Definitive Guide To Low Testosterone

What is testosterone?

Testosterone is the most important sex hormone in men. The steroid hormone is important at every stage of male development, from inside the womb to old age. Even as early as the first trimester, male fetuses need to have sufficient testosterone levels to develop normal genitalia. A lack of testosterone in the third trimester causes micropenis. Testosterone sends the signal when to start puberty and is responsible for secondary sex characteristics in men such as a deep voice, facial and chest hair, and increased muscle mass. In fact, testosterone deficiency before puberty can delay the onset of puberty—indefinitely, if testosterone deficiency is left untreated. When low testosterone occurs after puberty, it causes men to lose energy, muscle mass, and sex drive. Thus, maintaining a sufficient testosterone level is important in boys and men of every age.

What is low testosterone?

Low testosterone describes a clinical state in which testosterone levels are abnormally low in the bloodstream. In other words, the measured testosterone level in the blood is below the lower range of normal for a man of a particular age. The range of normal testosterone levels varies from laboratory to laboratory¹; however, in general, low testosterone is defined as a total testosterone level below 300 ng/dl (10.4 nm/L). A normal testosterone range also varies by age. Testosterone levels are very low before puberty, increase dramatically during puberty and stay rather constant during adulthood. At one time, it was believed that testosterone levels normally dropped as men got older. While the average level of testorsterone does decrease slightly as men age (perhaps as much as 100 ng/dL from age 20 to age 80²), reduced testosterone levels are not normal at any age.  Researchers now realize a low testosterone level in older men is not a normal part of aging, but actually means the man has low testosterone.³ In other words, low testosterone is a lower than normal testosterone for a given age, but the lower level of normal is not much lower for older men than it is in younger men.⁴

Normal testosterone ranges in men by age

How is testosterone production regulated in men?

The production of testosterone is regulated by three structures: the hypothalamus, the pituitary gland, and the testicles. The hypothalamus is a structure in the brain, the pituitary is a gland at the base of the brain, and Leydig cells in the testicles produce testosterone. Under normal circumstances, the hypothalamus releases a hormone called gonadotropin-releasing hormone or GnRH. GnRH stimulates the pituitary gland to produce two hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH are released into the bloodstream. These hormones travel to the vesicles where they stimulate the release of testosterone into the blood. Testosterone then acts on various tissues in the body such as muscles, hair follicles, and even on the testicles themselves. If testosterone levels get too high, the hormone then acts on the hypothalamus to reduce GnRH release, acting as a negative feedback loop.

Low testosterone is also known as hypogonadism. The two types of hypogonadism are primary hypogonadism and secondary hypogonadism. If the cause of low testosterone is in the testicles, it is called primary hypogonadism. On the other hand, if the cause of low testosterone is in the pituitary gland or hypothalamus, the condition is known as secondary hypogonadism. In both cases of hypogonadism, testosterone levels will be abnormally low. However, in primary hypogonadism LH and FSH levels will be high, while in secondary hypogonadism, LH and/or FSH levels will be normal or low.

What causes low testosterone in men and boys?

The causes of primary hypogonadism (also known as hypergonadotropic hypogonadism) are relatively few and usually related to a genetic issue, a chromosomal abnormality (e.g. Klinefelter syndrome, Turner’s syndrome, XX gonadal dysgenesis), an enzyme deficiency (e.g. 17α-hydroxylase deficiency) or an insensitivity to gonadotropin. Anything that severely injures the testicles can also result in primary testosterone deficiency. These include trauma, radiation, infection (e.g. orchitis), chemotherapy, and certain drugs and toxins.

Secondary hypogonadism, also referred to as central hypogonadism or hypogonadotropic hypogonadism, can also be caused by genetic or acquired causes. The genetic causes of secondary hypogonadism are relatively rare. On the other hand, many things cause acquired secondary hypogonadism, making it the most common cause of low testosterone.

