典型增生的结局及适宜的辅助生育策略。方法回顾性分析2002年1月～2007年4月18例不孕合并子宫内膜非典型增生的患者应用大剂量孕激素保守治疗的结果及妊娠结局。结果①14例患者在应用大剂量孕激素治疗3～36个月后病灶消退，4例病灶持续存在；②3例患者在停止治疗5～15个月后发展为子宫内膜癌。内膜非典型增生病变的再现率为33．3％；③8例患者接受了辅助生育治疗．5例分别经CC＋HMG促排卵治疗3～6周期无优势卵泡发育．1例在第6个促排卵周期获宫内单胎妊娠。4例（包括1例CC＋HMG促排卵未孕者）患者接受了5个周期IVF助孕，1例输卵管妊娠。1例自然流产。另2例冻存胚胎等待移植。结论多数子宫内膜非典型增生的患者对大剂量孕激素治疗有效。对这类患者．一旦内膜病变消退，应积极助孕．可以适当放宽IVF—ET指征。     

Cytoplasmic progesterone and estradiol receptors in normal, hyperplastic, and carcinomatous endometria: therapeutic implications

This study was designed to determine whether the presence of progesterone receptors (PR) and/or estradiol receptors (ER) could be used to predict progestin responsiveness of recurrent or advanced endometrial cancers. We have demonstrated the presence of physicochemically similar cytoplasmic progesterone and estradiol receptors in normal, hyperplastic, and carcinomatous endometria. All normal endometria contained both PR and ER. Seventy-three percent of endometrial hyperplasias were PR(+) and 93% were ER(+). A decreasing concentration of progesterone receptor activity was observed with increasing tumor anaplasia [grade 1, 84% PR(+); grade 2, 55% PR(+); grade 3, 22% PR(+)] and in irradiated tumors. A statistically significant (p less than 0.001) relationship has been demonstrated between the presence of specific cytoplasmic PR and response to progestin therapy in recurrent or advanced endometrial adenocarcinomas. Thus, we conclude that a PR assay may be used to help select the most appropriate therapy for patients with recurrent or advanced endometrial adenocarcinoma.     

Tamoxifen and endometrial carcinoma: alterations in estrogen and progesterone receptors in untreated patients and combination hormonal therapy in advanced neoplasia

Estrogen receptors and progesterone receptors were measured in tumors from patients with previously untreated endometrial carcinoma before and after a 5-day course of tamoxifen citrate. On initial biopsy, 13 of 25 tumors (52%) were progesterone receptor-positive, whereas 21 of 25 tumors (84%) were progesterone receptor-positive after tamoxifen. Grades 1 and 2 tumors were more likely to demonstrate this increased incidence of measurable progesterone receptors. Considering these results, and the work of others who have shown that progesterone receptor-positive metastatic endometrial cancer is more responsive to progestin therapy than are progesterone receptor-negative tumors, we instituted a phase II clinical trial of tamoxifen plus progestin for patients with recurrent endometrial carcinoma. Thus far, however, the 33% total response rate achieved with the combination therapy has not been superior to standard progestin therapy.     

Diagnosis of malignant mesenchymal uterine tumors by hysteroscopic excisional biopsy

STUDY OBJECTIVE: To emphasize the need for histologic evaluation of intrauterine lesions. Six cases of unexpected mesenchymal uterine tumors were diagnosed following pathologic review of specimens obtained during hysteroscopy to evaluate intrauterine lesions. DESIGN: Retrospective chart review (Canadian Task Force classification II-3). SETTING: Large tertiary care medical center. PATIENTS: Four postmenopausal and two perimenopausal women with uterine mesenchymal tumors. INTERVENTION: Hysteroscopy and staging laparotomy. MEASUREMENTS AND MAIN RESULTS: Mean age of the patients was 57.5 +/- 19.5 years (mean +/- 2SD). Four women (67%) were postmenopausal. Three patients had abnormal uterine bleeding, one had a cervical mass, and the other two were asymptomatic and referred for evaluation of thick endometrium detected by routine ultrasound, which had been preformed as part of their annual check-up. In all cases, the initial hysteroscopic diagnosis was endometrial polyp or submucous myoma. Following the pathologic review, all six women underwent complete staging laparotomy. In two women, there was no residual disease in the surgical specimen. None of the patients had extrauterine spread of the disease. At mean follow-up of 21.5 +/- 9.7 months (mean +/- 2SD), all women were asymptomatic. CONCLUSIONS: Intrauterine lesions erroneously considered to be benign endometrial polyps or myomas can turn out to be malignant mesenchymal uterine tumors. Hysteroscopic evaluation and biopsy might offer early diagnosis and treatment to these patients.     

