Influence of Phytoestrogen on Endometrium and Ectopic Endometrial Focus

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.     

SERMs对子宫内膜的影响

很多年以来人们关注雌激素受体及作用于这些受体的化合物,并简单得把这些化合物划分雌激素受体激动剂和雌激素受体拮抗剂。然而近年来的报道以及临床资料显示了这类化合物在不同组织会显示出不同的作用,因此把此类化合物称为选择性雌激素受体调节剂(SERMs)应该更准确。对SERMs的这种认识使我们希望找到一种化合物能在骨、心脏和中枢系统保持雌激素样作用,同时对那些雌激素可能致瘤的器官如子宫内膜、乳腺产生雌激素拮抗作用。这种化合物至今还没有发现。目前SERMs主要是三苯乙烯(triphemylethylene)家族,代表物为他莫昔芬;苯并噻吩(benzothiophenes)家族,代表物为拉乐西芬,以及一些新合成的化合物。作为传统的SERMs类化合物他莫昔芬对子宫内膜的作用一直是一个有争议的问题。大量数据都表明它对子宫内膜具有活性作用。有限的关于拉乐西芬的资料表明它对子宫内膜的作用是中性的。这里我们把SERMs主要两个家族的代表物他莫昔芬和拉乐西芬对子宫内膜的影响综述如下。     

芳香化酶与子宫内膜异位症

子宫内膜异位症(EMs)是雌激素依赖性疾病。芳香化酶是雌激素合成过程中的关键酶,而雌激素有利于EMs形成和生长。芳香化酶表达受许多因素调控,前列腺素E2(PGE2)能明显诱导芳香化酶活性和异位灶中雌激素生成。正常子宫内膜无芳香化酶表达,因而不产生雌激素,而EMs患者异位子宫内膜表达高水平芳香化酶,不表达17β-羟类固醇脱氢酶-II,结果导致大量雌激素生成,而雌激素灭活减少,在局部造成高水平雌激素微环境,是EMs发生的重要机制。     

芳香化酶与子宫内膜异位症

子宫内膜异位症(EMs)是雌激素依赖性疾病.芳香化酶是雌激素合成过程中的关键酶,而雌激素有利于EMs形成和生长.芳香化酶表达受许多因素调控,前列腺素E2(PGE2)能明显诱导芳香化酶活性和异位灶中雌激素生成.正常子宫内膜无芳香化酶表达,因而不产生雌激素,而EMs患者异位子宫内膜表达高水平芳香化酶,不表达17β-羟类固醇脱氢酶-Ⅱ,结果导致大量雌激素生成,而雌激素灭活减少,在局部造成高水平雌激素微环境,是EMs发生的重要机制.     

β-catenin在子宫内膜异位症患者在位内膜中的表达

目的:探讨β-catenin在子宫内膜异位症(EMs)患者在位内膜的增殖与凋亡活性的关联,及其在EMs发病中的作用。方法:共收集68例EMs患者在位内膜组织(EMs组)和70例非EMs患者子宫内膜(对照组),采用免疫组织化学技术分析子宫内膜组织β-catenin的表达情况。TUNEL检测分析子宫内膜组织的凋亡活性,Ki67免疫组织化学染色分析子宫内膜组织的增殖活性。结果:与对照组比,EMs患者在位内膜Ki67表达明显增强,TUNEL阳性细胞明显减少(P<0.05)。在位内膜腺上皮及间质β-catenin表达明显高于对照组(P<0.05)。β-catenin在胞质及胞核的表达明显高于对照组(P<0.05)。直线相关分析结果显示无论是正常内膜还是EMs患者在位内膜,β-catenin的表达与Ki67表达均呈正相关,与TUNEL结果均呈负相关。结论:EMs患者在位内膜β-catenin的异常高表达可能通过上调内膜组织的增殖活性,下调其凋亡性而参与EMs的发病。     

芳香化酶与子宫内膜异位症

子宫内膜异位症(endometriosis,EMs)是指具有活性的子宫内膜组织在子宫腔被覆内膜及肌层以外的部位生长,是引起盆腔疼痛和不孕的常见因素,也是育龄妇女的常见病,发病率为10%～15%。EMs具有侵袭性强、种植广泛、易复发等特点。近年来的研究均认为EMs是一种雌激素     

