Low testosterone (T), also called hypogonadism, is a failure of the testes to produce the male sex hormone testosterone. This can occur due to either a testicular disorder (primary) or the result of a disease process involving the hypothalamus and pituitary gland (secondary). Indicators of low T include symptoms of fatigue, depression, hair loss, loss of muscle mass, low sex drive, trouble getting or keeping an erection, osteoporosis, and infertility.
In a healthy individual, when T is low, the hypothalamus stimulates the pituitary gland through gonadotropin-releasing hormone (GnRH) to produce luteinizing hormone (LH). LH is then released into the bloodstream where it travels to the Leydig cell receptors in the testes. Once LH binds to the receptors, sperm and T are created and T levels rise which then negatively regulates the secretion of GnRH, FSH, and LH. Once in the bloodstream, T binds to androgen receptors in the liver, muscles, fat tissue, and other organs where it’s able to exert its effects of sperm production, increasing muscle mass, maintaining bone health, uptake of sugar from the blood, and hair growth.
The liver is also an important organ in T production and regulation. The liver produces healthy cholesterol as well as sex hormone-binding globulin (SHBG). Cholesterol is used as a skeleton to begin the production of T in the testes. Leydig cells in the testes convert cholesterol into T. If there is a low amount of cholesterol being produced, although the testes can produce a small amount, it is not enough to maintain healthy T levels.
About 40-50% of the total T is bound to SHBG. SHBG decreases the level of free T in the bloodstream due to the fact that once bound to SHBG, T is biologically inactive. Excess SHBG, which often occurs in patients with liver disease, can create a T deficiency because the SHBG binds itself to too much free T in the bloodstream which creates the symptoms seen in low T patients.3
The main causes of a T decline include poor circulation to the testes, pituitary gland deficiencies, and liver disease. Compromised blood flow can occur for a number of reasons including aging, radiation, and testicular injury. Because the testicles are located within the scrotum, which hangs outside the body, they do not have the protection of muscles or bones. This makes the testes vulnerable to injury. Testicular injury and trauma can cause a decrease in blood flow to the testes. The capacity of the testes to secrete testosterone is severely limited by decreased testicular blood flow.1
Pituitary gland dysfunction can occur from a pituitary gland tumor, anxiety/stress, or a traumatic brain injury. Anxiety and stress affect the pituitary gland through an increase in cortisol levels. High cortisol levels suppress GnRH activity which directly affects the pituitary gland’s ability to produce LH, which is critical in the production of testosterone.
Structural and functional damage to the liver can cause low T in the blood. Common health issues that can cause a liver deficiency include diabetes, alcoholism, obesity, and cirrhosis. There is a direct correlation between decreased insulin sensitivity and low free T. T deficiency is common in men with diabetes, regardless of the type. A study performed found that 43% of type 2 diabetic men have reduced total testosterone levels and 57% have lower free testosterone levels.2 T levels are partly influenced by insulin resistance. Increased blood sugar suppresses the pituitary gland production of LH. On the other hand, low T levels can also decrease the body’s sensitivity to insulin.4
Alcoholism can lead to low T through the damage that alcohol has on the testes, sperm count, and liver. In obese individuals, fat cells metabolize free T. When there are above average fat cells in the body, more T will be utilized from the bloodstream. Cirrhosis of the liver causes an increase in SHBG. A study performed found that SHBG was significantly increased in patients with liver cirrhosis compared with healthy subjects.3
Cholesterol is an organic molecule that is mainly synthesized in the cells of the liver. Cholesterol serves as a precursor for the biosynthesis of steroid hormones including T, aldosterone, cortisol, bile acid, and vitamin D. Cholesterol is a fat-soluble molecule and therefore is bound to lipoproteins including High-Density Lipoproteins (HDL) and Low-Density Lipoproteins (LDL). HDL and LDL are also synthesized by the liver. The LDL also called “bad” cholesterol carries cholesterol from the liver to the body’s cells. The HDL also called “good” cholesterol absorbs cholesterol in the tissue and blood and carries them back to the liver. The liver then flushes it from the body. A study of 293 men with type 2 diabetes showed that testosterone levels correlate positively with HDL cholesterol levels in men with type 2 diabetes.5
A new study that evaluated nearly 3,500 men who had erectile dysfunction found that Statin therapy prescribed to lower cholesterol also appears to lower testosterone levels.6 Statin lowers cholesterol by reducing the liver's production of cholesterol. Statin blocks an enzyme called HMG CoA reductase that the liver uses to make cholesterol. The reduction of liver’s cholesterol production depletes the substrate for testosterone synthesis leading to lower T.