Age-Related Testosterone Deficiency Merits Testosterone Treatment

April 2021

Guidelines published by most medical societies recommend that men with testosterone deficiency receive testosterone treatment, regardless of the underlying causes.^1-5 In contrast, the US Food and Drug Administration (FDA), while acknowledging that testosterone deficiency merits treatment, has made an artificial distinction between testosterone deficiency caused by rare diseases and organ failure, and testosterone deficiency caused by aging or obesity, and proclaiming that only testosterone deficiency due to rare diseases merits testosterone treatment.

This had led to debate among scientists and confusion among physicians. Prominent scientists have pointed out that that there is no evidence to support the claim of differences in benefits or risks among men with different forms of testosterone deficiency. As explained below,6 there is no basis for this distinction, and men suffering from testosterone deficiency associated with aging, obesity, metabolic syndrome and type 2 diabetes merit receiving testosterone treatment as much as men suffering from testosterone deficiency caused, for example, by genetic abnormalities or testicular failure.

KEY POINTS

Symptoms and signs of testosterone deficiency occur as a result of low testosterone levels, and may benefit from testosterone treatment regardless of its cause.
Historically recognized causes of testosterone deficiency (such as testicular failure, Klinefelter syndrome, pituitary tumor, radiation etc.) are rare. Only a small fraction of men have this form of testosterone deficiency, also known as classical testosterone deficiency.
Age-related testosterone deficiency, or testosterone deficiency caused by obesity or type 2 diabetes, is far more common.
All forms of testosterone deficiency, regardless of cause, merit testosterone treatment.

Testosterone deficiency caused by obesity or aging versus rare diseases

Testosterone deficiency, also known as low testosterone, is a medical condition characterized by low testosterone levels combined with characteristic signs/symptoms.⁷ Testosterone deficiency occurs as a result of reduced testosterone production by the body.

There are many causes of testosterone deficiency. When an underlying isolated disease cause has been identified, such as testicular failure, Klinefelter syndrome or chemotherapy, traumatic brain injury, pituitary gland cancer or radiation, the condition is called classical testosterone deficiency. Only a minority of men are affected by classical testosterone deficiency.

The most common causes of testosterone deficiency are obesity, type 2 diabetes and aging, as well as some medications, especially opioids and glucocorticoids.^{8, 9} With the rising prevalence of obesity and type 2 diabetes, and the aging demographic, the prevalence of testosterone deficiency is high.^10-14

Does testosterone deficiency that is caused by obesity, type 2 diabetes and/or aging merit testosterone treatment?

In contrast to the European Medicines Agency (EMA), the United States FDA has taken the position – despite data to the contrary - that only classical testosterone deficiency merits treatment with testosterone treatment.¹⁵ This has ignited a debate among scientists and confusion among physicians. Below is a summary of the rationale as to why age-related testosterone deficiency should be treated as any other clinical condition.

Evidence for benefits of testosterone treatment in men with testosterone deficiency

The wide range of health consequences of testosterone deficiency are well documented, and include sexual problems (reduced libido, impotence etc.), impaired general health, reduced wellbeing, lack of energy and enthusiasm, obesity, type 2 diabetes, osteoporosis, anemia, as well as increased risk of premature death.^16-20 These health consequences have been observed in all men with testosterone deficiency, regardless of what caused the testosterone deficiency.

Testosterone treatment has been used to successfully treat testosterone deficiency since the 1940s, and has become the first-line treatment for restoring testosterone levels.21 Long-term real-world evidence studies have shown that men with all forms of testosterone deficiency experience significant health benefits from testosterone treatment.^22-27

The importance of treating testosterone deficiency has been demonstrated in long-term real-world evidence studies that compared health outcomes among men with testosterone deficiency who received testosterone treatment, with those of men with testosterone deficiency who did not receive testosterone treatment.^24-27 These studies showed that men with testosterone deficiency who did not get testosterone treatment experienced a marked increase in body weight and waist size, along with worsening of impotence (also known as erectile dysfunction), wellbeing, cholesterol and blood sugar levels. Furthermore, men with untreated testosterone deficiency had a higher incidence of heart attack, stroke and premature death.^24-27 The largest studies of testosterone treatment to date - the Testosterone Trials ²⁸ and the T4DM trial ²⁹ - have provided convincing evidence of health benefits in men with age-related or obesity/diabetes-related testosterone deficiency. These studies also provided reassurance regarding the safety of testosterone treatment.

