June 30, 1999
Fathers Pass Infertility to Sons
Researchers have discovered that sons conceived with the aid of a popular
in vitro
fertilization technique can inherit the
same genetic defects that rendered their fathers infertile.
HHMI investigator
David Page
of the
Whitehead Institute for Biomedical Research at Massachusetts Institute of
Technology and his colleagues studied three men who fathered sons through a
widely used fertilization technique called intracytoplasmic sperm injection
(ICSI). In each case, the fathers passed on a Y chromosome genetic defect
called an AZFc deletion. Such deletions are the most frequent molecularly
defined cause of failure to produce sperm, affecting about five to ten
percent of infertile men with insufficient sperm production. The research
was published in the July issue of the journal
Human
Reproduction
.
“Now we have four families, including the one in Taiwan, in which there are
boys who in all likelihood will be infertile as adults.”
David C. Page
Page also noted that researchers in Taiwan published an article in the
June issue of the journal
Fertility and Sterility
that describes
another family in which a son conceived by ICSI inherited the AZFc defect
from his father.
In treating AZFc-deficient men with ICSI, clinicians isolate the few
sperm that are produced and inject a single sperm directly into an egg. The
fertilized egg is then implanted in the mother.
While fertility experts had strongly suspected that the AZFc deletion
could be inherited in such cases, that suspicion had not been clinically
confirmed until now. The finding raises thorny ethical questions about
assisted reproduction techniques. "I think this finding is going to change
genetic counseling," said Page, "because what had been a theoretical concern
is now concrete. Now we have four families, including the one in Taiwan, in
which there are boys who in all likelihood will be infertile as adults."
(Girls are unaffected by the defect, since they receive an X chromosome,
rather than the defective Y chromosome, from their fathers.)
Despite knowing about the defect and its inheritance pattern, couples
might not be deterred from trying to have sons, said Page.
"I am told by clinicians with whom I collaborate that most of the couples
they treat would simply wish to go ahead with having children via ICSI.
Some, in contrast, might elect to avoid transmitting the infertility by
using donor sperm or by adopting, and others could decide to have only
daughters by genetically testing the fertilized embryos to determine their
sex and only having female embryos implanted, " said Page.
Page cautioned that genetic engineering of sperm to correct the defect is
still a farfetched notion "because, of course, any such attempt at gene
repair would carry with it the potential for collateral damage."
A more likely remedy, says Page, is the possibility that affected males,
who may produce normal amounts of sperm during puberty and young adulthood,
may decide to have their sperm harvested for future use. To date, however,
scientists have not conducted careful clinical studies to explore the link
between changing sperm counts and age, he said.
"We only know now that men in their twenties and thirties with AZFc
deletions can have considerable variability in the number of sperm in their
semen." If sperm counts do prove to be higher in younger affected males,
said Page, they might have their sperm harvested and stored until they are
ready to start a family.
The latest findings emphasize the importance of basic research in
understanding the mechanisms by which Y chromosome deletions cause
infertility, said Page. "We really don't know why this missing piece of the
Y chromosome leads to spermatogenic failure, but we are learning more and
more about the missing genes," he said.
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