Publications by authors named "Mona Bungum"

23 Publications

  • Page 1 of 1

Sperm DNA fragmentation index and cumulative live birth rate in a cohort of 2,713 couples undergoing assisted reproduction treatment.

Fertil Steril 2021 12 8;116(6):1483-1490. Epub 2021 Aug 8.

Molecular Reproductive Medicine, Department of Translational Medicine, Lund University, Malmö, Sweden; Reproductive Medicine Centre, Skåne University Hospital, Malmö, Sweden.

Objective: To study how the choice of the first assisted reproductive technology treatment type affects the cumulative live birth rate (CLBR) in couples with high sperm DNA fragmentation index (DFI).

Design: Longitudinal cohort study.

Setting: University-affiliated fertility clinic.

Patient(s): A total of 2,713 infertile couples who underwent assisted reproductive technology treatment between 2007 and 2017 were included in the study. All in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatments (up to three fresh treatments and all associated frozen-thawed embryo transfers) offered to the couples by the public health care system were included, in total 5,422 cycles.

Intervention(s): None.

Main Outcome Measure(s): The primary outcome was the CLBR. The secondary outcomes were the fertilization rate and the miscarriage rate. The IVF and ICSI groups were defined according to the method applied in the first treatment cycle.

Result(s): In the IVF group, the CLBR values were higher for couples with normal DFI compared with those for couples with high DFI (≥20%) (48.1% vs. 41.6% for conservative CLBR estimate and 55.6% vs. 51.4% for optimal CLBR estimate after adjustment for female age, respectively). No DFI-dependent difference was seen in the ICSI group.

Conclusion(s): Our results demonstrated that a high DFI predicts a statistically significantly lower CLBR if IVF and not ICSI is applied in the first cycle of assisted reproduction.
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http://dx.doi.org/10.1016/j.fertnstert.2021.06.049DOI Listing
December 2021

Identification of a unique epigenetic profile in women with diminished ovarian reserve.

Fertil Steril 2021 03 4;115(3):732-741. Epub 2020 Dec 4.

Department of Obstetrics and Gynaecology, Department of Reproductive Medicine, Hospital Herlev, Copenhagen University, Copenhagen, Denmark.

Objective: To investigate whether epigenetic profiles of mural granulosa cells (MGC) and leukocytes from women with diminished ovarian reserve (DOR) differ from those of women with normal or high ovarian reserve.

Design: Prospectively collected material from a multicenter cohort of women undergoing fertility treatment.

Setting: Private and university-based facilities for clinical services and research.

Patient(s): One hundred and nineteen women of various ages and ovarian reserve status (antimüllerian hormone level) who provided blood samples and MGC.

Intervention(s): None.

Main Outcome Measure(s): Measures of epigenetic aging rates from whole-genome methylation array data: DNA methylation variability, age acceleration, DNA methylation telomere length estimator (DNAmTL), and accumulation of epimutations.

Result(s): Comparison of DOR or high ovarian reserve samples to controls (normal ovarian reserve) showed differential methylation variability between DOR and normal samples at 4,199 CpGs in MGC, and 447 between high and normal (false-discovery rate < 0.05). Variable sites in MGC from DOR were enriched in regions marked with the repressive histone modification H3K27me3, and also included genes involved in folliculogenesis, such as insulin growth factor 2 (IGF2) and antimüllerian hormone (AMH). Regardless of ovarian reserve, very few signals were detected in leukocytes, and no overlaps with those in MGC were found. Furthermore, we found a higher number of epimutations in MGC from women with DOR (Kruskal-Wallis test, difference in mean = 3,485).

Conclusion(s): The somatic cells of human ovarian follicles have a distinctive epigenetic profile in women with DOR. A high frequency of epimutations suggests premature aging. Ovarian reserve status was not reflected in the leukocyte epigenetic profile.
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http://dx.doi.org/10.1016/j.fertnstert.2020.09.009DOI Listing
March 2021

Interaction between serum levels of Anti-Mullerian Hormone and the degree of sperm DNA fragmentation measured by sperm chromatin structure assay can be a predictor for the outcome of standard in vitro fertilization.

PLoS One 2019 8;14(8):e0220909. Epub 2019 Aug 8.

Dept. of Translational Medicine, Lund University, Malmö, Sweden.

