**1. Introduction**

264 Dehydrogenases

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> Differentiation of the male phenotype including the outward development of secondary sex characteristics as well as the initiation and maintenance of spermatogenesis is stimulated by androgens (O'Shaughnessy et al., 2009; Verhoeven et al., 2010). There are two major androgens secreted by the testes: testosterone (T) and dihydrotestosterone (DHT). Weaker androgens: dehydroepiandrosterone (DHEA) and androstenedione are secreted in smaller amounts and converted metabolically to T and other androgens. Testosterone is the most abundant androgen. However, DHT is the most potent one.

> As the result of intensive research over the last 20 years it has been confirmed that estrogens, produced by androgen aromatization, are also important in the regulation of male reproductive function (Carreau et al., 2003). In mice deficient for the estrogen receptor α gene (αERKO) infertility, increased steroid acute regulatory protein (StAR) and 17βhydroxysteroid dehydrogenase (17β-HSD) mRNA levels together with elevated T level have been found (Akingbemi et al., 2003; Eddy et al., 1996).

> Specific receptors for androgens and estrogens have been found in both somatic and germ cells of the testis (Bilinska et al., 2000; Bilinska & Schmalz-Fraczek, 1999; Sierens et al., 2005; Wang et al., 2009). It has been confirmed that these receptors act as transcription factors regulating steroidogenesis at the transcription level. Furthermore, steroidogenesis requires the coordinated expression of related proteins and steroidogenic enzymes in response to hormonal stimulation. In Leydig cells luteinising hormone (LH) induce steroidogenesis by elaborating accumulation of intracellular cyclic adenosine monophosphate (cAMP), activation of protein kinase A (PKA) and expression of StAR resulting in subsequent T biosynthesis and secretion. Intratesticular T is maintained at constantly high levels. In the rat, endogenous T concentrations are the highest at stage VIII of the spermatogenic cycle (Parvinen, 1982). In addition, this stage together with stage VII have been found to be

© 2012 Kotula-Balak et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

particularly sensitive to androgen action, especially in four steps of germ cell development: spermatid adhesion and development, spermiation, progression through meiosis and spermatogonial differentiation (Verhoeven et al., 2010). Thus spermatogenesis is closely related and absolutely dependent on steroid hormone biosynthesis, action and control.

Hydroxysteroid Dehydrogenases – Localization, Function and Regulation in the Testis 267

endoplasmic reticulum. P450c17 catalyzes the conversion of C21 pregnenolone or progesterone (P4) to the C19 dehydroepiandrosterone or androstenedione, respectively, while 3β-HSD catalyzes the conversion of Δ5-3β-hydroxysteroids (pregnenolone or dehydroxypregnenolone, and DHEA, respectively) to the Δ4-3-ketosteroids (P4, or 17α-hydroxyprogesterone, and androstenedione, respectively). Depending on the animal species, biosynthesis of sex hormones proceeds down either one or both of the Δ4 and Δ5 pathways. In rodents, the Δ4 pathway is primary whereas in primates, pigs and rabbits Δ5 pathway is dominant (Fluck et al., 2003; Mathieu et al., 2002). In the final step of sex hormones biosynthesis, conversion of androstenedione into T, 17β-HSD is involved. It was reported that the balance between these

androgens depends on the type and activity of 17β-HSD present (Simard et al., 2005).

substrates converted from cholesterol to the 3β-HSD (Cherradi et al., 1995).

HSD I has been found (Payne & Hales, 2004).

3β-HSDs are membrane-bound enzymes that are distributed in both mitochondrial and microsomal membranes (Payne & Hales, 2004; Pelletier et al., 2001). The relevance of dual localization of these HSDs is related to substrate accessibility (Simard et al., 2005). Coprecipitation studies have shown that, in the inner mitochondrial membrane, 3β-HSD comprises a functional steroidogenic complex with P450scc, which immediately provides

During the past decade, multiple isoforms of 3β-HSDs have been isolated and characterized in human, mouse and rat tissues. Six, highly homologous in their amino acid sequence isoforms have been identified in the mouse, but only two of them: 3β-HSD type I (3β-HSD I), and 3β-HSD type VI (17β–HSD VI) are expressed in the testis. In human testis only 3β-

Similarly to 3β-HSDs, 17β-HSDs are membrane-bound enzymes, and their soluble forms have also been reported. To date, 14 different types of 17β–HSDs have been identified (Blanchard & Luu-The, 2007). Unlike 3β-HSDs there is very little homology among the different 17β-HSD enzymes. Only three types, 17β–HSD type 3 (17β–HSD 3), 17β–HSD type 5 and 17β–HSD type 12 (17β–HSD 12), have been detected to be exclusively expressed in the testis. 17β-HSD 3 converts androstenedione to T as well as it is an important partner of P450arom involved in conversion of C18 steroid, estrone to E2 (Andersson et al., 1995). Recently, it has been confirmed for mice, humans and primates that 17β-HSD 12 shares high homology and function with 17β-HSD 3 (Blanchard & Luu-The, 2007; Liu et al., 2007).

The hydroxysteroid dehydrogenases belong to the same phylogenetic protein family, namely the short-chain alcohol dehydrogenase reductase superfamily. These enzymes are involved in the reduction and oxidation of steroid hormones requiring NAD+/NADP+ as acceptors and their reduced forms as donors of reducing equivalents. Studies have shown that mouse 3β-HSD has different cofactor preference: 3β-HSD I requires NAD+ while 3β-HSD type IV and V requires NADP+ as cofactors. Interestingly, 17β-HSD 3 prefers NADPH as a cofactor, and its primary activity is reductive. Studies have shown that a mutation in *HSD3B3* gene leads to decreased NADPH binding to tyrosine that has been identified as a critical residue for binding. Substitution of tyrosine with different amino acids resulted in alterations in cofactor preference switching from NADPH to NADH (Andersson et al., 1995; McKeever et al., 2002). In addition, Schäfers et al. (2001) have reported different cofactor

preference for 17β-HSD 3 on different days of postnatal development in rat.
