Resumption of ovulation in anovulatory women with PCOS and obesity is associated with reduction of 11ß-hydroxyandrostenedione concentrations.

STUDY QUESTION: Is resumption of ovulation after a 6-month lifestyle intervention in women with PCOS and obesity associated with differential changes in endocrine and metabolic parameters (weight, insulin resistance, anti-Müllerian hormone (AMH), and androgens) compared to women with PCOS who remained anovulatory? SUMMARY ANSWER: Resumption of ovulation after a 6-month lifestyle intervention in women with PCOS and obesity is associated with changes in serum 11ß-hydroxyandrostenedione (11OHA4) concentrations. WHAT IS KNOWN ALREADY: Lifestyle interventions have been shown to reduce clinical and biochemical hyperandrogenism in women with PCOS. Weight loss of 5-10% may reverse anovulatory status, thereby increasing natural conception rates. However, the mechanisms underlying why some women with PCOS remain anovulatory and others resume ovulation after weight loss are unclear. Reproductive characteristics at baseline and a greater degree of change in endocrine and metabolic features with lifestyle intervention may be crucial for ovulatory response. STUDY DESIGN, SIZE, DURATION: We used data and samples originating from an earlier randomized controlled trial (RCT), which examined the efficacy of a 6-month lifestyle intervention prior to infertility treatment compared to prompt infertility treatment on live birth rate in women with obesity. A total of 577 women with obesity (BMI > 29 kg/m2) were randomized between 2009 and 2012. Anovulatory women with PCOS who were allocated to the intervention arm of the original RCT (n = 95) were included in the current analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: We defined women as having resumed ovulation (RO+) based on the following criteria: spontaneous pregnancy; or assignment to expectant management; or IUI in natural cycles as the treatment strategy after lifestyle intervention. Steroid hormones were measured using liquid chromatography tandem mass spectrometry. Generalized estimating equations with adjustment for baseline measures and interaction between group and time was used to examine differences in changes of endocrine and metabolic parameters between RO+ (n = 34) and persistently anovulatory women (RO-, n = 61) at 3 and 6 months after intervention. MAIN RESULTS AND THE ROLE OF CHANCE: At baseline, the mean ± SD age was 27.5 ± 3.6 years in the RO+ group and 27.9 ± 4.1 years in the RO- group (P = 0.65), and the mean ± SD weights were 101.2 ± 9.5 kg and 105.0 ± 14.6 kg, respectively (P = 0.13). Baseline AMH concentrations showed significant differences between RO+ and RO- women (median and interquartile range [IQR] 4.7 [3.2; 8.3] versus 7.2 [5.3; 10.8] ng/ml, respectively). Baseline androgen concentrations did not differ between the two groups. During and after lifestyle intervention, both groups showed weight loss; changes in 11OHA4 were significantly different between the RO+ and RO groups (P-value for interaction = 0.03). There was a similar trend for SHBG (interaction P-value = 0.07), and DHEA-S (interaction P-value = 0.06), with the most pronounced differences observed in the first 3 months. Other parameters, such as AMH and FAI, decreased over time but with no difference between the groups. LIMITATIONS, REASONS FOR CAUTION: No high-resolution transvaginal ultrasonography was used to confirm ovulatory status at the end of the lifestyle program. The small sample size may limit the robustness of the results. WIDER IMPLICATIONS OF THE FINDINGS: Reduction of androgen concentrations during and after lifestyle intervention is associated with recovery of ovulatory cycles. If our results are confirmed in other studies, androgen concentrations could be monitored during lifestyle intervention to provide individualized recommendations on the timing of resumption of ovulation in anovulatory women with PCOS and obesity. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by a grant from ZonMw, the Dutch Organization for Health Research and Development (50-50110-96-518). The Department of Obstetrics and Gynecology of the UMCG received an unrestricted educational grant from Ferring Pharmaceuticals BV, The Netherlands. A.H. reports consultancy for the development and implementation of a lifestyle App MyFertiCoach developed by Ferring Pharmaceutical Company. All other authors have no conflicts to declare. TRIAL REGISTRATION NUMBER: The LIFEstyle RCT was registered at the Dutch trial registry (NTR 1530).

