There are two main classifications of hypogonadism:
The distinction between primary, secondary and mixed hypogonadism is based on the anatomical location of the defect causing inadequate testosterone production (testicles vs. hypothalamus/pituitary). To diagnose primary and secondary hypogonadism, measurement of testosterone levels together with LH levels is required.
1. Primary hypogonadism (also known as hypergonadotropic hypogonadism)
2. Secondary hypogonadism (also known as hypogonadotropic hypogonadism)
3. Mixed hypogonadism (combination of primary and secondary hypogonadism)
Older men are more likely to have predominantly primary hypogonadism while obese men, regardless of age, commonly have secondary hypogonadism.1 Mixed hypogonadism is most likely to occur in older men who also have obesity.1
Measuring levels of testosterone along with LH can shed light on whether a man’s hypogonadism is caused by testicular or hypothalamic-pituitary dysfunction, and help guide therapeutic efforts. For example, because obesity and diabetes are strongly associated with secondary hypogonadism (low testosterone with low-normal LH),3,4 monitoring testosterone levels together with LH can give an indication about the adequacy of interventions designed to reduce excess body fat (obesity is a wellknown cause of impaired hypothalamic-pituitary function). In contrast, treatment options for primary hypogonadism are limited to testosterone therapy, since treatments that increase LH secretion rely on testicular function for production of testosterone.
The distinction between classical hypogonadism and functional hypogonadism is based on the cause of low testosterone:
Classical hypogonadism (which can be primary or secondary in origin) is caused by specific, well-recognised pathologies, such as Klinefelter’s syndrome, pituitary injury, prolactinoma, Cushing syndrome or toxic/traumatic damage to the testicles.5
Functional hypogonadism (which can be primary, secondary or mixed in origin) is caused by ageing, comorbidities and/or unhealthy lifestyle, in the absence of pathology of the hypothalamic-pituitary-testicular axis or testicles.6,7
Classical hypogonadism was first described in the 1950s and constitutes the medical textbook example of hypogonadism. Men with classical hypogonadism have extremely low testosterone levels and have severe symptoms and signs of testosterone deficiency. Nevertheless, classical hypogonadism is relatively rare.
More recently, additional causes of hypogonadism have been identified, including obesity, diabetes, the metabolic syndrome, HIV, chronic renal failure, and certain medications. For more information, see Risk Factors for Hypogonadism.
Men with functional hypogonadism are typically middle-aged and older men (≥50 years old), most of whom are obese and have comorbidities such as the metabolic syndrome, type 2 diabetes or dyslipidemia.6 These men, which constitute the large majority of men who suffer from hypogonadism, have no pathology characteristic of classical hypogonadisms.8
All modern studies of testosterone therapy were conducted mostly in men with functional hypogonadism because the historically recognised causes of classical hypogonadism are very rare. Therefore, the term hypogonadism usually refers to functional hypogonadism.
Importantly, the symptoms and signs of hypogonadism occur as a result of low testosterone levels, and the clinical response to testosterone therapy appears unrelated to underlying cause of hypogonadism.8,9 In other words, most men with hypogonadism may benefit from testosterone therapy, regardless of whether they have classical or functional hypogonadism. 8,10,11 This was clearly demonstrated in a registry study of long-term testosterone therapy with testosterone undecanoate injections for up to 9 years in men with classical and functional hypogonadism.11 Hence, there is no scientific support for the notion that testosterone treatment should be restricted to men with classical hypogonadism.5
A less well researched form of hypogonadism is compensated hypogonadism (also known as subclinical hypogonadism), which is characterised by normal testosterone levels combined with elevated LH levels.1 Compensated hypogonadism is significantly (P<0.001) associated with physical symptoms, which lends support to the conclusion that it represents a genuine clinical subgroup of hypogonadism the physical symptoms were significant compared to the eugonadal group.1 In the European Male Ageing Study, a community-based study of middle-aged and elderly men in eight European countries, the prevalence of compensated hypogonadism was nearly 10%.1
Because testosterone levels are not markedly reduced in men with compensated hypogonadism, intuitively one may think it is a harmless condition. However, emerging data suggest compensated hypogonadism should not be dismissed. Although testosterone levels in men with compensated hypogonadism may remain above the threshold for sexual symptoms, they may be insufficient to maintain “younger” levels of physical capacity.12,13 The inverse relationship between LH and muscle strength and lean mass, independent of testosterone levels, supports this.14 Given the wide normal range for testosterone,15,16 it is possible that testosterone levels in men with subclinical hypogonadism have declined from previously high normal to current low normal. High LH in this case may therefore be a marker for testosterone decline within the reference range, indicating a readjustment of the hypothalamic-pituitary-testicular feedback set point in an attempt to compensate for deficiencies in testicular function, and/or defective testosterone feedback at the hypothalamic-pituitary level.17 Furthermore, with compensated hypogonadism seem to have a similarly increased risk of heart disease and death from major adverse cardiovascular events, as do men with overt hypogonadism.18
Identifying men with compensated hypogonadism provides an opportunity for intervention (for example improving food and exercise habits) to prevent development of overt hypogonadism and health deterioration.1
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