Serum levels of Anti-Mullerian Hormone (AMH) have been shown to be biomarker for prediction of the quantitative aspects of ovarian reserve. On the male side, sperm chromatin structure assay (SCSA) DNA fragmentation index (DFI) has been demonstrated to be an important predictor of outcomes in standard IVF procedures but to less degree in intracytoplasmic sperm injection procedures (ICSI). The purpose of this study was to investigate whether the combination of female AMH serum levels and sperm DFI adds to prediction of the outcome of assisted reproduction. A total of 352 couples was included (ICSI-148: IVF-204) A venous blood sample was drawn for AMH analysis before IVF/ICSI treatment. DFI was measured in the ejaculate used for assisted reproduction. Regression models for the following odds ratio calculations were constructed: for obtaining at least one Good Quality Embryo; for live birth in all procedures; for pregnancy in procedures where embryo transfer was performed; for miscarriage. For DFI increase by 10 percentage points (not increased DFI as reference) odds ratio for Good Quality Embryo was statistically significantly lower when AMH was at lower quartile (AMH <12 pmol/L; OR = 0.29, 95% CI: 0.14-0.59,) but not when AMH was at upper quartile (AMH ≥ 36 pmol/L; OR = 0.95, 95% CI: 0.43-2.13,). The marginal effect of an increase in DFI by 10 percentage points was statistically significant only when AMH < 25.2 pmol/L. Similar results were obtained as considers live birth following standard IVF. No interactions were seen for standard IVF in relation to the risk of miscarriage and for any of the outcomes when ICSI was used as method of treatment. We conclude that the impact of high DFI on the outcome of standard IVF is most pronounced if the female partner has relatively low AMH levels. This finding may help in defining the role of sperm DNA integrity testing in management of infertile couples. It may also explain some of the heterogeneity in results of studies focusing on predictive value of DFI measurements in assisted reproduction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220909PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687174PMC
March 2020

Sperm chromatin structure assay high DNA stainability sperm as a marker of early miscarriage after intracytoplasmic sperm injection.

Fertil Steril 2019 07 28;112(1):46-53.e2. Epub 2019 Apr 28.

Department of Translational Medicine, Lund University, Malmö, Sweden. Electronic address:

Objective: To determine whether high DNA stainability (HDS), as assessed by the sperm chromatin structure assay (SCSA), predicts the risk of early miscarriage after in vitro fertilization with intracytoplasmic sperm injection (IVF-ICSI).

Design: Retrospective cohort study of consecutive pregnancies after IVF and ICSI treatment.

Setting: Reproductive medicine center.

Patient(s): A total of 1,602 pregnancies after 832 IVF and 770 ICSI treatments.

Intervention(s): HDS measured using SCSA.

Main Outcome Measure(s): Early miscarriage (≤12 weeks).

Result(s): The HDS represents the proportion of immature spermatozoa lacking the normal exchange of histone for protamine-complexed DNA, and the outcome parameter was early miscarriage (≤12 weeks). For all treatments, the odds ratio (OR) and 95% confidence interval (CI) for early miscarriage was 1.41 (1.07-1.85) if HDS >15% compared with HDS ≤15%. When comparing the two HDS categories, for ICSI, the OR was 1.44 (1.01-2.04) whereas for IVF the results were not statistically significant.

Conclusion(s): There is a small but increased risk of early miscarriage if HDS >15% compared with HDS ≤15%. This increased risk is seen only after ICSI, not after IVF. These findings suggest that HDS can be used as a predictor of an increased risk of miscarriage in ICSI treatments.
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http://dx.doi.org/10.1016/j.fertnstert.2019.03.013DOI Listing
July 2019

Vedolizumab Does Not Impair Sperm DNA Integrity in Men With Inflammatory Bowel Disease.

Gastroenterology 2019 06 5;156(8):2342-2344. Epub 2019 Mar 5.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

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http://dx.doi.org/10.1053/j.gastro.2019.02.041DOI Listing
June 2019

Semen Quality and Sperm DNA Integrity in Patients With Severe Active Inflammatory Bowel Disease and Effects of Tumour Necrosis Factor-alpha Inhibitors.

J Crohns Colitis 2019 Apr;13(5):564-571

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Background And Aims: The impact of severe inflammation on semen quality, including sperm DNA integrity, in men with inflammatory bowel disease [IBD] is unknown, as are the potential effects of anti-tumour necrosis factor-alpha [TNF-alpha] therapy. We investigated the influence of severe active IBD and anti-TNF-alpha treatment on semen quality.

Methods: We prospectively included 20 patients admitted with severe active IBD. Further, 19 patients who initiated and 17 who stopped anti-TNF-alpha therapy were included. Semen samples were obtained during active disease, and on/off treatment. For paired comparisons, samples were collected not less than 3 months after achieving remission, after treatment initiation, or after treatment cessation. Sperm DNA Fragmentation Index [DFI], concentration, morphology, and motility were evaluated. Sex hormones and seminal plasma anti-TNF-alpha drug levels were measured.

