Hyperestrogenism: a relevant risk factor for the development of cancer from endometriosis

OBJECTIVE: Endometriosis is extremely common in developed countries. Obesity is a major health concern and may cause hyperestrogenism. Hormonal replacement, particularly unopposed estrogens after hysterectomy, is becoming popular. Because endometriosis is ectopic endometrium, hyperestrogenism (either endogenous or exogenous) may cause hyperplasia or transformation into cancer. This study was conducted to describe the main clinical and pathologic features of malignancies in endometriosis and define the treatment and outcome and to compare patients who had cancer arising in endometriosis with patients who had endometriosis but no cancer. METHODS: Patients who had tumors from endometriosis diagnosed from 1986 to 1997 were analyzed retrospectively. Each patient was matched with two control patients (endometriosis without cancer) treated during the same study interval. Clinical and epidemiologic variables were compared to identify risk factors for the development of cancer. RESULT: We identified 31 patients with cancer developing from endometriosis. Fifteen women were obese, 9 had a history of endometriosis, and 9 were taking unopposed estrogen. Endometrioid adenocarcinoma was the most common histologic type (16 patients). When the patients with cancer were compared with controls, no significantly higher risk for the development of cancer was found with prolonged use of unopposed estrogens or with higher body mass index, but a trend was observed. When obesity and use of unopposed estrogens were considered together, the difference was statistically significant (P = 0.05). CONCLUSION: Hyperestrogenism, either endogenous or exogenous, is a significant risk factor for the development of cancer from endometriosis. The prevalences of endometriosis, obesity, and use of hormonal replacement therapy in women in developed countries are increasing, and this trend justifies the assumption that cancer developing in endometriosis might become more common in the future.     

Endometrial "sarcomas" complicating ovarian thecoma, polycystic ovarian disease and estrogen therapy

Unopposed endogenous and exogenous estrogenic stimulation has been considered by most investigators to have a role in the pathogenesis of carcinoma of the endometrium. Although a few cases of "sarcomas" of the endometrium that had developed in an estrogenic setting have been reported, a clear-cut association between estrogenic stimulation and these forms of endometrial cancer has not been established. We report six cases of endometrial sarcomas complicating ovarian thecomas, polycystic ovarian disease, or prolonged estrogen therapy. Three ovarian thecomas, which are considered to be estrogenic tumors, were associated with endometrial malignant mullerian mixed tumor, mullerian adenosarcoma, and low-grade stromal sarcoma in postmenopausal women. Polycystic ovarian disease, a condition characterized by unopposed estrinism due to the peripheral conversion of excessive androstenedione to estrone, was found in a 27-year-old infertile woman with an endometrial malignant mullerian mixed tumor. A pure osteogenic sarcoma of endometrial stromal origin developed in a 28-year-old woman with gonadal dysgenesis (Turner's syndrome) who had received estrogens for 18 years. The sixth woman, with an empty sella turcica after radiation therapy of a pituitary adenoma, had an endometrial mullerian adenosarcoma at the age of 40 years after 16 years of estrogen therapy. None of these patients had had pelvic radiation therapy. The evidence from this series of cases and from six additional cases identified in the literature suggests that the risk of endometrial sarcomas may be increased by estrogen therapy or endogenous disorders that lead to unopposed estrogenic stimulation of the uterus.     

Endometriosis and adenomyosis

Peristaltic activity of the non-pregnant uterus serves fundamental functions in the early process of reproduction. Hyperperistalsis of the uterus is significantly associated with the development of endometriosis and adenomyosis. In women with hyperperistalsis fragments of basal endometrium are detached during menstruation and transported into the peritoneal cavity. Fragments of basal endometrium have an increased potential of implantation and proliferation resulting in pelvic endometriosis. In addition, hyperperistalsis induces the proliferation of basal endometrium into myometrial dehiscencies. This results in endometriosis-associated adenomyosis with a prevalence of about 90%. Adenomyosis results in impaired directed sperm transport and thus constitutes an important cause of sterility in women with endometriosis. The principal mechanism of endometriosis/adenomyosis is the paracrine interference of endometrial estrogen with the cyclical endocrine control of archimyometrial peristalsis exerted by the ovary thus resulting in hyperperistalsis. Minimal endometriosis of the fertile women, endometriosis and adenomyosis of the infertile women and adenomyosis of the parous peri- and postmenopausal women are considered as phenotypes of a pathophysiological continuum with uterine peristalsis playing a prominent role.     

