Table II.
Studies associating telomere length with male infertility.
| Authors/(Refs.) | Sex | Association with infert | Relative TL | Method | Population no. | Population age (years) | Population country | Sample type | Infertility factor | Conclusions |
|---|---|---|---|---|---|---|---|---|---|---|
| Baird et al, 2006 (75) | M | + | Sh | RT-PCR, (TRF) (STELA) | (n=54), 10 samples analyzed | ~35 | UK | Sperm (semen) | C | • Human telomere truncation events occur with frequency of 3.6%, while 96.4% of telomeres at any one chromosomal end are normal • Telomere truncation in the male germline may contribute to the observed levels of aneuploidy (up to 1.55%) in human sperm range • Telomere truncation can limit replicative potential, and the subsequent loss of end capping can result in genomic instability |
| Moskovtsev et al, 2010 (74) | M | + | Disrupted T-T ixns | Q-F1SH | -(n=20), DNA damaged sperm | N/A | CA | Sperm (semen) | C | • Sperm DNA damage is correlated with disruption of the normal T-T interactions leading to possible loss of the looped chromosome configuration |
| Prescott et al, 2012 (73) | M | + | Ln | RT-PCR | N/A | N/A | US | Genomic DNA | Age | • + correlation for participant's relative LTL with paternal age at birth • Inverse relationship between maternal age at birth and relative LTL |
| Turner and Hartshorne, 2013 (39) | M/F | NIA, M | Q-FISH Sh, F | -(n=45), M -(n=32), F |
21-49 25-42 |
UK | Sperm (semen), oocytes | C | • STL not crucial for male fert • TL reset in embryo after fertilization • TL shortening during human oocyte maturation • Oocyte-induced sperm telomere DNA modification, via a recombination-based TL increase towards the blastocyst stage |
|
| Ferlin et al, 2013 (71) | M | + | Sh | RT-PCR | -(n=20), oligozoosp | 18-19 | IT | Sperm (DGC), leukocytes | Oligo zoosp | • + correlation between STL and LTL • Shorter STL in oligozoosp M • + correlation between STL and total SC • + correlation between STL and paternal age at conception |
| Thilagavathi et al, 2013 (72) | M | + | Sh | RT-PCR | -(n=32), idiopathic infert -(n=25), fert |
N/A | IN | Sperm (semen) | I MI | • Infert men had shorter STL • STL is not correlated with semen parameters |
| J0rgensen et al, 2013 (87) | M | − | N/A | Q-FISH | -(n=6), younger -(n=6), older |
31-40 43-60 |
DK | Testicular Bx | Age | • There is no difference in TL during spermatogenesis between older and younger men |
| Yan et al, 2014 (70) | M | + | Sh | RT-PCR | -(n=137), infert, non-OA -(n=125), infert, oligozoosp -(n=318), infert, normal SC |
24-42 | CN | Sperm (semen) | Azoosp | • Genetic variants such as polymorphisms in telomere- associated pathway genes affect TL and chromosomal stability • The polymorphism TERT rs2736100 was associated with male infert risk (adjusted odds ratio (OR)=0.66, 95% Cl: 0.47-0.92; Ptrend=0.011) • The polymorphism TEP1 rsl713449 was positively associated with risk of male infert (adjusted OR=1.39, 95% Cl: 1.20-1.62; Ptrend<0.001) |
| Reigh-Viader et al, 2014 (69) | M | + | Sh | TERRA and telomerase distribution | -(n=4), NO deficiency of spermatozoa due to unknown causes, seeking fert treatment -(n=l), fert, undergoing vasectomy at the time of tissue retrieval -CNTL, HeLa cells with known TL |
ES | Testicular Bx | Azoosp | • Telomere homeostasis is impaired in infert patients, shown by a decrease in TERRA levels and an alteration of the TERRA-protein component of telomerase telomeric association in primary spermatocytes. • Telomere structure and homeostasis in germ cells is compromised in infert individuals |
|
| Yang et al, 2015 (68) | M | + | Sh | RT-PCR | -(n=418), couples, idiopathic infert (IVF) | 30.3±4.0 | CN | Sperm (DGC) | C | • No significant correlation between TL and paternal age at the time of conception (rp=0.18) • + correlation between STL and total SC • + correlation between STL and paternal/maternal ages at conception • + correlation between STL and embryo quality |
| Yang et al, 2015 (84) | M | + | Sh | RT-PCR | -105 M undergoing IVF | 31.2±6.1 | CN | Sperm (DGC) | Oligo zoosp | • + correlated between STL and SC • Longer TL sperm selected for ART Tx |