Results: In patients with severe disease, progressive sperm motility was impaired and increased significantly [from 28.4% to 37.4%, p = 0.045] during remission. There was no difference in DFI [12.5% versus 12.0%, p = 0.55], concentration [55.0 mill/ml versus 70.0 mill/ml, p = 0.39], or normal morphology [4.7% versus 5.1%, p = 0.51] in these patients. During active disease, testosterone was decreased, and normalised after obtaining remission. Patients who started anti-TNF-alpha therapy had a statistically significant, but clinically irrelevant, reduction in DFI after treatment initiation [12.8% versus 10.0%, p = 0.02]. All other semen parameters were unaffected by therapy. Anti-TNF-alpha drugs were excreted in negligible amounts in semen.

Conclusions: Severe active IBD reduces progressive sperm motility and testosterone levels, but sperm DNA integrity is unaffected by active disease. Anti-TNF-alpha therapy does not impair sperm quality.
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http://dx.doi.org/10.1093/ecco-jcc/jjy198DOI Listing
April 2019

The Impact of the Biological Variability or Assay Performance on AMH Measurements: A Prospective Cohort Study With AMH Tested on Three Analytical Assay-Platforms.

Front Endocrinol (Lausanne) 2018 16;9:603. Epub 2018 Oct 16.

Department of Obstetrics and Gynecology, Herlev Gentofte Hospital, Herlev, Denmark.

This study examined longitudinal, age-related and intra-individual variation in Anti-Müllerian Hormone (AMH) in regular menstruating women and correlated the hormonal levels to the antral follicle count (AFC). The impact of variations on an algorithm for calculation of follitropin-dose for ovarian stimulation were also tested. The study was carried out at a fertility clinic of a tertiary university hospital and had a prospective trial design. Twenty-six healthy women not receiving infertility treatment aged 22 to 50 years participated. Blood sampling for hormonal analysis was done every fifth day throughout three consecutive menstrual cycles, AFC was determined with 3-dimentional ultrasound and AMH measured by different assays from Beckman Coulter, Roche and Ansh Labs. Outcome measures were maximum and minimum difference in absolute and relative terms for each study subject during the test-period, coefficient of variation (Cv) for AMH for each cycle and cycle-day and correlation between AMH and AFC. The impact from variable AMH levels on an algorithm calculating follitrophin-delta dose in ovarian stimulation was explored. A significant longitudinal age-independent variation in AMH-levels and coefficient of variation in cycles and cycle days was found. A strong correlation between AMH-levels and AFC was confirmed and a case of significant divergence between assays was seen. Variations in AMH had a significant impact on an algorithm calculated dosage of gonadotrophins in ovarian stimulation. The finding of a substantial longitudinal variation in AMH question one recording being sufficient in quantifying gonadotrophins for ovarian stimulation, decision making and prognostication related to infertility treatment and counseling. Occasionally, commercial assays may fail to recognize specific AMH cleavage-products.
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http://dx.doi.org/10.3389/fendo.2018.00603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232665PMC
October 2018

Sperm DNA Integrity is Unaffected by Thiopurine Treatment in Men With Inflammatory Bowel Disease.

J Crohns Colitis 2019 Jan;13(1):3-11

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Background And Aims: Sperm DNA integrity, concentration, and motility are suspected to be altered by thiopurines (azathioprine [AZA] and 6-mercaptopurine [6-MP]). We investigated the impact of thiopurines on semen quality in men with inflammatory bowel disease [IBD], by a comprehensive panel of semen analyses.

Methods: Semen from 40 men with IBD, in remission on AZA/6-MP therapy, was prospectively collected and compared with samples from 40 healthy volunteers. Paired samples [off and on AZA/6-MP] were obtained from a subset of IBD patients, and blood and semen were collected to determine 6-MP transmission to the ejaculate. Sperm DNA fragmentation was evaluated via sperm chromatin structure assay [SCSA] and Comet analysis. Conventional World Health Organization [WHO] parameters, i.e. semen volume and sperm concentration, motility, and morphology, were assessed. Additionally, we measured thioguanine nucleotide [TGN] incorporation in sperm cell DNA.

Results: Sperm DNA fragmentation levels did not differ between men with IBD on AZA/6-MP and healthy volunteers when evaluated by SCSA [p = 0.23] and Comet analysis [p = 0.72]. IBD patients on AZA/6-MP had significantly lower total and progressive sperm motility than healthy volunteers [48.5% versus 64.5%, p = 0.0003; 27.4% versus 43.3%, p = 0.0004; respectively], with no differences in concentration, volume, or morphology. The same trend was observed in the 10 paired samples. TGN incorporation was not detectable in sperm DNA, but 6-MP was detected in seminal plasma and correlated to blood levels [rs = 0.79, p = 0.02].

