Of the 15% of couples globally who experience infertility, male factors are solely responsible in 20% of cases and contributory in up to 50% of cases [1]. Out of those same 15% of infertile couples worldwide, 20% will receive a diagnosis of “unexplained infertility.” At present, if a couple experiences infertility (no pregnancy after 12 months of unprotected sexual intercourse when the female is under age 35, and six months if she is over 35), a primary care doctor or OB/GYN will typically order an initial medical workup of both the male and the female.
Рутина мужчина infertility workups include a comprehensive reproductive and medical history plus a sperm analysis (described below). But evidence increasingly suggests the importance of an additional test: sperm DNA fragmentation (SDF) testing. SDF testing may be helpful specifically for couples with “unexplained” infertility.
If the basic medical workup for the male and/or female doesn’t yield an identifiable cause for the couple’s inability to conceive, they may be referred on to an IVF clinic. Unfortunately, as noted by leading urologic and reproductive experts in 2021, assisted reproductive technologies (ART) centers like IVF clinics often don’t refer patients to urologists for in-depth male factor infertility workups until после a couple has had one or more failed rounds of IVF [2].
Fortunately, as the 2021 expert review observed, “Prompt assessment of the male partner, including the level of SDF may allow early identification of underlying pathological factors and can direct towards targeted treatment paths, reducing the cost and burden of unnecessary interventions or repeated failed ART.”
Seminal fluid analysis is routinely performed in male infertility evaluations
Sperm analysis or seminal fluid analysis (SFA) is a mainstay of male infertility workups. SFA involves examining seminal fluid (ejaculated fluid that contains sperm) under a microscope to assess markers of health such as number, shape, and motility (movement). SFA is performed several times, with at least a week and up to a month between tests, because results can vary dramatically from one day to the next. This is because caffeine, alcohol, smoking, certain medications (such as testosterone therapy and antidepressants), and illicit drug use can all negatively impact SFA results [3]. For this reason, the trend is more helpful than just one sample.
While on the one hand restorative reproductive medicine practitioners like Доктор Наоми Уиттакер consider sperm analysis “the single best snapshot into the body of a man just like cycle charting is for women,” it still has definitive drawbacks. Seminal fluid testing в одиночку cannot diagnose or even reliably predict infertility, though the more abnormal SFA parameters one has, the higher the likelihood of trouble conceiving. What’s more, SFA parameters only flag as “abnormal” when the results are in the 5th percentile or below, based on a 2010 World Health Organization laboratory manual [4]. (Of note: today’s 5th percentile is dramatically lower than yesteryear’s 5th percentile due to massive reductions in sperm counts over the last five decades.)
What about cases of “unexplained infertility” with normal sperm analysis results?
Perhaps most importantly, as отметил in a 2017 commentary on sperm DNA fragmentation testing guidelines, up to 30% of infertile couples may have a normal semen analysis and “no obvious reason for their inability to conceive” (emphasis added) [5]. Sperm DNA fragmentation testing may help reduce the number of infertility cases deemed “unexplained.” Here’s how.
Could sperm DNA fragmentation testing hold the key to explaining unexplained infertility?
Normal sperm DNA (deoxyribonucleic acid, the genetic material of the cell) is необходимо for successful fertilization, implantation, and embryo development [6]. Sperm are formed inside the testicles (also known as testes), and multiple causes may lead to sperm DNA damage inside the testicles или anywhere along the male reproductive tract. Sperm DNA damage occurring внутри the testes may result from problems with sperm maturation or from problems with apoptosis (programmed cell death to prevent the formation of defective sperm). Sperm DNA damage sustained elsewhere in the male reproductive tract occurs from оксидативный стресс (an imbalance between antioxidants and free radicals in the body).
Known risk factors for sperm DNA fragmentation (whether of single strand or double strand DNA) include age, varicoceles, genitourinary infections such as prostatitis, reproductive cancer, obesity, smoking, alcohol, testicular hyperthermia (caused by physical abnormalities or by exposure to high heat as from frequent sauna use or occupations like firefighting, welding, etc.), and, as recently discovered, metabolic syndrome or insulin resistance [7].
