Cancer and the use of estrogens

Although unopposed estrogen therapy, as well as persistent or increased endogenous estrogens, increases the risk for endometrial hyperplasia and cancer, added progestogen decreases the risk for adenocarcinoma of the endometrium to less than that observed in untreated women. The progestogen challenge test should be administered to all postmenopausal women with an intact uterus--including estrogen-treated postmenopausal women and those with sufficient endogenous estrogens to remain asymptomatic--and the progestogen continued for 13 days each month for as long as withdrawal bleeding results. Estrogen replacement therapy should not be withheld from postmenopausal women who are estrogen deficient, since there is no evidence that estrogens increase the risk for breast cancer. Progestogen added to estrogen replacement significantly reduces the risk for mammary malignancy; therefore, progestogens should be given, even to women who have had a hysterectomy, for 10 to 13 days each month whenever they are prescribed estrogen therapy.     

Endometrial patterns and endocrinologic characteristics of asymptomatic menopausal women

The endometrial histology and endocrinologic and demographic characteristics of 556 asymptomatic postmenopausal women ,who attended the menopause outpatient clinic at Ankara Numune Education and Research Hospital were studied before initiating estrogen replacement therapy. Of these women ,486 (87.4%) had atrophic endometrium ,37 (6.65%) had proliferative endometrium ,27 (4.86%) had endometrial hyperplasia without atypia ,three (0.54%) had endometrial hyperplasia with atypia and three (0.54%) had endometrial adenocarcinoma on their biopsy specimens. When demographic characteristics of the patients were considered, we found that the patients with endometrial adenocarcinoma and endometrial hyperplasia with atypia had potential risk factors for endometrial pathology such as chronic anovulation ,diabetes or hypertension. This study confirms that routine endometrial sampling in asymptomatic postmenopausal women is not warranted ,but patients with associated risk factors should be screened for endometrial pathology before starting estrogen replacement therapy.     

Endometrial patterns and endocrinologic characteristics of asymptomatic menopausal women.

The endometrial histology and endocrinologic and demographic characteristics of 556 asymptomatic postmenopausal women, who attended the menopause outpatient clinic at Ankara Numune Education and Research Hospital were studied before initiating estrogen replacement therapy. Of these women, 486 (87.4%) had atrophic endometrium, 37 (6.65%) had proliferative endometrium, 27 (4.86%) had endometrial hyperplasia without atypia, three (0.54%) had endometrial hyperplasia with atypia and three (0.54%) had endometrial adenocarcinoma on their biopsy specimens. When demographic characteristics of the patients were considered, we found that the patients with endometrial adenocarcinoma and endometrial hyperplasia with atypia had potential risk factors for endometrial pathology such as chronic anovulation, diabetes or hypertension. This study confirms that routine endometrial sampling in asymptomatic postmenopausal women is not warranted, but patients with associated risk factors should be screened for endometrial pathology before starting estrogen replacement therapy.     

The role of hormones in the etiology and prevention of endometrial cancer

Unopposed estrogens, both exogenous and endogenous, increase the risk of endometrial cancer although the magnitude of the association between estrogen replacement therapy and adenocarcinoma has been exaggerated by the epidemiologic case-control studies. Not all postmenopausal women need estrogen replacement therapy since some produce sufficient endogenous estrogens to remain asymptomatic and prevent atrophic vaginitis, osteoporosis and atherosclerosis. However, within this group may be those at risk for endometrial cancer, so they need to be identified and treated with cyclic progestogens. Sequential oral contraceptives did not protect young women from adenocarcinoma of the endometrium because of too little progestogen for too short a duration in view of the relatively high dosage of estrogen. However, combination birth control pills significantly decrease the risk for endometrial carcinoma. Endometrial hyperplasia is a precancerous lesion in some women and can be effectively reversed with 10-13 days of progestogen monthly in at least 98% of patients. The progestogen challenge test has been devised to identify postmenopausal women at greatest risk for adenocarcinoma. It should be administered to all postmenopausal women with an intact uterus. This includes asymptomatic women, patients receiving estrogen replacement therapy and women being evaluated for hormone therapy. If there is a positive response to the progestogen challenge, as manifested by withdrawal bleeding, then the progestogen should be continued for 13 days each month for as long as withdrawal bleeding results. If there is no response then the progestogen challenge test should be repeated at each annual examination. Universal use of the progestogen challenge test should prevent nearly all endometrial cancers.     

