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ObjectivesIn patients with an ovarian mass, a risk of malignancy assessment is used to decide whether referral to an oncology hospital is indicated. Risk assessment strategies do not perform optimally, resulting in either referral of patients with a benign mass or patients with a malignant mass not being referred. This process may affect the psychological well-being of patients. We evaluated cancer-specific distress during work-up for an ovarian mass, and patients’ perceptions during work-up, referral, and treatment.MethodsPatients with an ovarian mass scheduled for surgery were enrolled. Using questionnaires we measured (1) cancer-specific distress using the cancer worry scale, (2) patients’ preferences regarding referral (evaluated pre-operatively), and (3) patients’ experiences with work-up and treatment (evaluated post-operatively). A cancer worry scale score of ≥14 was considered as clinically significant cancer-specific distress.ResultsA total of 417 patients were included, of whom 220 (53%) were treated at a general hospital and 197 (47%) at an oncology hospital. Overall, 57% had a cancer worry scale score of ≥14 and this was higher in referred patients (69%) than in patients treated at a general hospital (43%). 53% of the patients stated that the cancer risk should not be higher than 25% to undergo surgery at a general hospital. 96% of all patients were satisfied with the overall work-up and treatment. No difference in satisfaction was observed between patients correctly (not) referred and patients incorrectly (not) referred.ConclusionsRelatively many patients with an ovarian mass experienced high cancer-specific distress during work-up. Nevertheless, patients were satisfied with the treatment, regardless of the final diagnosis and the location of treatment. Moreover, patients preferred to be referred even if there was only a relatively low probability of having ovarian cancer. Patients’ preferences should be taken into account when deciding on optimal cut-offs for risk assessment strategies.

Cervical screening can prevent cancer by detection and treatment of cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3). Screening also results in considerable overtreatment because many CIN2/3 lesions show spontaneous regression when left untreated. In this multicenter longitudinal cohort study of women with untreated CIN2/3, the prognostic value ofWomen with CIN2/3 were prospectively followed for 24 months. Surgical excision was replaced by a wait-and-see policy.One hundred fourteen women (median age, 30 years; range, 20-53 years) were included, 80 of whom were diagnosed with CIN2 and 34 with CIN3. During the study, 65.8% of women (75/114) did not receive surgical treatment. Women with aMost women with untreated CIN2/3 and a negative baseline

PURPOSE Cervical screening can prevent cancer by detection and treatment of cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3). Screening also results in considerable overtreatment because many CIN2/3 lesions show spontaneous regression when left untreated. In this multicenter longitudinal cohort study of women with untreated CIN2/3, the prognostic value of FAM19A4/miR124-2 methylation was evaluated for clinical regression. PATIENTS AND METHODS Women with CIN2/3 were prospectively followed for 24 months. Surgical excision was replaced by a wait-and-see policy. FAM19A4/miR124-2 methylation was evaluated on all clinician-collected samples and self-collected samples collected at baseline. Every 6 months, human papillomavirus (HPV) testing and cytology were conducted on a clinician-collected sample, and a colposcopic examination was performed by a gynecologist to exclude progression. At the final study visit, two biopsies were taken. Clinical regression was defined as histologically confirmed absence of CIN2+ or an HPV-negative clinician-collected sample with normal cytology. Regression incidences were estimated using the Kaplan-Meier method. RESULTS One hundred fourteen women (median age, 30 years; range, 20-53 years) were included, 80 of whom were diagnosed with CIN2 and 34 with CIN3. During the study, 65.8% of women (75/114) did not receive surgical treatment. Women with a negative FAM19A4/miR124-2 result on the baseline clinician-collected sample showed more clinical regression (74.7%) than women with a positive methylation result (51.4%, P = .013). Regression in women with a negative FAM19A4/miR124-2 methylation test was highest when cytology was atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion (88.4%) or HPV16 was negative (85.1%). CONCLUSION Most women with untreated CIN2/3 and a negative baseline FAM19A4/miR124-2 methylation test showed clinical regression. Methylation, in combination with cytology or HPV genotyping, can be used to support a wait-and-see policy in women with CIN2/3.

Contains fulltext : 215610.pdf (Publisher’s version ) (Open Access) BACKGROUND: Support for guiding and monitoring postoperative recovery and resumption of activities is usually not provided to patients after discharge from the hospital. Therefore, a perioperative electronic health (eHealth) intervention ("ikherstel" intervention or "I recover" intervention) was developed to empower gynecological patients during the perioperative period. This eHealth intervention requires a need for further development for patients who will undergo various types of general surgical and gynecological procedures. OBJECTIVE: This study aimed to further develop the "ikherstel" eHealth intervention using Intervention Mapping (IM) to fit a broader patient population. METHODS: The IM protocol was used to guide further development of the "ikherstel" intervention. First, patients' needs were identified using (1) the information of a process evaluation of the earlier performed "ikherstel" study, (2) a review of the literature, (3) a survey study, and (4) focus group discussions (FGDs) among stakeholders. Next, program outcomes and change objectives were defined. Third, behavior change theories and practical tools were selected for the intervention program. Finally, an implementation and evaluation plan was developed. RESULTS: The outcome for an eHealth intervention tool for patients recovering from abdominal general surgical and gynecological procedures was redefined as "achieving earlier recovery including return to normal activities and work." The Attitude-Social Influence-Self-Efficacy model was used as a theoretical framework to transform personal and external determinants into change objectives of personal behavior. The knowledge gathered by needs assessment and using the theoretical framework in the preparatory steps of the IM protocol resulted in additional tools. A mobile app, an activity tracker, and an electronic consultation (eConsult) will be incorporated in the further developed eHealth intervention. This intervention will be evaluated in a multicenter, single-blinded randomized controlled trial with 18 departments in 11 participating hospitals in the Netherlands. CONCLUSIONS: The intervention is extended to patients undergoing general surgical procedures and for malignant indications. New intervention tools such as a mobile app, an activity tracker, and an eConsult were developed. TRIAL REGISTRATION: Netherlands Trial Registry NTR5686; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5686.