子宫内膜异位症不孕患者子宫内膜整合素av、β3表达的初步探讨

目的:探讨子宫内膜异位症是否影响子宫内膜容受性而造成不孕。方法:前瞻性研究我院2004年1月到2005年6月经手术病理确诊的子宫内膜异位症不孕患者胚胎种植窗期血清孕激素、雌激素浓度,组织学分期和子宫内膜整合素av、β3的表达,并与同期已育妇女的指标作比较。结果:15例子宫内膜异位症不孕患者中Ⅰ期和Ⅱ期共8例(研究1组),Ⅲ期和Ⅳ期共7例(研究2组),与16例对照组比较,血清孕激素和雌激素浓度差异无统计学意义。病理组织学确诊的黄体功能不足差异无统计学意义。子宫内膜整合素β3的表达差异无统计学意义,子宫内膜整合素av的表达差异有统计学意义(P<0.05),且仅Ⅲ期和Ⅳ期子宫内膜异位症子宫内膜整合素av的表达差异有统计学意义(P<0.01)。结论:初步证实Ⅲ~Ⅳ期子宫内膜异位症不孕患者子宫内膜容受性标记物-子宫内膜整合素av的表达下降,与其导致不孕和流产相关,值得进一步进行大样本的研究。     

子宫内膜异位症裸鼠模型子宫内膜的雌、孕激素受体表达

目的:建立子宫内膜异位症裸鼠模型,观察子宫内膜的雌激素受体(ERs)、孕激素受体(PRs)及其亚型的表达情况,为进一步探讨内异症子宫内膜孕激素抵抗的发生机制提供研究模型。方法:建立子宫内膜异位症裸鼠模型,分别于造模后1月、2月、3月取裸鼠子宫内膜,利用RT-qPCR和Western blot法检测其孕激素受体(PRA、PRB)和雌激素受体(ERα、ERβ)表达情况。结果:与对照组相比,内异症组裸鼠内膜的PRB和ERα表达降低,在造模后3月最明显;PR和ERβ表达升高,PRB/PRA和ERα/ERβ比值降低,均在造模后3月最明显。结论:子宫内膜异位症裸鼠模型是研究内异症的理想模型之一,造模后的裸鼠内膜存在孕激素抵抗。     

子宫内膜息肉在子宫内膜异位症中的高发率

探讨子宫内膜息肉在子宫内膜异位症(EMs)妇女中的发病率。183例不孕症妇女中92例腹腔镜证实EMs(实验组,平均年龄30.6±3.9岁),无EMs 91例(对照组,平均年龄30.8±4.6岁)。腹腔镜和宫腔镜诊断:EMs和子宫内膜病变,病理确诊子宫内膜息肉。 结果:子宫内膜息肉在EMs妇女中发病率很高。EMs患者     

子宫内膜异位症在位和异位内膜的MMPS活性分析

目的 分析子宫内膜异位症(EM)患者在位及异位子宫内膜中活化型基质蛋白酶-2、-9(MMP-2、MMP-9)、非活化型基质蛋白酶12、19(proMMPl2、proMMP-9)的酶谱及在EM发病机制中的作用。方法 2000年3月至2002年9月采用酶谱法检测16例手术治疗EM患者的异位内膜和在位内膜，16例同期住院的月经正常的良性卵巢肿瘤或子宫肌瘤的子宫内膜中的pmMMP-2、MMP-2、proMMP-9、MMP-9。结果 EM同一个体的异位内膜proMMP-2、proMMP-9活性高于在位内膜；在位内膜的proMMP-9活性无论何期明显高于对照组正常的子宫内膜；proMMP-2活性在增生期在位内膜较对照组正常内膜有上升趋势。而MMP-2及MMP-9均未见规律性趋势。结论 同一个体的异位内膜的proMMP-2、pmMMP-9活性较在位内膜增高，提示异位内膜更具侵蚀性。同为在位内膜，EM的proMMp-9活性较正常对照为高，可能与EM的发病有关。而proMMP-2活性仅在增生期表现在位内膜较对照组正常为高，可能提示增生期内膜更具侵蚀性。     

Endometriosis during postmenopausal period--probable causes for its origin and development