Cost-effectiveness analysis of lifestyle intervention in obese infertile women.

STUDY QUESTION: What is the cost-effectiveness of lifestyle intervention preceding infertility treatment in obese infertile women? SUMMARY ANSWER: Lifestyle intervention preceding infertility treatment as compared to prompt infertility treatment in obese infertile women is not a cost-effective strategy in terms of healthy live birth rate within 24 months after randomization, but is more likely to be cost-effective using a longer follow-up period and live birth rate as endpoint. WHAT IS KNOWN ALREADY: In infertile couples, obesity decreases conception chances. We previously showed that lifestyle intervention prior to infertility treatment in obese infertile women did not increase the healthy singleton vaginal live birth rate at term, but increased natural conceptions, especially in anovulatory women. Cost-effectiveness analyses could provide relevant additional information to guide decisions regarding offering a lifestyle intervention to obese infertile women. STUDY DESIGN, SIZE, DURATION: The cost-effectiveness of lifestyle intervention preceding infertility treatment compared to prompt infertility treatment was evaluated based on data of a previous RCT, the LIFEstyle study. The primary outcome for effectiveness was the vaginal birth of a healthy singleton at term within 24 months after randomization (the healthy live birth rate). The economic evaluation was performed from a hospital perspective and included direct medical costs of the lifestyle intervention, infertility treatments, medication and pregnancy in the intervention and control group. In addition, we performed exploratory cost-effectiveness analyses of scenarios with additional effectiveness outcomes (overall live birth within 24 months and overall live birth conceived within 24 months) and of subgroups, i.e. of ovulatory and anovulatory women, women <36 years and ≥36 years of age and of completers of the lifestyle intervention. Bootstrap analyses were performed to assess the uncertainty surrounding cost-effectiveness. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Infertile women with a BMI of ≥29 kg/m2 (no upper limit) were allocated to a 6-month lifestyle intervention programme preceding infertility treatment (intervention group, n = 290) or to prompt infertility treatment (control group, n = 287). After excluding women who withdrew informed consent or who were lost to follow-up we included 280 women in the intervention group and 284 women in the control group in the analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Total mean costs per woman in the intervention group within 24 months after randomization were €4324 (SD €4276) versus €5603 (SD €4632) in the control group (cost difference of -€1278, P < 0.05). Healthy live birth rates were 27 and 35% in the intervention group and the control group, respectively (effect difference of -8.1%, P < 0.05), resulting in an incremental cost-effectiveness ratio of €15 845 per additional percentage increase of the healthy live birth rate. Mean costs per healthy live birth event were €15 932 in the intervention group and €15 912 in the control group. Exploratory scenario analyses showed that after changing the effectiveness outcome to all live births conceived within 24 months, irrespective of delivery within or after 24 months, cost-effectiveness of the lifestyle intervention improved. Using this effectiveness outcome, the probability that lifestyle intervention preceding infertility treatment was cost-effective in anovulatory women was 40%, in completers of the lifestyle intervention 39%, and in women ≥36 years 29%. LIMITATIONS, REASONS FOR CAUTION: In contrast to the study protocol, we were not able to perform the analysis from a societal perspective. Besides the primary outcome of the LIFEstyle study, we performed exploratory analyses using outcomes observed at longer follow-up times and we evaluated subgroups of women; the trial was not powered on these additional outcomes or subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS: Cost-effectiveness of a lifestyle intervention is more likely for longer follow-up times, and with live births conceived within 24 months as the effectiveness outcome. This effect was most profound in anovulatory women, in completers of the lifestyle intervention and in women ≥36 years old. This result indicates that the follow-up period of lifestyle interventions in obese infertile women is important. The scenario analyses performed in this study suggest that offering and reimbursing lifestyle intervention programmes in certain patient categories may be cost-effective and it provides directions for future research in this field. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by a grant from ZonMw, the Dutch Organization for Health Research and Development (50-50110-96-518). The department of obstetrics and gynaecology of the UMCG received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands. B.W.J.M. is a consultant for ObsEva, Geneva. TRIAL REGISTRATION NUMBER: The LIFEstyle RCT was registered at the Dutch trial registry (NTR 1530). http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 1530.

