**4.2.2 Pubertal**

At the time of puberty, patients initially reared as females who have not undergone gonadectomy may have primary amenorrhea and varying degrees of virilization, including development of male body habitus, increased body hair and deepening of the voice (Faienza et al., 2007; Lee et al., 2007; Mains et al., 2008; Mendonca et al., 2000; Rosler et al., 1992; Rosler et al., 1996;). The clitoris can enlarge to as much as 5–8 cm in length due to peripheral conversion of T (Balducci et al., 1985; Mendonca et al., 2000;), but still remains smaller than a normal-sized penis and may be affected by chordee (Farkas § Rosler, 1993).

The paradox of the failure of intrauterine virilization but virilization in puberty remains an enigma not fully explained. A limited capacity of the extragonadal tissues to convert 4-A to T in embryonic life might explain the lack of virilization at birth (Ulloa-Aguirre et al., 1985). This might then be overcome at puberty, when the levels of 4-A are more elevated and thus activate the peripheral conversion into T. It has been demonstrated that in these subjects more than 90% of circulating T derives from peripheral conversion of 4-A into T by other isoenzymes (Andersson et al., 1996; Goebelsmann et al.,1973). There is abundant evidence of the presence of 17-HSDs and other enzymes involved in androgen formation in a large series of human tissues, particularly liver, skin and adipose tissue (Martel et al., 1992).

This extragonadal activity is presumable under different genetic control (17-HSD type 1, 2 or 5 encoding gene) which is apparently unimpaired in these patients (Andersson et al., 1996; Luu-The et al., 1989).

Moreover, there seems to be a correlation between the type of mutation and the percentage of enzyme inactivation. There are several reports showing a residual enzymatic activity (15- 20%) in cultured mammalian cells carrying the R80Q mutation, after several hours of incubation with the substrate (androstenedione). On the contrary, most missense mutations seems to severely impair the enzyme activity (Andersson et al., 1996; Geissler et al., 1994;).

A late onset form of 17-HSD3 deficiency causing breast development was reported in up to 6% of the patients with idiopathic pubertal gynecomastia (Castro-Magana et al., 1993).

It appeared to be related to the functional inactivity of 17-HSD3 during puberty and increased aromatization of 4-A to produce excessive estrogens; however, the *HSD17B3*  gene was not studied for defects in this study (Balducci et al., 1985; Bertelloni et al., 2009b).
