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Background/aims: Ulipristal acetate ([UPA], Esmya®) is an orally active selective progesterone-receptor modulator that has been approved as preoperative treatment for uterine myomas. This systematic review aims to summarize the available data on surgical outcomes of patients undergoing myomectomy by hysteroscopy or by laparoscopy after preoperative treatment with UPA., Methods: this review was performed following PRISMA guidelines and was registered in PROSPERO (CRD42018092201). PubMed, EMBASE, and Medline databases were systematically searched electronically until March 2018 for keywords concerning this topic. There were included only peer-reviewed, English language journal articles., Results: two prospective studies and 4 retrospective studies were included. The effect of UPA on the endometrium does not increase the technical difficulty during hysteroscopic myomectomy, but it increases the chance of complete primary resection in complex hysteroscopic myomectomies. Moreover, UPA does not increase the overall technical difficulty of laparoscopic myomectomy. Contradictory results have been reported on the impact of UPA on the separation of the myoma from the myometrium and on the consistency of the myomas., Conclusion: current results support the use of UPA prior to both surgical procedures. Further studies should confirm these preliminary findings and to assess the long-term outcomes of myomectomies following UPA treatment., (© 2018 S. Karger AG, Basel.)

Objectives: To investigate the effect of metformin on endometrial receptivity in women with polycystic ovary syndrome (PCOS)., Methods: Twenty volunteer women with polycystic ovaries and oligomenorrhea were prospectively investigated. All women were treated with exogenous estradiol and progesterone to simulate a normal menstrual cycle (28-day duration) after GnRH-induced pituitary desensitization. Ten of the women received no other medication (group A, control), while the remaining 10 received metformin (group B, metformin). Endometrial biopsy was performed in all women on day 21 of the 2 simulated cycles., Results: The expression of corticotropin - releasing hormone and urocortin in the endometrium was investigated. There was no significant difference between the 2 groups. A 3-day delay in the secretory maturation of the glandular epithelium relatively to the stroma was observed in 7 out of 10 women of group B (70%) as compared to only 1 out of 10 women of group A (10%, p = 0.02)., Conclusions: It is shown for the first time that metformin administration to women with PCOS did not affect the expression of endometrial receptivity markers but delayed histological glandular maturation. It is suggested that metformin may have an impact on the function of the endometrium in PCOS., (© 2018 S. Karger AG, Basel.)

Objective: The study aimed to assess whether sub-endometrial contractility is reduced by the use of intramuscular (IM) progesterone., Design: This is a randomized clinical trial. Patients assigned to a medicated day 5 frozen embryo transfer (FET) were randomly allocated to "vaginal progesterone" or "IM progesterone": patients randomized to the vaginal arm were treated with 200 mg micronized progesterone 3 times daily while patients randomized into the IM progesterone arm were treated with a single daily injection of 50 mg progesterone in oil. The main outcome measure was the number of sub-endometrial contractions (waves) per minute 1 day before a blastocyst embryo transfer., Results: Thirty-four patients were enrolled. The progesterone serum concentration was significantly higher in patients using the IM progesterone (85.2 ± 50.1 vs. 30.3 ± 11.2 nmol/L, respectively) but this did not translate into a lower sub-endometrial contractility (2.4 ± 4.8 vs. 1.4 ± 1.1 contraction/min, respectively). Clinical pregnancy rates were comparable between groups. The number of sub-endometrial waves was significantly lower among pregnant patients (p = 0.02)., Conclusions: The use of IM progesterone in medicated FET cycles does not reduce the sub-endometrial activity compared to vaginal progesterone administration. Our data support a poor clinical pregnancy outcome with high wave activity, regardless of the progesterone mode., (© 2017 S. Karger AG, Basel.)

Aim: The study aimed to investigate the efficacy of a dopamine agonist, quinagolide, on experimentally induced endometriosis in a rat model., Methods: Twenty female Wistar rats were used in this experiment. Endometriosis was surgically induced by transplantation of autologous endometrial tissue. A second laparotomy was performed 4 weeks after the first one to assess the pre-treatment implant volumes, and peritoneal lavage with saline solution was performed to assess the peritoneal cytokine levels. Rats were randomized to treatment with quinagolide or saline. At the end of the treatment period, a third laparotomy was performed to compare pre- and post-treatment implant volumes and cytokine levels within the groups. Implants were excised to compare glandular tissue (GT) and stromal tissue (ST) scores between the groups., Results: In the quinagolide group, post-treatment volume was statistically significantly reduced compared with pre-treatment volume (p = 0.01). There were significant decreases in interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) levels in peritoneal fluid samples in quinagolide-treated rats when compared to pre-treatment levels (p = 0.03 and p < 0.01). Histopathologically, both GT and ST scores were significantly lower in the quinagolide group compared to the control group (p = 0.01 and p = 0.02)., Conclusions: Quinagolide caused a significant regression in endometriotic implants and it also significantly reduced the levels of IL-6 and VEGF in peritoneal fluid., (© 2016 S. Karger AG, Basel.)

Background: Several previous studies have examined the effect of CYP2D6 gene polymorphism on the efficacy and metabolism of tamoxifen (Tamoxifen Teva, Nolvadex) in the treatment of breast cancer. In the present study, the metabolic profiles associated with various CYP2D6 genotypes were evaluated., Method: In the present study 92 Turkish breast cancer patients with early-stage hormone receptor-positive tumors treated with adjuvant tamoxifen (20 mg) were evaluated for CYP2D6 genotype and metabolic profiles. Known side effects of tamoxifen treatment, including endometrial thickening, changes in serum lipid levels and bone density, and hepatosteatosis, were evaluated according to the CYP2D6 polymorphism., Result: The distribution of metabolic characteristics in the Turkish population was as follows: 77.1% normal metabolism, 11.5% intermediate metabolism, 5.2% ultrarapid metabolism, and 2.1% poor metabolism. The CYP2D6 genotypes associated with rapid metabolism were CYP2D6 3X*1/*1 duplication (DUP) and CYP2D6 2X*1/*2, while poor metabolism was associated with the genotypes CYP2D6 *3/*4 and CYP2D6 *6/*6. There was no statistically significant relationship between metabolic characteristics and bone density or hepatosteatosis. A statistically significant difference in total cholesterol and triglycerides was detected in lipid profile analysis (p = 0.003, p = 0.02). Assessment of endometrial thickness revealed a significant association of hyperplasia and poor metabolism, and an association between atrophy and ultrarapid metabolism (p = 0.01)., Conclusion: Significant development of endometrial hyperplasia was identified among individuals with poor tamoxifen metabolism. As a result, tamoxifen may be a significant predictor of endometrial thickening among individuals with poor metabolic characteristics., (© 2014 S. Karger AG, Basel.)