Effectiveness of lifestyle intervention in subgroups of obese infertile women: a subgroup analysis of a RCT.

STUDY QUESTION: Do age, ovulatory status, severity of obesity and body fat distribution affect the effectiveness of lifestyle intervention in obese infertile women? SUMMARY ANSWER: We did not identify a subgroup in which lifestyle intervention increased the healthy live birth rate however it did increase the natural conception rate in anovulatory obese infertile women. WHAT IS KNOWN ALREADY: Obese women are at increased risk of infertility and are less likely to conceive after infertility treatment. We previously demonstrated that a 6-month lifestyle intervention preceding infertility treatment did not increase the rate of healthy live births (vaginal live birth of a healthy singleton at term) within 24 months of follow-up as compared to prompt infertility treatment in obese infertile women. Natural conceptions occurred more frequently in women who received a 6-month lifestyle intervention preceding infertility treatment. STUDY DESIGN, SIZE, DURATION: This is a secondary analysis of a multicentre RCT (randomized controlled trial), the LIFEstyle study. Between 2009 and 2012, 577 obese infertile women were randomly assigned to a 6-month lifestyle intervention followed by infertility treatment (intervention group) or to prompt infertility treatment (control group). Subgroups were predefined in the study protocol, based on frequently used cut-off values in the literature: age (≥36 or <36 years), ovulatory status (anovulatory or ovulatory), BMI (≥35 or <35 kg/m2) and waist-hip (WH) ratio (≥0.8 or <0.8). PARTICIPANTS/MATERIALS, SETTING, METHODS: Data of 564 (98%) randomized women who completed follow-up were analyzed. We studied the effect of the intervention program in various subgroups on healthy live birth rate within 24 months, as well as the rate of overall live births (live births independent of gestational age, mode of delivery and health) and natural conceptions within 24 months. Live birth rates included pregnancies resulting from both treatment dependent and natural conceptions. Logistic regression models with randomization group, subgroup and the interaction between randomization group and subgroup were used. Significant interaction was defined as a P-value <0.1. MAIN RESULTS AND THE ROLE OF CHANCE: Neither maternal age, ovulatory status nor BMI had an impact on the healthy live birth rate within 24 months, nor did they influence the overall live birth rate within 24 months after randomization. WH ratio showed a significant interaction with the effect of lifestyle intervention on healthy live birth rate (P = 0.05), resulting in a lower healthy live birth rate in women with a WH ratio <0.8. WH ratio had no interaction regarding overall live birth rate (P = 0.27) or natural conception rate (P = 0.38). In anovulatory women, the effect of lifestyle intervention resulted in more natural conceptions compared to ovulatory women (P-value for interaction = 0.02). There was no interaction between other subgroups and the effect of the intervention on the rate of natural conception. LIMITATIONS, REASONS FOR CAUTION: Since this was a subgroup analysis of a RCT and sample size determination of the trial was based on the primary outcome of the study, the study was not powered for analyses of all subgroups. WIDER IMPLICATIONS OF THE FINDINGS: Our finding that lifestyle intervention leads to increased natural conception in anovulatory obese women could be used in the counselling of these women, but requires further research using an appropriately powered study in order to confirm this result. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a grant from ZonMw, the Dutch Organisation for Health Research and Development (50-50110-96-518). The Department of Obstetrics and Gynaecology of the UMCG received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands. Ben Mol is a consultant for ObsEva, Geneva. Annemieke Hoek received a speaker's fee for a postgraduate education from MSD pharmaceutical company, outside the submitted work. TRIAL REGISTRATION NUMBER: The LIFEstyle study was registered at the Dutch trial registry (NTR 1530).

