Testosterone deficiency or TD is exactly what it sounds like, a low amount of testostrone hormone in the body. TD increases with age, but can occur do to lifestyle choices such as steroid use as well. Testosterone levels decrease nearly 0.4% to 2% each year after the age of 30.  Approximately 20-40% of men 45 years old or older show symptoms of low serum testosterone levels. Unfortunately, due to the variety of symptoms associated with TD, diagnosing and treating the hormone imbalance can be difficult.

There are several reasons for the decline in testosterone including

• failure of the testes to produce testosterone,
• dysfunction of the HPG axis or androgen target tissue,
• medication or illness

Since there are many causes, this lead to multiple classifications of TD. Primary hypogonadism is the most common form of TD. Primary hypogonadism, also known as hypergonadotropic hypogonadism, is an inability to produce testosterone or sperm in the presence of high concentrations of gonadotropins. Causes of primary hypogonadism include infection, medication side effects, toxins, testicular atrophy or testicular removal due to trauma.

Secondary hypogonadism, or hypogonadotropic hypogonadism is caused by an alteration in the HPG axis, typically due to pituitary dysfunction or GNRH deficiency. This leads to a reduced level of FSH and LH production—hormones that stimulate sperm production and testosterone release. Patients with hypogonadism typically have a testosterone level of less than 231ng/dL.

Symptoms of TD

Common symptoms include decreased libido, reduced nocturnal erections, erectile dysfunction (ED), and infertility. Other more loosely associated symptoms include decreased energy, cognition, muscle mass and strength; increased fat; decreased bone density; sleep disturbances; and depression. Due to the multiple effects low testosterone may have on the body, it is no surprise that there are several diseases and medical conditions associated with TD. Some of the diseases that are significantly impacted by testosterone levels are described below.

Associated Diseases

Obesity

The relationship between obesity and low total (bound and unbound) testosterone has been well known for decades (Travison, Araujo, Kupelian, O’Donnell, & McKinlay, 2007). In fact, obesity is a major contributor to testosterone decline associated with age. In clear cases of obesity, a strong negative association can be found between obesity and unbound active testosterone levels. In these cases, there is a decrease in LH and FSH levels that is thought to be due to increased release of aromatase, the enzyme that converts testosterone into estrogen, from inflamed fat (adipose) tissue. Estrogen in turn decreases secretion of gonadotrophins from the pituitary.

There is also evidence that low testosterone can promote obesity. Mice transgenically altered to not produce receptors that androgens bind developed obesity, suggesting that body fat is sensitive to androgen levels (Rana, et al., 2011). Another study determined that similarly modified mice became obese on a high fat diet, but maintained healthy weigh on a regular diet. Taken together, the data provides evidence that low testosterone may enhance the effects of a high fat diets. The combination of obesity and low testosterone can also impact other aspects of life such as fertility, sleep, physical ability, and mood.

One of the most obvious solutions is weight loss, either by diet or surgical removal. A recent study revealed that a loss of more than 15% can cause a significant increase in testosterone levels which may be linked to increased release of gonadotrophins. Even a smaller increase in weight loss can cause increases in testosterone level (Camacho, et al., 2013).

Testosterone replacement therapy (TRT) for men with hypogonadism has been shown to reduce fat content up to 15% (Katznelson, et al., 1996; Brodsky, Balagopal, & Nair, 1996). Even men without diagnosed hypogonadism have been shown to respond to the treatment. However, more information on how it influences fat in specific areas has been inconsistent. The effect of this treatment on the secondary symptoms of low testosterone and obesity is also not well defined. Thus, there is a need for further investigation in this field.

Metabolic Syndrome

Metabolic syndrome, or MetS, is a collection of risk factors that increase the likelihood of developing diabetes and cardiovascular disease. These factors include waist circumference, high triglycerides, low HDL cholesterol, high blood pressure and insulin resistance. Several studies have found a link between low testosterone levels to Mets. This may be due to hyperinsulinism, which is an unusually high amount of insulin the blood that in turn suppresses production of SHBG. MetS is also associated with high estrogen levels, which has been shown to decrease gonadotrophin LH (Maggio, et al., 2010; Santen, 1975).

