Clinical outcomes of uninterrupted embryo culture with or without time-lapse-based embryo selection versus interrupted standard culture (SelecTIMO): a three-armed, multicentre, double-blind, randomised controlled trial.

BACKGROUND: Time-lapse monitoring is increasingly used in fertility laboratories to culture and select embryos for transfer. This method is offered to couples with the promise of improving pregnancy chances, even though there is currently insufficient evidence for superior clinical results. We aimed to evaluate whether a potential improvement by time-lapse monitoring is caused by the time-lapse-based embryo selection method itself or the uninterrupted culture environment that is part of the system. METHODS: In this three-armed, multicentre, double-blind, randomised controlled trial, couples undergoing in-vitro fertilisation or intracytoplasmic sperm injection were recruited from 15 fertility clinics in the Netherlands and randomly assigned using a web-based, computerised randomisation service to one of three groups. Couples and physicians were masked to treatment group, but embryologists and laboratory technicians could not be. The time-lapse early embryo viability assessment (EEVA; TLE) group received embryo selection based on the EEVA time-lapse selection method and uninterrupted culture. The time-lapse routine (TLR) group received routine embryo selection and uninterrupted culture. The control group received routine embryo selection and interrupted culture. The co-primary endpoints were the cumulative ongoing pregnancy rate within 12 months in all women and the ongoing pregnancy rate after fresh single embryo transfer in a good prognosis population. Analysis was by intention to treat. This trial is registered on the ICTRP Search Portal, NTR5423, and is closed to new participants. FINDINGS: 1731 couples were randomly assigned between June 15, 2017, and March 31, 2020 (577 to the TLE group, 579 to the TLR group, and 575 to the control group). The 12-month cumulative ongoing pregnancy rate did not differ significantly between the three groups: 50·8% (293 of 577) in the TLE group, 50·9% (295 of 579) in the TLR group, and 49·4% (284 of 575) in the control group (p=0·85). The ongoing pregnancy rates after fresh single embryo transfer in a good prognosis population were 38·2% (125 of 327) in the TLE group, 36·8% (119 of 323) in the TLR group, and 37·8% (123 of 325) in the control group (p=0·90). Ten serious adverse events were reported (five TLE, four TLR, and one in the control group), which were not related to study procedures. INTERPRETATION: Neither time-lapse-based embryo selection using the EEVA test nor uninterrupted culture conditions in a time-lapse incubator improved clinical outcomes compared with routine methods. Widespread application of time-lapse monitoring for fertility treatments with the promise of improved results should be questioned. FUNDING: Health Care Efficiency Research programme from Netherlands Organisation for Health Research and Development and Merck.

Prognostic model on niche development after a first caesarean section: development and internal validation.

OBJECTIVE: To develop and internally validate a prognostic prediction model for development of a niche in the uterine scar after a first caesarean section (CS). STUDY DESIGN: Secondary analyses on data of a randomized controlled trial, performed in 32 hospitals in the Netherlands among women undergoing a first caesarean section. We used multivariable backward logistic regression. Missing data were handled using multiple imputation. Model performance was assessed by calibration and discrimination. Internal validation using bootstrapping techniques took place. The outcome was 'development of a niche in the uterus', defined as an indentation of ≥ 2 mm in the myometrium. RESULTS: We developed two models to predict niche development: in the total population and after elective CS. Patient related risk factors were: gestational age, twin pregnancy and smoking, and surgery related risk factors were double-layer closure and less surgical experience. Multiparity and Vicryl suture material were protective factors. The prediction model in women undergoing elective CS revealed similar results. After internal validation, Nagelkerke R2 ranged from 0.01 to 0.05 and was considered low; median area under the curve (AUC) ranged from 0.56 to 0.62, indicating failed to poor discriminative ability. CONCLUSIONS: The model cannot be used to accurately predict the development of a niche after a first CS. However, several factors seem to influence scar healing which indicates possibilities for future prevention such as surgical experience and suture material. The search for additional risk factors that play a role in development of a niche should be continued to improve the discriminative ability.