On-the-road driving performance after use of the antihistamines mequitazine and l-mequitazine, alone and with alcohol.

OBJECTIVE: Previous studies demonstrated that mequitazine produces mild sedation after single doses. Its enantiomer, l-mequitazine, has a stronger potency for the H1 receptor. The aim of the current study was to assess the effects of l-mequitazine and mequitazine, alone and with alcohol, on driving. METHODS: Twenty-five healthy volunteers were treated with l-mequitazine 2.5, 5.0 and 10 mg, mequitazine 10 mg and placebo, alone and in combination with alcohol in a double-blind crossover design. Driving performance was assessed using the standardized highway driving test in normal traffic. Its primary measure is the Standard Deviation of the Lateral Position (SDLP). Secondary measures consisted of an auditory word learning test during driving, and subjective measures of driving performance. RESULTS: L-mequitazine 2.5 and 5.0 mg showed no effect on SDLP in the highway driving test, while SDLP significantly increased after l-mequitazine 10 mg (alone +1.59 cm; with alcohol +1.41 cm) and mequitazine 10 mg (with alcohol +1.17 cm). Alcohol significantly impaired all performance measures (SDLP +2.63 cm) but did not interact with the effects of treatment. Subjective measures indicated that participants were aware of the impairing effects of alcohol, but not of l-mequitazine and mequitazine. CONCLUSION: L-mequitazine can be considered safe to drive in dosages of 2.5 and 5.0 mg. L-mequitazine 10 mg led to mild driving impairment. Alcohol impaired all performance measures and added to the effects of l-mequitazine and mequitazine.

Communication at an online infertility expert forum: provider responses to patients' emotional and informational cues.

Online patient-provider communication has become increasingly popular in fertility care. However, it is not known to what extent patients express cues or concerns and how providers respond. In this study, we investigated cues and responses that occur in online patient-provider communication at an infertility-specific expert forum. We extracted 106 threads from the multidisciplinary expert forum of two Dutch IVF clinics. We performed the following analyses: (1) thematic analysis of patients' questions; and (2) rating patients' emotional and informational cues and subsequent professionals' responses using an adaptation of the validated Medical Interview Aural Rating Scale. Frequencies of themes, frequencies of cues and responses, and sequences (what cue is followed by what response) were extracted. Sixty-five infertile patients and 19 providers participated. The most common themes included medication and lifestyle. Patients gave more informational than emotional cues (106 versus 64). Responses to informational cues were mostly adequate (61%). The most common response to emotional cues was empathic acknowledgment (72%). Results indicate that an online expert forum could have a positive effect on patient outcomes, which should guide future research. Offering infertile patients an expert forum to communicate with providers can be a promising supplement to usual care in both providing information and addressing patients' concerns.

A randomized trial on the acute and steady-state effects of a new antidepressant, vortioxetine (Lu AA21004), on actual driving and cognition.

The aim of this study was to assess the effects of a novel antidepressant, vortioxetine 10 mg, on driving, cognitive, and psychomotor performance in 24 healthy subjects in a double-blind, placebo-controlled, three-way crossover design. Mirtazapine 30 mg was included as an active comparator. Drugs were administered in the evening of 15 consecutive days. Performance was measured in the morning of days 2 and 16, using standardized tests measuring on-the-road driving, memory, tracking, divided attention, and vigilance. The statistical analysis on the primary measure of driving, i.e., SD of lateral position showed noninferiority of vortioxetine on days 2 and 16, and inferiority for mirtazapine on day 2. Vortioxetine did not cause cognitive or psychomotor impairment. Mirtazapine, however, impaired cognitive and psychomotor performance on day 2. Most of these effects disappeared after multiple doses of mirtazapine. To conclude, vortioxetine did not impair driving, cognitive, or psychomotor performance after single or multiple doses.

A dose-ranging study of the effects of mequitazine on actual driving, memory and psychomotor performance as compared to dexchlorpheniramine, cetirizine and placebo.