Conclusions: Thiopurines do not increase sperm DNA fragmentation but may impair sperm motility in this IBD cohort. Our findings support existing epidemiological data that thiopurine therapy is safe during preconception and should not be abandoned.
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http://dx.doi.org/10.1093/ecco-jcc/jjy086DOI Listing
January 2019

Sperm DNA integrity testing-a valuable clinical tool.

Authors:
Mona Bungum

Transl Androl Urol 2017 Sep;6(Suppl 4):S329-S330

Head of Section/Laboratory Director, Reproductive Medicine Centre (RMC), Skåne University Hospital, Scania, Sweden. (Email:

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http://dx.doi.org/10.21037/tau.2017.09.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643720PMC
September 2017

Comparison of a 'freeze-all' strategy including GnRH agonist trigger versus a 'fresh transfer' strategy including hCG trigger in assisted reproductive technology (ART): a study protocol for a randomised controlled trial.

BMJ Open 2017 Jul 31;7(7):e016106. Epub 2017 Jul 31.

Department of Obstetrics and Gynaecology, The Fertility Clinic, Hvidovre University Hospital, Copenhagen, Denmark.

Introduction: Pregnancy rates after frozen embryo transfer (FET) have improved in recent years and are now approaching or even exceeding those obtained after fresh embryo transfer. This is partly due to improved laboratory techniques, but may also be caused by a more physiological hormonal and endometrial environment in FET cycles. Furthermore, the risk of ovarian hyperstimulation syndrome is practically eliminated in segmentation cycles followed by FET and the use of natural cycles in FETs may be beneficial for the postimplantational conditions of fetal development. However, a freeze-all strategy is not yet implemented as standard care due to limitations of large randomised trials showing a benefit of such a strategy. Thus, there is a need to test the concept against standard care in a randomised controlled design. This study aims to compare ongoing pregnancy and live birth rates between a freeze-all strategy with gonadotropin-releasing hormone (GnRH) agonist triggering versus human chorionic gonadotropin (hCG) trigger and fresh embryo transfer in a multicentre randomised controlled trial.

Methods And Analysis: Multicentre randomised, controlled, double-blinded trial of women undergoing assisted reproductive technology treatment including 424 normo-ovulatory women aged 18-39 years from Denmark and Sweden. Participants will be randomised (1:1) to either (1) GnRH agonist trigger and single vitrified-warmed blastocyst transfer in a subsequent hCG triggered natural menstrual cycle or (2) hCG trigger and single blastocyst transfer in the fresh (stimulated) cycle. The primary endpoint is to compare ongoing pregnancy rates per randomised patient in the two treatment groups after the first single blastocyst transfer.

Ethics And Dissemination: The study will be performed in accordance with the ethical principles in the Helsinki Declaration. The study is approved by the Scientific Ethical Committees in Denmark and Sweden. The results of the study will be publically disseminated.

Trial Registration Number: NCT02746562; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2017-016106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642760PMC
July 2017

Noninferiority, randomized, controlled trial comparing embryo development using media developed for sequential or undisturbed culture in a time-lapse setup.

Fertil Steril 2015 Dec 25;104(6):1452-9.e1-4. Epub 2015 Sep 25.

Fertilitetscentrum, Carlanderska Hospital, Gothenburg, Sweden.

Objective: To study whether a culture medium that allows undisturbed culture supports human embryo development to the blastocyst stage equivalently to a well-established sequential media.

Design: Randomized, double-blinded sibling trial.

Setting: Independent in vitro fertilization (IVF) clinics.

Patient(s): One hundred twenty-eight patients, with 1,356 zygotes randomized into two study arms.

Intervention(s): Embryos randomly allocated into two study arms to compare embryo development on a time-lapse system using a single-step medium or sequential media.

Main Outcome Measure(s): Percentage of good-quality blastocysts on day 5.

Result(s): Percentage of day 5 good-quality blastocysts was 21.1% (standard deviation [SD] ± 21.6%) and 22.2% (SD ± 22.1%) in the single-step time-lapse medium (G-TL) and the sequential media (G-1/G-2) groups, respectively. The mean difference (-1.2; 95% CI, -6.0; 3.6) between the two media systems for the primary end point was less than the noninferiority margin of -8%. There was a statistically significantly lower number of good-quality embryos on day 3 in the G-TL group [50.7% (SD ± 30.6%) vs. 60.8% (SD ± 30.7%)]. Four out of the 11 measured morphokinetic parameters were statistically significantly different for the two media used. The mean levels of ammonium concentration in the media at the end of the culture period was statistically significantly lower in the G-TL group as compared with the G-2 group.

Conclusion(s): We have shown that a single-step culture medium supports blastocyst development equivalently to established sequential media. The ammonium concentrations were lower in the single-step media, and the measured morphokinetic parameters were modified somewhat.

