**3.2 Disorders of androgen synthesis**

Disorders of androgen synthesis are characterized by a lack of Müllerian structures. The testes in 46, XY individuals produce Anti-Müllerian hormone and have genital abnormalities including normal female external genitalia.

Two categories can be used to describe Disorders of Androgen Synthesis:


Seven enzymes involved in the production of testosterone and dihydrotestosterone, responsible for 46, XY disorders of sex differentiation have been identified (**Figure 5**).

#### **Figure 5.**

*Steroid hormone synthesis pathway and associated biochemical abnormalities in 46, XY DSD. POR: P450 oxidoreductase; StAR: steroid acute regulatory protein; 17*α*-OH: 17*α*-hydroxylase; 3*β*-HSD: 3*β*-hydroxysteroid dehydrogenase; 21-OH: 21-hydroxylase; 18-OH: 18-hydroxylase; 11*β*-OH: 11*β*-hydroxylase; 17*β*-HSD: 17*β*-hydroxysteroid dehydrogenase; 5*α*-R: 5*α*-reductase; CAH: congenital adrenal hyperplasia (adapted from [17]).*

#### *3.2.1 Disorders of androgen synthesis associated with adrenal dysfunction*

Defects early in the pathway result in congenital adrenal hyperplasia and adrenal insufficiency. These enzymes are present in both the adrenal cortex and the gonads.

The first enzymatic step involves the steroidogenic acute regulatory (*StAR*) protein and p450 oxidoreductase (*POR*) (**Figure 5**), these enzymes cause the cleavage of cholesterol to pregnenolone. Pathogenic mutaions in the *StAR* gene lead to an autosomal recessive lipoid congenital adrenal hyperplasia (OMIM 201710). The condition is characterized by lipid accumulation, severe salt wasting and genital ambiguity. This genital involvement ranges from hypospadias to complete female external genitalia. P450 oxidoreductase defects are commonly associated with Antley-Bixler syndrome with genital anomalies and disorders in steroidogenesis (OMIM 201750). P450 oxidoreductase defects have been found with a non– syndromic presentation (OMIM 613571) with a similar picture to *StAR* mutations but lacking CAH [32].

3β-hydroxysteroid dehydrogenase (3β-HSD) is the next major enzyme involved in multiple steps including converting pregnelone to progesterone, 17α-OH pregenelone to 17α-OH progesterone and DHEA to androstenedione. Defects in 3β-HSD enzyme activity result in salt wasting and decreased testosterone production resulting in genital abnormalities in males. The findings include hypospadias, micropenis and bifid scrotum (OMIM 201810).

17α-hydroxylase is involved in the conversion pregnelone and progesterone to their 17α hydroxylated forms. Defects to this enzyme pathway also present with increased risk for adrenal insufficiency and ambiguous genitalia. Patients presenting with a combined deficiency in 17α-hydroxylase and 17,20-lyase present similarly to isolated 17α-hydroxylase deficiency. Patients with isolated 17,20-lyase deficiency have normal adrenal function and variable abnormalities of male phenotype. This is because 17,20-lyase is present in the gonads only.

#### *3.2.2 Disorders of androgen synthesis not associated with adrenal dysfunction*

17β-hydroxysteroid dehydrogenase type III (**Figure 5**) leads to the conversion of androstenedione into testosterone, this occurs within the gonads. Pathogenic variants cause an autosomal recessive disorder (OMIM 264300) with female external genitalia in 46, XY individuals, male gonadal derivatives, absent Müllerian structures, infertility and decreased testosterone [33]. These patients are sometimes difficult to distinguish from 5α-reductase deficiency and partial androgen insensitivity syndrome [34]. Further biochemical testing with ACTH stimulation or hCG stimulation may be needed [17] although DNA analysis is probably the easiest to perform.

Testosterone and dihydrotestosterone (DHT) are the end products for testis steroid hormone synthesis. Pathogenic variants occurring in the 5α-reductase gene (*SRD5A2*) lead to various biochemical changes including low levels of DHT, normal/increased levels of testosterone and high testosterone/DHT levels. Patients present with undermasculinization of the external genitalia due to low levels of DHT [34]. The presentation ranges from a female phenotype to a small phallus with severe hypospadias. These patients have normal male internal genitalia and some patients may have normal sperm production.

