Testosterone Deficiency

Concern re testosterone deficiency is a common cause for evaluation by an endocrinologist.

Testosterone replacement therapy in the United States has tripled during the last decade, now exceeding  the rest of the world, presumably due to the impact of direct to consumer marketing by Big Pharma.

This has led to guidelines, such as those published by the Endocrine Society in 2018, designed to limit use to men who are truly deficient and symptomatic.


Although "normal" testosterone levels vary, most labs define low testosterone ("hypogonadism") in men as a total testosterone of less than 300 ng/dl.

Testosterone levels decline with aging.

This has led some to suggest normal lower limits in older men: 216 ng/dl for men 50-59 years old, 196 ng/dl for men 60-69 years old and 156 ng/dl for men 70-79 years old (Mohr, Clin Endo 2005)

Symptoms of low testosterone include fatigue, loss of sex drive, depression, sleep disturbances, hot flashes, increased body fat, reduced quality of life and decreased strength (uncommon).

Although erectile dysfunction (ED) is often the reason for evaluation, the importance of testosterone is debatable.

Fatigue, sex drive, and hot flashes typically improve with replacement.

The treatment of ED may be enhanced when testosterone levels are normalized.

The impact on mood is inconsistent.

Signs of testosterone deficiency are often absent, especially if disease onset is after puberty or recent.

Signs may include delayed sexual development, breast swelling, loss of body hair, reduced muscle mass (uncommon), an appearance that is younger than chronological age, and small testes.

Clinical judgement is critical as there is no threshold to predict which men will respond to therapy.

Primary testosterone deficiency is diagnosed when testosterone levels are low because of disease in the testicles (where testosterone is produced).

This is uncommon in adult males.

Causes include Klinefelter Syndrome, cryptorchidism and testicular damage.

Secondary testosterone deficiency is when levels are low due to lack of stimulation by the pituitary gland.

Causes include pituitary or hypothalamic disease, alcohol, marijuana (controversial), chronic illness and morbid obesity.

MRI evaluation of the pituitary gland is typically recommended in this setting.

Type 2 diabetes, and opiod use have also been associated with low testosterone levels.

Some men have abnormalities at multiple levels.

Weight loss will cause testosterone levels to increase.

A low testosterone level should be confirmed by repeat testing, preferably before 11 AM, before eating.

Testing should not be conducted during an acute illness.

Although total testosterone is the most common screening test, some men may also require measurement of free testosterone levels. This is an area of ongoing discussion.

Replacement is available via injection (IM or SQ), pellets, gels, patches, as well as oral, nasal and buccal preparations.

IM injections, typically 1 cc every 2 weeks, are the least expensive, and most popular, form of therapy in the United States. The typical cost of $20-$30 per month.

Testosterone levels vary significantly from peak (1-3 days after injection) to trough (10-14 days after injection) when using IM injections.

Other negatives include difficulty/discomfort associated with IM injections and greater impact on red blood cell count (see below)

Weekly SQ injections with Xyosted are easier to administer, and provide more steady levels.

Administration is  limited by significant formulary restrictions.

Although testosterone pellets require surgical implantation and removal in the office, they offer the advantage of less frequent administration.

There is a risk of pellet loss.

A variety of testosterone gels available as pumps (typically 2-4 pumps) or packets.

Most are applied in the morning.

All are expensive, averaging $500-600 per month for branded preparations.

Their efficacy is similar.

Although gels are easy to apply, intraindividual variations in testosterone levels is common and frustrating.

There is also a risk, albeit very small if applied correctly, of transfer to another person.

Some men complain about gel smell or stickiness.

Testosterone patches are associated with a high frequency (up to 50%) of rashes at application site.

Gels have provided more stable testosterone levels than patches in several studies.

Oral (Jatenzo) and nasal (Natesto) testosterone preparations were recently approved by the FDA.

Jatenzo is dosed twice daily with food.

Natesto is dosed intranasally three times daily.

Once testosterone therapy is initiated, it’s important to monitor testosterone levels as up to 30% of men will require a dose adjustment.

Testosterone levels are typically measured at trough (the day prior to scheduled dosing) for IM, SQ or pellet injections.

Testosterone levels when using gels or patches are typically measured 2-3 hours after application.

Since testosterone therapy may result in side effects such as increased number of red blood cells and acne, close medical follow-up is very important.

Other potential side effects include infertility, swelling of the legs and breast enlargement.

The red blood cell count may also increase, most commonly with IM injections, presumably due to associated supraphysiologic testosterone levels.

CBC should regularly be monitored.

Although a careful prostate evaluation must be conducted before beginning therapy, evidence doesn't support an increased risk of prostate cancer.

PSA levels should nonetheless be monitored regularly especially in men 55 years and older, or those 40 years and older if Black or with a history of prostate cancer in a first degree relative.

A urologist should be consulted for elevations >1-1.4 ng/dl within 1 year or an absolute level of 4 ng/dl or higher.

Several studies published in 2013 and 2014 suggested that testosterone therapy may raise the risk of heart-related events.

Although the studies were plagued by a variety of methodological errors, and contradict prior reports, caution is recommended in the setting of active heart disease.

If left untreated, testosterone deficiency may cause thinning of the bone (osteopenia).

It is unknown if testosterone-induced bone thinning is associated with an increased fracture risk.

The evaluation and treatment of testosterone deficiency should be discussed with your physician, and never initiated or continued without regular medical follow-up.