Can serum human epididymis protein 4 (HE4) support the decision to refer a patient with an ovarian mass to an oncology hospital?

INTRODUCTION: The value of serum human epididymis protein 4 (HE4) in guiding referral decisions in patients with an ovarian mass remains unclear, because the majority of studies investigating HE4 were performed in oncology hospitals. However, the decision to refer is made at general hospitals with a low ovarian cancer prevalence. We assessed accuracies of HE4 in differentiating benign or borderline from malignant tumors in patients presenting with an ovarian mass at general hospitals. METHOD: Patients with an ovarian mass were prospectively included between 2017 and 2021 in nine general hospitals. HE4 and CA125 were preoperatively measured and the risk of malignancy index (RMI) was calculated. Histological diagnosis was the reference standard. RESULTS: We included 316 patients, of whom 195 had a benign, 39 had a borderline and 82 had a malignant ovarian mass. HE4 had the highest AUC of 0.80 (95%CI 0.74-0.86), followed by RMI (0.71, 95%CI 0.64-0.78) and CA125 (0.69, 95%CI 0.62-0.75). Clinical setting significantly influenced biomarker performances. Applying age-dependent cut-off values for HE4 resulted in a better performance than one cut-off. Addition of HE4 to RMI resulted in a 32% decrease of unnecessary referred patients, while the number of correctly referred patients remained the same. CONCLUSION: HE4 is superior to RMI in predicting malignancy in patients with an ovarian mass from general hospitals. The addition of HE4 to the RMI improved HE4 alone. Although, there is still room for improvement, HE4 can guide referral decisions in patients with an ovarian mass to an oncology hospital.

Single- versus double-layer closure of the caesarean (uterine) scar in the prevention of gynaecological symptoms in relation to niche development - the 2Close study: a multicentre randomised controlled trial.

BACKGROUND: Double-layer compared to single-layer closure of the uterus after a caesarean section (CS) leads to a thicker myometrial layer at the site of the CS scar, also called residual myometrium thickness (RMT). It possibly decreases the development of a niche, which is an interruption of the myometrium at the site of the uterine scar. Thin RMT and a niche are associated with gynaecological symptoms, obstetric complications in a subsequent pregnancy and delivery and possibly with subfertility. METHODS: Women undergoing a first CS regardless of the gestational age will be asked to participate in this multicentre, double blinded randomised controlled trial (RCT). They will be randomised to single-layer closure or double-layer closure of the uterine incision. Single-layer closure (control group) is performed with a continuous running, unlocked suture, with or without endometrial saving technique. Double-layer closure (intervention group) is performed with the first layer in a continuous unlocked suture including the endometrial layer and the second layer is also continuous unlocked and imbricates the first. The primary outcome is the reported number of days with postmenstrual spotting during one menstrual cycle nine months after CS. Secondary outcomes include surgical data, ultrasound evaluation at three months, menstrual pattern, dysmenorrhea, quality of life, and sexual function at nine months. Structured transvaginal ultrasound (TVUS) evaluation is performed to assess the uterine scar and if necessary saline infusion sonohysterography (SIS) or gel instillation sonohysterography (GIS) will be added to the examination. Women and ultrasound examiners will be blinded for allocation. Reproductive outcomes at three years follow-up including fertility, mode of delivery and complications in subsequent deliveries will be studied as well. Analyses will be performed by intention to treat. 2290 women have to be randomised to show a reduction of 15% in the mean number of spotting days. Additionally, a cost-effectiveness analysis will be performed from a societal perspective. DISCUSSION: This RCT will provide insight in the outcomes of single- compared to double-layer closure technique after CS, including postmenstrual spotting and subfertility in relation to niche development measured by ultrasound. TRIAL REGISTRATION: Dutch Trial Register ( NTR5480 ). Registered 29 October 2015.