#### **3.3 Disorders of androgen response**

The most common cause of 46, XY DSD are the androgen insensitivity syndromes (AIS) [OMIM # 300068]. The androgen receptor (AR) is unable to activate due to the inability of testosterone or DHT to bind to the receptor [35]

**69**

*Approach to the Newborn with Disorders of Sex Development*

(**Figure 5**). Androgens have a lack of effect on genital development. These conditions are X-linked inherited and present with a wide range in phenotypes. Complete Androgen Insensitivity Syndrome (CAIS) has an estimated prevalence of at least 1:99,000 [36] presenting with normal female genitalia and blind ending vaginal pouch. Partial Androgen Insensitivity Syndrome (PAIS) has an estimated prevalence of 1:8000. This conditions occurs when there is residual AR receptor function and hypospadias are the common finding. Mild Androgen Insensitivity Syndrome (MAIS) is the least severe. MAIS usually presents with no genital abnormalities. This condition can be suspected in the context of pubertal gynecomastia or unexplained infertility [33]. Pathogenic variants in AR have been associated with AIS. These pathogenic variants can be located outside of the coding region [37, 38]. There have been some cases where no pathogenic variants in AR have been detected. This suggests other proteins located beyond AR that influence testosterone signaling [39].

2.Excess androgen levels due to abnormal synthesis or androgen exposure.

There are two types of abnormal development that can cause XX sex reversal:

1.Patients who have the presence of the *SRY* gene. This can be caused by a translocation of the *SRY* gene to another chromosome, usually the X chromosome.

Loss of function mutations in genes coding for ovarian formation and function are associated with ovarian dysgenesis and/or accelerated loss of primordial follicles. This can cause premature ovarian failure (POF) and/or premature menopause. The gene responsible for the differentiation of the bipotential gonad into ovaries

is the *WNT4* gene (**Figure 4**). The *WNT4* gene is a member of the WNT family of secreted molecules. This family of genes function in a paracrine manner. The WNT proteins are ligands to members of the Frizzled (FZ) family of cell surface receptors. They are also possibly ligands to the single-pass transmembrane protein LDL-receptor-related proteins 5 and 6 (*LRP5* and *LRP6*) [40]. The binding of WNT to FZ leads to reduced degradation of β-catenin. This causes β-catenin-dependent activation of T-cell factor/lymphocyte enhancer factor transcription factors that lead to the induction of WNT – responsive genes [41]. *WNT4* is produced in ovarian pre-granulosa cells. *WNT4* up-regulates the gene *DAX1* [42], which antagonizes *NR5A1*, and inhibits steroidogenic enzymes. *WNT4* – knockout XX mice have been shown to have no Müllerian ducts derivatives, have present Wolffian ducts and masculinized with the expression of the steroidogenic enzymes, namely 3β hydroxy steroid dehydrogenase and 17α hydroxylase. They are critically important in the production of testosterone. Conversely, they are normally suppressed in the developing female ovary. Mice models showed ovaries with a decreased number of oocytes. This demonstrates the important role of *WNT4* in maintaining the female

In some rare cases a translocation to an autosome occurs.

2.Patients who are XX males and *SRY* – negative

*DOI: http://dx.doi.org/10.5772/intechopen.94570*

**4. 46, XX disorders of sex development**

46, XX DSD can occur due to:

**4.1 Ovarian development**

1.Abnormal ovarian development.

*Approach to the Newborn with Disorders of Sex Development DOI: http://dx.doi.org/10.5772/intechopen.94570*

*Congenital Anomalies in Newborn Infants - Clinical and Etiopathological Perspectives*

*3.2.1 Disorders of androgen synthesis associated with adrenal dysfunction*

but lacking CAH [32].

and bifid scrotum (OMIM 201810).

because 17,20-lyase is present in the gonads only.

patients may have normal sperm production.