BACKGROUND: Mequitazine is a so-called 'non-sedative' second-generation antihistamine even though it has never been firmly established that this drug's sedative potential actually differs from that of the 'sedative' first-generation antihistamines. OBJECTIVE: The present study compares the sedative effects of three doses of mequitazine on actual driving, psychomotor performance and memory with those of a first- and a second-generation antihistamine. METHODS: Eighteen healthy volunteers received on separate days a single dose of 5, 10 and 15 mg mequitazine, 10 mg cetirizine, 6 mg dexchlorpheniramine and placebo. Drug effects were assessed using two actual driving tests (highway-driving test and car-following test), cognitive and psychometric tests (tracking, divided attention, memory, reasoning and critical flicker fusion), pupil size and questionnaires. RESULTS: Highway-driving data revealed an overall effect of Treatment on the standard deviation of lateral position (SDLP). Dexchlorpheniramine impaired driving performance as indicated by a significant rise in SDLP. Mequitazine significantly increased SDLP in a dose-related manner, but the separate dose effects failed to reach statistical significance. Divided attention performance was also affected by Treatment. Reaction time (RT) during mequitazine treatments increased in a dose-related manner and significantly differed from placebo at the highest dose. Subjects reported to be less alert after treatment with dexchlorpheniramine. Cetirizine did not affect performance in any of the tasks. CONCLUSION: It was concluded that mequitazine is mildly sedating. The effects of mequitazine are comparable to those of other second-generation antihistamines, in that it causes mild driving impairment, particularly at higher doses.

Analysis of CD2 and TCR-beta gene expression in Jurkat cell mutants suggests a cis regulation of gene transcription.

Thirty CD2- J32 stable clones, derived by mutagenesis and subsequent immunoselection with anti-CD2 Ab, were used to study the regulation of CD2 and TCR gene expression. Analysis of RNA expression revealed that the loss of surface expression of CD2 was due to a lack of expression of CD2 mRNA and was associated with a lack of expression of VDJ TCR-beta transcripts in 12 of these mutants, sparing the expression of DJ TCR-beta, TCR-alpha, CD3 gamma, delta, epsilon, and zeta RNA. The expression of other differentiation molecules was unaffected, except for CD1, CD4, and CD5, which were either decreased or absent in most of these mutants. A gain in the expression of TCR-gamma transcripts was observed in each of these mutants, while, as expected, no TCR-gamma transcripts were detected in wild-type J32 cells. Several mutants were able to use the human CD2 enhancer and the murine TCR-beta enhancer and promoter to activate transcription from reporter genes in the context of heterologous promoters, indicating that the mutation(s) does not affect transcription pathways. Consistent with this finding is the adequate expression in these mutants of several lineage-specific transcription factors. The expression of CD2 in several of these mutants was rescued by gene transfer using a genomic 28.5-kb CD2 fragment, suggesting that the enhancer function of this gene may be dependent on the enhancer site. These observations suggest that the coordinate expressions of CD2 and TCR-beta genes share common regulatory mechanisms involving factors regulating chromatin structure and accessibility.

The sequence-specific high mobility group 1 box of TCF-1 adopts a predominantly alpha-helical conformation in solution.

The High Mobility Group (HMG) 1 box is a protein motif that mediates DNA binding in a novel family of transcription-regulating proteins. Several members of this family, including the lymphoid-specific proteins TCF-1 and LEF-1 and the mammalian sex-determining factor SRY, carry a single HMG box with affinity for the minor groove of the heptamer motif AACAAAG or variations thereof. To initiate studies on the structural characteristics of the TCF-1 HMG box, we have expressed the 87-amino acid HMG box in milligram quantities in Escherichia coli and purified the soluble peptide to > 95% homogeneity. The peptide bound DNA with the same specificity as the complete protein and was capable of inducing DNA bending. Circular dichroism (CD) analysis revealed the TCF-1 HMG box to adopt an approximately 60% alpha-helix/40% random coil conformation in solution. In the presence of an equimolar amount of double-stranded DNA containing the cognate motif, the CD spectrum changed significantly, implying the induction of a structural modification upon DNA/protein association.