Use of Hysterosalpingo-Foam Sonography for Assessment of the Efficacy of Essure Hysteroscopic Sterilization.

OBJECTIVES: Hysterosalpingo-foam sonography (HyFoSy) has been suggested to be a possible less invasive alternative to hysterosalpingography (HSG), which is the reference standard for confirmation of tubal occlusion after Essure (Bayer AG, Leverkusen, Germany) hysteroscopic sterilization. The purpose of our study was to evaluate the accuracy of HyFoSy compared to HSG for confirmation of tubal occlusion after Essure hysteroscopic sterilization. METHODS: A prospective study included 90 patients who underwent Essure hysteroscopic sterilization. Twelve weeks after the sterilization, 2-dimensional transvaginal ultrasonography was performed to assess the microinsert position and was followed by HyFoSy and HSG for evaluation of tubal occlusion. Patients with patent fallopian tubes on HSG were scheduled for additional HSG procedures at 3-month intervals until tubal occlusion was documented. RESULTS: Of 90 enrolled patients, 86 patients with 170 fallopian tubes underwent the complete imaging protocol. Tubal occlusion was evaluated by HyFoSy as an index test and HSG as a reference standard. The accuracy of HyFoSy was 97.1% (95% confidence interval [CI], 93%-99%). The sensitivity and specificity were 100% (95% CI, 97%-100%) and 54.6% (95% CI, 23%-83%), whereas the positive and negative predictive values were 97.0% (95% CI, 93%-99%) and 100% (95% CI, 42%-100%), respectively. No long-term complications were reported for HyFoSy or HSG. CONCLUSIONS: Given that the concordance rate for tubal occlusion between HyFoSy and HSG was not 100%, an occluded fallopian tube on HyFoSy should be confirmed by HSG, which remains the reference standard for confirmation of tubal occlusion after Essure hysteroscopic sterilization.

Incidence of positive peritoneal cytology in patients with endometrial carcinoma after hysteroscopy vs. dilatation and curettage.

BACKGROUND: The aim of the study was to compare the frequency of positive peritoneal washings in endometrial cancer patients after either hysteroscopy (HSC) or dilatation and curettage (D&C). PATIENTS AND METHODS: We performed a retrospective analysis of 227 patients who underwent either HSC (N = 144) or D&C (N = 83) and were diagnosed with endometrial carcinoma at the University Medical Centre Maribor between January 2008 and December 2014. The incidence of positive peritoneal cytology was evaluated in each group. RESULTS: There was no overall difference in the incidence of positive peritoneal washings after HSC or D&C (HSC = 13.2%; D&C = 12.0%; p = 0.803). However, a detailed analysis of stage I disease revealed significantly higher rates of positive peritoneal washings in the HSC group (HSC = 12.8%; D&C = 3.4%; p = 0.046). Among these patients, there was no difference between both groups considering histologic type (chi-square = 0.059; p = 0.807), tumour differentiation (chi-square = 3.709; p = 0.156), the time between diagnosis and operation (t = 0.930; p = 0.357), and myometrial invasion (chi-square = 5.073; p = 0.079). CONCLUSIONS: Although the diagnostic procedure did not influence the overall incidence of positive peritoneal washings, HSC was associated with a significantly higher rate of positive peritoneal cytology in stage I endometrial carcinoma compared to D&C.

Preoperative diagnosis of fallopian tube malignancy with transvaginal color doppler ultrasonography and magnetic resonance imaging after negative hysteroscopy for postmenopausal bleeding.

Primary fallopian tube carcinoma is a rare malignancy and is not often diagnosed preoperatively. We present a case of a 67-year-old woman who complained of postmenopausal vaginal bleeding. After a negative hysteroscopy, transvaginal ultrasound showed a well vascularized solid-cystic tumor in the adnexal region separate from the ovary. The presence of an adnexal mass was confirmed by MR imaging. Total abdominal hysterectomy with bilateral salpingoophorectomy, omentectomy and appendectomy, as well as pelvic and paraaortic lymphadenectomy was performed. The pathohistological diagnosis was poorly differentiated serous adenocarcinoma of the fallopian tube, FIGO stage IA. The patient was subsequently treated with platinum based adjuvant chemotherapy.

