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Testosterone has been available since at least the 1940s, first in injectable and then oral forms.[1],[2] However, it was not until the early 2000s[3] — when easy-to-use testosterone forms, such as transdermal gels (see table below), became available — that prescribing of these products soared. Overall, use of testosterone products in the U.S. grew by nearly 10-fold from 2000 to 2011, and by 2013, more than 5 million U.S. prescriptions for testosterone products were being filled annually.[4],[5]...
Testosterone has been available since at least the 1940s, first in injectable and then oral forms.[1],[2] However, it was not until the early 2000s[3] — when easy-to-use testosterone forms, such as transdermal gels (see table below), became available — that prescribing of these products soared. Overall, use of testosterone products in the U.S. grew by nearly 10-fold from 2000 to 2011, and by 2013, more than 5 million U.S. prescriptions for testosterone products were being filled annually.[4],[5]
The increased use of testosterone products is a direct result of lax regulation, as the Food and Drug Administration (FDA) did not historically require proof of clinical benefit for these products.[6] Instead, the agency required only that the drugs raise testosterone levels in the blood to normal levels. These lax rules have allowed testosterone makers to launch massive direct-to-consumer advertising campaigns[7] hailing the drug as a fountain of youth for men experiencing symptoms — including lack of energy and loss of sex drive — related to normal aging.[8]
Although recent studies have highlighted cardiovascular risks (in particular, heart attack and stroke) associated with testosterone products, strong evidence of the drugs’ benefits has been lacking for men with age-related declines in testosterone.
A recent study, conducted by researchers who are independent of the testosterone industry, was published online in PLOS ONE in September 2016.[9] The study showed that testosterone products have no consistent benefit for a variety of uses not approved by the FDA, often called “off-label uses.”
Testosterone and its uses
Testosterone is the primary sex hormone produced in men’s bodies. The majority of this hormone is made by the testicles, with a small amount produced by the adrenal glands.[10] Testosterone stimulates the development of male sexual characteristics and sexual behavior during puberty. It also plays an important role in maintaining sexual drive and potency, sperm production, muscle mass, bone mass and red blood cell production in adult males. Testosterone typically reaches normal male adult levels by age 17 and remains there until men are in their 30s or 40s, then subsequently decreases as part of normal aging.[11]
Troubled by the widespread misprescribing of testosterone, the FDA issued letters in February 2015 to all testosterone makers requiring labeling changes that limit the approved use of these products to men with “classic” hypogonadism (inadequate production of testosterone by the testicles) due to certain conditions:[12],[13].[14] genetic diseases, testicular damage from chemotherapy or infection, and disorders in the pituitary gland or the hypothalamus, a part of the brain that regulates many of the body’s hormones. Testosterone replacement is necessary for the development or maintenance of secondary sexual characteristics in these patients.[15]
The agency also issued a safety announcement in March 2015 cautioning against the use of testosterone products to relieve symptoms in men with low testosterone due to no apparent reason other than aging, because “the benefits and safety of this use have not been established.”[16]
It remains to be seen whether this recent effort will effectively tame the growing overuse of testosterone, as most men using this product do not have classic hypogonadism.[17]
The PLOS ONE study
The study analyzed 156 randomized clinical trials published from January 1950 to April 2016 that compared the benefits of testosterone therapy to those of a placebo in men with low testosterone.[18] It focused on trials that involved off-label uses of testosterone and excluded those involving FDA-approved uses in men who had missing or damaged testicles. It also excluded trials of testosterone use for bodybuilding, contraception and treatment in women or children.
Overall, the study found that testosterone therapy provided no consistent clinical benefits and that a placebo was just as effective.
Specifically, it showed that the trials examining clinical cardiovascular outcomes have not favored testosterone over a placebo. (See “Risks” for more on cardiovascular effects.)
It did not find consistent evidence to support testosterone’s effectiveness in improving sexual function, sexual satisfaction or erectile dysfunction.
The study noted that although substantial evidence supports a favorable effect of testosterone treatment on muscle mass, the evidence does not show that testosterone improves muscle strength or physical functioning.
