Predictive value of fetal growth trajectory from 20 weeks of gestation onwards for severe adverse perinatal outcome in low-risk population: secondary analysis of IRIS study.

OBJECTIVES: The placental dysfunction underlying fetal growth restriction (FGR) may result in severe adverse perinatal outcome (SAPO) related to fetal hypoxia. Traditionally, the diagnostic criteria for FGR have been based on fetal size, an approach that is inherently flawed because it often results in either over- or underdiagnosis. The anomaly ultrasound scan at 20 weeks' gestation may be an appropriate time at which to set a benchmark for growth potential of the individual fetus. We hypothesized that the fetal growth trajectory from that point onwards may be informative regarding third-trimester placental dysfunction. The aim of this study was to investigate the predictive value for SAPO of a slow fetal growth trajectory between 18 + 0 to 23 + 6 weeks and 32 + 0 to 36 + 6 weeks' gestation in a large, low-risk population. METHODS: This was a post-hoc data analysis of the IUGR Risk Selection (IRIS) study, a Dutch nationwide cluster-randomized trial assessing the (cost-)effectiveness of routine third-trimester sonography in reducing SAPO. In the current analysis, for the first ultrasound examination we used ultrasound data from the routine anomaly scan at 18 + 0 to 23 + 6 weeks' gestation, and for the second we used data from an ultrasound examination performed between 32 + 0 and 36 + 6 weeks' gestation. Using multilevel logistic regression, we analyzed whether SAPO was predicted by a slow fetal growth trajectory, which was defined as a decline in abdominal circumference (AC) and/or estimated fetal weight (EFW) of more than 20 percentiles or more than 50 percentiles or as an AC growth velocity (ACGV) < 10th percentile (p10). In addition, we analyzed the combination of these indicators of slow fetal growth with small-for-gestational age (SGA) (AC or EFW < p10) and severe SGA (AC/EFW < 3rd percentile) at 32 + 0 to 36 + 6 weeks' gestation. RESULTS: Our sample included the data of 6296 low-risk singleton pregnancies, among which 82 (1.3%) newborns experienced at least one SAPO. Standalone declines in AC or EFW of > 20 or > 50 percentiles or ACGV < p10 were not associated with increased odds of SAPO. EFW < p10 between 32 + 0 and 36 + 6 weeks' gestation combined with a decline in EFW of > 20 percentiles was associated with an increased rate of SAPO. The combination of AC or EFW < p10 between 32 + 0 and 36 + 6 weeks' gestation with ACGV < p10 was also associated with increased odds of SAPO. The odds ratios of these associations were higher if the neonate was SGA at birth. CONCLUSIONS: In a low-risk population, a slow fetal growth trajectory as a standalone criterion does not distinguish adequately between fetuses with FGR and those that are constitutionally small. This absence of association may be a result of diagnostic inaccuracies and/or post-diagnostic (e.g. intervention and selection) biases. We conclude that new approaches to detect placental insufficiency should integrate information from diagnostic tools such as maternal serum biomarkers and Doppler ultrasound measurements. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Implication of third-trimester screening accuracy for small-for-gestational age and additive value of third-trimester growth-trajectory indicators in predicting severe adverse perinatal outcome in low-risk population: pragmatic secondary analysis of IRIS study.

