**2.1 Family members of 17-HSDs**

The main function of 17HSD type 1 (17HSD1), which has its highest concentration in the ovaries and placenta, is the catalytic reduction of estrone to estradiol (Luu The et al., 1989). 17-HSD type 2 (17-HSD2) plays a major role in the inactivation of the sex steroid hormones by oxidizing estradiol and testosterone (T) to estrone and 4-Androstenedione (4-A), respectively (Wu et al., 1993), and has a broad tissue distribution (Casey et al., 1994). 17-HSD type 3 (17-HSD3) plays a predominant role in male T production from 4-A (Geissler et al., 1994). Although this enzyme is found primarily in the testes, it is also present in adipose tissue, brain, sebaceous glands and bone. 17-HSD type 4 (17HSD4) is expressed in the liver (Adamski et al., 1996) and in the peroxisomes (Markus et al., 1995); this isoenzyme plays a major function in the metabolism of fatty acids, as has been described in murine models, while it has a minor role in the metabolism of steroids. In humans, mutations of the gene encoding for 17HSD4 isoenzyme lead to serious illness and death within the first year of life (Moller et al., 2001). 17-HSD type 5 (17HSD5), which is highly expressed in the testes, prostate, adrenals and liver, is believed to play a major role in the conversion of 4-A to T and therefore could explain the virilization obtained in patients affected with alterations of 17-HSD3. 17-HSD type 7 (17-HSD7) has been shown to play a role in metabolism of cholesterol (Marijanovic Z et al., 2003). 17HSD type 8 (17-HSD8) has been linked to a recessive form of polycystic kidney disease (Fomitcheva et al., 1998). Several of the 17HSD enzymes show overlap with enzymes involved in lipid metabolism (Tab.1).

Since most of the 17-HSD enzymes are steroid metabolizing enzymes, they are possible drug targets in many cancers, such as breast and prostate cancer, as well as common diseases, such as obesity and metabolic syndrome.

### **2.2 The role of 17-HSDs**

In a study conducted to observe the tissue-specificity of the transcriptional profiles of the 17-HSDs, the expression of 17-HSDs type 1, 2, 3, 4, 5, 7 and 10 was observed both in the genital skin fibroblasts (both scrotal and foreskin) and in the peripheral blood, with the

metabolizing enzymes such as aromatase, steroid sulfatase, 3-HSD and 5-reductase are able to produce their own hormones at the peripheral cells (intracrine activity). In steroidogenic tissues (the gonads and adrenal cortex) they catalyze the final step in androgens, estrogens and progesterone byosinthesis; in peripheral tissues, they convert active steroid hormones into their metabolites, and regulate hormone binding to their nuclear receptor. So far, 14 17HSDs have been characterized in mammals, which show little amino acid homology but that are all members of the SDR family, with the exception of 17-HSD type 5 (17-HSD5) which is an aldo-keto reductase (Lukacik et al., 2006; Luu The, 2001; Prehn et al., 2009). These isoenzymes differ as regards tissue-specific expression, catalytic activity, substrate and cofactors specificity (NAD/NADH *vs* NADP/NADPH), and subcellular localization (Payne § Hales, 2004). Although *in vitro* they act both as reductase or as oxidase enzymes, *in vivo* they work in a predominat one-way, or reductive or oxidative, converting inactive 17-ketosteroids in their active 17-hydroxy forms (Khan et al., 2004). Thus, they can be grouped into *in vivo* oxidative enzymes (17-HSD types 2, 4, 6, 8, 9, 10, 11

The main function of 17HSD type 1 (17HSD1), which has its highest concentration in the ovaries and placenta, is the catalytic reduction of estrone to estradiol (Luu The et al., 1989). 17-HSD type 2 (17-HSD2) plays a major role in the inactivation of the sex steroid hormones by oxidizing estradiol and testosterone (T) to estrone and 4-Androstenedione (4-A), respectively (Wu et al., 1993), and has a broad tissue distribution (Casey et al., 1994). 17-HSD type 3 (17-HSD3) plays a predominant role in male T production from 4-A (Geissler et al., 1994). Although this enzyme is found primarily in the testes, it is also present in adipose tissue, brain, sebaceous glands and bone. 17-HSD type 4 (17HSD4) is expressed in the liver (Adamski et al., 1996) and in the peroxisomes (Markus et al., 1995); this isoenzyme plays a major function in the metabolism of fatty acids, as has been described in murine models, while it has a minor role in the metabolism of steroids. In humans, mutations of the gene encoding for 17HSD4 isoenzyme lead to serious illness and death within the first year of life (Moller et al., 2001). 17-HSD type 5 (17HSD5), which is highly expressed in the testes, prostate, adrenals and liver, is believed to play a major role in the conversion of 4-A to T and therefore could explain the virilization obtained in patients affected with alterations of 17-HSD3. 17-HSD type 7 (17-HSD7) has been shown to play a role in metabolism of cholesterol (Marijanovic Z et al., 2003). 17HSD type 8 (17-HSD8) has been linked to a recessive form of polycystic kidney disease (Fomitcheva et al., 1998). Several of the 17HSD enzymes show overlap with enzymes involved in lipid metabolism

Since most of the 17-HSD enzymes are steroid metabolizing enzymes, they are possible drug targets in many cancers, such as breast and prostate cancer, as well as common

In a study conducted to observe the tissue-specificity of the transcriptional profiles of the 17-HSDs, the expression of 17-HSDs type 1, 2, 3, 4, 5, 7 and 10 was observed both in the genital skin fibroblasts (both scrotal and foreskin) and in the peripheral blood, with the

and 14) and *in vivo* reductive enzymes (17-HSD types 1, 3, 5 and 7).

