Study Questions Whether Guidelines Are Being Followed
By Annette M. Boyle
EAST ORANGE, NJ — Across the VHA, more than 85,000 men receive testosterone supplementation therapy. The likelihood that any particular patient would be prescribed the steroid hormone, however, varies substantially by treatment site, with rates varying more than 12-fold across VHA facilities.
In the United States, the number of men taking testosterone therapy has quadrupled since 2000.
“It appears that testosterone is increasingly prescribed for symptoms of fatigue and erectile dysfunction rather than a confirmed diagnosis of hypogonadism,” said Leonard Pogach, MD, National Director of Medicine at the VA. Hypogonadism results from diseases, surgery or medications that damage the testicles or affect the hypothalamus and pituitary glands that regulate the testosterone production by the testicles.
The Endocrine Society’s Clinical Practice Guidelines on testosterone therapy in adult men recommend diagnosing androgen deficiency or low levels of testosterone “only in men with consistent symptoms and signs and unequivocally low serum testosterone levels.” Low levels of testosterone alone are not an indication for treatment as testosterone levels typically decline at a rate of about 1.5% per year after age 30.1
“While sometimes the diagnosis is obvious, the condition may be difficult to diagnose because a total testosterone level may be low due to obesity, and there is clearly a decline in testosterone due to age and other medical conditions. Confirmatory tests are necessary, and may require specialist consultation,” Pogach told U.S. Medicine.
In a study of 5,196,156 male patients without human immunodeficiency virus who had at least one visit to one or more of 129 VHA sites of care during fiscal year 2011, Guneet Jasuja, PhD, and colleagues at the Center for Health Quality, Outcomes, and Economic Research, Bedford, MA, VAMC and Boston University, found that 1.6% received exogenous testosterone treatments.
Looking at the age-adjusted proportion of those male veterans receiving testosterone by site revealed a huge variation, from a low of 0.3% to a high of 3.7%. “The magnitude of this variation cannot easily be attributed to biologic differences among patients but is instead likely to represent the effects of a limited evidence base and its uneven application in practice,” the researchers wrote in the American Journal of Pharmacy Benefits.2
The proportion of veterans receiving testosterone began rising at age 20, peaked between age 60 and 69, then dropped starting at age 70. Two-thirds of patients receiving therapy were between 50 and 69 years old, suggesting that “a proportion of patients were likely receiving testosterone therapy for age-related decline in testosterone levels, which is not an approved indication for testosterone therapy,” the authors concluded.
The variation in testosterone prescribing also could be related to variations in the number of those with diabetes, patients with sexual dysfunction or reduced strength, mobility or other physical function. While sometimes prescribed off-label in these circumstances, testosterone has not been shown to be effective for these conditions.
“Testosterone increases muscle mass, as anyone who has followed sports is aware, and can improve a sense of well-being and sexual motivation and functioning in individuals who are truly hypogonadal,” Pogach said. “In individuals who do not have the condition, there are no significant benefits. Indeed, a well-conducted clinical study indicated that the addition of testosterone to medications for erectile dysfunction in men who had low levels of testosterone did not improve sexual dysfunction.”
In the general population, men in this age group are increasingly being tested and treated for low testosterone, according to another recent study. Bradley Layton, PhD, of the University of North Carolina at Chapel Hill and colleagues found that rising numbers of men tested for “low T” had normal levels and nonspecific symptoms. The majority of men begin treatment without recent testing or with only one test, despite recommendations for multiple tests to account for normal fluctuations. Further, following testing, many initiate treatment with normal levels of testosterone.
“While direct-to-consumer advertising and the availability of convenient topical gels may be driving more men to seek treatment, our study suggests that many of those who start taking testosterone may not have a clear medical indication to do so,” Layton said.3
The same factors might be driving increased prescription rates in the VA, Pogach noted. “I can only speculate that VA clinicians and veteran patients have been influenced by external to VA marketing and continuing medical education activities related to ‘Low T.’”
Jasuja and her colleagues suggested another possibility, that the variation in prescription rates is driven by the choice of guidelines followed at the site. Currently, there is little agreement on the threshold for determining hypogonadism. The American Association of Clinical Endocrinologists set a cutoff of total testosterone of 200 ng/dL of less, while the Endocrine Society defines it as less than 300 ng/dL. The VA does not have its own guidelines.
Awareness of the substantial variation between sites and growing evidence that testosterone might pose significant risks could lead to the adoption of some standards for treatment. In addition to decreasing sperm production and symptomatically enlarging the prostate, testosterone therapy might increase the risk of prostate cancer.
Pogach noted that a recent, small National Institutes of Health-funded clinical trial was halted because of an increased number of deaths in men taking testosterone. Several other recent studies, including a VA-funded study published late last year in the Journal of the American Medical Association, have demonstrated an association with increased risk of cardiovascular events, stroke and death.4
1Bhasin S, Cunningham GF, Hayes FJ, et al. Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endoncrinol Metab. 2010;95(6):2536-2559.
2Jasuja GK, Bhasin S, Reisman JI, Rose AJ. Wide Variations in Use of Testosterone Therapy among VHA Facilities. Am J Pharm Beneﬁts. 2013;5(5):e122-e128.
3Layton JB, Li D, Meier CR, Sharpless J, Stürmer T, Jick SS, Brookhart MA. Testosterone Lab Testing and Initiation in the United Kingdom and the United States, 2000-2011. J Clin Endocrinol Metab. 2014 Jan 1:jc20133570. [Epub ahead of print].
4Vigen R, O’Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME, Plomondon ME, Rumsfeld JS, Ho PM. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013 Nov 6;310(17):1829-36. doi: 10.1001/jama.2013.280386. PubMed PMID: 24193080.