Clinical Trial Registration Number: NCT01939626.
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http://dx.doi.org/10.1016/j.fertnstert.2015.08.037DOI Listing
December 2015

Body Mass Index Is Associated with Impaired Semen Characteristics and Reduced Levels of Anti-Müllerian Hormone across a Wide Weight Range.

PLoS One 2015 12;10(6):e0130210. Epub 2015 Jun 12.

Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway.

There is still controversy as to how body mass index (BMI) affects male reproduction. We investigated how BMI is associated with semen quality and reproductive hormones in 166 men, including 38 severely obese men. Standard semen analysis and sperm DNA integrity analysis were performed, and blood samples were analysed for reproductive hormones. Adjusted for age and time of abstinence, BMI was negatively associated with sperm concentration (B = -0.088, P = 0.009), total sperm count (B = -0.223, P = 0.001), progressive sperm motility (B = -0.675, P = 0.007), normal sperm morphology (B = -0.078, P = 0.001), and percentage of vital spermatozoa (B = -0.006, P = 0.027). A negative relationship was observed between BMI and total testosterone (B = -0.378, P < 0.001), sex hormone binding globulin (B = -0.572, P < 0.001), inhibin B (B = -3.120, P < 0.001) and anti-Müllerian hormone (AMH) (B = -0.009, P < 0.001). Our findings suggest that high BMI is negatively associated with semen characteristics and serum levels of AMH.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130210PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466334PMC
February 2016

The impact of male overweight on semen quality and outcome of assisted reproduction.

Asian J Androl 2014 Sep-Oct;16(5):749-54

The Fertility Clinic, Viborg Hospital, Skive, Denmark.

It is well-documented that male overweight and obesity causes endocrine disorders that might diminish the male reproductive capacity; however, reports have been conflicting regarding the influence of male body mass index (BMI) on semen quality and the outcome of assisted reproductive technology (ART). The aim of this study was to investigate whether increased male BMI affects sperm quality and the outcome of assisted reproduction in couples with an overweight or obese man and a non-obese partner. Data was prospectively collected from 612 infertile couples undergoing ART at a Danish fertility center. Self-reported information on paternal height and weight were recorded and BMI was calculated. The men were divided into four BMI categories: underweight BMI < 20 kg m(-2) normal BMI 20-24.9 kg m(-2), overweight BMI 25-29.9 kg m(-2) and obese BMI > 30 kg m(-2). Conventional semen analysis was performed according to the World Health Organization guideline and sperm DNA integrity was analyzed by the Sperm Chromatin Structure Assay (SCSA). No statistically significant effect of male BMI was seen on conventional semen parameters (sperm concentration, total sperm count, seminal volume and motility) or on SCSA-results. Furthermore, the outcome of ART regarding fertilization rate, number of good quality embryos (GQE ), implantation and pregnancy outcome was not influenced by the increasing male BMI.
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http://dx.doi.org/10.4103/1008-682X.125398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215681PMC
June 2015

The circadian variation in Anti-Müllerian hormone in patients with polycystic ovary syndrome differs significantly from normally ovulating women.

PLoS One 2013 4;8(9):e68223. Epub 2013 Sep 4.

Reproductive Medicine Center, Skåne University Hospital, Lund University, Malmö, Sweden.

Objective: [corrected] To improve the biologic understanding of the Polycystic Ovarian Syndrome (PCOS) condition by examining the circadian variation and relationship between Anti Müllerian Hormone (AMH), gonadotropins and ovarian steroids in PCOS patients compared to normally ovulating and menstruating women. By comparing the pattern of co-variation between AMH and Luteinizing Hormone, two compounds closely linked to hyperandrogenism and anovulation in PCOS, the involvement of the Hypothalamic-Pituitary-Ovarian axis in PCOS pathology could be elucidated.

Patients: Eight normal-weighted young, anovulatory PCOS-women as study group and ten normal menstruating and ovulating women as controls.

Interventions: Observational prospective study of the circadian variation in AMH, gonadotropins, sex steroids and androgens in a study and a control group. A circadian profile was performed in each study and control subject during a 24-h period by blood sampling every second hour, starting at 8:00 a.m. and continuing until 8:00 a.m. the following day.

Results: Significant differences in hormonal levels were found between the groups, with higher concentrations of AMH, LH and androgens in the PCOS group and lower amounts of FSH and progesterone. A distinct difference in the circadian variation pattern of AMH and LH between PCOS patients and normal controls was seen, with PCOS patients presenting a uniform pattern in serum levels of AMH and LH throughout the study period, without significant nadir late-night values as was seen in the control group. In PCOS women, a significant positive association between LH/ FSH and testosterone was found opposite to controls.

