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A combination of direct-to-consumer product advertising (DTCPA) and lax consensus guidelines for testosterone prescribing have, over the past decade, led to 10- and 40-fold increases in testosterone prescriptions in the United States and Canada, respectively, with Internet pharmacies playing a major role in the latter's increase.[1] U.S. pharmaceutical sales of testosterone increased from $324 million in 2002 to $2 billion in 2012, and the number of testosterone doses prescribed climbed from 100 million in 2007 to half a billion in 2012, not including the additional contributions from compounding pharmacies, Internet, and direct-to-patient clinic sales.[1, 2] On September 17, 2014, the U.S. Food and Drug Administration (FDA) convened a meeting to address concerns that many men are receiving testosterone who should not and because of reports of adverse cardiovascular events in men using testosterone.[3] We join others who characterize the mass marketing of testosterone coupled with the permissive prescribing of testosterone for common, nonspecific, aging-related symptoms as disease mongering of declines in testosterone with advancing age.[4, 5] Disease mongering is defined as “the selling of sickness that widens the boundaries of illness and grows the markets for those who sell and deliver treatments.”[6] The prescribing of growth hormone for “antiaging” or “age management” is another example of disease mongering.

DTCPA is the mass marketing component of disease mongering of age-related declines in testosterone. With advertising directed primarily at baby boomers, age-related complaints such as “slowing down” and low libido are attributed to catchy medicalized sounding syndromes like “low T” and “andropause.”[7, 8] These syndromes are likened to menopause, which is a false and misleading analogy because middle-aged men do not experience any universal or sharp decline in serum testosterone.[9] The pharmaceutical industry asserts that DTCPA is an important service to the public that helps people and their doctors become aware of treatable medical problems.[10] However, when sophisticated mass marketing is directed toward people lacking the technical expertise to critically evaluate the deceptively simplified medical science claims that such advertising makes, there is ample opportunity for disease mongering. Because doctors are the prescription gatekeepers, these advertisements can effectively pit patients against their doctors, pressuring them for compliant prescribing on demand and distorting clinical judgment. As a result, recognizing the dangers, nearly all countries prohibit DTCPA, except Canada, New Zealand, and the United States.[10]

The other enabler of disease mongering of age-related declines in testosterone is lax professional consensus panel prescribing guidelines. Guidelines created over the last decade, some sponsored by manufacturers of testosterone products,[11] have stretched the definition of hypogonadism, a clinical disorder of the hypothalamus–pituitary–testicular axis that has a pathological basis, to include functional disorders so as to include men with an unexplained low serum testosterone level (without any underlying reproductive pathology) accompanied by complaints that are commonly associated with classical hypogonadism but also many age-related comorbidities. Marketers of “low T” have capitalized upon the nonspecificity of these age-related symptoms by encouraging men to take questionnaires of equally low specificity focusing on common complaints such as low energy, feeling sad, sleep problems, decreased physical performance, or increased fat.[12] Notably, in middle-aged and older men who report excellent health, aging is not associated with a decrease in serum testosterone,[13] highlighting the effect of age-associated comorbidities rather than age itself upon testosterone levels. These nonreproductive disorders, such as obesity,[14] may invoke adaptive responses of an intact reproductive system, the net effects of which, a priori, may be beneficial, neutral, or adverse. The appropriate treatment for such functional declines in serum testosterone is not testosterone but reversing the underlying condition. Because unselected aging men with comorbidities will display a gradual decrease in serum testosterone with age, using any fixed serum testosterone threshold, the proportion of men with a “low” serum testosterone will automatically increase with age and be mislabeled as “late-onset hypogonadism.” This has led to claimed prevalences of age-related hypogonadism of up to 40%,[15] representing an almost 100-times larger market size over the estimated age-invariant prevalence of 0.5% of men who have testosterone deficiency due to a pathological disruption of the hypothalamus–pituitary–testicular axis.[16]

In an attempt to define a more-specific syndrome of “late-onset hypogonadism,” the latest medicalized term for “low T” or “andropause,” Wu and colleagues compared men with low serum testosterone with those with normal levels and found no difference in the prevalence of 23 of 32 potentially associated symptoms or in clusters of physical or psychological symptoms. They reported a cluster of three sexual symptoms (low frequency of morning erection, low frequency of sexual thoughts, erectile dysfunction) that had a small but statistically significant association with serum testosterone levels less than 320 ng/dL,[17] but this definition had high rates of false positives and negatives, relied on an inaccurate calculation of “free” testosterone, and was nullified by adjustment for age and obesity.[9] Although it was a flawed definition, Wu and colleagues estimated the prevalence of “late-onset hypogonadism” as only 2.1% for men aged 40 to 79, 0.1% for men aged 40 to 49, and 0.6% for men aged 50 to 59.[17] Yet in 2013, reflecting the effectiveness of DTCPA's targeting of baby boomers, insured men aged 40 to 64 comprised 62.3% of those filling a testosterone prescription at a retail pharmacy.[18] Whatever the definition, Wu and colleagues[17] and recently the FDA[3] echoed the Institute of Medicine's 2004 report[19] that there is no convincing evidence that testosterone treatment of “age-related hypogonadism” is beneficial or safe.

