Testosterone replacement therapy: Understanding appropriate uses

There has been a recent flurry of marketing for products to provide men with supplementary testosterone. More specifically, these prescription products are marketed as testosterone replacement therapies. As a replacement therapy, the implication is that some men need to have testosterone replaced. However, it is not entirely clear if healthy men need testosterone replacement or if testosterone replacement therapy is actually beneficial for most men.

What is testosterone deficiency?

The concept of testosterone deficiency is somewhat murky. In women, the concept of oestrogen deficiency is rather straightforward. Once women progress through menopause, there is a profound drop in oestrogen levels. While it is true that testosterone levels decrease as men age, the decline is not nearly as abrupt and profound as oestrogen deficiency in women. It is unclear what “normal” levels should be for men at what point testosterone replacement therapy is needed. Moreover, a man's testosterone level changes throughout the day, which makes defining “normal” and “below normal” even more challenging.

Between the ages of 40 and 79, total testosterone can be expected to decline 0.4% each year and free testosterone (i.e. testosterone unbound to protein in the blood) decreases by 1.3% each year. a substantial number of men, however, will have lower than normal levels of testosterone in the blood as they age. For example, over 50% of men have abnormally low testosterone by the time they reach the age of 80. Since more than half of men have “abnormally low testosterone”, it is quite difficult to determine “normal” values.

Roughly 2% of men have testosterone deficiency syndrome which is an abnormally low testosterone level and at least three sexual symptoms. These men are likely to also experience abnormally low hemoglobin, decreased bone mineral density, decreased muscle mass, and reduce physical performance. In addition, men with very low testosterone levels also have increased rates of insulin resistance (a condition that is related to type 2 diabetes).

Normal Testosterone Levels

As with any blood measurement, normal and abnormal ranges vary by laboratory. Thus, normal and abnormal levels defined by a particular laboratory should be used. In one scientific study, normal testosterone levels were defined as being greater than 325ng/dL or 11.3nmol/L. Total testosterone levels below 200ng/dL or 6.9nmol/L are usually considered substantially low and usually indicate the need for additional investigation. Free testosterone—a measure that may more accurately reflect true testosterone levels in obese men—should be more than 35 pg/mL in men less than 70 years old and more than 30 pg/mL in older men. In some laboratories, however, the normal range for free testosterone may be 5–9 pg/ml (0.17–0.31 nmol/L).

Diagnosing Testosterone Deficiency: Measuring Testosterone Levels

Since testosterone levels change throughout the day, especially in younger men, diagnostic blood draws should be done between 8 and 10 AM every time. If the morning blood draw reveals normal free testosterone, the man should not receive testosterone replacement therapy unless there is some testosterone related deficiency in sperm production or other endocrine disease. 

If the first free testosterone measurement is abnormally low, the test should be repeated on a different day along with two other hormones: luteinizing hormone and follicle-stimulating hormone.

Again, a normal free testosterone level on the second test should be considered evidence of normal testosterone. If free testosterone is low, but luteinizing hormone and follicle-stimulating hormone are normal, the diagnosis is secondary hypogonadism. In cases of secondary hypogonadism, additional testing may be performed including:

• Prolactin
• Thyroid hormone (T4; thyroxine)
• Morning cortisol level
• Serum iron and transferring
• MRI imaging of the brain (in some cases)

If free testosterone is low and luteinizing hormone and follicle-stimulating hormone are high, the diagnosis is primary hypogonadism and a karyotype should be performed. A karyotype is a test in which the number of chromosomes is counted under microscope. Primary hypogonadism may indicate a genetic disorder and is usually diagnosed early in life rather than at the time men become concerned with testosterone deficiency.

The Effects of Low Testosterone

Low testosterone levels may be associated with a number of undesirable symptoms. While the causal link has yet to be shown definitively through clinical trials, evidence suggests that low testosterone causes:

• Problems with sexual function such as erectile dysfunction and decreased libido
• Decreased muscle mass
• Decreased fat mass
• Decreased muscular strength
• Anemia
• Depressed mood
• Mental slowing
• Increased cardiovascular risk factors such as metabolic syndrome

Effects of Low Restoring Testosterone

Testosterone supplementation has been shown to modestly help increase libido and sexual potency, mood, muscle mass and fat mass, and bone density.

Possible Harmful Effects of Testosterone Replacement Therapy

Older men are particularly prone to testosterone-related diseases. Testosterone replacement therapy theoretically increases the risk of prostate cancer, benign prostatic hyperplasia, sleep apnea, and an increase red blood cell count. At the current time, it is unclear whether testosterone replacement therapy poses a significant risk or if the benefits outweigh potential risk.

Restoring “Normal” Testosterone Levels

Since it is difficult to determine what is normal and abnormal for testosterone levels by age, it is also difficult to determine what an appropriate level of replacement should be. Since there are several negative effects of elevated testosterone in older men, is considered imprudent to attempt to restore testosterone to the levels of a young man.

Therefore, treatment goals for serum total testosterone concentration should be between 300 and 400 ng/dL or 10.4 and 13.9 nmol/L. The goal of treatment is to raise testosterone levels and treat the effects of low testosterone without greatly increasing the risk of testosterone-related side effects.

Types of Testosterone Replacement Therapy

Testosterone replacement drugs include oral preparations, long-acting injections, extra-long-acting injections and topical treatments. Oral testosterone preparations may be less effective at treating sexual symptoms of low testosterone and can cause several harmful effects on the liver including jaundice and liver cancer. Therefore, oral testosterone is rarely used for testosterone replacement therapy, if at all.