Main Outcome Measures: Circadian variation in Anti-Müllerian Hormone, gonadotropins and ovarian steroids and the covariation between them.

Conclusion: A significant difference in the circadian secretion of LH and AMH in PCOS women compared to normally ovulating women indicate an increased GnRH pulse, creating high and constant LH serum concentrations. A significant co-variation between LH and AMH may suggest LH as a factor involved in the control of AMH secretion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0068223PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762839PMC
April 2014

Sperm DNA integrity assessment: a new tool in diagnosis and treatment of fertility.

Authors:
Mona Bungum

Obstet Gynecol Int 2012 1;2012:531042. Epub 2011 Dec 1.

Reproductive Medicine Centre (RMC), Skane University Hospital, 205 02 Malmo, Sweden.

Infertility affects 15% of all couples. Although male infertility factors with reduced semen quality are contributing to about half of all involuntary childlessness, the value of standard semen parameters in prediction of fertility in vivo and choice of proper method for assisted reproduction is limited. In the search for better markers of male fertility, during the last 10 years, assessment of sperm DNA integrity has emerged as a strong new biomarker of semen quality that may have the potential to discriminate between infertile and fertile men. Sperm DNA Fragmentation Index (DFI) as assessed by the flow cytometric Sperm Chromatin Structure Assay (SCSA) can be used for evaluation of sperm chromatin integrity. The biological background for abnormal DFI is not completely known, but clinical data show that DFI above 30% is associated with very low chance for achieving pregnancy in natural way or by insemination, but not in vitro. Already when the DFI is above 20%, the chance of natural pregnancy may be reduced, despite other sperm parameters being normal. Thus this method may explain a significant proportion of cases of unexplained infertility and can be beneficial in counselling involuntary childless couples need of in vitro fertilisation.
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http://dx.doi.org/10.1155/2012/531042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236416PMC
August 2012

Does weight loss improve semen quality and reproductive hormones? Results from a cohort of severely obese men.

Reprod Health 2011 Aug 17;8:24. Epub 2011 Aug 17.

Danish Ramazzini Center, Department of Occupational Medicine, Aarhus University Hospital, Denmark.

Background: A high body mass index (BMI) has been associated with reduced semen quality and male subfecundity, but no studies following obese men losing weight have yet been published. We examined semen quality and reproductive hormones among morbidly obese men and studied if weight loss improved the reproductive indicators.

Methods: In this pilot cohort study, 43 men with BMI > 33 kg/m² were followed through a 14 week residential weight loss program. The participants provided semen samples and had blood samples drawn, filled in questionnaires, and had clinical examinations before and after the intervention. Conventional semen characteristics as well as sperm DNA integrity, analysed by the sperm chromatin structure assay (SCSA) were obtained. Serum levels of testosterone, estradiol, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH) and inhibin B (Inh-B) were measured.

Results: Participants were from 20 to 59 years of age (median = 32) with BMI ranging from 33 to 61 kg/m². At baseline, after adjustment for potential confounders, BMI was inversely associated with sperm concentration (p = 0.02), total sperm count (p = 0.02), sperm morphology (p = 0.04), and motile sperm (p = 0.005) as well as testosterone (p = 0.04) and Inh-B (p = 0.04) and positively associated to estradiol (p < 0.005). The median (range) percentage weight loss after the intervention was 15% (3.5-25.4). Weight loss was associated with an increase in total sperm count (p = 0.02), semen volume (p = 0.04), testosterone (p = 0.02), SHBG (p = 0.03) and AMH (p = 0.02). The group with the largest weight loss had a statistically significant increase in total sperm count [193 millions (95% CI: 45; 341)] and normal sperm morphology [4% (95% CI: 1; 7)].

Conclusion: This study found obesity to be associated with poor semen quality and altered reproductive hormonal profile. Weight loss may potentially lead to improvement in semen quality. Whether the improvement is a result of the reduction in body weight per se or improved lifestyles remains unknown.
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http://dx.doi.org/10.1186/1742-4755-8-24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177768PMC
August 2011

Sperm chromatin structure assay (SCSA): a tool in diagnosis and treatment of infertility.

Asian J Androl 2011 Jan 8;13(1):69-75. Epub 2010 Nov 8.

Reproductive Medicine Centre (RMC), Skane University Hospital, Malmö, Sweden.