A very rare--casuistic--case of endometriosis is presented, which appeared ten years after surgical menopause (hysterectomy and ovariectomy) without concomitant use of hormone replacement therapy or phytoestrogens. The possibilities of endogenous production and exogenous supply of estrogens in the female organism are discussed as well as the possible causes of proliferation of endometrial lesions during postmenopausal period. When menopause is induced by surgery (a stress for the organism) without exogenous supply of estrogens (HRT, phytoestrogens, xenoestrogens) the production of suprarenal hormones, including androgens, increases. The peripheral conversion of androgens into estrogens in fat tissue is increased and implanted during hysterectomy endometrial lesions in vagina walls are stimulated.     

Phytoestrogens and reproductive biology

Phytoestrogens are naturally occurring plant substances that can either mimic or antagonize the action of endogenous estrogens. This is because of the similarity of the functional structure of phytoestrogens and endogenous estrogens. In premenopausal women, phytoestrogen intake might induce a decrease in luteinizing hormone, follicle-stimulating hormone and estradiol (E₂), which are associated with a longer follicular phase. The circulating transport protein, sex hormone-binding globulin, is increased, resulting in less cellular availability of E₂. Phytoestrogens inhibit the activities of E₂ synthetic enzymes through adenylate cyclase and tyrosine kinase cascades. This might decrease of risk of hormone dependent cancers. A phytoestrogen-rich diet might reproduce normal body composition, affecting the course of polycystic ovary syndrome (PCOS). Some herbs used in traditional Japanese medicine contain phytoestrogens that influence endogenous hormone levels to directly regulate the pituitary-ovarian system, in particular, the chemotactic effects on ovaries. (Reprod Med Biol 2005; 4 : 225 –229)     

Adverse effects of phytoestrogens on reproductive health: a report of three cases

BACKGROUND: Phytoestrogens have been thought to have favorable effects on women's health and perhaps in offsetting cancers. The possible adverse effects of phytoestrogens have not been evaluated. CASES: Abnormal uterine bleeding with endometrial pathology in three women was found to be related to a high intake of soy products. The first woman had postmenopausal bleeding with uterine polyp, proliferative endometrium and a growing leiomyoma. The second woman presented with severe dysmenorrhea, abnormal uterine bleeding, endometriosis and uterine leiomyoma not responding to treatment. The third woman with severe dysmenorrhea, abnormal uterine bleeding, endometriosis and uterine leiomyomata presented with secondary infertility. All three women improved after withdrawal of soy from their diet. CONCLUSION: Additional information on phytoestrogens is necessary to ascertain their safety before they can be routinely used as supplements.     

Effects of phytoestrogens genistein and daidzein on production of human chorionic gonadotropin in term trophoblast cells in vitro.

BACKGROUND: Phytoestrogens are a diverse group of non-steroidal compounds that occur naturally in many plants. Because they possess a ring system similar to estrogens they are able to bind to estrogen receptors in humans. In the present study we tested the effects of the phytoestrogens genistein and daidzein on the production of human chorionic gondaotropin (hCG) in isolated trophoblast cells of term placentas in vitro. METHODS: Genistein and daidzein were incubated at different concentrations with trophoblast cells. Untreated cells were used as controls. At designated times aliquots were removed and tested for hCG production. RESULTS: Production of the protein hormone hCG was influenced by the phytoestrogens genistein and daidzein in trophoblast cells. We found a significant decrease of hCG production in genistein- and daidzein-treated trophoblast cells that was concentration-dependent. Compared with daidzein, genistein seems to be a more efficient inhibitor of the production of hCG. CONCLUSION: The phytoestrogens genistein and daidzein can reduce hCG production in human term trophoblasts. Both phytoestrogens belong to the group of isoflavones, which are enriched in soy-containing foods and are widely consumed by humans for putative beneficial health effects. Because both phytoestrogens have inhibitory effects on hCG production during pregnancy, exposure to these estrogen-like compounds during sensitive periods of development may have the capacity to alter the function of the reproductive system and thereby influence fertility.     