Word catheter and marsupialisation in women with a cyst or abscess of the Bartholin gland (WoMan-trial): a randomised clinical trial.

OBJECTIVE: To compare recurrence of a cyst or abscess of the Bartholin gland after surgical treatment using a Word catheter or marsupialisation. DESIGN: Multicentre, open-label, randomised controlled trial. SETTING: Eighteen hospitals in the Netherlands and one hospital in England. POPULATION: Women with a symptomatic cyst or abscess of the Bartholin gland. METHODS: Women were randomised to treatment with Word catheter or marsupialisation. MAIN OUTCOME MEASURES: The primary outcome was recurrence of the cyst or abscess within 1 year of treatment. The secondary outcomes included pain during and after treatment (measured on a 10-point scale), use of analgesics, and time from diagnosis to treatment. Analysis was by intention-to-treat. To assess whether marsupialisation would reduce the recurrence rate by 5% (from 20 to 15%) we needed to include 160 women (alpha error 0.05, beta error 0.2). RESULTS: One hundred and sixty-one women were randomly allocated to treatment by Word catheter (n = 82) or marsupialisation (n = 79) between August 2010 and May 2014. Baseline characteristics were comparable. Recurrence occurred in 10 women (12%) allocated to Word catheter versus eight women (10%) allocated to marsupialisation: relative risk (RR) 1.1, 95% confidence interval (CI) 0.64-1.91; P = 0.70. Pain scores after treatment were also comparable. In the first 24 hours after treatment, 33% used analgesics in the Word catheter group versus 74% in the marsupialisation group (P < 0.001). Time from diagnosis to treatment was 1 hour for placement of Word catheter versus 4 hours for marsupialisation (P = 0.001). CONCLUSIONS: In women with an abscess or cyst of the Bartholin gland, treatment with Word catheter and marsupialisation results in comparable recurrence rates. TWEETABLE ABSTRACT: Comparable recurrence rates for treatment of Bartholinic abscess/cyst with Word catheter and marsupialisation.

Performance of CADM1/MAL-methylation analysis for monitoring of women treated for high-grade CIN.

INTRODUCTION: Recent studies have shown that CADM1/MAL-methylation testing detects high-grade CIN lesions with a high short-term progression risk for cervical cancer. Women treated for CIN2/3 are at risk of post-treatment disease, representing either persistent (incompletely treated) or incident (early onset) lesions. Here, we evaluated CADM1/MAL-methylation analysis as potential tool for detecting recurrent high-grade CIN lesions (rCIN2/3). METHODS AND MATERIALS: A multicenter prospective clinical cohort study was conducted among 364 women treated for CIN2/3. Cervical scrapes were taken prior to treatment, and six and 12months post-treatment and tested for cytology, hrHPV (plus genotype) and CADM1/MAL-methylation. When at six months either of these tests was positive, a colposcopy-directed biopsy was obtained. At 12months, all women underwent an exit-colposcopy with biopsy. In case of rCIN2/3, re-treatment was done. RESULTS: We found 28 rCIN2 (7.7%) and 14 rCIN3 (3.8%), resulting in a total recurrence rate of 11.5%. All 14 women with rCIN3 and 15/28 (54%) with rCIN2 showed hrHPV type-persistence. Of these, 9/14 (64%) rCIN3 and 8/15 (53%) rCIN2 were CADM1/MAL-methylation positive. All incident rCIN2, characterized by hrHPV genotype-switch, were CADM1/MAL-methylation negative. All three carcinomas found after re-treatment were CADM1/MAL-methylation positive. CADM1/MAL-methylation positivity at both baseline and follow-up significantly increased the risk of ≥rCIN3 (from 0.7% to 18.4%), and ≥rCIN2 (from 8.2% to 36.8%), compared to a consistently CADM1/MAL-methylation negative result (p-value: <0.001). CONCLUSION: Post-treatment monitoring by CADM1/MAL-methylation analysis identifies women with an increased risk of rCIN2/3. Our results confirm previous data indicating that CADM1/MAL-methylation analysis provides a high reassurance against cancer.

