Infertility in the Aging Male

Andrology and Infertility (L Lipshultz, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Andrology and Infertility

Abstract

Purpose of Review

In many countries, the average age of paternity is rising. The negative effect of older age on fertility in women is well documented; however, less is known about the impact of paternal age on fecundity. In this review, we summarize the current knowledge of how paternal age affects semen parameters, reproductive success, and offspring health.

Recent Findings

Contemporary evidence confirms that aged men have worse semen parameters, including overall negative changes in sperm genetics. Reproductive outcomes with unassisted pregnancy tend to be worse with older fathers. While most current studies of assisted pregnancy do show a negative effect of paternal age, there are some conflicting results. Studies continue to show an overall increased risk of health problems, particularly neuropsychiatric conditions, in the offspring of older men.

Summary

While men can often maintain fertility potential throughout a lifetime, increasing evidence indicates worsening of semen parameters, including sperm genetics, and potentially worse reproductive success. Older men should also be counseled on their offspring’s possible increased risk of certain medical conditions.

Keywords

Male infertility Aging male Advanced paternal age 

Notes

Compliance with Ethical Standards

Conflict of Interest

Daniel J. Mazur declares no potential conflicts of interest.

Larry I. Lipshultz is a consultant for AbbVie, Lipocine, Aytu Bioscience, and Endo Pharmaceuticals and a speaker for American Medical Systems and Endo Pharmaceuticals.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Sauer MV. Reproduction at an advanced maternal age and maternal health. Fertil Steril. 2015;103(5):1136–43.  https://doi.org/10.1016/j.fertnstert.2015.03.004.CrossRefPubMedGoogle Scholar
  2. 2.
    Seymour FI, Duffy C, Koerner A. A case of authenticated fertility in a man, aged 94. JAMA. 1935;105(18):1423–4.CrossRefGoogle Scholar
  3. 3.
    Toriello HV, Meck JM, Professional P, Guidelines C. Statement on guidance for genetic counseling in advanced paternal age. Genet Med. 2008;10(6):457–60.  https://doi.org/10.1097/GIM.0b013e318176fabb.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    •• Khandwala YS, Zhang CA, Lu Y, Eisenberg ML. The age of fathers in the USA is rising: an analysis of 168 867 480 births from 1972 to 2015. Hum Reprod. 2017;32(10):2110–6.  https://doi.org/10.1093/humrep/dex267. A retrospective study demonstrating a mean increase in paternal age of 3.5 years (from 27.4 to 30.9 years) within the USA between 1972 and 2015. CrossRefPubMedGoogle Scholar
  5. 5.
    Bray I, Gunnell D, Davey SG. Advanced paternal age: how old is too old? J Epidemiol Community Health. 2006;60(10):851–3.  https://doi.org/10.1136/jech.2005.045179.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Selvin E, Burnett AL, Platz EA. Prevalence and risk factors for erectile dysfunction in the US. Am J Med. 2007;120(2):151–7.  https://doi.org/10.1016/j.amjmed.2006.06.010.CrossRefPubMedGoogle Scholar
  7. 7.
    Brewis A, Meyer M. Marital coitus across the life course. J Biosoc Sci. 2005;37(4):499–518.CrossRefPubMedGoogle Scholar
  8. 8.
    Agarwal A, Gupta S, Du Plessis S, Sharma R, Esteves SC, Cirenza C, et al. Abstinence time and its impact on basic and advanced semen parameters. Urology. 2016;94:102–10.  https://doi.org/10.1016/j.urology.2016.03.059.CrossRefPubMedGoogle Scholar
  9. 9.
    Travison TG, Vesper HW, Orwoll E, Wu F, Kaufman JM, Wang Y, et al. Harmonized reference ranges for circulating testosterone levels in men of four cohort studies in the United States and Europe. J Clin Endocrinol Metab. 2017;102(4):1161–73.  https://doi.org/10.1210/jc.2016-2935.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. 2002;87(2):589–98.  https://doi.org/10.1210/jcem.87.2.8201.CrossRefPubMedGoogle Scholar