The role of phytoestrogen therapy in relieving postmenopausal symptoms

Side effects and contraindications connected with hormonal replacement therapy in climacterium resulted in search for new methods of softening menopausal symptoms. The aim of the following study was to evaluate, based on literature analysis, the effectiveness of phytohormonal therapy as an alternative method of relieving the symptoms of menopausal period and preventing the diseases connected with deficiency of estrogens after menopause. Phytoestrogens therapy reduces the number and strength of the vasomotor symptoms and improves serum lipid profile. Moreover phytoestrogens show beneficial effects on bone tissue metabolism, skin and mucous membranes condition and are applicable in chemoprevention. This therapy is an effective method, allowing to avoid further changes in blood and urogenital systems, which result from estrogen stimulation deficiency. Phytoestrogens administration is an efficient method of relieving postmenopausal symptoms, facilitating the difficult menopausal period and keeping good health condition.     

Effects of phytoestrogens genistein and daidzein on progesterone and estrogen (estradiol) production of human term trophoblast cells in vitro

Objective.?Phytoestrogens are a diverse group of nonsteroidal plant compounds that occur naturally in many plants. Because they possess a ring system similar to estrogens they are able to bind on estrogen receptors alpha and beta in humans. The effects of the phytoestrogens genistein and daidzein on the production of progesterone and estrogen in isolated human term trophoblast cells in vitro were tested in this study.

Material and methods.?Cytotrophoblast cells were isolated from human term placentas. Phytoestrogens genistein and daidzein were incubated in different concentrations with trophoblast cells. Untreated cells were used as controls. After 24 h aliquots were removed and tested for progesterone and estrogen production.

Results.?The production of the steroid hormones progesterone and estrogen are influenced by phytoestrogens genistein and daidzein in human term trophoblast cells. A strong inhibition effect of both phytoestrogens tested in the production of progesterone was demonstrated. In addition, a significant stimulating effect on estrogen production by genistein and daidzein was observed.

Conclusion.?Results obtained with this study show that phytoestrogens (genistein and daidzein) sufficiently reduce progesterone production in human term trophoblast cells. Because blockade of progesterone is a possible mechanism involved in initiation of labor, we may speculate that high doses of phytoestrogens at the feto-maternal interphase could play a negative role in maintenance of pregnancy. Stimulation of estrogen production by genistein and daidzein in trophoblast cells is probably due to estrogen receptor blocking effects of both phytoestrogens. Trophoblast cells seem to compensate blocking of its estrogen receptors by higher estrogen production.     

Endokrinologie der Phytoöstrogene

Herbal estrogens are substances found in food, i.e., lignans or isoflavonoids, that induce biological responses in mammals including the human and can imitate or modulate the activity of endogenous estrogens. The intake of phytoestrogens might be associated with a lower risk of developing breast and prostate cancer. Furthermore, they might have positive preventive effects in cardiovascular disease, postmenopausal osteoporosis, climacteric symptoms, and cognitive disorders. Up to now there is no direct evidence for these postulated effects in humans supported by long-term intervention studies. Most if not all information is based on intake of herbal estrogen-enriched food in Asian populations or short-term interventions in Western populations. However, food products associated with lowered disease risk might contain other antioxidative or anticancer substances besides herbal estrogens, which might be responsible for the postulated protective effects. There are insufficient data concerning negative side effects of herbal estrogens. Further studies are needed to clarify the role of these drugs in prophylaxis and treatment of cancer.     

Upregulation of S100A6 in patients with endometriosis and its role in ectopic endometrial stromal cells

S100 calcium-binding protein A6 (S100A6) is up-regulated in many malignancies and overexpression of S100A6 has been identified associated with proliferation, migration and invasion phenotype in several cancer cells. In the present study, we explored whether S100A6 plays a role in the development of endometriosis. Significantly higher levels of mRNA and protein expression of S100A6 were observed in ectopic endometrial tissues compared to eutopic and normal endometrial tissues. Silencing of S100A6 in ectopic endometrial stromal cells (ESCs) significantly inhibited cell viability, migration and invasion. Moreover, knockdown of S100A6 suppressed p38/MAPK activity in ectopic ESCs, which can be partially attenuated by CacyBP/SIP phosphorylation inhibitor. In conclusion, our results suggest that the abnormal expression of S100A6 may contribute to the pathogenesis of endometriosis and the S100A6/CacyBP/p38 signaling may provide as a promising treatment target.     

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.