Inverse correlation of carotid intima-media thickness with raloxifene serum levels in osteoporosis.

BACKGROUND: Raloxifene is a selective oestrogen receptor modulator with effects on bone and breast cancer and cardiovascular disease risk. The aim of this study was to examine the influence of raloxifene treatment on surrogate markers of atherosclerosis and the correlation of these markers with raloxifene serum concentrations. METHODS: A prospective clinical trial on 53 postmenopausal osteoporotic women treated with raloxifene was performed. Surrogate markers of atherosclerosis (flow-mediated vasodilatation, glyceryltrinitrate-induced vasodilatation of the brachial artery, carotid intima-media thickness (c-IMT), inter-cell adhesion molecule-1, vascular-cell adhesion molecule-1 and E-selectin) were measured before and after 6 months of treatment. Serum concentrations of raloxifene and raloxifene metabolites were assessed after 12 months of treatment. The tested markers were correlated with measured serum concentrations of raloxifene species. RESULTS: Among the tested surrogate markers of atherosclerosis c-IMT, E-selectin and ICAM changed significantly during treatment. A negative correlation of the non-metabolized raloxifene serum levels with the percentage change of c-IMT during treatment (r = - 0.315, p = 0.048) was found. Likewise, the sum of the levels of three raloxifene metabolites, raloxifene-6-b-glucuronide (M1), raloxifene-4'-b-glucuronide (M2) and raloxifene-6,4'-diglucuronide (M3) in serum showed a negative correlation with the percentage change of c-IMT during treatment (r = - 0.375, p = 0.017). For the other tested parameters, no correlation with raloxifene serum levels was found. CONCLUSIONS: To the best of our knowledge, this is the first study correlating raloxifene species serum concentrations with changes in the surrogate markers of atherosclerosis. A greater decrease of c-IMT in patients with higher raloxifene concentrations could contribute to a lower risk of cardiovascular events in these patients.

XbaI polymorphism of the estrogen receptor alpha gene influences the effect of raloxifene on the endothelial function.

OBJECTIVES: Cardiovascular disease is the leading cause of death in postmenopausal women and estrogen deficiency may be an important factor in its development. The selective estrogen receptor modulator, raloxifene, exerts a part of its actions through the estrogen receptor alpha (ESR1) activation. We explored if polymorphisms of the ESR1 modify the effects of 6 months raloxifene treatment on endothelial function. METHODS: A total of 53 postmenopausal women, mean age 59.7+/-6.2, finished the prospective clinical trial. The PvuII, XbaI, and P325P polymorphisms of the ESR1 gene were analyzed. In all subjects endothelium-dependent flow mediated dilatation (FMD) and cell adhesion molecules (CAM) ICAM-1, VCAM-1 and E-selectin were measured before and after 6 months of raloxifene treatment. RESULTS: There was no difference in FMD between the ESR1 genotypes, at baseline. After raloxifene treatment, the FMD was significantly greater in subjects with XX genotype of XbaI polymorphism compared to xx (p=0.03) and borderline greater when compared to Xx genotype (p=0.053). The FMD increased significantly with raloxifene treatment in women with Xx genotype of XbaI and Pp genotype of PvuII polymorphisms (p=0.027 and p=0.034, respectively). The P325P polymorphism did not influence the FMD after raloxifene. None of the ESR1 gene polymorphisms had any impact on the levels of CAM before or after the treatment. When analysing the whole group, a significant decrease in E-selectin (p<0.001) and a small increase in ICAM-1 levels (p=0.029) was observed with raloxifene treatment, but no influence on VCAM-1 levels or FMD overall was seen. CONCLUSION: Our data suggest that XbaI and possibly PvuII polymorphisms of the ESR1 gene influence the impact of raloxifene treatment on endothelial function. This effect could be of pharmacogenomic and clinical importance.

Office hysteroscopy and the risk of microscopic extrauterine spread in endometrial cancer.