Use of progestogen therapy

Estrogen therapy for postmenopausal women has received adverse publicity since the mid-1970s because several reports implicated estrogens with an increased risk of endometrial cancer. Other studies indicated that the risk of endometrial malignancy is reduced when a progestogen is added to the estrogen. Not all postmenopausal women need estrogen replacement, since many are symptom free because they continue to produce endogenous estrogens. Within this group may be the women at greatest risk for adenocarcinoma of the endometrium. The progestogen challenge test was devised to identify women at greatest risk for endometrial cancer. The number of endometrial malignancies declined at Wilford Hall U.S. Air Force Medical Center with increasing use of this test from 1975 through 1983. The lowest incidence of endometrial cancer was observed in the estrogen-progestogen users (49.0 per 100,000) and was significantly lower than that found in either the unopposed estrogen users (390.6 per 100,000; p less than or equal to 0.0001) or in the untreated women (245.5 per 100,000; p less than or equal to 0.005). The incidence of breast cancer was also significantly lower in the estrogen-progestogen users (66.8 per 100,000) than in the untreated group (343.5 per 100,000) and lower than that expected from two national cancer surveys (188.3 and 229.2 per 100,000; p less than or equal to 0.01). Progestogens should be added to estrogen replacement therapy in women who have undergone a hysterectomy, as well as in those with an intact uterus.     

Expression of aromatase and estrogen sulfotransferase in eutopic and ectopic endometrium: evidence for unbalanced estradiol production in endometriosis

Endometriosis is an estrogen-dependent gynecological disease causing pelvic pain and infertility. Impaired estrogen metabolism is thought to play a pivotal role in the pathogenesis of the disease. While there is some information on factors involved in the synthesis of E2, information on E2-deactivating enzymes is still very limited. To elucidate the intracrinology of endometriotic tissues, the authors analyze the expression of aromatase and E2-inactivating estrogen sulfotransferase (EST) in paired biopsies obtained simultaneously from the endometrium and from endometrial lesions of each of 35 patients with peritoneal or ovarian endometriosis and in cycling endometria from 33 women without endometriosis. Protein localization was demonstrated by immunohistochemistry. Aromatase expression was found in endometriotic glands in 32 of 35 cases and was elevated in comparison to corresponding uterine endometria (25 of 35 cases, P = .021, chi(2) test). The difference was even more pronounced when uterine endometria from endometriosis patients were compared with that of healthy controls (8 of 33 cases, P < .001, chi(2) test). The EST levels were essentially unchanged. The elevated expression of aromatase in eutopic and ectopic endometrium from patients with endometriosis in the presence of comparable EST provides further evidence for unopposed local biosynthesis of estrogens in endometriosis.     

Malignancy arising in residual endometriosis following hysterectomy and hormone replacement therapy

Two women with adenocarcinoma of the endometrium and a past history of disseminated pelvic endometriosis presented with vaginal bleeding. One also had obstructive uropathy. The two patients had undergone total abdominal hysterectomy with removal of one or both ovaries three and 13 years previously and subsequently were treated with unopposed oestrogen replacement therapy. Adenocarcinoma of the endometrium following endometriosis is a rare condition and few cases are reported in the literature. A summary of the cases and related literature are presented.     

Ultrasound appearance of the uterus in women over 60 years of age on tibolone: is it a SERM?

