It's easy to forget that cholesterol isn't simply
a villain. The white, waxy substance is
famously intertwined with heart disease,
but cholesterol lives all over the body,
building cell membranes and hormones. A
small group of researchers is now wondering
whether cholesterol also helps maintain
fertility—and whether cholesterol abnormalities
impair a woman's ability to get and
stay pregnant. There's even speculation that
a cholesterol-lowering drug, which is no
longer on the market, could treat a subset of
women who are battling infertility.
The complicated story starts more than
15 years ago, when Monty Krieger, a
molecular geneticist at the Massachusetts
Institute of Technology in Cambridge, discovered
a cell membrane protein, scavenger
receptor class B, type I (SR-BI). The
receptor binds to high-density lipoproteins
(HDL) and sucks out their lipids, clearing
them from the blood. Unlike cholesterolladen
low-density lipoproteins (LDL),
which can harm the arteries, HDL is generally
considered the “good” cholesterol.
Researchers theorize that that's because
the particles remove cholesterol from arteries,
and companies are even seeking drugs
to raise HDL levels in the blood in order to
prevent heart disease.
Krieger engineered mice to lack SR-BI,
and as expected, they had high HDL cholesterol
levels because the receptor wasn't
available to facilitate their clearance. But the
mice had two surprising features: They had
severe heart disease despite high HDLs, and
the female rodents, but not the males, were
also infertile.
Krieger set to work trying to solve both
puzzles. The infertility puzzle also soon
intrigued Annabelle Rodriguez,
an endocrinologist at Johns
Hopkins University in Baltimore,
Maryland, who cares for
adults with cholesterol disorders.
“We said, ‘Could women
at an infertility clinic have a similar problem?’
” she recalls. The question was particularly
compelling as Krieger had found that he
was able to cure the infertility in the female
mice with a cholesterol drug called probucol
that lowers both LDL and HDL levels.
Admittedly, probucol is not the most
promising drug to give to women trying to
get pregnant: It was removed from the market
in the 1980s because it causes a potentially
fatal heart condition. Still, the idea
that a simple drug might cure some infertility
was so appealing that Rodriguez forged
ahead to see if Krieger's story held up in
humans. In 2009, Rodriguez found that people
whose cells have fewer SR-BI proteins
than normal tended to have higher HDL levels,
suggesting that its function was similar
in mice and humans. And last year, she
reported that the same receptor
deficiency was associated
with lower-than-average progesterone
levels.
More recently, Rodriguez
has turned to women coming
to the Johns Hopkins in vitro
fertilization (IVF) clinic
because of fertility issues.
There, she found that about
15% of the women tested had
one or two copies of SR-BI
gene variants previously
associated with low production
of the protein. Moreover,
those women also had, on average,
lower progesterone levels than women without
the variants, according to Rodriguez's
measurements of the hormone in the follicular
fluid that surrounds a woman's egg.
Nine women with one of the SR-BI variants
were also unable to sustain a pregnancy after
receiving their IVF embryo. In contrast,
among those without that variant who had
an embryo transfer, 207 women in all, about
30%, were able to get pregnant.
Rodriguez believes that the IVF clinic
findings, published in Human Reproduction
at the end of April, echo what Krieger
saw in mice. Why would a dearth of production
of SR-BI cause infertility? No
one's really sure, but there are theories.
An early one revolved around steroid hormones,
like estrogen and progesterone, to
which cholesterol is a precursor. Unlike
some hormones, such as insulin, which the
body stores and releases when needed, steroid
hormones are made from scratch on
demand, and cholesterol is the key ingredient.
But Krieger found that in his mice lacking
SR-BI, HDL cholesterol hangs around
in the blood because it moves more slowly
to other tissues. This could impair ovarian
production of hormones such as estrogen
and progesterone, which help control egg
production or ready the lining of the uterus
for implantation of a new embryo. Indeed,
a study by a group in Montreal, published
in April 2010 in the Journal of Lipid
Research, found that mice lacking SR-BI
had blood levels of progesterone about 50%
below normal. That's nearly identical to
what Rodriguez observed in the follicular
fl uid of the women with the gene variants
tied to poor SR-BI production.
Is the problem in mice and people too little
progesterone due to too much HDL cholesterol
in the blood? Krieger isn't convinced
by the theory, noting that his mice had a normal
menstrual cycle—something that's not
possible without passable hormone levels.
He has, however, found defects in the mouse
eggs as they are ovulated and hypothesizes
now that the problem, at least in mice, has
something to do with cholesterol's impact on
oocyte maturation. Rodriguez says she still
favors the idea that progesterone is a problem
for the women in her study, but she's
stymied by limited information. In particular,
she doesn't know the HDL levels of the
women with SR-BI variants, because fertility
clinics don't normally measure cholesterol,
nor does she know if they had a normal menstrual
cycle.
Muddling the picture further is a large
family in southern Holland, many members
of which were known to have high HDL levels.
Those members have one mutated copy
of the SR-BI gene, Jan Albert Kuivenhoven
of the Academic Medical Center in Amsterdam
and colleagues reported in January in
The New England Journal of Medicine. Yet
several of the affected women with a high
HDL level nevertheless had children. “Fertility
problems were certainly not in this family,”
Kuivenhoven says. Despite that, the
lipidologist doesn't discount Rodriguez's
work. The numbers in this family “are too
small” to say anything defi nitive about fertility,
he says.
Rodriguez says she has just submitted a
grant application to the U.S. National Institutes
of Health to study how SR-BI variants
affect the menstrual cycle in women of childbearing
age, not just those undergoing IVF.
She is also working on an investigational new
drug application to test probucol in infertile
women with SR-BI defi ciency.
“We are just in the infancy of trying to
understand” cholesterol's effects on fertility,
says Victor Fujimoto, a reproductive
endocrinologist at the University of California,
San Francisco, who has found that
a plentiful supply of HDL cholesterol helps
keep IVF embryos in good health in the lab
before they're transferred to women. Fujimoto
acknowledges that exactly how this
happens remains unclear, but whatever the
answer, the broad-brush strokes are forming
a clearer picture: Cholesterol seems to
matter when it comes to fertility, at least in
women.
