The case for mild stimulation for IVF: recommendations from The International Society for Mild Approaches in Assisted Reproduction.

The practice of ovarian stimulation for IVF is undergoing a fundamental re-evaluation as recent data begin to successfully challenge the traditional paradigm that ovarian stimulation should be aimed at the retrieval of as many oocytes as possible, in the belief that this will increase pregnancy rates. An opposing view is that live birth rate should not be the only end-point in evaluating the success of IVF treatment and that equal emphasis should be placed on safety and affordability. The International Society for Mild Approaches in Assisted Reproduction (ISMAAR) committee has carried out an up-to-date literature search, with the evidence being graded according to the University of Oxford's Centre for Evidence-Based Medicine. The recommendations were formulated taking into account the quality of evidence on the efficacy, risk and cost of each intervention. ISMAAR recommends adopting a mild approach to ovarian stimulation in all clinical settings as an increasing body of evidence suggests that mild stimulation is as effective as conventional stimulation, while being safer and less expensive. Mild ovarian stimulation could replace conventional stimulation, thus making IVF safer and more accessible worldwide.

The risk of asthma is increased among women with polycystic ovary syndrome: a twin study.

BACKGROUND: Recent registry studies have demonstrated a higher prevalence of asthma among women with polycystic ovary syndrome (PCOS). We aimed to assess the association and heritability of PCOS and asthma in a Danish twin cohort. METHODS: Data for 32 382 female twins from the Danish Twin Registry were included. Twins with PCOS were identified by searching the Danish National Patient Registry for International Classification of Diseases-10 code E28.2. Asthma was diagnosed by questionnaires. RESULTS: 103 (0.3%) women had a PCOS diagnosis. The risk of asthma was increased among women with PCOS compared with women without (18% versus 9%, respectively; OR 2.11 (95% CI 1.13-3.96); p=0.02). After adjustment for age, body mass index, alcohol consumption and smoking status, the risk of asthma was still increased, but was no longer statistically significant (OR 1.54 (95% CI 0.75-3.17); p=0.24). Variance components analysis showed that shared environmental factors explained 49% (95% CI 24-68%) and unique environmental factors explained 51% (95% CI 32-76%) of the susceptibility to PCOS. For asthma, 44% (95% CI 28-61%) of the variance was explained by genetic factors, whereas 25% (95% CI 11-38%) was ascribable to shared environmental factors and 31% (95% CI 26-36%) to unique environmental factors. CONCLUSION: The risk of asthma is twice as high among female twins with PCOS. The individual susceptibility to PCOS is mainly due to environmental factors and not genetics.

Asthma severity and fertility outcome in women with polycystic ovary syndrome: a registry-based study.

Recent research suggests that women with polycystic ovary syndrome (PCOS) have a higher risk of asthma. However, the severity of asthma, use of antiasthma medication and effect on fertility have yet to be investigated. In a case-control cross-sectional registry study using the Danish National Patient Register and other Danish registries, asthma prevalence, asthma severity, antiasthma medication use and fertility outcome were investigated among two groups of women with PCOS (n=1358 and n=17 123) and a healthy control group (n=5340). Both asthma prevalence (OR 1.45, 95% CI 1.24-1.70) and mean daily inhaled corticosteroid dose were higher among women with PCOS compared with healthy controls, whereas asthma severity was the same in women with and without PCOS. Women with PCOS and asthma had more in vitro fertilisation treatments than women in the control group with asthma, but the numbers of children per woman and spontaneous abortions were the same. Women with PCOS have a higher prevalence of asthma and a higher use of inhaled corticosteroids, whereas asthma severity is the same in women with and without PCOS. Asthma is associated with more in vitro fertilisation treatments in women with PCOS.

Is gonadotropin stimulation bad for oocytes?