**2.1 Family members of 17-HSDs** 

diseases, such as obesity and metabolic syndrome.

(Tab.1).

**2.2 The role of 17-HSDs** 


17β-Hydroxysteroid Dehydrogenase Type 3 Deficiency:

dehydrogenase deficiency (Geissler et al., 1994).

**3. Development of the male genitalia** 

lead to a child with a DSD.

**3.1 Disorders of sexual development** 

al., 1996).

2006).

Diagnosis, Phenotypic Variability and Molecular Findings 123

(Lukacik et al., 2006). It is encoded by *HSD17B3* gene which maps to chromosome 9q22; it is 60 kb in length and contains 11 exons. The cDNA encodes a protein of 310 amino-acids with a molecular mass of 34.5 kDa and no apparent membrane-spanning domain (Andersson et

It has been demonstrated that *HSD17B3* gene is constitutively suppressed and its transcription begins only upon removal of suppressors that act on the Alu repeat region located upstream of the translation site start of the gene promoter region (Xiaofei et al.,

*HSD17B3* gene alterations affecting the enzyme function have been associated with a rare form of 46,XY disorder of sexual development (DSD), termed 17-hydroxisteroid

The development of the male internal and external genitalia in an XY fetus requires a complex interplay of many critical genes, enzymes and cofactors (Hannema § Hughes, 2007). Wolffian ducts (mesonephric ducts) and mullerian ducts (paramesonephric ducts) are both present in early fetal life in the bipotential embryo. The wolffian ducts are the embryological structures that form the epididymis, vas deferens and seminal vesicles. T is produced by Leydig cells as early as 8 weeks of gestation and acts on the androgen receptor to stabilize the wolffian ducts (Tong et al., 1996). T and its 5-reduced end product, dihydrotestosterone (DHT), induce the formation of male external genitalia, including the urethra, prostate, penis and scrotum (Wilson, 1978). The mullerian ducts should regress in a male with the presence of the mullerian inhibiting substance produced by Sertoli cells in the testes. In addition, multiple other factors are necessary for the male phenotype to be congruent with a 46,XY genotype. The enzyme 17HSD3 is present almost exclusively in the testes and converts 4-A to T. The 5 -reductase type 2 enzyme is needed to convert T to DHT. In order for T and DHT to exert their androgenic role, there must be an intact androgen receptor. The lack of any one of these critical factors, including 17HSD3, can

Disorders of sexual development (DSDs) are congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical (Houk et al., 2006; Hughes et al., 2006). These disorders are classified into three major categories: sex chromosome DSD, 46,XX DSD and 46,XY DSD. This designation was proposed to replace the former term of pseudohermaphroditism, according to the consensus statement on management of intersex disorders (Hughes et al., 2006). 46,XY DSD are a heterogeneous group of clinical conditions characterized by 46,XY karyotype, either normal or dysgenetic testes and female or ambiguous phenotype of external (and possibly internal) genitalia (Hughes et al., 2006). This disorder can have several etiologies, but more frequently is due to a disruption in androgen production and/or action. Defects in androgen action and metabolism include mutations in the androgen receptor gene (complete, partial or mild androgen insensivity syndrome-AIS and Kennedy syndrome), or in the steroid 5-reductase type 2 gene, encoding the enzyme which convert T into DHT in the uro-genital tract (Quigley et al., 1995; Wilson et al., 1993). Instead, disorders of androgens biosynthesis are rare and usually due to alteration of enzyme involved in the conversion of cholesterol to T, such as the steroidogenic acute


E 1 = Estrone; E2 = 17-estradiol; 5-diol = androst-5-ene 3 DHEA = dihydroepiandrosterone;

NADPH/NADP+ = nicotinamide adenine di nucleotide phosphate;

4-A = androstenedione; T = testosterone;

FA = fatty acids

Table 1. The different types of identified 17-HSD with corresponding locations and function

exception of the 17-HSD-2 which was not seen in peripheral blood (Hoppe et al., 2006). All 17-HSDs except 17HSD1 showed a significantly higher mRNA concentration in the foreskin compared to the scrotal tissue, demonstrating a tissue-specific local control of steroid hormone synthesis and action in addition to systemic effects (Hoppe et al., 2006). It has been demonstrated that the expression of 17-HSD5 increases with aging in scrotal skin fibroblasts and in peripheral blood mononuclear cells, while the 17-HSD3 mRNA expression is higher in the younger age subjects (Hammer et al., 2005; Hoppe et al., 2006). This implicates that 17-HSD3 has a more important role in childhood, which later is taken over by the 17-HSD5 after puberty.

It was also demonstrated the existence of a large inter individual variability of the enzymatic transcription patterns (Hoppe et al., 2006). Microarray investigation of multiple blood samples taken on different days from the same individual showed time-dependent differences in gene clustering. The nature and extent of inter individual and temporal variation in gene expression patterns in specific cells and tissues is an important and relatively unexplored issue in human biology (Whitney et al., 2003). In light of such intraand inter individual variability, basal and after stimulation levels of the steroid hormones can vary a within wide range in normal subjects.
