The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models

Abstract

Disturbed action of sex steroid hormones, i.e. androgens and estrogens, is involved in the pathogenesis of various severe diseases in humans. Interestingly, recent studies have provided data further supporting the hypothesis that the circulating hormone concentrations do not explain all physiological and pathological processes observed in hormone-dependent tissues, while the intratissue sex steroid concentrations are determined by the expression of steroid metabolising enzymes in the neighbouring cells (paracrine action) and/or by target cells themselves (intracrine action). This local sex steroid production is also a valuable treatment option for developing novel therapies against hormonal diseases. Hydroxysteroid (17b) dehydrogenases (HSD17Bs) compose a family of 14 enzymes that catalyse the conversion between the low-active 17-keto steroids and the highly active 17b-hydroxy steroids. The enzymes frequently expressed in sex steroid target tissues are, thus, potential drug targets in order to lower the local sex steroid concentrations. The present review summarises the recent data obtained for the role of HSD17B1, HSD17B2, HSD17B7 and HSD17B12 enzymes in various metabolic pathways and their physiological and pathophysiological roles as revealed by the recently generated genetically modified mouse models. Our data, together with that provided by others, show that, in addition to having a role in sex steroid metabolism, several of these HSD17B enzymes possess key roles in other metabolic processes: for example, HD17B7 is essential for cholesterol biosynthesis and HSD17B12 is involved in elongation of fatty acids. Additional studies in vitro and in vivo are to be carried out in order to fully define the metabolic role of the HSD17B enzymes and to evaluate their value as drug targets.

Structural genomic changes underlie alternative reproductive strategies in the ruff (Philomachus pugnax)

“…2d). HSD17B2 and SDR42E1 both have important roles in the metabolism of sex hormones: HSD17B2 catalyzes conversion of the 17β-hydroxy forms of estrogen and androgens (including testosterone and dihydrotestosterone) into their less active 17-keto forms 16 . We postulate that one or more of these deletions constitute cis-acting regulatory mutations that alter the expression pattern of HSD17B2 and/or SDR42E1 and contribute to phenotypic differences among male morphs.…”

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review

“…Both estrogens and androgens have the highest afnity for their receptors in the 17 -hydroxy form and hence, 17HSD/KSR enzymes regulate the biological activity of the sex hormones.17KSR activities are essential for estradiol and testosterone biosynthesis in the gonads, but they are also present in certain extragonadal tissues and can convert lowactivity precursors to their more potent forms in peripheral tissues. Instead, 17HSD activities tend to decrease the potency of estrogens and androgens and consequently may protect tissues from excessive hormone action [10,225].…”

“…In the view of successful practice of inhibiting of non-HSD enzymes (aromatase and 5 -reductase) [8,9], recent attempt are made for development of HSD inhibitors as therapeutic strategy. Several of HSD enzymes are also considered as promising drug targets and inhibitors, for example most of the isoforms of 17 -HSD enzyme [10].…”

Understanding the diversity of sex steroid action

“…E 1 ) to highly active 17b-steroids (e.g. E 2 ), and vice versa, has also become apparent, and the enzymes are expected to be involved in the local production of both classical and novel ligands for ERs in several normal and diseased tissues (for example, Chang et al 2011, Mohler et al 2011, Saijo et al 2011, Saloniemi et al 2012. It is thus likely that yet unknown endogenous small molecular compounds modulating ERs are to be discovered in the future.…”

“…The regulation of the ligand availability for ERs by the family of HSD17B enzymes is discussed by Saloniemi et al (2012) with special emphasis on novel findings obtained by using genetically modified mouse models. In vivo models have proven to be essential in defining the physiological processes where HSD17B enzymes are involved.…”