Peripheral aromatization as a risk factor for breast and endometrial cancer in postmenopausal women: a review

In menopause, estrogens are produced almost exclusively through peripheral aromatization of androgens, especially androstenedione. Obesity increases the production rate of estrogens by means of the same mechanism. In postmenopause, plasma levels of SHBG diminish significantly. Obesity even further decreases the levels of SHBG, thus increasing "free" E2 available to target tissues. The increase in circulating estrogenic activity in menopause, whether as a result of obesity or of ingestion of estrogens, implies a risk factor for endometrial and breast cancer not only because of the permissive and stimulating effects of estrogens but also due to the special circumstance that they may act on target tissues in the almost absolute absence of the "protecting effect" of progesterone. The modifications performed by obesity on the values of SHBG and circulating estrogens are reversible, since they tend to normalize with weight loss.     

植物性雌激素对子宫内膜及异位子宫内膜的影响

植物性雌激素(phytoestrogens,PEs)是一类结构及生物学活性类似于雌激素的天然非甾体类化合物,可与雌激素受体结合,对内源性雌激素起双向调节作用。研究表明,植物雌激素可以缓解妇女围绝经期相关症状,且不会引起子宫内膜的复杂型增生及癌变;植物雌激素还能降低子宫内膜癌的发病风险,具有一定抗癌作用;此外,植物雌激素通过其弱的雌激素活性,既能抑制体内异位病灶的生长又能避免发生骨质疏松等副作用,将会给子宫内膜异位症(EMs)患者带来福音。     

Exogenous estrogen and endometrial carcinoma: case-control and incidence study.

Recent independent case-control studies have indicated that treatment with exogenous estrogen is associated with an increase in the risk of endometrial cancer. This question was studied in Olmsted County, Minnesota, by identifying all cases of endometrial cancer among residents over a 30 year period (1945 through 1974) and by matching four controls to each of the 145 patients. The rate of past exposure to any exogenous estrogen for any duration was about the same for patients as for controls. However, the estimated relative risk of endometrial cancer associated with conjugated estrogen treatment of 6 months or longer was 4.9 (P less than 0.01), and this increased to 7.9 (P less than 0.01) with exposure for 3 years or longer. The risk increased with larger doses (1.25 mg. or more) and continuous administration of conjugated estrogens. The incidence of endometrial carcinoma over the three decades of the study, corrected for an increasing rate of hysterectomy, was constant. Thus to this time, the low rate of use of conjugated estrogens in this region over the past 30 years apparently has not had an appreciable impact on the incidence of endometrial cancer.     

Clinical studies concerning the relationship of estrogens to the development of cancer of the corpus uteri

A total of 105 cases of endometrial carcinoma are studied with regard to (1) age at the onset of the menopause; (2) preceding periods of metrorrhagia; (3) presence or absence of menopausal complaints; (4) marital status and fertility; (5) histological picture of the possibly apparently normal part of the endometrium; (6) intensity and duration of estrogen therapy possibly given.The present studies show that in these cancer patients the menopause commences later and is more often preceded by periodic metrorrhagia, and less frequently accompanied by hot flushes, indicating that these patients have often been under the influence of endogenous estrogens through longer periods than the average woman. The women in this series suffering from cancer of the corpus uteri have often given a history of treatment with estrogens in a larger amount and for a longer duration than was recorded for the controls. Thus 16 of the cancer patients had had continuous treatment with estrogens for from 2 to 15 years (average 6.5 years, Table III).The difficulty in making the histological diagnosis in such cases is pointed out; and it is emphasized that in dubious cases it is essential to keep the patient under observation for a few months without administration of any estrogen before a conclusive biopsy can be performed. During this interval, in some instances a cancerlike hyperplasia of the endometrium will disappear.The conclusion is drawn that a continuous estrogenic stimulation (endogenous or exogenous) constitutes an important factor in the etiology of endometrial cancer.Precautions concerning estrogen therapy in the menopause are emphasized.     