A personalised eHealth programme reduces the duration until return to work after gynaecological surgery: results of a multicentre randomised trial.

OBJECTIVE: To evaluate the effectiveness of an eHealth intervention on recovery and return to work, after gynaecological surgery. DESIGN: Randomised multicentre trial that ran from March 2010 until September 2011. SETTING: Secondary care in seven general and university hospitals in The Netherlands. POPULATION: A cohort of 215 women (aged 18-65 years) who had a hysterectomy and/or laparoscopic adnexal surgery for a benign indication. METHODS: The women were randomly assigned to the intervention group (n = 110) or the control group (n = 105). The intervention group received an eHealth programme that provided personalised tailor-made pre- and postoperative instructions on the resumption of daily activities, including work, and tools to improve self-empowerment and to identify recovery problems. The control group was provided with access to a control website. MAIN OUTCOME MEASURES: The primary outcome was the duration of sick leave until a full sustainable return to work. Secondary outcome measures were quality of life, general recovery, and pain intensity. RESULTS: In intention-to-treat analysis the eHealth intervention was effective on time to return to work (hazard ratio 1.43; 95% confidence interval 1.003-2.040; P = 0.048). The median duration of sick leave until a full sustainable return to work was 39 days (interquartile range 20-67 days) in the intervention group and 48 days (interquartile range 21-69 days) in the control group. After 26 weeks pain intensity was lower (visual analogue scale, cumulative odds ratio 1.84; 95% confidence interval 1.04-3.25; P = 0.035) and quality of life was higher (Rand-36 health survey, between-group difference 30, 95% confidence interval 4-57; P = 0.024) in the intervention group, compared with the control group. CONCLUSIONS: The use of the eHealth intervention by women after gynaecological surgery results in a faster return to work, with a higher quality of life and less pain.

HrHPV-testing in a university hospital gynecology outpatient clinic: recommendations for clinical practice.

OBJECTIVE: To study the effect of hrHPV-testing on the detection of CIN2/3+ in women referred to a gynecology outpatient clinic, and to assess a useful risk profile in relation to the referral reason to identify who should be tested for cervical pathology. METHODS: This study was designed as an observational cohort study. In the first six months of 2007, we categorized the referral reason of 1149 consecutive women who visited our gynecology outpatient clinic and assessed the risk for CIN2/3+ as found by cytology or co-testing with a hrHPV-test and cytology. RESULTS: Three different categories of referral reasons were identified; women with presumed cervix pathology, women with presumed endometrial pathology and women with other referral indications. The cumulative 18-month CIN2+ and CIN3+ risks were highest in the group with presumed cervical disease (adjusted risks 11.1% and 5.4% respectively) and lowest in the miscellaneous group with no suspicion of cervical and/or endometrial pathology (adjusted risks 4.1% and 1.8% respectively). HrHPV-testing detected significantly more CIN2/3+ lesions than cytology (relative detection rate: 1.42 (95%CI 1.05-1.92) and 1.38 (95%CI 0.95-2.05) respectively). CONCLUSIONS: The high (>2%) cumulative 18-month CIN2/3+ risk in patients with presumed cervical and/or endometrial pathology warrants routine cervical testing. In these women a hrHPV-test should be added to cytology because this identifies a significant number of additional women with a substantial risk of CIN2/3+ lesions who would not be identified with cytology alone. Women referred for other reasons should not have cervical testing beforehand, because of their low risk of CIN2/3+.

From open radical hysterectomy to robot-assisted laparoscopic radical hysterectomy for early stage cervical cancer: aspects of a single institution learning curve.