| Liu et al, 2015 (82) | M | + | Sh | RT-PCR | -(n=126), idiopathic infert -(n=138), fert |
23-57 | CN | Sperm (semen) | SM/SC | • The relative sperm mean TL of infertile men was significantly shorter than the relative TL of fertile men (2.894±0.115 vs. 4.016±0.603, P=5.097×10 5) • TL is associated with SC and SM |
| Antunes et al, 2015 (83) | M | + | Lg | SCT-qPCR | -(n=10), IVF | 32-47 | US | Sperm (SU) | Age | • Longer and more variable STL associated with older age |
| Rocca et al, 2016 (81) | M | + | Sh | RT-PCR | -(n=100), normozoosp | 34.0±8.6 | IT | Sperm (DGC) | SM | • Positive association between STL and progressive motility, vitality, and protamination in normozoosp men • Shorter STL is associated with lower SM |
| Cariati et al, 2016 (79) | M | + | Sh | RT-PCR | -(n=19), oligozoosp -(n=54), normozoosp |
39.4±5.5 | IT | Sperm (DGC) | Oligo zoosp | • STL is negatively correlated with sperm diploidy. but positively correlated with SC • Oligozoosp men have shorter STL |
| Mishra et al, 2016 (80) | M | + | Sh | RT-PCR | -(n=112), infert -(n=102), fert |
31.71±4.45 32.22±4.0 |
IN | Sperm (semen) | C | • STL is shorter in infert males • Oxidative stress reduces STL |
| Biron-Shental et al, 2017 (76) | M | + | Sh | Q-FISH | -(n=16), sub-fert, ICSI -(n=10), fert |
37.4±5.0 36.5±7.0 |
IT | Sperm (semen) | C | • Shorter STL in sub-fertile men. Sperm from sub-fertile men has a higher percentage of telomere aggregates and lower TERT expressions |
| Vecoli et al, 2017 (77) | M | + | Ln | RT-PCR | -(n=112), normosp -(n=112), residents of unexposed areas |
18-42 | IT | Sperm (semen) | C | • Young male residents in areas with high environmental exposure had a significant increase in TL of their sperm |
| Lafuente et al, 2017 (78) | M | + | Sh | Q-FISH | (n=30) | N/A | ES | Sperm (pre/post DGC and SU) | C | • Exposure of sperm to increasing concentrations of H2O2 is associated with telomere shortening • STL of male partners of couples with primary infertility is lower than that of male partners of fertile couples • STL is the same pre/post sperm selection (either DGC and SU) • STL is the same in DGC and SU-selected sperm with respect to unselected sperm • STL is negatively correlated with SM and sperm concentration |
| Heidary et al, 2018 (86) | M | + | Sh | RT-PCR | -(n=30) idiopathic NOA -(n=30), HC, fert | 35.4±4.52 | IR | L | Azoosp | • Association between LTL shortening in a population of Iranian infert men affected by idiopathic azoosp |
| Yang et al, 2018 (85) | Male | + | Sh | RT-PCR | -(n=270), normosp -(n=247), OA -(n=349), non-OA |
25-38 | CN | L | Azoosp | • Significantly shorter relative LTL in men with NOA compared to those with OA or to the normozoosp controls (odds ratio [OR] 0.81,95% [Cl] 0.64-0.98 vs. OR0.92,95% Cl 0.70-1.24 vs. OR 0.99, 95% Cl 0.83-1.22), respectively) • Shorter telomeres are significantly associated with higher risk for NOA • Shorter LTL is strongly associated with NOA and defective spermatogenesis |
(+), positive; (−), negative; Assoc, association; ART, assisted reproductive techniques; Bx, biopsy; C, combination; CA, Canada; CI, confidence interval; CN, China; CNTL, control; DGC, density gradient centrifugation; DK, Denmark; ES, Spain; F, female; G, granulosa cells; ICSI, intracytoplasmic sperm injection; IMI, idiopathic male infertility; IN, India; IR, Iran; IT, Italy; IVF, in vitro fertilization; L, leukocytes; LTL, leukocyte telomere length; Ln, longer; M, male; N/A, not applicable; NO, non-obstructive; NOA, non-obstructive azoospermia; OA, obstructive azoospermia; OR, odds ratio; Q-FISH, quantitative fluorescent in situ hybridization; RT-PCR, reverse transcription-polymerase chain reaction; SC, sperm count; SCT-qPCR, stem cell transplantation quantitative polymerase chain reaction; SM, sperm motility; STL, sperm telomere length; SU, swim up; Sh, shorter; TEP1, telomerase-associated protein 1; TERRA, telomere repeat-containing RNA; TERT, telomerase reverse transcriptase; TL, telomere length; TRF, terminal restriction fragments; Tx, treatment; UK, United Kingdom; US, United States; azoosp, azoospermia; fert, fertile/fertility; infert, infertile/infertility; oligo(zoo)sp, oligo(zoo)spermia.