Known risk factors for sperm DNA fragmentation (whether of single strand or double strand DNA) include age, varicoceles, genitourinary infections such as prostatitis, reproductive cancer, obesity, smoking, alcohol, testicular hyperthermia (caused by physical abnormalities or by exposure to high heat as from frequent sauna use or occupations like firefighting, welding, etc.), and, as recently discovered, metabolic syndrome or insulin resistance.
For over 25 years now, исследование has linked sperm DNA damage with reduced fertility, including increased failure of assisted reproductive technologies (ART) such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and intrauterine insemination (IUI), and recurrent miscarriages.
Sperm DNA fragmentation testing isn’t for every (infertile male) body
В своем guideline for the diagnosis and treatment of male infertility, the Американское общество репродуктивной медицины (ASRM)—the “leading organization worldwide dedicated to to the advancement and practice of the science of reproductive medicine”—не encourage routine sperm DNA fragmentation testing in male infertility workups.
Specifically for couples who experience recurrent miscarriage, though, ASRM recommends, “For couples with [recurrent pregnancy loss] RPL, men should be evaluated with karyotype (Expert Opinion) and sperm DNA fragmentation.”
Why ASRM only recommends sperm DNA fragmentation testing for couples with recurrent miscarriage…
ASRM’s rationale for both recommendations is found later in the document. Importantly, ASRM acknowledges that “Sperm DNA fragmentation may adversely affect the outcome of [assisted reproductive technologies] ART treatments [such as in vitro fertilization, IVF, or intracytoplasmic sperm injection, ICSI] as well as attempts at natural fertility, including an increased miscarriage rate.”
Still, ASRM notes, “Since there are no prospective studies that have directly evaluated the impact of DNA fragmentation testing on the clinical management of infertile couples (i.e., that the fertility outcomes of those who had testing are different from those who did not), this assay should not be routinely performed in the initial evaluation of the infertile male.”
…even though some causes of sperm DNA fragmentation are “easily reversible”
ASRM hints at the potential relevance of sperm DNA fragmentation testing specifically for couples with unexplained infertility. They note “However, spermDNA fragmentation may affect male fertility, and some causes of abnormal sperm DNA fragmentation (such as antidepressant use or the presence of genitourinary infection) are easily reversible, whereas others may be managed by use of testicular sperm in selected cases.”
ASRM notes “However, spermDNA fragmentation may affect male fertility, and some causes of abnormal sperm DNA fragmentation (such as antidepressant use or the presence of genitourinary infection) are easily reversible, whereas others may be managed by use of testicular sperm in selected cases.”
Urologic and reproductive specialists produced their own evidence-based clinical guidelines
Back in 2016, leading urologists (Agarwal et al., 2016) and researchers from across the globe released guidelines for who specifically might benefit from sperm DNA fragmentation (SDF) testing [6]. While ASRM only recommends SDF testing for couples with recurrent miscarriage, Agarwal et al. identified multiple scenarios in which SDF testing would be appropriate based on decades of research.
These include men with varicoceles (whether found on physical exam or via imaging), couples with recurrent miscarriage, couples planning to undergo IUI or IVF, couples with recurrent failed IUI or IVF procedures, couples with recurrent miscarriage after ICSI procedures, men with known environmental exposure to causes of SDF, and couples with unexplained infertility.
In 2020, an even larger group of experts (Agarwal et al., 2020) released updated guidelines with even newer research supporting SDF testing in the above clinical scenarios [8]. They also reviewed the pros and cons of the four main kinds of SDF tests: TUNEL, Comet, SCSA, and SCD. Furthermore, they summarized dozens of research studies on the different risk factors for “high” SDF, with a suggested cutoff value of 20%-30% fragmented DNA in a sperm sample as “high” SDF, depending on the study.
Then in 2021, Agarwal et al., 2021 issued an additional review of the similarities and differences between their 2020 clinical practice guideline recommendations and those of Esteves et al, 2020 [2] [9]. The only significant difference between the two was that Agarwal et al. summarized the evidence about more ways to improve high SDF, including oral antioxidant therapy, recurrent ejaculation, varicocelectomy, lifestyle modifications (including quitting smoking and alcohol, losing weight, managing diabetes, and more), among others.