OBJECTIVES: To examine the implications of third-trimester small-for-gestational-age (SGA) screening accuracy on severe adverse perinatal outcome (SAPO) and obstetric intervention in a low-risk population. Furthermore, we aimed to explore the additive value of third-trimester sonographic growth-trajectory measurements in predicting SAPO and obstetric intervention. METHODS: This was a secondary analysis of a Dutch national multicenter stepped-wedge-cluster randomized trial among 11 820 low-risk pregnant women. Using multilevel multivariable logistic regression analysis, we compared SAPO and obstetric interventions in SGA neonates with and without SGA suspected prenatally (true positives and false negatives) and non-SGA neonates with and without SGA suspected prenatally (false positives and true negatives). In a subsample (n = 7989), we analyzed the associations of abdominal circumference (AC) and estimated fetal weight (EFW) < 10th centile (p10) and third-trimester growth-trajectory indicators AC and EFW crossing > 20 and AC crossing > 50 centiles and the lowest decile of AC growth-velocity Z-scores (ACGV < 10%) with SAPO and obstetric interventions. RESULTS: SGA infants, i.e. the true-positive and false-negative cases, had an increased risk of SAPO (adjusted odds ratio (aOR), 4.46 (95% CI, 2.28-8.75) and aOR 2.61 (95% CI, 1.74-3.89), respectively), and obstetric intervention (aOR for: induction of labor, 2.99 (95% CI, 2.15-4.17) and 1.38 (95% CI, 1.14-1.66); Cesarean section, 1.82 (95% CI, 1.25-2.66) and 1.27 (95% CI, 1.05-1.54); medically indicated preterm delivery, 2.67 (95% CI, 1.97-3.62) and 1.20 (95% CI, 1.03-1.40)). The false-positive cases did not differ from the true negatives for all outcomes, including obstetric intervention. Of the third-trimester growth-trajectory indicators, only ACGV < 10% was associated moderately with SAPO (aOR, 2.15 (95% CI, 1.17-3.97)), while AC and EFW crossing > 20 and AC crossing > 50 centiles were not. Both EFW < p10 alone (aOR, 1.95 (95% CI, 1.13-3.38)) and EFW < p10 combined with ACGV < 10% (aOR, 4.69 (95% CI, 1.99-11.07)) were associated with SAPO, and they performed equally well in predicting SAPO (area under the receiver-operating-characteristics curve, 0.71 (95% CI, 0.65-0.76) vs 0.72 (95% CI, 0.67-0.77), P = 0.51). CONCLUSION: Neonates who had been suspected falsely of being SGA during pregnancy had no higher rates of obstetric intervention than did those without suspicion of SGA prenatally. Our results do not support that third-trimester low fetal growth velocity (ACGV < 10%) may be of additive value for the identification of fetuses at risk of SAPO in populations remaining at low risk throughout pregnancy. AC and EFW crossing > 20 and AC crossing > 50 centiles performed poorly in identifying abnormal fetal growth. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Serious adverse events attributed to remifentanil patient-controlled analgesia during labour in The Netherlands.

BACKGROUND: During labour, remifentanil patient-controlled analgesia is used as an alternative to neuraxial analgesia. Remifentanil is associated with hypoventilation and respiratory depression but the frequency of serious maternal and neonatal adverse events is unknown. The aim of this study was to estimate the number of serious adverse events attributed to the use of remifentanil patient-controlled analgesia during labour in The Netherlands and to investigate the circumstances (e.g. monitoring, practice deviations) of these events and the subsequent management. METHODS: In a nationwide survey among obstetricians, anaesthetists and clinical midwives the frequency of serious adverse events was assessed. A questionnaire was sent by email to all 61 Dutch hospitals in which remifentanil patient-controlled analgesia is, or has been, available for labour analgesia. All reported cases were assessed independently by two expert teams. RESULTS: We received information from all hospitals. After independent assessments, 17 cases of single maternal desaturation; 10 maternal cases of apnoea, bradycardia and/or cardiac arrest; and two neonatal cases of respiratory depression, over a period of more than 10 years of remifentanil patient-controlled analgesia use, were identified as a serious adverse event. All serious adverse events were resolved without irreversible damage. CONCLUSIONS: The risk of a potentially life-threatening serious adverse event attributed to remifentanil patient-controlled analgesia seems to be low. All patients recovered without deficit. Adherence to strict monitoring and the attendance of trained healthcare providers is required to safely use remifentanil for labour analgesia.

Regional variations in childbirth interventions in the Netherlands: a nationwide explorative study.

