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”.

Primary and secondary hypogonadism

There are two main types of hypogonadism:

  • primary (or testicular) and
  • secondary (or hypothalamic-pituitary) 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

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
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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 1. 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

Figure1 : Age-related Decline in Testicular Function

Figure 1: Age-related Decline in Testicular Function

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. The classification of hypogonadism is summarized in the Figure 2.
Figure 2: Classification of hypogonadism
vergrößern Figure 2: Classification of hypogonadism
Regardless of the underlying cause of hypogonadism, the treatment approach is aimed at returning testosterone to physiologically normal levels.
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Risk factors for low testosterone

Many systemic diseases (e.g. diabetes mellitus, metabolic syndrome, coronary artery disease, liver disease, chronic obstructive pulmonary disease, rheumatoid arthritis, other inflammatory conditions and generalized infections) correlate with low testosterone levels.1-3,5-9 Therefore, signs or symptoms of hypogonadism can be an early indication leading to diagnosis of an underlying condition. In addition, obesity, injury to the testes, genetic factors and normal aging can contribute to hypogonadism.1,6 A summary of the risk factors can be found in the table below. Although many risk factors for low testosterone are not modifiable, improving diet, moderating alcohol consumption, losing weight and reducing stress can be helpful to men wanting to reduce the risk of hypogonadism.


Table. Risk factors for hypogonadism
Risk factor Comment
Obesity Up to 79% of obese men have hypogonadism.1
Diabetes Up to 45-50% of men with type 2 diabetes have hypogonadism.2,3
Metabolic syndrome Up to 35% of men with the metabolic syndrome have hypogonadism.4-6
Chronic diseases Chronic diseases such as cardiovascular diseases, liver or kidney disease, and rheumatoid arthritis may be risk factors for low testosterone.

In some instances it is not clear whether the chronic illness is a cause or a consequence of low testosterone. It is likely that the causal relationship is bi-directional.
Normal aging Testosterone levels decline with age in most men.

* After the age of 40 years:
  • total testosterone decreases on average -4 ng/dL ( -0.124 nmol/L) per year 7 or 0.4% - 2% per year.8
  • bioavailable testosterone decreases on average -2 to -3% per year.9
* In older men (over 60 years of age), the average rate of decrement in total testosterone levels has been found to be 110 ng/dL every decade.10
Medications Statins11-13 (which are widely prescribed for dyslipidemia), glucocorticoid medications14,15 and opioid treatment16-18 for chronic pain are well known medications that reduce testosterone levels and may precipitate hypogonadism.
Pituitary disorders Pituitary dysfunction can impair the release of LH and FSH, which are hormones that affect normal testosterone and sperm production, respectively.19,20
Cancer and cancer treatment Cancer of the testes or pituitary tumors can lead to low testosterone production.

Chemotherapy or radiation therapy can also interfere with testosterone production.19,20
Injury to the testes Damage to testes can cause reduced testosterone production.19,20
Hemochromatosis A genetic disorder causing the body to absorb too much iron from the diet) can result in the deposition of iron in various body organs, including the hypothalamus, pituitary and testes.

It is now recognized as a common disorder and 1 in 200 people of northern Europe may be at risk of developing iron overload.20
HIV/AIDS The HIV virus can cause low levels of testosterone by affecting the hypothalamus, pituitary and testes.19,20
Klinefelter’s syndrome A genetic deficiency in testosterone production. Affects between 1 in 500 and 1 in 1000 men.19,20
Hypothalamic disorder Abnormal development of the hypothalamus and is a risk factor for low testosterone (a.k.a. Kallmann's syndrome).19,20
Mumps orchitis A mumps infection that involves the testes as well as the saliva glands may result in long-term damage affecting testosterone production if it occurs during adolescence or adulthood.19,20
Undescended testes Failure of one or both of the testes to descend at birth (which occurs in approximately 1 in 4 boys born prematurely and 1 in 20 boys born at term) may lead to a failure of the testes to develop properly if the condition does not correct itself naturally within the first year of life or if not corrected in early childhood.19,20
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How important is it to treat hypogonadism?

There are clearly established links between hypogonadism and depression, cardiovascular risk, diabetes and metabolic syndrome, osteoporosis, and other chronic illnesses. Low testosterone values are also associated with increased mortality, even after adjusting for age, comorbidities, and other clinical covariates.

Testosterone replacement therapy can improve libido, mood, increase bone density, and improve body composition and quality of life in hypogonadal men. Treatment may also improve insulin resistance, reduce central obesity, and improve other risk factors for cardiovascular disease. Learn more about are the benefits of treating hypogonadism.
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References

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.

5 Laaksonen DE, Niskanen L, Punnonen K, et al. The metabolic syndrome and smoking in relation to hypogonadism in middle-aged men: a prospective cohort study. J. Clin. Endocrinol. Metab. 2005;90(2):712-719.

6 Singh SK, Goyal R, Pratyush DD. Is hypoandrogenemia a component of metabolic syndrome in males? Exp. Clin. Endocrinol. Diabetes. 2011;119(1):30-35.

7 Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J. Clin. Endocrinol. Metab. 2001;86(2):724-731.

8 Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J. Clin. Endocrinol. Metab. 2008;93(7):2737-2745.

9 Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J. Clin. Endocrinol. Metab. 2002;87(2):589-598.

10 Morley JE, Kaiser FE, Perry HM, 3rd, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism. 1997;46(4):410-413.

11 Schooling CM, Au Yeung SL, Freeman G, Cowling BJ. The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC medicine. 2013;11:57.

12 Corona G, Boddi V, Balercia G, et al. The effect of statin therapy on testosterone levels in subjects consulting for erectile dysfunction. The journal of sexual medicine. 2010;7(4 Pt 1):1547-1556.

13 Cohen PG. Statins and male hypogonadism. The journal of sexual medicine. 2011;8(6):1826.

14 Reid IR, Wattie DJ, Evans MC, Stapleton JP. Testosterone therapy in glucocorticoid-treated men. Arch. Intern. Med. 1996;156(11):1173-1177.

15 Crawford BA, Liu PY, Kean MT, Bleasel JF, Handelsman DJ. Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment. J. Clin. Endocrinol. Metab. 2003;88(7):3167-3176.

16 Brennan MJ. The effect of opioid therapy on endocrine function. Am. J. Med. 2013;126(3 Suppl 1):S12-18.

17 Aloisi AM, Aurilio C, Bachiocco V, et al. Endocrine consequences of opioid therapy. Psychoneuroendocrinology. 2009;34 Suppl 1:S162-168.

18 Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. The journal of pain : official journal of the American Pain Society. 2002;3(5):377-384.

19 Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2010;95(6):2536-2559.

20 Dohle GR, Arver S, Bettocchi C, Kliesch S, Punab M, de Ronde W. Guidelines on Male Hypogonadism. European Association of Urology 2012.
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Last updated: 2016
G.GM.MH.04.2015.0334