Women treated for high-grade cervical intraepithelial neoplasia (CIN) are at risk of recurrent CIN Grade 2 or worse (rCIN2+). Currently, posttreatment monitoring is performed using cytology or cytology/high-risk (hr)HPV cotesting. This study aimed to evaluate the performance of p16/Ki-67 dual-stained cytology (p16/Ki-67) for posttreatment monitoring. Three hundred and twenty-three women treated for high-grade CIN in the SIMONATH study underwent close surveillance by cytology, hrHPV and DNA methylation marker testing up to 12 months posttreatment. Histological endpoints were ascertained by colposcopy with biopsy at 6 and/or 12 months. p16/Ki-67 dual-staining was performed on residual liquid-based cytology samples obtained at, or shortly before biopsy collection. Clinical performance estimates of cytology, hrHPV, p16/Ki-67 testing and combinations thereof for the detection of rCIN2+ were determined and compared to each other. Sensitivity of p16/Ki-67 for rCIN2+ (69.2%) was nonsignificantly lower than that of cytology (82.1%; ratio 0.84, 95% CI: 0.71-1.01), but significantly lower than that of hrHPV testing (84.6%; ratio 0.82, 95% CI: 0.68-0.99). Specificity of p16/Ki-67 for rCIN2+ (90.4%) was significantly higher compared to both cytology (70.8%; ratio 1.28, 95% CI: 1.19-1.37) and hrHPV testing (76.2%; ratio 1.19, 95% CI: 1.12-1.26). Overall, hrHPV testing showed very high sensitivity, along with a good specificity. When considering cotesting, combined p16/Ki-67/hrHPV testing showed rCIN2+ sensitivity comparable to cytology/hrHPV cotesting (87.2% vs. 89.7%; ratio 0.97, 95% CI: 0.92-1.03), but with significantly increased specificity (74.2% vs. 58.1%; ratio 1.28, 95% CI: 1.19-1.38). Thus, when considered in combination with hrHPV, p16/Ki-67 might be an attractive approach for surveillance of women treated for high-grade CIN.

BACKGROUND Support for guiding and monitoring postoperative recovery and resumption of activities is usually not provided to patients after discharge from the hospital. Therefore, a perioperative electronic health (eHealth) intervention (“ikherstel” intervention or “I recover” intervention) was developed to empower gynecological patients during the perioperative period. This eHealth intervention requires a need for further development for patients who will undergo various types of general surgical and gynecological procedures. OBJECTIVE This study aimed to further develop the “ikherstel” eHealth intervention using Intervention Mapping (IM) to fit a broader patient population. METHODS The IM protocol was used to guide further development of the “ikherstel” intervention. First, patients’ needs were identified using (1) the information of a process evaluation of the earlier performed “ikherstel” study, (2) a review of the literature, (3) a survey study, and (4) focus group discussions (FGDs) among stakeholders. Next, program outcomes and change objectives were defined. Third, behavior change theories and practical tools were selected for the intervention program. Finally, an implementation and evaluation plan was developed. RESULTS The outcome for an eHealth intervention tool for patients recovering from abdominal general surgical and gynecological procedures was redefined as “achieving earlier recovery including return to normal activities and work.” The Attitude-Social Influence-Self-Efficacy model was used as a theoretical framework to transform personal and external determinants into change objectives of personal behavior. The knowledge gathered by needs assessment and using the theoretical framework in the preparatory steps of the IM protocol resulted in additional tools. A mobile app, an activity tracker, and an electronic consultation (eConsult) will be incorporated in the further developed eHealth intervention. This intervention will be evaluated in a multicenter, single-blinded randomized controlled trial with 18 departments in 11 participating hospitals in the Netherlands. CONCLUSIONS The intervention is extended to patients undergoing general surgical procedures and for malignant indications. New intervention tools such as a mobile app, an activity tracker, and an eConsult were developed. CLINICALTRIAL Netherlands Trial Registry NTR5686; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5686

Recently, DNA methylation analysis of FAM19A4 in cervical scrapes has been shown to adequately detect high-grade cervical intraepithelial neoplasia and cervical cancer (≥ CIN3) in high-risk HPV (hrHPV)-positive women. Here, we compared the clinical performance of FAM19A4 methylation analysis to cytology and HPV16/18 genotyping, separately and in combination, for ≥ CIN3 detection in hrHPV-positive women participating in a prospective observational multi-center cohort study. The study population comprised hrHPV-positive women aged 18-66 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy-directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed for FAM19A4 gene promoter methylation, cytology and HPV16/18 genotyping. Methylation analysis was performed by quantitative methylation-specific PCR (qMSP). Sensitivities and specificities for ≥ CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV-positive women, the sensitivities for ≥ CIN3 of cytology, FAM19A4 methylation analysis, and cytology combined with HPV16/18 genotyping were 85.6, 75.6 and 92.2%, respectively, with corresponding specificities of 49.8, 71.1 and 29.4%, respectively. Both sensitivity and specificity of FAM19A4 methylation analysis were associated with age (p ≤ 0.001 each). In women ≥ 30 years (n = 287), ≥ CIN3 sensitivity of FAM19A4 methylation analysis was 88.3% (95%CI: 80.2-96.5) which was noninferior to that of cytology [85.5% (95%CI: 76.0-94.0)], at a significantly higher specificity [62.1% (95%CI: 55.8-68.4) compared to 47.6% (95%CI: 41.1-54.1)]. In conclusion, among hrHPV-positive women from an outpatient population aged ≥ 30 years, methylation analysis of FAM19A4 is an attractive marker for the identification of women with ≥ CIN3.