Aims: To determine FOXO1 (forkhead box O1) expression in the human endometrium during the menstrual cycle and decidua of early pregnancy, as well as FOXO1 regulation in endometrial stromal cells (ESC)., Methods: Immunohistochemistry, RT-qPCR, and Western blot analyses evaluated cellular localization and altered FOXO1 expression in the endometrium during the menstrual cycle and decidua of early pregnancy (proliferative phase, n = 12; early-secretory phase, n = 7; mid-secretory phase, n = 10; late-secretory phase, n = 10; early pregnancy, n = 12). Using RT-qPCR and Western blot, we studied the regulation of FOXO1 by 8-bromo-cAMP, 4-pregnene-3,20-dione, 17β-estradiol, and human chorionic gonadotrophin in ESC (n = 5)., Results: The expression level of FOXO1 in human endometrial tissue fluctuated with the menstrual cycle. If pregnancy occurred, the expression of FOXO1 was further increased (p < 0.05) and cAMP regulated FOXO1 expression in ESC. In addition, 4-pregnene-3,20-dione cooperatively stimulated FOXO1 expression with cAMP. We also observed FOXO1 expression during in vitro cAMP-induced decidualization., Conclusions: The pattern of FOXO1 expression suggests a potential role for FOXO1 in implantation and decidualization., (Copyright © 2012 S. Karger AG, Basel.)

Objective: We previously reported that oral administration of the selective cyclooxygenase-2 (COX-2) inhibitor etodolac results in antitumor effects in endometrial cancer tissue. Herein, we investigated whether these antitumor effects could be assessed using endometrial cytological findings., Study Design: Etodolac (400 mg b.i.d. for 2 weeks) was administered preoperatively to 21 endometrial cancer patients: 16 had COX-2-positive disease and 5 had COX-2-negative disease. Twenty-one pairs of pre- and post-etodolac-treatment endometrial cytological samples were collected to review changes in the cytological features., Results: In the COX-2-positive patients, nuclear atypia was slightly decreased in 3 of the 16 cases, while the mitotic index was decreased in all cases. Cellular overlapping and tumor cell cluster outlines were somewhat affected in 6 and 8 cases, respectively. Nuclear/cytoplasmic ratio, anisokaryosis and hyperchromasia were also reduced in 6, 4, and 2 cases, respectively; however, tumor diathesis and nucleoli features were unchanged. In contrast, endometrial cytological features did not appear to be affected in the 5 COX-2-negative patients., Conclusions: We conclude that the antitumor effects observed in endometrial cancer tissues following oral administration of etodolac are reflected in and can be easily assessed by evaluating endometrial cytological features., (Copyright © 2012 S. Karger AG, Basel.)

Background: The nuclear factor-κB (NF-κB) pathway activates many of the target genes that are critical to the initiation and establishment of endometriosis. We sought to examine the potential application of pyrrolidine dithiocarbamate (PDTC), a potent NF-κB inhibitor, in the treatment of endometriosis., Methods: The phosphorylation of IκB, expression of nuclear p65 protein and NF-κB DNA binding in endometriotic epithelial cells (EECs), endometriotic eutopic epithelial cells (EuECs) and normal epithelial cells (NECs) were detected by Western blot analysis and electrophoretic mobility shift assay. Cyclooxgenase-2 (COX-2) gene and protein expressions in EECs were measured by RT-PCR and Western blot analysis. Prostaglandin E(2) (PGE(2)) production of EECs was measured by ELISA., Results: PDTC in the absence or presence of tumor necrosing factor-α (TNF-α) showed stronger inhibitory effects on IκB phosphorylation, expression of nuclear p65 protein and NF-κB DNA-binding activity in EECs than in EuECs or NECs. Pretreatment of EECs with PDTC resulted in a dose-dependent reduction in the TNF-α-induced expressions of COX-2 at gene and protein levels, as well as a reduction of PGE(2) synthesis., Conclusion: PDTC may represent a novel therapeutic strategy for treatment of endometriosis., (Copyright © 2011 S. Karger AG, Basel.)

Aim: We studied morphologic modifications of the endometrium induced by leuprorelin acetate, a gonadotropin-releasing hormone agonist, in women with uterine myomata., Methods: Transmission and scanning electron microscopy observations were performed after 2 or 6 cycles of therapy (every 28 days)., Results: A near-normal endometrium was observed after 2 months of therapy, while treatment with 6 cycles of leuprorelin acetate induced a uniform morphologic regression of the uterine mucosa., Conclusions: The study demonstrates that leuprorelin acetate induces a unique and time-dependent regression of the endometrial mucous membrane., (Copyright (c) 2009 S. Karger AG, Basel.)

Aim/methods: In vitro binding tests to human receptors and in vivo functional activities in animals were used to compare the effects of the progestin chlormadinone acetate (CMA) and its 3alpha- and 3beta-hydroxy metabolites (3alpha-OH-CMA and 3beta-OH-CMA) on progesterone, androgen and glucocorticoid receptors., Results: CMA, 3alpha-OH-CMA, 3beta-OH-CMA and the reference progestin R5020 bound to human progesterone receptor with Ki values of 2.5 nm, 13 nm, 6.0 nm and 4.3 nm, respectively. Binding affinities to the human androgen receptor were characterized by Ki values of 3.8 nM for CMA, 83 nM for 3alpha-OH-CMA, 20 nM for 3beta-OH-CMA and 2.9 nM for the reference androgen methyltrienolone. The Ki values for binding to the human glucocorticoid receptor were 16 nM for CMA, 69 nM for 3alpha-OH-CMA, 21 nM for 3beta-OH-CMA and 1.2 nM for the glucocorticoid dexamethasone. In the rabbit endometrial proliferation test CMA, 3alpha-OH-CMA and 3beta-OH-CMA (5 and 45 microg/kg p.o. for 5 days) had similar progestomimetic activities. CMA, 3alpha-OH-CMA and, to a lesser extent, 3beta-OH-CMA (4.64 and 21.5 mg/kg p.o. for 7 days) inhibited testosterone-stimulated growth of prostate and seminal vesicles in castrated rats showing antiandrogenic activities. Glucocorticoid properties were demonstrated for CMA and 3alpha-OH-CMA (21.5 and 100 mg/kg p.o. for 6 days) but not for 3beta-OH-CMA as reduction in thymus and adrenal gland weights in immature rats., Conclusion: Binding assays at human receptors showed similarly high affinities of CMA with the progesterone and androgen receptors and a 5 times lower affinity with the glucocorticoid receptor. At all receptor types, CMA had the highest, 3alpha-OH-CMA the lowest and 3beta-OH-CMA an intermediate affinity. Animal studies revealed progestomimetic and antiandrogenic activities of CMA, 3alpha-OH-CMA and 3beta-OH-CMA and glucocorticoid activities of CMA and 3alpha-OH-CMA.

