Functional assessment and clinical classification of androgen sensitivity in patients with mutations of the androgen receptor gene. German Collaborative Intersex Study Group.

Eur J Pediatr. 1997 Jan;156(1):7-14.

Functional assessment and clinical classification of androgen sensitivity in
patients with mutations of the androgen receptor gene. German Collaborative
Intersex Study Group.

Sinnecker GH, Hiort O, Nitsche EM, Holterhus PM, Kruse K.

Department of Paediatrics, Medical University of Lübeck, Germany.

In the genetic male, mutations of the androgen receptor (AR) gene cause
phenotypes ranging from female to subfertile male. Binding assays on genital skin
fibroblasts and DNA analysis alone provide incomplete information about receptor
function. We used the sex hormone-binding globulin (SHBG) response to stanozolol
as a measure of AR function and correlated the results with phenotypes which were
classified according to the degree of defective masculinization. Of the 34
patients investigated, 9 had complete, and 14 had partial androgen insensitivity
syndrome (AIS) with predominantly female, ambiguous, or predominantly male
phenotype. Eleven subjects served as controls. Mutations were characterized using
polymerase chain reaction-single strand conformation polymorphism analysis and
direct DNA sequencing. DNA analysis revealed two major deletions, two minor
defects leading to premature stop codons in exon 1, and 19 point mutations in the
DNA- and hormone-binding domains of the AR gene. After stanozolol, SHBG remained
unchanged in patients with complete AIS (102.0 +/- 3.8 [SE]%; range 92.4%-129% of
the initial value). The SHBG decrease was diminished in partial AIS with
predominantly female (83.8% +/- 1.7%; range 81.3%-87.0%), ambiguous (80.4% +/-
4.4%, range 68.4%-89.1%), and predominantly male (mean 65.9% +/- 4.9%, range
48.6%-80.8%) phenotypes, and normal in controls (51.4% +/- 2.1%, range
35.6%-62.1%). Differences between controls and each AIS group were statistically
significant (P < 0.05 - < 0.0001). A close correlation was found between the
degree of undermasculinization (AIS phenotype) and the SHBG response.

CONCLUSIONS: The SHBG test provides functional information about the severity of
the receptor defect in vivo and hence adds to the structural information provided
by DNA analysis. It detects receptor defects due to mutations within the entire
gene, including the DNA-binding domain, and is a rapid, simple, and cost
effective procedure. It may provide useful information for the diagnosis and
management of affected children.