Furthermore, studies have shown that older men over 65 years of age with age-related testosterone deficiency benefit as much from testosterone treatment as do younger men with testosterone deficiency, and that testosterone treatment is a safe treatment for men of all ages.³⁰

Does it matter what the cause of testosterone deficiency is?

Whether testosterone deficiency is a result from classical causes or not is mostly an issue of scientific inquiry, with less clinical practice relevance.

In 2015, an international expert consensus panel convened to discuss the negative impact of testosterone deficiency on men’s health and quality of life, and evaluated the merits of testosterone treatment in men with testosterone deficiency.⁷ Experts included a broad range of medical specialties including urology, endocrinology, diabetology, internal medicine and basic science researchers, as well as a representative from the European Medicines Agency. It was concluded that:

Symptoms and signs of testosterone deficiency occur as a result of low testosterone, and may benefit from testosterone treatment regardless of whether there is an identified underlying cause.
Testosterone treatment confers a wide range of health benefits in men with testosterone deficiency, regardless of age.

Conclusion

Guidelines published by most medical societies recommend testosterone treatment for men with testosterone deficiency, regardless of whether it is caused by genetic abnormalities, testicular failure, aging, obesity or type 2 diabetes.

Clinical practice guidelines only require a diagnosis of testosterone deficiency, which is made in men who have symptoms/signs of testosterone deficiency combined with low testosterone levels.^1-5 Depending on the clinical situation, additional testing may be recommended for individual patients. For more information, see “How to diagnose testosterone deficiency?”

As stated by the FDA itself, “Once the FDA approves a drug, a health care provider may prescribe the drug for an unapproved use when the health care provider judges that it is medically appropriate for the patient. FDA does not regulate this off-label use, which is considered the practice of medicine.”³¹

Therefore, physicians do not have to worry about getting charged for malpractice if they prescribe testosterone treatment to men who suffer from symptoms/signs of testosterone deficiency and have low testosterone levels, even if the actual cause of their testosterone deficiency has not been identified.

