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Endocrine Abstracts (2015) 37 S9.1 | DOI: 10.1530/endoabs.37.S9.1

ECE2015 Symposia Steroid hormone action in target tissues (3 abstracts)

Tissue-specific sex steroid action: role of HSD17B-enzymes

Matti Poutanen


Institute of Biomedicine, University of Turku, Turku, Finland.


Recent data from us and others have evidently shown that steroid metabolism at the target tissues is a key determinant regulating the availability of high affinity ligands for steroid receptors. Thus, the serum concentrations of the steroids do not necessary mimic their target tissue concentrations in several physiological and pathophysiological settings. Accordingly, among the other steroid metabolizing enzymes, the expression of hydroxysteroid dehydrogenase- (HSD17B) enzymes catalyzing the conversion between 17-keto and 17-hydroxysteroids are expressed in various sex steroid target tissues. So far, among the various HSD17B enzymes the expression of HSD17B1, HSD17B2, HSD17B3, HSD17B5 (AKR1C3) and HSD17B6 has shown the strongest association with steroid metabolism in both preclinical models and clinical specimens. HSD17B1 and HSD17B2 enzymes are the ones with the strongest association with altered estrogen metabolism, and are, for example, differentially expressed in endometriosis lesions and in the eutopic endometrium. This results into an altered estradiol/estrone balance in the endometriosis, being one of the mechanisms promoting the growth of the lesions. Role of HSD17B1 in the activation of the sex steroids is also supported by multiple phenotypic alterations in the transgenic mice expressing the human HSD17B1, as well as by the data obtained in the HSD17B1 knockout (KO) mice. Similarly to that of endometriosis, novel routes for the local sex steroid synthesis in the castration resistant prostate cancer have been identified, and the strong intra-tumor androgen production is associated with up-regulation of HSD17B5 and HSD17B6 expression. However, especially the phenotypes of the KO mouse models have predicted also other metabolic roles for several other HSD17B enzymes, and thus, a critical evaluation of physiological role of all HSD17B-enzymes in vivo is essential. For example, HSD17B7 KO mice showed a role for the enzyme in cholesterol synthesis, and HSD17B12 and HSD17B13 KO mice indicated a role of the enzymes in lipid metabolism. In conclusion, novel HSD17B-enzyme dependent pathways for sex steroid synthesis and metabolism are emerging at target tissues, and provides new possibilities for the treatment of sex steroid-dependent diseases by HSD17B-inhibitors.

Disclosure: Academy of Finland, Tekes: Finnish Funding Agency for Innovation, European Regional Development Fund, Novo Nordisk Foundation, The Finnish Cancer Organisations.

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