Testosterone Levels, Low Testosterone Symptoms, and Testosterone Replacement Therapy

Most men want to live to a ripe old age. But this could come at a price. We may have to depart with masculinity and vigor. Manliness may become a myth.

But, what if there was a simple way to retain the strength and hardiness of the 20s? Well, I guess most of us would at least give it a thought.

Could testosterone be the issue? We all know that testosterone is what makes men, men. The deep voice, the large muscles. It’s all about testosterone, isn’t it?

And, isn’t it true that testosterone levels start to fall in men by about 1% a year, beginning in the 40s?

And, isn’t low testosterone associated with weight gain, lack of energy, loss of muscle, and low sexual drive? Well, indeed it is.

So, could testosterone replacement therapy help us retain our hunkiness until old age?

Probably too good to be true.

Interestingly, there has been a dramatic increase in the use of testosterone therapy in healthy middle-aged and older men (1,2). The increased testosterone prescribing is primarily for age-related testosterone deficiency sometimes called andropause or age-related hypogonadism (2).

In other words, testosterone treatment is being used to correct a “normal” decline in testosterone levels that occurs with aging. Unfortunately, the evidence for the benefit of such therapy is somewhat limited (3).

Lately, the condition of “low T” among older men has been highlighted as an easily treated phenomenon. Direct-to-customer advertising (DTCA) has been guilty of encouraging the use of testosterone treatment for symptoms such as decreased energy and lack of sexual interest which have not always been proven to be caused by declining testosterone levels (4).

Furthermore, although the data are somewhat conflicting, some studies have suggested increased cardiovascular risk associated with testosterone replacement therapy (5).

However, although there is lack of general agreement among specialists, testosterone replacement therapy may be justified in selected cases. Hence, it is of utmost importance for clinicians and patients to understand when testosterone replacement therapy is appropriate and when it is not.

Testosterone Levels, Free Testosterone and Sex Hormone Binding Globulin (SHBG)

Testosterone is a hormone secreted by the testicles of males and in small amounts by the ovaries in females. It has several essential biologic functions, particularly in men.

Testosterone is defined as an androgen. Andro means male in ancient Greek, and as an androgen, testosterone is responsible for the typical characteristics of the male human being such as the deep voice, the large muscle mass, and the facial and body hair.

Most of the testosterone in the blood is attached to two proteins: albumin and sex hormone binding globulin (SHBG).

Testosterone that is not attached to proteins is called free testosterone. Free testosterone and albumin-bound testosterone are also referred to as bioavailable testosterone.

The normal range for serum total testosterone in males is about 270 – 1070 ng/dL or 9 – 38 nmol/L. The normal levels in adult men are approximately 300 – 800 ng/dl or 10 – 27 nmol/L

There is a diurnal variation in testosterone levels, particularly in young men (highest values are at approximately 8 in the morning and lowest at about 8 in the evening). It is recommended that serum total testosterone should be measured between 8-10 in the morning.


Hypogonadism is a term that refers to a decrease in either of two important functions of the testicles; sperm production and testosterone production.

Hypogonadism may be caused by an abnormality of the testicles themselves (primary hypogonadism) or by a disorder of the pituitary or hypothalamus (secondary hypogonadism).

Hypogonadism may be congenital or may begin before puberty or during adulthood. The symptoms of hypogonadism depend on the age it develops. For example, hypogonadism that occurs during fetal development may prevent the formation of healthy male genitals.

The development of hypogonadism in adult males may cause erectile dysfunction, loss of libido, infertility, decreased muscle mass, decreased facial and body hair growth, development of breast tissue (gynecomastia), loss of bone mass (osteoporosis), and emotional changes. These symptoms will be reflected by low blood levels of testosterone.

Testosterone replacement therapy is used for the treatment of hypogonadism caused by the failure of the testicles to produce testosterone. Such treatment may increase well-being, sex drive, and erectile function, restore muscle strength and reduce bone loss.

Laboratory Findings in Hypogonadism

Males with hypogonadism have low levels of serum testosterone and free testosterone.

The two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are produced by the pituitary. If testosterone production by the testicles drops, a normal hypothalamic-pituitary-testicular axis will respond by increasing the production of LH and FSH.

The serum levels of LH and FSH are above normal in primary hypogonadism. However, in secondary hypogonadism, serum concentrations of LH and FSH will be normal or low.

Testosterone Levels, Low Testosterone Symptoms, and Testosterone Replacement Therapy
The term age-related hypogonadism has been used to describe the clinical condition associated with declining testosterone levels in middle-aged and older men.

Age-Related Hypogonadism

Several studies show a declining serum total testosterone concentration with increasing age (6,7). The decline in free testosterone levels is even more pronounced.

SHBG concentrations increase gradually with age. As SHBG tends to bind to testosterone with high affinity, there will be less free or biologically active testosterone available with increasing age.

Serum gonadotropin concentrations increase with age, FSH more than LH, but the rise is usually less than would be expected from the fall in testosterone levels. Hence, it has been suggested that the drop in testosterone levels with aging is due to both primary and secondary hypogonadism (8).

The term age-related hypogonadism has been used to describe the clinical condition associated with declining testosterone levels in middle-aged and older men. The condition, also referred to as “late-onset hypogonadism,” is typically diagnosed if, for no discernible reason other than older age, serum testosterone concentrations fall below the normal range and signs and symptoms that may or may not be caused by low testosterone concentrations occur (9).

