Review of Testosterone Products

Testosterone, a hormone that is made mainly in the testicles, is the primary male sex hormone. It is essential for growth, development of sex organs and maintenance of masculine characteristics. Testosterone levels in the blood reach normal adult levels by age 17 and remain steady until the third and fourth decade of life in men.[1] These levels decrease naturally as men age, and sometimes that decline is associated with decreases in energy levels and sexual function. However, there is no conclusive evidence that these changes are consistently caused by lowered testosterone levels.[2]

The Food and Drug Administration (FDA) has approved different forms of synthetic testosterone products (see Table, below for a list of these products).

Approved Forms of Prescription Testosterone Products in the U.S.

*Designated as Limited Use
**Designated as Do Not Use

Benefit limited to a narrow group

Historically, the FDA did not require proof of clinical benefit when it approved testosterone products.[3] Instead, the agency required only proof that these products raised testosterone levels in the blood to normal levels.

Approximately 10 years ago, testosterone makers launched a massive direct-to-consumer advertising campaign that portrayed age-related declines in testosterone in men as a disease — so-called low T syndrome[4],[5] — that is supposedly responsible for numerous symptoms, including lack of energy and loss of sex drive, that often are related to normal aging.[6]

This low T campaign caused a surge in the use of testosterone products, especially after the introduction of easy-to-use forms of these products (such as transdermal gels).[7] Furthermore, most of that use has been by men between the ages of 40 and 64 with predictably declining testosterone levels due to normal aging, rather than due to certain medical conditions that reduce testosterone production.[8]

In February 2015, the FDA finally required testosterone makers to implement labeling changes indicating that the approved use of these products is limited to replacement therapy in a small group of men: those with "classic hypogonadism — defined as a lack or inadequate production of testosterone by the testicles due to certain medical conditions.[9],[10] These conditions include (1) failure of the testicles to produce testosterone because of genetic diseases or testicular damage from chemotherapy or inflammation and (2) disorders of two brain structures (the hypothalamus and the pituitary gland) that control the production of testosterone. The FDA took this action after acknowledging that the benefit of testosterone replacement has not been established in men with low testosterone levels for no reason other than normal aging.[11]

In 2017, results were published from seven coordinated randomized, controlled trials, called the Testosterone Trials (T Trials), which were jointly funded by the federal government and industry. The T Trials examined the effect of testosterone replacement therapy on symptoms and age-associated conditions in elderly men who did not have classic hypogonadism. Collectively, these trials showed that testosterone treatment corrected anemia and increased bone density but did not improve memory or other cognitive functions compared with a placebo after 12 months of follow-up.[12],[13], [14]

Serious risks

In 2014, the FDA required testosterone makers to include a general warning on the labeling of their products regarding the risk of blood clots in the veins.[15]

In the same year, Public Citizen's Health Research Group petitioned the FDA to add a black-box warning (the strongest warning the agency can require) to the labeling of all testosterone-containing products in the U.S about an increased risk of adverse cardiovascular events (including heart attack and stroke).[16] We based our petition on evidence from randomized clinical trials and observational studies that showed that men who used testosterone products were more likely to experience such events than nonusers. The FDA denied our petition in July 2014. A few months later, the agency convened an advisory committee that examined the same studies included in our petition, as well as a few others.[17]

In 2015, the FDA acknowledged "possible" increased cardiovascular risks associated with testosterone use and required general labeling changes, including a new warning — but not a black-box warning as we requested — for testosterone products.[18]

Since then, the cardiovascular trial, which focused on a subsample of 138 subjects from the main aforementioned T Trials, showed that the amount of noncalcified coronary artery plaque was significantly higher in the testosterone-treated men than in those who received a placebo.[19] This trial also showed that testosterone therapy caused greater increases in the amount of total plaque — both calcified and noncalcified — in coronary arteries. Although the investigators of this trial cautioned that their sample was not large enough to draw definitive conclusions, they concluded that their findings are concerning because any narrowing of the coronary arteries with plaque can be detrimental.

In 2016, the FDA required another general warning for the labeling of testosterone products regarding an increased risk of abuse, dependence (need for higher doses) and withdrawal symptoms (including depression, fatigue, irritability, loss of appetite and insomnia) associated with use of these products by adults and adolescents.[20] The warning indicates that such abuse usually occurs at doses higher than those prescribed and in conjunction with use of anabolic steroids (substances that act like testosterone). Abuse of testosterone can cause heart attack, heart failure, stroke, depression, hostility, aggression and liver toxicity.