Are cytosol estrogen and progestin receptors of prognostic significance in the management of epithelial ovarian cancers?

Cystosol estrogen and progestin receptor levels in tumor samples from 101 patients with previously untreated primary epithelial ovarian cancers were correlated with patient survival. Patients with stage I and II disease whose tumors contained elevated levels of cytosol progestin receptors had an improved survival over patients with tumors containing low levels of cytosol progestin receptors. However, patients with advanced ovarian cancers and low cytosol progestin receptors had significantly longer survival. The four-year estimated duration of survival with advanced disease and cytosol progestin receptors less than seven was 82%, whereas if the cytosol progestin receptors were seven or more, the four-year estimated duration of survival was only 10%. The explanation for this dichotomy is not evident at this time. In this study cytosol estrogen receptor levels were not associated with survival. These results suggest that measurement of cytosol progestin receptors is of prognostic value in advanced epithelial ovarian cancers.     

Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review

OBJECTIVE: We reviewed reported cases of grade 1 endometrial adenocarcinoma that were conservatively managed with hormonal therapy in an effort to identify the most effective treatment regimen. METHODS: We searched MEDLINE and other databases for English-language articles describing patients with grade 1 endometrial adenocarcinoma who were treated with hormonal therapy. The search included articles published between January 1966 and December 2003. The following key words were used: endometrial cancer, uterine cancer, adenocarcinoma, hormones, progesterone, medroxyprogesterone acetate, megestrol acetate, conservative therapy, fertility, and female. A total of 79 articles were found. Studies were excluded for the following reasons: advanced stage, metastatic or recurrent disease, progestin use after radiation, chemotherapy, or surgery, concurrent with radiation therapy or chemotherapy, administration of progestin other than orally or intramuscularly, tumor confined to a polyp, grade 2 or 3 disease, undocumented grade, nonendometrioid histology, progestin use in conjunction with ovarian wedge resection or other hormones, and hyperplasia. Our study ultimately included 81 patients in 27 articles. RESULTS: Sixty-two patients (76%) responded to treatment. The median time to response was 12 weeks (range, 4-60 weeks). Fifteen patients (24%) who initially responded to treatment recurred. The median time to recurrence was 19 months (range, 6-44 months). Ten (67%) of the patients with recurrence ultimately underwent total abdominal hysterectomy. Residual endometrial carcinoma was found in six patients (60%). Nineteen patients never responded. Twenty patients were able to become pregnant at least once after completing treatment. The median follow-up was 36 weeks (range, 0 weeks-30 years). No patients died of their disease. CONCLUSION: The majority of patients reported with well-differentiated endometrial adenocarcinoma who undergo conservative treatment with a progestational agent respond to treatment. When an initial response is not achieved or when disease recurs, carcinoma extending beyond the uterus is rare.     

Apoptosis may be an early event of progestin therapy for endometrial hyperplasia

OBJECTIVE: The aim of this study was to investigate the role of apoptosis during progestin therapy for the treatment of endometrial hyperplasia. METHODS: Pre- and posttreatment paraffin-embedded endometrial tissue samples from 19 women with endometrial hyperplasia were examined for changes in glandular cellularity and apoptotic activity related to the administration of progestins. Twelve patients were successfully treated with progestin therapy and 7 patients failed treatment. Glandular cellularity was assessed based on calculating the average number of cells per gland obtained on histologic examination of hematoxylin and eosin stained tissue sections. Apoptotic activity was assessed on the same tissue sections by counting the average number of apoptotic cells per 10 high power fields (hpf) using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. The effects of progesterone on apoptotic activity in a low-grade endometrial adenocarcinoma cell line (Ishikawa cells) was also examined using an ELISA cell death detection kit. RESULTS: Glandular cellularity significantly decreased with progestin therapy in both treatment outcome groups. The reduction in cells per gland was significantly greater in the group of successfully treated cases compared to the treatment failures (P = 0.005). However, within the successfully treated group, in situ detection of apoptotic cells using the TUNEL assay showed no statistical difference between pre- and posttreatment endometrial samples. Interestingly, a significant decrease in apoptosis was found in posttreatment samples of the group with persistent hyperplasia. The average number of apoptotic cells detected in 10 hpf was reduced from 7.9 prior to treatment to 3.1 after progestin therapy (P = 0.03). In the progesterone-treated Ishikawa cell line, an increase in apoptotic activity started at 24 h, reached a peak at 48 h, and continued up to 72 h of hormone treatment. At 48 h, apoptotic activity was 42.6% greater than in the untreated control (P = 0.04). By 72 h of progesterone treatment, apoptosis was 37.2% greater in the treated cells compared to the noninoculated cells (P = 0.04). CONCLUSIONS: Progestin-induced apoptosis may occur during the early period of treatment for endometrial hyperplasia. Compared to the fully responsive group, persistent endometrial hyperplasia may have intrinsically different molecular mechanisms in response to progestin therapy.     

