Etiology of hypogonadism

What causes hypogonadism?

Male hypogonadism is characterized by a deficiency of endogenous testosterone production resulting in abnormally low levels of circulating testosterone. Hypogonadism can be caused by a number of disorders, the most frequently observed being idiopathic hypogonadotrophic hypogonadism, hypopituitarism, Klinefelter’s syndrome, and late-onset hypogonadism. Most circulating testosterone (98%) is bound to transport proteins, with approximately 60% bound with high affinity to the sex hormone binding globulin (SHBG), and 38% weakly bound and transported by albumin.1 Only 2% of circulating testosterone is free and hence biologically active. Several lines of evidence suggest that not only free testosterone but also albumin bound testosterone is available to the target tissues, in case of an increased testosterone need. Therefore, the non-SHBG-bound testosterone is called "the bioavailable testosterone".

    Classification of hypogonadism

    Hypogonadism can be classified into different types which are listed and explained below.

    Classification of hypogonadism

    Figure 1: Classification of hypogonadism

    Primary hypogonadism

    Primary hypogonadism is characterized by low testosterone levels, impairment of spermatogenesis, and elevated levels of gonadotrophins, which can be due to a genetic cause (e.g. Klinefelter’s syndrome, in which males have an extra X sex chromosome) or to damage to the testes (such as injury or infection).

    Secondary hypogonadism

    Secondary Hypogonadism is characterized by low testosterone levels in association with low or low-normal gonadotrophin levels, and may result from conditions such as Kallmann syndrome, characterized by insufficient production of gonadotrophin-releasing hormone by hypothalamus, leading to a deficiency in the production of luteinizing hormone and follicle-stimulating hormone by the pituitary.2

    Late-onset hypogonadism

    Late-onset hypogonadism is associated with advancing age and characterized by low testosterone levels (below the young healthy adult male reference range) and symptoms.3 Some decline in testosterone level is normal as men age, due to reduced function of the testes and the hypothalamic-pituitary system Figure 2. Therefore, LOH is a mixture between primary and secondary hypogonadism. However, late-onset hypogonadism may lead to a significant decline in the quality of life and may adversely impact various organ systems. About 34% of men aged between 45 and 54 years have total testosterone levels below the physiological range for younger men, reaching 40% in men aged 55 to 74 years, 45.5% in men aged 75 to 84 years and 50.0% in men aged 85 years or older.4


    Figure 2: Age-related Decline in Testicular Function

    Target organ resistance

    Additionally, target organ resistance (androgen resistance) is a rare form of hypogonadism, usually resulting from a genetic defect of the androgen receptor. Despite high testosterone levels, the target organs cannot respond to available testosterone. Regardless of the underlying cause of hypogonadism, the treatment approach is aimed at returning testosterone to physiologically normal levels.


    What are the symptoms of hypogonadism?

    Risk factors of hypogonadism


    1. Pellitero S, Olaizola I, Alastrue A, et al. Hypogonadotropic hypogonadism in morbidly obese males is reversed after bariatric surgery. Obes Surg. 2012;22(12):1835-1842.
    2. Biswas M, Hampton D, Newcombe RG, Rees DA. Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life. Clin. Endocrinol. (Oxf). 2012;76(5):665-673.
    3. 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. 
    4. Caldas AD, Porto AL, Motta LD, Casulari LA. Relationship between insulin and hypogonadism in men with metabolic syndrome. Arq. Bras. Endocrinol. Metabol. 2009;53(8):1005-1011.
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