Two infertile patients are presented with complex atypical endometrial hyperplasia becoming pregnant following conservative treatment with a levonorgestrel-releasing intrauterine system (LNG-IUS) insertion. Histological morphology of endometrial samples after 6 months' exposure to LNG-IUS showed secretory or atrophic glands with decidualized stroma. Two healthy babies were born following ovulation induction after removal of the LNG-IUS., ((c) 2008 S. Karger AG, Basel)

Treatment of immortalized stromal-like and epithelial-like endometriotic cells with capsaicin resulted in inhibition of proliferation in a concentration-dependent manner. In addition, endometriotic cells are more sensitive to capsaicin treatment than immortalized endometrial cells, suggesting that capsaicin may be an admissible drug candidate for treating endometriosis., (Copyright 2008 S. Karger AG, Basel.)

Objective: To determine the impact of adding a qualifying educational note when exfoliated endometrial cells were present in the first half of the menstrual cycle., Study Design: We identified all Pap smears that had endometrial cells in women > or = 40 years, between July and November, 2004. When endometrial cells were seen in the first half of menstrual cycle, it was stated that, "endometrial cells correlate with the menstrual history provided." We then attempted to determine if this qualifying comment had an impact on the decision to obtain a follow-up endometrial biopsy., Results: A total of 325 women were identified. Of these, 51 (15.7%) had follow-up endometrial biopsy without clinical evidence of endometrial pathology, compared to a rate of 36.9% before implementation of the note (p < 0.0001). Biopsies were performed in 21 of 195 (10.8%) when the note indicated that endometrial cells correlated with menstrual history, compared to 30 of 130 (23%) in whom a different note was appended because endometrial cells were out of phase or patients were postmenopausal (p = 0.0032). Biopsies did not reveal significant endometrial pathology in any of the 51 patients., Conclusion: Adding an educational note when endometrial cells are reported in the first half of the menstrual cycle in women > or = 40 years may help reduce unnecessary biopsies.

Background: The aim of this study was to evaluate the expression of Bcl-2 and Ki-67 in tamoxifen (TAM)-associated endometrial polyps and postmenopausal polyps., Material and Methods: For this purpose, a retrospective analysis of paraffin-embedded specimens was carried out. Polyps of 20 postmenopausal and 14 TAM-treated patients, 11 simple endometrial hyperplasia, 10 atypical complex endometrial hyperplasia and 8 endometrial adenocarcinoma specimens were included in the study. Hematoxylin/eosin-stained sections were evaluated. Immunohistochemical staining was performed to investigate the expression of Bcl-2 protein and the Ki-67 proliferation index., Results: There was no statistically significant difference between the 5 groups with regard to Bcl- 2 staining (p > 0.05). However, Bcl-2 expression in TAM-associated polyps was higher (86%) than in the postmenopausal control group (80%). Positive Ki-67 was highest in the endometrial adenocarcinoma specimens, followed by the atypical complex endometrial hyperplasia group (p < 0.0001). Compared to these 2 groups, Ki- 67 expression was lower in TAM-associated polyps, but Ki-67 indexes were significantly higher in the TAM-associated group than in the control group (p < 0.0001)., Conclusion: Since TAM-associated polyps tend to have higher proliferation indexes and Ki-67 ratios than control groups, we suggest that they are likely to have a higher malignant potential.

Objectives: We investigated the effect of a novel synthesized histone deacetylase inhibitor (HDACI), CBHA, on three endometrial cancer cell lines, two ovarian cancer cell lines, and normal human endometrial epithelial cells., Methods: Endometrial and ovarian cancer cells were treated with various concentrations of CBHA, and its effect on cell growth, cell cycle, apoptosis, and related measurements was investigated., Results: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that all endometrial and ovarian cancer cell lines were sensitive to the growth-inhibitory effect of CBHA, although normal endometrial epithelial cells were viable after treatment with the same doses of CBHA that induced growth inhibition in endometrial and ovarian cancer cells. Cell cycle analysis indicated that their exposure to CBHA decreased the proportion of cells in the S-phase and increased the proportion in the G(0)/G(1) phases of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with altered expression of genes related to cell growth, malignant phenotype, and apoptosis. Furthermore, CBHA treatment of these cell lines increased acetylation of H3 and H4 histone tails., Conclusions: These results raise the possibility that CBHA may prove particularly effective in the treatment of endometrial and ovarian cancers., (Copyright 2006 S. Karger AG, Basel.)

Genital tuberculosis is reported to be a major pelvic factor causing infertility in Indian women and often exists without any apparent signs and symptoms. The role of latent tuberculosis in repeated IVF failure in unexplained infertility is examined. 81 women with unexplained infertility having repeated IVF failure tested for Mycobacterium tuberculosis using PCR, ZN staining and BACTEC-460 culture were selected. Fresh IVF-ET or frozen embryo transfer (FET) was attempted on patients successfully treated with anti-tubercular drugs (ATD). ATD-treated fresh cycles (group A1) and frozen cycles (group B1) were compared to previously failed fresh cycles (group A2) and FET attempts (group B2), respectively. Main outcome measures were gonadotropin required, terminal E2, number of oocytes retrieved, fertilization rate, embryo quality, endometrial thickness and sub-endometrial blood flow (V(max)). Gonadotropin required in group A1 was significantly less as compared to group A2. Number of oocytes retrieved and grade I embryos, endometrial thickness and V(max) were significantly higher in group A1. Endometrial thickness and V(max) were significantly increased in group B1 as compared to B2. The study indicates that latent tuberculosis should be considered in young Indian patients presenting with unexplained infertility with apparently normal pelvic and non-endometrial tubal factors and repeated IVF failure., (Copyright (c) 2006 S. Karger AG, Basel.)

Background: All current major medications in treating endometriosis are effective in treating pain, most likely through suppression of proliferation of the implants, yet their effectiveness is relatively short term and they all have many undesirable, and sometimes severe, side effects. There is pressing need for novel, more effective medications in treating endometriosis with less and/or milder side effects., Methods: Using a recently established immortalized endometrial stromal cell line, we carried out cell proliferation assays for cells treated with trichostatin A (TSA), RU486, CDB-2914, and N-acetylcysteine, and ICI 182780. Gene expression levels for PR-A, PR-B, AR, Fas and FasL were measured. Protein expression levels for ERalpha, ERbeta, and AR were also measured., Results: Cell proliferation assay results for NAC, H2O2, CDB, and RU486 were nearly identical or similar to what have been reported based on primary cell cultures or in vivo studies. TSA, CDB, RU486 and NAC all had various antiproliferative effects. TSA had a more potent and longer lasting antiproliferative effect than CDB and NAC, even in the presence of an oxidant, H2O2. Its antiproliferative effect was concentration-dependent. ICI did not have a significant antiproliferative effect. PR-A, PR-B, AR, and FasL expression were all increased as compared with untreated cells., Conclusions: The cell line appears to be an adequate model for stromal components of endometriotic implants. That ICI has no inhibitory effect on endometrial proliferation may explain why a phase II clinical trial on its use to treat endometriosis did not advance to later stages. The upregulation of PR-B and AR may be responsible for antiproliferative effects induced by TSA, a histone deacetylase inhibitor (HDACI). HDACIs may be promising therapeutics in treating endometriosis due to their antiproliferative effects as well as the potential to restore gene dysregulation through chromatin remodeling., (Copyright 2006 S. Karger AG, Basel.)

