Pitfalls in the diagnosis of testosterone deficiency

The paper by Morales and colleagues focuses on the ‘pitfalls in the diagnosis of testosterone deficiency’ and poses important questions regarding the reliance on serum testosterone levels [1]. It also raises questions about the complex nature and the concept of the male hypogonadal state as well as the non-specificity of both the signs and symptoms.

It is now clear that testosterone deficiency often represents only one component of the hypoandrogenic anabolic deficiency state [2]. Therefore, the expectation that a single static laboratory test would confirm such a specific diagnosis for a complex hormonal-metabolic-somatic disorder is not to be expected. Furthermore, the reference to ‘serum testosterone levels’ (total versus free?) is by itself confusing as these values change, along with other factors over time and attempts to ‘age normalize’ laboratory data ranges tend to obscure the fact that physiologic responses may not be concerned with this type of correction.

The male hypogonadal state is a dynamic process that unfolds and evolves and can be viewed as the hypogonadal-metabolic-atherogenic disease and aging connection [3]. Therefore a single test value at a given point in time may fail to reflect the changing nature of this process.

While it is beyond the present purpose to review this area, it is nevertheless critical that early detection of decreasing total anabolic function be recognized. This is necessary for the provision of meaningful and early therapeutic interventions for this set of chronic disease processes.

The complexity of diagnosis and treatment involve very costly interventions. While it is apparent that endocrine, metabolic and cardiovascular evaluations are expensive, the issue needs to be restated to focus beyond the ‘short term’ costs and to consider the ‘true cost’ of health impairment and function over time. It is now clear that many of the obesity-related states, including aging, are associated with anabolic deficiency, which often begins many years before diseases reach clinical detection. It may be that it is this lack of recognition of the complexity and pathophysiology of these anabolic deficient and metabolically directed processes [4] that contributes to the uncertainty regarding both diagnosis and treatment of these states as well as their outcomes.

Finally, many studies of male hypogonadism frequently do not include data about estrogen measurements. Estradiol may be a sensitive and dynamic component of this metabolic direction and increases of urinary estrogen excretion and blood levels may give important information regarding total aromatase activity and the peripheral conversion of androgens to estrogens [5].

Increased urinary estrogen excretion may precede increases in blood estrogen concentrations and pituitary gonadotropin suppression that can eventually cause hypotestosteronemia and result in a hypogonadal obesity cycle. Therefore including estrogen measurements is necessary for the evaluation of the hypogonadal component of anabolic deficiency as well as for its treatment.

Note

The authors of ‘Adding to the controversy: Pitfalls in the diagnosis of testosterone deficiency syndromes with questionnaires and biochemistry’, Aging Male 2007;10:57–65, were invited to comment on this letter but declined.