Endometrial leucocytes: expression of steroid hormone receptors.

BACKGROUND: Stromal leucocyte populations in human endometrium comprise T cells, macrophages, and phenotypically unusual endometrial granulated lymphocytes. Their proportions vary during the menstrual cycle and, in particular, endometrial granulated lymphocytes increase in number in the late secretory phase. The stimulus responsible for these cyclical changes is unknown but it is likely that the steroid hormones oestrogen and progesterone play a role. AIMS: To define further the expression of steroid hormone receptors by leucocytes in non-pregnant and pregnant human endometrium. METHODS: Frozen and paraffin wax embedded sections of endometrium from non-pregnant women and early pregnancy decidua were labelled using single and double immunohistochemical techniques with monoclonal antibodies directed against oestrogen and progesterone receptors and various leucocyte subpopulations. RESULTS: Despite the prominence of CD56 positive endometrial granulated lymphocytes in late secretory phase endometrium and early pregnancy decidua, double immunohistochemical labelling showed no evidence of expression of either progesterone or oestrogen receptors by these cells or other endometrial leucocyte populations. CONCLUSIONS: Rather than acting directly, steroid hormones are likely to influence endometrial leucocyte populations indirectly via products of endometrial stromal or epithelial cells that express steroid hormone receptors.     

Effects of social status and moderate alcohol consumption on mammary gland and endometrium of surgically postmenopausal monkeys

OBJECTIVE: To evaluate the effects of social subordination stress and chronic moderate alcohol consumption on indices of breast and endometrial cancer risk. DESIGN: Forty-six adult, ovariectomized, cynomolgus monkeys (Macaca fascicularis) were trained to voluntarily drink a placebo or a two-drink/day equivalent of ethanol (0.5 g/kg), 5 days a week for 26 months, the latter resulting in average blood alcohol levels of 42 mg/100 mL. Indices of cell proliferation and sex steroid receptor abundance were measured. RESULTS: Compared with dominants, socially subordinate females had increased cell proliferation and proportions of glandular (P < 0.02) and epithelial tissue (P = 0.009) and less stroma (P < 0.02) in endometrium, and increased tissue thickness in breast (P < 0.05). There was no evidence of increased risk of breast or endometrial cancer with chronic moderate alcohol consumption, as indicated by markers of cell proliferation and sex steroid receptor abundance. Chronic moderate alcohol consumption did not effect circulating sex steroid concentrations (all P > 0.10). The adipocyte hormones leptin and adiponectin were correlated with indices of cell proliferation and sex steroid receptor abundance. CONCLUSIONS: These observations suggest that social status was more important than chronic moderate alcohol consumption in endometrial and breast biology of surgically postmenopausal females. Endogenous sex steroid metabolism was not significantly affected by chronic moderate alcohol exposure consistent with the lack of estrogen-like effects on breast and endometrium. Social subordination stress was associated with initial cellular changes that may increase endometrial cancer risk. Ovariectomized cynomolgus monkeys may be a useful model for the study of effects of social factors and obesity on breast and endometrial cancer risk.     

The ATAC ('Arimidex', Tamoxifen, Alone or in Combination) adjuvant breast cancer trial: baseline endometrial sub-protocol data on the effectiveness of transvaginal ultrasonography and diagnostic hysteroscopy

BACKGROUND: The 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial is a randomized, double-blind trial comparing anastrozole ('Arimidex'), alone or in combination with tamoxifen, relative to tamoxifen alone as 5 year adjuvant treatment for post-menopausal women with early breast cancer. Since tamoxifen is associated with endometrial pathology, the ATAC endometrial sub-protocol was initiated to establish the background prevalence of intrauterine pathology, and to assess prospectively the incidence and nature of intrauterine changes following endocrine therapy. Another aim was to provide data from which advice could be generated on the best endometrium screening method for patients receiving tamoxifen. METHODS: Patients underwent endometrial assessments at entry to the sub-protocol. The baseline investigations comprised transvaginal ultrasound scanning (TVUS), a hysteroscopy and an endometrial biopsy. RESULTS: A total of 285 gynaecologically asymptomatic women from 31 centres in 10 countries entered the endometrial sub-protocol. The mean uterine volume was 47.7 cm3. The median endometrial thickness overall was 3 mm. Twenty-four histologically confirmed, pathological changes were observed. Twenty-three pathologies were confirmed by TVUS, and 21 were identified by hysteroscopy and confirmed by histopathology. Women with or without intrauterine pathology had median endometrial thickness of 5 and 3 mm respectively. CONCLUSIONS: The presence of pathology was associated with increased endometrial thickness. The relative sensitivity and specificity of hysteroscopy and endometrial thickness for the diagnosis of endometrial pathology was comparable to other studies. If screening of the endometrium prior to treatment is appropriate, this study supports the use of an endometrial thickness of 3 mm, as assessed by TVUS, as a threshold for needing further investigation. This study demonstrates that if the endometrial thickness is >3 mm, hysteroscopy and biopsy is the optimal method of detecting intrauterine pathology in women with breast cancer who are about to commence endocrine treatment.     

