Ultrasonic evaluation of endometrial changes induced by cyclic sequential hormone substitution therapy

BACKGROUND: At present the hormonal replacement therapy on postmenopausal women with uterus needs the use of progestins additionally to estrogens, to eliminate the risk of endometrial hyperplasia and carcinoma connected with the use of estrogens alone. The check of the endometrium during these therapies can be made by transvaginal ultrasound that permits the evaluation of the thickness, structure, and contour of the endometrial rima. The aim of this study was to establish the changes of endometrial thickness during cyclic sequential hormonal replacement therapy on healthy postmenopausal women with transvaginal ultrasound. METHODS: The endometrial thickness with transvaginal ultrasound has been evaluated during the cyclic sequential hormonal replacement therapy on 20 healthy women in physiological menopause before the treatment, during the phase of treatment with estrogens alone and during the phase of treatment with the addition of the progestins. RESULTS: Significant differences during the estrogenic phase compared to before treatment have been underlined (5.7 mm vs 3.5 mm p = 0.002), but not during progestinic phase compared to estrogenic (6 mm vs 5.7 mm p = 0.712). CONCLUSIONS: Transvaginal ultrasound is a useful investigation to evaluate the modifications of the thickness and structure of the endometrium during hormonal replacement therapy and can help early diagnosis of endometrial diseases during these treatments.     

Ultrasound, hysteroscopy and endometrial biopsy in the investigation of endometrial cancer

Over the course of the last two decades hysteroscopy with endometrial biopsy has begun to replace dilation and curettage as the method of choice for the diagnosis of endometrial carcinoma. In the majority of women this can be performed as an outpatient procedure with no loss in diagnostic accuracy. Transvaginal ultrasound measurement of endometrial thickness provides a highly sensitive and less invasive alternative means of assessing the endometrium but has a low positive predictive value for cancer, especially in women taking hormone replacement therapy. The cut-off value used to define normality needs to take into account patient age and ethnic origin. Ultrasound screening may not be suitable for women taking tamoxifen and those with recurrent or late-onset abnormal uterine bleeding.     

Uterine effects of raloxifene in comparison with continuous-combined hormone replacement therapy in postmenopausal women

OBJECTIVE: We sought to compare the uterine effects of raloxifene with those of continuous-combined hormone replacement therapy. STUDY DESIGN: This randomized, double-blind 24-month study involved 136 postmenopausal women who received raloxifene 150 mg/d or conjugated equine estrogens 0.625 mg/d with medroxyprogesterone acetate 2.5 mg/d. After baseline evaluations, endometrial biopsy specimens were obtained, and endometrial thickness was measured annually by means of transvaginal ultrasonography. Statistical analyses were performed with an intention-to-treat approach. RESULTS: In the raloxifene group at the end point of the study 94.4% of biopsy specimens showed normal benign postmenopausal endometrium and 5.6% were classified as benign stimulatory endometrium. In the continuous-combined hormone replacement therapy group at the end point of the study 78.7% of biopsy specimens showed normal benign postmenopausal endometrium, 19. 1% were classified as benign stimulatory endometrium, and 2.1% showed benign abnormal postmenopausal endometrium. Mean endometrial thickness was unchanged from baseline with raloxifene and was increased significantly by 0.5 mm at 12 months with continuous-combined hormone replacement therapy. CONCLUSION: Raloxifene 150 mg/d did not increase endometrial thickness or cause endometrial proliferation in healthy postmenopausal women.     

