SEMEN QUALITY

Large cohort study finds no link between parental subfertility and sons’ reproductive health

Published 24 August 2022

A new population study based on a large Danish cohort has found no major difference in semen quality or reproductive hormones in sons conceived by subfertile couples or with ART.(1) The results will be reassuring for the boys growing up and their parents, but they do additionally raise a question mark over several previous studies which have suggested a link between parental subfertility and suboptimal sperm quality in sons.

Three early studies are cited by the investigators to illustrate the potentially negative effect of subfertility on male reproductive health: two cohort studies, and one after ICSI specifically.(2,3,4) The first, based like this latest on a Danish cohort (of volunteers for military service), found that men whose mothers had received ‘fertility treatment’ had a lower sperm concentration and count than control subjects (33 million/ml vs 48 million/ml and 129 million/ml vs 152 million/ml); the second study tried to replicate these findings in another cohort of mothers where treatment for infertility was known – and which could control for BMI. The investigators could not explain the findings, but in the first study warned that ‘they raise concern about possible late effects of fertility treatment’.

The concerns about the adverse effects of ICSI – as generationally inheritable - seemed more explicable, as indicated by Gianpiero Palermo in an interview with Focus on Reproduction at ESHRE 2022 for ICSI’s 30th anniversary.(5) When tested by the Brussels group in a small study of young men conceived spontaneously and by ICSI, results indeed suggested a lower semen quantity and quality in those born after ICSI.

The latest study from Denmark recruited 1058 young men (born between 1998 and 2000) from a subgroup of the Danish National Birth Cohort, whose mothers were already in the database with details about their pregnancy (including time to pregnancy and any fertility treatment). After recruitment, the men provided blood and semen samples for analysis (volume, total sperm count, concentration, motility, and morphology). There were six exposure categories in the analysis, designed to measure any effect of parental fertility on the reproductive health of the male offspring: first, the reference exposure (spontaneous conception within a TTP of five months or less); then, spontaneous conception with TTP of 6–12 months; spontaneous conception with TTP >12 months; conception following ovulation induction or IUI; conception following IVF or ICSI; and unplanned pregnancy.

Reconciling these exposures after a complex statistical analysis, the authors report that any absolute differences seen were ‘small’, and the clinical significance of these differences ‘unknown’. For example, semen quality and levels of reproductive hormones were not lower in the sons of parents reporting a TTP >6 months or having had IUI than found in the reference exposure. There was a non-significant trend of higher sperm concentration and morphology in sons conceived after IVF or ICSI – but overall, add the authors, ‘no major differences’ were evident in semen quality or reproductive hormone levels in sons conceived by subfertile couples or following ART. The data, therefore, ‘do not support the hypothesis that parental subfecundity was inherited’.

The authors propose two possible explanations for the inconsistency with the earlier cohort study results: first, the small numbers of ART children in the original studies; and second, the later dates of birth in the present study, when both ICSI and IVF were increasingly applied in non-male factor cases.

The study cited by the present investigators of sperm quality in young men conceived by ICSI was presented at the 2018 ESHRE annual meeting as the Human Reproduction keynote lecture.(4) The study, as noted above, had found that men conceived by ICSI had a lower average sperm concentration, total sperm count and motile sperm count than those conceived naturally. In her lecture first author Florence Belva from the Brussels group noted that the fathers in this study ‘all had severe male factor infertility’, but that a low sperm concentration and total motile sperm count in individual fathers did not correlate with corresponding values in their own sons, ‘suggesting that semen characteristics in the ICSI fathers do not necessarily predict semen values in their sons’.(6)

This too was a small study - 54 men conceived by ICSI and 57 naturally conceived – which too may explain the inconsistent findings with the latest study. Thus, while recognising the contradictory results, the Danish authors reaffirm their results as ‘reassuring’ for many couples, but add that further studies are still needed to replicate the findings.

Meanwhile, as emerging studies indicate – and as discussed at a recent Campus meeting – more and more genes are now implicated in male infertility alongside the known chromosomal anomalies of microdeletions and Klinefelter syndrome.(7) Indeed, this meeting heard that genetic causes affecting sperm quantity are commonly chromosomal in origin, but as yet any link between a more generalised indication of subfertility, as reflected in TTP or fertility treatment, seems elusive in its prediction.

1. Arendt LH, Gaml-Sørensen A, Ernst A, et al. Semen quality and reproductive hormones in sons of subfertile couples: a cohort study, Fertil Steril 2022; doi.org/10.1016/j.fertnstert.2022.06.035

2. Jensen TK, Jørgensen N, Asklund C, et al. Fertility treatment and reproductive health of male offspring: a study of 1,925 young men from the general population.

Am J Epidemiol 2007; 165: 583-590.

doi: 10.1093/aje/kwk035

3. Ramlau-Hansen CH, Thulstrup AM, Bonde JP, Olsen J.

Parental infertility and semen quality in male offspring: a follow-up study. Am J Epidemiol 2007; 166: 568-570.

doi: 10.1093/aje/kwm117.

4. Belva F, Bonduelle M, Roelants M, et al. Semen quality of young adult ICSI offspring: the first results.

Hum Reprod 2016; 31: 2811-2820.

doi:10.1093/humrep/dew245.

5. See https://www.focusonreproduction.eu/article/ESHRE-News-ESHRE-2022-Palermo

6. See https://www.focusonreproduction.eu/article/ESHRE-Meetings-Belva-Barcelona

7. See https://www.focusonreproduction.eu/article/ESHRE-News-male

ANNUAL MEETING 2018 KEYNOTE LECTURE

Semen quality in young men conceived by ICSI

MALE INFERTILITY

The number of genotype-phenotype associations validated in male infertility continues to grow