The possible causes of secondary hypogonadism include⁵:

• Brain tumors
• Pituitary adenomas
• Pituitary apoplexy
• Infiltrative disorders
• Sarcoidosis
• Hemochromatosis
• Histiocytosis X
• Head trauma
• Radiation therapy
• Excessive exercise
• Anorexia nervosa or severe calorie restriction
• Anabolic steroids (i.e. “doping”)
• Glucocorticoid therapy (i.e. chronic steroid use)
• Narcotics
• Critical illness (e.g., heart attack, major surgery, long time in intensive care unit)
• Obesity
• Sleep apnea
• Type 2 Diabetes mellitus
• Metabolic syndrome

Most genetic causes of hypogonadism become apparent before or at puberty. Other causes of hypogonadism usually occur during adulthood, typically in a middle-aged man. Because they occur so often—and often occur together—obesity, sleep apnea, metabolic syndrome, are diabetes mellitus are common and important causes of low testosterone levels in men. Insidiously, the causes of low testosterone may not cause noticeable symptoms, and therefore many men have low testosterone and do not even know it.

Signs and symptoms of low testosterone in men

Not all men with low testosterone will have every sign and symptom of low testosterone. That said, the most common signs (things you can see or measure) and symptoms (things you can feel or experience) of androgen deficiency include⁶:

• Low/absent sex drive or reduced sex drive from a previous level
• Fewer erections in the morning/spontaneous erections
• Very small testicles or testicles that have gotten smeller over time
• Hair loss from the armpit and pubic regions
• Slower facial hair growth
• Development of glandular breast tissue in men (i.e. Gynecomastia)
• Incomplete or delayed sexual development (when low testosterone occurs before/during puberty
• Hot flashes
• Breast/chest tenderness

Other, less specific signs and symptoms of low testosterone include:

• Fatigue
• Depressed mood
• Decreased ability to concentrate or remember things
• Daytime sleepiness
• Anemia (low red blood cell counts)
• Reduced muscle mass (reduced muscle mass also causes reduced muscle strength)
• Reduced bone density (i.e. low mineral bone density)
• Increased body fat and body mass index

Do I have low testosterone (How is low testosterone diagnosed)?

Low testosterone can be diagnosed in several ways. The most common method is to order a blood test measure total testosterone between 8 and 10 am after a good night’s sleep. Why 8 to 10 am? Because testosterone levels can vary substantially during the day—morning levels are usually when testosterone levels are highest. If your testosterone level is normal, that ends testing; you do not have low testosterone. However, if your total testosterone level is below normal, a repeat blood test is done to confirm the diagnosis. During the second testosterone test, your doctor will usually also test FSH and LH. Two blood tests that show an abnormally low level of testosterone confirm the diagnosis of low testosterone. LH and FSH levels help distinguish between primary and secondary hypogonadism.

Most physicians will continue to investigate the cause of low testosterone after the diagnosis is made. In primary hypogonadism, your doctor may order a karyotype to test for a chromosomal abnormality such as Klinefelter syndrome. Most men with low testosterone will have secondary hypogonadism. In this case, your doctor may order a number of tests to determine the precise cause including:

• Prolactin levels
• Thyroxine levels (thyroid hormone)
• Cortisol levels
• Iron and transferrin levels
• MRI of the brain

In some cases, it may be necessary to order different set of tests to diagnose the cause of low testosterone. Your doctor may measure also measure sex hormone-binding globulin (SHBG) with total testosterone. About half of all testosterone in the blood is tightly bound to SHBG and the rest is either dissolved in the blood (“free”) or loosely bound to another serum protein, albumin. The testosterone that is bound to SHBG is biologically inactive. The rest (free or albumin-bound) is biologically active; it is the bioavailable testosterone in the blood. The ratio of total testosterone to sex hormone-binding globulin is the free androgen index (FAI). It is a measure of free testosterone in the blood. For complex reasons, the free androgen index is usually a more accurate measure of free testosterone in woman than in a man. Thus, only low testosterone specialists (e.g. at a “man clinic”) order and interpret the FAI in men.

Low testosterone treatment

The treatment of boys with low testosterone who have not yet entered puberty is complex, and beyond the scope of this report. That said, testosterone treatment may help boys start to undergo and progress through puberty, and can help them fully or nearly fully develop into men of average height and secondary sexual characteristics. The rest of the discussion will focus on low testosterone treatment in adult men.

The Endocrine Society has published clinical practice guidelines that help physicians determine how to provide testosterone therapy to men with androgen deficiency syndromes.⁶ They specifically “recommend testosterone therapy for symptomatic men with classical androgen deficiency syndromes aimed at inducing and maintaining secondary sex characteristics and at improving their sexual function, sense of well-being, and bone mineral density.” In other words, the society recommends treating men with low testosterone who show symptoms of low testosterone (e.g., reduced sex drive, loss of body hair, infertility, erectile dysfunction, and other symptoms listed previously).