Diagnosis of male infertility has mainly been based on the World Health Organization (WHO) manual-based semen parameter's concentration, motility and morphology. It has, however, become apparent that none of these parameters are reliable markers for evaluation of the fertility potential of a couple. A search for better markers has led to an increased focus on sperm chromatin integrity testing in fertility work-up and assisted reproductive techniques. During the last couple of decades, numerous sperm DNA integrity tests have been developed. These are claimed to be characterized by a lower intraindividual variation, less intralaboratory and interlaboratory variation and thus less subjective than the conventional sperm analysis. However, not all the sperm chromatin integrity tests have yet been shown to be of clinical value. So far, the test that has been found to have the most stable clinical threshold values in relation to fertility is the sperm chromatin structure assay (SCSA), a flow cytometric test that measures the susceptibility of sperm DNA to acid-induced DNA denaturation in situ. Sperm DNA fragmentation as measured by SCSA has shown to be an independent predictor of successful pregnancy in first pregnancy planners as well as in couples undergoing intrauterine insemination, and can be used as a tool in investigation, counseling and treatment of involuntary childlessness. More conflicting data exist regarding the role of sperm DNA fragmentation in relation to fertilization, pre-embryo development and pregnancy outcome in in vitro fertilization and intracytoplasmic sperm injection (ICSI).
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http://dx.doi.org/10.1038/aja.2010.73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739398PMC
January 2011

[Promising method for investigation and treatment of infertility. Sperm chromatin analysis--useful marker for male infertility].

Lakartidningen 2010 Aug 11-24;107(32-33):1845-7

Reproduktionsmedicinskt centrum, Skånes universitetssjukhus, Malmö.

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September 2010

Sperm chromatin structure assay as an independent predictor of fertility in vivo: a case-control study.

Int J Androl 2010 Feb 15;33(1):e221-7. Epub 2009 Oct 15.

Reproductive Medicine Centre, Malmö University Hospital, Lund University, Malmö, Sweden.

Standard sperm parameters have a limited power for prediction of the chance of natural conception. Recent studies have indicated that the sperm chromatin structure assay (SCSA) DNA fragmentation index (DFI), a measure for the fraction of sperms with DNA damage, is associated with fertility in vivo. The aim of this study was to evaluate the value of this parameter for prediction of infertility. One hundred and twenty-seven men from infertile couples with no known female factor and 137 men with proven fertility were included. Semen analysis was performed as recommended by the WHO. DFI was assessed using SCSA. Logistic binary regression was used to compute the odds ratios (OR) for infertility. As compared with men with a DFI <10%, men with a DFI between 10% and 20% had an increased risk for infertility (OR 2.5, 95% CI: 1.0-6.1). This was also true for men with a DFI >20% (OR 8.4; 95% CI: 3.0-23). In men with normal standard semen parameters (sperm concentration, motility and morphology) the OR for infertility was increased with DFI >20% (OR 5.1, 95% CI: 1.2-23), whereas if one of the standard semen parameters was abnormal, the OR for infertility was increased already at DFI above 10% (OR 16, 95% CI: 4.2-60). We conclude that SCSA DFI adds to the value of semen analysis in prediction of the chance of natural conception.
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http://dx.doi.org/10.1111/j.1365-2605.2009.00995.xDOI Listing
February 2010

Polymorphisms in the protein C inhibitor gene in in vitro fertilization failure.

Fertil Steril 2010 Jan 17;93(1):277-9. Epub 2009 Sep 17.

Reproductive Medicine Centre, Malmö University Hospital, Malmö, Sweden.

The aim of this study was to determine whether total fertilization failure in human IVF can be partially explained by alterations in the gene that codes for protein C inhibitor. Forty-six men had IVF total fertilization failure and 51 controls with normal fertilization were screened for mutations in the protein C inhibitor gene by direct sequencing. The main finding was that in men involved in total fertilization failure, a heterozygous adenosine/guanine (A/G) base combination in position 1389 (rs2069990) (exon 6) in the protein C inhibitor gene was significantly more common compared with controls (10.9% vs. 0).
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http://dx.doi.org/10.1016/j.fertnstert.2009.07.984DOI Listing
January 2010

Sperm chromatin structure assay parameters measured after density gradient centrifugation are not predictive for the outcome of ART.

Hum Reprod 2008 Jan 6;23(1):4-10. Epub 2007 Nov 6.

Centre of Reproductive Medicine, Malmö University Hospital, 205 02 Malmö, Sweden.

Background: The sperm chromatin structure assay (SCSA) parameter DNA fragmentation index (DFI) has been shown to predict in vivo and in vitro fertility. So far most SCSA studies have been based on SCSA analysis performed on neat semen. The aim of this study is to assess whether SCSA analysis of sperm prepared by density gradient centrifugation (DGC) could add more information in regard to the prediction of treatment outcome.

Methods: The study included 510 assisted reproductive technique (ART) cycles. SCSA was performed in neat semen and post DGC. SCSA results were expressed in terms of DFI and high DNA stainability (HDS) cell fractions. The outcome parameter was clinical pregnancy (CP).