  11. 11.
    Bhasin S, Pencina M, Jasuja GK, Travison TG, Coviello A, Orwoll E, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab. 2011;96(8):2430–9.  https://doi.org/10.1210/jc.2010-3012.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Corona G, Isidori AM, Buvat J, Aversa A, Rastrelli G, Hackett G, et al. Testosterone supplementation and sexual function: a meta-analysis study. J Sex Med. 2014;11(6):1577–92.  https://doi.org/10.1111/jsm.12536.CrossRefPubMedGoogle Scholar
  13. 13.
    Cunningham GR, Stephens-Shields AJ, Rosen RC, Wang C, Bhasin S, Matsumoto AM, et al. Testosterone treatment and sexual function in older men with low testosterone levels. J Clin Endocrinol Metab. 2016;101(8):3096–104.  https://doi.org/10.1210/jc.2016-1645.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    •• Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, et al. Effects of testosterone treatment in older men. N Engl J Med. 2016;374(7):611–24.  https://doi.org/10.1056/NEJMoa1506119. Part of the Testosterone Trials, this prospective study showed that treatment of symptomatic hypogonadism in older men showed benefit with respect to sexual function, mood, and depressive symptoms. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013;173(15):1465–6.  https://doi.org/10.1001/jamainternmed.2013.6895.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ko EY, Siddiqi K, Brannigan RE, Sabanegh ES Jr. Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association. J Urol. 2012;187(3):973–8.  https://doi.org/10.1016/j.juro.2011.10.137.CrossRefPubMedGoogle Scholar
  17. 17.
    World Health Organization Task Force on methods for the regulation of male fertility. Contraceptive efficacy of testosteroneinduced azoospermia in normal men. Lancet. 1990;336(8721):955–9.Google Scholar
  18. 18.
    Turek PJ, Williams RH, Gilbaugh JH 3rd, Lipshultz LI. The reversibility of anabolic steroid-induced azoospermia. J Urol. 1995;153(5):1628–30.CrossRefPubMedGoogle Scholar
  19. 19.
    Samplaski MK, Loai Y, Wong K, Lo KC, Grober ED, Jarvi KA. Testosterone use in the male infertility population: prescribing patterns and effects on semen and hormonal parameters. Fertil Steril. 2014;101(1):64–9.  https://doi.org/10.1016/j.fertnstert.2013.09.003.CrossRefPubMedGoogle Scholar
  20. 20.
    Hsieh TC, Pastuszak AW, Hwang K, Lipshultz LI. Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol. 2013;189(2):647–50.  https://doi.org/10.1016/j.juro.2012.09.043.CrossRefPubMedGoogle Scholar
  21. 21.
    •• Wenker EP, Dupree JM, Langille GM, Kovac J, Ramasamy R, Lamb D, et al. The use of HCG-based combination therapy for recovery of spermatogenesis after testosterone use. J Sex Med. 2015;12(6):1334–7.  https://doi.org/10.1111/jsm.12890. This was a restrospective study of 49 men who had azoospermia or severe oligospermia while taking testosterone. They were given human chorionic gonadotropin (HCG) supplementated with clomiphene, tamoxifen, anastrazole, or recombinent follicle-stimulating hormone (or combination) with improvements in sperms counts seen in 47 (95.9%) of the men. CrossRefPubMedGoogle Scholar
  22. 22.
    •• Kohn TP, Louis MR, Pickett SM, Lindgren MC, Kohn JR, Pastuszak AW, et al. Age and duration of testosterone therapy predict time to return of sperm count after human chorionic gonadotropin therapy. Fertil Steril. 2017;107(2):351–7 e1.  https://doi.org/10.1016/j.fertnstert.2016.10.004. This study retrospectively examined 66 men who presented for an infertility evaluation after testosterone use and were placed on a human chorionic gonadotropin (HCG) + SERM regimen. The authors demonstrated that increasing age and duration of testosterone use reduced the likelihood of recovery of sperm in the ejaculate at both 6 and 12 months. Only 64.8% of azoospermic men achieved a total motile sperm count > 5 million sperm by 12 months. CrossRefPubMedGoogle Scholar
