Stress hormone may
contribute to breast cancer deaths
BY RUTHANN RICHTER
Women with advanced breast
cancer who have abnormal daytime levels of cortisol, a
hormone released in response to stress, are significantly
more likely to die sooner than patients with normal
levels of the hormone, Stanford researchers report in a
newly published study. The researchers also found that
women with these abnormal cortisol levels had fewer
immune system cells known as natural killer cells, and
this reduced immunity was associated with higher
mortality.
The study involved 104 San
Francisco Bay Area women with metastatic cancer, or
disease that had spread beyond the breast. The
researchers extracted cortisol from the saliva of the
volunteers, which was taken at regular intervals during
the course of three days. They then observed the women's
daytime rhythms as reflected in their cortisol levels,
which are generally high in the morning and then
gradually decrease to a low point in the evening, said
David Spiegel, MD, Stanford professor of psychiatry and
behavioral sciences and principal investigator of the
study. The researchers found that some of the study
volunteers had abnormal patterns of cortisol secretion,
with levels of the hormone that remained relatively flat
or peaked at abnormal times during the day.
"We found that
patients who had abnormal cortisol patterns died
significantly sooner," Spiegel said. "There was
no relationship in the first year. It's only down the
road that it occurs. It's as if we're tapping into some
physiologic system that is a marker for rapid tumor
growth."
The latest study was
published in the June 21 issue of the Journal of the
National Cancer Institute. The work is a follow-up to an
earlier, landmark study published by Spiegel and his
colleagues in the journal Lancet in 1989. In that study,
the researchers found that women with metastatic cancer
who attended weekly support groups lived about twice as
long on average as those who did not have the benefit of
psychosocial intervention.
"We said, 'Look, if
there is an effect of intervention, there's got to be a
mechanism that mediates it,' " Spiegel said.
Based on evidence from
other studies, Spiegel and Sandra Sephton, PhD, a
post-doctoral fellow in his laboratory, decided to look
to the cortisol system for a possible physiologic
explanation for the difference in mortality. The cortisol
system is one of two primary systems for responding to
stress. For instance, the body may release the hormone
when an individual perceives a danger. Cortisol, in turn,
causes cells to release glucose so the individual has the
energy to respond and fend off an attack. Cortisol also
slows nonessential activities including the immune
system so the individual can devote its full energy to
fighting off the imminent threat, Spiegel said.
The researchers found that
only 37 percent of the women had cortisol patterns that
were normal, starting high in the morning and maintaining
a steady decline into the evening. The other 63 percent
of the volunteers had levels that had a relatively flat
pattern or peaked abnormally later in the day. These
hormone levels were directly related to survival time,
the researchers found. Women with abnormal cortisol
rhythms survived an average of 3.2 years, while those
with normal rhythms survived an average of 4.5 years
more than a year longer. The difference in survival times
began to emerge about a year after the testing and
continued for at least six more years, the researchers
reported.
Patients with a flatter
cortisol pattern also had fewer natural killer cells,
immune system cells that spontaneously kills abnormal
cells in their vicinity, including tumor cells and
infected cells. The researchers found that patients were
more likely to survive longer if they had higher numbers
of these cells in the blood.
After controlling for
natural killer cell numbers, the researchers also found
that these cells were less active among patients with
flatter cortisol rhythms. Previous studies have shown
that the absence of natural killer cells is related to
the progression of breast cancer, Spiegel said.
"I think one of the
problems these cancer patients may have is that their
immune system is overregulated. Cortisol suppresses
immune function and may hamper the immune system's
ability to counter the spread of cancer," Spiegel
said.
He said there are other,
more direct ways in which cortisol might have an impact
on the progression of the disease. For instance, cortisol
causes normal cells to release glucose into the blood,
but tumor cells ignore this signal. Thus high cortisol
levels tend to favor the nourishment of tumor cells over
normal ones.
The researchers explored
other factors that might influence cortisol levels and
found that women who were widowed, divorced or separated
were more likely to have abnormal cortisol patterns.
Spiegel said the abnormal cortisol profile might reflect
the stress associated with loss of marital support, which
has been found in other studies to be associated with
poorer outcomes.
The researchers also found
that women with abnormal cortisol patterns during the day
were more likely to have sleep disruptions at night. It
could be that the cortisol abnormalities contributed to
these disturbances, or that sleep problems were a source
of daytime stress for these women, Spiegel said.
Spiegel and his colleagues
are now hoping to learn whether cortisol also predicts
poorer disease outcomes early in the course of breast
cancer. The researchers also are studying different types
of group interventions offered to patients to see whether
women can improve abnormal cortisol rhythms. Women
interested in participating can contact project
coordinator Vickie Chang at (877) 447-7457.
Spiegel's colleagues in
the study are Sephton, a former Stanford postdoc who is
now at the University of Louisville School of Medicine;
Robert Sapolsky, PhD, Stanford professor of biological
sciences; and Helena Kraemer, PhD, a Stanford professor
of biostatistics in the psychiatry and behavioral
sciences. SR
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