Late follicular phase administration of levonorgestrel as an emergency contraceptive changes the secretory pattern of glycodelin in serum and endometrium during the luteal phase of the menstrual cycle

This study examined serum glycodelin concentrations and endometrial expression during the luteal phase following oral administration of levonorgestrel (LNG) at different stages of the ovarian cycle. Thirty women were recruited and allocated into three groups. All groups were studied during two consecutive cycles, a control cycle and the treatment cycle. In the treatment cycle, each woman received two doses of 0.75 mg LNG taken 12 h apart on days 3–4 before the luteinizing hormone (LH) surge (Group 1), at the time of LH rise (Group 2) and 48 h after the rise in LH was detected (Group 3). Serum progesterone (P) and glycodelin were measured daily during the luteal phase, and an endometrial biopsy was taken at day LH +9 for immunohistochemical glycodelin-A staining. In Group 1, serum P levels were significantly lower, serum glycodelin levels rose earlier and endometrial glycodelin-A expression was weaker than in Groups 2 and 3, in which no differences were found between control and treatment cycles. Levonorgestrel taken for emergency contraception (EC) prior to the LH surge alters the luteal phase secretory pattern of glycodelin in serum and endometrium. Based on the potent gamete adhesion inhibitory activity of glycodelin-A, the results may account for the action of LNG in EC in those women who take LNG before the LH surge.     

Endometrial cancer in Israel, 1969–1975

Epidemiological data on 1017 cases of primary cancer of endometrium in Israel diagnosed over a 7-year period are presented. Incidence of corpus cancer in Israel has not changed in the last decade; the mean incidence for the current study is 18.73/100,000 women above the age of 25. Eight percent of patients were above the age of 51, with a steep increase of incidence being found above the age of 35. Endometrial carcinoma was four to five times more prevalent in Jewish women of European-American origin than in those of Asian-African background. In 85% of the patients diagnosis was made while the disease was in Stage I. A strong correlation was found between endometrial cancer and infertility, but no correlation was found with diabetes and hypertension. The five-year survival rate in the present survey was 65.0%. Factors affecting prognosis and clinical stage of the disease at diagnosis, degree of myometrial invasion, tumor differentiation, age of the patient and type of treatment are discussed.     

The endometrial echo revisited: have we created a monster?

Transvaginal ultrasound has been explored as an inexpensive, noninvasive, convenient way to indirectly visualize the endometrial cavity. For more than a decade numerous studies have indicated that a thin, distinct, well-visualized echo (<4-5 mm) in postmenopausal women with bleeding is as effective as any diagnostic modality in excluding endometrial cancer (99% negative predictive value). Unfortunately, this is not the same as saying that a thick endometrial echo is pathologic. In fact, the positive predictive value of an echo greater than 5 mm is less than 10% for any disease and only 4% for serious disease (cancer or hyperplasia). No studies validating the clinical significance of a nonthin endometrial echo observed in an incidental imaging study have ever been performed. Because 5 mm has been a "cutoff" for excluding endometrial cancers in women with bleeding, many clinicians have assumed that any findings greater than 5 mm need endometrial sampling to exclude disease. The number of postmenopausal women with quiescent fibroids, or polyps, or heterogeneous uterine echoes for technical reasons (previous scarring, axial uterus) is unknown but not insignificant. Furthermore, if transvaginal ultrasound is to be used, it must be performed appropriately, further recognizing that in a substantial number of patients it may not be possible to obtain technically adequate endometrial assessment. So, although transvaginal ultrasound can be a reliable method of excluding disease in many postmenopausal women with bleeding, the incidental finding of a non-thin endometrial echo has not been investigated and should not automatically trigger a need for formal tissue sampling.     

Leukemia inhibitory factor: an important regulator of endometrial function

PROBLEM: Leukemia inhibitory factor (LIF) is multifunctional cytokine that displays biological activities in different cells, including endometrial cells. The aim of this study is to describe implications of LIF on a physiological function of endometrium. METHOD OF STUDY: The role of LIF in the endometrial function is reviewed and summarized from the available literature. RESULTS: LIF plays an important role in a physiological function of endometrium. In human endometrial LIF expression depends on cellular localizations, steroid hormones, menstrual stages and a local cytokine network. Stronger LIF expression exists in an endometrial epithelium during a luteal phase of the menstrual cycle, which coincides with the time of an implantation. The impairments of the endometrial LIF expression may play a significant role in the pathological processes involving implantation and the infertility. CONCLUSIONS: There is a substantial evidence that LIF is a potential regulator of the endometrial function and might be one of the factors that play a key role in human reproduction.     