Background: High-risk human papillomavirus (hrHPV)-positive women require triage to identify those with cervical high-grade intraepithelial neoplasia and cancer (>= CIN3 (cervical intraepithelial neoplasia grade 3)). FAM19A4 methylation analysis, which detects advanced CIN and cancer, is applicable to different sample types. However, studies comparing the performance of FAM19A4 methylation analysis in hrHPV-positive self-samples and paired physician-taken scrapes are lacking. Methods: We compared the performance of FAM19A4 methylation analysis (and/or HPV16/18 genotyping) in self-samples and paired physician-taken scrapes for >= CIN3 detection in hrHPV-positive women (n = 450,18-66 years). Results: Overall FAM19A4 methylation levels between sample types were significantly correlated, with strongest correlation in women with >= CIN3 (Spearman's rho 0.697, P= 30 years, >= CIN3 sensitivity of FAM19A4 methylation analysis was 78.4% in self-samples and 88.2% in scrapes (ratio 0.89; CI: 0.75-1.05). In women = CIN3 sensitivities were 37.5% and 45.8%, respectively (ratio 0.82; CI: 0.55-1.21). In both groups, >= CIN3 specificity of FAM19A4 methylation analysis was significantly higher in self-samples compared with scrapes. Conclusions: FAM19A4 methylation analysis in hrHPV-positive self-samples had a slightly lower sensitivity and a higher specificity for >= CIN3 compared with paired physician-taken scrapes. With a similarly good clinical performance in both sample types, combined FAM19A4 methylation analysis and HPV16/18 genotyping provides a feasible triage strategy for hrHPV-positive women, with direct applicability on self-samples.

Women treated for high-grade cervical intraepithelial neoplasia (CIN) are at risk of recurrent CIN Grade 2 or worse (rCIN2+). Currently, posttreatment monitoring is performed using cytology or cytology/high-risk (hr)HPV cotesting. This study aimed to evaluate the performance of p16/Ki-67 dual-stained cytology (p16/Ki-67) for posttreatment monitoring. Three hundred and twenty-three women treated for high-grade CIN in the SIMONATH study underwent close surveillance by cytology, hrHPV and DNA methylation marker testing up to 12 months posttreatment. Histological endpoints were ascertained by colposcopy with biopsy at 6 and/or 12 months. p16/Ki-67 dual-staining was performed on residual liquid-based cytology samples obtained at, or shortly before biopsy collection. Clinical performance estimates of cytology, hrHPV, p16/Ki-67 testing and combinations thereof for the detection of rCIN2+ were determined and compared to each other. Sensitivity of p16/Ki-67 for rCIN2+ (69.2%) was nonsignificantly lower than that of cytology (82.1%; ratio 0.84, 95% CI: 0.71-1.01), but significantly lower than that of hrHPV testing (84.6%; ratio 0.82, 95% CI: 0.68-0.99). Specificity of p16/Ki-67 for rCIN2+ (90.4%) was significantly higher compared to both cytology (70.8%; ratio 1.28, 95% CI: 1.19-1.37) and hrHPV testing (76.2%; ratio 1.19, 95% CI: 1.12-1.26). Overall, hrHPV testing showed very high sensitivity, along with a good specificity. When considering cotesting, combined p16/Ki-67/hrHPV testing showed rCIN2+ sensitivity comparable to cytology/hrHPV cotesting (87.2% vs. 89.7%; ratio 0.97, 95% CI: 0.92-1.03), but with significantly increased specificity (74.2% vs. 58.1%; ratio 1.28, 95% CI: 1.19-1.38). Thus, when considered in combination with hrHPV, p16/Ki-67 might be an attractive approach for surveillance of women treated for high-grade CIN.

Women who test positive for a high-risk type of the human papillomavirus (HPV) require triage testing to identify those women with cervical intraepithelial neoplasia grade 3 or cancer (>= CIN3). Although Pap cytology is considered an attractive triage test, its applicability is hampered by its subjective nature. This study prospectively compared the clinical performance of p16/Ki-67 dual-stained cytology to that of Pap cytology, with or without HPV16/18 genotyping, in high-risk HPV-positive women visiting gynecologic outpatient clinics (n=446 and age 18-66 years). From all women, cervical scrapes (for Pap cytology, HPV16/18 genotyping, and p16/Ki-67 dual-stained cytology) and colposcopy-directed biopsies were obtained. The sensitivity of p16/Ki-67 dual-stained cytology for >= CIN3 (93.8%) did neither differ significantly from that of Pap cytology (87.7%; ratio 1.07 and 95% confidence interval (CI): 0.97-1.18) nor from that of Pap cytology combined with HPV16/18 genotyping (95.1%; ratio 0.99 and 95% CI: 0.91-1.07). However, the specificity of p16/Ki-67 dual-stained cytology for >= CIN3 (51.2%) was significantly higher than that of Pap cytology (44.9%; ratio 1.14 and 95% CI: 1.01-1.29) and Pap cytology combined with HPV16/18 genotyping (25.8%; ratio 1.99 and 95% CI: 1.68-2.35). After exclusion of women who had been referred because of abnormal Pap cytology, the specificity of p16/Ki-67 dual-stained cytology for >= CIN3 (56.7%) remained the same, whereas that of Pap cytology (60.3%) increased substantially, resulting in a similar specificity of both assays (ratio 0.94 and 95% CI: 0.83-1.07) in this sub-cohort. In summary, p16/Ki-67 dual-stained cytology has a good clinical performance and is an interesting objective microscopy-based triage tool for high-risk HPV-positive women.

a b s t r a c t Background: Studies have shown that self-sampling for hrHPV testing (HPV self-sampling) is highly acceptable to women, increases screening participation rate, and may therefore further reduce cervi- cal cancer incidence. However, it is important to clinically validate HPV self-sampling procedures for screening purposes. Objectives: Clinical validation of combined brush-based self-sampling with GP5+/6+-PCR EIA for primary cervical screening. In addition, HPV type-specific agreement between sample types and acceptability of brush-based self-sampling were evaluated. Study design: 135 women referred for colposcopy took a self-sample at home prior to vaginal- and cervical sampling by a gynaecologist. All women were biopsied for histology. HPV testing was done by GP5+/6+- PCR EIA, with genotyping by reverse line blotting (RLB). Acceptability of sampling methods was measured with a questionnaire. Results: In this outpatient population, hrHPV test results showed good concordance between self-samples and physician-taken cervical scrapes (86%, k = 0.70), with sensitivities and specificities for CIN2+ that did not differ significantly (93% and 51%, 91% and 51%, respectively (P = 1.0)). The clinical sensitivity of brush-based self-sampling combined with GP5+/6+-PCR EIA hrHPV testing for detection of CIN2+ was non-inferior to that of hrHPV testing on physician-taken cervical samples (P = 0.018). In addition, hrHPV genotyping results were highly concordant between sample types, with almost perfect agreement for HPV16 (k = 0.81) and HPV18 (k = 0.92). Finally, 91% of participants described brush-based self-sampling as easy-to-use. Conclusions: Brush-based self-sampling in combination with GP5+/6+-PCR EIA hrHPV testing is acceptable to women and valid for assessing the risk of CIN2+ in comparison to hrHPV testing on physician-taken scrapes. In addition, there was high concordance of HPV genotyping results. Therefore, this HPV self

