IVF Reads / Sperm Epigenetics: What Is Actually Established
Sperm Epigenetics: What Is Actually Established
There is no validated clinical sperm epigenetics test, and no fertility guideline recommends one. The systematic review of this literature (Asenius F, Danson AF, Marzi SJ, Human Reproduction Update 2020;26(6):841-873), which GRADE-appraised 135 studies, concluded that male subfertility and abnormal semen parameters do appear to be associated with abnormal sperm DNA methylation of imprinted regions, but that "no specific DNA methylation signature of either subfertility or abnormal semen parameters has been convincingly replicated in genome-scale, unbiased analyses" and that "from a clinical point of view, there is no convincing evidence that changes in spermatozoal DNA methylation influence pregnancy outcomes or offspring health". Smoking, advanced age and environmental pollutants do appear to influence the sperm methylome, with the same caveat that findings require independent replication. Claims that epigenetic changes in sperm are inherited across generations in humans rest on plant and animal work; in humans the question is confounded by genetic, ecological and cultural inheritance and conclusive proof is difficult to provide (Horsthemke B, Nature Communications 2018;9:2973).
- Asenius F, Danson AF, Marzi SJ. DNA methylation in human sperm: a systematic review. Human Reproduction Update 2020;26(6):841-873, PMID 32790874. 446 records identified, 135 studies included and appraised against GRADE criteria; 56 on fertility and semen parameters, 20 on pregnancy outcomes and offspring health, 59 on environmental influences. Findings: subfertility and abnormal semen parameters, particularly oligozoospermia, appear associated with abnormal methylation of imprinted regions; "no specific DNA methylation signature of either subfertility or abnormal semen parameters has been convincingly replicated in genome-scale, unbiased analyses"; the methylome appears influenced by cigarette smoking, advanced age and environmental pollutants, with findings requiring independent replication; "from a clinical point of view, there is no convincing evidence that changes in spermatozoal DNA methylation influence pregnancy outcomes or offspring health".
- Horsthemke B. A critical view on transgenerational epigenetic inheritance in humans. Nature Communications 2018;9(1):2973, PMID 30061690. Transgenerational epigenetic inheritance has been observed in plants, nematodes and fruit flies; "its occurrence in mammals — and humans in particular — is the matter of controversial debate, mostly because the study of transgenerational epigenetic inheritance is confounded by genetic, ecological and cultural inheritance". The paper sets out the difficulty of providing conclusive proof in both experimental and observational human studies.
- Jenkins TG, Aston KI, Pflueger C, Cairns BR, Carrell DT. Age-associated sperm DNA methylation alterations: possible implications in offspring disease susceptibility. PLoS Genetics 2014;10(7):e1004458, PMID 25010591. 17 fertile donors, each sampled twice 9 to 19 years apart: 139 regions significantly and consistently hypomethylated with age and 8 hypermethylated, associated with 117 genes, a subset previously linked to schizophrenia and bipolar disorder; a subset confirmed in an independent cohort. Authors' caveat, quoted in full: "While our data does not establish a causative relationship, it does raise the possibility that the age-associated methylation of the candidate genes that we observe in sperm might contribute to the increased incidence of neuropsychiatric and other disorders in the offspring of older males. However, further study is required to determine whether, and to what extent, a causative relationship exists."
- Aston KI, Uren PJ, Jenkins TG, Horsager A, Cairns BR, Smith AD, Carrell DT. Aberrant sperm DNA methylation predicts male fertility status and embryo quality. Fertility and Sterility 2015;104(6):1388-97, PMID 26361204. Retrospective cohort at a university fertility centre: 127 men undergoing IVF where major female factor had been ruled out, and 54 normozoospermic fertile men; methylation measured at more than 485,000 sites. Predictive models classified fertility status with 82% sensitivity and 99% positive predictive value. This is the strongest single paper behind the idea of a methylation test; it is single-centre and retrospective, and its signature is among those the 2020 systematic review found had not been convincingly replicated in genome-scale unbiased analyses.
