Androgens in Health and Disease.pdf - E Library

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risk of impaired spermatogenesis (64–68). This association has been identified in studies
of patient populations evaluated for causes azooligospermia or oligospermia. The mechanism
responsible for this association is postulated to represent the effects of the decreased
function of the AR that has been associated with increases in the length of this segment.
THE RELATIONSHIP BETWEEN PHENOTYPE AND AR MUTATIONS
Although AR-binding assays provided a useful tool with which to classify patients
with AR defects, it was clear that no precise correlation existed between with the extent
of virilization and the type of binding abnormality (5). The existence of information
defining the molecular defects in a large number of patients with different forms of androgen
insensitivity has permitted an examination of whether such a correlation exists when
the answer is sought using more precise measurements of AR abundance or function.
A number of generalizations can now be made. First, with few exceptions, truncations
of the AR protein result in the phenotype of complete androgen insensitivity
(complete testicular feminization). This is observed because most truncations of the
receptor protein either remove essential functional domains (the LBD or DBD) or
result in greatly reduced levels of AR protein (18,29). This stands in contrast to aminoacid-substitution
mutations, which have been associated with the complete range of
androgen-resistant phenotypes.
Second, although there is broad agreement between the degree of defect that is defined
in functional assays of receptor function (and abundance) and the phenotype that is
observed in individual patients; at times, this relationship is clearer than at others. In
circumstances in which the AR is absent or the genetic defect completely inactivates the
receptor, it is not difficult to understand the association with the clinical phenotype of
complete testicular feminization. In contrast to these clear-cut situations, when the
receptor is not completely defective, precise quantitation of the degree of AR impairment
can be more difficult. In such circumstances, the results can be subject to considerable
variability introduced by the methods that are used to assess AR function. An
example of how such methodological changes could affect measures of AR function was
demonstrated by Marcelli et al., who demonstrated that variations in hormone dosing
could dramatically alter the levels of receptor function that were measured (27). One
avenue to circumvent the effects of transfection is the use of an adenovirus to deliver a
model androgen-responsive reporter gene directly into patient fibroblasts. Such a method
permits the measurement of AR function and represents one way to minimize the artifacts
inherent in assays performed using transfection into heterologous cells (69).
VARIATIONS IN PHENOTYPE
In some syndromes of hormone resistance, such as the generalized resistance to thyroid
hormone, identical genotypes have been associated with considerable phenotypic
variation. By contrast, similar phenotypes are usually observed in pedigrees in which
androgen resistance is caused by mutation of the AR.
Exceptions to this statement clearly exist. In most such instances, the degrees of
phenotypic variation have been relatively minor and are seen in patients with intermediate
phenotypes, such as the Reifenstein phenotype (70–72). When analyzed at the
molecular level, the mutant receptors are only partially defective. Contributions to the
extent of this variation have not been exhaustively studied, but have been postulated to