PURPOSE OF REVIEW: Gonadotrophin in IVF increases the number of oocytes retrieved, and many doctors regard a high number of oocytes as a measurement of success in IVF. Thus, the dogma of more oocytes provides better IVF success has been broadly accepted. However, some European fertility specialists have argued against this concept, saying fewer eggs might, in some instances, be a better option for the patient. RECENT FINDINGS: The concept of 'one size fits all' stimulation in artificial reproductive technologies is not broadly supported by the current literature. The ovarian stimulation strategy has to be viewed in relation to cost, infrastructure and economics, expectations from the doctors and the patients, and more importantly the local legislation. Furthermore, also luteal phase, epigenetic factors and patient safety is a matter of concern. Studies show that in the fresh cycle, ovarian stimulation might have an impact on the epigenetics, quality of the embryo and increase the risk of ovarian hyper stimulation. Strategies like agonist triggering or 'freeze all' can help during a fresh cycle. However, there is an ongoing debate whether these strategies might increase time to pregnancy or not. SUMMARY: In conclusion, each fertility clinic setup has its own benefits and gonadotropin hyperstimulation in IVF has to be related to this and the specific patient demographic in the clinic; however, epigenetics and time to pregnancy are still issues open to debate.

Coexistence of asthma and polycystic ovary syndrome: A concise review.

Asthma may be associated with polycystic ovary syndrome (PCOS), and possibly patients with PCOS have a more severe type of asthma. The purpose of this systematic literature review is to summarize evidence of a coexistense of PCOS and asthma using the available literature. The search was completed on 01.01.2016. English language articles were retrieved using the search terms 'Asthma' AND 'PCOS', 'Asthma' AND 'systemic inflammation', 'Asthma' AND 'metabolic syndrome', 'asthma' AND 'gynaecology', 'PCOS' AND 'systemic inflammation', 'PCOS' AND 'metabolic syndrome', 'PCOS' AND 'allergy'. Five papers meeting prespecified search criteria were found of which two were registry studies of relevance. The current literature supports a coexistense of PCOS and asthma and gives us an indication of the causes for the possible link between PCOS and asthma. Further research in the area must be conducted to determine the exact nature and magnitude of the association.

Fertility outcomes in asthma: a clinical study of 245 women with unexplained infertility.

Evidence is increasing of an association between asthma and aspects of female reproduction. However, current knowledge is limited and furthermore relies on questionnaire studies or small populations. In a prospective observational cohort study to investigate whether time to pregnancy, the number of fertility treatments, and the number of successful pregnancies differ significantly between women with unexplained infertility with and without asthma.245 women with unexplained infertility (aged 23-45 years) underwent questionnaires and asthma and allergy testing while undergoing fertility treatment. 96 women entering the study had either a former doctor's diagnosis of asthma or were diagnosed with asthma when included. After inclusion they were followed for a minimum of 12 months in fertility treatment, until they had a successful pregnancy, stopped treatment, or the observation ended.The likelihood of achieving pregnancy was lower in women with asthma compared with those without asthma: median total time to pregnancy was 32.3 months in non-asthmatic women versus 55.6 months in those with asthma, hazard ratio 0.50 (95% confidence interval 0.34-0.74) p<0.001.Women with asthma had fewer successful pregnancies during fertility treatment, 39.6 versus 60.4% (p=0.002). Increasing age was of negative importance for expected time to pregnancy, especially among asthmatic women (interaction between age and asthma on time to pregnancy, p=0.001). Female asthmatics had a longer time to pregnancy and less often became pregnant than non-asthmatic women. Increasing age reduced the chances of conceiving especially among asthmatic women. The causal relationship between asthma and subfertility remains unclear.

Lower values of VEGF in endometrial secretion are a possible cause of subfertility in non-atopic asthmatic patients.

OBJECTIVE: Using endometrial secretion analysis, we assessed whether altered inflammatory cytokine levels can be detected in the uterine environment in asthma patients, thereby providing a possible cause of reduced fertility in asthmatics. METHODS: Forty-four unexplained infertile women (aged 28-44) underwent asthma and allergy testing, questionnaires, endometrial secretion and blood samples in the mid-secretory phase of the menstrual cycle (day 19-23) during assisted reproduction. Differences in cytokines and growth factors were analyzed. RESULTS: Mean log-VEGF in uteri was lower in asthma patients compared with controls (2.29 versus 2.70, p = 0.028). This was mainly due to lower values of VEGF among women with non-atopic asthma compared with women with atopic asthma (1.86 versus 2.72, p = 0.009) and with healthy controls (1.86 versus 2.70, p = 0.01). Asthma treatment status had no effect on VEGF levels in uteri. Serum high sensitivity CRP was negatively correlated with VEGF in endometrial secretions. No other significant correlations were observed between peripheral blood values and markers found in utero. CONCLUSION: Asthma is associated with lower values of VEGF in uterine endometrial secretions, which might affect the receptiveness of the endometrium and thereby increase time to pregnancy. The effect appears to be associated with non-atopic asthma with general increased systemic inflammation.