Ovarian preservation in stage I low-grade endometrial stromal sarcomas

OBJECTIVE: To examine the impact of ovarian preservation in a case-control study of women with stage I low-grade endometrial stromal sarcomas. METHODS: Patients with low-grade endometrial stromal sarcomas were identified at 5 institutions from 1976 to 2002. Cases were defined as patients who retained ovarian function; each case was matched to 2 control patients who underwent bilateral salpingo-oophorectomy (BSO). Immunostaining for estrogen and progesterone receptors was performed. Data were examined with Student t, chi(2), Cox regression, and Kaplan-Meier analyses. RESULTS: Twelve premenopausal patients with low-grade endometrial stromal sarcomas who did not undergo BSO were matched to 24 controls. Of the 36 patients in the entire cohort, disease recurred in 14 (39%). Recurrences were identified in the pelvis, abdomen, lung, or lymphatics in both cases and controls. Disease recurred in 4/12 (33%) case patients, compared with 10/24 (42%) control patients (P = .63). When case patients were compared with controls, no differences in progression-free (91.3 months versus 68.6 months, P = .44) or overall survival (median survival not yet reached versus 406 months, P = .82) were identified. This study had 13% power to detect the observed difference in median disease-free survival. After controlling for use of adjuvant therapy and BSO, older age remained the only independent poor prognostic factor for progression-free survival (P = .008). Twenty-two available tumors demonstrated positivity for both estrogen and progesterone receptors. CONCLUSION: Bilateral salpingo-oophorectomy did not appear to affect time to recurrence or overall survival. Retention of ovarian function may be an option for premenopausal women with low-grade endometrial stromal sarcomas.     

Treatment of non-atypic endometrial hyperplasia using thermal balloon endometrial ablation therapy

BACKGROUND/AIM: Traditionally endometrial hyperplasias have been treated with progestins. Unfortunately, quite often hyperplasias are resistant to treatment, or they recur after therapy. The aim of the study was to compare traditional progestin administration with thermal balloon endometrial ablation in the treatment of non-atypic endometrial hyperplasia. METHODS: Women with endometrial hyperplasia (n = 34) were randomized in a 1:1 allocation ratio. Endometrial biopsy samples were taken 6 and 12 months after the treatment; if any signs of hyperplasia were detected, hysterectomy was performed. In addition, the hospital records were checked in September 2003 to observe for any later hysterectomy. Main outcome measures were recovery from hyperplasia and avoidance of hysterectomy. RESULTS: In patients treated with thermal ablation, the hyperplasias persisted at 6 or 12 months in 4 out of 17 patients, whereas the rate was 6 out of 17 patients in the progestin therapy group. According to patient records, 1 further patient treated with thermal ablation and 3 further patients treated with progestin were hysterectomized after the last visit. A total of 14 of the 34 patients (41%) have been hysterectomized so far. CONCLUSIONS: These preliminary results suggest that thermal balloon endometrial ablation therapy seems to be as effective as traditional progestin administration in the treatment of non-atypic endometrial hyperplasia. The hysterectomy rate during the follow-up period was, however, considerably high, and, therefore, hysterectomy might be considered even a first-choice treatment for endometrial hyperplasias.     