Interestingly, they also state the targets of testosterone therapy as sexual function, a sense of health and well-being, and bone density. This “sense of well-being” criterion is particularly important because it gives doctors and patients the freedom to provide testosterone replacement to men who have poor quality of life because of their low testosterone.

Testosterone supplementation is not appropriate for some men even if they have testosterone deficiency. For example, testosterone treatment should not be given to men with prostate cancer or breast cancer. In fact, your doctor may perform tests to determine your risk of prostate cancer such as a digital rectal examination and/or prostate specific antigen (PSA) test. Moreover, people with a hematocrit above 50% (requires a blood test), severe untreated obstructive sleep apnea (requires a sleep apnea test), severe lower urinary tract disease, and poorly controlled heart failure should probably not receive testosterone replacement.

Low testosterone treatment options

The clinical practice guidelines also recommend several forms of testosterone therapy that may be helpful for men. Indeed, the guidelines suggest that men and their doctors choose the testosterone treatment regimen based on patient preference, ease of use, cost, and certain other factors. Initial treatments for low testosterone include:

• Testosterone enanthate 75–100 mg administered intramuscularly every week
• Testosterone enanthate 75–100 mg administered intramuscularly every week
• Testosterone cypionate 150–200 mg administered intramuscularly every 2 weeks
• Testosterone cypionate 150–200 mg administered intramuscularly every 2 weeks
• Testosterone patches (5 mg; 1-2 patches) applied each night to the back, thigh, or upper arm
• Testosterone gel (1%; 5 to 10 g) applied each day to an area of skin away from the genitals
• Testosterone tablet 30 mg placed under the tongue twice a day
• Testosterone pellets implanted under the skin every 3 to 6 months

The Endocrine Society guidelines do not specifically mention the use of bio-identical testosterone or natural testosterone supplementation. This may be because it is difficult to judge the potency of unregulated testosterone supplements. Importantly, the goal of testosterone supplementation is to raise blood testosterone levels into the normal range, to level that can reduce low testosterone symptoms and improve quality of life. This may be difficult to accomplish or perhaps even unsafe using testosterone preparations with unknown androgen concentrations and inactive ingredients.

Monitoring the effects of testosterone treatment

Once testosterone therapy has begun, men should be followed by their prescribing physician every 3 to 6 months. At that time, testosterone levels in the blood should be measured to determine if the treatment has created the intended effect. Perhaps more importantly, these visits should be used for the doctor to confirm that testosterone supplementation is reducing symptoms of low testosterone and is not causing side effects. Certain other tests need to be performed during these follow-up visits. For example, testosterone therapy is known to increase hematocrit, which is a concentration of rail blood cells in the blood. His hematocrit goes above 54%, hormone therapy may need to be stopped or reduced, at least temporarily.

The benefits of testosterone treatment

Much of what we know about the benefits of testosterone treatment come from a set of fascinating clinical studies called the Testosterone Trials.⁷ The Testosterone Trials are an assortment of seven placebo-controlled clinical trials conducted at multiple sites and institutions. The goal of the Testosterone Trials was to determine the benefits of testosterone replacement therapy in adult men over the age of 65 with initial total testosterone levels less than 275 ng/dL. Men participating in the trial received either testosterone gel or a placebo gel that they were to use as directed for entire year. In men who receive the active testosterone gel, blood testosterone levels reached the mid-normal range for men ages 19 to 40 years old.

Compared to placebo gel, men taking testosterone therapy had improvement in sexual function, increased man sex drive, frequency of sexual activity, and reduced erectile dysfunction. Treated men were able to walk farther on treadmill testing than placebo treated men were. Men treated with testosterone gel reported better mood and fewer symptoms of depression than men treated with placebo gel. On the other hand, scores of vitality and cognitive function were no different between the testosterone- and placebo-treated groups. Testosterone treatment significantly increased bone density after 12 months compared to placebo. In men who had anemia, testosterone increased red blood cell count and hematocrit. On the other hand, 7% of men treated with testosterone in the study developed a hemoglobin level that was too high, which is considered an adverse event.