Sonographic, hysteroscopic, and histologic evaluation of the endometrium in postmenopausal women with breast cancer receiving tamoxifen

STUDY OBJECTIVE: To evaluate the estrogenic effects of tamoxifen on the endometrium in postmenopausal women with breast cancer. DESIGN: Consecutive study (Canadian Task Force classification II-2). SETTING: University-affiliated hospital. PATIENTS: Thirty-three women. Interventions. All patients underwent transvaginal sonography (TVS) and color flow Doppler of endometrial vessels, hysteroscopy, and, if necessary, endometrial biopsy or other operative hysteroscopic procedures. MEASUREMENTS AND MAIN RESULTS: In four women the endometrium was thin on TVS and atrophic at hysteroscopic assessment. In 29 women with thick endometrium on TVS, hysteroscopy and endometrial biopsy showed atrophy (11 patients), hyperplasia (5), polyps (11), and well-differentiated adenocarcinoma (2). The two endometrial cancers were present in women with uterine bleeding. In women with positive histologic findings, the endometrium was significantly thicker (p = 0.04) and duration of tamoxifen therapy longer than in those with negative findings, although this was not statistically significant (p = 0.067). CONCLUSION: We believe regular assessment of the endometrium by TVS should be performed in postmenopausal patients at the start of the tamoxifen therapy, and hysteroscopy in women with a thick endometrium or postmenopausal bleeding. We believe that patients with thin endometrium on TVS at the beginning of tamoxifen therapy, who have no abnormal uterine bleeding should be screened with these examinations for 2 years.     

Effects of trimonthly progestin administration on the endometrium in elderly postmenopausal women who receive hormone replacement therapy: a pilot study

OBJECTIVE: The purpose of this study was to determine the effect of trimonthly progestin administration on the endometrium in elderly postmenopausal women who receive hormone replacement therapy. STUDY DESIGN: This was a prospective, randomized, double-blind, placebo-controlled study at a university teaching program. Twenty-five postmenopausal women who were >or=75 years old with an intact uterus were assigned randomly to receive conjugated equine estrogens (0.625 mg/d plus medroxyprogesterone acetate 5 mg/d for 13 days every 3 months (n = 13) or placebo (n = 12) for 9 months). At the end of the 9 months, patients in the hormone replacement therapy arm continued therapy for an additional 9 months. Statistical analysis was performed with the Student t test, the chi(2) test, and the Fisher exact test. RESULTS: Transvaginal sonography was performed at baseline and at 9 and 18 months. Endometrial biopsy was performed if the endometrial thickness was >4 mm or as clinically indicated at 18 months. Patients in the hormone replacement therapy group demonstrated a significant increase in endometrial thickness between baseline (3.9 + 0.8 mm) and 9 months (8.0 + 4.8 mm). There were no cases of endometrial hyperplasia at the 18-month endometrial biopsy. CONCLUSION: Trimonthly progestin administration in elderly postmenopausal women who receive hormone replacement therapy may be a reasonable alternative to the monthly administration of progestin in hormone replacement therapy.     

Continuous Low-Dose Combined Hormone Replacement Therapy and the Risk of Endometrial Cancer

Hormone replacement therapy (HRT) provides relief of menopausal symptoms, reverses atrophic urogenital changes, prevents osteoporosis, and produces favorable lipoprotein effects. Continuous combined HRT using 2.5 mg of medroxyprogesterone was designed to increase patient compliance by eliminating withdrawal bleeding while at the same time retaining the beneficial effects of HRT. There are limited long-term data, however, regarding the safety of continuous combined HRT. Of concern are reports of endometrial carcinoma arising in women receiving continuous HRT with low-dose progestin. Eight cases of women who developed endometrial carcinoma while on this regimen are presented. The possible increased risk of endometrial cancer associated with this regimen may be related to inadequate progestin dose, prior use of unopposed estrogen, poor patient compliance, use of less effective progestins, less efficient reversal of hyperplasia, and the use of progestin continuously.     

Effects of subdermal implants of estradiol and testosterone on the endometrium of postmenopausal women.