OBJECTIVES: To evaluate the effects of long-term tibolone on the endometria of asymptomatic women over the age of 60 years. METHODS: An observational study of the ultrasound appearance of the endometria of women aged 60 years or older taking long-term tibolone. Those found to have a double-layer endometrial thickness greater than 4 mm were offered endometrial biopsy. RESULTS: Seventeen asymptomatic patients with a mean age of 61 years (range 60-73 years) and an average duration of tibolone use of 5 years (range 3-12 years) were recruited. Seven patients (41%) showed a thickened endometrium of more than 4 mm. Three of these had an area of translucency in the subendometrial space. Of the ten women with an endometrial thickness of less than 4 mm, four showed the presence of subendometrial fluid. Hysteroscopy was performed in five out of the seven women, as two did not accept further investigations. In all five women, the endometrial cavity was reported as atrophic and the histology showed an inactive basal type. In two of the five cases examined histologically, there were additional changes suggesting endometrial polyp, although the samples were from macroscopically non-polypoid endometrium. DISCUSSION: Endometrial thickness is increased in 41% of elderly women on long-term treatment with tibolone. However, at hysteroscopy, the endometrium was uniformly atrophic. Similar finding have been described in women using selective estrogen receptor modulators and a similar mechanism of action of these drugs on the uterus should be considered.     

Role of prolonged excessive estrogen stimulation in the pathogenesis of endometrial sarcomas: two cases and a review of the literature

Two cases of endometrial sarcoma that developed many years after exposure to unopposed exogenous and endogenous estrogens, with no previous pelvic irradiation, are described. The literature is reviewed and the possible effect of prolonged unopposed estrogen stimulation is suggested as an etiologic factor in such extremely rare conditions. These cases add additional support to the assumption that prolonged and excessive endogenous or exogenous unopposed estrogen stimulation of the uterus may increase the risk of endometrial sarcoma.     

Endometrial adenocarcinoma arising from endometriosis of the rectosigmoid colon

BACKGROUND: Only 21.3% of cases of malignant transformation of endometriosis occur at extragonadal pelvic sites. Forty cases of endometriosis-associated intestinal tumors are reported in the literature. Of these, 17 cases are primary adenocarcinomas arising in the rectosigmoid colon. In 8 of the 17 case reports the patients were using unopposed estrogen replacement therapy. CASE: The patient had previously undergone a total abdominal hysterectomy and bilateral salpingo-oophorectomy for deeply infiltrating rectovaginal endometriosis, and was using estrogen replacement therapy. She presented with rectal bleeding 12 years later, and a polyp was detected arising from the sigmoid colon. A biopsy detected malignant transformation of endometriosis to adenocarcinoma. CONCLUSION: This is the ninth case of a patient with this condition reported in the literature.     

Endometrial hormone receptors in women with dysfunctional uterine bleeding

Objective The objective was to study the estrogen receptor (ER) and progesterone receptor (PR) expression in endometrium of women with dysfunctional uterine bleeding (DUB) as compared to women with normal menstrual cycles.Methods In this study, 30 patients and 20 controls were selected. Transvaginal ultrasound and endometrial sampling for histology and ER and PR estimation immunohistochemically was carried out for all the subjects. Students t-test and linear correlation was used for statistical analysis. Their response to treatment was assessed by clinical follow-up.Results Endometrial thickness and ER and PR levels in DUB patients were significantly higher. In cases showing hyperplastic endometria, ER and PR levels were higher than patients with normal histology. In contrast to hyperplastic tissue, steroid receptor levels decrease in hyperplastic tissue containing atypia.Conclusion Altered endometrial morphology and increased receptor levels in DUB patients suggest that unopposed estrogen effect could have an important role in the pathogenesis of DUB. Cases of DUB, which showed atypical hyperplasia, may have a down-regulation of these receptors and could be a precursor lesion to carcinoma and thus do not respond to medical therapy by hormones.     