Long-acting injections and extra-long-acting injections can be effective in normalising testosterone levels and only need to be administered once a month or once every three months, respectively. The drugs are injected deep within a muscle, and testosterone slowly leaks into the bloodstream over time. While treatment is convenient because it only is required in frequently, more or less testosterone may leak out over time leading to fluctuations in blood testosterone.

Modern treatment for testosterone replacement therapy usually involves some sort of topical treatment. This may include transdermal patches or topical ointments. Androderm is a patch worn on the arm or abdomen that delivers between 2 to 4 mg of testosterone every day. Other testosterone patches are available in some countries. AndroGel, Axiron, Fortesta, and Testim are testosterone gels that deliver varying amounts of testosterone. While the percent of testosterone varies from 1 to 2% by drug, the amount of testosterone delivered varies much more than that. Because of the potency of testosterone gels, it is important to follow prescribed treatment recommendations precisely to achieve treatment benefit and avoid complications.

Other forms of testosterone that may be used to treat testosterone deficiency include a tablet that dissolves in the mouth (Striant SR), a testosterone pellet that is placed under the skin (Testopel), and a nasal testosterone gel (Natesto).

References

1. Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab. Jul 2008;93(7):2737-2745. doi:10.1210/jc.2007-1972
2. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. Feb 2001;86(2):724-731. doi:10.1210/jcem.86.2.7219
3. Tajar A, Huhtaniemi IT, O'Neill TW, et al. Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). J Clin Endocrinol Metab. May 2012;97(5):1508-1516. doi:10.1210/jc.2011-2513
4. 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:doi:10.1210/jc.2009-2354
5. 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. Dec 12 2008;73(13):1311-1317. doi:10.1016/j.steroids.2008.07.003
6. Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. Jun 1983;56(6):1278-1281. doi:10.1210/jcem-56-6-1278
7. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. Jul 8 2010;363(2):123-135. doi:10.1056/NEJMoa0911101
8. Forbes GB, Reina JC. Adult lean body mass declines with age: some longitudinal observations. Metabolism. Sep 1970;19(9):653-663.
9. Murray MP, Gardner GM, Mollinger LA, Sepic SB. Strength of isometric and isokinetic contractions: knee muscles of men aged 20 to 86. Phys Ther. Apr 1980;60(4):412-419.
10. Ferrucci L, Maggio M, Bandinelli S, et al. Low testosterone levels and the risk of anemia in older men and women. Arch Intern Med. Jul 10 2006;166(13):1380-1388. doi:10.1001/archinte.166.13.1380
11. Joshi D, van Schoor NM, de Ronde W, et al. Low free testosterone levels are associated with prevalence and incidence of depressive symptoms in older men. Clin Endocrinol (Oxf). Feb 2010;72(2):232-240. doi:10.1111/j.1365-2265.2009.03641.x
12. Moffat SD, Zonderman AB, Metter EJ, Blackman MR, Harman SM, Resnick SM. Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab. Nov 2002;87(11):5001-5007. doi:10.1210/jc.2002-020419
13. Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab. Mar 2006;91(3):843-850. doi:10.1210/jc.2005-1326
14. Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E. Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab. Aug 1997;82(8):2386-2390. doi:10.1210/jcem.82.8.4163
15. Bhasin S, Storer TW, Berman N, et al. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab. Feb 1997;82(2):407-413. doi:10.1210/jcem.82.2.3733
16. Bolona ER, Uraga MV, Haddad RM, et al. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. Jan 2007;82(1):20-28. doi:10.4065/82.1.20
17. Seidman SN, Orr G, Raviv G, et al. Effects of testosterone replacement in middle-aged men with dysthymia: a randomized, placebo-controlled clinical trial. J Clin Psychopharmacol. Jun 2009;29(3):216-221. doi:10.1097/JCP.0b013e3181a39137
18. Hajjar RR, Kaiser FE, Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab. Nov 1997;82(11):3793-3796. doi:10.1210/jcem.82.11.4387
19. Liu PY, Yee B, Wishart SM, et al. The short-term effects of high-dose testosterone on sleep, breathing, and function in older men. J Clin Endocrinol Metab. Aug 2003;88(8):3605-3613. doi:10.1210/jc.2003-030236
20. Gormley GJ, Stoner E, Bruskewitz RC, et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. N Engl J Med. Oct 22 1992;327(17):1185-1191. doi:10.1056/nejm199210223271701
21. Iversen P, Christensen MG, Friis E, et al. A phase III trial of zoladex and flutamide versus orchiectomy in the treatment of patients with advanced carcinoma of the prostate. Cancer. Sep 1 1990;66(5 Suppl):1058-1066.
22. Johnson FL, Lerner KG, Siegel M, et al. Association of androgenic-anabolic steroid therapy with development of hepatocellular carcinoma. Lancet. Dec 16 1972;2(7790):1273-1276.
23. Westaby D, Ogle SJ, Paradinas FJ, Randell JB, Murray-Lyon IM. Liver damage from long-term methyltestosterone. Lancet. Aug 6 1977;2(8032):262-263.
24. Meikle AW, Mazer NA, Moellmer JF, et al. Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men. J Clin Endocrinol Metab. Mar 1992;74(3):623-628. doi:10.1210/jcem.74.3.1740497