The effect of liraglutide on weight loss in women with polycystic ovary syndrome: an observational study.

OBJECTIVE: The aim of the present study was to evaluate the effect of the glucagon-like peptide-1 analog liraglutide on weight loss in overweight and obese women with polycystic ovary syndrome (PCOS). METHODS: In an observational study, 84 overweight or obese women with PCOS were treated with liraglutide. Baseline characteristics and weight changes at clinical follow-up were recorded. Main outcome measures were absolute and relative weight loss. RESULTS: In overweight or obese women with PCOS treated with liraglutide for a minimum of 4 weeks, a mean weight loss of 9.0 kg (95% CI: 7.8-10.1, p < 0.0001) and a mean decrease in BMI of 3.2 kg/m(2) (95% CI: 2.8-3.6, p < 0.0001) were found. A weight loss of more than 5 and 10% of baseline weight was seen in 81.7 and 32.9% of patients, respectively. The mean duration of treatment with liraglutide was 27.8 weeks (SD 19.2). CONCLUSION: Treatment with liraglutide in combination with metformin and lifestyle intervention resulted in a significant weight loss in overweight and obese women with PCOS, indicating that liraglutide may be an effective alternative for weight loss in this group of patients. However, larger placebo-controlled studies are needed to confirm this.

Female asthma has a negative effect on fertility: what is the connection?

Reproductive changes such as impaired fertility and adverse pregnancy outcomes have been related to female asthma. We recently found that time to pregnancy is prolonged in asthmatic females especially in women with moderate to severe asthma and in those above 30 years of age. Despite their reproductive difficulties the asthmatics ultimately conceived just as many biological children as healthy throughout their reproductive lives. This knowledge therefore raises questions about how asthma affects fertility pathophysiologically. The purpose of this review is to describe the existing knowledge in this field and suggest hypotheses of causal relationships, which may form the basis for future studies in this field. The aim is, in particular, in the literature to examine whether there is any evidence to suggest that the systemic inflammation that characterizes asthma, can affect fertility. The issue is potentially clinically important for asthmatic, infertile individuals and society because treatment of the general systemic inflammation associated with the asthmatic disease combined with hormone stimulation might be the optimal target for an effective infertility therapy, possibly decreasing the need for in vitro fertilization.

Differential expression of inflammation-related genes in the ovarian stroma and granulosa cells of PCOS women.

Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder. Ovarian changes in PCOS women are well characterized by ultrasound. However, the ovarian pathophysiology is not fully understood. The aim of this study was to characterize the expression, in both the central ovarian stroma and in granulosa cells (GCs), of a number of genes, including several inflammation-related genes, which have been hypothesized to be involved in the pathophysiology of PCOS. Biopsies of the central ovarian stroma were obtained from PCOS women (Rotterdam criteria) and from normally ovulating women in follicular phase. GCs were retrieved from PCOS-women and non-PCOS women, undergoing in vitro maturation. The expressions of 57 genes were analyzed by quantitative-PCR using a low-density-gene array. The main outcome measures were over-expression or under-expression of the specific genes. The results showed that in the central stroma of PCOS ovaries, five inflammation-related genes (CCL2, IL1R1, IL8, NOS2, TIMP1), the leukocyte marker CD45, the inflammation-related transcription factor RUNX2 and the growth factor AREG were under-expressed. The growth factor DUSP12 and the coagulation factor TFPI2 were over-expressed. In the GC of PCOS, all of the differentially expressed genes were over-expressed; the inflammation-related IL1B, IL8, LIF, NOS2 and PTGS2, the coagulation-related F3 and THBS1, the growth factors BMP6 and DUSP12, the permeability-related AQ3 and the growth-arrest-related GADD45A. In conclusion, the results indicate major alterations in the local ovarian immune system of PCOS ovaries. This may have implications for the PCOS-related defects in the inflammation-like ovulatory process and for the susceptibility to acquire the inflammatory state of ovarian hyperstimulation syndrome.

Asthma affects time to pregnancy and fertility: a register-based twin study.