  23. 23.
    Blanker MH, Bosch JL, Groeneveld FP, Bohnen AM, Prins A, Thomas S, et al. Erectile and ejaculatory dysfunction in a community-based sample of men 50 to 78 years old: prevalence, concern, and relation to sexual activity. Urology. 2001;57(4):763–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Avellino G, Theva D, Oates RD. Common urologic diseases in older men and their treatment: how they impact fertility. Fertil Steril. 2017;107(2):305–11.  https://doi.org/10.1016/j.fertnstert.2016.12.008.CrossRefPubMedGoogle Scholar
  25. 25.
    Wang C, Swerdloff RS. Limitations of semen analysis as a test of male fertility and anticipated needs from newer tests. Fertil Steril. 2014;102(6):1502–7.  https://doi.org/10.1016/j.fertnstert.2014.10.021.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kidd SA, Eskenazi B, Wyrobek AJ. Effects of male age on semen quality and fertility: a review of the literature. Fertil Steril. 2001;75(2):237–48.CrossRefPubMedGoogle Scholar
  27. 27.
    •• Johnson SL, Dunleavy J, Gemmell NJ, Nakagawa S. Consistent age-dependent declines in human semen quality: a systematic review and meta-analysis. Ageing Res Rev. 2015;19:22–33.  https://doi.org/10.1016/j.arr.2014.10.007. A meta-analysis demonstrating a decline in semen parameters (volume, motility, morphology) and an increase in DNA fragmenation as men age. CrossRefPubMedGoogle Scholar
  28. 28.
    Begueria R, Garcia D, Obradors A, Poisot F, Vassena R, Vernaeve V. Paternal age and assisted reproductive outcomes in ICSI donor oocytes: is there an effect of older fathers? Hum Reprod. 2014;29(10):2114–22.  https://doi.org/10.1093/humrep/deu189.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Garcia-Ferreyra J, Luna D, Villegas L, Romero R, Zavala P, Hilario R, et al. High aneuploidy rates observed in embryos derived from donated oocytes are related to male aging and high percentages of sperm DNA fragmentation. Clin Med Insights Reprod Health. 2015;9:21–7.  https://doi.org/10.4137/CMRH.S32769.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Moskovtsev SI, Willis J, Mullen JB. Age-related decline in sperm deoxyribonucleic acid integrity in patients evaluated for male infertility. Fertil Steril. 2006;85(2):496–9.  https://doi.org/10.1016/j.fertnstert.2005.05.075.CrossRefPubMedGoogle Scholar
  31. 31.
    Das M, Al-Hathal N, San-Gabriel M, Phillips S, Kadoch IJ, Bissonnette F, et al. High prevalence of isolated sperm DNA damage in infertile men with advanced paternal age. J Assist Reprod Genet. 2013;30(6):843–8.  https://doi.org/10.1007/s10815-013-0015-0.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Brahem S, Mehdi M, Elghezal H, Saad A. Detection of DNA fragmentation and meiotic segregation in human with isolated teratozoospermia. J Assist Reprod Genet. 2011;28(1):41–8.  https://doi.org/10.1007/s10815-010-9482-8.CrossRefPubMedGoogle Scholar
  33. 33.
    • Garcia-Ferreyra J, Hilario R, Duenas J. High percentages of embryos with 21, 18 or 13 trisomy are related to advanced paternal age in donor egg cycles. JBRA Assist Reprod. 2018;  https://doi.org/10.5935/1518-0557.20180004. This was a restropective review of IVF/ICSI cycles with PGD which demonstrated that the sperm of aged men had higher rates of DNA fragmentation and aneuploidy. Additonally, there were significantly elevated rates of global aneuploidy and trisomy 21, 18, and 12 in embryos of fathers of advanced paternal age.
  34. 34.
    Cocuzza M, Athayde KS, Agarwal A, Sharma R, Pagani R, Lucon AM, et al. Age-related increase of reactive oxygen species in neat semen in healthy fertile men. Urology. 2008;71(3):490–4.  https://doi.org/10.1016/j.urology.2007.11.041.CrossRefPubMedGoogle Scholar