Intra-uterine fluid collection in postmenopuasal women with cervical stenosis

OBJECTIVES: The aim of the study was to assess the clinical significance of intra-uterine fluid collection in postmenopausal women with cervical stenosis with and without vaginal bleeding. METHODS: A group of 82 consecutive postmenopausal women with cervical stenosis and sonographically confirmed intra-uterine fluid collection underwent D&C with or without hysteroscopy. Diagnostic hysteroscopy was performed in all patients with an endometrial thickness (ET) was greater than 8mm, or with irregular endometrium at any degree of ET. The patients were divided and evaluated prospectively into two groups according to the presence or absence of postmenopausal bleeding (PMB). Twenty-six women were with PMB and 56 women were asymptomatic. RESULTS: The groups were similar as far as endometrial thickness and histopathological results were concerned. Atrophic endometrium was found in 69 patients (84%), 23 in the PMB group (89%) and 46 in the other group (82%), proliferative endometrium in 7 (9%) and endometrial polyps were found in 35 patients (43%), 12 in the PMB group (46%) and 23 in the other group (41%). When ET was > or =8 mm, in 93% of the cases an endometrial polyp was found (25 out of 27). No case of endometrial cancer was found. A premalignant condition was diagnosed in one patient with an endometrial polyp in the PMB group. All patients with endometrial thickness of less than 3 mm in ultrasound had atrophic endometrium. The incidence of intrauterine pathology increased with the increasing thickness of endometrium as observed by ultrasound. CONCLUSIONS: The presence of intra-uterine fluid collection in postmenopausal patients with cervical stenosis seems to be a benign condition. Normal endometrium of less than 3mm observed by ultrasound in postmenopausal women without vaginal bleeding does not necessarily need further surgical investigation.     

Regression of endometrial thickness in combination with reduced withdrawal bleeding as a progestational effect of tibolone in postmenopausal women on oestrogen replacment therapy

For 176 postmenopausal women on HRT with progestogen addition ‘on demand’ medroxyprogesterone acetate (MPA), noresthisterone and tibolone were used to protect the endometrium in 214 cases. Tibolone is a gonadomimetic steroid with combined progestogenic and estrogenic effects. In this study tibolone has been used as a progestogen. The results of these three progestogens were compared. The endometrial thickness before and after the use of progestogen was determined by vaginosonography. In 175 out of 214 cases progestogen addition during oestrogen therapy caused endometrial regression. Withdrawal bleeding was observed 166 times. If the endometrial thickness on the onset of progestogen addition was 5 mm or more, in nearly all cases withdrawal bleeding occurred when MPA or norethisterone was used. If tibolone was used, no withdrawal bleeding occurred in over half the cases studied. We report the first observation of induced endometrial regression without withdrawal bleeding.     

Endometrial oestrogen and progesterone receptors and their relationship to sonographic appearance of the endometrium

The rapid development of ultrasonographic equipment now permits instantaneous assessment of follicles and endometrium. The sonographic appearance of the endometrium has been discussed in relation to in-vitro fertilization (IVF) cycles. However, a generally agreed view of the relationship of the sonographic appearance to fecundity in IVF cycles has not emerged. We have studied the relationship between steroid receptors and the sonographic appearance of the preovulatory endometrium in natural cycles and ovulation induction cycles. Preovulatory endometrial thickness was not found to be indicative of fecundity, although a preovulatory endometrial thickness of <9 mm related to an elevated miscarriage rate. The preovulatory endometrial echo pattern did not predict fecundity. No relationships were found among endometrial appearance, endometrial steroid receptors and steroid hormone concentrations in serum. Oestrogen or progesterone receptor concentrations were not related to endometrial thickness or to concentrations of serum oestradiol, the only significant correlation being found between the endometrial concentrations of oestrogen and progesterone receptors. The ratio of progesterone:oestrogen receptor concentration was somewhat less in echo pattern B (not triple line) endometrium compared with pattern A (triple line) endometrium. Oestrogen and progesterone receptor concentrations appeared stable on gonadotrophin induction, though fewer numbers were found during clomiphene cycles than in natural cycles. With regard to the distribution of receptor concentration between clomiphene and natural cycles, most women using clomiphene had very low oestrogen receptor populations. Pregnancy rates were low, in spite of high ovulatory rates during clomiphene treatment and were mainly related to low oestrogen receptor concentrations in preovulatory endometrium.     