Ultrastructural effects of estrogen replacement on postmenopausal endometrium

Endometrial adenocarcinoma occurs almost exclusively in postmenopausal women, and excessive or unopposed estrogen stimulation is suspect as a causative factor in its pathogenesis. Furthermore, the incidence of endometrial adenocarcinoma has increased in women undergoing estrogen replacement therapy. In the present study, the cellular response of premenopausal and postmenopausal endometrium to estrogenic stimulation was compared with endometrial adenocarcinoma by the electron microscope. Tissues were obtained at hysterectomy, endometrial biopsy, or endometrial curettage and were processed routinely for light and electron microscopy. Ultrastructurally the endometrium from postmenopausal patients undergoing estrogen replacement therapy was similar to normal cyclic endometrium in the late proliferative phase. At least three features of the estrogen-treated postmenopausal tissue resembled those observed in adenocarcinoma of the endometrium: accumulation of lipid droplets, irregular nuclei, and perinuclear whorls of microfibrils.     

Contraception and endometriosis

Choosing a contraceptive method for a woman with endometriosis is an uncommon problem because endometriosis is relatively rare and because an estimated 30-50% of women with endometriosis are infertile. Uterine or internal endometriosis or adenomyosis is characterized by a congestive and pseudoinflammatory uterus slightly increased in volume. It must be distinguished from pelvic or external or peritoneo-ovarian endometriosis. Pelvic implants may involve destruction of the ovaries by cysts or their imprisonment in adhesions. They may cause stenosis in the proximal portion of the tubes or entrap them in adhesions. 4 stages of endometriosis have been distinguished according to the significance of the lesions and a scoring system. Stage 4 patients with scores over 70 or with a score over 50 for adhesions have been unable to conceive despite treatment. No contraception is necessary in these cases. The choice of a contraceptive for other patients is conditioned by the features of endometriosis. Endometriosis refers to the abnormal localization of a normal endometrium. The implants are sensitive to estrogen. Each implant behaves like a miniature uterus; the mucus proliferates and bleeds if estrogen secretions are present, or atrophies if not. Endometriosis may be completely asymptomatic, or cause sterility, or be accompanied by pain and metrorrhagia. Several earlier treatments of endometriosis have been abandoned because of side effects. The current treatment of choice is an LHRH analog administered by parenteral injections every 4 weeks to bring about a state of pseudomenopause. The treatment produces a rapid desensitization of the pituitary LHRH receptors and a diminution of gonadotrophins, estrogens, and progesterone. The secondary effects are those of hypoestrogenism: hot flashes, vaginal dryness, and increased bone loss after 6 months of treatment. It is also an expensive medication. Contraception is provided by the treatment itself for the first 6 months. Subsequently, a hydroxyprogesterone derivative such as cyproterone acetate can be used, as can a norpregnane derivative or a combined oral contraceptive with predominant progestin action. Monophasic pills containing norethisterone are also acceptable. In case of metabolic problems, a pill containing gestodene may be used. A vaginal contraceptive should be used in cases of adenomyosis.     

Endometriosis and malignoma

Malignant tumors arising from endometriosis are rare. A frequency of about 1% has been reported with in 80% the ovary, and in 20% extragonadal sites being affected. The most common extragonadal manifestations are the rectosigmoid and the rectovaginal septum. For extragonadal malignant tumors arising from endometriosis, complete resection followed by post-operative radiotherapy, possibly plus adjuvant progestin therapy, is the treatment of choice. Endometriosis-associated ovarian carcinomas are likely to present with lower stage disease and predominantly lower grade tumors. While their treatment follows that of common ovarian cancer, a poorer response to chemotherapy must be considered. As unopposed estrogen replacement therapy has been identified as a risk factor for the development of endometriosis-associated cancer, it is not recommended for hormone replacement therapy in women with a history of endometriosis. Loss of heterozygosity and mutations of the PTEN tumor suppressor gene may be early events of tumorigenesis. Endometriosis and its malignant transformation, perhaps, may serve as a suitable model in this regard. According to recent studies, endometriosis is associated with an increased relative risk of non-Hodgkin lymphoma.     