  35. 35.
    Sabeti P, Pourmasumi S, Rahiminia T, Akyash F, Talebi AR. Etiologies of sperm oxidative stress. Int J Reprod Biomed (Yazd). 2016;14(4):231–40.CrossRefGoogle Scholar
  36. 36.
    • Kaarouch I, Bouamoud N, Madkour A, Louanjli N, Saadani B, Assou S, et al. Paternal age: negative impact on sperm genome decays and IVF outcomes after 40 years. Mol Reprod Dev,  https://doi.org/10.1002/mrd.22963. 2018; In this study, 83 couples undergoing IVF for male factor infertility were evaluated. The sperm of older men demonstrated increased DNA fragmentation and aneuploidy rates compared to younger men. IVF outcomes were also worse in the older men.
  37. 37.
    Donate A, Estop AM, Giraldo J, Templado C. Paternal age and numerical chromosome abnormalities in human spermatozoa. Cytogenet Genome Res. 2016;148(4):241–8.  https://doi.org/10.1159/000446724.CrossRefPubMedGoogle Scholar
  38. 38.
    Wyrobek AJ, Eskenazi B, Young S, Arnheim N, Tiemann-Boege I, Jabs EW, et al. Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. Proc Natl Acad Sci U S A. 2006;103(25):9601–6.  https://doi.org/10.1073/pnas.0506468103.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Blackburn EH, Gall JG. A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. J Mol Biol. 1978;120(1):33–53.CrossRefPubMedGoogle Scholar
  40. 40.
    Ehrlenbach S, Willeit P, Kiechl S, Willeit J, Reindl M, Schanda K, et al. Influences on the reduction of relative telomere length over 10 years in the population-based Bruneck Study: introduction of a well-controlled high-throughput assay. Int J Epidemiol. 2009;38(6):1725–34.  https://doi.org/10.1093/ije/dyp273.CrossRefPubMedGoogle Scholar
  41. 41.
    Kimura M, Cherkas LF, Kato BS, Demissie S, Hjelmborg JB, Brimacombe M, et al. Offspring’s leukocyte telomere length, paternal age, and telomere elongation in sperm. PLoS Genet. 2008;4(2):e37.  https://doi.org/10.1371/journal.pgen.0040037.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Eisenberg DT, Hayes MG, Kuzawa CW. Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants. Proc Natl Acad Sci U S A. 2012;109(26):10251–6.  https://doi.org/10.1073/pnas.1202092109.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Jenkins TG, Aston KI, Cairns BR, Carrell DT. Paternal aging and associated intraindividual alterations of global sperm 5-methylcytosine and 5-hydroxymethylcytosine levels. Fertil Steril. 2013;100(4):945–51.  https://doi.org/10.1016/j.fertnstert.2013.05.039.CrossRefPubMedGoogle Scholar
  44. 44.
    Jenkins TG, Aston KI, Pflueger C, Cairns BR, Carrell DT. Age-associated sperm DNA methylation alterations: possible implications in offspring disease susceptibility. PLoS Genet. 2014;10(7):e1004458.  https://doi.org/10.1371/journal.pgen.1004458.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Kawai K, Harada T, Ishikawa T, Sugiyama R, Kawamura T, Yoshida A, et al. Parental age and gene expression profiles in individual human blastocysts. Sci Rep. 2018;8(1):2380.  https://doi.org/10.1038/s41598-018-20614-8.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Ford WC, North K, Taylor H, Farrow A, Hull MG, Golding J. Increasing paternal age is associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men. The ALSPAC Study Team (Avon Longitudinal Study of Pregnancy and Childhood). Hum Reprod. 2000;15(8):1703–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Hassan MA, Killick SR. Effect of male age on fertility: evidence for the decline in male fertility with increasing age. Fertil Steril. 2003;79(Suppl 3):1520–7.CrossRefPubMedGoogle Scholar
  48. 48.
    de La Rochebrochard E, Thonneau P. Paternal age >or=40 years: an important risk factor for infertility. Am J Obstet Gynecol. 2003;189(4):901–5.CrossRefGoogle Scholar
  49. 49.