We analysed the introduction of the robot-assisted laparoscopic radical hysterectomy in patients with early-stage cervical cancer with respect to patient benefits and surgeon-related aspects of a surgical learning curve. A retrospective review of the first 14 robot-assisted laparoscopic radical hysterectomies and the last 14 open radical hysterectomies in a similar clinical setting with the same surgical team was conducted. Patients were candidates for a laparoscopic sentinel node procedure, pelvic lymph node dissection and open radical hysterectomy (RH) before August 2006 and were candidates for a laparoscopic sentinel node procedure, pelvic lymph node dissection and robot-assisted laparoscopic radical hysterectomy (RALRH) after August 2006. Overall, blood loss in the open cases was significantly more compared with the robot cases. Median hospital stay after RALRH was 5 days less than after RH. The median theatre time in the learning period for the robot procedure was reduced from 9 h to less that 4 h and compared well to the 3 h and 45 min for an open procedure. Three complications occurred in the open group and one in the robot group. RALRH is feasible and of benefit to the patient with early stage cervical cancer by a reduction of blood loss and reduced hospital stay. Introduction of this new technique requires a learning curve of less than 15 cases that will reduce the operating time to a level comparable to open surgery.

Effects of transdermal and oral oestrogen replacement therapy on C-reactive protein levels in postmenopausal women: a randomised, placebo-controlled trial.

To investigate the effect of postmenopausal oral and transdermal hormone therapy on plasma levels of C-reactive protein (CRP), we performed a randomised, double-blind, double-dummy, placebo-controlled, 15-month study. One hundred and fifty-two healthy hysterectomised postmenopausal women received daily either placebo (n = 49), or transdermal 17beta-oestradiol (E(2)) 50 micro g (tE(2) group, n = 33), or oral E(2) 1 mg (oE(2) group, n = 37), or oral E(2) 1 mg combined with gestodene 25 micro g (oE(2) + G group, n = 33) for thirteen 28-day treatment cycles, followed by four cycles placebo for each group. Data were collected at baseline and in cycles 4, 13 and 17. In cycle 13, CRP was significantly increased in the oE(2) group compared to placebo (P = 0.004). The median percentage change from baseline versus placebo was +75% (P <0.001). In cycle 17, significantly lower values were observed in the oE(2) group compared to cycle 13 and to the placebo group (-49%, P <0.001). There were no significant changes versus placebo in the other groups. In conclusion, oral E(2) significantly increased CRP levels. This change was larger than the increase found during oral E(2) + G. Transdermal E(2) did not affect CRP levels.

Effects of hormone replacement therapy on blood platelets.

BACKGROUND: Hormone replacement therapy (HRT) increases the risk of cardiovascular morbidity in postmenopausal women under certain circumstances. Part of this effect may be the result of the influence of HRT on blood platelets. We studied the effect of short-term oral hormone replacement therapy (unopposed oestradiol or sequentially combined oestradiol and trimegestone or dydrogesterone) on platelet activation parameters in healthy postmenopausal women. DESIGN: We designed a prospective, randomised, placebo-controlled 12-week study. Sixty healthy, normotensive, nonhysterectomised, postmenopausal women received daily micronised oestradiol (E2) 2 mg (n = 16), or 2 mg E2 daily sequentially combined with either trimegestone 0.5 mg daily (n = 14) or dydrogesterone 10 mg daily (n = 14), or placebo (n = 16). Data on platelet activation were collected at baseline and after 12 weeks of treatment using flow cytometry. RESULTS: Twelve weeks of treatment with combined HRT was associated with an increase in platelet activation parameters P-selectin and glycoprotein 53 (by 17% and 14%, respectively, P = 0.04 vs. the placebo group for both comparisons), suggesting alpha granule and lysosome degranulation. E2 replacement therapy was associated with an increase in P-selectin labelling by 22% (P = 0.04 vs. the placebo group). CONCLUSION: Short-term treatment with oestradiol or combined HRT increases the amount of circulating activated platelets as measured by flow cytometry. This could be a mechanism by which short-term HRT might increase the risk of thrombosis.

