There are two main classifications of hypogonadism:

Classical vs. functional
hypogonadism

Classification of hypogonadism

Figure 1: Classification of hypogonadism

    Primary, secondary and mixed 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)

    • low testosterone with elevated LH; caused by impaired testicular function.
    • 1.

    • Primary hypogonadism

      (also known as hypergonadotropic hypogonadism)

      • low testosterone with elevated LH; caused by impaired testicular function.

    2.  Secondary hypogonadism

    (also known as hypergonadotropic hypogonadism)

    • low testosterone with low-normal LH; caused by impaired hypothalamic-pituitary function.

    3.  Mixed hypogonadism

    (combination of primary and secondary hypogonadism)

    • 1. 

    • Primary hypogonadism

      (also known as hypergonadotropic hypogonadism)

      • low testosterone with elevated LH; caused by impaired testicular function.
    • 2. 

    • Secondary hypogonadism

      (also known as hypergonadotropic hypogonadism)

      • low testosterone with low-normal LH; caused by impaired hypothalamic-pituitary function.
    • 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. 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),2,3 monitoring testosterone levels together with LH can give an indication about the adequacy of interventions designed to reduce excess body fat (obesity is a well-known 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.

    Classical vs. functional hypogonadism

    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-recognized pathologies, such as Klinefelter’s syndrome, pituitary injury, prolactinoma, Cushing syndrome or toxic/traumatic damage to the testicles.4

    Functional hypogonadism (which can be primary, secondary or mixed in origin) is caused by aging, comorbidities and/or unhealthy lifestyle, in the absence of pathology of the hypothalamic-pituitary-testicular axis or testicles.5,6

    Classical hypogonadism

    Alt tag

    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.

    Functional hypogonadism

    Alt tag

    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 (>45 years old), most of whom are obese and have comorbidities such as the metabolic syndrome, type 2 diabetes or dyslipidemia.5,7 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.

    Response to treatment with testosterone therapy

    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, all men with hypogonadism significantly benefit from testosterone therapy, regardless of whether they have classical or functional hypogonadism.8,10,11 This was clearly demonstrated in a notable 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.4

    Compensated subclinical hypogonadism

    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 associated with physical symptoms, which lends support to the conclusion that it represents a genuine clinical subgroup of hypogonadism.1 In the European Male Aging Study, a community-based study of middle-aged and elderly men in eight European countries, the prevalence of compensated hypogonadism was nearly 10%.1

    Alt tag

    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, men 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

    Primary, secondary and mixed 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)

     

    • low testosterone with elevated LH;
      •   caused by impaired testicular function.

     

    2. Secondary hypogonadism (also known as hypogonadotropic hypogonadism)

     

    • low testosterone with low-normal LH;
      •   caused by impaired hypothalamic-pituitary function.

     

    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.

     

    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),2,3 monitoring testosterone levels together with LH can give an indication about the adequacy of interventions designed to reduce excess body fat (obesity is a well-known 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.

     

    Classical vs. functional hypogonadism

    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-recognized pathologies, such as Klinefelter’s syndrome, pituitary injury, prolactinoma, Cushing syndrome or toxic/traumatic damage to the testicles.4

     

    Functional hypogonadism (which can be primary, secondary or mixed in origin) is caused by aging, comorbidities and/or unhealthy lifestyle, in the absence of pathology of the hypothalamic-pituitary-testicular axis or testicles.5,6

     

    Classical hypogonadism

     

    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.

     

    Functional hypogonadism

     

    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 (>45 years old), most of whom are obese and have comorbidities such as the metabolic syndrome, type 2 diabetes or dyslipidemia.5,7 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.

    Response to treatment with testosterone therapy

    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, all men with hypogonadism significantly benefit from testosterone therapy, regardless of whether they have classical or functional hypogonadism.8,10,11 This was clearly demonstrated in a notable 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.4

    Compensated (subclinical) hypogonadism

    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 associated with physical symptoms, which lends support to the conclusion that it represents a genuine clinical subgroup of hypogonadism.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

    References

    • Tajar A, Forti G, O'Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Aging Study. J Clin Endocrinol Metab. 2010;95(4):1810-1818. Return to content
    • Dandona P, Dhindsa S. Update: Hypogonadotropic hypogonadism in type 2 diabetes and obesity. J Clin Endocrinol Metab. 2011;96(9):2643-2651. Return to content
    • Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab. 2004;89(11):5462-5468. Return to content
    • Nguyen CP, Hirsch MS, Moeny D, Kaul S, Mohamoud M, Joffe HV. Testosterone and "Age-Related Hypogonadism"--FDA Concerns. N Engl J Med. 2015;373(8):689-691. Return to content
    • Grossmann M, Matsumoto AM. A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management. J Clin Endocrinol Metab. 2017;102(3):1067-1075. Return to content
    • Deslypere JP, Kaufman JM, Vermeulen T, Vogelaers D, Vandalem JL, Vermeulen A. Influence of age on pulsatile luteinizing hormone release and responsiveness of the gonadotrophs to sex hormone feedback in men. J Clin Endocrinol Metab. 1987;64(1):68-73. Return to content
    • Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60(7):762-769. Return to content
    • Morgentaler A, Zitzmann M, Traish AM, et al. Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions. Mayo Clin Proc. 2016;91(7):881-896. Return to content
    • Hackett G, Kirby M, Edwards D, et al. British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice. The journal of sexual medicine. 2017;14(12):1504-1523. Return to content
    • Corona G, Rastrelli G, Reisman Y, Sforza A, Maggi M. The safety of available treatments of male hypogonadism in organic and functional hypogonadism. Expert opinion on drug safety. 2018;17(3):277-292. Return to content
    • Zitzmann M, Nieschlag E, Traish A, Kliesch S. SUN-222 Testosterone Treatment in Men with Classical vs. Functional Hypogonadism: A 9-Year Registry. Journal of the Endocrine Society. 2019;3(Supplement_1). Return to content
    • Bhasin S, Woodhouse L, Casaburi R, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab. 2005;90(2):678-688. Return to content
    • Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab. 2006;91(11):4335-4343. Return to content
    • van den Beld A, Huhtaniemi IT, Pettersson KS, et al. Luteinizing hormone and different genetic variants, as indicators of frailty in healthy elderly men. J Clin Endocrinol Metab. 1999;84(4):1334-1339. Return to content
    • Yun YM, Botelho JC, Chandler DW, et al. Performance criteria for testosterone measurements based on biological variation in adult males: recommendations from the Partnership for the Accurate Testing of Hormones. Clin Chem. 2012;58(12):1703-1710. Return to content
    • Collier CP, Morales A, Clark A, Lam M, Wynne-Edwards K, Black A. The significance of biological variation in the diagnosis of testosterone deficiency, and consideration of the relevance of total, free and bioavailable testosterone determinations. J Urol. 2010;183(6):2294-2299. Return to content
    • Liu PY, Pincus SM, Takahashi PY, et al. Aging attenuates both the regularity and joint synchrony of LH and testosterone secretion in normal men: analyses via a model of graded GnRH receptor blockade. Am J Physiol Endocrinol Metab. 2006;290(1):E34-E41. Return to content
    • Corona G, Maseroli E, Rastrelli G, et al. Characteristics of compensated hypogonadism in patients with sexual dysfunction. The journal of sexual medicine. 2014;11(7):1823-1834. Return to content