**4.1. Pituitary hormones and other peptides**

Primary control of 3β-HSD expression occurs through the activation by LH its receptor and the induction of the cAMP second messenger system (Simard et al., 2005). Recent findings from our own laboratory have revealed that bank vole Leydig cells treated with LH have increased steroidogenic capacity and T secretion (Gancarczyk et al., 2003). A profound hypogonadal effect and suppression of T production has been demonstrated in boars treated with deslorelin, an agonist of gonadotropin-releasing hormone (GnRH), (Kopera et al., 2008). In Leydig cells of treated boars very weak or lack of LHR and 3β-HSD expression has been detected. In contrast, Lin et al. (2008) who treated mouse Leydig cells with GnRH agonists (I and II) have demonstrated that 3β-HSD has been stimulated directly resulting in increase of T production. On the contrary, 17β-HSD was not induced in treated cells.

Formation of cAMP activates steroidogenesis by temporally distinct manners either, acutely (minutes) due to StAR action or chronically (hours) related on P450scc, P450c17, 3β-HSD and 17β-HSD activities. The delivery of cholesterol into the inner mitochondrial membrane is the rate-determining step in steroidogenesis. Also the differences in the way that cultured Leydig cells respond to cAMP have been reported. In mouse Leydig cells, cAMP has stimulated T production which then suppressed 3β-HSD at the mRNA level, whereas addition of cAMP to cultured rat Leydig cells increases 3β-HSD activity and expression at both the mRNA and protein level after 24–72 h (Keeney & Mason 1992; Payne & Sha 1991).

Interestingly, expression of 3β-HSD has been reported to be dependent upon steroidogenesis factor 1 (SF1). SF1 response element has been detected in the proximal promoter region of the human 3β-HSD type II gene. Recently Scott et al. (2009) have confirmed that the mouse 3β-HSD I gene promoter has three potential SF1 consensus binding sites. However, it is currently unknown whether SF1 regulates the expression of 17β–HSD.

A series of studies show that pituitary hormone-prolactin (PRL) and thyroid hormones regulate activity of HSDs. In Leydig cells of hypophysectomized rats treated with PRL, a significant increase in number of 3β-HSD immunopositive cells together with an increase in T and E2 concentrations was found (Dombrowicz et al., 1992; Manna et al., 2001). Also our

own studies have revealed that in bank voles treated with PRL, the levels of androgens and estrogens have increased markedly within the testis (Gancarczyk et al., 2006). These results point the role of PRL in promoting multiplication, differentiation and regulation of steroidogenic function of Leydig cells. Similar functions have been confirmed for thyroid hormones. In physiological levels these hormones have profoundly increased the number of mesenchymal precursors of ALCs and supported their further differentiation (Maran, 2003; Mendis-Handagama et al., 1998; Teerds et al., 1998).

Hydroxysteroid Dehydrogenases – Localization, Function and Regulation in the Testis 273

synthesis, whereas TNF also reduced basal enzyme expression. In contrast, epidermal growth factor (EGF) increased activity and expression of 3β-HSD, which has also been demonstrated for transforming growth factor (TGF). Acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF) inhibited 3β-HSD. In pig Leydig cells, bFGH has been reported to increase 17β-HSD expression (Sordoillet et al., 1992). Our own studies in bank voles have revealed that insulin like growth factor I (IGF-I) stimulates whereas IL-1 and interleukin 1α (IL-1α) inhibit testis steroidogenic and spermatogenic function in sexually active males (Gancarczyk et al., 2006; Kmicikiewicz & Bilinska, 1997; Kmicikiewicz et al., 1999). Interesting results have been recently reported by Ivell et al. (2011) who demonstrated that 17β-HSD 10 mRNA expression in mice testis is regulated by locally

In seasonal breeders the function of the pituitary-testicular axis undergoes annual cyclic variations. Multiple studies including our own have shown that photoperiod is an important factor regulating steroidogenesis. Changes in LH and FSH secretion depending on the light length are responsible for seasonal variations in size, structure and function of the testis (Bartke & Steger, 1992). Under laboratory conditions, bank voles kept in long light regime show higher testis weight and increased steroidogenic activity than animals exposed to short one (Bilinska et al., 2000, 2001; Tähkä et al., 1982). In several seasonal breeders, the serum and testicular concentrations of steroid hormones have exhibited seasonal fluctuations and are always lower in regressed animals (Frungieri et al., 1999; Hance et al.,

In addition, the Leydig cell morphology as well as localization and expression of HSDs have been found to change seasonally in the sika deer, black bear and northern fur seal (Hayakawa et al., 2010; Ibluchi et al., 2010; Tsubota et al., 1997, 2001). In black bears during their mating season, 17β-HSD 3 has been detected both in Leydig cells and in Sertoli cells. Moreover, in these animals expression of 3β-HSD was the highest in June. In Syrian hamster, specific melatonin receptors (mel1a) have been reported in Leydig cells via which melatonin down-regulated the gene expression of both 3β-HSD, and 17β-HSD (Frungieri et

A large body of information concerning the effects of endocrine disrupting compounds (EDCs) on Leydig cells steroidogenesis during fetal development and in adult mammals has been accumulated in the past decades. EDCs can disturb morphology and normal endocrine functions of the Leydig cells or oppose the actions of androgen through their estrogenic or anti-androgenic properties (Hejmej et al., 2011a). A number of compounds act directly on Leydig cells to diminish T production by interfering with the expression of steroidogenic

enzymes, at the protein and/or mRNA level (Skakkebaek, et al., 2001).

produced relaxin (RLN) dependently of animal age.

**4.4. Photopheriod**

2009; Kotula-Balak et al., 2003).

**4.5. Endocrine disrupting chemicals**

al., 2005).