Coexistence of infertility and asthma has been observed clinically. Therefore, we investigated the association between asthma and delayed pregnancy in a nationwide population-based cohort of twins. A cohort of 15 250 twins living in Denmark (aged 12-41 years) participated in a questionnaire study including questions about the presence of asthma and fertility. Differences in time to pregnancy and pregnancy outcome were analysed in subjects with asthma, allergy and in healthy individuals using multiple regression analysis. Asthma was associated with an increased time to pregnancy, the percentage of asthmatics with a time to pregnancy >1 year was 27% versus 21.6% for non-asthmatics (OR (95% CI) 1.31 (1.1-1.6); p=0.009). The association remained significant after adjustment for age, age at menarche, body mass index and socioeconomic status (OR (95% CI) 1.25 (1.0-1.6); p=0.05), and was more pronounced in those >30 years of age (32.2% versus 24.9%, OR (95% CI) 1.44 (1.1-1.9); p=0.04). Untreated asthmatics had a significant increased risk of prolonged time to pregnancy compared to healthy individuals (OR (95% CI) 1.79 (1.20-2.66); p=0.004), while asthmatics receiving any kind of treatment for asthma tended to have a shorter time to pregnancy than untreated asthmatics (OR 1.40; p=0.134). Asthma prolongs time to pregnancy. The negative effect of asthma on fertility increases with age and with disease intensity, indicating that a systemic disease characterised by systemic inflammation also can involve reproductive processes.

New approach in patients with polycystic ovaries, lessons for everyone.

In vitro maturation is a safe and simple procedure for both the clinician and the patient. The discrepancy between the early clinical results and today's pregnancy rates (PR) of 30% is primarily due to the following modification of the original protocol recently reported by several groups: Priming with FSH and hCG, timing oocyte collection from follicles larger than 12 mm in diameter, and using blastocyst transfer. Furthermore, the endometrial priming should start 2 days before oocyte pick-up. This provides a PR of 40% per ET.

A prospective randomized multicentre study comparing vaginal progesterone gel and vaginal micronized progesterone tablets for luteal support after in vitro fertilization/intracytoplasmic sperm injection.

UNLABELLED: SUMMARY QUESTION: Is vaginal progesterone gel equivalent to vaginal micronized progesterone tablets concerning ongoing pregnancy rate and superior concerning patient convenience when used for luteal support after IVF/ICSI? SUMMARY ANSWER: Equivalence of treatments in terms of ongoing live intrauterine pregnancy rate has not been demonstrated; the 95% confidence interval (CI) for the difference in ongoing pregnancy rate (-8.2 to 0.1%) did not lie entirely within the pre-specified equivalence interval -7 to 7%. WHAT IS KNOWN ALREADY: No significant differences in clinical pregnancy rates have been observed between vaginal progesterone gel and other vaginal progesterone products in earlier studies. However, all previous studies included a limited number of patients. STUDY DESIGN, SIZE AND DURATION: This was a randomized, multicentre, controlled, assessor-blinded equivalence trial in 18 fertility centres in Denmark and Sweden between March 2006 and January 2010. A web-based randomization program was used with concealed allocation of patients. Patients were randomized to one of two groups: vaginal progesterone gel or vaginal micronized progesterone tablets. There was no blinding of patients. PARTICIPANTS AND SETTING: A total of 2057 women ≤ 40 years of age were included and down-regulated, using the long agonist protocol and rFSH for stimulation. Luteal support was given for 19 days after embryo transfer or until a negative pregnancy test Day 14 after embryo transfer. Patient convenience was assessed using questionnaires to be filled in 14 days after embryo transfer, before pregnancy test. MAIN RESULTS AND THE ROLE OF CHANCE: Ongoing intrauterine pregnancy rates were 299/991 (30.2%) (95% CI 27.3-33.0%) in the progesterone gel group and 324/992 (32.7%) (29.7-35.6%) in the micronized progesterone tablet group. The difference in ongoing pregnancy rates between the groups was -4.1% (-8.2 to 0.1%) and the difference in live birth rates was -3.4% (-7.4 to 0.7%), both calculated after correction for significant confounders. Patient convenience and ease of use (1 = very convenient, 10 = very inconvenient) was in favour of progesterone gel, as the overall score was 2.9 (2.7-3.0) for progesterone gel and 4.8 (4.7-5.0; P < 0.0001) for micronized progesterone tablets. This large equivalence trial shows that, even though equality could not be demonstrated, there is no substantial difference in ongoing pregnancy rate between vaginal progesterone gel and vaginal micronized progesterone tablets. It also shows that progesterone gel is considered more convenient by the patients. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: Blinding of patients was not possible in this study, but since the outcome (pregnancy) is robust, blinding would have been unlikely to affect the results. Unfortunately, owing to an error in the randomization, the intended age distribution allocated older women to the micronized progesterone tablet group. In the analysis of results, adjustments were made for age and number of embryos transferred. GENERALIZABILITY TO OTHER POPULATIONS: The results can be generalized to other women ≥ 18 and ≤ 40 years of age undergoing IVF/ICSI who have regular menstrual cycles (25-35 days), both ovaries present and no more than two previous failed IVF attempts. STUDY FUNDING/COMPETING INTEREST: Merck Serono supported the study but had no influence on the design of the study and was not involved in the analysis of the results or preparation of the manuscript. TRIAL REGISTRATION NUMBER: The trial was issued with the EudraCT number 2005-001248-22 with the Protocol code number 95576471.

