Infertility in the Aging Male
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.
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.
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.
KeywordsMale infertility Aging male Advanced paternal age
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.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 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
- 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.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.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
- 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
- 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
- 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.•• 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
- 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
- 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
- 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.
- 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.
- 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
- 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
- 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
- 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.
- 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
- 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
- 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.• 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
- 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
- 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.
- 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.• 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
- 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