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ANDROGEN RESISTANCE SYNDROME (ARS)
Malcolm Carruthers
Medical Director, Centre for Men's Health, 20/20 Harley Street, London
W1G 9PH, UK. carruthers@centreformenshealth.co.uk
Introduction
The concept of insulin resistance introduced by Sir Harold Himsworth
nearly 70 years ago revolutionized thinking and clinical practice
in maturity onset diabetes. He devised a standardised insulin-glucose
tolerance test, the forerunner of modern glucose-insulin clamp techniques,
and used this to distinguish between "insulin-sensitive" and "insulin-insensitive"
types of diabetes1. He also noted the association of obesity, hypertension
and arterial disease with "insulin-insensitive" diabetes, which
led on to modern theories of 'Metabolic Syndrome', one of the novel
risk factors in which is androgen deficiency.
It is suggested that the concept of an androgen deficiency syndrome
(ARS) is needed to explain the poor correlation between total testosterone
levels and androgen deficiency symptoms, and studies showing that
'Each person had a consistent testosterone threshold for androgen
deficiency symptoms that differed markedly between individuals'2.
This leads to a new definition of androgen deficiency in the adult
male in accordance with that of diabetes mellitus:
'An absolute or relative deficiency of testosterone or its metabolites
according to the needs of that individual at that time in his life'.
Sites of Androgen Resistance and Insufficiency:
1. Androgen Synthesis
2. Androgen Binding
3. Reduced Tissue Responsiveness
4. Androgen Receptor Insensitivity - age, polymorphism, up and down
regulation.
5. Transcription Factors, Heat Shock Proteins and Post-translational
Modifications
The many parallels and interactions between Maturity Onset Diabetes
and Androgen Deficiency in the Adult Male (ADAM)3 suggest that a
mixture of lack of testosterone and its metabolites is combined
with resistance to its action at multiple sites. Just as insulin
resistance is thought to vary between tissues, so is androgen resistance,
and therefore different organs may suffer diverse consequences.
As in diabetes, there can be genetic predispositions to ADAM, both
racial and familial, which interact with life-style, age, and disease
related factors. Similarly, after a period of compensation, the
ability of the testis to overcome the androgen resistance may fail,
with structural changes in the Leydig cells, and signs and symptoms
of endocrine failure developing.
The 5 levels at which androgen resistance can occur are reviewed.
Because of the complexity of the regulation of androgen activity
at every level, the characteristic androgen deficiency symptoms,
taken together with the clinical consequences such as metabolic
syndrome or osteoporosis, could be considered as the best currently
available bio-assay of androgen action.
This concept of an 'Androgen Resistance Syndrome' (ARS) has important
consequences in the definition, diagnosis and treatment of Androgen
Deficiency in the Adult Male.
References
1. Himsworth HP. Mechanism of diabetes mellitus. Lancet 1939;65:118-71.
2. Kelleher S, Conway AJ, Handelsman DJ. Blood testosterone threshold
for androgen deficiency symptoms. J Clin.Endocrinol.Metab 2004;89:3813-7.
3. Carruthers M. ADAM:Androgen Deficiency in the Adult Male - causes,
diagnosis and treatment. London and New York: Taylor & Francis,
2004.
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