Effect of long-term progestin treatment on endometrial vasculature in normal cycling mice

The aim of this study was to develop a mouse model to investigate the effects of long-term progestin-only exposure on endometrial vascular structure. Normal cycling mice received Silastic implants containing either medroxyprogesterone acetate (MPA) or levonorgestrel (LNG) and were dissected after 1, 3 or 6 weeks. Endometrial vascular density increased significantly within 1 week of MPA (482 +/- 40.2 vessels/mm2) or LNG (440 +/- 26.5 vessels/mm2) treatment compared with normal cycling mice (293 +/- 10.5 vessels/mm2). MPA increased stromal cell density within 1 week of treatment (13813 +/- 1450 cells/mm2) compared with normal cycling mice (8256 +/- 928 cells/mm2). However, although LNG significantly increased stromal cell density overall, the increase did not reach significance within the individual weeks examined. There was no significant change in the ratio of vascular to stromal cell density among treated and normal cycling mice. Epithelial cell height significantly decreased within 1 week of LNG (17.6 +/- 1.3 microm) treatment compared with normal cycling mice (23.5 +/- 1.3 microm); epithelial cell height also decreased within 1 week of MPA treatment (16.6 +/- 2.1 microm), although this did not reach statistical significance. VEGF immunostaining increased significantly in luminal epithelium after MPA or LNG treatment, and in glandular epithelium after LNG treatment. These observations are similar to those reported in human endometrium, suggesting that this mouse model may facilitate further investigations into breakthrough bleeding due to long-term progestin use.     

Significantly decreased P27 expression in endometrial carcinoma compared to complex hyperplasia with atypia (correlation with p53 expression)

P27 expression was examined on paraffin-embedded specimens in proliferative, secretory, hyperplastic and neoplastic human endometrium by immunohistochemistry. The results of p27 immunoreactivity in endometrial carcinomas were compared with clinicopathological indicators as well as with p53 expression. Thirty-eight cases of endometrial carcinoma, 30 normal functional (15 proliferative, 15 secretory), 24 hyperplastic endometrium (12 without atypia, 12 with atypia) specimens were studied by using monoclonal p27 and p53 antibodies. The streptavidin-biotin-peroxidase detection system was used and the intensity and the distribution of immunoreactivity was evaluated semiquantitatively. p27 expression was present both in the proliferative and secretory phases; the expression being stronger in the secretory period. In complex hyperplasia with atypia, p27 expression was even higher and it was significantly reduced in the endometrial carcinoma group (p<0.05). No significant correlation was found between p27 expression and any of the clinicopathologic prognostic parameters (p>0.05). Nuclear p53 expression was detected in 13 (34.2%) patients with endometrial carcinoma and was higher in non-endometrioid carcinomas and in tumors with increasing FIGO grade (p<0.05). High expression of p53 was not found to be a significant prognostic indicator of survival (p> 0.05). No p53 expression was detected in the endometria with proliferation, secretion or hyperplasia either simple without atypia or complex with atypia. Surprisingly, tumors with absent/low p27 expression showed absent/low p53 expression. Our data suggest that p27 is necessary to control the proliferation of endometrium and its loss of expression seems to play a role in some aspects of endometrial carcinogenesis.     

Successful pregnancies after combined pentoxifylline-tocopherol treatment in women with premature ovarian failure who are resistant to hormone replacement therapy

OBJECTIVE: To determine whether treatment with combined pentoxifylline (PTX) and tocopherol (Vit.E) can improve uterine parameters in hormonal replacement therapy (HRT)-resistant women with premature ovarian failure (POF), for whom the outcome of assisted reproductive technology is usually negative. We previously reported that uterine radiation-induced fibrosis is reversible by combined PTX-Vit.E treatment. DESIGN: Case report. SETTING: Volunteer participants in an oocyte donation (OD) program in a French public hospital. PATIENT(S): Three women with POF (ages 36 +/- 2 years) using HRT exhibited uterine hormonoresistance, although they had high E(2) plasma levels. Their mean endometrial thickness was 4.9 mm, and they had an echogenic endometrium and thin uterine crosses. INTERVENTION(S): Between May 1998 and April 1999, treatment consisted of 800 mg of PTX combined with 1,000 IU of Vit.E daily for at least 9 months. MAIN OUTCOME MEASURE(S): Endometrial thickness, echogenicity, and pulsatility index of the uterine arteries, assessed by ultrasound and Doppler before and after treatment, and embryo implantation by IVF-OD. RESULT(S): PTX-Vit.E treatment was well tolerated and induced improvements, as mean edematous endometrial thickness increased to 7.4 mm, with nice uterine crosses. Three frozen-thawed ETs resulted in two viable pregnancies. CONCLUSION(S): In women with POF and uterine resistance to HRT, combined PTX-Vit.E reduces fibroatrophic uterine lesions and improves the uterine response to HRT, thus allowing embryo implantation and ongoing pregnancy.     