Results: Scatter-plot diagrams demonstrated that for DGC samples, no DFI cut-off values could be set for in vivo or in vitro fertility. In intrauterine insemination, IVF and ICSI groups the mean difference (95% CI) in DFI post DGC between those who achieved CP and those who did not was 0.2% (-1.7 to 2.0%), 0.4% (-1.9 to 2.8%) and 1.3% (-3.1 to 5.9%), respectively, none of these being statistically significant. The corresponding differences for HDS were 0.1% (-1.3 to 1.5%), 0.1% (-0.7 to 0.9%) and 0.6% (-1.6 to 2.7%), respectively (all P-values >0.6).

Conclusions: SCSA performed in semen prepared by DGC cannot predict the outcome of ART.
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http://dx.doi.org/10.1093/humrep/dem353DOI Listing
January 2008

A prospective study, using sibling oocytes, examining the effect of 30 seconds versus 90 minutes gamete co-incubation in IVF.

Hum Reprod 2006 Feb 20;21(2):518-23. Epub 2005 Oct 20.

The Fertility Clinic, Viborg Hospital (Skive), Resenvej 25, DK 7800 Skive, Denmark.

Background: Traditionally oocytes have been exposed to sperm overnight, for 16-20 h. This long period of co-incubation, however, has been shown to create problems with high levels of reactive oxygen species (ROS), which may affect embryo viability and cause hardening of the zona pellucida. Recently, a positive effect of reducing the co-incubation time to 90-120 min was reported. The objective of this study was to evaluate whether a further reduction of the co-incubation period could benefit the outcome of IVF.

Methods: In this prospective study, 777 sibling oocytes from 81 women undergoing IVF were divided via alternate allocation to co-incubation for either 30 s (ultrashort co-incubation) (group A) or for 90 min (standard co-incubation) (group B). Endpoints were normal fertilization (two-pronuclear, 2PN), polyspermy (>2PN), embryo quality (EQ), clinical pregnancy (CP) and implantation (IR).

Results: The normal fertilization rates of the two groups were comparable: group A 58.6% versus group B 58.0%. Significantly lower rates of polyspermy were seen in group A compared to group B (2.8 versus 7.2%, P = 0.008). No statistically significant differences in EQ, CP or IR were seen.

Conclusion: This is the first study demonstrating the achievement of good fertilization rates in IVF with ultrashort co-incubation. Significantly lower rates of polyspermy were seen in the group with ultrashort compared to the standard co-incubation group. Further studies are, however, needed in order to evaluate whether ultrashort co-incubation has any effect on the outcome of IVF.
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http://dx.doi.org/10.1093/humrep/dei350DOI Listing
February 2006

Impact of follicular-fluid meiosis-activating sterol in an albumin-based formulation on the incidence of human pre-embryos with chromosome abnormalities.

Fertil Steril 2005 Oct;84 Suppl 2:1269-76

The Fertility Clinic, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objective: To evaluate the effect of adding follicular-fluid meiosis-activating sterol (FF-MAS) in a novel 0.2% recombinant human albumin-based formulation to cumulus-enclosed oocytes on chromosomal status and development of pre-embryos.

Design: Multicenter, prospective, randomized, open (double-blind for vehicle and FF-MAS groups), four parallel groups, controlled trial.

Setting: Four public IVF clinics in Denmark.

Patient(s): Two hundred eighteen women undergoing IVF donated 483 oocytes.

Intervention(s): Follicle-stimulating hormone/hCG-primed cumulus-enclosed oocytes randomized to 4 hours of exposure to medium with 1 or 10 micromol/L of FF-MAS dissolved in 0.2% recombinant human albumin, medium with 0.2% recombinant human albumin (vehicle control), or medium alone (control) before insemination.

Main Outcome Measure(s): Primary endpoint: incidence of human pre-embryos with chromosomal abnormalities. Secondary endpoint: fertilization rate, cleavage rate, and pre-embryo quality assessed after 68 hours of culture.

Result(s): At pre-embryo level, the overall abnormality rates in the control, vehicle control, and 1- and 10-micromol/L FF-MAS groups were 53%, 39%, 42%, 53%, respectively, and at blastomere level 49%, 44%, 44%, and 48%, respectively. After 20 and 26 hours, the fertilization rates were between 67% and 71% in all groups. No differences in the cleavage rates were observed.

Conclusion(s): The concentrations of FF-MAS in a novel 0.2% recombinant human albumin-based formulation of FF-MAS did not increase the risk of chromosomal abnormalities in pre-embryos or blastomeres. No statistically significant differences in fertilization rate, cleavage rate, or number of good quality pre-embryos were found among the four groups.
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http://dx.doi.org/10.1016/j.fertnstert.2005.05.017DOI Listing
October 2005
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