Pseudohypogonadism — Making Men Believe They Need Testosterone
Hormones have long been pitched as a fountain of youth. In the early 1900s, snake oil salesmen and charlatans hawked testicular extract as an elixir of youth, strength, and virility.1,2 A simple explanation for what causes aging and an equally simple cure prompt a red flag signifying antiaging quackery.3 A classic example is hormone levels fall with age and therefore, it is the decline in hormones that causes aging and problems associated with aging. In the 1970s and '80s, equating hormones with youth resurged with the far too simple assumption that the abrupt decline in estrogen levels during menopause was responsible for the increased incidence of heart attacks and strokes among women in their 60s and 70s. A wholesale promotion of estrogen as effective prevention of cardiovascular disease and stroke in peri- and postmenopausal women ensued, despite the lack of longer-term dependable evidence of both efficacy and safety. In 2003, results from the Women's Health Initiative put a sudden halt to this practice with the demonstration of a marked excess of both heart attacks and strokes among women who were taking estrogen compared with those who were not.4
In the late 1980s, some physicians and drug companies pitched the notion that men experienced a similar decline in testosterone and that this "andropause" was responsible for a broad range of complaints that commonly befall men aged 40 and older. There was even the assertion that andropause, like menopause, caused the observed increased incidence with age of heart attack and stroke. Of course, "andropause" is a false analogy.5 Unlike the marked and relatively sudden decline of estrogen production associated with menopause, no ubiquitous and programed abrupt cessation of testicular production of testosterone occurs. Furthermore, far from being common, true adult-onset hypogonadism, defined as a pathological interruption somewhere in the hypothalamic-pituitary-testicular axis, occurs in about 0.5% of adult men.6,7
Men aged 40 and older are targeted with marketing that essentially medicalizes exceptionally common complaints.8 For example, feeling tired, depressed, or weak; being overweight; and experiencing difficulty sleeping or decreased libido are advertised as being due to low testosterone. These symptoms are exceedingly more likely to be due to unhealthful diets, lack of exercise, smoking, alcohol use, and/or obesity. If a low testosterone level is noted, it is much more likely a functional decline resulting from problems such as obesity9 rather than a disruption of the endocrine axis regulating testosterone production. The medically appropriate treatment of this "pseudohypogonadism" is effectively addressing the underlying cause rather than administering testosterone, particularly given the adverse effects associated with testosterone.
Professional medical groups bear part of the responsibility for expanding the definition of adult hypogonadism to include millions of men. Consensus guidelines emerged in the 2000s recognizing the existence of late-onset hypogonadism.10,11 Somehow, despite the absence of even a single randomized controlled trial demonstrating long-term safety and efficacy for the prescribing of testosterone for low serum testosterone levels unrelated to pituitary-testicular axis pathology, prescribing testosterone was still condoned.
An important and likely wayward influence upon these recommendations is the drug company sponsorship of at least some of these consensus meetings, participants, and reports that would go on to reap billions of dollars in profits.12 These guidelines removed the crucial distinction between pathological hypogonadism and the far more frequent functional, and mostly reversible, causes of a low blood testosterone (eg, obesity) while the reproductive system is intact. By including functional causes of low blood testosterone, the number of men potentially qualifying for testosterone use was vastly expanded. Lax guidelines helped to legitimize the marketing of "Low T."
A scientific-appearing questionnaire was devised as part of the marketing ploy to make men believe their problems could be cured with testosterone. Conveying scientific validity with made-up claims, scientific-appearing studies, or questionnaires raises yet another red flag of antiaging quackery.3 The drug company Organon BioSciences commissioned a physician scientist to construct an easy-to-fail screening quiz for whether or not a man would benefit from taking testosterone. The physician indicated that the company instructed him, "Don't make it too long, and make it somewhat sexy."13 Creating questions such as "Do you feel tired after dinner?" and "Do you have decreased libido?" took only 20 minutes to construct. The quiz's author indicated that it is a "crappy questionnaire,"13 but it is this 10-item questionnaire, called the ADAM (Androgen Deficiency in Aging Males) test that has played a key role in marketing testosterone for supposed age-associated or late-onset hypogonadism.14 In 20% of new cases, physicians and clinics base the decision to recommend and prescribe testosterone simply upon symptoms, without determining a testosterone level.15 If a physician does measure a testosterone level, and he or she is intent on telling a patient he has a testosterone deficiency, he or she is free to adopt arbitrary thresholds to conveniently define a testosterone deficiency state. Or, a physician might obtain a testosterone level in the evening when diurnal levels are at their lowest.
The disease mongering proved to be a profit windfall. Testosterone sales increased from $324 million in 2002 to $2 billion in 2012, and the number of prescribed testosterone doses increased from 100 million in 2007 to 500 million in 2012, not including the additional sales from compounding pharmacies, the Internet, and direct-to-patient clinic sales.16-17 AbbVie, the maker of AndroGel, had sales of $1.37 billion in 2012, an increase of 19% from the previous year.18 The pharmaceutical industry defends direct-to-consumer product advertising (DTCPA) as an important service to the public because it makes potential patients aware of a treatable medical problem they might have.