BACKGROUND: Although interventions in childbirth are important in order to prevent neonatal and maternal morbidity and mortality, non-indicated use may cause avoidable harm. Regional variations in intervention rates, which cannot be explained by maternal characteristics, may indicate over- and underuse. The aim of this study is to explore regional variations in childbirth interventions in the Netherlands and their associations with interventions and adverse outcomes, controlled for maternal characteristics. METHODS: Childbirth intervention rates were compared between twelve Dutch regions, using data from the national perinatal birth register for 2010-2013. All single childbirths from 37 weeks' gestation onwards were included. Primary outcomes were induction and augmentation of labour, pain medication, instrumental birth, caesarean section (prelabour, intrapartum) and paediatric involvement. Secondary outcomes were adverse neonatal and maternal outcomes. Multivariable logistic regression analyses were used to adjust for maternal characteristics. Associations were expressed in Spearman's rank correlation coefficients. RESULTS: Most variation was found for type of pain medication and paediatric involvement. Epidural analgesia rates varied from between 12 and 38% (nulliparous) and from between 5 and 14% (multiparous women). These rates were negatively correlated with rates of other pharmacological pain relief, which varied from between 15 and 43% (nulliparous) and from between 10 and 27% (multiparous). Rates of paediatric involvement varied from between 37 and 60% (nulliparous) and from between 26 and 43% (multiparous). For instrumental vaginal births, rates varied from between 16 and 19% (nulliparous) and from between 3 and 4% (multiparous). For intrapartum caesarean section, the variation was 13-15% and 5-6%, respectively. A positive correlation was found between intervention rates in midwife-led and obstetrician-led care at the onset of labour within the same region. Adverse neonatal and maternal outcomes were not lower in regions with higher intervention rates. Higher augmentation of labour rates correlated with higher rates of severe postpartum haemorrhage. CONCLUSIONS: Most variation was found for type of pain medication and paediatric involvement, and least for instrumental vaginal births and intrapartum caesarean sections. Care providers and policy makers should critically audit remarkable variations, since these may be unwarranted. Limited variation for some interventions may indicate consensus for their use. Further research should focus on variations in evidence-based interventions and indications for the use of interventions in childbirth.

Pharmacokinetics of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women.

OBJECTIVES: Estetrol (E4) is a natural fetal estrogen. In this open-label, multiple-rising-dose study, the pharmacokinetic effects of E4 in postmenopausal women were investigated as a secondary objective. METHODS: In total, 49 postmenopausal women were randomized to receive either 2 mg E4 or 2 mg estradiol valerate (E2V) for 28 days, or were (non-randomized) assigned to 10, 20, or 40 mg E4. The main outcome measures were: E4 plasma concentrations at trough, and on days 1 and 28; and E4 pharmacokinetic parameters AUC, Cmax and tmax on days 1 and 28. RESULTS: After oral administration, E4 showed a very fast absorption, followed by a multiphasic elimination with an initial rapid decline, gradually continuing with a slower elimination, suggesting a long terminal half-life. Steady state was reached within 2 weeks of dosing and pharmacokinetic results were generally proportional to the dose. Estetrol concentrations on day 28 were slightly higher compared to day 1, indicating some accumulation. CONCLUSION: The pharmacokinetic profile of estetrol is characterized by a very fast absorption phase, followed by an initial rapid decline, and a slow terminal elimination phase. Based on its kinetic properties, estetrol seems suitable for use as a once-daily oral drug.

Labour pain with remifentanil patient-controlled analgesia versus epidural analgesia: a randomised equivalence trial.

OBJECTIVE: To distinguish satisfaction with pain relief using remifentanil patient-controlled analgesia (RPCA) compared with epidural analgesia (EA) in low-risk labouring women. DESIGN: Randomised controlled equivalence trial. SETTING: Eighteen midwifery practices and six hospitals in the Netherlands. POPULATION: A total of 408 pregnant women at low risk for obstetric complications initially under the care of primary-care midwives. METHODS: Women randomised before active labour to receive analgesia with RPCA or EA, if requested. MAIN OUTCOME MEASURES: Primary outcome was satisfaction with pain relief measured hourly using a visual analogue scale and summed as area under the curve (AUC). Secondary outcomes were overall satisfaction with pain relief, pain intensity scores during labour, mode of delivery, and maternal and neonatal outcomes. RESULTS: We randomised 418 women, of whom 409 could be followed for the primary endpoint. Analgesia was received by 46% (94/203) in the remifentanil group and 37% (76/206) in the epidural group. The AUC for satisfaction with pain relief was 32 in the remifentanil group and 31 in the epidural group (mean difference -0.50; 95% CI -6.8 to 5.9). Among women who actually received analgesia, these values were 23 and 35, respectively (mean difference -12; 95% CI -22 to -1.5). Secondary outcomes were comparable. CONCLUSIONS: In low-risk labouring women, we could not demonstrate equivalence between a strategy with RPCA to EA with respect to satisfaction with pain relief assessed during the total duration of labour. However, once applied satisfaction was higher in women who received epidural analgesia. TWEETABLE ABSTRACT: Satisfaction with pain relief is higher in women receiving epidural analgesia compared with Remifentanil PCA.