- Donkin I, Versteyhe S, Ingerslev LR, Qian K, Mechta M, Nordkap L, et al. Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans. Cell Metabolism 2016;23(2):369-78, PMID 26669700. Sperm from lean and obese men showed similar histone positioning but markedly different small non-coding RNA expression and DNA methylation patterns; in a separate cohort of morbidly obese men, surgery-induced weight loss was associated with "a dramatic remodeling of sperm DNA methylation, notably at genetic locations implicated in the central control of appetite". Set against this: the EAU 2025 male infertility guideline records a meta-analysis of 28 cohort studies and 1,022 patients finding that bariatric surgery did not improve sperm quality and function in morbidly obese males (Minhas S et al, European Urology 2025;87(5):601-616). The marks move; the sperm measurements do not.
- Two studies of smoking and the sperm methylome disagree, and both are reported. Jenkins TG, James ER, Alonso DF, et al, Andrology 2017;5(6):1089-1099, PMID 28950428: 78 men who smoke against 78 never-smokers, 141 significantly differentially methylated CpGs identified plus a trend towards increased genome-wide variance. Al Khaled Y, Tierling S, Laqqan M, et al, Andrologia 2018;50(1), PMID 28503748: of approximately 485,000 CpG sites analysed, only seven differed by more than 20% and the top six of those overlapped common SNP sites; the authors state the study could not detect biologically relevant altered positions beyond individual-specific effects.
Should I pay for a sperm epigenetics or DNA methylation test?
No. There is no validated clinical sperm epigenetics test, and no fertility guideline recommends one. The systematic review of this field appraised 135 studies and found that no methylation signature of subfertility or of abnormal semen parameters has been convincingly replicated in genome-scale, unbiased analyses.
Neither the European Association of Urology's 2025 male infertility guideline nor the World Health Organization's 2026 infertility guideline contains a recommendation for sperm epigenetic testing. The EAU mentions epigenetic abnormalities only as one of several suspected but unidentified factors in idiopathic male infertility.
That is the whole practical answer. The rest of this page is about what is genuinely known, because the biology is real even though the test is not.
What does 'sperm epigenetics' actually refer to?
Marks sitting on top of DNA that change whether a gene is read, without changing the DNA sequence itself. The one most often measured is DNA methylation — a small chemical group attached to the DNA at particular points. Histone changes and small RNAs carried in sperm are the other two.
A semen analysis counts sperm and watches them move. A methylation study asks a different question: which instructions in this sperm are switched on. It is a legitimate question and a genuinely active research field.
The gap between that and a useful test is where most of the confusion lives. Measuring something reliably, showing it differs between groups, showing it predicts an outcome in an individual, and showing that changing it changes the outcome are four separate achievements. This field has the first two in places, and not the second two.
What is genuinely associated with sperm methylation differences?
Three things, according to the systematic review, all with the same caveat attached — the findings need independent replication:
- Subfertility and abnormal semen parameters, oligozoospermia in particular, appear associated with abnormal methylation of imprinted regions.
- Cigarette smoking appears to influence the sperm methylome.
- Advanced paternal age and environmental pollutants appear to as well.
On age, the primary study is worth knowing in detail because it is unusual: 17 fertile donors gave a sample twice, 9 to 19 years apart. Comparing each man against his younger self, 139 regions were consistently less methylated with age and 8 more methylated, across 117 genes, some of which had previously been linked to schizophrenia and bipolar disorder. The authors then write the sentence that most coverage of their work drops: their data does not establish a causative relationship.
On smoking, the two best-matched studies disagree. One compared 78 men who smoke with 78 never-smokers and found 141 differentially methylated sites. The other analysed approximately 485,000 sites and found only 7 of 485,000 differing by more than 20%, with six of those seven sitting on common genetic variants; its authors concluded they could not detect biologically relevant changes attributable to smoking. Both are on this page because that is the actual state of the evidence.
Will this be passed on to my children?
Nobody has shown that it is, in humans. The confident version of that story comes from animals. Transgenerational epigenetic inheritance has been observed in plants, nematodes and fruit flies; in mammals, and humans in particular, it remains a matter of controversial debate.