A separate set of trials showed that men treated with testosterone had increased lean muscle mass and reduce body fat.^8,9,10 In one of these studies, the increase in muscle mass also occurred with an increase in muscle strength.¹⁰

Risks of testosterone treatment

One of the main concerns among older men who receive testosterone therapy is the risk of prostate cancer. Prostate cancers are fed by testosterone. For example, one of the main treatments for prostate cancer is to block the effect of testosterone on prostate gland. Thus, men at risk for prostate cancer should not receive testosterone replacement in most cases. Moreover, men who do receive testosterone treatment should be monitored closely for prostate cancer.

While testosterone does influence benign prostatic hyperplasia or BPH, studies have shown that testosterone supplementation does not significantly worsen BPH symptoms in men.

As previously mentioned, testosterone stimulates the production of red blood cells. This can be helpful in men with anemia, but may be unhelpful in people who begin treatment with a normal red blood cell count or hematocrit. These values should be followed in anyone receiving testosterone therapy.

Lastly, testosterone may or may not increase cardiovascular risk in men. Some studies show that older men taking testosterone have an increased risk of cardiovascular events, while other studies have failed to show this effect. In any case, heart and blood vessel health should be monitored in any men taking testosterone supplementation.

Summary

Testosterone is important for normal development, growth, health, and function. As such, may need to have sufficient levels of testosterone throughout development. Low testosterone can occur at any age causing various symptoms. In older men, the most common symptoms of low testosterone are low sex drive, erectile dysfunction, hair loss, fatigue, reduced muscle mass, and increase body fat. Low testosterone can be diagnosed with a series of blood tests, usually total testosterone level in blood. Various forms of testosterone replacement are available, ranging from gels to pills to injections. Symptoms of low testosterone are not a part of normal aging. As such, men who are experiencing symptoms of low testosterone should make an appointment to visit a specialist in low testosterone treatment. In select men, testosterone replacement can increase muscle mass, decrease body fat, improve sex drive and performance, increase bone mineral density, and lead to overall better health and well-being.

References

1. Bhasin S, Zhang A, Coviello A, et al. The Impact of Assay Quality and Reference Ranges on Clinical Decision Making in the Diagnosis of Androgen Disorders. Steroids. 2008;73(13):1311-1317. doi:10.1016/j.steroids.2008.07.003
2. Purifoy FE, Koopmans LH, Mayes DM. Age Differences in Serum Androgen Levels in Normal Adult Males. Hum Biol. 1981;53(4):499-511.
3. Kelsey TW, Li LQ, Mitchell RT, Whelan A, Anderson RA, Wallace WHB. A Validated Age-Related Normative Model for Male Total Testosterone Shows Increasing Variance but No Decline after Age 40 Years. PLoS ONE. 2014;9(10):e109346. doi:10.1371/journal.pone.0109346
4. Mohr BA, Guay AT, O’Donnell AB, McKinlay JB. Normal, Bound and Nonbound Testosterone Levels in Normally Ageing Men: Results from the Massachusetts Male Ageing Study. Clin Endocrinol (Oxf). 2005;62(1):64-73. doi:10.1111/j.1365-2265.2004.02174.x
5. Hayes F, Dwyer A, Pitteloud N. Hypogonadotropic Hypogonadism (Hh) and Gonadotropin Therapy. 2013.
6. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone Therapy in Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 2010;95(6):2536-2559. doi:10.1210/jc.2009-2354
7. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611-624. doi:10.1056/NEJMoa1506119
8. Snyder PJ, Peachey H, Hannoush P, et al. Effect of Testosterone Treatment on Body Composition and Muscle Strength in Men over 65 Years of Age. J Clin Endocrinol Metab. 1999;84(8):2647-2653. doi:10.1210/jcem.84.8.5885
9. Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG. Effects of Transdermal Testosterone on Bone and Muscle in Older Men with Low Bioavailable Testosterone Levels. J Gerontol A Biol Sci Med Sci. 2001;56(5):M266-272.
10. Page ST, Amory JK, Bowman FD, et al. Exogenous Testosterone (T) Alone or with Finasteride Increases Physical Performance, Grip Strength, and Lean Body Mass in Older Men with Low Serum T. J Clin Endocrinol Metab. 2005;90(3):1502-1510. doi:10.1210/jc.2004-1933

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2265.2004.02174.x/full

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