However, according to health insurance data, only one-half of men receiving testosterone were associated with a diagnosis code of "testicular hypofunction, not elsewhere classified."19 Of the other one-half, 34% were diagnosed with fatigue, 32% with erectile dysfunction, and 12% with psychosexual dysfunction.20
Regarding erectile dysfunction, only about 10% of isolated erectile dysfunction is secondary to hypogonadism. The major problem with DTCPA is that it is inherently biased toward sales and therefore leads people to seek a drug they don't need or for which the risk outweighs the benefit. Thus, DTCPA of testosterone has led to needless exposures to adverse drug effects and unwarranted drug costs. It is no wonder that despite repeated attempts by the pharmaceutical industry to introduce DTCPA in Europe and elsewhere, only Canada and New Zealand have joined the United States in allowing it.21 In 2013, AndroGel's "Is it Low-T?" campaign received accolades from the marketing industry, winning the "All-Star Large Pharma Marketing Team of the Year" award.18 The article highlighting the award noted how the drug company and its marketing teams overcame the challenges of scientific opinion indicating unproven benefit and, later, concerns that testosterone was being marketed for an off-label use.
Class Action Law Suits Abound
While package labeling for testosterone has warned of increased risk for deep venous thromboembolism, pulmonary embolus, and obstructive sleep apnea, the advisory committee reviewed recent studies addressing heart attack and stroke risk. In its May 14, 2015, safety advisory, the FDA warned of a possible increased risk of heart attack and stroke.19,23 Health Canada has indicated more definitively that there is "a risk of serious and possibly life-threatening cardiovascular (heart and blood vessel) problems."24
With reports of deaths, heart attacks, strokes, and other serious adverse events among men receiving testosterone for "Low T" and the most recent actions by the FDA, there are now many individual and class action law suits, with the latter aggressively seeking plaintiffs.25 The FDA urges physicians and patients to report any testosterone-associated adverse events to the FDA's MedWatch program (call 800-332-1088 or visit www.accessdata.fda.gov/scripts/medwatch).
— Thomas T. Perls, MD, MPH, FACP, is a professor of medicine and geriatrics at Boston University School of Medicine and a senior attending physician in geriatrics at Boston Medical Center. He is the founder and director of the New England Centenarian Study and a principal investigator of the National Institute on Aging's Long Life Family Study. A vocal critic of the antiaging industry, particularly its medical and legal misuse of growth hormone, testosterone, and other drugs for "antiaging," he has testified before the US Congress about antiaging quackery.
2. Weintraub A. Selling the Fountain of Youth: How the Anti-Aging Industry Made a Disease Out of Getting Old—and Made Billions. New York, NY: Basic Books; 2010.
3. Perls TT. Anti-aging quackery: human growth hormone and tricks of the trade—more dangerous than ever. J Gerontol A Biol Sci Med Sci. 2004;59(7):682-691.
4. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349(6):523-534.
5. Tariq SH, Haren MT, Kim MJ, Morley JE. Andropause: is the emperor wearing any clothes? Rev Endocr Metab Disord. 2005;6(2):77-84.
6. Handelsman DJ. Androgen physiology, pharmacology and abuse. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 6th ed. Philadelphia, PA: Elsevier Saunders: 2010.
7. Perls T, Handelsman D. Disease mongering of age-associated declines in testosterone and growth hormone levels. J Am Geriatr Soc. 2015;63(4):809-811.
8. Mintzes B, Health Action International. Direct-to-consumer prescription drug advertising: the European Commission's proposals for legislative change. http://www.haiweb.org/campaign/DTCA/BMintzes_en.pdf. Published December 2001. Accessed July 25, 2015.
9. Goncharov NP, Katsya GV, Chagina NA, Gooren LJ. Testosterone and obesity in men under the age of 40 years. Andrologia. 2009;41(2):76-83.
10. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
11. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2006;91(6):1995-2010.
12. Braun SR. Promoting "low T": a medical writer's perspective. JAMA Intern Med. 2013;173(15):1458-1460.
13. Toler L. SLU doctor John Morley invents boner quiz on toilet, earns $40,000. River Front Times. December 11, 2013. http://blogs.riverfronttimes.com/dailyrft/2013/12/saint_louis_university_morley_testosterone_toilet.php
14. Schwartz LM, Woloshin S. Low "T" as in "template": how to sell disease. JAMA Intern Med. 2013;173(15):1460-1462.
15. Layton JB, Li D, Meier CR, et al. Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011. J Clin Endocrinol Metab. 2014;99(3):835-842.
16. Handelsman DJ. Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse. Med J Aust. 2013;199(8):548-551.
17. Singer N. Selling that new-man feeling. The New York Times. November 23, 2013. www.nytimes.com/2013/11/24/business/selling-that-new-man-feeling.html?pagewanted=all&_r=0. Accessed July 25, 2015.
18. Dobrow L. 2013 all-star large pharma marketing team of the year: AndroGel. Medical Marketing & Media. January 2, 2013. http://www.mmm-online.com/features/2013-all-star-large-pharma-marketing-team-of-the-year-androgel/article/273242/
19. 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. US Food and Drug Administration website. http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm. Updated May 14, 2015. Accessed July 25, 2015.
20. Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013;173(15):1465-1466.
21. Ventola CL. Direct-to-consumer pharmaceutical advertising: therapeutic or toxic? P T. 2011;36(10):669-684.
22. Briefing information for the September 18, 2014 Joint Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management (DSaRM) Advisory Committee Meeting. U.S. Food and Drug Administration website. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugs
23. Testosterone products and venous thromboembolic events label change. US Food and Drug Administration website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm402877.htm. Updated June 15, 2014.
24. Summary safety review—testosterone replacement products—cardiovascular risk. Health Canada website. http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/testosterone-eng.php. Updated July 15, 2014.
25. Testosterone lawsuits. drugwatch.com website. http://www.drugwatch.com/testosterone/lawsuit/. Accessed July 26, 2015.