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


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

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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.
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Figure 2: Classification of hypogonadism Regardless of the underlying cause of hypogonadism, the treatment approach is aimed at returning testosterone to physiologically normal levels.


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
Klinefelter’s syndrome A genetic deficiency in testosterone production. Affects between 1 in 500 and 1 in 1000 men.
Injury to the testes Damage to testes can cause reduced testosterone production.

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.

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.
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.
Hormone system imbalance Kallmann syndrome involves abnormal development of the hypothalamus and is a risk factor for low testosterone.
Pituitary disorders can impair the release of hormones affecting normal testosterone production.

Chronic illnesses Chronic illnesses such as liver or kidney disease, diabetes, metabolic syndrome 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.
Normal aging There is some normal decline in testosterone level as men age.

Hemochromatosis 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.
Other HIV/AIDS virus can cause low levels of testosterone by affecting the hypothalamus, pituitary and testes. Certain medications can affect testosterone production. Obesity.


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.


References

1 Jockenhövel F, Schubert M. Male Hypogonadism. 3rd edition. Bremen: UNI-MED Science; 2009

2 Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006; 91(6): 1995-2010

3 Wang, C., E. Nieschlag, R. Swerdloff, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations. Eur J Endocrinol 2008, 159(5): 507-514.

4 Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 2006; 60(7): 762-9

5 Tung DS, Cunningham GR. Androgen deficiency in men. The Endocrinologist 2007; 17(2): 101-115

6 Stanworth RD, Jones TH. Testosterone for the aging male; current evidence and recommended practice. Clin Interv Aging 2008; 3(1): 25-44

7 Traish AM, Guay A, Feeley R, et al. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction. J Androl 2009; 30(1): 10-22

8 Traish AM, Saad F, Guay A. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl 2009; 30(1): 23-32

9 Traish AM, Saad F, Feeley RJ, et al. The dark side of testosterone deficiency: III. Cardiovascular disease. J Androl 2009; 30(5): 477-94