The Hedgehog signaling pathway is known to be involved in embryogenesis, tissue remodeling, and carcinogenesis. Because of its involvement in carcinogenesis, it seems an interesting target for cancer therapy. Indeed, Sonidegib, an approved inhibitor of the Hedgehog receptor Smoothened (Smo), is highly active against diverse carcinomas, but its use is also reported to be associated with several systemic side effects. Our former work in adult mice demonstrated hepatic Hedgehog signaling to play a key role in the insulin-like growth factor axis and lipid metabolism. The current work using mice with an embryonic and hepatocyte-specific Smo deletion describes an adverse impact of the hepatic Hedgehog pathway on female fertility. In female SAC-KO mice, we detected androgenization characterized by a 3.3-fold increase in testosterone at 12 weeks of age based on an impressive induction of steroidogenic gene expression in hepatocytes, but not in the classic steroidogenic organs (ovary and adrenal gland). Along with the elevated level of testosterone, the female SAC-KO mice showed infertility characterized by juvenile reproductive organs and acyclicity. The endocrine and reproductive alterations resembled polycystic ovarian syndrome and could be confirmed in a second mouse model with conditional deletion of Smo at 8 weeks of age after an extended period of 8 months. We conclude that the down-regulation of hepatic Hedgehog signaling leads to an impaired hormonal balance by the induction of steroidogenesis in the liver. These effects of Hedgehog signaling inhibition should be considered when using Hedgehog inhibitors as anti-cancer drugs.
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We thank PD Dr. Knut Krohn for Affymetrix microarray analysis. We cordially thank Kerstin Heise, Doris Mahn, Claudia Merkwitz and Markus König for excellent technical assistance. Further, we would like to thank Petra Hirrlinger, Petra Fink-Sterba, Sigrid Weisheit and Manuela Liebig from the Experimental Centre of the Faculty of Medicine (Leipzig University) for taking excellent care of the mice.
Compliance with ethical standards
This work was supported by the Federal Ministry of Education and Research (Germany) within the research network Systems Medicine of the Liver (LiSyM) [grant number 031L0054 and 031L0037] and the Virtual Liver Network (VLN) [grant number 0315735, 0315736, 0315755, and 0315775], the Deutsche Forschungsgemeinschaft (Bonn, Germany) [grant MU 1727/2-1, SCHR 1323/2-1], and the Robert Bosch Foundation (Stuttgart, Germany).
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.
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