Genetic and hormonal effects on sexual differentiation. Paradoxically women require androgens and men estrogens

It had been established that the sexual structure of a person was determined by the type of hormonal production, what gave biological specificity of the estrogens to women and androgens to men, but recently this functional specificity has lost base due to the biological activity described in different tissues of men and women, today known as endocrine paradox. There are hormonal events that show the need of estrogens to correct development in men and androgens to women. In men the absence of effect of the estrogens produces deficient ossification of skeleton, persistence of the growth cartilage and osteoporosis in adult men. In women the production of androgens by suprarenal glandules is required to obtain the complete feminization. In women with chirurgic-induced menopause, the relation between androgens and the stimulation of sexual response has been established. It has been described a hormone called kisspeptin, that it is attributed the potential to initiate the puberty because stimulates the hypothalamus; in absence of this hormone the women do not present their secondary sex characters, remaining immature sexually. The understanding of individuals needs of androgens and estrogens contribute to improve the control and care of the patient with hormonal deficiencies in any phase of the life.     

Cyclooxygenase-2 expression in endometrial polyps during menopause.

OBJECTIVE: To determine whether cyclooxygenase-2 (COX-2) is expressed in endometrial polyps during menopause and how previous hormone use may affect this expression. PATIENTS AND METHODS: Fifty-two postmenopausal patients with endometrial polyps were enrolled for this study. Eighteen patients had no history of previous hormone use, while the remaining patients had used vaginal conjugated estrogens for short periods of time (n = 25) or were long-term users of tibolone (n = 5) or tamoxifen (n = 4). The endometrial polyps were removed by hysteroscopy, and COX-2 and Ki-67 expression were measured in tissue samples by immunohistochemistry. RESULTS: Endometrial polyps expressed COX-2 in the glandular epithelium and this expression was not significantly greater in patients who had previously used tibolone, tamoxifen or vaginal estrogens. However, Ki-67 expression was greater in the group using vaginal estrogens compared with the group of non-users; while in the other two treatment groups Ki-67 expression was less than in hormone never-users. CONCLUSION: COX-2 expression is present in endometrial polyps during menopause and may play a role in their growth regulation.     

Is aromatase cytochrome P450 involved in the pathogenesis of endometrioid endometrial cancer?

Prospectively, the relationship between androgen levels in the utero-ovarian circulation, aromatase activity in endometrial and body fat tissue, and the presence or absence of endometrioid endometrial cancer was studied in postmenopausal women. In 43 women with endometrioid endometrial cancer and 8 women with a benign gynecological condition, a hysterectomy with bilateral salpingo-oophorectomy was performed. Using tritium water-release assays, aromatase activities in endometrial and body fat tissue were determined and related to the steroid levels from the peripheral and the utero-ovarian venous circulation (estradiol, androstenedione, testosterone) and to the presence or absence of endometrial cancer. Significant aromatase activity was found in both benign and malignant endometrial tissue samples. Aromatase activity in samples of endometrial tissue and in samples of body fat did not correlate with steroid levels in peripheral or utero-ovarian venous blood. Aromatase activity in samples of benign or malignant endometrium did not differ. Remarkably, in four women with mainly poorly differentiated endometrial cancer, very high aromatase activity was found in endometrial tissue. It is likely that multiple pathogenetic pathways exist that eventually lead to the formation of endometrioid endometrial cancer. The local availability of androgens and the finding that aromatase activity is present in both endometrial cancer and benign endometrial tissue support the hypothesis that aromatase activity in the endometrium may play a role in malignant transformation by converting androgens into mitogenic estrogens in the endometrial tissue.     