Objective: To examine the effect of clomiphene citrate (CC) on the ovarian, endometrial, and cervical histologies in a rat model., Methods: The rats (n = 40) were randomly assigned to 4 treatment groups: CC 50 (repetitive doses of 0.2 mg CC); CC 100 (repetitive doses of 0.4 mg CC); CC 200 (repetitive doses of 0.8 mg CC), and control (repetitive doses of normal saline). Each study group received its CC dose intraperitoneally in 2 ml saline for 5 days and the controls received 2 ml saline only. Each treatment cycle was repeated six times. Six months later the rats were euthanized. Their ovaries, uterine horns, and cervices were removed and examined for histologic changes., Results: We found no significant difference in the number of follicles and corpora lutea of the study groups (p > 0.05). The numbers of granulosa, theca, and luteal cells of the CC 100 and CC 200 groups were significantly higher than those of the CC 50 group and controls (p < 0.05). There was no important finding related to pre-malign and malign changes in ovarian, endometrial and cervical samples of the control and CC 50 groups. Focal atypia and atypical mitoses were noted in 2 cases of granulosa cells in the CC 100 and CC 200 groups., Conclusion: We did not find an association between the use of CC and ovarian, endometrial, and cervical neoplasms; nevertheless, we noticed an increase in granulosa, theca and luteal cells with high doses of CC, which may be a risk factor for granulosa, theca, and luteal cell tumors., (Copyright 2005 S. Karger AG, Basel.)

Background: Present human data reveal that gonadotropin stimulation for in vitro fertilization and embryo transfer (IVF-ET) is detrimental to uterine receptivity. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is important in the early stage of mouse embryonic implantation since it is expressed in the murine endometrium before the attachment reaction. Gonadotropin receptors have been found on the murine endometrium. In this study, we assessed the expression of HB-EGF mRNA on the gonadotropin-stimulated murine endometrium and sought evidence of whether the gonadotropin-induced, altered uterine receptivity is associated with a change in the HB-EGF expression., Methods: Quantitative, competitive reverse-transcription polymerase chain reaction (PCR) and immunohistochemistry were performed to evaluate the expression of HB-EGF mRNA on the stimulated murine endometrium from pregnant uteri of gestation day (g.d.) 5.0 after injection of saline, or pregnant mare serum gonadotropin (PMSG) 5 or 10 IU., Results: The expression of HB-EGF mRNA showed no significant increase or decrease in the endometrial expression in PMSG groups, compared to the control group (natural coitus with saline injection), on g.d. 5.0. This finding was consistent with the immunostaining of HB-EGF protein, and there was no significant difference in the staining intensity among the 3 groups., Conclusion: This study reveals that ovarian stimulation by gonadotropin may not influence the expression of HB-EGF in the murine endometrium. Further investigations are necessary to elucidate whether embryonic HB-EGF receptor status relative to endometrial HB-EGF expression is affected by ovarian stimulation., (Copyright 2005 S. Karger AG, Basel)

Objective: To determine the prevalence of pathologic changes in the endometrium of tamoxifen-treated asymptomatic postmenopausal patients with breast cancer., Subjects and Methods: Fifty postmenopausal asymptomatic breast cancer patients with positive estrogen receptor status were treated with 20 mg of tamoxifen daily for a period of 5-60 months. The control group consisted of 30 asymptomatic postmenopausal breast cancer patients who were negative for estrogen receptor and therefore did not receive tamoxifen. Endometrial biopsies were performed using Pipelle endometrial suction curette at least 5 months after the study began. The endometrium was classified as atrophic (negative finding) and proliferative or hyperplastic (positive findings). The study and control groups were compared for demographic characteristics, risk factors for endometrial cancer, histological findings and the duration of tamoxifen treatment., Results: A significantly greater prevalence of endometrial abnormalities existed among the tamoxifen-treated than control patients (76 vs. 33%, p < 0.001). The abnormal endometrial changes were further demarcated in both groups into proliferative (54 vs. 26.7%, p = 0.02) and hyperplastic (22 vs. 6.6%, p = NS). In the study group, 63.6% of hyperplastic endometrium was simple hyperplasia and 36.4% was complex/no atypia hyperplasia, while in the control group all the cases were simple hyperplasia. No endometrial cancer was detected in either group. In addition, there was a positive association between the duration of tamoxifen exposure (<1 year vs. >/=1 year) and the endometrial abnormalities (46.6 vs. 88.6%, p = 0.003; proliferative 57.1 vs. 74.1%, p = 0.015; hyperplastic 42.8 vs. 25.8%, p = NS)., Conclusion: The adjuvant use of tamoxifen is associated with significant time-dependent abnormal endometrial changes among patients with cancer of the breast., (Copyright 2004 S. Karger AG, Basel)

Background/aim: Tibolone, a synthetic derivative of the 19-nortestosterone family, induces atrophy of the endometrium, especially via its progestogenic Delta(4) isomer. The aim of the study was to determine whether tibolone induces apoptosis in the endometrium of postmenopausal women., Methods: Twenty healthy postmenopausal women (mean age +/- SD 52.4 +/- 4.21 years) who had amenorrhea for at least 1 year and who had no history of any systemic illness and estrogen replacement therapy were enrolled in the study. All patients were offered office endometrial samplings, and then tibolone was prescribed (2.5 mg/day p.o., once daily) to all patients. Repeat endometrial samples were obtained after completion of the 6-month course of tibolone therapy. All samples were immunohistochemically analyzed for the presence of apoptotic cells., Results: There was no significant difference in the median proportion of apoptotic nuclei between the pre- and posttreatment samples (2 vs. 3%; p > 0.05)., Conclusions: The results showed that tibolone did not affect the rate of apoptosis in the postmenopausal endometrium. Further studies are needed to clarify the role of apoptosis in overall effects of hormonal compounds on the postmenopausal endometrium., (Copyright 2003 S. Karger AG, Basel)

Objective: Most endometrial cancers are related to hormonal imbalance, and antipsychotics are a common cause of hyperprolactinemia. We investigated the possible relation between the use of antipsychotics and the risk of endometrial cancer., Methods: A case-control study was conducted on premenopausal women at the Chiba University Hospital between 1989 and 2000. The cases were 41 patients with histologically confirmed endometrial cancer. For each case, there were 3 controls matched by age and date of visit. Subsequently 123 women without endometrial cancer were enrolled as controls. Detailed information including obesity, parity, hypertension, diabetes mellitus, use of exogenous estrogen and use of antipsychotics was analyzed. Odds ratios, two-sided p values and 95% confidence intervals were estimated by a conditional logistic regression analysis. Radioimmunoassays of serum luteinizing hormone, follicle-stimulating hormone, prolactin, estradiol and progesterone were performed in 4 of 5 patients with endometrial cancer who were using antipsychotics., Results: Use of antipsychotics, diabetes mellitus and obesity were identified as independent variables with risk estimates of 5.4, 9.3 and 4.9, respectively. Serum progesterone, estradiol and prolactin levels ranged from 0.4 to 0.7 ng/ml, 32 to 110 pg/ml and 34 to 258 ng/ml, respectively., Conclusions: Use of antipsychotics is a risk factor for endometrial cancer, and hyperprolactinemia associated with antipsychotics may impart the risk of endometrial cancer in premenopausal women., (Copyright 2003 S. Karger AG, Basel)