Midpregnancy Cervical Length in Nulliparous Women and its Association with Postterm Delivery and Intrapartum Cesarean Delivery.

OBJECTIVE: To evaluate the association between midpregnancy cervical length and postterm delivery and cesarean delivery during labor. STUDY DESIGN: In a multicenter cohort study, cervical length was measured in low-risk singleton pregnancies between 16 and 22 weeks of gestation. From this cohort, we identified nulliparous women who delivered beyond 34 weeks and calculated cervical length quartiles. We performed logistic regression to compare the risk of postterm delivery and intrapartum cesarean delivery to cervical length quartiles, using the lowest quartile as a reference. We adjusted for induction of labor, maternal age, ethnicity, cephalic position, preexisting hypertension, and gestational age at delivery. RESULTS: We studied 5,321 nulliparous women. Women with cervical length in the 3rd and 4th quartile were more likely to deliver at 42(+0) to 42(+6) weeks (adjusted odds ratio [aOR] 2.02, 95% confidence interval [CI] 1.07-3.79 and aOR 1.97, 95% CI 1.06-3.67, respectively). The frequency of intrapartum cesarean delivery increased with cervical length quartile from 9.4% in the 1st to 14.9% in the 4th quartile (p = 0.01). This increase was only present in intrapartum cesarean delivery because of failure to progress and not because of fetal distress. CONCLUSION: The longer the cervix at midtrimester the higher the risk of both postterm delivery and intrapartum cesarean delivery.

Effect of physiological determinants and cardiac disease on plasma adiponectin concentrations in dogs.

BACKGROUND: In humans, a high concentration of adiponectin is associated with a favorable cardiovascular risk profile whereas, in patients with heart failure (HF), a high concentration of adiponectin is associated with a less favorable prognosis. HYPOTHESIS/OBJECTIVES: To evaluate the physiological determinants of plasma adiponectin concentration in dogs and the influence of heart disease, myxomatous mitral valve disease (MMVD), and dilated cardiomyopathy (DCM). ANIMALS: One hundred and fourteen client-owned dogs and 9 Beagles from the research colony of the Clinical Veterinary Unit of the University of Liège. METHODS: We prospectively measured circulating adiponectin concentration in healthy control dogs (n = 77), dogs with MMVD (n = 22) and dogs with DCM (n = 15) of various degrees of severity. Diagnosis was confirmed by Doppler echocardiography. Plasma adiponectin concentration was measured by a canine-specific sandwich ELISA kit. RESULTS: An analysis of covariance showed an association between adiponectin concentration and age, neuter status, and heart disease. No association between adiponectin concentration and class of HF, sex, body condition score, body weight, circadian rhythm, or feeding was found. Plasma adiponectin concentration was negatively correlated with age (P = .001). Adiponectin was lower in neutered (P = .008) compared to intact dogs. Circulating adiponectin concentration was increased in dogs with DCM compared to healthy dogs (P = .018) and to dogs with MMVD (P = .014). CONCLUSIONS AND CLINICAL IMPORTANCE: Age and neutering negatively influence circulating adiponectin concentration. Plasma adiponectin concentration increased in dogs with DCM. Additional research is required to investigate if this hormone is implicated in the pathophysiology of DCM and associated with clinical outcome.

