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Epigenetic heterogeneity of developmentally important genes in human sperm: implications for assisted reproduction outcome.

ABSTRACT: The molecular basis of male infertility is poorly understood, the majority of cases remaining unsolved. The association of aberrant sperm DNA methylation patterns and compromised semen parameters suggests that disturbances in male germline epigenetic reprogramming contribute to this problem. So far there are only few data on the epigenetic heterogeneity of sperm within a given sample and how to select the best sperm for successful infertility treatment. Limiting dilution bisulfite sequencing of small pools of sperm from fertile donors did not reveal significant differences in the occurrence of abnormal methylation imprints between sperm with and without morphological abnormalities. Intracytoplasmic morphologically selected sperm injection was not associated with an improved epigenetic quality, compared to standard intracytoplasmatic sperm injection. Deep bisulfite sequencing (DBS) of 2 imprinted and 2 pluripotency genes in sperm from men attending a fertility center showed that in both samples with normozoospermia and oligoasthenoteratozoospermia (OAT) the vast majority of sperm alleles was normally (de)methylated and the percentage of epimutations (allele methylation errors) was generally low (<1%). However, DBS allowed one to identify and quantify these rare epimutations with high accuracy. Sperm samples not leading to a pregnancy, in particular in the OAT group, had significantly more epimutations in the paternally methylated GTL2 gene than samples leading to a live birth. All 13 normozoospermic and 13 OAT samples leading to a child had <1% GTL2 epimutations, whereas one (7%) of 14 normozoospermic and 7 (50%) of 14 OAT samples without pregnancy displayed 1-14% GTL2 epimutations.

SUBMITTER: Kuhtz J

PROVIDER: S-EPMC4622742 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Epigenetic heterogeneity of developmentally important genes in human sperm: implications for assisted reproduction outcome.

Kuhtz Juliane J Schneider Eberhard E El Hajj Nady N Zimmermann Lena L Fust Olga O Linek Bartosz B Seufert Rudolf R Hahn Thomas T Schorsch Martin M Haaf Thomas T

Epigenetics 20141201 12

The molecular basis of male infertility is poorly understood, the majority of cases remaining unsolved. The association of aberrant sperm DNA methylation patterns and compromised semen parameters suggests that disturbances in male germline epigenetic reprogramming contribute to this problem. So far there are only few data on the epigenetic heterogeneity of sperm within a given sample and how to select the best sperm for successful infertility treatment. Limiting dilution bisulfite sequencing of ...[more]

PMID: 25625849

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Project description:BackgroundSubfertility is a condition found in up to 15% of couples of reproductive age. Gamete micromanipulation, such as intracytoplasmic sperm injection (ICSI), is very useful for treating couples with compromised sperm parameters. An alternative method of sperm selection has been described; the spermatozoa are selected under high magnification (over 6000x) and used for ICSI. This technique, named intracytoplasmic morphologically selected sperm injection (IMSI), has a theoretical potential to improve reproductive outcomes among couples undergoing assisted reproduction techniques (ART). However, our previous version of this Cochrane Review was unable to find evidence that supported this possible beneficial effect. This is an update of Teixeira 2013.ObjectivesTo identify, appraise, and summarise the available evidence regarding efficacy and safety of IMSI compared to ICSI in couples undergoing ART.Search methodsWe searched for randomised controlled trials (RCTs) in these electronic databases: the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, and in these trial registers: ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. We also handsearched the reference lists of included studies and similar reviews. We performed the last electronic search on 18 November 2019.Selection criteriaWe only considered RCTs that compared ICSI and IMSI; we did not include quasi-randomised trials. We considered studies that permitted the inclusion of the same participant more than once (cross-over or per cycle trials) only if data regarding the first treatment of each participant were available.Data collection and analysisTwo review authors independently performed study selection, data extraction, and assessment of the risk of bias and quality of the evidence; we solved disagreements by consulting a third review author. We corresponded with study investigators to resolve any queries, as required.Main resultsThe updated search retrieved 535 records; we included 13 parallel-designed RCTs comparing IMSI and ICSI (four studies were added since the previous version), comprising 2775 couples (IMSI = 1256; ICSI = 1519). We are uncertain if IMSI improves live birth rates (risk ratio (RR) 1.11, 95% confidence interval (CI) 0.89 to 1.39; 5 studies, 929 couples; I² = 1%), miscarriage rates per couple (RR 1.07, 95% CI 0.78 to 1.48; 10 studies, 2297 couples; I² = 0%, very-low quality evidence), and miscarriage rate per pregnancy (RR 0.90, 95% CI 0.68 to 1.20; 10 studies, 783 couples; I² = 0%, very-low quality evidence). We are uncertain if IMSI improves clinical pregnancy rates (RR 1.23, 95% CI 1.11 to 1.37; 13 studies, 2775 couples; I² = 47%, very-low quality evidence). None of the included studies reported congenital abnormalities. We judged the evidence for all outcomes to be of very low-quality. We downgraded the quality of the evidence due to limitations of the included studies (risk of bias), inconsistency of results, and a strong indication of publication bias.Authors' conclusionsThe current evidence from randomised controlled trials does not support or refute the clinical use of intracytoplasmic sperm injection (intracytoplasmic morphologically selected sperm injection (IMSI). We are very uncertain of the chances of having a live birth and of the risk of having a miscarriage. We found very low-quality evidence that IMSI may increase chances of a clinical pregnancy, which means that we are still very uncertain about any real difference. We did not find any trials reporting on the risk of congenital abnormalities. Well-designed and sufficiently powered trials are still required.

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Epigenetic heterogeneity of developmentally important genes in human sperm: implications for assisted reproduction outcome.

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Epigenetic heterogeneity of developmentally important genes in human sperm: implications for assisted reproduction outcome.

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