It found no positive effect of testosterone treatment on psychological well-being or mood. Instead, it noted that several trials linked testosterone treatment to increased anger, aggression and hostility.
Similarly, the study showed that testosterone is not beneficial in treating cognitive impairment or Alzheimer’s disease; neither does it improve memory or other measures of cognition in men without classic hypogonadism.
The researchers identified no population of men who do not have classic hypogonadism for whom the benefits of testosterone use outweigh its risks.
| The Testosterone Trap: A Fertility Treatment that Causes Infertility |
|---|
| It is hard to imagine that a doctor, faced with a male patient seeking fertility treatment, would prescribe a drug that shuts down the body’s production of sperm. Yet shockingly, one out of every four urologists have reported they would consider doing just that. In a 2012 survey by the American Urological Association (AUA), 25 percent of urologists reported that they would use testosterone to increase sperm production in men with unexplained infertility. Normally, sex hormone production is controlled by the hypothalamus — a part of the brain that regulates many of the body’s hormones — and the nearby pituitary, a gland located near the base of the brain. These organs monitor testosterone levels in the body and send chemical signals to the testicles to increase sex hormone production when testosterone is low, much like the thermostat in a home measures temperature and signals the furnace to switch on when the house is too cold. Testosterone treatment floods the body with synthetic testosterone, triggering the hypothalamus and pituitary to shut down the body’s natural testosterone production. Sperm count plummets, approaching zero after six months of treatment in most men, and the testicles may visibly shrink. The impact on sperm production may be long-term or even permanent. Fewer than half of men treated with testosterone for six months are able to recover their original sperm levels, although the majority do recover some sperm production. The negative effect of testosterone treatment on sperm count has been known for decades. In fact, the World Health Organization even explored using testosterone as a contraceptive in a well-known multinational study published in 1990. So why do some doctors continue to view testosterone as a fertility treatment? A number of them may simply have failed to educate themselves about male fertility, which is particularly inexcusable for urologists. The 2012 AUA study found that only 7 percent of urologists specially trained in fertility would use testosterone to treat low sperm count, compared with nearly 30 percent of urologists who lacked such training. Doctors may also wrongly believe that a course of testosterone, stopped abruptly, can stimulate rebound sperm production, a theory that has been refuted repeatedly when tested in clinical trials. In spite of the high number of poorly informed doctors offering testosterone as a fertility treatment, most men appear to be avoiding the testosterone trap. A recent study of 4,400 patients visiting one male infertility specialty clinic in Canada found that only about 1 percent had been taking testosterone. The bottom line: If your doctor prescribes testosterone for infertility, it’s time to find a new doctor! Men seeking to start a family now or in the future should avoid testosterone products, as these can cause long-term or even permanent male infertility. |
Risks
The above study is not the first to raise concerns about testosterone products. In February 2014, Public Citizen’s Health Research Group petitioned the FDA to add a black-box warning about increased risk of adverse cardiovascular events, including heart attack and stroke, to the product labels of all testosterone-containing drugs available in the U.S. Our petition was based on evidence from both randomized clinical trials and observational studies that showed that men who received testosterone products were more likely to experience such events.
Demonstrating additional regulatory laxity when it comes to promptly warning about new dangers of drugs, the FDA denied our petition in July 2014. It was not until March 2015 that the agency required testosterone makers to make a labeling change, but not a black-box warning as we requested, to inform prescribers and consumers of possible increased risk of heart attack and stroke with the use of these products.
Additional side effects associated with testosterone products include increased risk of blood clots (see article, page 3), infertility (see box, page 6) and increased potential for abuse and dependence.
What You Can Do
Unless you are a man with confirmed hypogonadism due to a problem with your testicles, pituitary gland or hypothalamus, you should not use testosterone products.
You should not use these products to treat symptoms associated with normal aging that are sometimes attributed to low testosterone levels because they are not a useful treatment for aging and can increase your risk of cardiovascular and other serious side effects.
Simpler remedies, such as exercising and maintaining a healthy weight, may provide more benefits than testosterone products for improving cardiovascular fitness, one’s sense of well-being and overall functioning.
Women and children should not be exposed to testosterone products.