Transvaginal sonographic assessment of cervical length and wedging for predicting outcome of labor induction at term: a systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis to assess the predictive capacity of transvaginal sonographic assessment of the cervix for the outcome of induction of labor. METHODS: We searched MEDLINE, EMBASE and the Cochrane Library, and manually searched reference lists of review articles and eligible primary articles. Studies in all languages were eligible if published in full. Two reviewers independently selected studies and extracted data on study characteristics, quality and test accuracy. We then calculated pooled sensitivities and specificities (with 95% CIs) and summary receiver-operating characteristics (sROC) curves. Outcome measures were test accuracy of sonographically measured cervical length and cervical wedging for Cesarean section, not achieving vaginal delivery within 24 h and not achieving active labor. RESULTS: We included 31 studies reporting on both cervical length and outcome of delivery. The quality of the included studies was mediocre. Sensitivity of cervical length in the prediction of Cesarean delivery ranged from 0.14 to 0.92 and specificity ranged from 0.35 to 1.00. The estimated sROC curve for cervical length indicated a limited predictive capacity in the prediction of Cesarean delivery. Summary estimates of sensitivity/specificity combinations of cervical length at different cut-offs for Cesarean delivery were 0.82/0.34, 0.64/0.74 and 0.13/0.95 for 20, 30 and 40 mm, respectively. For cervical wedging in the prediction of failed induction of labor summary point estimates of sensitivity/specificity were 0.37/0.80. CONCLUSIONS: Cervical length and cervical wedging as measured sonographically at or near term have moderate capacity to predict the outcome of delivery after induction of labor.

Ultrasonographic fetal head position to predict mode of delivery: a systematic review and bivariate meta-analysis.

OBJECTIVE: We performed a systematic review to determine whether sonographic assessment of occipital position of the fetal head can contribute to the prediction of the mode of delivery. METHODS: We performed a systematic literature search of electronic databases from inception to May 2011. Two reviewers independently extracted data from the included studies. We used a bivariate model to estimate point estimates for sensitivity and specificity curves for the outcome Cesarean delivery. Eligible studies were cohort studies or cross-sectional studies that reported on both the position of the fetal head, as assessed by ultrasound, before or at the beginning of active labor as well as the outcome of labor in women at term. RESULTS: We included 11 primary articles reporting on 5053 women, of whom 898 had a Cesarean section. All studies indicated disappointing values for sensitivity and specificity in the prediction of Cesarean section. Summary point estimates of sensitivity and specificity were 0.39 (95% CI, 0.32-0.48) and 0.71 (95% CI, 0.67-0.74), respectively. CONCLUSION: Sonographic assessment of occipital position of the fetal head before delivery should not be used in the prediction of mode of delivery.

Goal commitment to finding a partner and satisfaction with life among female singles: the mediating role of rumination.

In this cross-sectional study among 1502 female singles between the ages of 18 and 50, commitment to the goal of finding a partner was negatively related to satisfaction with life. In line with our expectations, this relationship was fully mediated by ruminating about being and remaining single. The relationship between rumination and lower satisfaction with life was stronger in the older age groups. The findings support the notion that rumination is an important mechanism through which goal commitment may negatively influence well-being, and that reducing one's level of commitment to the pursuit of stage-specific life goals may be beneficial when reaching a new developmental stage.

Validation of models that predict Cesarean section after induction of labor.

OBJECTIVE: Models for the prediction of Cesarean delivery after induction of labor can be used to improve clinical decision-making. The objective of this study was to validate two existing models, published by Peregrine et al. and Rane et al., for the prediction of Cesarean section after induction of labor. METHODS: We studied consecutive women in whom labor was induced. In all women, we recorded maternal age, height, body mass index, parity, gestational age and the Bishop score prior to induction. Cervical length was measured by transvaginal ultrasound immediately prior to induction of labor. The primary end-point was delivery by Cesarean section. The calibration of the two prediction models was assessed by comparison of predicted and observed Cesarean delivery rates. The discriminative capacity of the models, i.e. the ability of the models to distinguish subjects who had Cesarean section from those who did not (discrimination), was assessed by receiver-operating characteristics (ROC) analysis. RESULTS: We included 240 women in the study, of whom 27 (11%) had Cesarean delivery. The capacity of cervical length in the prediction of Cesarean delivery was limited. In our study population, both prediction models overestimated the risk of Cesarean delivery. Calibration was better for the Peregrine et al. model than for the Rane et al. model, and the two models had areas under the ROC curve of 0.76 and 0.67, respectively. CONCLUSION: Current models that predict the occurrence of Cesarean section after induction of labor have only a moderate predictive capacity when applied within a Dutch practice. We do not recommend the use of these prediction models in clinical practice.

