The use of growth hormone therapy has been linked in some people to the development of colon polyps, a possible precursor to colorectal cancer - but medical researchers have debated the extent of a cancer risk.
In addition, the reason for a polyp link to growth hormone has been unclear. But new research from the University of North Carolina at Chapel Hill indicates the probable answer: loss of function of one of a pair of genes that normally would inhibit growth hormone signals inside the cell.
The study also offers a possible molecular marker that could help determine which people taking growth hormone therapy are at increased risk for colon polyps. Researchers already know that colon polyps tend to occur in people who already have excessive amounts of growth hormone, such as those with a disease called acromegaly, or gigantism.
A report of the study appears in the April issue of the medical journal Endocrinology.
Study senior author Dr. P. Kay Lund, professor of cell and molecular physiology within UNC's School of Medicine and a member of the UNC Lineberger Comprehensive Cancer Center, said she and her team had been interested in looking at the effect of a newly discovered inhibitor of cellular growth hormone signaling, suppressor of cytokine signaling-2, or SOCS2.
This molecule limits growth hormone action on the body and organ growth, but its role in growth hormone action on intestine is unknown, Lund said.
"Much of the work on SOCS2 had been done in cell cultures. We wanted to study it in vivo, in laboratory animals, with a focus on how it stops the action of cellular growth hormone."
The researchers thought an ideal way to study this issue would be to use an animal model of acromegaly, laboratory mice having excessive amounts of growth hormone.
The animals were crossed with animals in which the SOCS2 gene was deleted. The breeding generated animals with excessive growth hormone and one or two functional SOCS2 genes, but none with excessive growth hormone and no SOCS2 genes, an unexpected result.
"This meant that excessive growth hormone and no functional SOCS2 is incompatible with successful embryonic development," Lund said.
But there was another surprise: While colon polyps did not develop in animals with excessive growth hormone and two functional SOCS genes, multiple polyps did develop in animals with excessive growth hormone and only one functioning SOCS2 gene.
"We discovered that losing this one copy of SOCS2, this 'haplotype insufficiency,' is enough to cause spontaneous polyp formation in these animals," Lund said, adding that the findings may have implications for humans.
"Haplotype insufficiency animal models are much closer to the normal human variation. Animals expressing just 50 percent normal levels of a protein can be thought of as reflecting the physiological variation that occurs in the general population."
According to Lund, expression levels of SOCS2 measured in, say, 100 people would almost certainly vary by at least 50 percent.
"So this really raises the issue that in a situation of growth hormone excess, such as acromegaly or, possibly, growth hormone therapy, SOCS2 may really be fundamental to dictating your risk of getting abnormalities in the colon."