miRNAs及其靶基因在子宫内膜容受性中的作用

子宫内膜容受性（ER）是指子宫内膜接受胚胎的能力，即允许受精卵定位、黏附、侵入并使内膜间质发生改变从而植入子宫内膜的一种能力。子宫内膜的“种植窗”期也称为容受期，需要由黄体分泌的雌、孕激素的支持，同时也受多种基因、蛋白质、细胞因子和粘附分子的影响，其中miRNA及其靶基因对子宫内膜容受性的具有一定的调节作用。miRNAs在女性生殖系统疾病中的作用是当前研究的热点，如子宫内膜异位症、输卵管积水、多囊卵巢综合征、子宫内膜癌等疾病中都存在miRNAs的差异化表达。miRNAs及其靶基因在子宫内膜容受性中的作用也引起学者的重视，多项研究表明，子宫内膜容受性缺陷者存在miRNAs及其靶基因的差异表达，本文将对miRNAs及其靶基因在子宫内膜容受性中的研究作一综述。     

Transvaginal ultrasonography for identifying endometrial pathology in postmenopausal women

The objective of this study was to evaluate the usefulness of transvaginal ultrasonography in postmenopausal women with a clinical indication for a dilatation and curettage (D&C). Of the 167 postmenopausal women included in the study, 88% were referred for a D&C because of vaginal bleeding and 12% of the women had other clinical indications such as myomas, gynecological pain or suspected gynecological tumors. Hormone replacement therapy (HRT) was used by 37% of the women. The women were examined with transvaginal ultrasonography before the D&C. The endometrial thickness and texture were used as indicators of endometrial abnormalities. The ultrasonographical findings were related to the histological diagnosis obtained from the D&C. Histologically, 31% of the women had an atrophic endometrium and the corresponding ultrasonographically mean endometrial thickness was 4.6 mm (range 0–14 mm). Endometrial cancer was histologically found in 10% of the women and the endometrial thickness of the malignant endometrium, measured by ultrasonography, was 13.9 mm (range 6–31 mm). All the malignancies were found in the group of women with vaginal bleeding, but only one was in the group of women on HRT. Histologically, endometrial hyperplasia was found in 6.5% of the women and endometrial polyps in 8.5% after the D&Cs. In these postmenopausal women it was demonstrated that if the endometrium was < 6 mm thick, no endometrial cancer was found at histopathological investigation. By using a cut-off point of 6 mm of ultrasonographically measured endometrial thickness for identification of endometrial pathology in our study, at least 50% of the D&Cs could be spared.     

A survey of physicians' attitude towards women with postmenopausal bleeding

Objective: To study how gynaecologist manage postmenopausal bleeding in women not using HRT. The impact on the physicians’ attitude of risk factors for endometrial cancer and of the endometrial thickness was essentially accounted for. Methods: Two different case-types were defined by modifying the risk level of developing endometrial cancer. Also the level of endometrial thickness, assessed by ultrasound, was made to vary. In total four case-types were constructed. One case-type was sent at random to each Belgian gynaecologist (n=970). Results: Response rate: 55%. The proportion of physicians who would not investigate the patients’ endometrium varied between 2% (high-risk patient with abnormal ultrasound) and 34% (low risk patient, normal ultrasound). Significant differences were observed in relation to the level of risk factors for endometrial cancer and in relation to endometrial thickness. No significant relationship was found between the choice of the method of endometrial investigation and the risk situation or the ultrasound result. Conclusions: The attitude of Belgian gynaecologists towards postmenopausal bleeding is modified by the presence of risk factors and by the level of endometrium thickness. About one third of physicians would not further investigate the endometrium of a patient with a low risk profile and a normal endometrium as assessed by ultrasound.     