Superior cycle control with a contraceptive vaginal ring compared with an oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel: a randomized trial.

BACKGROUND: This trial was conducted to compare cycle control with vaginal ring a combined contraceptive vaginal ring, and a combined oral contraceptive (COC) delivering 30 mug ethinylestradiol (EE) and 150 mug levonorgestrel. METHODS: This open-label, randomized, multi-centre, Phase III study involved adult women from 11 countries. Subjects were treated with either vaginal ring or a COC for 13 cycles (12 months). RESULTS: A total of 1030 subjects (vaginal ring, n=512; COC, n=518) comprised the intention-to-treat (ITT) population. The percentage of women in the ITT population who completed the trial was 70.9% for vaginal ring and 71.2% for the COC group. The incidence of breakthrough bleeding and spotting over cycles 2-13, the primary efficacy parameter, was lower with vaginal ring (range 2.0-6.4%) than the COC (range 3.5-12.6%), and for cycles 2 and 9 the lower incidence with vaginal ring was confirmed as statistically significant (P=0.003 and P=0.002 respectively). The incidence of intended bleeding was significantly higher over all cycles with vaginal ring (58.8-72.8%) than with the COC (43.4-57.9%). CONCLUSIONS: Cycle control with vaginal ring was excellent and superior to that of a COC containing 30 mug EE.

The contraceptive vaginal ring, NuvaRing, and antimycotic co-medication.

We investigated the effect of antimycotic co-medication on the systemic exposure to etonogestrel (ENG) and ethinylestradiol (EE) released from the contraceptive vaginal ring, NuvaRing. Different formulations of miconazole nitrate and single as well as multiple dosing were investigated during two separate randomized, open-label, crossover studies. The first study recruited 12 women to compare the effects of co-use of NuvaRing and a single dose of antimycotic to NuvaRing alone. The second study recruited 14 women to compare the effects of multiple doses of an antimycotic vaginal suppository to an antimycotic vaginal cream equivalent. Co-administration of all three antimycotic formulations resulted in a slight increase in systemic exposure to ENG and EE over time, with suppositories having a more pronounced effect than a cream formulation in the multiple-dosing study. The increases in serum levels observed with the different antimycotic formulations are not expected to compromise NuvaRing's contraceptive efficacy or tolerability.

The in vivo metabolism of tibolone in animal species.

The in vivo tissue distribution and metabolism of tibolone was studied in different animals to further investigate the compound's tissue-specificity. Tibolone's metabolism was studied in vivo in rats and rabbits by administration of [16-3H]-tibolone and the metabolic pattern was determined in urine and faeces after oral administration to female rats and dogs. The main excretory pathway was found to be excretion in the faeces. Important phase-I metabolic routes were the reduction of the 3-keto to the 3a- or 3beta-hydroxy functions with a preference for 3alpha-OH in rats and for 3beta-OH in dogs. To a lesser extent, hydroxylation reactions at C2 and C7, and a shift of the delta5(10)-double bond to a delta4(5)-position also occurred. The main phase-II metabolic route was sulphate conjugation of the hydroxyl groups at C3 and C17. Since the oxidation reactions form only a minor part of the metabolism of tibolone, it is concluded that the cytochrome P450 enzymes do not play an important role in tibolone's metabolism. For both phases, quantitative differences were found between the species. In human similar metabolites are found. Profiling of the target organs in female rats and rabbits showed a tissue-specific distribution of metabolites. The majority of the metabolites existed as sulphate conjugates and no glucuronidated conjugates were observed. The same metabolites were found in both the circulation and the tissues. However, different tissues had quantitatively different metabolic profiles.