Given the lower specificity for high-grade cervical lesions of high-risk human papillomavirus (hrHPV) testing compared to cytology, additional triage testing for hrHPV test-positive women is needed to detect high-grade cervical lesions. Here, we tested whether combined methylation analysis for cell adhesion molecule 1 (CADM1) and T-lymphocyte maturation associated protein (MAL), both functionally involved in cervical carcinogenesis, could serve as such a triage marker. Four quantitative methylation-specific PCRs (qMSP), two for CADM1 (regions M12 and M18) and MAL (regions M1 and M2) each, were applied to 261 cervical tissue specimens ranging from no neoplasia to carcinoma. When qMSPs were combined and positivity for at least one of the qMSPs in the combination was taken into account, the highest positivity rates for cervical intraepithelial neoplasia grade 3 (CIN3) lesions (97%) and squamous cell- and adeno-carcinomas (99%) were obtained by combining a single CADM1 marker with a single MAL marker. Subsequent qMSP analysis of 70 GP5+/6+-PCR hrHPV-positive scrapings revealed that a two-marker panel consisting of CADM1-M18 and MAL-M1 was most discriminative, detecting 90% of women with CIN3 (n = 30), whereas it showed a positive result in only 13.5% of women without cervical disease (n = 40). Finally, we applied hrHPV GP5+/6+-PCR testing followed by CADM1-M18/MAL-M1 methylation analysis to a cohort of 79 women visiting the outpatient colposcopy clinic. hrHPV testing revealed a sensitivity of 97% and a specificity of 33% for CIN3+. Additional CADM1-M18/MAL-M1 methylation analysis on the hrHPV-positive women increased the specificity to 78% with a sensitivity of 70%. In conclusion, the methylation marker panel CADM1-M18 and MAL-M1 may serve as an alternative molecular triage tool for hrHPV-positive women.

Recently, DNA methylation analysis of FAM19A4 in cervical scrapes has been shown to adequately detect high-grade cervical intraepithelial neoplasia and cervical cancer (≥ CIN3) in high-risk HPV (hrHPV)-positive women. Here, we compared the clinical performance of FAM19A4 methylation analysis to cytology and HPV16/18 genotyping, separately and in combination, for ≥ CIN3 detection in hrHPV-positive women participating in a prospective observational multi-center cohort study. The study population comprised hrHPV-positive women aged 18-66 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy-directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed for FAM19A4 gene promoter methylation, cytology and HPV16/18 genotyping. Methylation analysis was performed by quantitative methylation-specific PCR (qMSP). Sensitivities and specificities for ≥ CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV-positive women, the sensitivities for ≥ CIN3 of cytology, FAM19A4 methylation analysis, and cytology combined with HPV16/18 genotyping were 85.6, 75.6 and 92.2%, respectively, with corresponding specificities of 49.8, 71.1 and 29.4%, respectively. Both sensitivity and specificity of FAM19A4 methylation analysis were associated with age (p ≤ 0.001 each). In women ≥ 30 years (n = 287), ≥ CIN3 sensitivity of FAM19A4 methylation analysis was 88.3% (95%CI: 80.2-96.5) which was noninferior to that of cytology [85.5% (95%CI: 76.0-94.0)], at a significantly higher specificity [62.1% (95%CI: 55.8-68.4) compared to 47.6% (95%CI: 41.1-54.1)]. In conclusion, among hrHPV-positive women from an outpatient population aged ≥ 30 years, methylation analysis of FAM19A4 is an attractive marker for the identification of women with ≥ CIN3.

Objective: To compare the effect of transdermal and oral estrogen therapy, the latter with or without the addition of gestodene, on plasma concentrations of markers of endothelial function and on ultrasonographic parameters of vascular function in healthy postmenopausal women. Design: In a 15-month, randomized, double-blind, placebo-controlled study, 152 healthy hysterectomized postmenopausal women received daily doses of placebo (n = 49), 50 μg of transdermal 17β-estradiol (tE 2 , n = 33), 1 mg of oral E 2 (oE 2 , n = 37), or 1 mg of oral estradiol combined with 25 μg of gestodene (oE 2 + G, n = 33) for 13 cycles of 28 days, followed by four washout cycles with placebo in each group. At baseline and in cycles 4, 13, and 17, we measured plasma levels of endothelial markers and ultrasonographic markers of vascular function (pulsatility index [PI] and, at baseline and cycle 13, arterial stiffness). Results: Compared with placebo, we found reductions in soluble vascular cell adhesion molecule (oE 2 , P < 0.01; oE 2 + G, P < 0.001), sE-selectin (oE 2 + G, P < 0.05), von Willebrand factor (tE 2 , P < 0.05), and divergent effects in PI and stiffness parameters in the carotid artery. We found no effect on PI in the retinal and femoral arteries, or on stiffness parameters in the femoral and brachial artery. Conclusions: Oral hormone therapy reduced plasma levels of adhesion molecules, whereas transdermal estrogen therapy reduced von Willebrand factor. Effects on ultrasonographic parameters of vascular function in the carotid artery were inconclusive.