OBJECTIVE: The aim of this study was to evaluate the incidence of tumor cell dissemination according to diagnostic modality in patients with endometrial cancer. METHODS: A retrospective study was conducted on 146 patients with endometrial cancer in whom one of the following diagnostic methods was performed: dilation and curettage (D&C, n=122) or office hysteroscopy (HSC, n=24). No selection or randomization of patients was applied to the groups. The presence of suspicious or positive peritoneal cytology as well as adnexal or abdominal metastases was considered the endpoint of this analysis. RESULTS: Suspicious or positive peritoneal cytology was present in two patients (1.6%) after D&C and in three patients (12.5%) after HSC (chi2=4.2455; p<0.05). Adnexal metastases were present in 10 (8.2%) patients after D&C and in 1 patient (4.2%) after HSC (chi2=0.0680; p>0.05). Metastases to abdominal cavity were found in 3 (2.5%) patients after D&C and in 1 patient after HSC (chi2=0.0464; p>0.05). Lymph node metastases were found in 7 patients (5.7%) after D&C and in 2 patients (8.3%) after HSC (chi2=0.0004; p>0.05). After complete histopathological analysis, upstaging due to positive peritoneal cytology and adnexal or abdominal metastases was necessary in 11 patients (9.0%) from the D&C group and in 3 patients (12.5%) from the HSC group, but the difference was not significant (chi2=0.2227; p>0.05). CONCLUSIONS: These data show that diagnostic HSC significantly increases the risk of positive peritoneal cytology, but not the risk of adnexal, abdominal or retroperitoneal lymph node metastases in patients with EC.

Role of endothelial function and inflammation in patients with cardiovascular risk factors, with and without a history of myocardial infarction.

BACKGROUND: Endothelial dysfunction and inflammation, in particular their lack of improvement after risk reduction, might better reflect advanced atherosclerosis than just the presence of risk factors. The aim of this study was to compare endothelial function and inflammatory parameters in high-risk patients who had no history of myocardial infarction and in patients in a stable phase after myocardial infarction. METHODS: We compared endothelial function of the brachial artery, measured using high-resolution ultrasound, in 45 patients with hyperlipidaemia (Group 1), and in 45 patients in a stable period after myocardial infarction (Group 2). Forty-five healthy individuals served as a control group (Group 3). RESULTS: Compared to patients with treated hyperlipidaemia, patients after myocardial infarction had lower values of total and LDL cholesterol (p = 0.015; 0.005) and homocysteine (p < 0.005), but marginally higher IL-6 levels (p = 0.1). Other measurements were comparable. However, flow-mediated dilation of the brachial artery was significantly diminished in patients after myocardial infarction (10.6 +/- 3.0; 5.9 +/- 4.0; 14.0 +/- 1.9% for Groups 1-3; ANOVA p = 0.0001; respectively). CONCLUSIONS: We found that patients with previous myocardial infarction have substantially lower endothelial function and increased some inflammatory parameters than patients with a similar level of atherosclerotic risk profile but without clinically evident coronary artery disease.

The effect of various menopausal hormone therapies on markers of inflammation, coagulation, fibrinolysis, lipids, and lipoproteins in healthy postmenopausal women.