    Mathieu C, Ecochard R, Bied V, Lornage J, Czyba JC. Cumulative conception rate following intrauterine artificial insemination with husband's spermatozoa: influence of husband’s age. Hum Reprod. 1995;10(5):1090–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Belloc S, Cohen-Bacrie P, Benkhalifa M, Cohen-Bacrie M, De Mouzon J, Hazout A, et al. Effect of maternal and paternal age on pregnancy and miscarriage rates after intrauterine insemination. Reprod BioMed Online. 2008;17(3):392–7.CrossRefPubMedGoogle Scholar
  51. 51.
    • McPherson NO, Zander-Fox D, Vincent AD, Lane M. Combined advanced parental age has an additive negative effect on live birth rates—data from 4057 first IVF/ICSI cycles. J Assist Reprod Genet. 2017;  https://doi.org/10.1007/s10815-017-1054-8. A retrospective review of 4057 first IVF cycles showing an additive negative effect on pregnancy and live birth rates when both parents are of advanced age.
  52. 52.
    de La Rochebrochard E, de Mouzon J, Thepot F, Thonneau P, French National IVFRA. Fathers over 40 and increased failure to conceive: the lessons of in vitro fertilization in France. Fertil Steril. 2006;85(5):1420–4.  https://doi.org/10.1016/j.fertnstert.2005.11.040.CrossRefGoogle Scholar
  53. 53.
    Robertshaw I, Khoury J, Abdallah ME, Warikoo P, Hofmann GE. The effect of paternal age on outcome in assisted reproductive technology using the ovum donation model. Reprod Sci. 2014;21(5):590–3.  https://doi.org/10.1177/1933719113506497.CrossRefPubMedGoogle Scholar
  54. 54.
    Whitcomb BW, Turzanski-Fortner R, Richter KS, Kipersztok S, Stillman RJ, Levy MJ, et al. Contribution of male age to outcomes in assisted reproductive technologies. Fertil Steril. 2011;95(1):147–51.  https://doi.org/10.1016/j.fertnstert.2010.06.039.CrossRefPubMedGoogle Scholar
  55. 55.
    Gu L, Zhang H, Yin L, Bu Z, Zhu G. Effect of male age on the outcome of in vitro fertilization: oocyte donation as a model. J Assist Reprod Genet. 2012;29(4):331–4.  https://doi.org/10.1007/s10815-012-9719-9.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012;488(7412):471–5.  https://doi.org/10.1038/nature11396.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Alio AP, Salihu HM, McIntosh C, August EM, Weldeselasse H, Sanchez E, et al. The effect of paternal age on fetal birth outcomes. Am J Mens Health. 2012;6(5):427–35.  https://doi.org/10.1177/1557988312440718.CrossRefPubMedGoogle Scholar
  58. 58.
    •• Urhoj SK, Andersen PK, Mortensen LH, Davey Smith G, Nybo Andersen AM. Advanced paternal age and stillbirth rate: a nationwide register-based cohort study of 944,031 pregnancies in Denmark. Eur J Epidemiol. 2017;32(3):227–34.  https://doi.org/10.1007/s10654-017-0237-z. A restrospective study based on a large sample from Denmark examing the impact of paternal age on the rate of stillbirth. It showed advanced paternal age, particularly in those > 40 years of age, was associated with an increased risk of still birth. CrossRefPubMedGoogle Scholar
  59. 59.
    Doamekpor LA, Amutah NN, Ramos LJ. Fathers matter: the role of paternal age in infant mortality. Am J Mens Health. 2014;8(2):175–82.  https://doi.org/10.1177/1557988313511492.CrossRefPubMedGoogle Scholar
  60. 60.
    Penrose LS. Parental age and mutation. Lancet. 1955;269(6885):312–3.CrossRefPubMedGoogle Scholar
  61. 61.
    Glaser RL, Broman KW, Schulman RL, Eskenazi B, Wyrobek AJ, Jabs EW. The paternal-age effect in Apert syndrome is due, in part, to the increased frequency of mutations in sperm. Am J Hum Genet. 2003;73(4):939–47.  https://doi.org/10.1086/378419.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Bunin GR, Needle M, Riccardi VM. Paternal age and sporadic neurofibromatosis 1: a case-control study and consideration of the methodologic issues. Genet Epidemiol. 1997;14(5):507–16.  https://doi.org/10.1002/(SICI)1098-2272(1997)14:5<507::AID-GEPI5>3.0.CO;2-Y.CrossRefPubMedGoogle Scholar