Intracrinology and dehydroepiandrosterone--a new perspective for the use of androgens in hormone replacement therapy in postmenopausal women

During menopausal transition not only ovarian production of estrogens but also marked decrease of adrenal androgen production are observed Decreased secretion of adrenal DHEA and DHEA-S result in reduction of peripheral conversion of these steroids into active estrogens and androgens. Intracrinology describes the biosynthesis of active steroids in peripheral target tissues in which the action of theses steroids takes place, without release into the extracellular space or general circulation. DHEA administration to postmenopausal women significantly increases bone mineral density decreases insulin resistance and amount of fat tissue and exerts an estrogenic effect on vaginal cytology in the absence of endometrial stimulation. Moreover animal experiments proved that DHEA suppresses the growth of breast cancer which is yet another reason to consider this steroid as a part of hormone replacement therapy in women.     

Long-term outcome of hysteroscopic endometrial resection with or without myomectomy in patients with menorrhagia

Objectives  To evaluate the long-term outcomes and hysterectomy rates after hysteroscopic endometrial resection with or without myomectomy for menorrhagia. Study design  Fifty-three women who had submucous myomas with intramural extension of less than 50% and smaller than 5 cm in diameter underwent endometrial resection and concomitant hysteroscopic myomectomy. Each of them was matched with a patient who had no submucous myomas and who had been treated by endometrial resection only. These two groups were compared for operative outcomes, additional procedures, outcome of menstrual bleeding and for subsequent hysterectomy, which was the endpoint of this study. Results  During the mean follow-up period of 6.5 years, 18 (34.6%) women with endometrial resection and myomectomy and 21 (39.6%) without myomectomy underwent at least one gynecological procedure. Hysterectomy was performed in 26.9% [95% confidence interval (CI) 16.8–40.3] of the patients with myomectomy and in 17.0% (95% CI 9.2–29.2) of the patients without myomectomy (P = 0.22). The main indications for hysterectomy were pain and spotting bleeding in seven out of 14 cases with myomectomy and in four out of nine with endometrial resection only. Leiomyomas were found in 12 out of the 14 women who had hysterectomy after hysteroscopic myomectomy and in four out of nine with hysterectomy after endometrial resection only (P = 0.06). Most (75.6%) of the 82 women who had not required hysterectomy had reached menopause. All the patients without hysterectomy in both groups reported amenorrhea or slight bleeding, and this response maintained for years after the treatment. Conclusion  Endometrial resection may be combined with hysteroscopic myomectomy without a significant increase or decrease in hysterectomy rates during a long-term follow-up.     

Sexualsteroide und ihre onkogene Potenz

The extent of exposure to endogenous and exogenous estrogens is clearly associated with the risk of breast, endometrial, and ovarian cancers. There is also evidence for an association between exposure to androgens and progestagens and breast cancer risk. Estrogens are mitogens and potent tumor promoters. In the breast, the combination with progestagens increases this mitogenic effect. In addition, genotoxic estrogen metabolites can induce DNA damage and thus initiate tumors. Androgens act primarily through their aromatization to estrogens. The blockade of estrogen action through receptor antagonists, aromatase inhibitors, or medical or surgical castration has become a potent strategy both in the therapy and prevention of estrogen-dependent breast cancer.     

Hormonodependence and hormonosensibility of the gynecological neoplasias. III. The breast carcinoma

The pathogenesis of breast cancer is Extensive tests isolate 3 distinct factors: genetic, hormonal and viral. Thus, the risk factor is increased 2-3 times by hereditary predisposition whereas (bilateral) ovariectomy, blocking production of ovarian hormones, reduces the risk by 10 times. Childbirth reduces the risk in reverse proportion to its frequency; however, less protection is afforded if not accompanied by lactation. Nulliparity was recognized as a risk factor in 1926, but recent studies have proven less conclusive. Also included as risk factors are the intake of fatty nutrients and obesity. Further indications include older age at 1st pregnancy, menstrual disorders, and a prolonged reproductive life as a result of precocious menarche and/or delayed menopause. The longer menopause is delayed, the greater the premenopausal period characterized by hyperestrinization, anovulation, and a modest production of progesterone. Metabolism of estrogens oriented towards more active metabolites compounds the risk factors. It has been impossible to verify an etiologic connection between estrogenic preparations administered during post-menopause and breast cancer. Oral contraceptives, in general, do not seem to pose any risk. A connection between prolactin and cancer has been demonstrated in rodents, but not in humans. Antiprolactin pharmaceuticals are capable of inducing regression of neoplasia, indicating a plausible, however unproven, active role of prolactin. Progesterone acting as an antiestrogen reduces the levels of cytoplasmic receptors, thus probably acting protectively. Basically, two approaches are possible for endocrine treatment of metastasized breast carcinoma: ablative surgery based on hormone deprivation (ovariectomy, suprarenalectomy, hypophysectomy) or additive therapy based on hormonal interference (estrogens, androgens, progestins, antiestrogens).     