Итоги
As Natural Womanhood has been reporting for years, “unexplained” infertility это не всегда unexplainable. Restorative reproductive medicine practitioners are trained to dig for the root causes of reproductive issues, including infertility. Sperm DNA fragmentation testing may represent an additional tool in their arsenal to treat, rather than override, male infertility and restore health in both men and women.
Ссылки
[1] Leslie SW, Soon-Sutton TL, Khan MAB. Male Infertility. [Updated 2024 Feb 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK562258/
[2] Agarwal A, Farkouh A, Parekh N, Zini A, Arafa M, Kandil H, Tadros N, Busetto GM, Ambar R, Parekattil S, Boitrelle F, Sallam H, Jindal S, Ko E, Simopoulou M, Park HJ, Sadighi MA, Saleh R, Ramsay J, Martinez M, Elbardisi H, Alvarez J, Colpi G, Gosalvez J, Evenson D, Shah R. Sperm DNA Fragmentation: A Critical Assessment of Clinical Practice Guidelines. World J Mens Health. 2022 Jan;40(1):30-37. doi: 10.5534/wjmh.210056. Epub 2021 Apr 21. PMID: 33988000; PMCID: PMC8761233.
[3] Ding J, Shang X, Zhang Z, Jing H, Shao J, Fei Q, Rayburn ER, Li H. FDA-approved medications that impair human spermatogenesis. Oncotarget. 2017 Feb 7;8(6):10714-10725. doi: 10.18632/oncotarget.12956. PMID: 27801671; PMCID: PMC5354694.
[4] Boitrelle F, Shah R, Saleh R, Henkel R, Kandil H, Chung E, Vogiatzi P, Zini A, Arafa M, Agarwal A. The Sixth Edition of the WHO Manual for Human Semen Analysis: A Critical Review and SWOT Analysis. Life (Basel). 2021 Dec 9;11(12):1368. doi: 10.3390/life11121368. PMID: 34947899; PMCID: PMC8706130.
[5] Tadros NN, Sabanegh E Jr. Commentary on clinical utility of sperm DNA fragmentation testing: Practice Recommendations of Sperm DNA Fragmentation Testing: Expert Commentaries by Invited Authors and Replies by Guest Editors Contributors from North America. Transl Androl Urol. 2017 Sep;6(Suppl 4):S374-S376. doi: 10.21037/tau.2017.01.16. PMID: 29082147; PMCID: PMC5643698.
[6] Agarwal A, Majzoub A, Esteves SC, Ko E, Ramasamy R, Zini A. Clinical utility of sperm DNA fragmentation testing: practice recommendations based on clinical scenarios. Transl Androl Urol. 2016 Dec;5(6):935-950. doi: 10.21037/tau.2016.10.03. PMID: 28078226; PMCID: PMC5182232.
References Continued…
[7] Rong, J., Leng, X., Jiang, K. et al. Systemic impacts of diabetes on spermatogenesis and intervention strategies: multilayered mechanism analysis and cutting-edge therapeutic approaches. Reprod Biol Endocrinol 23, 122 (2025). https://doi.org/10.1186/s12958-025-01454-4
[8] Agarwal A, Majzoub A, Baskaran S, Panner Selvam MK, Cho CL, Henkel R, Finelli R, Leisegang K, Sengupta P, Barbarosie C, Parekh N, Alves MG, Ko E, Arafa M, Tadros N, Ramasamy R, Kavoussi P, Ambar R, Kuchakulla M, Robert KA, Iovine C, Durairajanayagam D, Jindal S, Shah R. Sperm DNA Fragmentation: A New Guideline for Clinicians. World J Mens Health. 2020 Oct;38(4):412-471. doi: 10.5534/wjmh.200128. Epub 2020 Aug 6. PMID: 32777871; PMCID: PMC7502318.
[9] Esteves SC, Zini A, Coward RM, Evenson DP, Gosálvez J, Lewis SEM, Sharma R, Humaidan P. Sperm DNA fragmentation testing: Summary evidence and clinical practice recommendations. Andrologia. 2021 Mar;53(2):e13874. doi: 10.1111/and.13874. Epub 2020 Oct 27. PMID: 33108829; PMCID: PMC7988559.
