Testosterone-induced persistent dysregulations and transdifferentiation to exocrine pancreas in the female liver

Androgenic steroids are increasingly used for hormone therapy of postmenopausal women and abused as life style drugs and for doping purposes, though knowledge about associated health risks in females is very limited. In order to understand more about short- and long-term androgen effects on a molecular level, we have analyzed hepatic gene expression in female C57BL/6 mice immediately after subcutaneous treatment with testosterone for 3 weeks and after 12 weeks hormone withdrawal using Affymetrix array technology and quantitative real-time RT-PCR. Among about 14,000 genes examined, 48 were up- and 65 genes were downregulated by testosterone after 3-weeks treatment and about 50% of these changes persisted even 12 weeks after testostrone withdrawal. In addition to obvious risks such as induction of hepatocellular carcinomas and virilization of liver metabolism, testosterone induced a series of changes, as e.g. dysregulation of hepatic gene expression due to incomplete conversion of female to male phenotype in particular downregulation of cytochrom P450 isoforms and sulfotransferases. As a long-term testosterone effect, transcripts emerged in the liver that are normally specific for the exocine pancreas including amylase 2, ribonuclease 1, and several trypsin-, chymotrypsin-, and elastase-like proteases. This transdifferentiation of hepatic to exocrine pancreatic tissue indicates that testosterone can initiate long-lasting differentiation programs, which once induced progress even after androgen withdrawal. This may have far-reaching consequences difficult to foresee implying long-term hazards of testosterone-treatment for female health that have not been taken into account yet.

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Delić D, Grosser C, Dkhil M, Al-Quraishy S, Wunderlich F