**3.3 Disorders of androgen response**

Defects early in the pathway result in congenital adrenal hyperplasia and adrenal insufficiency. These enzymes are present in both the adrenal cortex and the gonads. The first enzymatic step involves the steroidogenic acute regulatory (*StAR*) protein and p450 oxidoreductase (*POR*) (**Figure 5**), these enzymes cause the cleavage of cholesterol to pregnenolone. Pathogenic mutaions in the *StAR* gene lead to an autosomal recessive lipoid congenital adrenal hyperplasia (OMIM 201710). The condition is characterized by lipid accumulation, severe salt wasting and genital ambiguity. This genital involvement ranges from hypospadias to complete female external genitalia. P450 oxidoreductase defects are commonly associated with Antley-Bixler syndrome with genital anomalies and disorders in steroidogenesis (OMIM 201750). P450 oxidoreductase defects have been found with a non– syndromic presentation (OMIM 613571) with a similar picture to *StAR* mutations

3β-hydroxysteroid dehydrogenase (3β-HSD) is the next major enzyme involved in multiple steps including converting pregnelone to progesterone, 17α-OH pregenelone to 17α-OH progesterone and DHEA to androstenedione. Defects in 3β-HSD enzyme activity result in salt wasting and decreased testosterone production resulting in genital abnormalities in males. The findings include hypospadias, micropenis

17α-hydroxylase is involved in the conversion pregnelone and progesterone to their 17α hydroxylated forms. Defects to this enzyme pathway also present with increased risk for adrenal insufficiency and ambiguous genitalia. Patients presenting with a combined deficiency in 17α-hydroxylase and 17,20-lyase present similarly to isolated 17α-hydroxylase deficiency. Patients with isolated 17,20-lyase deficiency have normal adrenal function and variable abnormalities of male phenotype. This is

17β-hydroxysteroid dehydrogenase type III (**Figure 5**) leads to the conversion of androstenedione into testosterone, this occurs within the gonads. Pathogenic variants cause an autosomal recessive disorder (OMIM 264300) with female external genitalia in 46, XY individuals, male gonadal derivatives, absent Müllerian structures, infertility and decreased testosterone [33]. These patients are sometimes difficult to distinguish from 5α-reductase deficiency and partial androgen insensitivity syndrome [34]. Further biochemical testing with ACTH stimulation or hCG stimulation may be needed [17] although DNA analysis is probably the easiest to perform. Testosterone and dihydrotestosterone (DHT) are the end products for testis steroid hormone synthesis. Pathogenic variants occurring in the 5α-reductase gene (*SRD5A2*) lead to various biochemical changes including low levels of DHT, normal/increased levels of testosterone and high testosterone/DHT levels. Patients present with undermasculinization of the external genitalia due to low levels of DHT [34]. The presentation ranges from a female phenotype to a small phallus with severe hypospadias. These patients have normal male internal genitalia and some

The most common cause of 46, XY DSD are the androgen insensitivity syndromes (AIS) [OMIM # 300068]. The androgen receptor (AR) is unable to activate due to the inability of testosterone or DHT to bind to the receptor [35]

*3.2.2 Disorders of androgen synthesis not associated with adrenal dysfunction*

**68**

(**Figure 5**). Androgens have a lack of effect on genital development. These conditions are X-linked inherited and present with a wide range in phenotypes. Complete Androgen Insensitivity Syndrome (CAIS) has an estimated prevalence of at least 1:99,000 [36] presenting with normal female genitalia and blind ending vaginal pouch. Partial Androgen Insensitivity Syndrome (PAIS) has an estimated prevalence of 1:8000. This conditions occurs when there is residual AR receptor function and hypospadias are the common finding. Mild Androgen Insensitivity Syndrome (MAIS) is the least severe. MAIS usually presents with no genital abnormalities. This condition can be suspected in the context of pubertal gynecomastia or unexplained infertility [33]. Pathogenic variants in AR have been associated with AIS. These pathogenic variants can be located outside of the coding region [37, 38]. There have been some cases where no pathogenic variants in AR have been detected. This suggests other proteins located beyond AR that influence testosterone signaling [39].