We have investigated whether there are any differences in the release of urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) from cultured endometrial and endometriotic stromal cells, and whether the release is regulated by epidermal growth factor (EGF) or transforming growth factor beta1 (TGFbeta1). The cells were isolated from endometriomas and endometrium from women with and without endometriosis. After treatment with EGF or TGF and in untreated controls, incubated media collected at 0, 24, 48 and 72 h were analyzed by ELISA. Stromal cells from all three types of tissues released uPA and PAI-1, but the soluble receptor of uPA was not measurable in any group. The basal release of uPA and PAI-1 from endometriotic cells was higher than from endometrial cells. The uPA release in endometriotic cells was reduced with and without the addition of EGF (p < 0.05) or TGFbeta1 (p < 0.05). EGF increased the release of PAI-1 from stromal cells from women without endometriosis (p < 0.05) but decreased the release of PAI-1 from stromal cells from endometriotic women (p < 0.05). TGFbeta1 increased the release of PAI-1 from endometriotic cells (p < 0.05) but had no effect in endometrial cells., (Copyright 2003 S. Karger AG, Basel)

Objective: To evaluate the estrogenic effect of tamoxifen (TAM) therapy in postmenopausal women., Study Design: The subjects were 26 postmenopausal women. The maturation index (MI), maturation value (MV) and karyopyknotic index (KPI) were evaluated based on hormonal cytology. Endometrial cytologic examinations and transvaginal ultrasonography were also performed., Results: Of the 26 patients, 16 had low estrogenic activity from the viewpoint of hormonal cytology before TAM administration. During administration, their mean MV rose significantly, from 25.8 +/- 17.7 to 68.8 +/- 13.2, (mean +/- SD) and their mean KPI rose from 9.0 +/- 8.3 to 47.1 +/- 23.1. In contrast, among the 10 patients with high estrogenic activity, mean MV and KPI decreased from 62.9 +/- 8.4 and 27.2 +/- 16.9 to 58.4 +/- 7.7 and 17.7 +/- 16.1, respectively, with TAM administration. Mean endometrial thickness increased more significantly with TAM administration in the low estrogenic activity group than in the high estrogenic activity group., Conclusion: TAM had a reciprocal effect; no additional estrogenic effect was seen in patients with high estrogenic activity. Conversely, an estrogenic effect was seen in those with low estrogenic activity. An individualized gynecologic evaluation based on hormonal cytology is useful in selecting patients who will be more susceptible to TAM-induced endometrial abnormality.

Objective: To evaluate the efficacy of depot medroxy progesterone acetate (DMPA) as a preparatory agent for endometrial resection., Study Design: Endometrial resection was performed on 50 women for excessive uterine bleeding. The patients were randomly divided into 2 equal groups, with the first group receiving DMPA and the second group not receiving any hormonal pre-medication. The resected tissue was sent for histopathology and all the patients were followed up regularly for a maximum period of 4 years., Results: DMPA was found to increase the thickness of the endometrium, making it more fluffy and oedematous. The procedure in these patients was associated with a significantly greater fluid consumption and deficit. A power analysis showed the overall power of the study to be >90%. Forty-four percent of group 1 and 64% of group 2 patients achieved amenorrhoea or spotting. Three patients in all underwent a repeat procedure, and 1 a hysterectomy, following a dissatisfactory result. However, no statistically significant difference was found in the outcomes of the 2 groups., Conclusion: As a preparatory agent, DMPA, seems to have no added benefit. Larger studies are required to bring out differences in outcomes, if any., (Copyright 2001 S. Karger AG, Basel)

Fifty healthy, voluntary patients aged between 20 and 30 years with regular menstruation and plasmatic progesterone level >10 ng/ml at the midluteal phase have been enrolled in this study. They were randomly treated with clomiphene citrate (CC; group A) or CC + ethinyl estradiol (0.05 mg group B, or 0.02 mg group C). We estimated the difference in uterine artery pulsatily index, endometrial thickness and histological dating and morphometric analysis of endometrium. No significant differences in Pulsatility Index values and in the number of preovulatory follicles were noted. The difference between endometrial thickness, histological dating and morphometric analysis of the endometrium were statistically different between groups B and C vs. A. Our study shows that CC has a deleterious effect on endometrium maturity and that adding ethinyl-E(2) produces a favorable endometrial response even with very low doses., (Copyright 2001 S. Karger AG, Basel.)

Approximately 20-25% of hysterectomies are done for the relief of menorrhagia, excessive menstrual bleeding without gynecologic pathology. Menorrhagia represents a widespread clinical problem, and it is one of the leading causes of elective hysterectomy in women with a normal uterus in the US as well as in Europe. The current management of dysfunctional bleeding includes medical or different types of surgical therapies. When patients wish a nonsurgical therapy for menorrhagia we can offer them different medical treatments, a IUD releasing levonorgestrel or a therapeutic dilatation and curettage (D&C). Until recently, women who did not respond to medication were limited to either hysterectomy or continued cycles of heavy menstrual bleeding. Methods for hysteroscopic endometrial ablation were introduced in the 1980s including Nd:YAG laser ablation, transcervical resection of the endometrium (TCRE) and 'rollerball' electrocoagulation (RBE). These first-generation procedures are nowadays the gold standard for the hysteroscopic treatment of menorrhagia. In the 1990s different types of therapeutic alternatives were introduced. The second generation of hysteroscopic ablation techniques include: balloon heating methods, methods with intrauterine instillation of heated saline, the endometrial laser intrauterine thermal therapy procedure ELITT using a diode laser, global 3-D bipolar ablation method, punctual vaporizing methods, photodynamic endometrial ablation method, microwave endometrial ablation method, the radiofrequency method menostat and a cryotherapy method.

