Tetrahydrogestrinone is a potent but unselective binding steroid and affects glucocorticoid signalling in the liver
Friedel A, Geyer H, Kamber M, Laudenbach-Leschowsky U, Schanzer W, Thevis M, Vollmer G, Zierau O, Diel P
Toxicol Lett. 2005 Dec 12;
In the literature THG is referred to be a typical anabolic steroid. However, the data of the receptor binding tests indicate that it has a high binding affinity to the PR, MR and GR and therefore may be also a functional progestin, glucocorticoid or mineralocordicoid.
Whereas it is unlikely that a progestin like action in a male organism will result in adverse side effects MR and GR binding is often associated with an interference of glucocorticoid and mineralocordicoid hormone signalling and therefore an alarming signal for potential serious adverse side effects.
Therefore we investigated in vivo, whether the high binding affinity of THG to the MR and GR results in physiological changes. As a marker for a MR activation, body weight was observed.
Activation of the MR may result in effects of the fluid retention and effect the weight gain. Activation of the GR may induce the alteration of glucocorticoid sensitive marker genes in the liver.
Male orchiectomised rats were treated with THG and TP, using the classical design of the Hershberger assay. Intact animals and orchiectomised (GDX) animals served as references.
Treatment with THG and TP resulted in a stimulation of the growth and weight of androgen sensitive tissues like the prostate and the seminar vesicle in GDX animals. With respect to these parameters THG in an equimolar dose was as potent as TP. This is another clear indication for a high androgenic potency of this
substance.
Like TP, THG is also able to stimulate the weight of the androgen sensitive levator ani muscle , a classical biomarker for anabolic activities. These findings are in good agreement to recently published data, demonstrating androgenic and anabolic activity of THG in orchiectomised rats and mice.
Because an additional aim of our study was to identify potential side effects, we carefully examined physiological parameters like the body weight and the anatomy of viscera. Body weight was not statistically different between the respective treatment groups.
This can be taken as an indication that the high binding affinity of THG to the MR does not result in physiological effects like an alteration of fluid retention.
With respect to the anatomy of the viscera no macroscopic alterations, neither of the heart nor of the liver could be observed. However, it has to be considered that the chosen 12 day period of treatment, is probably to short for causing such changes.
To identify a possible glucocorticoid like activity of THG, the liver expression of the glucocorticoid sensitive TAT gene was investigated by real time PCR. TAT is a gene containing functional glucocorticoid responsetive elements (GREs) in its promotor region. Its expression is directly regulated by glucocorticoids.
In contrast to TP, treatment with THG resulted in a significant down regulation of TAT expression in the liver. The modulation of TAT expression after THG treatment can be taken as an indication for a functional in vivo interference of this substance with the GR.
However THG binding does not
activate TAT expression, like it is observed for GR agonistic ligands as dexamethasone. Treatment of THG resulted in a decrease of TAT expression. Such a regulatory pattern has been described to be typical for liver toxic and carcinogenic substances such as dimethylnitrosamine or xenobiotics like tolylfluanid and ketoconazole. Therefore our observation points to a potential for hepatotoxic activities of THG.
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