Hysteroscopy for asymptomatic postmenopausal women with sonographically thickened endometrium

Endometrial carcinoma is the most common genital cancer in women. While patients usually present with vaginal bleeding, in 10–20% this characteristic symptom is absent. Endometrial thickness (double layer) is measured by transvaginal sonography and thickening indicates an increased risk of malignancy or other pathology (hyperplasia or polyps). Objective: We sought to correlate hysteroscopic and pathological findings in asymptomatic postmenopausal women with sonographically thickened endometrium (>6 mm). Study design: A prospective observational study in a university hospital of 304 postmenopausal women referred between 1996 and 2006 because of a sonographically thickened endometrium in the absence of abnormal bleeding, who underwent continuous flow hysteroscopy (4.5 mm Storz hysteroscope) and fractionated curettage of the uterine cervix and corpus (D & C) in addition to vaginal sonography (5 MHz probe). Results: The mean age of the women was 64.8 (range 57.7–71.9) years. Average endometrial thickness measured by ultrasound was 12 mm ± 6.7 mm. Hysteroscopy suggested the presence of endometrial polyps in 226 women (74.3%), simple endometrial hyperplasia in 34 (11.2%), atrophic endometrium in 18 (5.9%), complex endometrial hyperplasia in 2 (0.7%), atypical hyperplasia in 3 (1%) and leiomyoma in 9 (3.0%). In 12 women (3.9%), the hysteroscopic appearance suggested malignancy and histology revealed endometrial adenocarcinoma. All hysteroscopic results were confirmed by histological examination. Conclusion: Hysteroscopy represents an easy, safe and effective method for the investigation of asymptomatic women with a thickened endometrium found with transvaginal ultrasound. The commonest pathology was endometrial polyps.     

Comparison of transvaginal ultrasonography and endometrial biopsy in endometrial surveillance in postmenopausal HRT users

Objectives: To compare transvaginal ultrasonography with histological findings in endometrial evaluation of postmenopausal women using hormone replacement therapy and to evaluate endometrial safety of three hormone replacement therapy regimens. Methods: in a randomized, comparative study in postmenopausal women, endometrial safety was evaluated using (1) no hormone replacement therapy, (2) oral micronized 17β-estradiol/oral sequential dydrogesterone, (3) transdermal 17β-estradiol/oral sequential dydrogesterone, or (4) oral tibolone. 85 Non-hysterectomised subjects underwent transvaginal ultrasonography immediately before Pipelle biopsy at baseline and subsequently after 12 and 24 months. Endometrial thickness and uterine dimensions were determined by transvaginal ultrasonography, and endometrial thickness (double-layer) was compared with biopsy results. Results: Endometrial evaluation was conveniently performed by transvaginal ultrasonography, and endometrial thickness correlated well with biopsy findings. If endometrial thickness was <5 mm, the endometrial biopsy sample was either inactive/atrophic or insufficient for histopathological diagnosis. Hyperplastic or malignant changes were not reported. After 24 months, endometrial thickness was increased both in the oral (P<0.001) and transdermal (P<0.001) 17β-estradiol/dydrogesterone groups, whereas with tibolone the change in endometrial thickness was not different from controls. Conclusion: transvaginal ultrasonography of the endometrium reliably predicts the histological picture in hormone replacement therapy users. Using 5 mm endometrial thickness as cut-off point, more than 75% of biopsies could be avoided. All three hormone replacement therapies were safe with respect to the endometrium. With sequential 17β-estradiol/dydrogesterone the expected progestogen-induced secretory pattern was observed, whereas endometrial histology under tibolone closely mimicked the natural atrophic postmenopausal state.     

Ultrasonographic endometrial monitoring during continuous-sequential hormonal replacement therapy regimen in postmenopausal women