The skin, the largest organ in the human body, is composed of a series of androgen-sensitive components that all express the steroidogenic enzymes required to transform dehydroepiandrosterone (DHEA) into dihydrotestosterone (DHT). In fact, in post-menopausal women, all sex steroids made in the skin are from adrenal steroid precursors, especially DHEA. Secretion of this precursor steroid by the adrenals decreases progressively from the age of 30 years to less than 50% of its maximal value at the age of 60 years. DHEA applied topically or by the oral route stimulates sebaceous gland activity, the changes observed being completely blocked in the rat by a pure antiandrogen while a pure antiestrogen has no significant effect, thus indicating a predominant or almost exclusive androgenic effect. In human skin, the enzyme that transforms DHEA into androstenedione is type 1 3beta-hydroxysteroid dehydrogenase (type 1 3beta-HSD) as revealed by RNase protection and immunocytochemistry. The conversion of androstenedione into testosterone is then catalyzed in the human skin by type 5 17beta-HSD. All the epidermal cells and cells of the sebaceous glands are labelled by type 5 17beta-HSD. This enzyme is also present at a high level in the hair follicles. Type 1 is the 5alpha-reductase isoform responsible in human skin for the conversion of testosterone into DHT. In the vagina, on the other hand, DHEA exerts mainly an estrogenic effect, this effect having been demonstrated in the rat as well as in post-menopausal women. On the other hand, in experimental animals as well as in post-menopausal women, DHEA, at physiological doses, does not affect the endometrial epithelium, thus indicating the absence of DHEA-converting enzymes in this tissue, and avoiding the need for progestins when DHEA is used as hormone replacement therapy., (Copyright 2001 S. Karger AG, Basel)

The objective of this study was to evaluate the endometrial response to sexual steroids in organ culture using two means: prostaglandin (PG) F(2alpha) output in medium culture and steroid receptor immunoexpression in tissue. Human endometrium samples were classified in homogeneous and heterogeneous proliferative or secretory subsets. In proliferative endometrium explant culture, progesterone (10(-7) M) induced a significant decrease in PGF(2alpha) output, but this was not the case in secretory endometrium, whereas no significant effect of estradiol (10(-8) M) was observed. Before culture, homogeneous and heterogeneous proliferative endometrium presented the same pattern of estradiol receptor (ER) and progesterone receptor (PR) expression evaluated by quantitative immunocytochemistry. After culture, immunoreactive ER and PR were detected on the explant. PR immunoexpression rates after culture were lower than before culture in glands on homogeneous proliferative and in stroma on heterogeneous proliferative endometrium explants without in vitro steroid addition. In secretory endometrium, no significant difference was observed between ER or PR immunoexpression rates before culture and after culture. These results provided the hormonal receptivity status of endometrium after culture and will thus serve as a reference for evaluating in vitro steroid effects on endometrium explants. Our preliminary results suggest that cultures of endometrium explants are a valid model for studying the effects of hormonal treatment on homogeneous as well as heterogeneous endometrium. These data could be particularly relevant for evaluating the potential response to hormone stimulation and treatment of endometria sampled in perimenopausal patients., (Copyright 2000 S. Karger AG, Basel)

Greatly thickened endometria are often observed in vaginal sonography in patients taking tamoxifen. The incidence of type I carcinoma of the endometrium is also raised under tamoxifen. Both effects are ascribed to the known partial estrogenic effect of tamoxifen. However, if sonographically hyperplastic endometria are abraded, mostly only atrophic material is obtained. To clarify this contradiction, 89 patients treated with tamoxifen were investigated by means of vaginal sonography at intervals of 6 months. In 33 of them (37%), an endometrial thickness > 8 mm was found. In order to investigate the endometrial thickness throughout, a hysteroscopic loop resection (polyps n = 18, diffuse hyperplasia n = 15) and afterwards histological work-up of the endometrium in serial sections were carried out in all these patients. Hyperplasia of the endometrial stroma without cellular atypia was found in all cases. However, the glandular epithelium was always atrophic. This explains the contradiction between sonographically thick endometrium (stromal hyperplasia) and the scanty abrasion material (atrophy of the glandular epithelium). The 'hyperplasia' found sonographically is not necessarily estrogen-dependent hyperplasia of the glandular epithelium leading to a carcinoma. This raised the question as to the etiological reasons for the increased incidence of carcinomas. We discuss the hypothesis that tamoxifen may also promote the conversion of pre-existent subclinical lesions into manifest carcinomas.

Environmental contaminants that are known to disrupt steroid action can influence the development of reproductive diseases. Our group has focused on whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) can disrupt steroid regulation of endometrial matrix metalloproteinase (MMP) expression. The MMPs regulate extracellular matrix turnover in normal tissues, but the inappropriate expression of these enzymes is associated with numerous disease states that involve invasive processes. We have previously shown that secretion of MMPs by human endometrium is critical for establishment of ectopic lesions in a nude mouse model of experimental endometriosis. In this report, we show that TCDD exposure promotes establishment of experimental endometriosis by interfering with the ability of progesterone to suppress endometrial MMP expression. Copyrightz1999S. KargerAG,Basel

Most patients with chronic renal failure who are on maintenance hemodialysis are anovulatory and have menstrual abnormalities. This study was designed to determine the prevalence of organic causes of abnormal uterine bleeding in this group of patients exposed to unopposed estrogens. Eighteen patients with chronic renal failure and abnormal uterine bleeding underwent vacuum curettage. The histopathologic findings were compared with a group of 154 premenopausal women who had abnormal uterine bleeding without detectable organic causes. Excluding patients with secretory and atrophic endometrium, only 2 of 8 patients (25%) with chronic renal failure had endometrial lesions while 44 of 131 patients (33.6%) had either endometrial polyp, simple or atypical endometrial hyperplasia or endometrial carcinoma (p > 0.05). The uremic environment caused by chronic renal failure does not alter the endometrial responsiveness to unopposed estrogens and may lead to the development of endometrial lesions.

Peritoneal fluid in women with endometriosis contains an increased number of activated macrophages that secrete a variety of cytokines, including interleukin (IL)-6, IL-8, vascular endothelial growth factor, and tumor necrosis factor-alpha (TNF-alpha). Cytokines may be involved in the control of implantation and the growth of endometrial cells outside the uterus. In addition, several cytokines have been implicated in or directly associated with angiogenic activity in endometriosis. There could be a relationship between the levels of cytokines in the peritoneal fluid of patients with endometriosis and the status of the lesions in such patients. Peritoneal endometriosis can be classified as having red, black, or white lesions. Red lesions are known to be an active form of early endometriosis, because vascularization and mitotic activity are shown to be most prominent in these lesions. We found that the peritoneal fluid levels of TNF-alpha and IL-8 were significantly higher in patients with endometriosis, and correlated with the size and number of active lesions. In addition, TNF-alpha and IL-8 stimulated the growth of ectopic endometrial stromal cells. These cytokines with angiogenic activity may therefore have significant roles in the pathogenesis of endometriosis.

The objective of this study was to examine the effect of transdermal estrogen therapy on the endometrial thickness and serum hormone levels in anovulatory patients treated with clomiphene citrate (CC). There was a significant difference in endometrial thickness between the CC + transdermal estrogen group and the CC only group from day -2 to day +2. Serum estradiol (E2) levels in the CC + transdermal estrogen group were significantly higher than those in the CC only group on day -2 and day 0. Our results support that addition of transdermal E2 to the treatment protocol of the women treated with CC elicited a favorable response of the endometrium.