TWEAK在子宫内膜异位症在位和异位内膜上的表达

目的:探讨肿瘤坏死因子样凋亡的微弱诱导剂(TWEAK)在子宫内膜异位症(EMs)发病的关系。方法:采用实时定量逆转录-聚合酶链反应(Real-time RT-PCR)和免疫组化、Western Blot方法检测EMs患者在位内膜、异位病灶中TWEAK mRNA和蛋白的表达,并与正常对照子宫内膜比较。结果:TWEAK蛋白表达于子宫内膜的腺上皮细胞和间质细胞的胞浆内。与正常对照组内膜和在位组内膜相比,TWEAK mRNA和蛋白在异位内膜上表达量下调(P<0.05),且无论是EMs在位内膜还是对照组内膜,其增生期TWEAK mRNA表达明显低于分泌期(P<0.05)。结论:TWEAK在子宫内膜中表达,表达量在分泌期明显升高。EMs患者异位子宫内膜TWEAK表达降低,可能导致子宫内膜细胞的凋亡水平下降,参与EMs的发生发展过程。     

Raloxifene: A Review

women can now expect to live up to one-third of their lives in the post-menopausal state. This low estrogen state is a major risk factor for the development of osteoporosis and cardiovascular disease. The Osteoporosis Society of Canada currently recommends estrogen as the treatment of choice for preventing post-menopausal osteoporosis. Sustained unopposed estrogen use is associated with an increased risk of endometrial hyperplasia and endometrial cancer, necessitating the concomitant use of a progestin in those with an intact uterus. Recent large cohort studies suggest that estrogen and estrogen/progestin therapy may also be associated with an increased risk of breast cancer thus diminishing the beneficial effects of estrogen on overall mortality. Bisphosphonates are also available for the treatment and prevention of osteoporosis. They do not have the other beneficial effects that estrogen may provide. Selective estrogen receptor modulators (SERMs) represent a new therapeutic class of medications that have been developed to act as estrogen agonists in some tissues and estrogen antagonists in others. Raloxifene (Evista®) is a selective estrogen receptor modulator that, in pre-clinical and clinical studies, demonstrates estrogen agonist activity on bone and lipid metabolism, and shows estrogen antagonist activity on uterine and breast tissue. It is the first estrogen receptor active agent that has been shown in adequately powered, placebo-controlled, randomized clinical trials, to reduce the risk of new vertebral fractures in post-menopausal women with osteoporosis.     

The role of endometrium in endometriosis

Endometriosis is defined as the presence of endometrial glands and stroma outside the uterus. Several theories have been proposed to explain the pathogenesis of this disease. According to Sampson's retrograde menstruation theory, endometrial cells are refluxed through the fallopian tubes during the menstruation and implant onto peritoneum or pelvic organs. Since retrograde menstruation is a very common phenomenon among women of reproductive age, there must be other factors that may contribute to the pathophysiology and/or pathogenesis of endometriosis. Genetic predisposition, environmental factors, and alterations in immune and endocrine functions are believed to play significant roles in the establishment and maintenance of endometriosis. Although the eutopic endometriums of women with and without endometriosis are histologically similar, studies revealed that there are many fundamental differences between these two tissues. Invasive properties, decreased apoptosis, alterations in expression of specific gene and proteins, and increased steroid and cytokine production have been identified in eutopic endometrium of women with endometriosis. Furthermore, significant biochemical differences exist even between ectopic and autologous eutopic endometrium. These differences can be explained by the direct effects of an inflammatory peritoneal environment.     