Item does not contain fulltext OBJECTIVE: This study was undertaken to investigate the effect of transdermal and oral estrogen replacement therapy in healthy postmenopausal women on markers of coagulation and fibrinolysis associated with coronary artery disease. STUDY DESIGN: In a randomized, placebo-controlled, double-blind study, healthy hysterectomized postmenopausal women received daily either placebo (n=49), transdermal 17beta-estradiol (E(2)) 50 microg (tE(2) group, n=33), oral E(2) 1 mg (oE(2) group, n=37), or oral E(2) 1 mg combined with gestodene 25 microg (oE(2)+G group, n=33) for thirteen 28-day treatment cycles. Hemostatic variables were measured in blood samples collected at baseline and in cycles 4 and 13. RESULTS: No significant changes versus baseline and placebo were found in the tE(2) group, except for plasminogen activator inhibitor type-1 (PAI-1) in cycle 13 (-32.4%, P=.01). In the oE(2) group, significant percentage changes from baseline versus placebo in cycle 13 were found in fibrinogen, -5.4% (P

Objective— The purpose of this study was to investigate whether the effect of transdermal estrogen therapy in postmenopausal women differs from that of oral therapy with regard to resistance to activated protein C (APC), an important risk factor for venous thrombosis, and levels of related proteins, such as protein S, protein C, and prothrombin. Methods and Results— In a randomized, double-blind, placebo-controlled study, 152 healthy hysterectomized postmenopausal women received daily either placebo (n=49), transdermal 17β-estradiol (E 2 ) 50 μg (tE 2 group, n=33), oral E 2 1 mg (oE 2 group, n=37), or oral E 2 1 mg combined with gestodene 25 μg (oE 2 +G group, n=33) for 13 28-day treatment cycles, followed by 4 cycles of placebo for each group. Plasma samples were collected at baseline and in cycles 4, 13, and 17. In cycle 13, significant increases versus baseline and placebo were found in normalized APC sensitivity ratios (nAPCsr) in all treated groups (tE 2 , +26.9%; oE 2 , +102.7%; oE 2 +G, +69.9%). Increases in nAPCsr were significantly higher in the oral treatment groups than in the tE 2 group. In addition, compared with baseline and placebo, after 13 cycles, decreases were observed in total protein S (tE 2 , −4.1%; oE 2 , −7.9%; oE 2 +G, −5.8%), free protein S (tE 2 , −7.1%; oE 2 , −8.4%; oE 2 +G, −5.2%), and protein C in the oE 2 +G group (−6.4%), but these changes did not explain the increase in nAPCsr. Changes in prothrombin were small and also did not affect the nAPCsr. Conclusions— Increases were observed in resistance to APC, which were more pronounced in the oral treatment groups than in the transdermal group. The increase in resistance to APC was not explained by changes in protein S, protein C, or prothrombin and may contribute to the increased incidence of venous thrombosis in users of hormone replacement therapy.

As hormone replacement therapy is associated with an early excess risk of venous thrombosis, we investigated the effect of different oral hormone replacement therapies on resistance to activated protein C, and on levels of factor VIII antigen (FVIII:Ag) and factor XI antigen (FXI:Ag). In a prospective, randomized, placebo-controlled 12-week study, 60 healthy post-menopausal women daily received either placebo (n = 16) or 2 mg of micronized 17beta-oestradiol, either alone (E2, n = 16) or sequentially combined with dydrogesterone 10 mg (E2 + D, n = 14) or trimegestone 0.5 mg (E2 + T, n = 14). Medication was given orally. Normalized activated protein C sensitivity ratios (nAPCsr) were determined by quantifying the effect of activated protein C on the endogenous thrombin potential. FVIII:Ag and FXI:Ag were determined by enzyme-linked immunosorbent assay. Compared with baseline and placebo, the nAPCsr increased (92% to 142%; all P < 0.001) in all active treatment groups after both 4 and 12 weeks. Compared with placebo, hormone replacement therapy was not associated with significant changes in FVIII:Ag. After 4 and 12 weeks, FXI:Ag levels were significantly decreased in the E2 group (mean percentage changes from baseline versus placebo: -15.0%, P = 0.001 at 4 weeks and -16.6%, P = 0.003 at 12 weeks) and in the E2 + D group (-10.4%, P = 0.02 and -10.4%, P = 0.02). In conclusion, all hormone replacement regimens were associated with a large increase in resistance to activated protein C. In contrast, hormone replacement therapy had no effect on FVIII:Ag. Oral E2 and E2 + D had a small, favourable effect on FXI:Ag.

Objective: We sought to investigate the long-term effect of raloxifene and continuous combined hormone replacement therapy (ccHRT) on impedance to flow within the uterine artery in postmenopausal women. Study Design: A prospective, randomized, double-blind, placebo-controlled 2-year study was performed in 95 postmenopausal women. They received either 60 mg of raloxifene daily (raloxifene 60 group), 150 mg of raloxifene daily (raloxifene 150 group), ccHRT, or placebo. At baseline and thereafter every 6 months, color Doppler ultrasonography was used to measure the pulsatility index (PI) of the uterine artery. Results: After 24 months of treatment, compared with placebo, significant decreases were found in the PI in the raloxifene 150 group ( P =.021) and in the ccHRT group ( P =.007). In the raloxifene 150 group compared with the placebo group, after 6 and 24 months, decreases were observed in median PI of –5% and –15%, respectively, and in the ccHRT group decreases of –2% and –19%, respectively, were found. Conclusion: Long-term use of 150 mg of raloxifene daily or ccHRT reduces impedance to flow within the uterine artery. This indicates that high-dose raloxifene may exert cardiovascular protection. (Am J Obstet Gynecol 2001;185:557-62.)

Objective: Our goal was to investigate the short-term and intermediate effects of low-dose hormone replacement therapy on echocardiographic parameters of cardiac function in healthy postmenopausal women. Study Design: In a prospective, controlled study 30 healthy postmenopausal women (mean age, 52 ± 3 years) were randomly assigned to 2 groups. Women in the hormone replacement therapy group (n = 15) received 1 mg micronized 17β-estradiol daily sequentially combined with 5 or 10 mg dydrogesterone for 14 days of each 28-day cycle during 12 months and thereafter 2 mg 17β-estradiol combined with 10 mg dydrogesterone for a period of 3 months. The control group (n = 15) received no treatment. M-mode, quantitative 2-dimensional, and Doppler echocardiographic measurements were performed at baseline and within the 17β-estradiol phase at 3, 12, and 15 months. Results: After 12 months significant differences in change between the 2 groups were found for left ventricular end-diastolic and left ventricular end-systolic diameters, left ventricular mass index, and stroke volume index. These differences were caused by changes in the control group rather than in the hormone replacement therapy group, in which no significant within-group changes were found. All other parameters measured showed no effect. Conclusion: Within 15 months of 17β-estradiol and dydrogesterone treatment no clinically relevant differences were found in the M-mode, quantitative 2-dimensional, and Doppler echocardiographic parameters measured in this study. It is suggested that 15 months of treatment probably is too short a period for detection of direct effects on the heart itself. (Am J Obstet Gynecol 2001;184:910-6.)