It has been suggested that the following symptoms may be associated with age-related hypogonadism:

  • a decline in muscle strength
  • reduced bone mineral density
  • a decline in sexual function
  • mood changes and depressive symptoms
  • anemia
  • central obesity
  • insulin resistance and metabolic syndrome

Nobody doubts that these symptoms may be present in men with hypogonadism due to pituitary or testicular disease. However, whether the same symptoms may occur with low testosterone levels for no apparent reason other than age has frequently been a matter of debate.

The European Male Aging Study (EMAS) found that the combination of low serum testosterone (<317 ng/dl or 11 nmol/L) and three sexual symptoms (occurring in 2.1% of the men) in men aged 40-79 years was associated with lower hemoglobin levels, heel bone mineral density, muscle mass, and physical performance (10). More severe hypogonadism was associated with insulin resistance.

So, there appears to be evidence suggesting that low testosterone levels in middle-aged and older men may be associated with a myriad of symptoms.

The final question remaining, however, is whether testosterone replacement therapy will improve these symptoms. If so, when and how should testosterone be administered?

Testosterone Replacement Therapy for Age-Related Hypogonadism

In 2002, the Institute of Medicine of the National Academy of Sciences Committee concluded that no beneficial effects of administering testosterone in older men had been well established (11).

The US Food and Drug Administration (FDA) reached the same conclusion in 2015 and directed manufacturers of testosterone products to state in their labels that these products are approved only for men with low testosterone due to known causes (12).

However, other expert groups suggest that there may be a place for testosterone replacement therapy for selected patients with age-related hypogonadism.

The following approach is recommended by many experts (8):

  • Testosterone replacement therapy may be recommended in the presence of clinical symptoms (decreased libido, low energy, depressive mood, osteoporosis or anemia) if low serum testosterone concentration has been documented on more than one occasion.
  • If the total serum testosterone concentration is consistently less than 200 ng/dL (6.9 nmol/L) in the presence of symptoms, testosterone replacement therapy can be administered.
  • The target serum testosterone concentration during treatment in these men should be lower than that for young men, thus in the range of 300-400 ng/dL (10.4-13.9 nmol/L).
  • It is essential to exclude other causes of hypogonadism such as testicular or pituitary disease before treatment is initiated.

Results from the Testosterone Trials suggest that testosterone replacement therapy for age-related hypogonadism in men aged 65 or older has beneficial effects on sexual function, depressive symptoms, mood, and possibly physical function (13).

The Potential Risks of Testosterone Replacement Therapy

Older men may be prone to testosterone dependent diseases. In other words, the presence of testosterone may promote disease.

Prostate cancer is an example of a prostate dependent disease. This is well illustrated by the fact that gonadotropin-releasing hormone analogs which lower testosterone levels are used for the treatment of prostate cancer.

Short-term trials have not shown that testosterone replacement therapy increases the risk of prostate cancer. However, more extensive trials of longer duration are needed to rule out an effect on prostate cancer risk.

Elevated hematocrit (increase in red blood cell count) is the most common adverse effect of testosterone replacement therapy. The clinical implication of this phenomenon is uncertain. However, elevated hematocrit has been associated with increased overall mortality and cardiovascular mortality in epidemiological studies (14).

Testosterone replacement therapy may reduce HDL-cholesterol which may be undesirable (15).

In March 2015, the FDA issued a Safety Announcement requiring manufacturers of testosterone products to include a warning of the possible increased risk of heart attacks and strokes associated with testosterone use (5).

However, a recent meta-analysis did not support any causal role between testosterone treatment and adverse cardiovascular events. The authors concluded that this is especially true when hypogonadism is properly diagnosed, and replacement therapy is correctly performed (16).

Testosterone Products 

Several testosterone products are available for the treatment of hypogonadism, age-related or not.

Oral preparations, although available, are seldom used due to lack of efficacy and risk of liver-related adverse effects.

Long-acting injections (Delatestryl, Depo-Testosterone) are often used. These can be administered every one to two weeks in most men and every three weeks in a few.

Extra-long acting injections (Nebido, Aveed) may be administered every 10-14 weeks.

Transdermal patches (Androderm, Andropatch) and gel (Testogel, Testim, Androgel, Fortesta, Axiron, Tostran) are popular but have to be administered daily.

The Bottom-Line

Serum testosterone levels decline with increasing age. This may negatively affect energy, sexual function, mood, physical strength, muscle mass, and bone mineral density in some middle-aged and older men.

Testosterone replacement therapy in older men with low testosterone levels (less than 200 ng/dL (6.9 nmol/L)) may improve sexual function, mood, depressive symptoms and possibly physical function.

Other causes of hypogonadism such as testicular or pituitary disease should be excluded before treatment is initiated.

Testosterone replacement therapy may make prostate cancer worse. Hence it is important to screen for prostate cancer before testosterone treatment is initiated and patients should be monitored for signs of the disease during treatment.

Elevated hematocrit (increased red blood cell count) represents the most common adverse event related to testosterone replacement therapy. The clinical significance of this side effect is unclear, but elevated hematocrit has been associated with increased cardiovascular and total mortality.

In 2015, the FDA issued a Safety Announcement requiring manufacturers of testosterone products to include a warning of the possible increased risk of heart attacks and strokes associated with testosterone use.

However, a recent meta-analysis did not support any causal role between testosterone treatment and adverse cardiovascular events. The authors concluded that this is especially true when hypogonadism is properly diagnosed, and replacement therapy is correctly performed.

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