Transvaginal ultrasonographic measurement of endometrial thickness in postmenopausal women receiving estrogen replacement therapy

OBJECTIVE: This study was undertaken to evaluate endometrial thickness by transvaginal ultrasonography in asymptomatic postmenopausal women receiving estrogen replacement therapy. The endometrial thickness in this study group was compared with endometrial thickness measurements in a group of women who had abnormal postmenopausal bleeding. The recent literature was reviewed.STUDY DESIGN: Asymptomatic postmenopausal women receiving estrogen replacement, seen for routine examination during the 1-year period from Jan. 1, 1994, to Dec. 31, 1995, had the endometrium evaluated by transvaginal ultrasonography. Women with abnormal postmenopausal bleeding were likewise evaluated and their measurements compared with those of the study group.RESULTS: Twenty-seven different estrogen and estrogen-progestin combinations in 327 asymptomatic women were studied. Additionally, 24 women who were bleeding, not receiving estrogen, and 46 women with abnormal bleeding on estrogen therapy underwent ultrasonography of the endometrium. Endometrial thickness ranged from 1 to 15 mm in women on a regimen of combined estrogen-progestin therapy, 1 to 14 mm in women using sequential estrogen-progestin, and 3 to 15 mm for women receiving unopposed estrogen in the study group. For women with abnormal bleeding not using estrogen, the endometrium measured an average of 12.3 mm (range 2 to 29 mm), with unopposed estrogen 8.3 mm (range 4 to 13 mm), and for estrogen with progestin 6.5 mm (range 2 to 15 mm). Significant pathologic features were found in those women who had bleeding and endometrial measurements between 5.0 and 29 mm.CONCLUSION: There was no significant difference between endometrial thickness measurements in women receiving various combinations of estrogen replacement. In general, expected endometrial measurements can range from 1 to 15 mm. In women with postmenopausal bleeding, however, significant pathologic features may exist with an endometrium measuring as little as 5 mm. (Am J Obstet Gynecol 1997;176:1334-9.)     

Endometrial carcinoma using GnRH analogues therapy in endometriosis

Endometriosis affects a 10 % of women during their reproductive years. Unequoral statistics concerning the incidence of adenomyosis are not available although a combined occurrence of both diseases is found in a 20 % of cases. The risk that malignancy arises from endometrioid tissue typical for endometriosis is between a 0.3-1 %. 75 % of these malignancies are ovarian cancer in conjunction with pre-existing ovarian endometriosis; less frequently extraovarian malignancies are found. The development of malignancy of adenomyosis is very rarely reported. In this report we present the case of a 35 year old patient who suffered from both, endometriosis and adenomyosis and who underwent a therapy using GnRH analogues. After five months and before the completion of the therapy a hysterectomy with conservation of the ovaries was performed at the request of the patient (carcinophobia). The histology confirmed the diagnosis of adenomyosis and demonstrated the unexpected finding of an endometrium carcinoma. This latter arose from a complex atypical hyperplasia surrounded by hypoplastic endometrium. There is some evidence that suggests a slightly elevated risk of breast and ovarian cancer as well as haematological malignancies amongst patients with endometriosis. However, there does not appear to be an increased risk of endometrial carcinoma. Adipositas leads to an increased risk for the development of endometrial carcinoma due to the increased conversion of testosterone to estrone in fat. The peripheral synthesis of estrone is unaffected by GnRHa-therapy. A progesterone containing HRT should be added to a GnRHa-therapy in overweight patients to prevent the development of endometrial hyperplasia and/or carcinoma. In conclusion a careful indication has to be made for GnRHa-therapy in overweight patients and before and during the therapy high resolution ultrasound scan should be performed to evaluate the endometrium in those patients.     

Sex steroids and cancer

Hormones, particularly estrogens, have been suspected for many years of being carcinogens. Retrospective studies from the mid-1970s indicate that unopposed estrogen replacement therapy increases the risk for endometrial cancer. However, recent reports have failed to incriminate even unopposed estrogens for any significantly increased risk of breast cancer. Added progestogen, in proper duration and dosage, almost completely negates the estrogen-increased risk for adenocarcinoma of the endometrium. There is increasing evidence that progestogen added to estrogen replacement may decrease the risk for carcinoma of the breast in some women.