孕激素刺激试验对绝经后无症状妇女子宫内膜病变筛查的研究

目的 探讨孕激素刺激试验对绝经后无症状妇女子宫内膜病变筛查的意义。方法对106例无症状的绝经后妇女行孕激素刺激试验,口服安宫黄体酮10 mg/d,共10 d。无论孕激素刺激试验阳性或阴性,均给予分段诊刮术,以确定子宫内膜的生理或病理状态。结果11例妇女PCT为阳性,其中9例为异常子宫内膜。PCT用于检测子宫内膜疾病的敏感性、特异性分别为81.8％,97.9％。结论PCT是一种简单、安全、较可靠子宫内膜癌的筛查方法,易被绝经后无症状妇女接受。     

Combined use of progesterone challenge test and endometrium thickness evaluated by transvaginal ultrasonography in the preventive management of postmenopausal women.

Endometrial thickness was evaluated in apparently normal postmenopausal women by transvaginal ultrasonography and the results were compared with the response to the progesterone challenge test (PCT). A positive correlation between amount of withdrawal bleeding after PCT and endometrial thickness was found, also demonstrated by the significative correlation between bleeding length and endometrial thickness. Among women referring withdrawal bleeding, 100 and 22% of cases classified as overt flow and spotting, respectively, were characterized by pathologic histological findings. The combined use of these two procedures is suggested as an effective screening mean in the preventive endometrial management of apparently normal postmenopausal women to select candidates for diagnostic invasive procedures.     

Postmenopausal endometrial patterns and serum estradiol concentrations

Eighty postmenopausal women were subjected to endometrial biopsy. Inadequate biopsy was recorded in 30 cases. In the remaining cases (n = 50) the correlation between endometrial patterns and serum estradiol (E2) was performed. These cases were presenting with uterine bleeding (n = 38) or minor gynecological symptoms (n = 12). Proliferative endometrium was the predominant endometrial pattern whereas endometrial malignancy was only present in 15.8% of the bleeding cases. Serum E2 was significantly elevated in cases having malignant endometrium or adenomatous hyperplasia compared to cases having other endometrial patterns. Serum E2 measurement is recommended as a simple screening test for the detection of postmenopausal endometrial hyperplasia and/or malignancy.     

Endometrial histology and bleeding patterns after 8 years of continuous combined estrogen and progestogen therapy in postmenopausal women.

Continuous combined estrogen and progestogen preparations enable the postmenopausal woman to enjoy the benefits of estrogen replacement without the inconvenience of regular progestogen-induced withdrawal bleeding. The endometrium appears to be adequately protected in the short term, but no published data are available on the bleeding patterns or endometrial response after more than 18 months of therapy. Therefore, we reviewed 41 patients who continued on such preparations for up to 10 years (mean duration of use 8.0 years). Six women had experienced episodes of breakthrough bleeding after achieving amenorrhea, two of whom had benign endometrial polyps and two with adenocarcinoma of the endometrium. The remaining 35 women each had prolonged amenorrhea and were found to have an atrophic inactive endometrium. It is too early to comment on the long-term endometrial effects of these preparations because the numbers are too small; however, any breakthrough bleeding occurring after a period of prolonged amenorrhea must be investigated by means of endometrial biopsy.     

The role of vaginal scan in measurement of endometrial thickness in postmenopausal women

Summary. Transvaginal ultrasound scanning was performed on 111 postmenopausal women. Of these women, 103 had postmenopausal bleeding, and eight were undergoing hysterectomy. Of the 103 women with bleeding, 93 had dilatation and curettage (D&C) and 10 patients were treated conservatively with a repeat scan in six months. A correlation of ultrasound findings and endometrial histopathology was possible in 94 patients. In 59 of these (63%) the endometrium was atrophic and the ultrasound endometrial thickness was 5 mm or less. In 29 (31%) patients the endometrial histology was abnormal and ultrasound endometrial thickness was greater than 5 mm. In six patients the endometrium was atrophic, but the ultrasonic endometrial thickness was apparently greater than 5 mm due to intracavity fluid. We suggest that an endometrial thickness of 5 mm is an appropriate cut-off level for conservative management of patients with postmenopausal bleeding, or in screening for endometrial carcinoma.     

