Biochemical evidence for defective androgen receptor

3.3.1.1 Pituitary-testicular axis

In patients with AIS, assessment of the pituitary-gonadal axis is age-dependent. In the normal male, a rise of gonadotropins and testosterone is seen during the first months of life, usually starting after the first week postnatally with a decline after six months to prepubertally low levels (Forest etal. 1973). Recently, Bouvattier described infants with CAIS and PAIS with regard to postnatal changes in testosterone and gonadotropins (Bouvattier et al. 2002). Interestingly, in CAIS testosterone as well as gonadotropin levels were lower than in normal 46,XY male infants in the second months of life. However, in patients with PAIS, while there were overall normal values for gonadotropins, the testosterone values in serum were markedly increased compared to CAIS and to the normal age range. This has also been described earlier (Hiort etal. 1993).

This observation of elevated testosterone may also be seen as a response to stimulation with human chorionic gonadotropin (hCG) in prepubertal children with PAIS after the first months of life. However, in other cases, mainly in CAIS, the testosterone response to hCG maybe subnormal, falsely indicative of a testosterone biosynthesis defect (Ahmed etal. 1999; Hellwinkel etal. 1999). This makes diagnosis of androgen insensitivity in the hormonal quiescence of childhood very difficult.

After puberty, androgen insensitivity can be inferred from both elevated LH and testosterone levels. The elevation of LH and testosterone is most likely due to an impaired negative feedback control of the hypothalamic-pituitary-testicular axis in AIS (Aiman etal. 1979). It is discernible even in patients with the minimal form of AIS (Hiort et al. 2000); however, the androgen sensitivity index derived from the product of the values for LH and testosterone is not a specific parameter of AIS. In a recent study by Melo et al. (2003), the androgen sensitivity index was elevated in all postpubertal patients with AIS; however, the LH levels were higher in CAIS. The higher elevation of LH in patients with CAIS was attributed to the severity of the underlying molecular defect. These authors found the androgen sensitivity index a valuable parameter in postpubertal patients to distinguish AIS from other forms of intersex disorders.

3.3.1.2 SHBG androgen sensitivity test

Especially in infants and children with ambiguous genitalia, the diagnosis of AIS may be difficult due to the uninformative hormonal profile. Alternatively, ligand binding analysis in genital skin fibroblasts derived from a genital biopsy has been employed although this is a cumbersome, invasive and costly diagnostic approach to AIS (Hiort etal. 1993). In contrast, DNA analysis of the AR gene allows a definitive diagnosis (see below), but is also costly and time consuming, nor does it lead to a functional prognosis of future development in the tested infant. Therefore, a specific test of androgen sensitivity in vivo has been applied to children with AIS, based on the ability of the anabolic steroid stanozolol to induce a decline in serum sex hormone binding globulin (SHBG) (Sinnecker et al. 1989). Stanozolol is a non-virilizing anabolic steroid, inducing very promoter-specific effects via the AR in in vitro experiments (Holterhus et al. 2002). In a cohort of pre- and postpubertal patients with AIS, stanozolol given at a dose of 0.2 mg/kg per day on three consecutive days led to a decline in serum SHBG levels between days 5 and 8 after start of the test, which was correlated to the phenotype (Sinnecker etal. 1997).

Thus, the SHBG-androgen sensitivity test is the only in vivo test known today to assess AR function in a given individual. This may be useful in the discussion of gender assignment and prognosis of future development. However, this test has two major drawbacks. Firstly, it is not sensitive during the first six months of life, the period when discriminative evaluation of a child with ambiguous genitalia is most needed. Secondly, the test is not sensitive in children bearing de novo or mosaic mutation of the AR gene as in these patients the normal AR function maybe present in liver tissue and thus lead to false negative results (Hiort et al. 1998; Holterhus etal. 2001). Furthermore, stanozolol is not available as a prescriptive drug any more. However, the decline of SHBG has also been observed after stimulation of Leydig cells with hCG (Bertelloni et al. 1997) and may thus be employed as an alternative androgen sensitivity test.

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