Ovarian cysts in postmenopausal tamoxifen-treated breast cancer patients with endometrial thickening detected by transvaginal sonography

OBJECTIVE: To investigate the frequency of ovarian cysts in tamoxifen-treated postmenopausal breast cancer patients with endometrial thickening detected by transvaginal sonography. METHODS: Medical records and transvaginal sonographies of 38 postmenopausal women treated for breast cancer with adjuvant tamoxifen therapy who had undergone endometrial sampling due to abnormal endometrial thickness were reviewed retrospectively. RESULTS: During the study period five of 38 tamoxifen-treated postmenopausal patients (13.2%) had ovarian cysts. The mean tamoxifen treatment interval of the patients with an ovarian cyst was 22.4 +/- 18.4 months (p = 0.17). The mean endometrial thickness of the patients with an ovarian cyst was 12.6 +/- 5.9 mm (p = 0.17). Endometrial biopsy detected six cases of abnormal endometria, including endometrial carcinoma (n = 1), endometrial polyp (n = 1) and simple endometrial hyperplasia without atypia (n = 4). Three patients with ovarian cysts underwent laparatomy revealing simple cysts on histopathological examination. Two patients with ovarian cysts declined laparatomy and are currently under follow-up. CONCLUSION: Ovarian cysts a common side-effect of tamoxifen treatment in postmenopausal tamoxifen-treated breast cancer patients. Transvaginal sonography should be performed to detect any concomitant endometrial pathology.     

Down-regulation of bcl-2 is a potential marker of the efficacy of progestin therapy in the treatment of endometrial hyperplasia

OBJECTIVE: The objective of this study was to evaluate the expression of bcl-2, a regulatory protein in programmed cell death, in endometrial hyperplasia before and after progestational therapy. METHODS: Pre- and posttreatment paraffin-embedded endometrial tissue samples from 20 women with an initial diagnosis of endometrial hyperplasia were obtained from archived files. Cases were evaluated and classified as either complete resolution of hyperplasia or persistent hyperplasia in response to progestin treatment. Sections were examined for bcl-2, estrogen receptor, and progesterone receptor expression using immunohistochemistry and compared within the treatment response groups. RESULTS: Among the 20 women studied, 13 had complete regression of their hyperplasia with progestin treatment and 7 had evidence of persistent disease after therapy. Bcl-2 expression was significantly decreased after treatment from a mean reactivity score of 2.08 to 0.31 (P = 0.0005) in the group of patients whose hyperplasia completely regressed with progestin administration. Among the women who had persistent hyperplasia after therapy, no significant change was observed between pre- and posttreatment bcl-2 expression, with a mean reactivity of 1.86 to 1. 29, respectively (P = 0.075). Progestational therapy significantly decreased the status of estrogen receptors from a mean score of 2.08 to 0.46 (P = 0.0005) in completely resolved cases of hyperplasia and from 2.00 to 0.43 (P = 0.0025) in persistent hyperplasias. Treatment also significantly decreased the status of progesterone receptors from a mean reactivity score of 1.92 to 0.31 (P = 0.0005) in cases of regressed hyperplasia and from a mean reactivity of 1.86 to 0.29 (P = 0.005) in persistent cases of hyperplasia. CONCLUSIONS: Bcl-2 expression decreases following successful progestin treatment of endometrial hyperplasias, whereas it remains expressed in hyperplasias which persist despite progestational therapy. This suggests that bcl-2 expression may represent a component of the therapeutic effects exerted in the endometium during progestational therapy in the treatment of hyperplasia. The activity of the oncoprotein may be a potential measure of the progress of treatment.     

Survival and prognostic factors in patients with synchronous ovarian and endometrial cancers and endometrial cancers metastatic to the ovaries

PURPOSE: To compare the survival and prognostic factors of patients with synchronous primary ovarian and endometrial cancers, and endometrial cancers metastatic to the ovaries. PATIENTS AND METHODS: Fifty-three patients with synchronous primary ovarian and endometrial cancer and 64 patients with endometrial cancer metastatic to the ovaries were evaluated. RESULTS: Mean follow-up time was 47.2 months (18-170 months). There was no statistical difference in age, gravidity and parity between the two groups. Abnormal vaginal bleeding was the most common symptom in both groups. All patients were subjected to a surgical staging procedure. Overall survival of the synchronous group was significantly higher than that of the metastatic group (98 +/- 12 vs 59 +/- 6 months; p = 0.048). The significant prognostic factors for synchronous cancers after multivariate analysis were age, stage of ovarian cancer, grade of endometrial cancer, and adjuvant therapy status. CONCLUSION: Patients with synchronous ovarian and endometrial cancers appear to have a good prognosis and should undergo primary surgical staging since the stage of tumors is a significant prognostic factor.     