Ganirelix for luteolysis in poor responder patients undergoing IVF treatment: a Scandinavian multicenter 'extended pilot study'.

To enhance oocyte yield and pregnancy outcome in poor responder women undergoing IVF treatment, daily low dose GnRH antagonist administration was given during the late luteal phase to induce luteolysis and possibly secure a more synchronous cohort of recruitable follicles. An open extended pilot study in four Scandinavian fertility centers was done including 60 patients. Poor response was defined as when < or = 5 follicles developed in a preceding cycle following a long agonist protocol with the use of > 2000 IU FSH. GnRH antagonist (ganirelix) was given, 0.25 mg s.c. daily, from days 3 to 5 before expected start of menstruation and continued for 4-7 days. On cycle day 2-3 a starting dose of rFSH (300-400 IU/day) was given. At a leading follicle diameter of 14 mm, ganirelix administration was resumed until final oocyte maturation was induced with 10,000 IU hCG. GnRH antagonist only marginally affected the intercycle FSH rise; basal levels of FSH remained similar to those seen after 4 days of antagonist administration. The protocol effectively induced low LH levels and luteolysis, but daily administration of 350 IU rFSH (median) for 11 days only led to the collection of 3 oocytes in 49 oocyte retrievals resulting in 5 pregnancies (4 delivered). Despite GnRH antagonist administration in the late luteal phase and menstrual bleeding, FSH was not sufficiently reduced to secure a more synchronic cohort of recruitable follicles. Novel GnRH antagonists more specifically targeting FSH release may improve the stimulation results in poor responders.

Male hormonal contraception: a double-blind, placebo-controlled study.

BACKGROUND: This study was performed to assess spermatogenesis suppression and safety of a new combination of an etonogestrel (ENG) implant combined with testosterone undecanoate (TU) injections for male contraception. This is the first large placebo-controlled study for male hormonal contraception. DESIGN AND STUDY SUBJECTS: In this double-blind, multicenter study, we randomly assigned 354 healthy men to receive either a low- or high-release ENG implant sc combined with im TU injections (750 mg every 10 or 12 wk or 1000 mg every 12 wk) or placebo implant and injections. Treatment duration was 42 or 44 wk and posttreatment follow-up at least 24 wk. RESULTS: Overall, spermatogenesis was suppressed to 1 million/ml or less at wk 16 in 89% of men, with approximately 94% in two high-release ENG groups. Suppression was maintained up to the end of the treatment period in 91% of men. For all men who completed the treatment period, 3% never achieved 1 million/ml or less. Median recovery time to a sperm concentration above 20 million/ml was 15 wk (mean 17 wk, 95% confidence interval 16-18 wk). Treatment was well tolerated. As compared with the placebo group, more men in the active treatment groups reported adverse events such as weight gain, mood changes, acne, sweating, or libido change. For both spermatogenesis suppression and safety, differences were small between the active treatment groups. CONCLUSIONS: The combination of an ENG implant with TU injections is a well-tolerated male hormonal method, providing effective and reversible suppression of spermatogenesis. Although the results are good, there is still room for improvement, possibly by adjusting the dose regimen or changing the mode of application.

