Dr Bebb responds

“Damnant quod non intelligent”
Dr Tevaarwerk has suggested that pharmaceutical association on the part of the Hypogonadism in Men (HIM) study[1] authors invalidates the results. While I applaud academic rigor in review of literature, to propose one “stop reading” if the authors disclose pharmaceutical industry association boarders on paranoia. 

The reality is that most authors, myself included, have at some point accepted speaking honoraria, consultancy fees, or re­search funding from industry. If his suggestion were rigorously applied this would exclude the vast majority of all peer-reviewed publications. 

The HIM study has provided us with useful data regarding the prevalence of hypogonadism and specific disease associations. Indeed, the HIM study contributed to the Endocrine Society recommendations for case finding of hypogonadism in men with type 2 diabetes.[2] To endocrinologists, the Endocrine Society is the most pres­tigious, academically rigorous association we have, and any Endocrine Society practice recommendations are highly scrutinized.

Dr Tevaarwerk claims that the HIM study overestimates the prevalence of hypogonadism in men. In his letter he has misquoted the Massachusetts Male Aging Study (MMAS).[3] The HIM study reported a hypogonadism prevalence of 38.7% in men over age 45. The age range was 45 to 96 with a mean age of 60.5 years. 

Dr Tevaar­werk’s use of the crude 6.0% prevalence in the MMAS for his calculation is inappropriate, as it does not compare similarly aged men. If one uses the reported prevalence at baseline and follow-up for the closest comparable age group of 60 to 70 years, the results are 9.4% and 11.5% respectively, or an average of 10.5%.

It is important to note that the MMAS had some limitations. First, the men included in this study had to pass an unvalidated screening questionnaire or no testosterone samples were measured, and the questionnaire used did not correlate with the testosterone results. 

Second, the MMAS cohort has been preselected to include healthy men.[4] By excluding men who did not pass the questionnaire, or had comorbid illnesses, many of which have an associated increased risk ofhypogonadism, the MMAS has an inherent selection bias of decreased detection.[4] 

Third, it has been postulated that the prevalence of hypogona­dism is increasing.[3] The MMAS dates back to 1995, and reported that the prevalence of hypogonadism increas­ed over the 9 years studied. It has been postulated that this may be related to an increase in obesity.[4] The HIM study was published in 2006 and hence an increased prevalence with time would be a consistent trend.

The HIM study is also consistent with many other prevalence studies. In men aged 60 to 69 years, the Baltimore Longitudinal Study[5] reported a prevalence of a low free androgen in­dex of 34%; the Mayo Clinic[6] reported a low bioavailable testosterone (BAT) prevalence of 20%; and the Canadian Physician Study7 reported a prevalence of low BAT of 45%. Hence, it is the MMAS that is in fact the outlier.

Dr Tevaarwerk suggested that the HIM data set does not represent the population targeted in my article. I believe just the opposite is true as the HIM measured all men in a primary care setting without excluding patients that we now know have a higher pre­test probability of hypogonadism.

Dr Tevaarwerk states that testoster­one levels should be measured be­fore 8 a.m. In fact, the accepted time for measurement is from 7 a.m. to 11 a.m.,[8] although any time prior to 10 a.m. has been the standard in British Columbia.

Dr Tevaarwerk suggests that “grad­ually declining testosterone levels may be part of the normal aging pro­cess.” While some decline in bodily functions with aging is expected, when a physiological state, in this case hypogonadism, has been associated with an increased risk of osteoporosis, osteoporotic fractures, the metabolic syndrome, type 2 diabetes, and shortened life expectancy, that is no longer “normal aging” but a disease condition worthy of medical attention.[9]

As an analogy, would Dr Tevaarwerk suggest not treating older pa­tients with hypothyroidism? After all, fatigue is common and perhaps the norm in the elderly. Eleven percent of men and 16% of women have an elevated TSH by the age of 65 to 74 years.[10] Would he therefore state that hypothyroidism is so common that physicians should consider this to be normal aging and leave these patients untreated? 

In the absence of long-term, randomized, placebo-controlled outcome studies, treatment of hypo­thyroidism has historically been based on resolution of symptoms and is today the standard of care. To treat hypogonadism differently than hypo­thyroidism would seem illogical and based only on an unjustified bias against testosterone.
—Richard Bebb, MD
Vancouver

References

1. Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in males aged at least 45 years: The HIM study. Int J Clin Pract 2006;60:762-769.
2. 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:
2536-2559.
3. Araujo AB, O’Donnell AB, Brambilla DJ, et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: Estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2004;89:5920-5926.
4. McLachlan RI, Allan CA. Defining the prevalence and incidence of androgen deficiency in aging men: Where are the goal posts? J Clin Endocrinol Metab 2004;89:5916-5919.
5. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 2001;86:724-731.
6. Morley JE, Perry HM 3rd. Andropause: An old concept in new clothing. Clin Geriatr Med 2003;19:507-528.
7. Morley JE, Charlton E, Patrick P, et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism 2000;49:1239-1242.
8. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations. Eur J Endocrinol 2008;
159:507-514.
9. Bebb R. Testosterone deficiency: Practical guidelines for diagnosis and treatment. BCMJ 2011;53:474-479.
10. Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526-534.