Identification of the human P450 enzymes involved in the in vitro metabolism of the synthetic steroidal hormones Org 4060 and Org 30659.

1. The type of human P450 enzymes involved in the in vitro metabolism of Org 4060 and Org 30659, two synthetic steroidal hormones currently under clinical development by NV Organon for use in oral contraceptive and hormone replacement therapy, was investigated. 2. Both steroids were mainly hydroxylated at the 6beta-position in incubations with human liver microsomes. 3. The results from experiments with supersomes, correlation studies as well as inhibition studies with ketoconazole, a selective inhibitor of CYP3A, strongly suggest that the CYP3A family plays a significant role in the 6beta-hydroxylation of both steroids. 4. Measurements of kinetic parameters of P450 enzymes that could metabolize both steroids, combined with the fact that CYP3A4 is known to be the most abundant P450 enzyme in the human liver, indicate that CYP3A4 will be of major importance for the in vivo human metabolism of Org 4060 and Org 30659.

The in vivo human metabolism of tibolone.

In vivo metabolism of tibolone was studied in three healthy postmenopausal volunteers after daily oral administration of 2.5 mg of tibolone for 5 days and a single dose of 2.5 mg approximately equal 555 kBq of [(14)C]tibolone on day 6. The 0- to 192-h recovery of radioactivity in urine and feces was 31.2 +/- 10.5 and 53.7 +/- 5.1%, respectively. Total 0- to 192-h recovery ranged from 78.5 to 94.2% of the dose and averaged 84.9%. Metabolites were putatively identified using high-pressure liquid chromatography in plasma, urine, and feces. The most important phase I metabolic reactions were reduction of the 3-keto group to 3alpha- and 3beta-hydroxy metabolites, a shift of the Delta(5(10))-double bond to a Delta(4(5))-double bond, a reduction of the Delta(4(5))-double bond to 5alpha,10-dihydro or 5beta,10-dihydro metabolites, and hydroxylation at C2 and C7. The most important phase II metabolic reaction is sulfation of the C17 hydroxy group of tibolone and sulfation of the C3 hydroxy groups. In the circulation, over 75% of tibolone and its metabolites are present in the sulfated form. Local metabolism and local sulfatases may contribute to the tissue-specific activity. Using human microsomes, tibolone, 3alpha-hydroxy tibolone, 3beta-hydroxy tibolone, and Delta(4)-tibolone appeared to be at least 50-fold less potent inhibitors of CYP1A2, CYP2C9, CYP2E1, and CYP3A4 compared with enzyme-selective inhibitors. Tibolone and its metabolites, therefore, are not likely to play a clinically significant role at the level of these cytochrome P450 enzymes with regard to the metabolism of coadministered drugs.

Excretion and metabolism of desogestrel in healthy postmenopausal women.

The metabolism of desogestrel (13-ethyl-11-methylene-18,19-dinor-17alpha-pregn-4-en-20-yn-17-ol), a progestagen used in oral contraceptives and hormone replacement therapy, was studied in vivo after a single oral administration of 150 microg [14C]-labeled desogestrel and 30 microg ethinylestradiol under steady state conditions to healthy postmenopausal women. After this oral administration, desogestrel was extensively metabolized. The dosed radioactivity was predominantly ( approximately 60%) excreted via urine, while about 35% was excreted via the feces. Desogestrel was metabolized mainly at the C3-, C5-, C6- and C13-CH(2)CH(3) positions. At the C3-position, the 3-keto moiety was found and in addition, 3beta-hydroxy and 3alpha-hydroxy groups were observed in combination with a reduced Delta(4)-double bond (5alpha-H). Hydroxy groups were introduced at the C6- (6beta-OH), the C13-ethyl (C13-CH(2)CH(2)OH) and possibly the C15- (15alpha-OH) position of desogestrel. Conjugation of the 3alpha-hydroxy moiety with sulfonic acid and conjugation with glucuronic acid were also major metabolic routes found for desogestrel in postmenopausal women. The 3-keto metabolite of desogestrel (the biologically active metabolite) was the major compound present in plasma at least up to 24 h after administration of the radioactive dose. Species comparison of the metabolic routes of desogestrel after oral administration indicates that in rats and dogs desogestrel is also mainly metabolized at the C3-position, similar to what is now found for postmenopausal women. Most other metabolic routes of desogestrel were found to differ between species. Finally, major metabolic routes found in the present study in postmenopausal women are in line with outcome of previous in vitro metabolism studies with human liver tissue (microsomes and postmitochondrial liver fractions) and intestinal mucosa.