A retrospective review of the medical records of 258 postmenopausal patients using estradiol and testosterone implants as combined hormone therapy was carried out to evaluate the effects of testosterone on the endometrium after two years of continuous use. Endometrial thickness was measured by ultrasonography. Histology was performed on samples of thickened endometria obtained during hysteroscopy with biopsy. In the 44 patients in whom endometrial thickening was >5 mm at the end of the second year of implant use, the most frequent finding at hysteroscopy was polypoid lesion in 61.3% of cases, followed by normal uterine cavity in 31.8% of cases and submucous myoma in 6.8%. Histology of the endometrial samples confirmed endometrial polyp in 38.6% of cases, a histologically normal endometrium in 31.8% of cases, simple endometrial hyperplasia in 20.4% of cases, and myoma and atrophic endometrium in 4.5%. It is possible that testosterone may exert its antiproliferative effects on the endometrium but not on polyps in an action similar to that exerted by combined estrogen/progestin therapies. A greater incidence of simple, low-grade endometrial hyperplasia was found in our study compared with studies using continuous estrogen/progestin regimens. The use of progestins as the ideal endometrial protection should therefore be reconsidered.     

Effects of subdermal implants of estradiol and testosterone on the endometrium of postmenopausal women

A retrospective review of the medical records of 258 postmenopausal patients using estradiol and testosterone implants as combined hormone therapy was carried out to evaluate the effects of testosterone on the endometrium after two years of continuous use. Endometrial thickness was measured by ultrasonography. Histology was performed on samples of thickened endometria obtained during hysteroscopy with biopsy. In the 44 patients in whom endometrial thickening was >5 mm at the end of the second year of implant use, the most frequent finding at hysteroscopy was polypoid lesion in 61.3% of cases, followed by normal uterine cavity in 31.8% of cases and submucous myoma in 6.8%. Histology of the endometrial samples confirmed endometrial polyp in 38.6% of cases, a histologically normal endometrium in 31.8% of cases, simple endometrial hyperplasia in 20.4% of cases, and myoma and atrophic endometrium in 4.5%. It is possible that testosterone may exert its antiproliferative effects on the endometrium but not on polyps in an action similar to that exerted by combined estrogen/progestin therapies. A greater incidence of simple, low-grade endometrial hyperplasia was found in our study compared with studies using continuous estrogen/progestin regimens. The use of progestins as the ideal endometrial protection should therefore be reconsidered.     

Transvaginal ultrasonographic assessment of the endometrium in asymptomatic, postmenopausal women using different HRT regimens containing tibolone or estrogen

OBJECTIVE: To assess the effects of hormone replacement therapy (HRT) on endometrial thickness as measured by transvaginal ultrasonography in asymptomatic, postmenopausal women. STUDY DESIGN: Between 1997 and 2001, 307 women who had no risk factors for endometrial cancer or abnormal vaginal bleeding were enrolled in a study. Patients received 1 of the following HRT modalities: (1) oral equine HRT modalities: (1) oral equine estrogen, (2) oral 17beta-estrogen, (3) transdermal 17beta-estrogen, or (4) oral tibolone. All women taking estrogens were also taking a progestin. Only the patients with endometrial thickness >7 mm underwent endometrial biopsy while taking HRT. RESULTS: Although we observed an increase in serum estrogen levels as compared to the levels before tibolone therapy, changes in endometrial thickness were not statistically significant in patients taking tibolone. CONCLUSION: Endometrial thickness with tibolone closely mimics the naturally atrophic postmenopausal state. Thus, tibolone is suggested for those postmenopausal women who have concerns about HRT.     

Transvaginal endometrial sonography in postmenopausal women taking tamoxifen

OBJECTIVE: To evaluate sonographic measurements of endometrial thickness in postmenopausal women taking adjuvant tamoxifen therapy for breast cancer, and to correlate sonographic and pathologic findings to symptoms and duration of tamoxifen therapy. METHODS: Medical records and sonograms of 80 postmenopausal women treated for breast cancer with adjuvant tamoxifen therapy were reviewed retrospectively. Endometrial thickness was recorded as a single-layer thickness and considered abnormal when greater than 2.5 mm for postmenopausal women. Sonographic endometrial thickness was correlated to histologic findings, symptoms, and duration of tamoxifen therapy. RESULTS: Fifty-seven of 80 postmenopausal women (69%) had single-layer endometrial thicknesses of 2.5 mm or greater, measured by transvaginal sonography, and 55 of 57 had endometrial biopsies or dilatations and curettage. Biopsies detected 24 cases of abnormal endometria, including endometrial carcinoma (two), breast carcinoma metastatic to the endometrium (one), endometrial polyps (13), tubal metaplasia (three), and benign endometrial hyperplasia (five). Using a single-layer endometrial thickness greater than 2.5 mm by transvaginal ultrasound, 21 of 24 (87.5%) women with abnormal endometria were detected. Women with abnormal pathologic findings had a significantly thicker mean single-layer endometrial thickness than those with normal findings, 7 mm versus 4 mm (P < .01). Twelve women had postmenopausal bleeding, all of whom had a single-layer endometrial thickness greater than 2.5 mm on transvaginal sonography. CONCLUSION: With a sensitivity of detecting endometrial abnormalities of 84%, transvaginal sonography was useful for studying postmenopausal tamoxifen-treated women.     