The role of vaginal scan in measurement of endometrial thickness in postmenopausal women

Transvaginal ultrasound scanning was performed on 111 postmenopausal women. Of these women, 103 had postmenopausal bleeding, and eight were undergoing hysterectomy. Of the 103 women with bleeding, 93 had dilatation and curettage (D&C) and 10 patients were treated conservatively with a repeat scan in six months. A correlation of ultrasound findings and endometrial histopathology was possible in 94 patients. In 59 of these (63%) the endometrium was atrophic and the ultrasound endometrial thickness was 5 mm or less. In 29 (31%) patients the endometrial histology was abnormal and ultrasound endometrial thickness was greater than 5 mm. In six patients the endometrium was atrophic, but the ultrasonic endometrial thickness was apparently greater than 5 mm due to intracavity fluid. We suggest that an endometrial thickness of 5 mm is an appropriate cut-off level for conservative management of patients with postmenopausal bleeding, or in screening for endometrial carcinoma.     

Estrogens, progestogens and endometrial cancer.

At the Wilford Hall U.S. Air Force Base Medical Center, Texas, about 4000 postmenopausal women received estrogen replacement therapy during 1975. Of these, 2700 took estrogens only and 1240 were given a progestogen along with estrogen. Hysterectomy had been done previously on 1700 patients (42%), leaving 2300 with intact uteri and a risk of endometrial cancer. Adenocarcinoma of the endometrium was diagnosed in 7 patients. Of these, 6 had received estrogen therapy. There was 1 endometrial malignancy in a patient also receiving a progestogen. Among 510 untreated postmenopausal women with intact uteri, 1 adenocarcinoma of the endometrium was found. Type and dosage of estrogen were unrelated to endometrial malignancy. In addition to the 7 endometrial cancers from the clinic, 22 cases were diagnosed elsewhere and referred for treatment, 11 of these had received no hormones. 10 were taking estrogens and 1 was receiving Oracon for birth control. The incidence of endometrial malignancy in the U.S. is reported to be 21/100,000 women/year. There is a 3-fold to 9-fold increased risk of endometrial cancer associated with obesity alone. The probability that untreated postmenopausal women with intact uteri will develop carcinoma of the endometrium is 1/1000/year. With estrogen users, it is reported to be increased -7.6/1000 women/year. In the author's clinic during 1975, the incidence among those receiving only estrogen was 4.7/1000. Among those also receiving a progestogen the incidence was .8/1000. Unopposed estrogens apparently have a role in the etiology of endometria hyperplasia and neoplasia through incomplete shedding of the endometrium. Progesterone produces more complete sloughing of the endometrium and also converts all degrees of hyperplasia into secretory endometrium. Nulliparity, infertility, and anovulation are predisoposing factors to endometrial carcinoma. Progestogens are palliative therapy for endometrial cancer.     

Progesterone challenge test and estrogen assays in menopausal women with endometrial adenomatous hyperplasia

In an attempt to detect asymptomatic endometrial adenomatous hyperplasia in postmenopausal women, 40 cases were subjected to progesterone challenge test (PCT), measurement of serum estrogen and endometrial curettage. Group A (n = 30) included asymptomatic postmenopausal women, while group B (control group; n = 10) were cases with adenomatous hyperplasia (AH) diagnosed by biopsy. PCT showed a 100% sensitivity, 92% specificity, 71.4% predictive value of a positive test and 100% predictive value of a negative test in the detection of AH. Mean serum concentrations of E1 and E2 were significantly higher in patients with AH compared to cases with other endometrial histologies. Serum E1 and E2 and PCT can be used as screening tests to identify postmenopausal women with endometrial AH and thus at a greater risk of developing carcinoma.     

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.     

Postablative risk of endometrial carcinoma in New Zealand white rabbits given high-dose estrogen

OBJECTIVE: To follow a population at high risk for endometrial carcinoma after endometrial ablation, to determine if ablation alters the incidence or detection of endometrial pathology. STUDY DESIGN: The animal model included 33 New Zealand white rabbits. Of this cohort, 17 underwent surgical ablation of the endometrium via laparotomy, while 16 served as controls. Vaginal bleeding was assessed with monthly cotton swab examinations as well as daily observation of the subjects. All animals received unopposed estrogen for 18 months prior to necropsy. RESULTS: No animal in either arm of the study demonstrated vaginal bleeding. Two rabbits from the ablation group and three controls showed histologic evidence of atypical endometrial hyperplasia or adenocarcinoma (P > .20). One additional animal from each group had hyperplasia without atypia. CONCLUSION: This animal model suggests that endometrial ablation does not decrease the risk of endometrial carcinoma in patients at high risk of developing endometrial pathology. Detection of hyperplasia or carcinoma in such a population may prove difficult due to the absence of traditional signs of endometrial abnormalities.     