Since 2009,[21] topical gel testosterone product labels (including ANDROGEL) have contained black-box warnings pertaining to virilization (development of adult physical traits, including enlargement of the penis or clitoris or development of pubic hair) in children who are accidentally exposed to these products.[22]

Additional testosterone-related adverse effects include male infertility; worsening of benign prostatic enlargement (resulting in difficulty urinating); problems breathing during sleep; and swelling of the ankles, feet or body.[23] These products should not be used in men with breast or prostate cancer.

We have classified the recently approved JATENZO and XYOSTED brands as Do Not Use because, unlike other testosterone products, they have black-box warnings in their labeling indicating that they cause increased blood pressure, which increases the risk of heart attacks and strokes. All other testosterone products are classified as Limited Use (for confirmed classic hypogonadism).

What You Can Do

Unless you are a man with a confirmed diagnosis of classic hypogonadism, you should not take testosterone. Do not use the Jatenzo or Xyosted brands for any reason because of their higher risks. You should never use testosterone to relieve aging symptoms. Simpler remedies, including exercising and maintaining a healthy weight, can provide more benefits than testosterone.

If you use testosterone, watch for warning symptoms of cardiovascular adverse effects: chest pain or pressure, trouble breathing, rapid or irregular heart rate, slurred speech or weakness on one side of the body. Also, be alert for symptoms of other reactions, including blood clots in your legs (pain or swelling) or lungs (difficulty breathing). Seek medical attention immediately if you experience any of these symptoms.
 

References

[1] 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.

[2] 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. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM436270.pdf. Accessed March 6, 2019.

[3] 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.

[4] 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.

[5] Morden NE, Woloshin S, Brooks CG, Schwartz LM. Trends in testosterone prescribing for age-related hypogonadism in men with and without heart disease [published online ahead of print December 28 2018]. JAMA Intern Med. doi:10.1001/jamainternmed.2018.6505.

[6] 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 March 6, 2019.

[7] Handelsman DJ. Irrational exuberance in testosterone prescribing: When will the bubble burst? Med Care. 2015;53(9):743-745.

[8] 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. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM436270.pdf. Accessed March 6, 2019.

[9] 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 March 6, 2019.

[10] Food and Drug Administration. Auxilium Pharmaceuticals, Inc. May 11, 2015. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/021543Orig1s011ltr.pdf. Accessed March 6, 2019.

[11] 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. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM436270.pdf. Accessed March 6, 2019.

[12] Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al. Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA. 2017;317(7):717-727.

[13] Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of testosterone treatment on volumetric bone density and strength in older men with low testosterone: A controlled clinical trial. JAMA Intern Med. 2017;177(4):471-479.

[14] Roy CN, Snyder PJ, Stephens-Shields AJ, et al. Association of testosterone levels with anemia in older men: A controlled clinical trial. JAMA Intern Med. 2017;177(4):480-490.

[15] Food and Drug Administration. FDA adding general warning to testosterone products about potential for venous blood clots. June 19, 2014. https://wayback.archive-it.org/7993/20170112003957/http:/www.fda.gov/Drugs/DrugSafety/ucm401746.htm. Accessed March 6, 2019.

[16] Public Citizen. Petition to the FDA for black box warnings on all testosterone products. February 25, 2014. https://www.citizen.org/sites/default/files/21841.pdf. Accessed March 6, 2019.

[17] 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. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM436270.pdf. Accessed March 6, 2019.

[18] Ibid.

[19] Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA. 2017;317(7):708-716.

[20] Food and Drug Administration. FDA approves new changes to testosterone labeling regarding the risks associated with abuse and dependence of testosterone and other anabolic androgenic steroids (AAS). October 25, 2016. https://www.fda.gov/Drugs/DrugSafety/ucm526206.htm. Accessed March 6, 2019.

[21] Food and Drug Administration. Letter to Solvay Pharmaceuticals, Inc. re. NDA 21-015/S-022: new boxed warning for AndroGel (testosterone gel) 1% for topical. September 18, 2009. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/021015s022ltr.pdf. Accessed March 6, 2019.

[22] AbbVie Inc. Label: testosterone gel (ANDROGEL). October 2016. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8677ba5b-8374-46cb-854c-403972e9ddf3&type=display. Accessed March 6, 2019.

[23] Allergan, Inc. Label testosterone patch (ANDRODERM). June 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e58a5328-fdd9-40cb-a19f-8ed798989b9c&type=display. Accessed March 6, 2019.