Growth Hormone Linked to Male Thrombosis Risk

By Michael Smith
SAN FRANCISCO, 12 july 2008 -- The well-known increased thrombosis risk among men compared with women may be related to differences in the way they secrete growth hormone and its effects on liver gene expression, researchers said here.
Men secrete the hormone in pulses and women secrete it continuously, according to Ethan Weiss, M.D., of the University of California San Francisco, and colleagues.
Because the production of coagulation proteins by the liver is controlled by growth hormone, the differences in secretion may be related to differences in clotting time and therefore to thrombosis risk, Dr. Weiss and colleagues said online in the Journal of Clinical Investigation.
And, at least in mice, the hypothesis appears to be correct, they said.
In a series of animal experiments, changing the way growth hormone is secreted also altered the clotting time of blood, Dr. Weiss and colleagues reported.
Male sex is known to be an independent risk factor for several thrombin-dependent processes, including myocardial infarction, venous thromboembolism (VTE), and thrombotic stroke, the researchers noted.
For instance, men are on average 50% more likely to suffer recurrent VTE
than females, they said.
But while the difference in risk is known, the causes are not, they said.
In wild-type mice, they found, clotting times were significantly shorter (P=0.0001) in males than in females -- 50.57 versus 55.76 seconds on average.
When the researchers used thromboplastin to induce pulmonary embolism, female animals were protected to a significantly greater degree (P=0.01) than males. On average, males survived 210 seconds versus 480 and male survival percentages were 12.5% versus 41%.

But in mice genetically altered to have a deficiency in growth hormone, both males and females had significantly longer clotting times (P<0.001) than male mice with normal growth hormone secretion.
The hormone-deficient mice were also significantly better able (P<0.0001) to withstand the thromboplastin-induced pulmonary embolism, Dr. Weiss and colleagues said.
The researchers also found that inducing a male secretion pattern in both male and female hormone-deficient mice (by periodic injection) restored their clotting times to those seen in male controls.
In-vitro analysis of liver tissue showed that expression of coagulation
inhibitors (Proc, Serpinc1, Serpind1, and Serpina5) were "strongly modulated" by sex-specific growth hormone patterns, the researchers said.
And growth hormone modulated resistance to activated protein C, which degrades Factor Va and Factor VIIIa.
The results "reveal what we believe to be a novel mechanism" of thrombosis involving growth hormone and a suite of changes in expression of coagulation inhibitor genes in the liver, the researchers said.
"We believe this is an important step in understanding the biological mechanism underlying important sex differences in disease susceptibility," Dr. Weiss and colleagues said.
"There is great value in understanding the mechanisms underlying such differences, as they may lead to novel paradigms of diagnosis or management of thrombotic disorders," they added.
The study was supported by the NIH, the American Society of Hematology, the American Heart Association, and the UCSF Office of Student Research. The researchers reported no conflicts.

Additional source: Journal of Clinical InvestigationSource reference: Wong JH, et al "Sex differences in thrombosis in mice are mediated by sex-specific growth hormone secretion patterns" J Clin Invest DOI: 10.1172/JCI34957.