OBJECTIVE: Androgenic progestins such as norethisterone acetate (NETA) may influence the effect of estradiol (E(2)) therapy. We compared the influence of oral E(2), with and without NETA, and transdermal E(2) on markers of coagulation, fibrinolysis, and inflammation and on lipids and lipoproteins in healthy postmenopausal women. DESIGN: A total of 112 healthy postmenopausal women were randomized to receive treatment with either oral E(2), with or without NETA, transdermal E(2), or placebo. At baseline and after 28 weeks, levels of serum lipids and lipoproteins and markers of coagulation, fibrinolysis, and inflammation were determined. RESULTS: Of the fibrinolytic parameters, oral E(2) (P < 0.05) and E(2) with NETA (P < 0.01) shortened euglobulin clot lysis time. Oral E(2) decreased plasminogen activator inhibitor-1 activity (P < 0.05). Oral E(2) with NETA reduced plasminogen activator inhibitor-1 antigen levels (P < 0.01) and increased D-dimer antigen levels (P < 0.001). All three modes of menopausal hormone therapy reduced tissue type plasminogen activator antigen. Of the coagulation parameters, both routes of E(2) therapy decreased fibrinogen levels (P = 0.002 for oral and P = 0.007 for transdermal E(2)), whereas E(2) with NETA showed no effect. The decrease of fibrinogen was larger after oral E(2) (P = 0.02). Oral E(2) with NETA reduced antithrombin III (P < 0.001) and protein C (P < 0.001) activity. Oral E(2) (P = 0.04) and E(2) with NETA (P < 0.01) increased C-reactive protein (CRP). Transdermal E(2) showed no influence on CRP. The addition of NETA influenced the change in CRP, as the increase in CRP was more pronounced after E(2) without NETA (P = 0.005). The levels of serum amyloid A, interleukin-6, and tumor necrosis factor-alpha did not change significantly after any of the modes of hormone therapy. Of the lipids and lipoproteins, oral E2 decreased low-density lipoprotein cholesterol (P < 0.01), lipoprotein (a) (P < 0.05), and increased high-density lipoprotein cholesterol (P < 0.05). Transdermal E(2) decreased triglycerides (P < 0.02) and increased high-density lipoprotein cholesterol (P < 0.03). Oral E(2) with NETA decreased total cholesterol (P < 0.01) and high-density lipoprotein cholesterol (P < 0.005). CONCLUSIONS: Oral E(2), with or without NETA, produced no net activation of coagulation but improved fibrinolysis. Both modes of oral menopausal hormone therapy have a greater impact on markers of inflammation, coagulation, fibrinolysis, lipids, and lipoproteins than transdermal E(2). NETA attenuates some E(2) effects. Further studies are needed to elucidate the impact of these effects on clinical endpoints.

Determinants of endothelial dysfunction and carotid intima-media thickness in combined hyperlipidemia.

BACKGROUND: Early functional and morphological changes in the course of the atherosclerotic process are manifested as endothelial dysfunction and increased intima-media thickness (IMT) of the arterial wall. These are both associated with various atherosclerotic risk factors. We investigated whether the same factors are associated with functional and morphological changes of the arterial wall in men with combined hyperlipidemia. METHODS: Flow-mediated dilatation (FMD) of the brachial artery and carotid IMT were measured in 72 male patients aged 46+/-5 years with combined hyperlipidemia. Serum lipoproteins, fibrinolytic and coagulation parameters, blood glucose, proinflammatory cytokines and C-reactive protein were also measured. RESULTS: Tumor necrosis factor-alpha, interleukin 6 and apolipoprotein (apo) B were found to be independent predictors of FMD, explaining 87% of FMD variability in multivariate analysis. On the other hand, total tissue factor pathway inhibitor and apo B were independent predictors of increased carotid IMT, explaining 82% of the variation in carotid IMT. CONCLUSIONS: Apo B, which is a marker for the presence of the atherogenic lipoproteins, is associated with both functional and morphological changes of the artery wall. In addition, in asymptomatic overweight middle-aged men with combined hyperlipidemia, functional changes are associated with proinflammatory cytokines, while morphological changes are associated with coagulation parameters.

Statin and fibrate treatment of combined hyperlipidemia: the effects on some novel risk factors.