The reason is not squeamishness, it is confounding. Parents and children share genes, they share households, diets, air and money, and they share habits. Separating an inherited chemical mark from all of that is very hard, and the review of the problem describes the difficulty of providing conclusive proof in both experimental and observational human studies.
The systematic review reaches the clinical version of the same conclusion: there is no convincing evidence that changes in sperm DNA methylation influence pregnancy outcomes or offspring health. If you are being told that your smoking, weight or age has already written something into your future child, that is a claim ahead of its evidence.
Want your own results explained?
IVY can read your reports alongside your history and set out what the evidence supports for your situation — and what it does not.
Can anything actually change these marks?
Yes, and this is where the field's most interesting result sits — along with its most useful disappointment. Sperm from lean and obese men had similar histone positioning but markedly different small RNA and methylation patterns. In morbidly obese men who then had weight-loss surgery, sperm methylation was substantially remodelled, including at sites involved in appetite control.
The other half of that finding is the part worth acting on. The EAU guideline records a pooled analysis of 28 cohort studies and 1,022 patients in which bariatric surgery did not improve sperm quality or function in morbidly obese men. So the marks moved and the sperm measurements did not. A visible change in a laboratory measure is not the same as a change in fertility.
This is also the reason the page does not recommend supplements for this purpose. The live version of this page recommended folate, zinc and omega-3 to support healthy epigenetic patterns. The only large randomised test of that exact combination measured a different kind of DNA damage and found it went the wrong way: among 2,370 couples randomised, men taking folic acid with zinc for six months ended with higher sperm DNA fragmentation than placebo, 29.7% against 27.2%, and live birth was 404 of 1,185 against 416 of 1,185. That is fragmentation rather than methylation, and it is the nearest randomised evidence there is.
What is worth doing instead, and over what timescale?
The things that are worth doing here are worth doing for reasons that have nothing to do with epigenetics, which is convenient, because it means you do not need a test to decide on them. Stopping smoking. Addressing weight if it is high. Not waiting longer than you have to, if age is a factor you can still act on.
The timescale for any of it is about three months. A cycle of sperm production was measured directly in 11 men who drank deuterium-labelled water: labelled sperm appeared in the ejaculate after a mean of 64 days, give or take eight, with a range of 42 to 76 days. Anything you change today reaches the sperm being produced now, not the sperm in the next sample next week.
The tests that do change management are unglamorous and already standard: at least two semen analyses, a physical examination, and hormones where the count is low. If someone is offering an epigenetic panel before those are done, the order is wrong.
What the evidence does not establish
On this page that list is longer than the list of things that are known, and saying so is the point.
- It does not establish a usable test. No methylation signature of subfertility or of abnormal semen parameters has been convincingly replicated in genome-scale, unbiased analyses, and neither the EAU 2025 nor the WHO 2026 guideline recommends epigenetic testing.
- It does not establish an effect on your child. The systematic review states there is no convincing evidence that changes in sperm DNA methylation influence pregnancy outcomes or offspring health.
- It does not establish transgenerational inheritance in humans. That has been shown in plants, nematodes and fruit flies; in humans it is confounded by genetic, ecological and cultural inheritance and remains debated.
- It does not establish that smoking alters the sperm methylome in a biologically meaningful way. Two studies using the same array technology reached opposite conclusions, and both are cited here.
- It does not establish that any supplement improves a sperm epigenetic measure. No retrieved study tested one against a methylation outcome, and the randomised trial of folic acid with zinc in 2,370 couples found higher DNA fragmentation and no live-birth benefit.
- It does not establish that epigenetic sperm selection exists as a clinical option. No retrieved source describes a validated technique for selecting sperm on epigenetic marks in human treatment, and the live version of this page should not have said otherwise.
- It does not establish that reversing a mark reverses anything else. Methylation marks can change; no retrieved human study shows that changing one changes a fertility or offspring outcome.
If the appeal of this test is that it might finally explain an unexplained result, that is a reasonable thing to want and it is worth naming. It is also the thing that makes a page like this hard to read. An expensive answer that has not been validated is not better than an honest gap.
Related reading
- The sperm DNA fragmentation test: is it worth paying for?