Objective To exclude pre-existing endometrial pathology in asymptomatic early post-menopausal women before starting hormone replacement therapy by transvaginal ultrasound (TVS) and saline infusion sonohysterography (SIS). Methods In a cross-sectional study, 148 healthy women (mean age, 51.1 years; range, 46–59 years) underwent ultrasound evaluation of the endometrium before participation in a clinical trial. TVS was used to measure double-layer endometrial thickness. SIS was performed at the same visit to measure anterior and posterior single-layer endometrial thickness, and to identify endometrial abnormalities when present. Ultrasound results were defined as informative if the endometrium could be adequately visualized. Findings on TVSs were defined as abnormal if a double-layer endometrial measurement >5.0 mm was obtained. Findings on SIS were defined as abnormal if one or both single layers of the endometrium measured >2.5 mm, or if focal endometrial thickening or a polyp was present. Results Of the 148 eligible women, informative TVS results were obtained from 134 women, SIS results from 133 women and both procedures combined from 119 women. TVS scans gave abnormal results in 8.2% of women (11 of 134) and SIS gave abnormal results in 36.8% of women (49 of 133). Of the 14 women with a non-informative TVS, eight had abnormal SIS results. Of the 15 women with a non-informative SIS, three had abnormal TVS results. In the 119 women with both informative TVS and SIS, abnormal TVS scans were found in 6.7% of women (eight of 119) and abnormal SIS in 34.5% of women (41 of 119). All eight women with abnormal TVS had an abnormal SIS, whereas 29.7% (33 of 111) of the women with a normal TVS had an abnormal SIS. Conclusions Ultrasound evaluation demonstrated endometrial abnormalities in 34.5% (41 of 119) of asymptomatic post-menopausal women. SIS is more accurate than TVS in the detection of endometrial abnormalities. Copyright © 2000 International Society of Ultrasound in Obstetrics and Gynecology

Epidemiological data suggest that the use of oestrogen replacement therapy (ERT) and combined oestrogen / progestagen replacement therapy (HRT) in healthy postmenopausal women is associated with a decreased risk of cardiovascular events. In sharp contrast, the HERS study, a secondary prevention trial in postmenopausal women with established coronary heart disease, did not show a favourable effect, with a trend towards an increased risk of cardiovascular disease in the first year of treatment. This paper provides an overview of randomised, controlled trials (RCTs) in postmenopausal women published in the literature and discusses possible explanations for the contrast between data from the epidemiological studies and the results of the HERS study. ERT and HRT are associated with 1) an improved lipid profile and 2) a decrease in homocysteine and endothelin levels. Data on factor VII and fibrinogen were not consistent. There were insufficient data on the effects on blood pressure, glucose metabolism, vasomotor regulation, arterial stiffness, thrombomodulin, adhesion molecules, and clotting and fibrinolysis, as well as on the effects of route of administration and the role of progestagens. Finally, endothelium-dependent vasodilatation appears to increase with ERT, but the effects of HRT are less clear This paucity of controlled data indicates that, although ERT and HRT improve surrogate measures of risk of atherothrombosis, adverse effects of ERT and HRT on biological mechanisms related to risk of atherothrombosis can by no means be excluded.

SummaryIn this randomised, placebo-controlled 12-week study, sixty healthy postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or combined with a progestagen for 14 days of each cycle (N = 28, E2+P group).As compared to placebo, plasma levels of AT III were reduced only in the E2 group (∼28%), plasma levels of protein C decreased only in the E2+P group (∼4%) and plasma levels of protein S decreased in both the E2 and E2+P group (∼21%). In both the E2 and E2+P groups, the plasma levels of factor VII (antigen and activity) showed a borderline significant increase (∼10%), whereas no significant change was observed in active factor VII. Plasma levels of tissue-type plasminogen activator (∼22%), urokinase plasminogen activator (∼25%) and plasminogen activator inhibitor type-1 (∼43%) decreased in the E2 and E2+P groups, whereas those of plasminogen increased (∼12%). Treatment was associated with an increase in levels of prothrombin fragment 1+2 (∼31%), but levels of thrombin-antithrombin III complexes, and of plasmin-α2-antiplasmin complexes and total fibrin(ogen) degradation products did not change significantly.Short-term E2 and E2+P treatment is associated with a shift in the procoagulant-anticoagulant balance towards a procoagulant state. A substantial proportion of women do not have a net increase in fibrinolytic activity. These data may be relevant in explaining the increased risk of venous thromboembolism associated with ERT and HRT, and possibly also in explaining the negative results of the Heart and Estrogen/progestin Replacement Study.

Objective: The purpose of this study was to investigate the long-term effects of combined hormone replacement therapy on the impedances of the uterine, central retinal, and ophthalmic arteries in healthy postmenopausal women. Study Design: In a prospective controlled study we randomly assigned 30 healthy postmenopausal women (mean age, 52 ± 3 years) to 2 groups. Women in the hormone replacement therapy group (n = 15) received 1 mg micronized 17β-estradiol daily sequentially combined with 5 or 10 mg dydrogesterone for 14 days of each 28-day cycle during 12 months and 2 mg 17β-estradiol combined with 10 mg dydrogesterone thereafter for a period of 3 months. The control group (n = 15) received no treatment. Color Doppler ultrasonography was used to measure the impedance to flow (pulsatility index) within the uterine, central retinal, and ophthalmic arteries in the 17β-estradiol phase at baseline and after 3, 12, and 15 months. Results: With respect to values in the control group, 12 months of hormone replacement therapy was associated with a significantly lower (by 39%) mean pulsatility index of the uterine artery (decrease from baseline of 25% in hormone replacement therapy group and increase of 14% in control group) and a significantly lower (by 29%) mean pulsatility index of the central retinal artery (decrease of 9% in hormone replacement therapy group and increase of 20% in control group). After 3 months this effect was already evident. During hormone replacement therapy the reductions in mean pulsatility index values of the uterine and central retinal arteries with respect to baseline were larger (both P = .002) in the women with high pretreatment pulsatility index values than in those with low pretreatment values. The baseline pulsatility index of the uterine artery correlated positively with age and with duration of amenorrhea ( r = 0.42, P = .01; r = 0.48, P = .008; respectively). Conclusion: These results suggest that 12 months of sequentially combined hormone replacement therapy with a low dose of estradiol (1 mg) lowers arterial impedance in specific vascular territories. These data may help in understanding the effects of hormone replacement therapy on the cerebral circulation. (Am J Obstet Gynecol 1999;181:1365-73.)