Objective: To evaluate the endometrial thickness in different periods of a continuous–sequential HRT regimen and to correlate the ultrasonographic findings with the histological patterns. Methods: The study was structured in two phases. In the 1st phase, 37 postmenopausal women (group A) treated by at least 6 months with a conventional continuous–sequential hormonal replacement therapy (cs–HRT) regimen were enrolled. In all patients, the endometrial thickness was measured at the 7th, 14th, 21st and 25th day of the cycle using transvaginal ultrasonography (TV-USG). In the 2nd phase of the study, other 41 postmenopausal women (group B) were enrolled and treated with the same sc-HRT regimen. At entry and after six cycles of cs–HRT, an endometrial biopsy was performed. The endometrial pattern was related with endometrial thickness. Either the evaluations were performed immediately after progestogen withdrawal bleeding, as showed by 1st phase results. Results: The results of the 1st phase of the study showed a mean endometrial thickness significantly lower at 7th day of the cycle compared to 14th, 21st and 25th day (4.3±1.2 versus 6.6±2.9, 7.8±4.2 and 7.4±4.6 mm±SD, respectively). After six cycles of cs–HRT (2nd phase of the study), the mean endometrial thickness was significantly increased in comparison with basal values (4.2±1.5 versus 2.8±1.2 mm±SD; P<0.05). Endometrial biopsies showed 13 cases (39.4%) of atrophy and 20 cases (60.6%) of proliferative endometrium. Mean endometrial thickness in case of atrophy was lower than in presence of a proliferative endometrium (3.7±1.2 versus 4.4±1.4 mm±SD; not significant). Endometrial thickness was <4 mm in 16 cases (11 of atrophic and five of proliferative endometrium), between 4 and 5 mm in 15 cases (13 of proliferative and two of atrophic endometrium) and between 5 and 6 mm in two cases (either case of proliferative endometrium). Conclusions: The best timing for monitoring endometrial thickness during cs–HRT regimens is the period immediately after withdrawal bleeding improving the reliability of the ultrasonographic exam to identify endometrial pathologies.     

Endometrial safety after 5 years of continuous combined transdermal estrogen and intrauterine levonorgestrel delivery for postmenopausal hormone substitution

OBJECTIVE: To investigate endometrial histology and thickness of the endometrium after long-term use of continuous transdermal estrogen substitution combined with intrauterine release of levonorgestrel (LNG) in postmenopausal women. DESIGN: A 5-year non-comparative prospective clinical trial. SUBJECTS: Out of 182 symptomatic postmenopausal women using estrogen substitution therapy (EST) combined with a novel T-shaped LNG-releasing intrauterine system (Femilis Slim LNG-IUS), to prevent endometrial proliferation and bleeding, only those women (n=102) who used two consecutive LNG-IUSs, were isolated with the aim to study the long-term effects on the endometrium. The mean age of the women was 57 years (range 47-71). The majority of women received percutaneous 17beta estradiol, 1.5mg daily, or an equivalent dose by patch or orally, on a continuous basis. MAIN OUTCOME MEASURES: Endometrial histology and ultrasonographic evidence of endometrial suppression, after a period of approximately 5 years of use. The mean duration of use of the regimen was 70 months (range 25-98). RESULTS: The dominant endometrial histologic picture was that of inactive endometrium characterized by glandular atrophy and stroma decidualization (Kurman classification 5b). No cases of endometrial hyperplasia were found. On transvaginal ultrasound, this corresponds with a thin endometrium (< or = 5 mm). CONCLUSION: The results of this 5-year study in 102 postmenopausal women using EST demonstrates that the LNG-IUS effectively opposes the estrogenic effect on the endometrium resulting in strong suppression during the entire period of EST. Due to its high efficacy and absence of systemic effects on organ tissues (e.g., breasts), target delivery in the uterine cavity could be a preferred route to administer a progestagen in women using EST.     

The effect of endometrial thickness on IVF/ICSI outcome

BACKGROUND: During the menstrual cycle the endometrium undergoes cyclic proliferative and secretory changes in preparation for implantation. If this preparation is not sufficient, then implantation will fail. The impact of endometrial thickness on the day of embryo transfer on IVF outcome was investigated in the present study. METHODS: A retrospective analysis was conducted of 1228 IVF/ICSI cycles. Stimulation was with clomiphene citrate (CC) + hMG in one-third of the cycles, and ultrashort GnRH agonist stimulation in two-thirds. Cycle parameters were compared between pregnant and non-pregnant patients. A similar comparison was made between ongoing pregnancies and those that resulted in a loss. RESULTS: There were more follicles, oocytes and embryos, the endometrium was thicker and the embryo quality was higher among women who became pregnant when compared with non-pregnant women after assisted reproduction. The pregnancy rate improved as endometrial thickness increased. No difference in cycle parameters and endometrial thickness was found between ongoing pregnancies and pregnancies that resulted in a first-trimester loss. CC had no measurable adverse endometrial effect, but the pregnancy rate was lower in CC+hMG cycles. CONCLUSIONS: Increased endometrial thickness is associated with higher pregnancy rates. However, neither attainment of pregnancy nor pregnancy outcome was predicted by endometrial thickness alone.