- How to read your semen analysis report, line by line
- The role of genetics in couple infertility
- Does smoking lower sperm count? What the numbers show
- Male fertility and lifestyle: what has actually been measured
- Antioxidants for sperm quality: what the trials found
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11 Sources
- Asenius F, Danson AF, Marzi SJ. DNA methylation in human sperm: a systematic review. Human Reproduction Update. 2020;26(6):841-873. PMID 32790874. Systematic review searching PubMed, Web of Science and Cochrane Library for human sperm DNA methylation studies from 1 January 2003 to 2 March 2020; 446 records identified, 135 included, each appraised against GRADE criteria. 56 studies on fertility and abnormal semen parameters, 20 on pregnancy outcomes and offspring health, 59 on environmental influences. Key findings, verbatim: male subfertility and abnormal semen parameters, particularly oligozoospermia, "appear to be associated with abnormal spermatozoal DNA methylation of imprinted regions"; "However, no specific DNA methylation signature of either subfertility or abnormal semen parameters has been convincingly replicated in genome-scale, unbiased analyses"; "although findings require independent replication, current evidence suggests that the spermatozoal DNA methylome is influenced by cigarette smoking, advanced age and environmental pollutants"; "Importantly however, from a clinical point of view, there is no convincing evidence that changes in spermatozoal DNA methylation influence pregnancy outcomes or offspring health." Integrity check 28 September 2026: no retraction, expression of concern or erratum. This is the primary anchor for the whole page. Human Reproduction Update
- Horsthemke B. A critical view on transgenerational epigenetic inheritance in humans. Nature Communications. 2018;9(1):2973. PMID 30061690. States that transgenerational epigenetic inheritance "has been observed in plants, nematodes and fruit flies", but that "its occurrence in mammals — and humans in particular — is the matter of controversial debate, mostly because the study of transgenerational epigenetic inheritance is confounded by genetic, ecological and cultural inheritance", and discusses "the difficulty of providing conclusive proof for it in experimental and observational studies". No retraction, expression of concern or erratum. Supports the correction to the live article's assertion that transgenerational inheritance in humans is established. Nature Communications
- Jenkins TG, Aston KI, Pflueger C, Cairns BR, Carrell DT. Age-associated sperm DNA methylation alterations: possible implications in offspring disease susceptibility. PLoS Genetics. 2014;10(7):e1004458. PMID 25010591. Methylation array study of 17 fertile donors, each providing two samples collected 9 to 19 years apart. 139 regions significantly and consistently hypomethylated with age; 8 significantly hypermethylated; 117 genes associated with those regions, a portion previously associated with schizophrenia and bipolar disorder; a representative subset confirmed in an independent cohort. Authors' caveat, quoted: "While our data does not establish a causative relationship, it does raise the possibility that the age-associated methylation of the candidate genes that we observe in sperm might contribute to the increased incidence of neuropsychiatric and other disorders in the offspring of older males. However, further study is required to determine whether, and to what extent, a causative relationship exists." No retraction, expression of concern or erratum. Supports the paternal-age section and its caveat. PLoS Genetics
- Aston KI, Uren PJ, Jenkins TG, Horsager A, Cairns BR, Smith AD, Carrell DT. Aberrant sperm DNA methylation predicts male fertility status and embryo quality. Fertility and Sterility. 2015;104(6):1388-97. PMID 26361204. Retrospective cohort at a university-based fertility centre: 127 men undergoing IVF where major female-factor causes had been ruled out (55 with good embryogenesis and a positive pregnancy, 72 with poor embryogenesis), against 54 normozoospermic fertile men; genome-wide methylation measured at more than 485,000 sites. Predictive models classified fertility status with 82% sensitivity and 99% positive predictive value; hierarchical clustering identified clusters enriched for IVF patients and for poor-quality-embryo samples. Single centre, retrospective. Two commentaries are linked on the PubMed record (PMIDs 26453980 and 27628829). No retraction, expression of concern or erratum. Cited as the strongest paper behind the test idea, with its limits stated. Fertility and Sterility