Oral oestradiol/trimegestone replacement reduces procarboxypeptidase U (TAFI): a randomized, placebo- controlled, 12-week study in early postmenopausal women.

OBJECTIVE: To investigate the effects of short-term postmenopausal oral hormone administration on plasma levels of procarboxypeptidase U (proCPU, thrombin-activatable fibrinolysis inhibitor, EC 3.4.17.20), an inhibitor of fibrinolysis, in healthy early postmenopausal women. DESIGN: A prospective, randomized, placebo-controlled study. SETTING: Outpatient clinic of the Department of Obstetrics and Gynaecology. SUBJECTS: Seventy-seven healthy early postmenopausal women were screened of whom 65 were randomized. Analyses were based on 60 participants. INTERVENTIONS: The women received oral micronized oestradiol 2 mg either alone (E2 group, n=16), or sequentially combined with dydrogesterone 10 mg (E2 + D group, n=14) or trimegestone 0.5 mg (E2 + T, n=14), or placebo (n=16) for 12 weeks. MAIN OUTCOME MEASURE: ProCPU concentrations at baseline, and at 4 and 12 weeks of treatment. RESULTS: Four weeks of E2 + T was associated with a significant decrease in the fasting proCPU concentration, which was sustained after 12 weeks [t=0: 636 +/- 57 U L(-1) (mean +/- SD); t=4: 583 +/- 63UL-1; t=12: 589 +/- 48 U L(-1); ANCOVA versus placebo: P=0.011]. The percentage change from baseline versus placebo in this group was -8.4% [95% confidence interval (CI) -15.7 to -1.1] after 4 weeks and -5.9% (95% CI -11.7 to -0.1) after 12 weeks. There were no significant changes versus placebo in the E2 group nor in the E2 + D group. CONCLUSION: Short-term treatment with E2 + T, but not E2 alone or E2 + D, lowers proCPU concentration. These findings add to accumulating evidence suggesting that different progestagens added to oestrogen replacement may differentially affect the risk of arterial and venous disease.

The mechanisms of thrombotic risk induced by hormone replacement therapy.

OBJECTIVES: 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.

Raloxifene reduces impedance to flow within the uterine artery in early postmenopausal women: a 2-year randomized, placebo-controlled, comparative study.

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.

Effects of 15 months of 17 beta-estradiol and dydrogesterone on systolic cardiac function according to quantitative and Doppler echocardiography in healthy postmenopausal women.

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 17 beta-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 17 beta-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 17 beta-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 17 beta-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.

Cardiovascular disease risk and hormone replacement therapy (HRT): a review based on randomised, controlled studies in postmenopausal women.

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.

Impaired procoagulant-anticoagulant balance during hormone replacement therapy? A randomised, placebo-controlled 12-week study.

UNLABELLED: In 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). RESULTS: As compared to placebo, plasma levels of AT III were reduced only in the E2 group (approximately 28%), plasma levels of protein C decreased only in the E2+P group (approximately 4%) and plasma levels of protein S decreased in both the E2 and E2+P group (approximately 21%). In both the E2 and E2+P groups, the plasma levels of factor VII (antigen and activity) showed a borderline significant increase (approximately 10%), whereas no significant change was observed in active factor VII. Plasma levels of tissue-type plasminogen activator (approximately 22%), urokinase plasminogen activator (approximately 25%) and plasminogen activator inhibitor type-1 (approximately 43%) decreased in the E2 and E2+P groups, whereas those of plasminogen increased (approximately 12%). Treatment was associated with an increase in levels of prothrombin fragment 1+2 (approximately 31%), but levels of thrombin-antithrombin III complexes, and of plasmin-alpha2-antiplasmin complexes and total fibrin(ogen) degradation products did not change significantly. CONCLUSION: 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.