  63. 63.
    Blumsohn A, McAllion SJ, Paterson CR. Excess paternal age in apparently sporadic osteogenesis imperfecta. Am J Med Genet. 2001;100(4):280–6.CrossRefPubMedGoogle Scholar
  64. 64.
    Polednak AP. Paternal age in relation to selected birth defects. Hum Biol. 1976;48(4):727–39.PubMedGoogle Scholar
  65. 65.
    Herkrath AP, Herkrath FJ, Rebelo MA, Vettore MV. Parental age as a risk factor for non-syndromic oral clefts: a meta-analysis. J Dent. 2012;40(1):3–14.  https://doi.org/10.1016/j.jdent.2011.10.002.CrossRefPubMedGoogle Scholar
  66. 66.
    Su XJ, Yuan W, Huang GY, Olsen J, Li J. Paternal age and offspring congenital heart defects: a national cohort study. PLoS One. 2015;10(3):e0121030.  https://doi.org/10.1371/journal.pone.0121030.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Zhu JL, Madsen KM, Vestergaard M, Olesen AV, Basso O, Olsen J. Paternal age and congenital malformations. Hum Reprod. 2005;20(11):3173–7.  https://doi.org/10.1093/humrep/dei186.CrossRefPubMedGoogle Scholar
  68. 68.
    Crane E, Morris JK. Paternal age and birth defects: how strong is the association. Hum Reprod. 2007;22(8):2349–50.  https://doi.org/10.1093/humrep/dem134.CrossRefPubMedGoogle Scholar
  69. 69.
    Nybo Andersen AM, Urhoj SK. Is advanced paternal age a health risk for the offspring? Fertil Steril. 2017;107(2):312–8.  https://doi.org/10.1016/j.fertnstert.2016.12.019.CrossRefPubMedGoogle Scholar
  70. 70.
    •• Urhoj SK, Raaschou-Nielsen O, Hansen AV, Mortensen LH, Andersen PK, Nybo Andersen AM. Advanced paternal age and childhood cancer in offspring: a nationwide register-based cohort study. Int J Cancer. 2017;140(11):2461–72.  https://doi.org/10.1002/ijc.30677. This was a retrospective study examining the Danish health registries from 1978 to 2010. It showed a 13% increased hazard ratio for acute lymphoblastic leukemia (ALL) for every 5-year increase in paternal age. CrossRefPubMedGoogle Scholar
  71. 71.
    • Sergentanis TN, Thomopoulos TP, Gialamas SP, Karalexi MA, Biniaris-Georgallis SI, Kontogeorgi E, et al. Risk for childhood leukemia associated with maternal and paternal age. Eur J Epidemiol. 2015;30(12):1229–61.  https://doi.org/10.1007/s10654-015-0089-3. A meta-analysis examing the risk of childhood leukemias associated with advanced parental age. It demonstrated that both older maternal and paternal ages were associated with an increased risk of acute lymphoblastic leukemia (ALL) in their offspring. It also showed that children of mothers at the extremes of both ends of age and younger fathers had an increased risk for acute myeloid leukemia (AML). CrossRefPubMedGoogle Scholar
  72. 72.
    Heck JE, Lombardi CA, Meyers TJ, Cockburn M, Wilhelm M, Ritz B. Perinatal characteristics and retinoblastoma. Cancer Causes Control. 2012;23(9):1567–75.  https://doi.org/10.1007/s10552-012-0034-7.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    •• Levine H, Keinan-Boker L, Leiba A, Derazne E, Rais A, Kark JD. Paternal age and risk of testicular germ cell tumors: a cohort study of 1,000,000 men. Andrology. 2017;5(6):1124–30.  https://doi.org/10.1111/andr.12422. A retrospective analysis of a large population-based cohort that demonstrated an increased risk of testicular germ cell tumors, especially seminoma, in the male offspring of younger fathers. CrossRefPubMedGoogle Scholar
  74. 74.
    McGrath JJ, Petersen L, Agerbo E, Mors O, Mortensen PB, Pedersen CB. A comprehensive assessment of parental age and psychiatric disorders. JAMA Psychiatry. 2014;71(3):301–9.  https://doi.org/10.1001/jamapsychiatry.2013.4081.CrossRefPubMedGoogle Scholar
  75. 75.