- Donkin I, Versteyhe S, Ingerslev LR, Qian K, Mechta M, Nordkap L, et al. Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans. Cell Metabolism. 2016;23(2):369-78. PMID 26669700. Comprehensive epigenome profiling of sperm from lean and obese men showed similar histone positioning but markedly different small non-coding RNA expression and DNA methylation patterns. In a separate cohort of morbidly obese men, surgery-induced weight loss was associated with "a dramatic remodeling of sperm DNA methylation, notably at genetic locations implicated in the central control of appetite". The authors frame this as evidence that the spermatozoal epigenome changes under environmental pressure; they do not report a fertility or offspring outcome. One commentary is linked on the record (PMID 26678808). No retraction, expression of concern or erratum. Supports the first half of the weight-loss section. Cell Metabolism
- Minhas S, Boeri L, Capogrosso P, Cocci A, Corona G, Dinkelman-Smit M, et al. European Association of Urology Guidelines on Male Sexual and Reproductive Health: 2025 Update on Male Infertility. European Urology. 2025;87(5):601-616. PMID 40118737. Practice guideline; chapter text retrieved from uroweb.org on 28 September 2026. Contains NO recommendation for sperm epigenetic testing; epigenetic abnormalities appear only as one of several "previously unidentified pathological factors" that idiopathic male infertility "may be associated with", alongside endocrine disruption from environmental pollution and reactive oxygen species. On weight loss, the chapter records: "A meta-analysis of 28 cohort studies and 1,022 patients documented that bariatric surgery did not improve sperm quality and function in males that are morbidly obese", and that data on assisted reproduction outcomes are lacking. No retraction, expression of concern or erratum. Supports the absence of a guideline recommendation and the second half of the weight-loss section. European Association of Urology
- Jenkins TG, James ER, Alonso DF, Hoidal JR, Murphy PJ, Hotaling JM, et al. Cigarette smoking significantly alters sperm DNA methylation patterns. Andrology. 2017;5(6):1089-1099. PMID 28950428. 78 men who smoke against 78 never-smokers on the Infinium Human Methylation 450 beadchip, testing two models: consistently altered methylation at specific CpGs or regions, and stochastic alterations manifesting as increased genome-wide variability. 141 significantly differentially methylated CpGs identified, plus a trend towards increased variance in men who smoke. The authors state the findings "warrant further investigation to identify the specific mechanism" and whether changes can be transmitted to offspring — that is, they do not claim transmission. No retraction, expression of concern or erratum. Cited as one side of the smoking disagreement. Andrology
- Al Khaled Y, Tierling S, Laqqan M, Lo Porto C, Hammadeh ME. Cigarette smoking induces only marginal changes in sperm DNA methylation levels of patients undergoing intracytoplasmic sperm injection treatment. Andrologia. 2018;50(1). PMID 28503748. Infinium 450K arrays comparing smokers and non-smokers, followed by local deep bisulphite sequencing of a significantly altered site. Of approximately 485,000 CpG sites analysed, only seven showed a methylation difference greater than 20%, and the top six of those overlapped common SNP sites; the remaining site (cg19455396, intron 12 of TAP2) showed only a tendency towards hypomethylation on deep sequencing. Authors' conclusion: the study "could not detect biologically relevant CpG positions that are altered in sperm DNA methylation on the influence of cigarette smoking beyond individual-specific effects that may be caused by other environmental factors". No retraction, expression of concern or erratum. Cited as the other side of the smoking disagreement. Andrologia
- Schisterman EF, Sjaarda LA, Clemons T, Carrell DT, Perkins NJ, Johnstone E, et al. Effect of folic acid and zinc supplementation in men on semen quality and live birth among couples undergoing infertility treatment: a randomized clinical trial. JAMA. 2020;323(1):35-48. PMID 31910279. 2,370 couples randomised; men received 5 mg folic acid with 30 mg elemental zinc (n=1,185) or placebo (n=1,185) daily for six months. Live birth 404 of 1,185 against 416 of 1,185, risk difference -0.9% (95% CI -4.7 to 2.8). DNA fragmentation significantly higher on supplement: 29.7% against 27.2%, mean difference 2.4% (95% CI 0.5 to 4.4). Cited here because it is the only large randomised test of the exact supplement the live version of this page recommended for epigenetic support; it measures DNA fragmentation rather than methylation, and the page says so. Integrity check 28 September 2026: no retraction, no expression of concern; carries ErratumIn PMID 32207776, retrieved — JAMA 2020;323(12):1194, "Two Rows Transposed in Table 1", which does not affect these results. JAMA
