*Clinical importance of 3β-HSD genetic deficiency:*

Homozygous mutations in *HSD3B1* are lethal in human due to interruption of pregnancy before the end of the first trimester because 3β-HSD I protein is required for progesterone synthesis in the placenta (as described above for *CYP11A).* Many mutations in the *HSD3B2*  gene have been identified and are summarized in a review by Simard et al. 2005 [31]. The classical 3β-HSD deficiency results from mutations in the *HSD3B2* gene (the *HSD3B1* gene in these patients is normal) and it can be divided, depending upon the severity of the saltwasting (salt-wasting or non-salt-wasting forms). The classical 3β-HSD deficiency is a rare form of congenital adrenal hyperplasia (CAH) accounting for about 1–10% of cases of CAH. The salt-losing forms of CAH are a group of life-threatening diseases that require prompt recognition and treatment. Indeed, the autosomal recessive mutations in the *CYP21*, *CYP17*, *CYP11B1*, and *HSD3B2* genes encoding steroidogenic enzymes can cause CAH, each resulting in different biochemical consequences and clinical features. In these cases the cortisol secretion is impaired resulting in compensatory hypersecretion of ACTH and consequent hyperplasia of the adrenal cortex. However, only deficiencies in 21-hydroxylase (*CYP21*) and 11β-hydroxylase (*CYP11B1*) predominantly result in virilizing disorders. Indeed, in patients with the classical form of these two defects, the most noticeable abnormality in the sexual phenotype is the masculinization of the female fetus due to oversynthesis of adrenal DHEA. Male individuals suffering from classical 3β-HSD deficiency present hypospadias. On the other hand, the complete or partial inhibition of 3β-HSD activity in the adrenals and ovaries was not accompanied by a noticeable alteration in the differentiation of the external genitalia of female patients. The reason for this striking difference in phenotype between the male and female individuals is that the deficiency of 3β-HSD in the fetal testis results in lowering of the T levels below the levels required for the normal development of male external genitalia.

The basal plasma levels of ∆5-3β-hydroxy steroids such as pregnenolone (PREG), 17OH-PREG, and DHEA are elevated in affected individuals. An elevated ratio of ∆5/∆4-steroids is considered to be the best biological parameter for the diagnosis of 3β- HSD deficiency. The best criteria for the correct diagnosis of this disorder now appears to be a plasma level of 17OH-PREG but 17OH Progesterone (17OH-PROG) also should be measured for correct diagnosis of 3β-HSD deficiency. It is well recognized that plasma levels of 17OH-PROG and ∆4-DIONE and other ∆4-steroids are frequently elevated in 3β-HSD-deficient patients. Such observations are consistent with a functional type I 3β-HSD enzyme that is expressed in peripheral tissues. Moreover, the peripheral type I 3β-HSD activity could explain why certain patients were initially misdiagnosed as suffering from 21-hydroxylase deficiency, in view of elevated levels of 17OH-PROG and mild virilization seen in girls at birth. Therefore, measurement of the levels of 17OH-PREG should be performed when an elevated level of 17OH-PROG has been observed in a female neonate without ambiguity of external genitalia or if the patient is a male pseudohermaphrodite [31].

126 Dehydrogenases

regulated transcription?

*Clinical importance of 3β-HSD genetic deficiency:* 

normal development of male external genitalia.

expression such as adrenal insufficiency, male pseudohermaphroditism and polycystic ovary syndrome (PCOS) [31]. Immune cell populations in the ovary undergo changes during the reproductive cycle and cytokines from these immune cells (Interleukin-4, IL-4) have been shown to affect steroidogenesis, mediated by Stat [94]. Some growth factors like members of the TGFβ family and nerves growth factor have been shown to regulate *HSD3B2* gene expression [95-97]. There is growing evidence in the literature that steroid hormones modulate type II 3β-HSD expression. For example, glucocorticoids stimulate the expression of 3β-HSD in adrenal cells [98], whereas androgens inhibit 3β-HSD expression in the adrenal cortical cells and in testicular Leydig cells [99, 100]. There are number of questions concerning the mechanisms of steroids and the action of their receptors. In relation to structure-function aspects the question is what is the influence of known steroid agonists and antagonists on the efficacy of activation? What is the effect of other nonsteroid factors, which are known to activate other intracellular signaling pathways on steroid-

Homozygous mutations in *HSD3B1* are lethal in human due to interruption of pregnancy before the end of the first trimester because 3β-HSD I protein is required for progesterone synthesis in the placenta (as described above for *CYP11A).* Many mutations in the *HSD3B2*  gene have been identified and are summarized in a review by Simard et al. 2005 [31]. The classical 3β-HSD deficiency results from mutations in the *HSD3B2* gene (the *HSD3B1* gene in these patients is normal) and it can be divided, depending upon the severity of the saltwasting (salt-wasting or non-salt-wasting forms). The classical 3β-HSD deficiency is a rare form of congenital adrenal hyperplasia (CAH) accounting for about 1–10% of cases of CAH. The salt-losing forms of CAH are a group of life-threatening diseases that require prompt recognition and treatment. Indeed, the autosomal recessive mutations in the *CYP21*, *CYP17*, *CYP11B1*, and *HSD3B2* genes encoding steroidogenic enzymes can cause CAH, each resulting in different biochemical consequences and clinical features. In these cases the cortisol secretion is impaired resulting in compensatory hypersecretion of ACTH and consequent hyperplasia of the adrenal cortex. However, only deficiencies in 21-hydroxylase (*CYP21*) and 11β-hydroxylase (*CYP11B1*) predominantly result in virilizing disorders. Indeed, in patients with the classical form of these two defects, the most noticeable abnormality in the sexual phenotype is the masculinization of the female fetus due to oversynthesis of adrenal DHEA. Male individuals suffering from classical 3β-HSD deficiency present hypospadias. On the other hand, the complete or partial inhibition of 3β-HSD activity in the adrenals and ovaries was not accompanied by a noticeable alteration in the differentiation of the external genitalia of female patients. The reason for this striking difference in phenotype between the male and female individuals is that the deficiency of 3β-HSD in the fetal testis results in lowering of the T levels below the levels required for the

The basal plasma levels of ∆5-3β-hydroxy steroids such as pregnenolone (PREG), 17OH-PREG, and DHEA are elevated in affected individuals. An elevated ratio of ∆5/∆4-steroids is