Adipose tissue distribution in postmenopausal women with adenomatous hyperplasia of the endometrium

OBJECTIVE: To investigate body fat distribution in postmenopausal women with adenomatous and atypical hyperplasia of the endometrium. METHODS: A prospective population-based case control study was performed in a health care county in Sweden. General obesity, as reflected by body mass index (BMI), and adipose tissue distribution, expressed as waist to hip circumference ratio (WHR), were evaluated in a cohort of 367 postmenopausal women who underwent dilatation and curettage because of uterine bleeding. The study group consisted of 29 women with adenomatous or atypical hyperplasia of the endometrium. The controls consisted of 49 age-matched postmenopausal women randomly selected from the computerized population register of the same region. RESULTS: The frequency of endometrial adenomatous and atypical hyperplasia in postmenopausal women with bleeding was 7.2%. In the total population of postmenopausal women the incidence of these endometrial lesions was 44 per 100,000 per year. Body weight (P = 0.039), BMI (P = 0.007), and WHR (P = 0.022) were higher in postmenopausal women with endometrial adenomatous and atypical hyperplasia than in controls. In multivariate analysis only BMI remained statistically associated with adenomatous hyperplasia (P = 0.012). CONCLUSIONS: General obesity, but neither upper nor lower body fat distribution, was characteristic of postmenopausal women with adenomatous and atypical hyperplasia of the endometrium. Overall obesity is a risk factor for these endometrial precancerous lesions, as it is also claimed to be for endometrial cancer.     

Ultrasonographic evaluation of the endometrium in postmenopausal women to select the high risk group of endometrial carcinoma of the uterus

We examined the usefulness of ultrasonography (USG) for endometrial cancer screening in postmenopausal women. 207 postmenopausal women were ultrasonographically examined. The endometrial echo was classified into 4 types: 1, anechoic; 2, hair-line; 3, linear; and 4, navicular, and was compared with histological findings. No abnormal histological findings were observed in the cases showing type 1 and 2. On the other hand, abnormal histological findings including endometrial hyperplasia, atypical hyperplasia, and endometrial cancer, were seen in 57.7% (15/26) of type 3 cases, and 65.6% (21/32) of type 4 cases. Furthermore, type 3 and 4 women had enlargement of the uterus, and an increased incidence of postmenopausal bleeding. Positive rates in the progesterone challenge test (PCT) and karyopicnotic index (KPI) were higher in type 3 and 4 cases than in type 1 and 2. It was concluded that USG is able to accurately determine the endometrial condition and is useful for identifying high-risk patients in endometrial cancer screening.     

Can ultrasound replace dilation and curettage? A longitudinal evaluation of postmenopausal bleeding and transvaginal sonographic measurement of the endometrium as predictors of endometrial cancer

OBJECTIVE: The purpose of this study was to evaluate postmenopausal bleeding and transvaginal sonographic measurement of endometrial thickness as predictors of endometrial cancer and atypical hyperplasia in women whose cases were followed for > or =10 years after referral for postmenopausal bleeding. STUDY DESIGN: Women (n = 394) who had postmenopausal bleeding from November 1987 to October 1990 underwent transvaginal sonographic measurement of endometrial thickness and curettage. It was possible to assess the medical records (regarding recurrence of a postmenopausal bleeding, development of endometrial cancer, and death) in 339 of the 394 women (86%) > or =10 years after referral for postmenopausal bleeding. RESULTS: Thirty-nine of the 339 women (11.5%) had endometrial cancer, and 5 women (1.5%) had atypical hyperplasia. The relative risk of endometrial cancer in women who were referred for postmenopausal bleeding was 63.9 (95% CI, 46.0-88.8); the corresponding relative risk for endometrial cancer and atypical hyperplasia together was 72.1 (95% CI, 52.8-98.5) compared with women of the same age from the general population of the same region of Sweden. No woman with an endometrial thickness of < or =4 mm was diagnosed as having endometrial cancer. The relative risk of the development of endometrial cancer in women with an endometrial thickness of >4 mm was 44.5 (95% CI, 6.5-320.1) compared with women with an endometrial thickness of < or =4 mm. The reliability of endometrial thickness (cutoff value, < or =4 mm) as a diagnostic test for endometrial cancer was assessed: Sensitivity, 100%; specificity, 60%; positive predictive value, 25%; and negative predictive value, 100%. The incidence of endometrial cancer or atypical hyperplasia in women with an intact uterus whose cases had been followed for > or =10 years was 5.8% (15/257 women) compared with 22.7% (15/66 women) in women who had < or =1 episode of recurrent bleeding. No endometrial cancer was diagnosed in women with a recurrent postmenopausal bleeding who had an endometrial thickness of < or =4 mm at the initial scan. CONCLUSION: Postmenopausal bleeding incurs a 64-fold increase risk for endometrial cancer. There was no increased risk of endometrial cancer or atypia in women who did not have recurrent bleeding, whereas women with recurrent bleeding were a high-risk group. No endometrial cancer was missed when endometrial thickness measurement (cutoff value, < or =4 mm) was used, even if the women were followed up for < or =10 years. We conclude that transvaginal sonographic scanning is an excellent tool for the determination of whether further investigation with curettage or some form of endometrial biopsy is necessary     