- Mburu G, Santesso N, Brignardello-Petersen R, Kennedy R, Farquhar C, Boivin J, et al. Recommendations from the WHO guideline for the prevention, diagnosis, and treatment of infertility. Human Reproduction. 2026;41(1):25-38. PMID 41312724. WHO guideline summary: 40 recommendations and six good practice statements, GRADE-based. For males the diagnostic recommendations concern when a semen test should be repeated; there is no recommendation regarding epigenetic or DNA methylation testing. Most recommendations were conditional because the relevant evidence was absent or of low to very low certainty, and critical research gaps were identified. No retraction or expression of concern. Supports the statement that no current guideline recommends sperm epigenetic testing. Human Reproduction / World Health Organization
- Misell LM, Holochwost D, Boban D, Santi N, Shefi S, Hellerstein MK. A stable isotope-mass spectrometric method for measuring human spermatogenesis kinetics in vivo. Journal of Urology. 2006;175(1):242-6. PMID 16406920. Eleven men with normal sperm concentrations ingested deuterated water for three weeks, with semen collected every two weeks for up to 90 days. Labelled sperm were detected after a mean of 64 plus or minus 8 days, range 42 to 76. No retraction, expression of concern or erratum. Supports the three-month window. Journal of Urology
Frequently asked questions
Common questions on this topic.
A clinic has offered me a sperm epigenetic or 'sperm epigenetic age' panel. What should I ask?
Ask three things, in this order. Which published study validated this specific test, in how many men, and was it replicated by an independent group. What result would change my treatment, and to what. And what does it cost. The reason those questions are enough is that the systematic review of 135 studies found no methylation signature of subfertility convincingly replicated in genome-scale unbiased analyses, so the first question is the one that has no good answer yet.
Does my age mean I have already damaged my future child's DNA?
No study retrieved for this page establishes that. What has been measured is that sperm methylation changes with age — in 17 men each sampled twice, 9 to 19 years apart, 139 regions were consistently less methylated and 8 more methylated with age. The authors of that study write explicitly that their data does not establish a causative relationship with any outcome in offspring. Paternal age is worth factoring into timing decisions; it is not a verdict already delivered.
If I stop smoking, do the marks go back to normal?
Nobody has shown that in sperm, and the two studies that looked hardest at smoking and the sperm methylome disagreed about whether there is a meaningful signal to reverse. What is not in doubt is that stopping smoking is worth doing for reasons measured elsewhere, and that any change takes about three months to reach the sperm being produced. Treat it as worthwhile in itself rather than as a way to correct a mark.
Is this why our IVF cycles have failed?
It cannot be answered by a test that does not yet exist in validated form, and it should not be presented as if it could. One retrospective single-centre study did find that methylation patterns clustered with poor embryo quality, which is why the idea persists; that signature has not been convincingly replicated. After repeated cycle failure, the steps with actual guideline support are a full andrological assessment, a physical examination, hormones, and — if there has also been recurrent pregnancy loss — karyotype and sperm DNA fragmentation.
Are there drugs that fix sperm epigenetics?
Not in human fertility practice. The earlier version of this page said pharmacological approaches were being explored to correct aberrant epigenetic marks; no source retrieved for this rewrite supports that as an available or validated treatment, and the claim has been removed. If a drug is being offered on that basis, ask which trial tested it and what the outcome measure was.
Is IVF or ICSI itself going to affect my child's epigenetics?
That is a different question from this page's and it is not answered by the sources retrieved here. What the systematic review of sperm methylation says is narrower: there is no convincing evidence that changes in sperm DNA methylation influence pregnancy outcomes or offspring health. That is a statement about the father's sperm, not about the laboratory procedure, and this page does not extend it to one.