In July 2014, Health Canada issued new safety information for testosterone products, warning of “a risk of serious and possibly life-threatening cardiovascular (heart and blood vessel) problems” and that testosterone should not be used for nonspecific symptoms if other possible causes more common than hypogonadism have not been excluded.[20] Also this summer, the FDA stipulated new general product information for all testosterone products indicating “reports of venous thromboembolic events, including deep vein thrombosis and pulmonary embolism.”[21]

The FDA reiterated that, because it originally intended testosterone replacement to be used for individuals with testosterone deficiency “due to documented testicular or hypothalamic/pituitary disease” (classic hypogonadism), it was reasonable that testosterone products be approved based solely upon their ability to normalize serum testosterone levels in hypogonadism without requiring proof of clinical efficacy.[18] Manufacturers have exploited this loophole to market testosterone products that raise serum testosterone concentrations without having to provide proof of efficacy when treatment was directed at conditions other than organic or classic hypogonadism.

Following their review of background material, expert presentations by advocates and critics of testosterone prescriptions for “age-related hypogonadism,” the joint meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committees concluded that:[3] age-related hypogonadism has not yet been established as a disease, testosterone is indicated “only for classical hypogonadism and not age-related hypogonadism,” package labeling for testosterone should indicate that “the efficacy and safety for testosterone therapy in age-related hypogonadism have not been established,” and there is biological plausibility for so-far weak cardiovascular safety signals and “the potential signal for cardiovascular risk should be added to the labeling.” The FDA followed through with these recommendations March 3, 2015, requiring changes in product labeling to warn of possible increased risk of heart attack and stroke and that testosterone should not be used for low testosterone levels associated with aging.[22]

Another example of disease mongering is the marketing of growth hormone (GH) for antiaging. GH and testosterone are major constituents of what antiaging or age-management clinics and websites market as “hormone replacement therapy.”[23] Many claim that GH levels fall with aging, and therefore, GH supplementation will reverse aging, obesity, wrinkles, and decreased sex drive and have other panacea-like benefits.[24] Clinical studies belie these claims, and GH treatment in older adults frequently produces adverse reactions such as carpal tunnel-like syndrome, arthralgias, diabetes mellitus, hypertension, and edema that outweigh claimed but unproven benefits.[24] Providing GH for antiaging is illegal and medically unjustified.[24] Thus, it is illegal for pharmaceutical companies to market GH for antiaging. DTCPA of GH for antiaging takes the form of Internet advertising of antiaging clinics espousing the wonders of GH, airplane magazine advertisements, celebrity spokespersons, magazine articles and press releases, and appearances of antiaging doctors on popular television and radio shows. Another important influence is athletes who have been caught using GH (having been duped into believing GH is an effective adjunct to androgens, including testosterone, to enhance athletic performance), and people think that if athletes believe GH will help their performance, why shouldn't they believe the same?[25]

GH has just three medically valid but rare indications in adults.[24] The most frequent of these but still very rare is adult GH deficiency (AGHD), primarily caused by pituitary tumors and their treatment, occurring in approximately three per 10,000 adults. The other two allowed indications are short bowel syndrome and acquired immunodeficiency syndrome wasting syndrome.[24] Numerous antiaging clinics claim to prescribe GH for AGHD, but only after classic disease mongering claims to elastically redefine AGHD to include normal age-related decline in GH production.[24] These doctors and clinics do not perform a GH stimulation test or establish a pathological cause for AGHD, as required by the GH package labeling because, for almost all adults, one or both of these criteria will not be met.[24] Consistent with these deceptive and medically unprofessional practices, GH sales far exceed plausible estimates of valid indications for adult GH therapy, with half of the 340,000 prescriptions in 2011 being for nonvalid purposes.[26] Even this figure greatly underestimates GH prescribing because GH use for antiaging and body-building is a cash-only business, undetected by the monitoring of retail pharmaceutical sales.[24] Thus, GH manufacturers experienced at least a 69% inflation-adjusted increase in GH sales to adults from 2005 to 2011 ($1.4 billion in sales in 2011)[26] while appearing to ignore that much of their profit must be due to medically illegitimate and illegal distribution of GH.[27]

We applaud the FDA's recent joint committee meeting and labeling changes to address what we and others view as disease mongering of age-related declines in testosterone for “age-related hypogonadism” or “antiaging.” We call upon Health Canada, the U.S. FDA, and the Federal Trade Commission to ban educational and product advertising of testosterone for these contrived “indications.” Without demonstrated underlying reproductive system pathology, a set of common complaints plus or minus a low serum testosterone cannot constitute “hypogonadism.” To discourage medically inappropriate prescribing of growth hormone, the FDA requires that a pathological basis for growth hormone deficiency be demonstrated to provide and dispense a prescription. To discourage disease mongering of testosterone, the FDA and Health Canada should similarly require demonstration of pathology to provide and fill a lawful prescription for testosterone.

Acknowledgments

  1. Top of page
  2. Acknowledgments
  3. References

The opinions expressed by the authors are not necessarily those of the American Geriatrics Society or the editors of the Journal of the American Geriatrics Society.

Conflict of Interest: Dr. Handelsman's institutions expect to receive support in 2015 for his investigator-initiated studies of testosterone pharmacology (Lawley Pharmaceuticals) or treatment (Besins Healthcare). He has acted as an unpaid consultant to many companies that market testosterone products, but he does not receive any personal funding.

Author Contributions: The authors contributed equally to the writing of this manuscript.

Sponsor's Role: There is no sponsor.

References

  1. Top of page
  2. Acknowledgments
  3. References