04 April 2019

Testosterone is to blame

Castration saved male mice from liver cancer

Maxim Abdulaev, Naked Science

Liver cancer develops more often in men than in women, due to the fact that testosterone suppresses the production of a hormone that prevents cancerous tumors from growing. Scientists from Spain came to this conclusion after conducting a series of experiments on mice, which included knockout and gene activation, as well as castration.

Liver cancer ranks fourth among the causes of death associated with cancer. At the same time, men face this disease several times more often than women – for example, in the USA twice, and in EU countries and three times more men with liver cancer than women. One of the reasons for this inequality is the hormonal background, which is different for men and women. There is a difference not only in sex hormones, but also in those produced by adipose tissue cells – among such, for example, adiponectin, which regulates glucose levels and the breakdown of fatty acids. The female body produces about 20% more adiponectin than the male body.


Drawings from the article by Manieri et al. Adiponectin accounts for gender differences in hepatocellular carcinoma incident, published in the Journal of Experimental Medicine.

Scientists from Spain conducted several experiments that were supposed to test the role of this hormone in protecting the liver from cancer. The experiments were carried out on mice, because they also have gender inequality in terms of liver cancer and adiponectin production.

The first experiment involved mice with overexpression of the hormone. Males of such mice were caused cancer by injections of diethyl nitrosamine, a strong carcinogen, and the introduction of mouse liver hepatoma cells (Hep-53.4). After eight months, the mice were opened and compared with the control ones: it turned out that mice with overexpression of adiponectin had twice as many tumors in the liver on average, and the liver itself was not so enlarged.


On the left – the liver of an ordinary male, on the right – with increased production of adiponectin.

Another experiment is related to the JNK protein, which controls the activity of other proteins, including adiponectin. Scientists conducted experiments with mice in which the gene encoding JNK was disabled, and compared it with ordinary mice. The animals developed cancer in the same way, and also after eight months they looked at their livers. The picture was similar – the number of tumors in mice without the JNK protein was half as much, the tumors themselves were also about half as small, and the liver did not look as big as in the wild type.


On the left is the liver of a mouse with a normal JNK protein gene, on the right – with a knockout one.

Scientists assumed that there was something behind the activity of JNK, and they came up with the idea that it was testosterone, because the level of JNK is just as higher in males than in females. They turned off testosterone production by simply castrating mice, and indeed, the level of JNK in castrates did not exceed that in females. In the same way, the level of adiponectin leveled out.

Scientists have concluded that the high mortality from liver cancer in men is due to the production of testosterone, which increases the production of JNK, and that, in turn, reduces the activity of adiponectin. Adiponectin transmits a signal to the liver through two substances – p38a and AMPK, which inhibit proliferation, that is, growth by cell division. This will explain why when the level of adiponectin drops due to testosterone, the risk of liver cancer increases. Scientists believe that based on new information about the role of adiponectin, it will be possible to develop new methods of treating liver cancer.

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