Saline sonohysterography for monitoring asymptomatic postmenopausal breast cancer patients taking tamoxifen.

OBJECTIVES: To evaluate the effectiveness of sonohysterography for monitoring asymptomatic postmenopausal breast cancer patients on long-term tamoxifen therapy. METHODS: Thirty-eight asymptomatic postmenopausal patients receiving tamoxifen for breast cancer were enrolled into the study. The endometrium of study subjects was measured by transvaginal ultrasound. If a distinct echo measured < or = 5 mm, no further procedure was performed. For thickened or inadequately visualized endometrium by transvaginal ultrasound (TVS), sonohysterography was performed. Endometrial biopsies were performed for patients with generalized symmetrical changes on sonohysterography. In cases with focal changes, or inadequate SHG, hysteroscopy/dilatation and curettage (D&C) were performed. RESULTS: Transvaginal ultrasound examination showed 12 (31.6%) patients with thin endometrium < or = 5 mm, 18 (47.4%) cases with thickened endometrium while eight (21%) cases were not adequately visualized by TVS. Sonohysterography was satisfactorily performed in 22 of 26 (84.6%) cases. Of these, three cases showed thin endometrium, 10 patients had endometrial polyps (45.5%) and nine patients showed abnormal endometrial-myometrial junction. Histology revealed hyperplasia in three cases and well differentiated adenocarcinoma associated with one polyp. Endometrial curettage for cases with abnormal endometrial-myometrial junction showed endometrial hyperplasia in two cases. Hysteroscopy and D&C were performed for four (15.4%) patients where SHG was unsuccessful, histopathology revealed inactive endometrium in three cases and one was hyperplastic. CONCLUSIONS: Sonohysterography is superior to unenhanced transvaginal sonography in specifying the abnormal ultrasonographic appearance induced by prolonged tamoxifen therapy, it is easily performed, cost-effective and very well tolerated by the patients with no complications. Sonohysterography is recommended as a minimally invasive diagnostic tool for the assessment of endometrial changes in asymptomatic postmenopausal breast cancer patients on long-term tamoxifen therapy with thickened endometrium or inadequately visualized endometrial echo on transvaginal sonography.     

Compliance considerations with estrogen replacement: Withdrawal bleeding and other factors

Withdrawal bleeding and other side effects such as edema, bloating, premenstrual irritability, lower abdominal cramps, dysmenorrhea, and breast tenderness limit compliance with hormonal replacement therapy. Although many of these troublesome side effects can be managed by adjusting the dose or changing the source of the estrogen or progestin components, postmenopausal women view withdrawal bleeding as the most negative factor influencing their decision to use hormonal replacement therapy. Additionally, the potential link between postmenopausal estrogen use and subsequent endometrial hyperplasia and cancer concerns potential users. Cyclic progestins protect the endometrium from hyperplastic changes but may not prevent withdrawal bleeding. Both patient and physician education, including the nature of menopause and the protective role of estrogens in osteoporosis and cardiovascular disease, are critical to improving compliance with hormonal replacement therapy.     

