The Paradox Dividing Testosterone Deficiency Symptoms and Androgen Assays: A Closer Look at the Cellular and Molecular Mechanisms of Androgen Action

Abstract

Central to the diagnosis and treatment of testosterone deficiency syndrome in the adult male is the remarkable paradox that there is a very poor correlation between the characteristic symptoms and levels of serum androgens. Because androgen deficiency can be associated with severe symptomatology, as well as diverse conditions such as coronary heart disease, diabetes, and metabolic syndrome, the aim was to present an evidence-based working hypothesis to resolve this confusing clinical paradox. A review of the possible mechanisms in testosterone deficiency syndrome was carried out, and a hypothesis to explain this paradox and associated problems in the diagnosis and clinical management of androgen deficiency was established on the basis of a review of the literature. The mechanisms by which androgen deficiency could arise were studied at five different levels: 1. Impaired androgen synthesis or regulation. 2. Increased androgen binding. 3. Reduced tissue responsiveness. 4. Decreased androgen receptor activity. 5. Impaired transcription and translation. As with insulin in maturity onset diabetes mellitus, there can be both insufficient production and variable degrees of resistance to the action of androgens operating at several levels in the body simultaneously, with these factors becoming progressively worse with aging, adverse lifestyle, other disease processes, and a wide range of medications. Using this model, androgen deficiency can be redefined as an absolute or relative deficiency of androgens or their metabolites according to the needs of that individual at that time in his life. There are important ways in which the considerations raised by this hypothesis affect the etiology, terminology, diagnosis, and treatment of androgen-deficient states.