Histological findings of endometrial specimens collected by hysteroscopy from 261 postmenopausal breast cancer patients with tamoxifen treatment (group I) and from endometrial specimens obtained following hysterectomy from 40 similar patients (group II) were compared. This comparison was performed in order to assess whether endometrial pathologies are more frequently diagnosed in specimens collected by hysterectomy than by those collected during hysteroscopy in such patients. Overall positive endometrial histological findings were significantly more common in group II patients than in group I patients (82.5 and 24.5%, respectively; p < 0.0001). Atrophic endometrium was significantly more common in group I patients than in group II patients (75.5 and 15.0%, respectively; p < 0.0001). All other different endometrial pathologies, except for proliferative endometrium, were significantly more common in group II patients than in group I patients (endometrial hyperplasia = 17.5 and 4.2%, respectively; p < 0.0003; endometrial polyps = 30.0 and 11. 5%, respectively; p < 0.006; endometrial polyps with hyperplasia = 17.5 and 4.2%, respectively; p < 0.0003; endometrial carcinoma = 15. 0 and 0.4%, respectively; p < 0.0001). These findings suggest that in postmenopausal breast cancer patients treated with tamoxifen, the frequency of various endometrial histological findings and of overall positive endometrial histological findings were significantly higher in specimens collected by hysterectomy than in specimens obtained by hysteroscopy.

Enterococcus faecalis plays an important role as a pathogen in polymicrobial infections. We evaluated the efficacy of cefozopran (CZOP) using polymicrobial pyometra rats. Rats were infected with a mixed intrauterine inoculation of E. faecalis plus either Bacteroides fragilis or Prevotella bivia (minimal inhibitory concentration of CZOP; E. faecalis: 6.25 micrograms/ml, B. fragilis: 12.5 micrograms/ml, P. bivia: 12.5 micrograms/ml). Immediately after inoculating 10(5) CFU of each organism/rat, CZOP (either 40 mg/kg, i.v., q.i.d., for 5 days or 80 mg/kg, i.v., b.i.d., for 5 days) was administered. The intrauterine inflammatory change and bacterial counts in the CZOP-treated group were compared with those in the nontreated control group. CZOP significantly (p < 0.01) decreased the bacterial counts except for B. fragilis in the regimen of 80 mg/kg b.i.d. However, the 40 mg/kg, q.i.d., regimen significantly (p < 0.05) reduced bacterial counts compared to 80 mg/kg, b.i.d. These results suggest that CZOP in a more divided dose is efficacious for the treatment of polymicrobial infections associated with E. faecalis in pyometra.

To know the biological functions of the adherens junction in uterine endometrium, mRNA expressions of E-cadherin and alpha- and beta-catenin. which mainly comprise the adherens junction, were determined. Furthermore, to understand various functions related to V-cadherin in the placenta. vessel permeability was determined by assessing V-cadherin mRNA expression in HUV-EC-C cells, derived from the endothelial cells in human umbilical cord. The levels of E-cadherin and alpha- and beta-catenin mRNAs in the endometria of the proliferative phase were significantly less than those of the secretory phase. Treatment with estradiol dipropionate significantly reduced their levels in the endometria of the secretory phase. These suggest that the functions of the adherens junction in endometrial epithelial cell are controlled by sex steroids. On the other hand, estradiol decreased the endothelial cell barrier properties in HUV-EC-C cells, whereas progesterone partly reversed the changes induced by estradiol. While estradiol decreased the level of V-cadherin mRNA in HUV-EC-C cells, progesterone partly reversed the level decreased by estradiol. Therefore, sex steroids play a role in placental development and function related to cadherins on the endothelial cells, probably via placental vessel permeability.

Objective: Our objective was to evaluate the direct effect of tamoxifen citrate (TAM) on the endometrium, liver, breast tissue and the lipid profile in oophorectomized (OX) rats., Study Design: An experimental animal study., Material and Methods: Forty-one mature rats (33 OX) were randomly divided into four groups and received either TAM (0.4 or 0.8 mg/kg p.o.) therapy or placebo over 60 days as follows: (1) sham; (2) OX + TAM (0.4 mg/kg); (3) OX + TAM (0.8 mg/kg); (4) OX. All histological changes in the endometrium, liver and breast tissue were evaluated under the light microscope by comparing the TAM-treated groups with the OX and sham-operated groups. Blood total cholesterol and low-density lipoprotein cholesterol levels were also analyzed., Results: TAM-treated rats showed a significant reduction in body weight, blood cholesterol and low-density lipoprotein cholesterol levels, but the wet uterine weight was not affected. Estrogenic effects of TAM were not detected with either dosage on the endometrium. TAM-treated groups showed atrophic breast tissue. No histopathological changes were detected in the liver with TAM treatment., Conclusion: The data suggests that TAM may not act as an estrogen receptor agonist with the given dosage on the endometrium in OX rats. Two different doses of TAM do not cause histological changes in liver over 60 days of treatment.

We investigated the effect of long-term administration of roxithromycin (RXM) on clinical responses and immune responses to chronic intrauterine infection, pyometra. One hundred and fifty milligrams of RXM were orally administered once a day for 3 months to patients with pyometra. Neutrophils and interleukin-8 (IL-8), which is a neutrophil chemotactic factor, in the lavage fluid of the uterine endometrial cavity obtained from 5 normal women and 18 patients with pyometra were investigated. Sixteen (88.9%) of the 18 patients showed a clinical improvement at the end of treatment. The immune responses occurred in the lavage fluid from the uterine endometrial cavity. Neutrophils accumulated in the lavage fluid of the uterine endometrial cavity before RXM treatment (p < 0.001 vs. normal subjects and decreased after RXM treatment (p < 0.001). The levels of IL-8 were significantly higher in the lavage fluid of pyometra patients than in normal women (p < 0.001), and tended to decrease after RXM treatment (p < 0.01). These results indicate that RXM decreases uterine endometrial cavity inflammation through reduction of neutrophil migration in inflammatory sites and is effective in treating chronic intrauterine infection.

In an attempt to assess the hypothesis that different endometrial sites may respond differently to tamoxifen exposure in postmenopausal women, hysteroscopic selected endometrial histology was investigated in 175 postmenopausal breast cancer patients who received continuous treatment with tamoxifen, and in 27 similar patients not treated with tamoxifen who served as controls. In the tamoxifen-treated patients 14 (8.0%) developed endometrial polyps. Of 14 patients, 8 (57.2%) each displayed atrophic endometrium in the same histologic specimen, 5 (35.7%) each had coexisting simple hyperplasia, and 1 (7.1%) other had complex hyperplasia. Another 21 (12.0%) developed simple or complex hyperplasia. The endometrial hyperplasia coexisted with atrophic endometrium in all these patients. All these lesions were selectively identified by hysteroscopic examination prior to the endometrial biopsy. In the control group 3 (11.0%) had simple hyperplasia and 2 (7.4%) had endometrial polyps. The above results support the hypothesis that the endometrium of postmenopausal breast cancer patients on tamoxifen treatment may possess different responses to tamoxifen exposure.