绝经后子宫内膜出血的临床病理分析

目的：研究绝经后子宫出血的病因,诊刮子宫内膜的病检及意义。方法：我院85例绝经后子宫出血的患者行诊刮术后子宫内膜组织送病检,标本以中性甲醛液固定,常规行石蜡包埋,HE染色后光镜下划分病理类型,作出结果统计。结采恶性肿瘤8例,腺癌为主;良性病变42例,单纯性增生及子宫内膜炎为主;非器质性病变35例,萎缩性子宫内膜占多数。结论：患者一旦出现绝经后子宫出血,需及时诊刮作病理检查,特别是老年妇女并绝经时间长者,在常规妇检后,须对可疑者行分段刮宫取子宫内膜作病理诊断。     

Diagnostic fibrohysteroscopic evaluation of perimenopausal and postmenopausal uterine bleeding: A comparative study with Belgian and Japanese data

The most appropriate hysteroscope is the smallest that allows one to perform a biopsy. We use a 3.5- or 4.9-mm Olympus flexible hysteroscope with a failure rate below 3% for office or hospital ambulatory procedures without anesthesia or cervical dilatation. In postmenopausal women (with no hormone treatment) with uterine bleeding, we do not perform hysteroscopy if vaginal sonography detects endometrial thickness less than 4 mm. At this cut-off limit the calculated risk for not detecting an endometrial abnormality is 5.5%. In al other patients we prefer fibrohysteroscopy because its diagnostic accuracy is higher than that of vaginal ultrasound, vaginal ultrasound can easily miss a focal lesion of hyperplasia or adenocarcinoma incipiens, and abnormal endometrial findings detected by vaginal ultrasound or sonohysterography require directed biopsy during hysteroscopy. A comparative study evaluated the experience in our two series (286 patients), a Belgian report (251), and a Japanese report (444). Apart from myoma, 50% of findings were atrophic normal endometrium, and concordance was good for detecting adenocarcinoma (±3%). The results suggest using the fibrohysteroscope rather than the rigid scope because of its excellent accuracy.     

Endometrial thickness screening in premenopausal women with abnormal uterine bleeding

AIM: To assess the role of measuring endometrial thickness by transvaginal ultrasonography (TVS) as a screening tool for abnormal uterine bleeding triage in premenopausal women. METHODS: Between November 2002 and October 2004, endometrial thickness was measured by TVS in 111 premenopausal women with non-cyclic abnormal uterine bleeding before dilatation and curettage. RESULTS: Of the 111 women, 31 (27.9%) had an abnormal endometrium (hyperplasia 13.5%, polyps 5.4%, submucous myoma 5.4%, and adenocarcinoma 3.6%). An endometrial thickness of 8 mm showed optimal sensitivity and specificity (83.9% and 58.8%, respectively) and 90.4% negative predictive value (NPV) for an abnormal endometrium. When submucous myoma was excluded, the sensitivity, specificity, and NPV were 80%, 53.8%, and 89.6%, respectively. CONCLUSION: Endometrial thickness of 8 mm or less is less likely to be associated with malignant pathologies in premenopausal uterine bleeding.