If you are prescribed testosterone for an FDA-approved use, you should be alert for warning signs of cardiovascular side effects, such as chest pain or pressure, shortness of breath, rapid or irregular heart rate, neurologic weakness, or numbness or tingling on one side of the body. If you experience any of these warning signs, seek medical help immediately.
We recommend reporting all serious adverse events related to testosterone products to the FDA’s MedWatch adverse event reporting program by visiting http://www.fda.gov/MedWatch or by calling 800-FDA-1088.
References
[1] Aub JC, Kety SS. Recent advances in testosterone therapy. N Engl J Med. 1943;228(11):338-343.
[2] Nieschlag E, Behre HM, Bouchard P, et al. Testosterone replacement therapy: Current trends and future directions. Hum Reprod Update. 2004;10(5):409-419.
[3] Handelsman DJ. Irrational exuberance in testosterone prescribing: When will the bubble burst? Med Care. 2015;53(9):743-745.
[4] Handelsman DJ. Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse. Med J Aust. 2013;199(8):548–551.
[5] QuantilesIMS data on U.S. testosterone prescriptions for gel, patch and oral dosage forms, 2013.
[6] Food and Drug Administration. Background documents for the joint meeting for Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management Advisory Committee (DSARM AC). September 17, 2014. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM412536.pdf. Accessed February 7, 2017.
[7] Perls T, Handelsman DJ. Disease mongering of age-associated declines in testosterone and growth hormone levels. J Am Geriatr Soc. 2015;63(4):809-811.
[8] Weintraub A. Why all those testosterone ads constitute disease mongering. Forbes. March 24, 2015. http://www.forbes.com/sites/arleneweintraub/2015/03/24/why-all-those-testosterone-ads-constitute-disease-mongering. Accessed February 7, 2017.
[9] Huo S, Scialli AR, McGarvey S, et al. Treatment of men for “low testosterone”: A systematic review. PLOS ONE. 2016;11(9):e0162480.
[10] Testosterone and Aging: Clinical Research Directions. Catharyn T. Liverman, Dan G. Blazer, editors; Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy. The National Academies Press; 2004.
[11] Ibid.
[12] Food and Drug Administration. Letter to Eli Lilly and Company. May 11, 2015. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/022504Orig1s012ltr.pdf. Accessed February 7, 2017.
[13] Food and Drug Administration. Auxilium Pharmaceuticals, Inc. May 11, 2015. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/021543Orig1s011ltr.pdf.
[14] Food and Drug Administration. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. March 3, 2015. http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm. Accessed February 7, 2017.
[15] Food and Drug Administration. Background documents for the joint meeting for Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management Advisory Committee (DSARM AC). September 17, 2014. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM412536.pdf. Accessed February 7, 2017.
[16] Food and Drug Administration. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. March 3, 2015. http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm. Accessed February 7, 2017.
[17] Jasuja GK, Bhasin S, Reisman JI, et al. Who gets testosterone? Patient characteristics associated with testosterone prescribing in the Veteran Affairs System: A cross-sectional study. J Gen Intern Med. 2016;32(3):304-311.
[18] Huo S, Scialli AR, McGarvey S, et al. Treatment of men for “low testosterone”: A systematic review. PLOS ONE. 2016;11(9):e0162480.
[19] Public Citizen. Petition to the FDA for black box warnings on all testosterone products. February 25, 2014. http://www.citizen.org/hrg2184. Accessed February 7, 2017.
[20] Public Citizen. Statement: Contrasting actions by Health Canada and the FDA on testosterone. July 16, 2014. http://www.citizen.org/hrg2208. Accessed February 7, 2017.
[21] Food and Drug Administration. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. March 3, 2015. http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm. Accessed February 7, 2017.
[22] Public Citizen. FDA belatedly warns about testosterone risks of heart attack and stroke. March 5, 2015. http://www.citizen.org/pressroom/pressroomredirect.cfm?ID=5430. Accessed February 7, 2017.
[23] Food and Drug Administration. Testosterone and other anabolic androgenic steroids (AAS): FDA statement — risks associated with abuse and dependence. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm526151.htm. Accessed February 7, 2017.