Metabolism of norethisterone and norethisterone derivatives in rat uterus, vagina, and aorta.

The 19-nor-progestogen norethisterone is used as a progestogen component in contraceptives and in continuous- and sequential combined hormone replacement therapy (HRT) in postmenopausal women. Metabolism of norethisterone in HRT target tissues may play a role in its biological response. The aim of this study was to investigate which steroid-metabolizing enzymes are present in rat uterus, vagina, and aorta, three HRT target tissues. Next, the ability of the tissues to metabolize norethisterone was assessed. Furthermore, to investigate the effect of substituents at the 7- and 11-position, the metabolism of Org OM38 (7alpha-methyl-norethisterone), Org 4060 (11beta-ethyl-norethisterone), and Org 34694 (7alpha-methyl,11-ethylidene-norethisterone) was studied. Using radiolabeled progesterone, the presence of 20alpha-hydroxysteroid dehydrogenase, 5alpha-reductase, and 3alpha-hydroxysteroid dehydrogenase activity could be demonstrated in uterus, vagina, and to a lesser extent in aorta. The combined action of the latter two enzyme activities resulted in 3alpha-OH,5alpha-H-norethisterone as the major metabolite of radiolabeled norethisterone in uterus (26.9%), vagina (37.1%), and aorta (1.4%). The norethisterone derivatives, however, were metabolized to a much lesser extent (1.0-7.6%). No formation of 5alpha-reduced forms of Org 4060, Org OM38, or Org 34694 was found, while formation of minor amounts of 3alpha-OH-Org 4060 and 3alpha-OH-Org OM38 could be demonstrated in both uterus, vagina, and aorta. These findings confirm the role of 5alpha-reductase as a rate-limiting step in the metabolism of norethisterone derivatives and show important inhibitory effects of substituents at the 7alpha- and 11-position of the steroid skeleton on 5alpha-reduction.

T-cell reactivity to multiple myelin antigens in multiple sclerosis patients and healthy controls.

Myelin proteins, including myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) are candidate autoantigens in MS. It is not clear whether MS patients show a predominant reactivity to one or several myelin antigens. We evaluated the IFN-gamma production induced by MBP and MOG and selected MBP-, MOG- and PLP-peptides in MS patients and healthy controls using the IFN-gamma ELISPOT assay. Most MS patients and healthy controls showed a heterogeneous anti-myelin T-cell reactivity. Interestingly in MS patients a positive correlation was found between the anti-MOG and anti-MBP T-cell responses. No myelin peptide was preferentially recognized among the peptides tested (MBP 84-102, 143-168, MOG 1-22, 34-56, 64-86, 74-96, PLP 41-58, 184-199, 190-209). In addition the frequency of IL2R+ MBP reactive T-cells was significantly increased in blood of MS patients as compared with healthy subjects, indicating that MBP reactive T-cells exist in an in vivo activated state in MS patients. Most of the anti-MBP T-cells were of the Th1-type because reactivity was observed in IFN-gamma but not in IL-4 ELISPOT-assays. Using Th1 (IL-12) and Th2 (IL-4) promoting conditions we observed that the cytokine secretion pattern of anti-MBP T-cells still is susceptible to alteration. Our data further indicate that precursor frequency analysis of myelin reactive T-cells by proliferation-based assays may underestimate the true frequency of myelin specific T-cells significantly.