Summary Objective: To study the short-term effect of unopposed oestradiol (E2) and sequentially combined hormone replacement therapy (E2 + P) on C-reactive protein (CRP) in healthy postmenopausal women. Design: Prospective, randomised, placebo-controlled 12-week study. Sixty healthy, normotensive, non-hysterectomised postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or sequentially combined with a progestagen on 14 days of each cycle (N = 28, E2+P group). Data were collected at baseline and at 4 and 12 weeks. Results: CRP levels increased significantly during the 12 weeks in the E2 and the E2+P groups compared to placebo. No differences were found between the E2 group and the E2+P group [E2 and E2+P group together (N = 44) versus placebo: P = 0.01; E2 versus E2+P: P = 0.75]. To give a quantitative estimate of the increase, the median change calculated from baseline in both treatment groups together was +87% (P = 0.02) at 4 weeks, and +114% (P = 0.08) at 12 weeks, as compared to the placebo group. Conclusion: In healthy postmenopausal women, short-term treatment with E2 or E2+P was associated with a rapid rise in CRP concentrations. These observations raise the possibility that the increased risk of cardiovascular events is related to an initial increase in CRP levels after starting hormone replacement therapy.

Hormone replacement therapy (HRT, estrogen plus progestagen) in postmenopausal women has beneficial effects on the cardiovascular system. However, effects on blood pressure, determined with office measurements, remain controversial. We studied the effects of HRT in 29 healthy normotensive postmenopausal women (mean age 52.3 [3.8] years, median duration of amenorrhea 34.5 months), using ambulatory blood pressure monitoring at baseline and at 3 and 12 months of follow-up. Women were randomized to two groups: an HRT group (N = 14), treated with 1 mg 17beta-estradiol once daily and 5 or 10 mg dydrogesterone once daily during the third and fourth week of every 4 weeks; and a control group (C-group, N = 15), which did not receive therapy. Blood pressures did not differ between the groups at baseline (HRT group 117.1 (9.2)/74.4 (6.6) mm Hg, C-group 113.8 (11.2)/71.3 (7.4) mm Hg). During the follow-up period, changes from baseline of office blood pressures did not differ significantly between the groups. However, changes (95% CI) of mean 24-h blood pressures differed significantly between the two groups after 1 year of follow-up: a decrease of blood pressures was observed in the HRT group (delta systolic/delta diastolic = -5.54 [-8.86 to -2.21]/-4.23 [-6.66 to -1.80] mm Hg), whereas an increase was found in the C-group (+3.33 [-0.69 to +7.35]/+1.67 [-1.75 to +5.09] mm Hg; P [HRT v control group] = .001/.005). We conclude that HRT may have blood pressure lowering properties in healthy, normotensive postmenopausal women.

Objectives We analyzed pretreatment SCC-Ag levels, lymph node (LN) status and disease outcome in early stage squamous cell (SCC) cervical cancer. Methods Serum SCC-Ag was measured before primary treatment in 91 patients (FIGO stage IB1 72, IB2 10, and IIA 9). Of these, 58 underwent laparoscopic sentinel lymph node (SLN) procedure followed by pelvic lymphadenectomy. Results No false negative SLN were observed. SCC-Ag levels were higher in patients with positive LN compared to patients with negative LN (p = 0.010), but no difference was found in the SLN patients (p = 0.344). The accuracy to predict LN metastases of SCC-Ag at ROC established cutoff of 1.65 ng/mL and 5.5 ng/mL was 76% and 78%, respectively, in stage IB1, and 53% and 79%, respectively, in stages IB2+ IIA. Whereas no deaths were observed in patients with negative LN and negative SCC-Ag levels (at previously established cutoff of 1.1 ng/mL), overall survival (OS) for patients with negative LN but elevated SCC-Ag was similar to that of patients with positive LN, irrespective of their marker levels (Kaplan–Meier analysis of all patients and in stage IB1, p = 0.002 and p = 0.026, respectively). Conclusions SCC-Ag (> 1.65 ng/mL) can predict LN metastases more accurately in stage IB1 than in stage IB2+ IIA. Since SCC-Ag levels above 1.1 ng/mL are already associated with a poor prognosis, the marker seems to identify a subgroup of LN negative patients with occult disease that may benefit from full lymphadenectomy following a SLN procedure.

As hormone replacement therapy is associated with an early excess risk of venous thrombosis, we investigated the effect of different oral hormone replacement therapies on resistance to activated protein C, and on levels of factor VIII antigen (FVIII:Ag) and factor XI antigen (FXI:Ag). In a prospective, randomized, placebo-controlled 12-week study, 60 healthy post-menopausal women daily received either placebo (n = 16) or 2 mg of micronized 17beta-oestradiol, either alone (E2, n = 16) or sequentially combined with dydrogesterone 10 mg (E2 + D, n = 14) or trimegestone 0.5 mg (E2 + T, n = 14). Medication was given orally. Normalized activated protein C sensitivity ratios (nAPCsr) were determined by quantifying the effect of activated protein C on the endogenous thrombin potential. FVIII:Ag and FXI:Ag were determined by enzyme-linked immunosorbent assay. Compared with baseline and placebo, the nAPCsr increased (92% to 142%; all P0.001) in all active treatment groups after both 4 and 12 weeks. Compared with placebo, hormone replacement therapy was not associated with significant changes in FVIII:Ag. After 4 and 12 weeks, FXI:Ag levels were significantly decreased in the E2 group (mean percentage changes from baseline versus placebo: -15.0%, P = 0.001 at 4 weeks and -16.6%, P = 0.003 at 12 weeks) and in the E2 + D group (-10.4%, P = 0.02 and -10.4%, P = 0.02). In conclusion, all hormone replacement regimens were associated with a large increase in resistance to activated protein C. In contrast, hormone replacement therapy had no effect on FVIII:Ag. Oral E2 and E2 + D had a small, favourable effect on FXI:Ag.