Expression of matrix metalloproteinase-26 and tissue inhibitors of metalloproteinases TIMP-3 and -4 in benign endometrium and endometrial cancer

OBJECTIVE: Matrix metalloproteinases (MMPs) and their physiological inhibitors, the tissue inhibitors of MMPs (TIMPs), play a key role in tumor cell invasion, angiogenesis, and growth. The aim of this study was to determine the expression and cellular distribution of MMP-26, TIMP-3, and TIMP-4 in endometrial cancers and benign endometrium throughout the menstrual cycle and the correlation with tumor histological subtype, stage, and grade. METHODS: Immunohistochemical analysis using polyclonal antibodies generated against pro- and active MMP-26, and mono- and polyclonal antibodies specific to TIMP-3 and TIMP-4, respectively, was performed. RESULTS: MMP-26, TIMP-3, and TIMP-4 are expressed in endometrial carcinomas (N = 86) and benign endometrium (N = 50) from various stages of the menstrual cycle. Semi-quantitative analysis of staining intensity indicated that endometrial carcinomas expressed more MMP-26, TIMP-3, and TIMP-4 compared to benign endometrium from the postmenopausal period, but not from the secretory phase of the menstrual cycle. The highest staining intensity was associated with endometrial epithelial cells, followed by vascular endothelial cells, myometrial smooth muscle cells, and endometrial stromal cells. Increased staining intensity of MMP-26 and TIMP-3 correlated with grade III tumors and MMP-26 and TIMP-4 with the depth of myometrial invasion in tumors histologically characterized as endometrioid adenocarcinoma, clear-cell, and papillary serous carcinoma staged/graded based on FIGO criteria. CONCLUSION: MMP-26 and TIMP-4 are expressed in endometrium and endometrial carcinoma and their elevated expression and correlation with myometrial invasion suggests that MMP-26 and TIMP-4 may play a key role in endometrial tumor progression.     

HOXA10基因在子宫内膜组织中的表达及与不孕的关系

目的　探讨HOXA10基因在正常育龄妇女及不明原因不孕患者子宫内膜中的表达 ,在着床过程中的作用及与不孕的关系。方法　采用原位杂交和逆转录聚合酶链反应 (RT PCR)技术 ,检测 5 2例正常育龄妇女及 38例不明原因不孕患者子宫内膜组织中HOXA10基因mRNA的表达。其中 ,正常育龄妇女子宫内膜周期为 10例增殖早期、10例增殖晚期、9例分泌早期、16例分泌中期、7例分泌晚期 ,不明原因不孕患者子宫内膜周期为增殖早期 7例、增殖晚期 8例、分泌早期 6例、分泌中期 11例、分泌晚期 6例。结果　 (1)HOXA10基因mRNA在正常育龄妇女子宫内膜腺体及间质中均有表达。原位杂交法检测 (以显色区灰度阳性单位表示 )显示 ,分泌中期腺体为 5 6 9± 0 5 7、间质为 7 48± 0 6 7,分泌晚期腺体为 5 99± 0 40、间质为 7 98± 1 0 8,显著高于增殖早期 (腺体 3 0 4± 0 30 ,间质3 2 5± 0 31)、晚期 (腺体 3 35± 0 2 0 ,间质 3 2 0± 0 37)和分泌早期 (腺体 3 0 7± 0 2 6 ,间质 3 18± 0 2 7)(P <0 0 1) ;分泌中、晚期间质表达高于腺体 (P <0 0 1)。RT PCR法检测显示 ,HOXA10基因mRNA表达 ,分泌中期为 (5 7 0± 3 4) %、晚期为 (5 6 2± 2 9) % ,显著高于增殖早期的 (31 8± 2 6 ) %、晚期的(32 2± 2 3) %和     

Effects of exogenous estrogen on uterine leukocyte recruitment

OBJECTIVE: To determine the role of estrogen in leukocyte recruitment to the human endometrium. DESIGN: Prospective, controlled in vivo study. SETTING: Academic research laboratory. PATIENT(S): Ten patients presenting for donor oocytes. INTERVENTION(S): Endometrial biopsies for the evaluation of leukocyte populations were collected from perimenopausal women in two consecutive regulated cycles who were given two different regimens of estrogen with identical progesterone treatment. MAIN OUTCOME MEASURE(S): Immunohistochemical identification of endometrial leukocyte populations and relative levels of expression of three chemokine genes. RESULT(S): The total uterine leukocyte population increased significantly when the women received oral estrogen, which resulted in higher serum estrogen levels. This rise in leukocytes was due to a significant increase in both the uterine natural killer cells and the macrophage populations. T-cell numbers did not change relative to circulating estrogen levels. The relative abundance of mRNA from three chemokines was also determined. No changes were found in the expression of M-CSF or MCP-1. Interleukin 8 decreased in glands relative to estrogen levels. CONCLUSION(S): These data demonstrate that changes in circulating levels of estrogen can regulate the recruitment of bone marrow-derived cells to the uterine endometrium; however, the mechanism whereby that occurs remains elusive.