    D'Onofrio BM, Rickert ME, Frans E, Kuja-Halkola R, Almqvist C, Sjolander A, et al. Paternal age at childbearing and offspring psychiatric and academic morbidity. JAMA Psychiatry. 2014;71(4):432–8.  https://doi.org/10.1001/jamapsychiatry.2013.4525.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Fountoulakis KN, Gonda X, Siamouli M, Panagiotidis P, Moutou K, Nimatoudis I, Kasper S Paternal and maternal age as risk factors for schizophrenia: a case-control study. Int J Psychiatry Clin Pract. 2017:1–7.  https://doi.org/10.1080/13651501.2017.1391292.
  77. 77.
    Merikangas AK, Calkins ME, Bilker WB, Moore TM, Gur RC, Gur RE. Parental age and offspring psychopathology in the Philadelphia Neurodevelopmental Cohort. J Am Acad Child Adolesc Psychiatry. 2017;56(5):391–400.  https://doi.org/10.1016/j.jaac.2017.02.004.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Fond G, Godin O, Boyer L, Llorca PM, Andrianarisoa M, Brunel L, et al. Advanced paternal age is associated with earlier schizophrenia onset in offspring. Results from the national multicentric FACE-SZ cohort. Psychiatry Res. 2017;254:218–23.  https://doi.org/10.1016/j.psychres.2017.04.002.CrossRefPubMedGoogle Scholar
  79. 79.
    • Hvolgaard Mikkelsen S, Olsen J, Bech BH, Obel C. Parental age and attention-deficit/hyperactivity disorder (ADHD). Int J Epidemiol. 2017;46(2):409–20.  https://doi.org/10.1093/ije/dyw073. Using a large Danish population cohort, the authors retrospectively reviewed the risk of parental age on ADHD. When comparing full siblings, there was increased risk of ADHD with younger mothers, but no association with paternal age. PubMedGoogle Scholar
  80. 80.
    Saha S, Barnett AG, Foldi C, Burne TH, Eyles DW, Buka SL, et al. Advanced paternal age is associated with impaired neurocognitive outcomes during infancy and childhood. PLoS Med. 2009;6(3):e40.  https://doi.org/10.1371/journal.pmed.1000040.CrossRefPubMedGoogle Scholar
  81. 81.
    Gajos JM, Beaver KM. The role of paternal age in the prediction of offspring intelligence. J Genet Psychol. 2017;178(6):319–33.  https://doi.org/10.1080/00221325.2017.1377678.CrossRefPubMedGoogle Scholar
  82. 82.
    Janecka M, Rijsdijk F, Rai D, Modabbernia A, Reichenberg A. Advantageous developmental outcomes of advancing paternal age. Transl Psychiatry. 2017;7(6):e1156.  https://doi.org/10.1038/tp.2017.125.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Eisenberg DT, Kuzawa CW. Commentary: The evolutionary biology of the paternal age effect on telomere length. Int J Epidemiol. 2013;42(2):462–5.  https://doi.org/10.1093/ije/dyt027.CrossRefPubMedGoogle Scholar
  84. 84.
    Eisenberg ML, Li S, Behr B, Cullen MR, Galusha D, Lamb DJ, et al. Semen quality, infertility and mortality in the USA. Hum Reprod. 2014;29(7):1567–74.  https://doi.org/10.1093/humrep/deu106.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    •• Eisenberg ML, Li S, Cullen MR, Baker LC. Increased risk of incident chronic medical conditions in infertile men: analysis of United States claims data. Fertil Steril. 2016;105(3):629–36.  https://doi.org/10.1016/j.fertnstert.2015.11.011. This was a retrospective review using the Truven Health MarketScan claims database from 2001 to 2009 to determine the incidence of chronic medical conditions in infertile men. The authors demonstrated that men diagnosed with male factor infertility had a significantly higher risk of adverse health outcome in later years. CrossRefPubMedGoogle Scholar
  86. 86.
    Braverman AM. Old, older and too old: age limits for medically assisted fatherhood? Fertil Steril. 2017;107(2):329–33.  https://doi.org/10.1016/j.fertnstert.2016.12.006.CrossRefPubMedGoogle Scholar
  87. 87.
    Jennings MO, Owen RC, Keefe D, Kim ED. Management and counseling of the male with advanced paternal age. Fertil Steril. 2017;107(2):324–8.  https://doi.org/10.1016/j.fertnstert.2016.11.018.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Male Reproductive Medicine and Surgery, Scott Department of UrologyBaylor College of MedicineHoustonUSA

Personalised recommendations