Testosterone Therapy for Men: More Evidence of Blood Clot Risk

Testosterone is a sex hormone produced mainly in men by the testicles. It is essential for growth, development of sex organs and maintenance of adult male characteristics, including muscle mass, facial hair, sperm production and libido.[1],[2]

Testosterone levels in the blood peak by age 17 and remain steady until the third and fourth decades of life in men, after which they decrease gradually.[3] These natural age-related declines in testosterone are sometimes associated with decreases in energy levels and sexual function.[4],[5] However, there is no conclusive evidence that these symptoms are consistently caused by lowered testosterone levels or can benefit from treatment with testosterone.[6]

The Food and Drug Administration (FDA) has approved multiple different forms of synthetic testosterone products (see Table, below, for a list). Prescription testosterone products are approved only for treatment of a small group of male patients: those with “classic hypogonadism” — defined as an inadequate production of testosterone due to certain medical conditions. These conditions include genetic disease, testicular damage from chemotherapy or inflammation, and damage to the parts of the brain (including the pituitary gland) that stimulate testosterone production by the testicles.[7]

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

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

Importantly, testosterone drugs are not approved by the FDA to treat men with normal age-related declines in natural testosterone levels — an “off-label” use that had been encouraged by pharmaceutical companies for many years. In 2015, the FDA cautioned against using these products for this purpose because such use has not been shown to be effective and may increase the risk of heart attack and stroke.[8]

Risks of testosterone therapy include venous thromboembolisms (blood clots in deep veins, usually in the leg, or lungs), which can be life-threatening and require immediate medical attention.[9] Across the total U.S. population, blood clots occur in about 900,000 adults each year, and 10% to 30% of those events result in death within one month.[10]

A recent large observational study provides added support for the concern that testosterone therapy heightens the risk of blood clot formation. This study was published in the February issue of the Journal of the American Medical Association (JAMA) Internal Medicine.

The JAMA Internal Medicine study[11]

The researchers of the new study used commercial health insurance and Medicare records to identify 39,622 cancer-free men who, from 2011 to 2017, experienced a first venous or lung blood clot and had at least 12 months of continuous insurance enrollment preceding that event. The researchers divided this sample into two groups. One group was of 3,110 men who had medical claims indicating that they had classic hypogonadism. The second group included 36,512 men who did not have medical claims for classic hypogonadism.

Then, the researchers determined whether the patients received testosterone prescriptions in the six months immediately preceding (six to zero months before) the blood clot event, and separately in the six months most distant from the blood clot (12 to six months prior). The rate of prescribing testosterone was then compared between the two time periods.

In this type of study design, each patient serves as their own control 12 to six months before the clot, and then “crosses over” into the exposure period of interest six to zero months prior to the clot. Such a design has the advantage of automatically accounting for individual personal factors that typically do not vary much over a 12-month time period, such as socio-economic status and the presence of other chronic diseases that may affect the risk of clots. This design advantage is important because these factors can easily bias the results of observational studies that assess risks of drugs.

The researchers found that 43% of those with hypogonadism and 1% of those without this diagnosis had testosterone prescriptions during the 12-month study period. Their main analysis revealed that for both groups of patients testosterone prescriptions were approximately two times more likely in the six months immediately prior to clot formation than in the earlier six-month “control” period. The highest rates of testosterone use occurred in the three months just prior to blood clot formation. These findings are consistent with recent exposure to testosterone therapy being associated with an increased short-term risk of blood clots. Accordingly, the study provides new evidence that testosterone use increases the short-term risk of blood clots, with or without a previous diagnosis of 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 testosterone brands Jatenzo or Xyosted for any reason 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. Never use testosterone to relieve changes attributable to normal aging. Other remedies, including exercising and maintaining a healthy weight, are safer and overall more beneficial.

If you use testosterone, watch for blood clot symptoms in your legs (pain or swelling) or lungs (difficulty breathing), particularly during the first several months of treatment. Also, be alert 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. Seek medical attention immediately if you experience any of these symptoms.
 

References

[1] Review of testosterone products. Worst Pills, Best Pills News. May 2019 /newsletters/view/1262. Accessed July 6, 2020.

[2] Testosterone levels test. MedlinePlus. https://medlineplus.gov/lab-tests/testosterone-levels-test/. Accessed July 6, 2020.

[3] 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.

[4] Considering testosterone therapy to help you feel younger and more vigorous as you age? Know the risks before you decide. https://www.mayoclinic.org/healthy-lifestyle/sexual-health/in-depth/testosterone-therapy/art-20045728?p=1. Accessed July 6, 2020.

[5] Review of testosterone products. Worst Pills, Best Pills News. May 2019 /newsletters/view/1262. Accessed July 6, 2020.

[6] 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 July 14, 2020.

[7] AbbVie Inc. Label: testosterone gel (ANDROGEL). February 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021015s045lbl.pdf. Accessed July 6, 2020.

[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 July 14, 2020.

[9] New research links testosterone to risk of dangerous blood clots. Worst Pills, Best Pills News. April 2017. /newsletters/view/1099. Accessed July 6, 2020.

[10] Centers for Disease Control and Prevention. Data and statistics on venous thromboembolism. https://www.cdc.gov/ncbddd/dvt/data.html. Accessed July 6, 2020.

[11] Walker RF, Zakai NA, MacLehose RF, et al. Association of testosterone therapy with risk of venous thromboembolism among men with and without hypogonadism. JAMA Internal Medicine. 2020;180(2);190-197.