The role of hormones for the treatment of endometrial hyperplasia and endometrial cancer

PURPOSE OF REVIEW: Hormone therapy has been palliative for advanced/ recurrent endometrial cancer. High remission rates are seen in well-selected stage I, grade 1 endometrial cancer of young women using hormone therapy (usually progestins) as fertility-preserving treatment. Many other hormones, such as gonadotropin-releasing hormone analogs (GnRHa), selective estrogen receptor modulators, aromatase inhibitors, intrauterine progestins, and others are potential modalities. This review updates the recent publications in this area. RECENT FINDINGS: Two reports investigating different scheduling of tamoxifen and progestins indicated that tamoxifen may be a valuable adjunct to progestin therapy. GnRHa has been used adjunctively to tamoxifen as second-line hormone therapy for fertility sparing after progestin failed. Aromatase inhibitors have shown their potential in treating endometrial cancer and endometrial hyperplasia as single agent or in combination with progestins. Intrauterine progestins seem efficacious in treating endometrial hyperplasia; its applications on endometrial cancer patients, however, have been limited to postmenopausal women with poor surgical risk. SUMMARY: Translational research based on molecular mechanisms is mandatory to a more appropriate utilization of hormone therapy. The role of dose, scheduling, route of administration of progestins as well as the addition of other hormonal agents should be further explored by well designed randomized controlled trials.     

Endometrial ablation versus hysterectomy in women treated with tamoxifen

AIM: The aim of our study is the assessment of the importance of the endometrial ablation versus hysterectomy in patients treated with tamoxifen for previous breast cancer. METHODS: Fifty-eight outpatients in therapy with tamoxifen for 1 year were controlled in the Department of Gynaecology of the University of Naples. We have selected these patients in two groups: group A, with 28 women with abnormal uterine bleeding and endometrial thickness >8 mm and group B, with 30 normal endometrium asymptomatic women. All patient of group A and 18 of group B were treated with endometrial ablation. RESULTS: Next follow-up showed normal hysteroscopy figures in 89% of cases and 5% of cases needed a hysterectomy for new abnormal uterine bleeding and cytology. CONCLUSION: Our results show the utility of endometrial ablation especially in selected cases in therapy with tamoxifen for previous breast cancer.     

绝经后子宫内膜增厚的阴道超声诊断进展

随着我国女性健康意识的提高,绝经后子宫内膜增厚越来越受到重视。子宫内膜癌是女性生殖器官常见恶性肿瘤之一,在绝经后妇女中常表现为子宫内膜增厚和绝经后阴道出血。经阴道超声测量绝经后妇女的子宫内膜厚度是常用的子宫内膜癌早期筛查手段。在医学上,对于无阴道出血症状的绝经期女性,子宫内膜厚度与子宫内膜癌相关性尚不明确。无症状绝经期子宫内膜增厚的患者要根据是否存在高危因素个体化评估患子宫内膜癌的风险。适当的诊断不仅对子宫内膜病变的早发现早治疗有重要意义,也可避免造成绝经女性的过度恐慌和减少不必要的有创诊疗,在临床中有现实意义。综述绝经后子宫内膜增厚疾病的特点以及经阴道超声检查的评估价值。     

Endometrial effects of etonogestrel (Implanon) contraceptive implant

The subdermal contraceptive implant etonogestrel (Implanon; NV Organon International, Oss, The Netherlands) exerts complex effects on the endometrium. These include direct effects on the endometrium through endometrial progestin target sites, and indirect effects through suppression of the hypothalamic-pituitary-ovarian axis. The resulting effects are categorized by alterations in endometrial histology, endometrial thickness, dysmenorrhoea and menstrual bleeding pattern. The exact mechanism of action of progestins on the endometrium has not been determined. The contraceptive effect in Implanon users is mainly due to inhibition of ovulation. Current research is concentrating on the potential of the progestin implant to modify endometrial vascular, angiogenic, steroid receptor and proto-oncogene function. These processes may be involved in the causation of progestin-induced breakthrough bleeding.     