绝经后阴道出血414例临床与病理分析

探讨绝经后阴道出血的年龄,绝经年限和病理类型的关系。方法分析４１４例经经后阴道出血并行诊断性刮宫及子宫切除患者的临床和病理资料。结果绝经后阴道出血的主要病理诊断分别是功能性子宫内膜,恶性肿瘤和功能失调性内膜。结论年老,绝经年限愈全的妇女、恶性肿瘤发生率愈高。     

Androgens and ovarian cancers

Ovarian cancer is one of the most lethal malignancies in women. Numerous studies indicate that the steroid hormones have been implicated in the etiology and/or progression of epithelial ovarian cancer and support a role for androgens, including: 1) androgen receptor (AR) is present in primate ovaries at almost all stages of the menstrual cycle and involve folliculogenesis and ovulation; 2) high androgen serum levels show high risk of ovarian cancer and ovarian cancer occurring after menopause when the balance of ovarian steroid production shifts from estrogens to androgens; 3) ovarian cancer tissue shows a 90% AR positive rate and is associated with favorable outcomes; 4) androgens promote or inhibit ovarian cancer cell growth; 5) chemotherapy decreases androgen production from cancer cells. This review seeks to summarize our current understanding about the roles of androgens, AR and AR coregulators in the initiation and/or progression of ovarian cancers.     

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.     

Xenobiotics influence on estrogen activity

Many chemical compounds which imitate estrogens effect are present in the environment. There are natural substances (phytoestrogens), as well as synthetic (xenoestrogens, metaloestrogens) ones. A lot of xenobiotics are inductors or inhibitors of enzymes, also those enzymes which take part in estrogens metabolism. However, little is still known about the influence of xenobiotics on estrogens activity, there can be no question of the importance of the problem. One of them are the diminished effects of endogenous estrogens in women smokers, also weakness or lack of oral hormonal replacement therapy (HRT) effect among women smokers, as well as the influence of estrogens on dioxins toxicity. The issue of estrogen compounds presence in cosmetics deserves special attention. It is essential for us to remember, that estrogens are compounds with high biological activity. Thus, hormonal balance disturbance can have serious health consequences, including tumors. In this research we have attempted to present a review of studies which concern exogenous factors influence on estrogens activity and have summarized current state of knowledge.     

Detection of benign intracavitary lesions in postmenopausal women with abnormal uterine bleeding: a prospective comparative study on outpatient hysteroscopy and blind biopsy