The effectiveness of two treatment regiments in inducing withdrawal bleeding in secondary amenorrhea was compared and correlated with the endometrial thickness and endogenous E2 and progesterone concentrations. A prospective, randomized and double-blind study was designed at the Outpatient Clinic of Reproductive Endocrinology, Central Emek Hospital, Afula, Israel. Seventy-seven premenopausal women with oligomenorrhea or amenorrhea, 48 of whom qualified for the study, underwent a 5-day course of either medroxyprogesterone acetate (MPA) 5 mg b.i.d. or dydrogesterone (DG) 10 mg b.i.d. Endogenous pretreatment values of E2 and progesterone and endometrial thickness (by transvaginal ultrasonography) were correlated with the bleeding response. Withdrawal bleeding occurred in 93% of women taking either MPA or DG. Side effects occurred similarly among the groups. Lipid concentrations were unchanged. Endogenous E2 and progesterone were limited predictive value for withdrawal bleeding. Endometrial thickness as measured by transvaginal sonography correlated significantly with the bleeding response.

The effects of gonadal steroids on the secretion and gene expression of macrophage colony-stimulating factor (M-CSF) and on the secretion of transforming growth factor (TGF)-beta 1 and TGF-beta 2 by human endometrial stromal cells (ESCs) were examined by an in vitro system of ESC differentiation (decidualization). M-CSF production by ESCs was dose-dependently enhanced by the addition of progesterone or testosterone, while estradiol treatment had no effect. TGF-beta 2 secretion by ESCs was inhibited by progesterone, estradiol and testosterone treatment, and on the contrary, slight enhancement by estradiol was observed in TGF-beta 1 secretion. These findings indicate that human ESCs produce cytokines of M-CSF and TGF-beta s, which are important for the growth and differentiation of the peri-implantation embryo as well as local immune cells under direct control of gonadal steroidal actions, and suggest a novel network between endocrine and immune systems in the human endometrium.

The direct effect of danazol on the DNA synthesis and ultrastructure of human cultured endometrial stromal cells was studied. The analysis of the [3H]thymidine incorporation in the endometrial stromal cells cultured for 10 days indicated that the DNA synthesis was inhibited in a dose-dependent manner by danazol and testosterone, but not by medroxyprogesterone. The effect of 10(-7) M of danazol was blocked by cyproterone acetate, but RU-486 did not show any influence. The observation of the ultrastructure of the cultured cells revealed that 10(-7) M of danazol increased cytoplasmic lysosomes; however, 10(-5) M of danazol destroyed cell organelles and cytoskeleton resulted from the cell death. These results indicated that the biological effects of danazol were mainly mediated by androgen receptors, and 10(-5) M of danazol exhibited the toxic effect on the endometrial stromal cells.

To the best of our knowledge, this is the first report of in vivo endometrial estrogen and progesterone receptor induction as a result of tamoxifen exposure in a postmenopausal breast cancer patient. The following observations, that the postmenopausal endometrium is sensitive to tamoxifen, that this agent can act as an estrogen-like substance, and that it may cause proliferation of the endometrium in the absence of progestin, may explain the endometrial decidual changes described herein as a protective mechanism against possible neoplastic endometrial changes.

To examine antiestrogenic effects of danazol through the receptor system and to clarify its direct effects on the endometrium in vivo, we applied danazol jelly directly into the rabbit uterine cavity and measured uterine estrogen, progesterone and androgen receptors (ER, PR and AR, respectively). Danazol significantly reduced ER, PR and AR (p < 0.05). Treatment with receptor-blocking agents (RU 486 and oxendolone) showed that the decrease in the ER level showed a closer association with that in PR than with AR. These results indicate that danazol directly administered into the uterine cavity is absorbed by the endometrial tissue and exerts its antiestrogenic effects possibly through PR in the cells.

The antiestrogenic action of clomiphene citrate (CC) is claimed to have an adverse effect on the development of the secretory endometrium. This effect can be assessed: (1) sonographically by measuring endometrial thickness, and (2) by serum hormone levels. The aim of this study was to evaluate whether administering ethinyl estradiol (EE) during CC treatment has any effect on endometrial thickness and/or hormone levels. Seventeen patients were treated with CC for one cycle and with CC plus EE in an adjacent cycle either before or after. The patients were followed by daily assessment of endometrial thickness, follicular growth and serum estradiol levels as well as midluteal prolactin and progesterone levels. We did not find any significant difference in either endometrial thickness, estradiol level, midluteal prolactin or progesterone levels between the two treatment protocols. We conclude that exogenous EE, in the dosage used in this study, does not overcome CC-induced alterations in endometrial thickness.

Scanning electron microscopy was used to evaluate the uterine luminal epithelium from ovariectomized rats treated with a single minimal physiological dose of clomiphene citrate, oestradiol-17 beta or progesterone. It was found that clomiphene treatment produced some ultrastructural surface features which were similar to those seen with both oestrogen and progesterone treatment, but in addition it produced features unique to clomiphene treatment.

Hormonal alterations and pregnancy rates were compared between the clomiphene citrate (CC)-hMG combination cycle and the hMG cycle alone in an in vitro fertilization and embryo transfer program. In the CC-hMG cycle, the numbers of follicles developed, oocytes recovered and embryos transferred were higher than those in the hMG cycle (p less than 0.01, p less than 0.01 and p less than 0.05, respectively). Pregnancy rates of the CC-hMG cycle (6.7%/operation, 7.1%/embryo transfer), however, were lower than those of the hMG cycle (25%/operation, 31.6%/embryo transfer). PRL levels in the hMG cycle increased according to estradiol levels. In the CC-hMG cycle, CC might inhibit estradiol-induced hyperprolactinemia and the increase was lower even if the estradiol level was much higher than that of the hMG cycle until day 2. On day 4, the PRL level in the CC-hMG cycle further increased. The thickness of endometrium on day -2 in the hMG cycle alone was much thicker than that in the CC-hMG cycle (9.8 +/- 0.4 vs. 6.8 +/- 0.4 mm, mean +/- SEM).

We report the effects of PRL on cultured human endometrial cells (epithelial cells and stromal cells) and discuss the role of PRL in implantation. Essentially similar responses to PRL in cell attachment and growth were obtained both in epithelial and stromal cells: a low concentration of PRL (3-30 ng/ml of PRL) enhanced cell attachment and growth. In contrast, the presence of a high concentration of PRL (over 100 ng/ml) resulted in a decrease in cell attachment and growth in normal culture conditions. Morphological analysis of epithelial glandular reformation on basement membrane extracts indicated that PRL had dual effects on endometrial epithelial cells: as a stimulator in low concentrations and an inhibitor in high concentrations. These data suggest that PRL may influence the functions of human endometrial cells in a dual way depending on its level and plays an important role in the implantation process.

The glandular structure in the uterine epithelium of three groups of patients on standard superovulatory regimes was studied using a fully automated image analysis system. It was found that one treatment (buserelin stimulation) produced more glandular area than either of the other two. We suggest that buserelin gives the morphometric appearance of the most normal endometrial glands and find that our morphometric analysis is a reliable means to evaluate glandular structure in patients on superovulatory therapy.