The role of transvaginal colour Doppler sonography in evaluation of abnormal uterine bleeding

Introduction Treatment of abnormal uterine bleeding understands a prompt diagnostic procedure, for the sake of defining the etiological factor of disease. The abnormal uterine bleeding is more common in the perimenopausal than in the postmenopausal women, and it is more frequent sign of an endometrial proliferative or hyperplastic changes. Fewer percentages of women with unexpected and/or acyclic and prolonged bleeding have endometrial cancer.Materials and methods Seventy-one (71) patients with abnormal uterine bleeding, older than 40 years, of which 10 were in post-menopause, have been tested. Prior to explorative curettage and histopathological analysis, ultrasonographic and hemodynamic studies, at the uterine blood vessels level (uterine artery bilaterally) had been performed by transvaginal colour Doppler method.Results Histopathological results indicated four types of represented changes, on the basis of how the patients were divided into the groups: I, proliferative endometrium—20 patients; II, endometrial adenocarcinoma—23 patients; III, various forms of endometrial hyperplasia—26 patients, IV, atrophic endometrium—2 patients. Significant statistical difference in the endometrial thickness was established between groups I and II, and endometrial cancer was not found in less than 8 mm thick endometrium. By analysing hemodynamic parameters, significantly lower PI values were obtained in the group of patients with pathologically altered endometrium, compared to other groups.Conclusion Transvaginal colour Doppler has significant role in the diagnostic process for evaluation of abnormal uterine bleeding in perimenopausal and postmenopausal women. Doppler sonography can help in differentiating physiological from malignant endometrial changes and in deciding on the most efficient therapeutical regime.     

Evaluation of endometrium during tamoxifen therapy of breast cancer

Tamoxifen is one of most common drugs for breast cancer therapy. But its weak estrogenic activity in endometrium can be the source of different abnormalities including even endometrial cancer. OBJECTIVES: The aim of this clinical trial was to compare ultrasound scan results, hysteroscopy and pathomorphological findings of tamoxifen treated patients with breast cancer who complained of bleeding. MATERIALS AND METHODS: Analyzed group consisted of 10 patients treated for abnormal endometrium during breast cancer tamoxifen therapy. RESULTS: Among 10 examined women 7 presented no pathological changes, there was 1 case of simple benign hypertrophy and 2 cases of endometrial polyps. CONCLUSIONS: There is no exact correlation between ultrasound scan results and pathomorphological findings in patients treated with tamoxifen for of breast cancer. Transvaginal ultrasound examination is not efficient screening test for endometrial abnormalities during tamoxifen therapy.     

A case of early detection of uterine cancer in a program of genital screening of postmenopausal patients by transvaginal ultrasonic scanning]

Transvaginal ultrasound scanning was performed on 59 years old women with postmenopausal bleeding in anamnesis. Endometrial thickness was measured at its maximum in both longitudinal and transverse sections of the uterus. Also the thickness of uterus walls and ovaries in 3 planes were measured. Endometrium was irregular of 14 mm thickness. The patient had dilatation and curettage. Histology showed: adenocarcinoma I degree, and endometrial polyp. After hysterectomy the sonographic evaluation was compared with postoperative histologic measurements. Vaginal sonography is a good method of screening for uterine neoplasms in presymptomatic women. In postmenopausal patients who are not receiving hormonal replacement an endometrium of greater than 5 mm should be considered abnormal and undergo curettage and histological examination.     

Hormone replacement therapy and bleeding disorders.

Bleeding disorders encountered during administration of hormone replacement therapy (HRT) are reviewed. The incidence of bleeding disorders is dependent on the phase of HRT and the age of the patient. In the diagnosis of these bleedings transvaginal sonography and minihysteroscopy are very important methods. Endometrial thickness can be monitored exactly by transvaginal sonography. Outpatient minihysteroscopy without anesthesia results in higher compliance to HRT after the procedure. In hormonal treatment of bleeding disorders during HRT, the sonographically supported progestogen test is very useful and can reduce endometrium thickness. Operative treatments include myoma and polyp resection as well as endometrial ablation. By these methods a high rate of bleeding-free HRT can be reached. The problem of endometrial cancer during HRT is discussed on the basis of new literature and critical statements. The review shows the importance of individual diagnostic and treatment schedules for bleeding disorders during HRT.