References

Salonia A, Bettocchi C, Carvalho J, et al. EAU Guidelines on Sexual and Reproductive Health (available at https://uroweb.org/guidelines/sexual-and-reproductive-health accessed March 16, 2022). Return to content
Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline (unabridged). J Urol. Aug 2018;200(2):423-432. Return to content
Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. May 1 2018;103(5):1715-1744. Return to content
Hackett G, Kirby M, Edwards D, et al. British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice. The journal of sexual medicine. Dec 2017;14(12):1504-1523. Return to content
Lunenfeld B, Mskhalaya G, Zitzmann M, et al. Recommendations on the diagnosis, treatment and monitoring of testosterone deficiency in men. The Aging Male. 2021/01/01 2021;24(1):119-138. Return to content
Traish AM. Age-Related Testosterone Deficiency Merits Treatment. Androgens: Clinical Research and Therapeutics. 2021/12/01 2021;2(1):46-55. Return to content
Morgentaler A, Zitzmann M, Traish AM, et al. Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions. Mayo Clin Proc. Jul 2016;91(7):881-96. Return to content
Grossmann M, Matsumoto AM. A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management. J Clin Endocrinol Metab. Mar 1 2017;102(3):1067-1075. Return to content
Nieschlag E. Late-onset hypogonadism: a concept comes of age. Andrology. Nov 2020;8(6):1506- 1511. Return to content
Pellitero S, Olaizola I, Alastrue A, et al. Hypogonadotropic hypogonadism in morbidly obese males is reversed after bariatric surgery. Obes Surg. Dec 2012;22(12):1835-42. Return to content
Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. Jul 2006;60(7):762-9. Return to content
Escobar-Morreale HF, Santacruz E, Luque-Ramírez M, Botella Carretero JI. Prevalence of 'obesity-associated gonadal dysfunction' in severely obese men and women and its resolution after bariatric surgery: a systematic review and meta-analysis. Hum Reprod Update. Jul 1 2017;23(4):390-408. Return to content
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):2737-45. Return to content
Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. Feb 2002;87(2):589-98. Return to content
Nguyen CP, Hirsch MS, Moeny D, Kaul S, Mohamoud M, Joffe HV. Testosterone and "Age- Related Hypogonadism"--FDA Concerns. N Engl J Med. Aug 20 2015;373(8):689-91. Return to content
Traish AM, Guay A, Feeley R, Saad F. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction. J Androl. Jan-Feb 2009;30(1):10-22. Return to content
Traish AM, Saad F, Guay A. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl. Jan-Feb 2009;30(1):23-32. Return to content
Traish AM, Saad F, Feeley RJ, Guay A. The dark side of testosterone deficiency: III. Cardiovascular disease. J Androl. Sep-Oct 2009;30(5):477-94. Return to content
Traish AM. Adverse health effects of testosterone deficiency (TD) in men. Steroids. Oct 2014;88:106-16. Return to content
Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc. Feb 2015;90(2):224-51. Return to content
Morgentaler A, Traish A. The History of Testosterone and the Evolution of its Therapeutic Potential. Sex Med Rev. Apr 2020;8(2):286-296. Return to content
Zitzmann M, Kliesch S, Traish A. Differential effects of testosterone treatment on bone density and body composition in men with classical vs functional hypogonadism. J Urol. 2020/04/01 2020;203(Supplement 4):e547-e548. Return to content
Zitzmann M, Nieschlag E, Traish A, Kliesch S. Testosterone treatment in men with classical vs functional hypogonadism a 9-year-registry J Urol. 2018/04/01 2018;199(4S):e1174-e1175. Return to content
Saad F, Doros G, Haider KS, Haider A. Differential effects of 11 years of long-term injectable testosterone undecanoate therapy on anthropometric and metabolic parameters in hypogonadal men with normal weight, overweight and obesity in comparison with untreated controls: real-world data from a controlled registry study. Int J Obes (Lond). Jun 2020;44(6):1264-1278. Return to content
Saad F, Caliber M, Doros G, Haider KS, Haider A. Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality. The aging male : the official journal of the International Society for the Study of the Aging Male. Feb 20 2020;23(1):81-92. Return to content
Haider KS, Haider A, Saad F, et al. Remission of type 2 diabetes following long-term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11-year data from a real-world registry study. Diabetes, obesity & metabolism. Nov 2020;22(11):2055-2068. Return to content
Yassin A, Haider A, Haider KS, et al. Testosterone Therapy in Men With Hypogonadism Prevents Progression From Prediabetes to Type 2 Diabetes: Eight-Year Data From a Registry Study. Diabetes Care. Jun 2019;6(42):1104-1111. Return to content
Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. Feb 18 2016;374(7):611-24. Return to content
Wittert G, Bracken K, Robledo KP, et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebocontrolled, 2-year, phase 3b trial. The lancet Diabetes & endocrinology. Jan 2021;9(1):32-45. Return to content
Saad F, Yassin A, Haider A, Doros G, Gooren L. Elderly men over 65 years of age with late-onset hypogonadism benefit as much from testosterone treatment as do younger men. Korean journal of urology. Apr 2015;56(4):310-7. Return to content
Nguyen CP, Hirsch M, Kaul S, Woods C, Joffe HV. Testosterone Therapy for the Treatment of Age-Related Hypogonadism: Risks with Uncertain Benefits. Androgens: Clinical Research and Therapeutics. 2021/12/01 2021;2(1):56-60. Return to content

Research news