STUDY OBJECTIVE: To evaluate the specificity of blind biopsy in detecting benign intracavitary lesions as causes of postmenopausal bleeding in comparison with directed biopsy via hysteroscopy. DESIGN: Prospective trial without randomization (Canadian Task Force classification II-1). SETTING: University hospital. PATIENTS: Three hundred nineteen postmenopausal women with abnormal uterine bleeding. INTERVENTIONS: All patients underwent both blind biopsy (Novak's curette) and directed biopsy via hysteroscopy (after at least a week). All patients with benign intracavitary lesions underwent operative hysteroscopy to enable the removal of polyps and intracavitary myomas or endometrial resection if required. All patients with pathologic reports of complex hyperplasia and atypical hyperplasia (20 patients) underwent vaginal hysterectomy with bilateral adnexectomy. All patients with histology reports of endometrial carcinoma (15 patients) underwent abdominal hysterectomy, bilateral adnexectomy, and pelvic lymphadenectomy. Histopathologic findings from endometrial specimens obtained after operative hysteroscopy or uterine specimens obtained after hysterectomy were used as a reference test to establish the prevalence of disease. MEASUREMENTS AND MAIN RESULTS: The sensitivity, specificity, accuracy, and positive and negative predictive values of blind biopsy and hysteroscopy were assessed to distinguish benign intracavitary formations such as polyps, submucous myomas, and endometrial hyperplasia in postmenopausal patients with abnormal uterine bleeding. The level of agreement was evaluated by use of the coefficient of concordance kappa. Blind biopsy showed a sensitivity of 11% and a specificity of 93%, with an accuracy of 59% in detecting endometrial polyps, a sensitivity and specificity of 13% and 100%, respectively, with an accuracy of 98% for submucous myomas, and values of 25%, 92%, and 80%, respectively, in diagnosing hyperplasia. On the other hand, hysteroscopy demonstrated a sensitivity of 100% and a specificity of 97%, with an accuracy of 91% in diagnosing endometrial polyps, a sensitivity and specificity of 100% and 98%, respectively, with an accuracy of 99% for submucous myomas. The coefficient of concordance kappa (95% CI) was 0.12 for blind biopsy and 0.82 for hysteroscopy, corresponding, respectively, to slight concordance and almost perfect agreement with final pathologic diagnosis. CONCLUSIONS: Blind biopsy (Novak's curette) demonstrates very low sensitivity and accuracy in the diagnosis of benign focal intracavitary lesions. Hysteroscopy is confirmed as the gold standard in the assessment of abnormal uterine bleeding in menopause, permitting the elimination of the false-negative results of blind biopsy through direct visualization of the uterine cavity and the performance of targeted biopsy in case of doubt.     

Aspiration curettage for asymptomatic patients receiving estrogen

Recent epidemiologic data suggest that patients treated with exogenous estrogens have an increased risk of developing endometrial carcinoma and support the concept that patients taking estrogens must be monitored with special vigor. The hypothesis that endometrial aspiration curettage might be an appropriate modality to accomplish adequate surveillance was tested from January 1, 1976, to January 1, 1977, on a group of 208 consecutive patients undergoing hormonal replacement therapy. Although no patient in the test group experienced abnormal or unusual bleeding, focal adenomatous hyperplasia or a more severe lesion was found in 16.0% of the specimens. Among these were 4 cases of endometrial adenocarcinoma and 2 of atypical adenomatous hyperplasia. This study demonstrated that routine endometrial aspiration curettage of patients receiving exogenous hormone replacement therapy can not only help diagnose very early lesions which are amenable to definitive and completely corrective treatment, but also can uncover significant endometrial pathology before it becomes symptomatic. It further suggests the possibility that the incidence of such pathology among this category of patients might be higher than previously suspected.     

The value of curettage in diagnosis of endometrial hyperplasia.