高分化子宫内膜样癌及子宫内膜重度不典型增生患者孕激素治疗的临床分析

目的探讨35岁以下高分化子宫内膜样癌及子宫内膜重度不典型增生患者采用孕激素治疗以保留患者子宫的疗效,并随访其治疗后的生育情况.方法采用回顾性分析的方法对1991年至2005年北京协和医院收治的35岁以下、接受孕激素治疗（以醋酸甲羟孕酮为主）的25例高分化子宫内膜样癌及子宫内膜重度不典型增生患者的临床病理资料进行研究.其中,子宫内膜样癌8例（内膜癌组）,子宫内膜重度不典型增生17例（不典型增生组）.孕激素治疗前对患者进行全面的分期评估,治疗后每1～6个月诊刮以评价疗效,对有生育要求者随访其生育情况.结果内膜癌组患者孕激素治疗前经全面的分期评估,证实为早期、高分化子宫内膜样癌.除1例子宫内膜样癌患者尚未评估疗效外,内膜癌组其他7例及不典型增生组17例患者治疗后有效者分别为6例（6/7）、17例（100%）;缓解者分别为5例（5/7）、14例（82%）;缓解后复发者分别为1例（1/5）、3例（21%）,复发时间为缓解后6～30个月;随访缓解后要求生育的14例患者中,内膜癌组4例患者尚未生育,不典型增生组10例患者中4例妊娠共7次.1例自然受孕后失访;3例经促排卵治疗后受孕并足月分娩,其中1例产后人工流产3次.结论对于要求保留子宫的高分化子宫内膜样癌及子宫内膜重度不典型增生的年轻患者,孕激素治疗是一种治疗选择.孕激素治疗前应对子宫内膜样癌患者进行详细全面的分期评估,辅助生殖措施的介入有望提高治疗后的妊娠率.     

Molecular tools to reestablish progestin control of endometrial cancer cell proliferation

OBJECTIVE: Endometrial cancers often arise in a setting of estrogen stimulation unopposed by the differentiating effects of progesterone. Our laboratory and others have previously shown that progesterone receptor down-regulation or perturbation of progesterone receptor isoform A or B expression is associated with the development of poorly differentiated endometrial cancers that are not growth inhibited by progestins. The purpose of these studies was to reestablish high progesterone receptor isoform A and B gene expressions in such endometrial cancer cells and to examine the effects of progestin treatment on cell growth and metastatic potential after this transformation. STUDY DESIGN: To induce high levels of expression of the progesterone receptor isoforms in KLE and Hec50 endometrial cancer cells, adenoviral vectors encoding the genes for progesterone receptor isoforms A and B were created. The characteristic ability of cancer cells to grow independently of anchorage to the surrounding solid matrix was measured by counting colony formation on soft agar for 8 to 14 days. Cell proliferation in response to a time course of progestin treatment was tested with flow cytometry. RESULTS: After treatment with a control vector without a progesterone receptor--encoding insert, no effect of progestin treatment on cell proliferation was found; after treatment with vectors encoding progesterone receptor isoform A or B, however, progestin treatment resulted in significant inhibition of cell growth. The anchorage-independent cell growth on soft agar assay showed that by 8 to 14 days the number of cell colonies was reduced by 50% relative to control preparations in the presence of progesterone receptor isoform A plus progestin (P <.0001, both Hec50 and KLE cell lines) and by 90% in the presence of progesterone receptor isoform B plus progestin (P <.0001, both Hec50 and KLE cell lines). Progestin treatment also resulted in a time-dependent reduction in cell proliferation as measured by flow cytometry. Although transfection with both progesterone receptor isoforms A and B reduced cell proliferation according to our assays, progesterone receptor isoform B caused a much more dramatic decrease in cell growth (P =.001, Hec50 cells; P <.0001, KLE cells). CONCLUSION: In poorly differentiated endometrial cancer cells that are resistant to progestin therapy, adenovirus-induced expressions of progesterone receptors A and B reestablish progestin control of endometrial cancer cell proliferation.     