Testosterone therapy hormone has been shown to improve MetS symptoms, particularly waist circumference and insulin sensitivity, in short term clinical trials (Kalinchenko, et al., 2010; Francomano, Lenzi, & Aversa, 2014; Yassin, Doros, Hammerer, & Yassin, 2014; Traish, Haider, Doros, & Saad, 2014; Bhattacharya, et al., 2011).

Cardiovascular Disease and Hyperlipidemia

Studies indicate there is a direct relationship between low testosterone and cardiovascular disease (CVD). Reports in the early 2000s revealed that low testosterone levels were linked to an increased risk for aortic atherosclerosis in older men. Support for the role of low testosterone in CVD is provided by several studies demonstrating a link between hypogonadism and increased coronary artery disease. Hypogonadism is also linked to MetS which is known to increase the risk for CVD.

Another finding supporting the relationship between low testosterone and CVD is the changes in the vascular system during androgen deprivation therapy (ADT). ADT uses androgen blockers or chemical castration to reduce testosterone levels.  Patients may undergo ADT for various ailments such as insulin resistance and vascular disease  (Smith, et al., 2001; Basaria, Muller, Carducci, Egan, & Dobs, 2006; Basaria, 2008; Shahani, Braga-Basaria, & Basaria, 2008). ADT however, can also increase a male patient’s risk of CVD. Smith et al (2001) found that men who undergoing ADT for prostate cancer developed stiffness in the larger arteries which increased arterial pressure.  Other studies have also found that ADT increases the risk of CVD, diabetes and death.

Some studies have found that treatment with TRT leads to reduced bad cholesterol and increased good cholesterol. Total cholesterol and low-density lipoprotein (LDL) cholesterol, the form of cholesterol that can cause plaque buildup in the arteries is lowered with TRT while high-density lipoprotein (HDL) cholesterol, the cholesterol that removes harmful LDL from inappropriate places increased(Tenover, 1992; Zgliczynski, et al., 1996; Tripathy, Shah, Lakshmy, & Reddy, 1998; Howell, et al., 2001; Ly, et al., 2001). In addition, low HDL or “good cholesterol” is also associated with low testosterone levels in aging men.

Diabetes

Because of the relationship between MetS and obesity with low testosterone, it is no surprise that low levels of testosterone have been linked to diabetes. A meta-analysis found that men with low levels of testosterone had a higher incidence of diabetes compared to men with normal levels (Corona G1, et al., 2011). In turn, men with high levels of testosterone have a lower risk (42%) for type 2 diabetes than men with lower levels.

There are several suggestions on the connection between low testosterone and diabetes.

• One theory is that low levels of SHBG, which is also correlated with diabetes (Haffner, Shaten, Stern, Smith, & Kuller, 1996; Stellato, Feldman, Hamdy, Horton, & McKinlay, 2000; Ding, et al., 2009; Oh, Barrett-Connor, Wedick, Wingard, & Study, 2002).
• Another possible mechanism could be the increase in adipose tissue which has been shown to further reduce testosterone in hypogonadal men (Zumoff, et al., 1990; Haffner, Valdez, Stern, & Katz, 1993).
• Leptin, a hormone that regulates body weight and food intake, can stimulate release of LH from GRH nerve cells in the brain and suppress the stimulating effect of gonadotrophins on Leydig cells (Finn, et al., 1998).

Erectile dysfunction (ED)

Animal studies have revealed a link between TD and erectile dysfunction (ED). In one study it was determined that low testosterone led to a reduction in smooth involuntary muscle and an increase in connective tissue in the erectile tissue and in fat cells in related regions. These results led the investigators to believe that without testosterone, immature connective tissue cells become fat cells, and that this increase in fat cells obstructs the veins (a common cause of ED) in the penis (Traish, Toselli, Jeong, & Kim, 2005; Traish & Kim, 2005). TRT may improve ED by stimulating the sodium channels to open and regulating nitric oxide (an agent that mediates relaxation of the muscles in the penis) in the penile bodies which allows the muscle to relax and improves erection.

Mortality

Declining testosterone levels have been shown as predictors of mortality in men for multiple diseases and disorders including cardiovascular disease, dialysis related diseases, ischemic heart disease and respiratory-related conditions. In a study by Khaw et al (2007), they found that the level of testosterone in men between 40 and 79 years of age inversely correlated with mortality. A study by Jeppesen et al (1996)found that while all patients with coronary artery disease displayed varying testosterone levels, patients that died of the disease had lower levels than those that survived.