Murine pre-embryo oxygen consumption and developmental competence.

PURPOSE: In search for a new marker of preimplantation embryo viability the present study investigated oxygen consumption of individual cleavage stage murine embryos, and evaluated the predictive value regarding subsequent development to expanded blastocysts. METHODS: In all, 248 embryos were investigated from 2 cell stage until blastocyst stage with individual measurement of oxygen consumption and recording of developmental stage. Cleavage stage embryos and morula were divided in groups according to their oxygen consumption, and odds ratios (OR) for subsequent development to expanded blastocyst were calculated. RESULTS: Cleavage stage (2-8 cell) individual oxygen consumption was 0.16-0.20 nl O(2) h(-1), with a significant increase to 0.21-0.23 nl O(2) h(-1) at the morula stage followed by a more than twofold increase for the expanded blastocyst 0.47 nl O(2) h(-1). A significantly higher chance of reaching the expanded blastocyst stage was found in 4-cell embryos with high oxygen consumption, than embryos with low consumption (OR 2.25, 95% CI 1.04-4.90). Among 2-cell embryos the chance of low and high consumers was not significantly different. The method used in the present study somewhat compromised embryo development (51% blastocyst rate) compared to controls (80% blastocystrate) which could make our results less robust. CONCLUSION: Preliminary data from the present study suggest that oxygen consumption in cleavage stage embryos may be an indicator, but a not a strong predictor, of subsequent development to expanded blastocysts.

The impact of oxygen tension on developmental competence of post-thaw human embryos.

The present study compares the culture of human embryos using two different culture systems: a conventional culture incubator with humidified atmospheric air supplemented with 5% CO(2) and a closed culture incubator with a humidified 5% O(2) and 5% (5.2-5.5) CO(2) and 90% N(2) partial pressure. A total of 225 cryopreserved embryos were donated after informed consent and thawed in two batches of 100 and 125 embryos separated by 1 week. A total of 126 (56%) embryos survived the thawing procedure having at least one living blastomere. After thawing, the embryos were randomly allocated to culture in a 5% oxygen partial pressure (n = 65) or to culture in a 20% oxygen partial pressure (n = 61). The embryos were hereafter cultured for 4 days and the number of embryos developed to morula stage or blastocyst stage was examined. The results of the embryo culture in the two trials performed showed an increase from 43% to 68% (19 to 68%) morula formation in trial 1 (trial 2), i.e. on the whole the morula yield more than doubled in favor of culture in a 5% oxygen partial pressure compared with a 20% oxygen partial pressure.

Time interval between FSH priming and aspiration of immature human oocytes for in-vitro maturation: a prospective randomized study.

This prospective randomized controlled study was performed to examine the influence of coasting for 2 days versus 3 days following a fixed daily dose of FSH for 3 days. The outcome was 2-fold. In the first experiment (n = 50 cycles), the incidence of apoptosis in granulosa cells was compared. In the second experiment (n = 28 cycles), the rates of maturation, fertilization, cleavage, pregnancy and implantation were compared. In addition, clinical pregnancy rate per aspiration was registered. Granulosa cells were collected from follicular aspirates and pooled for each patient. The APOPTAG Detection Kit was used for staining of the granulosa cells and detection of apoptosis. Oocytes were matured in vitro for 28-30 h before intracytoplasmic sperm injection. The incidence of apoptosis in granulosa cells did not differ between granulosa cells obtained after 2 days coasting (n = 25 cycles) compared with granulosa cells obtained after 3 days coasting (n = 25 cycles) (26.2 versus 26.2%). When oocytes obtained after coasting for 2 days (n = 12 cycles) were compared with oocytes obtained after coasting for 3 days (n = 16 cycles), no significant difference was found between rates of maturation (63 versus 65%), fertilization (60 versus 68%), cleavage (86 versus 92%) or implantation [5/12; 42 versus 1/12 (8%)]. A higher clinical pregnancy rate per aspiration [5/16 (31%) versus 1/12 (8%)] was obtained after coasting for 3 days compared with coasting for 2 days. The difference was not significant. This randomized study showed no difference in apoptosis of granulosa cells and no difference in developmental competence of oocytes obtained after coasting for 3 days compared with 2 days coasting.