OBJECTIVES: The aim of this study was to assess the value of diagnosis of endometrial hyperplasia by curettage and to determine the results of proliferating cell nuclear antigen (PCNA) immunostaining in differentiating endometrial carcinoma from endometrial hyperplasia. METHODS: According to Kurman's criteria, we treated 150 patients with endometrial hyperplasia detected by curettage and compared retrospectively the diagnosis by curettage with that by hysterectomy. PCNA expression was examined using immunohistochemostaining on 60 patients with complex atypical hyperplasia detected by curettage. RESULTS: Simple hyperplasia was found by curettage in 53 patients, complex hyperplasia in 11, simple atypical hyperplasia in 26, and complex atypical hyperplasia in 60. All patients were rediagnosed after hysterectomy. As a result, 65 were found to have simple hyperplasia, 7 complex hyperplasia, 15 simple atypical hyperplasia, 29 complex atypical hyperplasia, and 34 endometrial carcinoma. The accuracy of histological diagnosis by curettage was 76.7-92.0% and was dependent on different types of hyperplasia. Simple atypical hyperplasia and complex atypical hyperplasia were more likely to coexist with endometrial carcinoma than both simple hyperplasia and complex hyperplasia (chi2 = 26.3, P < 0.001), and complex atypical hyperplasia was more likely to coexist with endometrial carcinoma than simple atypical hyperplasia (chi2 = 9.78, P < 0.005). In complex atypical hyperplasia patients, coexistence with endometrial carcinoma was more common after menopause than before menopause (chi2 = 3.93, P < 0.05). In complex atypical hyperplasia patients, the expression of PCNA in cases associated with endometrial carcinoma was higher or stronger than in cases associated without endometrial carcinoma (chi2 = 7.68, P < 0.01, or U = 252.00, P < 0.01). Conclusions. Curettage tends to be more highly accurate in diagnosing simple hyperplasia than complex atypical hyperplasia, which is often found by hysterectomy to be associated with endometrial carcinoma. The expression of PCNA may be helpful in differentiating complex atypical hyperplasia from endometrial carcinoma.     

The effect of insulin on aromatase activity in isolated human endometrial glands and stroma

Hyperinsulinemic states have been associated with an increased incidence of estrogen-dependent endometrial neoplasia. To study the effect of insulin on the ability of endometrium to aromatize androgens to estrogens, late proliferative endometrium was obtained from normally cycling women at the time of indicated surgery, separated into component glands and stroma, and grown to confluence. Separated gland and stromal cultures were incubated in triplicate with increasing insulin concentrations and epidermal growth factor. Aromatase activity was assayed by the production of tritiated water from tritium-labeled androstenedione. The activity was noted to increase proportionally with increasing concentrations of insulin greater than 10 U/ml, and the effect was specific. These data suggest the following conclusions: (1) Insulin stimulates aromatase activity in both endometrial glands and stroma; (2) hyperinsulinemia may predispose to endometrial neoplasia by enhancing endogenous endometrial estrogen production.     

778例绝经后阴道出血患者的临床病理分析

目的：探讨绝经后阴道出血的临床特点及病理类型。方法：回顾性分析自2008年1月1日—2013年12月31日于中国医科大学附属盛京医院妇科病房收治的778例绝经后阴道出血患者,每例均行盆腔超声、宫腔镜检查及手术,且取得病理及确切诊断。结果：778例患者中,子宫内膜息肉所占比例最高49.23%（383例）,其次是子宫内膜癌16.71%（130例）,第三位是黏膜下肌瘤11.44%（89例）;绝经后阴道出血在绝经5年内发病例数最多（311例）,其中以子宫内膜息肉为主（175例）,绝经≥21年发病例数最少（78例）,其中以子宫内膜癌为主（44例）;＜49岁阴道出血例数最少（7例）,55～59岁阴道出血例数最多（228例）,两者均以子宫内膜息肉为主,≥75岁出血的71例中以子宫内膜癌为主（38例）;子宫内膜良恶性病变患者在子宫内膜厚度、体质量指数（BMI）及是否反复出血方面差异有统计学意义（均P＜0.01）,子宫内膜恶性病变患者与良性病变患者相比其子宫内膜更厚、BMI更高且更易发生反复出血。结论：引起绝经后阴道出血的主要病因为子宫良性病变;随着绝经时间的增加,子宫内膜息肉、子宫内膜增生及黏膜下肌瘤的发生率整体呈下降趋势,子宫内膜炎及子宫内膜癌的发生率整体呈上升趋势;随着绝经后发生阴道出血年龄的增加,子宫内膜息肉、子宫内膜增生及黏膜下肌瘤的发生率整体呈下降趋势,子宫内膜炎及子宫内膜癌的发生率整体呈上升趋势。