Objectives: Lipoprotein(a) (Lp(a)) and homocysteine (Hcy) are independent cardiovascular risk factors, which have been shown to be lowered by hormone replacement therapy (HRT). In this 2-year study, the long-term effects of raloxifene (Rlx) in two doses, on Lp(a) and Hcy, were studied and compared with the effects of continuously combined hormone replacement therapy (ccHRT). Methods: In a prospective, randomized, double-blind, placebo-controlled 2-year study, 95 healthy, non-hysterectomized, early postmenopausal women, received daily either oral Rlx 60 mg ( N =24) or 150 mg ( N =23), ccHRT (conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg; N =24) or placebo ( N =24). Fasting serum Lp(a) and plasma Hcy concentrations were measured at baseline and at 6, 12 and 24 months. Results: The mean individual changes compared to baseline after 24 months were for Lp(a): Rlx 60: −5%, Rlx 150: −7%, ccHRT: −34%, placebo: +1% and for Hcy: Rlx 60: −3%, Rlx 150: −4%, ccHRT: −4%, placebo: +6%. ANCOVA was significant for Lp(a) under ccHRT versus placebo ( P =0.001) and for Lp(a) under ccHRT versus each of the two Rlx groups ( P Conclusions: Long-term treatment with Rlx was not as effective as ccHRT in lowering Lp(a). Although not significant and without an obvious dose-related response, the Hcy values showed the same trend for each treatment arm, which is in line with data reported earlier.

Objective : To review the available information on the action of hormones on the mechanisms involved in thrombotic risk. Results and Conclusions : Thrombosis plays a crucial role in the genesis and progression of both coronary heart disease (CHD) and venous thromboembolic disease (VTED), the two main forms of cardiovascular disease. Two main determinants of the thromboembolic phenotype, hypercoagulable state and altered endothelium, accumulate much of the work performed on the influence of hormones on thrombosis. Information has accumulated mainly for oestrogens, but increasing evidences support a role for progestogens. The sensitivity of each of the three components of the hemostatic balance, the coagulation cascade, the anticoagulant system and fibrinolysis, to oestrogens has been widely examined in the literature. Functional tests suggest that HRT is accompanied by a procoagulant state. Much of the work has concentrated on changes induced on reputable indicators of risk for either CHD or VTED. Distinct indicators of increased coagulability, such as resistance to activated C protein, antithrombin or tissue factor pathway inhibitor have been selected for VTED, whereas factor VII, fibrinogen, and defective fibrinolysis, for CHD. Different states of genetic susceptibility have been involved in both forms of the disease. The status of health of endothelium, defines another scenario for attention in CHD. A long-term anti-atherogenic action of oestrogens, which may be associated with short-term risk in cases of atherosclerosis-induced endothelial dysfunction, may most adequately explain much of the clinical observation. In both CHD and VTED, the procoagulant changes initiate soon after HRT administration.

To exclude pre-existing endometrial pathology in asymptomatic early post-menopausal women before starting hormone replacement therapy by transvaginal ultrasound (TVS) and saline infusion sonohysterography (SIS).In a cross-sectional study, 148 healthy women (mean age, 51.1 years; range, 46-59 years) underwent ultrasound evaluation of the endometrium before participation in a clinical trial. TVS was used to measure double-layer endometrial thickness. SIS was performed at the same visit to measure anterior and posterior single-layer endometrial thickness, and to identify endometrial abnormalities when present. Ultrasound results were defined as informative if the endometrium could be adequately visualized. Findings on TVSs were defined as abnormal if a double-layer endometrial measurement5.0 mm was obtained. Findings on SIS were defined as abnormal if one or both single layers of the endometrium measured2.5 mm, or if focal endometrial thickening or a polyp was present.Of the 148 eligible women, informative TVS results were obtained from 134 women, SIS results from 133 women and both procedures combined from 119 women. TVS scans gave abnormal results in 8.2% of women (11 of 134) and SIS gave abnormal results in 36.8% of women (49 of 133). Of the 14 women with a non-informative TVS, eight had abnormal SIS results. Of the 15 women with a non-informative SIS, three had abnormal TVS results. In the 119 women with both informative TVS and SIS, abnormal TVS scans were found in 6.7% of women (eight of 119) and abnormal SIS in 34.5% of women (41 of 119). All eight women with abnormal TVS had an abnormal SIS, whereas 29.7% (33 of 111) of the women with a normal TVS had an abnormal SIS.Ultrasound evaluation demonstrated endometrial abnormalities in 34.5% (41 of 119) of asymptomatic post-menopausal women. SIS is more accurate than TVS in the detection of endometrial abnormalities.

Hormone replacement therapy (HRT) in postmenopausal women is associated with a reduction in the risk of developing coronary artery disease (CAD) of about 50%. Women with an elevated risk for CAD appear to benefit most by HRT. The HRT-associated cardiovascular protection may be related to favourable changes in several important cardiovascular risk estimators, such as circulating blood concentrations of cholesterol, lipoprotein(a) (Lp(a)) and homocysteine. This paper reviews the literature presently available on the effects of HRT on cholesterol, Lp(a) and homocysteine concentrations, and special attention will be given to the effects on their elevated concentrations. The effect of HRT in women with hypertension is reviewed as well. From this overview it can be concluded that risk factors such as cholesterol, Lp(a), and homocysteine can be favourably modulated by HRT, and especially, that the strongest reductions can be achieved in those women with the highest concentrations. Although clinical trials still need to demonstrate the impact of lowering concentrations of Lp(a) and homocysteine, HRT appears to be a promising risk reduction strategy in this respect.