Sequentially combined hormone replacement therapy reduces impedance to flow within the uterine and central retinal arteries in healthy postmenopausal women.

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 17beta-estradiol daily sequentially combined with 5 or 10 mg dydrogesterone for 14 days of each 28-day cycle during 12 months and 2 mg 17beta-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 17beta-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.

Short-term hormone replacement therapy: reduced plasma levels of soluble adhesion molecules.

BACKGROUND: Epidemiological data have suggested that the use of hormone replacement therapy (HRT) is associated with a decreased risk of cardiovascular disease. Vascular endothelium and adhesion molecules play an important role in the initiation and progression of atherosclerosis. MATERIAL AND METHODS: Prospective, randomized, placebo-controlled 12-week study. Sixty healthy, normotensive postmenopausal women received either micronised oestradiol 2 mg alone (n = 16, E2 group), or sequentially combined with a progestagen; E2 + P groups trimegestone 0.5 mg (E2 + T, n = 14) or dydrogesterone 10 mg (E2 + D group, n = 14) or placebo (n = 16). Data were collected at baseline and at 4 and 12 weeks. RESULTS: Twelve weeks of treatment with E2 or E2 + P was associated with a significant decrease in the plasma concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and thrombomodulin (sTM). The average decrease in these markers was about 9%. In women treated with trimegestone the decreases were larger than in those treated with dydrogesterone; for sICAM-1 (-15% vs. -2%; P < 0.0001), sVCAM-1 (-15% vs. +3%; P = 0. 003) and sTM (-9% vs. -4%; P = 0.11). Plasma levels of endothelin-1 (ET-1) decreased (by 13%) only in women treated with E2 + P. In the E2 group, flow-mediated, endothelium-dependent vasodilatation increased by 6 percentage points after 12 weeks (P = 0.07 vs. baseline, P = 0.02 vs. E2 + P, and P = 0.17 vs. placebo). CONCLUSION: Short-term treatment with E2 or E2 + trimegestone reduces plasma levels of sICAM-1, sVCAM-1 and sTM. ET-1 decreased only in the E2 + P groups. Different types of progestagens may differentially affect sICAM-1, sVCAM-1 and sTM levels, which may be relevant for the choice of type HRT.

Hormone replacement therapy and plasma homocysteine levels.

OBJECTIVE: To compare the effects of 4 and 12 weeks of combined estradiol-progestogen replacement with unopposed estradiol therapy on fasting plasma total homocysteine concentrations in healthy postmenopausal women. METHODS: In this prospective, 12-week study in healthy postmenopausal women, we randomly assigned 59 women to sequentially combined daily 2 mg estradiol (E2) plus either trimegestone 0.5 mg daily or dydrogesterone 10 mg daily (n = 28), or to unopposed daily 2 mg estradiol (n = 16), or to placebo (n = 15). RESULTS: Fasting plasma total homocysteine concentrations decreased by 9.4% in the combined estradiol-progestogen group and by 5.1% in the estradiol-only group, and they increased by 2.4% in the placebo group (analysis of covariance: combined hormone replacement therapy compared with placebo (P = .02); combined therapy compared with estradiol (P = .23); and estradiol compared with placebo (P = .26). Reductions were detectable after 4 weeks of combined estradiol-progestogen treatment. The data suggest an additional progestogen-related reduction in homocysteine levels of 0.7 micromol/L and 0.4 micromol/L after 4 and 12 weeks, respectively. Women with a baseline homocysteine concentration in the highest quartile had significantly greater reductions in homocysteine compared with women with an initial homocysteine value in the lowest quartile. CONCLUSION: Fasting total homocysteine concentrations were significantly reduced by combined estradiol-progestogen replacement. Women with high homocysteine levels at baseline benefit the most. The progestogens used in this study did not have an unfavorable effect on homocysteine metabolism.