The effects of cerivastatin and fenofibrate on proteins involved in haemostasis and on markers of inflammation were investigated in otherwise healthy middle-aged males with combined hyperlipidemia. Besides classical risk factors, other so-called novel risk factors for coronary artery disease are seen to be playing an increasingly important role in the development and progression of atherosclerosis. Thirty-eight males, aged 49 +/-5 years were randomised to 12 weeks treatment either with cerivastatin at a daily dose of 0.2 mg to 0.4 mg to achieve the LDL cholesterol goal of <3.0 mM, or with fenofibrate 250 mg daily. Fasting serum lipids, homocysteine, total and free tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor (PAI-1) and tissue plasminogen activator (t-PA) antigen and activity, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured. No change in homocysteine level was observed in the cerivastatin group, while after fenofibrate administration it increased (p <0.0001). Total TFPI decreased significantly after cerivastatin (p = 0.002), but not after fenofibrate. Free TFPI did not decrease after either drug. Neither drug affected (t-PA) antigen and activity, while fenofibrate increased PAI-1 antigen (p <0.05) and activity (p <0.05). Cerivastatin decreased serum CRP values by 49.5% (p = 0.001), and fenofibrate by 29.8% (p = 0.03). The decreases of CRP in the two groups differed significantly (p = 0.04). IL-6 levels decreased significantly in the fenofibrate group (39%; p <0.0001), but not in the cerivastatin group (15%; p = 0.24) No significant decreases were observed for TNF-alpha. Cerivastatin had neutral effects on fibrinolysis, homocysteine or coagulation. On the other hand, fenofibrate increased PAI-1 antigen and activity and homocysteine, and did not affect coagulation. Both cerivastatin and fenofibrate reduced CRP levels, the decrease being significantly greater after cerivastatin. Fenofibrate also significantly decreased IL-6.

Orally and transdermally replaced estradiol improves endothelial function equally in middle-aged women after surgical menopause.

OBJECTIVE: Improvement in endothelial function may be an important mechanism by which estrogen replacement therapy protects postmenopausal women against coronary artery disease. We determined whether the vascular effects of estradiol depend on the route of administration. STUDY DESIGN: Six weeks after surgically induced menopause, 43 healthy women were assigned randomly to 28 weeks of treatment by either orally or transdermally replaced estradiol. Endothelium-dependent and endothelium-independent dilation were calculated with the use of the diameters of the brachial artery that were measured at rest by high resolution ultrasound scanning after reactive hyperemia and after sublingual glyceryl trinitrate. RESULTS: Endothelium-dependent dilation increased after oral estradiol replacement from 6% +/- 3.9% to 13.2% +/- 4.4% (P <.0001) and after transdermal estradiol replacement from 7% +/- 4.9% to 14.9% +/- 5.6%(P <.0001). Endothelium-independent dilation did not change significantly in either group. The improvements in endothelium-dependent dilation after estrogen substitution were independent of the changes in blood lipids and lipoproteins. CONCLUSION: Both oral and transdermal long-term replacement of estradiol lead to improved endothelial function in healthy middle-aged women after surgically induced menopause.

Double blind, randomized study of estradiol replacement therapy on markers of inflammation, coagulation and fibrinolysis.

Estrogen replacement therapy (ERT) has been found to be associated with increased cardiovascular risk in the first year after initiation of ERT. We compared the effects of oral and transdermal estradiol (E2) replacement therapy on markers of inflammation, coagulation and fibrinolysis in a randomized double-blind trial. Forty-three healthy women were randomized 6 weeks after surgically induced menopause to receive treatment with either oral or transdermal E2 over a period of 28 weeks. At baseline and after 28 weeks, levels of serum lipids and lipoproteins, and markers of coagulation, fibrinolysis and inflammation were determined. Among fibrinolytic parameters, oral E2 shortened euglobulin clot lysis time (P<0.05) and reduced tissue type plasminogen activator antigen (P=0.01) and plasminogen activator inhibitor activity (P<0.05). Among coagulation parameters, both routes of E2 replacement decreased fibrinogen levels (P=0.002 for oral and P=0.007 for transdermal E2). Oral E2 resulted in an increase in C-reactive protein (CRP) from 2.15 (0.71-4.05) to 3.41 (1.12-5.92) mg/l (P=0.04), while transdermal E2 showed no effect. Levels of serum amyloid A (SAA), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) did not change significantly after oral and transdermal E2. Oral E2 significantly improved the lipid profile, while transdermal E2 had a less pronounced effect. Both oral and transdermal E2 significantly reduced fasting glucose. Oral E2 was associated with a pro-inflammatory response, but at the same time improved fibrinolytic capacity, showed no pro-coagulatory effects, and acted beneficially on lipids and lipoproteins. There was no influence of transdermal E2 on markers of coagulation activation, fibrinolysis and inflammation, but it decreased fibrinogen levels significantly. Further studies are needed to explore the clinical relevance of these observations.