Endometrial carcinoma remaining after term pregnancy following conservative treatment with medroxyprogesterone acetate

BACKGROUND: Successful pregnancies after conservative progestin treatment to young women with endometrial carcinoma have recently been reported. However, it is not known for certain whether the lesion is completely eradicated in such patients. We present a case of residual endometrial carcinoma after term pregnancy which had been treated conservatively before the pregnancy began. CASE: A 28-year-old woman with endometrial carcinoma received conservative treatment with high-dose medroxyprogesterone acetate (MPA) and then conceived. After delivery at term, atypical cells were found in the endometrial curettage specimen. A hysterectomy was performed 6 months after delivery and revealed the presence of a small focus of intramucosal, grade 1, endometrioid-type adenocarcinoma. Immunohistochemically, the tumor cells were positive for estrogen and progesterone receptors. CONCLUSION: We concluded that while MPA treatment had been effective, it had not completely eradicated the carcinomatous lesion, which remained during and after the term pregnancy.     

Steroid receptors and clinical outcome in patients with adenocarcinoma of the endometrium

Progesterone receptor content was measured in tissue samples from 175 patients with endometrial adenocarcinoma by use of the dextran-charcoal method. The estradiol receptor content was determined in 138 of these samples. Ninety-two tumors (52.6%) tested positive for progesterone receptors (greater than 50 fmol/mg cytosol protein) and 111 (80.4%) tested positive for estradiol receptors (greater than 6 fmol/mg). Median follow-up was 27.3 months (range 1 to 152 months). Progesterone receptor status correlated significantly with grade, histology, adnexal spread, age, and recurrence rate in stage I cancer. There was no correlation between progesterone receptor status and clinical stage, myometrial invasion, peritoneal cytology, retroperitoneal lymph node involvement, or spread to the cervix. Estradiol receptor status correlated with adnexal spread and recurrence rate. Recurrence in patients with stage I disease was significantly more common if tumors were negative for progesterone receptor (16 of 43, 37.2%) than if they were positive (four of 57, 7%; p less than 0.001). Recurrence was also more common if tumors were negative for estradiol receptor (seven of 17, 41.2%) than if they were positive (eight of 63, 12.7%; p = 0.02). In recurrent or advanced disease, response to progestin was independent of estradiol receptor content, but tumors positive for progesterone receptors responded significantly more often than those lacking progesterone receptors. Overall survival was superior for patients with progesterone receptor-positive tumors (p = 0.001). Although survival in clinical stages I and II was also superior in patients with lesions positive for progesterone receptors (p = 0.13), there was no statistical difference in survival between patients with progesterone receptor-positive or -negative cancers and surgical stages I and II disease (p = 0.12). Estradiol receptor status had no apparent correlation with survival.     

Clinical and pathological responses of progestin therapy for non-atypical endometrial hyperplasia: a prospective study

AIMS: To evaluate the clinical and pathological responses and factors predicting non-responders to various progestins currently prescribed for the treatment of non-atypical endometrial hyperplasia. METHODS: A prospective observational study was conducted in the Gynecologic Endocrinology Unit, Faculty of Medicine, Siriraj Hospital, Thailand, from 1998 to 2003. A 6-month course of progestin therapy was offered to all patients. The clinical response was evaluated from the vaginal bleeding pattern during the first 4 months of treatment. The pathological response was evaluated from the histopathology of the endometrium after completion of the 6-month therapy. RESULTS: Of 250 registered patients, the number of cases qualified for the evaluation of the clinical and pathological response were 198 and 134 cases, respectively, revealing the overall clinical and pathological response rates of 93.4% and 92.5%, respectively. Among 13 clinical non-responders, 84.6% might have associated pelvic pathology. Among 10 pathological non-responders, three had surgical treatment, and progressive disease was found in one case. Significant factors predicting clinical non-responders included a history of prior bleeding (odds ratio [OR] = 8.79, 95% confidence interval [CI] = 1.63, 47.53), the presence of associated pelvic pathology (OR = 25.52, 95% CI = 3.21, 203.01), and treatment using progestins other than medroxyprogesterone acetate. Factors predicting pathological non-responders were not statistically significant. CONCLUSIONS: The current regimens of progestin therapy for non-atypical endometrial hyperplasia have high response rates. Patients who fail to have a clinical response should be evaluated for associated pelvic pathology. Follow-up endometrial biopsy should be offered to the patients, because 7.5% have persistent or progressive lesions, necessitating aggressive treatment.