Relationship between advanced paternal age
and male fertility highlights an impending
paradigm shift in reproductive biology
Traditionally, men have been viewed from a fertility
perspective as exempt from the consequences of old age.
Recent studies, however, have begun to develop a different
scenario. The advent of genome-wide sequencing technolo-
gies and population-based screening has begun to associate
paternal age with autism as well as several other diseases,
including cancer
(1, 2)
. As such, we seem to be moving
toward an era in which a male's reproductive age is
considered as important as a female's. Indeed, with couples
routinely
delaying
pregnancy
in
favor
of
career
advancement or educational aspirations
(2)
, this new
concept of genetic fragility within the aged male may lead
some men to develop a newfound concern into the health of
their sperm.
In the study by Katz-Jaffe et al.
(3)
, the authors investi-
gated the effects of advanced paternal age (APA) by routinely
mating, over a 15-month period, 10 aging male mice to young
females. Both in vivo and in vitro reproductive endpoints
were assessed, including natural conception outcomes,
implantation potential, and blastocyst development, as well
as the expression of numerous possible candidate infertility
genes
(3)
. Several conclusions were drawn, all of which
pointed to a decrease in fecundity occurring around paternal
middle age. With male mice of APA, natural conceptions were
signi
fi
cantly decreased, and fetuses were signi
fi
cantly smaller
and weighed less
(3)
. Furthermore, only one of the 15-month-
old males was able to impregnate a young female, hinting at
the idea that older mice may have even more dif
fi
culties
beyond what was reported.
In vitro embryo development was also affected. The
cohort of mice with APA showed a signi
fi
cant decrease in
total blastocyst development, poorer blastocyst quality, and
lower blastocyst cell number
(3)
. Furthermore, when using
sperm from mice of APA (12
–
15 months), a decreased
proportion of oocytes were fertilized during IVF
(3)
. Four
genes previously associated with impaired spermatogenesis
(
Ace-1
,
Prm1
,
Prm2
, and
Smcp
) exhibited decreased
expression with APA
(3)
. If these
fi
ndings prove translational,
men are at an increased risk for reproductive deterioration
beginning in midlife.
Several large studieshave attemptedtobetterdelineate this
notion of APA within a human cohort. As an example, an ob-
servational study of 2,112 consecutive pregnant women in the
United Kingdom found that when a man's age was
>
45 years,
a concomitant
fi
vefold increase in the time required to achieve
a pregnancy was observed
(4)
. Furthermore, when compared
with men aged
<
25 years, men of APA were 4.6 times more
likely to not achieve a pregnancy after 1 year of trying
(4)
.
Another prospective study (reviewed in reference
2
) from seven
European centers identi
fi
ed 782 couples seeking natural family
planning. In those couples that achieved a pregnancy using
intercourse alone, male age became a signi
fi
cant factor when
women reached their late 30s.
In cases of assisted reproduction, both fertilization and
pregnancy rates are signi
fi
cantly decreased in men aged
>
50 years
(2)
. Furthermore, in results reminiscent of the
present study by Katz-Jaffe et al.
(3)
, Frattarelli et al.
(5)
found
that men aged
>
50 years contributed to an increased number
of pregnancy losses as well as a decreased blastocyst
formation rate and lower live birth rate. Although other
studies (reviewed in reference
2
) have denied a connection
between APA and fetal outcomes, the evidence for such
a connection continues to grow. The results of the study by
Katz-Jaffe et al.
(3)
, published in this issue of
Fertility and
Sterility
, highlight that under controlled scienti
fi
c conditions,
older male mice exhibit decreased reproductive outcomes,
both in vivo and in vitro.
Unfortunately, dif
fi
culties exist on translation of basic
science and animal work to humans. For example, the ability
to estimate human APA given the context of a mouse model is
fraught with inconsistencies. Moreover, the variability that
underlies human experiences, exposures, and general
health is so diverse that it is impossible to calculate. Further-
more, the possible contributions of hypogonadism, sexual
dysfunction, and metabolic syndrome lend to the multifacto-
rial nature of reproductive decline in men and require further
investigation.
Katz-Jaffe et al.
(3)
also examined gene expression of
sperm from 15-month-old male mice and identi
fi
ed altered
transcript levels of several spermatozoal genes. Recent esti-
mates indicate that genetic abnormalities cause 15%
–
30%
of male factor infertility
(1)
. The
fi
rst genetic marker of
male infertility, the azoospermia factor, has been known since
1995. New genes are currently being found daily, many of
which may act as novel genetic biomarkers of male infertility
(1)
. Thus, although selection of genes based on the
current literature and screening with reverse transcription
–
polymerase chain reaction (as done in the present study)
provides an accurate assessment of expression levels, it is
not practical when considering the vast amounts of
genetic information that exist. A more expedient method
would be to use a genome-wide screening test such as
a DNA microarray that, when coupled with bioinformatics
analyses, can yield many potentially more novel genes.
It seems that society is moving toward a paradigm shift in
reproductive biology wherein the potential risks of APA will
be considered along with maternal factors. It is also likely
that formal guidelines for the evaluation and counseling of
older potential fathers will soon follow.
Jason R. Kovac, M.D., Ph.D.
Ryan P. Smith, M.D.
Larry I. Lipshultz, M.D.
Scott Department of Urology, Baylor College of Medicine,
Houston, Texas
You can discuss this article with its authors and with other
ASRM members at
58
VOL. 100 NO. 1 / JULY 2013
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