Study results show a highly significant age-independent decline in total testosterone serum levels over the years 2006–2019 for a large population of Israeli patients referred for the first time for a testosterone blood test. These results are in accordance with previous studies which showed a secular decline in testosterone serum levels in earlier years (1970's to 2000's) in other countries (Table 2).
Table 2
Previous studies on secular trends in serum testosterone in men
Paper | Design | Participants | Years | Parameters adjusted for | Is decline significant before adjustment? | Is decline significant after adjustment? |
Travison et al 2007 | Prospective cohort | 1532 randomly selected men in Massachusetts, USA | 1987–2004, collected in three collection waves: 1987–1999, 1995–1997, 2002–2004 | BMI, smoking, medications, chronic illnesses, employment, marital status, general health | Yes, approximated age matched time trend of -1.2% per year | Yes |
Andersson et al 2007 | Observational, based on Danish population surveys | 5350 men who participated in population surveys at Glostrup University Hospital, Denmark | 1982–2001, in 4 surveys: 1982–1983, 1986–1987, 1991–1992, 1999–2001 | BMI | Yes | No, an increase in SHBG remained significant |
Perheentupa et al 2013 | Observational, based on Finnish population surveys | 3271 men who participated in population surveys of the Finnish National Public Health Institute | 1972–2002, in 3 surveys: 1972, 1977, 2002 | BMI | Yes | Yes |
Nyante et al 2012 | Observational, based on American population surveys | 2315 men who participated in National Health and Nutrition population surveys conducted by the CDC | 1988–2004 in 2 surveys: 1988–1991, 1999–2004 | BMI/percent body fat, waist circumference ethnicity, alcohol use, smoking, chronic illnesses, general health, medications | Yes | No |
Mazur et al 2013 | Longitudinal cohort | 991 US air force veterans | 1982–2002, in 6 health evaluations of the same group of men: 1982, 1985, 1987, 1992, 1997, 2002 | BMI | Yes | Yes |
In this analysis we did not adjust for BMI, as this is unclear whether BMI is a potential mediator or confounder since BMI has not been established as a sole explaining parameter in previous studies on longitudinal trends of testosterone. Analysis performed on the research population with available data on BMI showed little variation (< 1 kg/m2) in the mean age-specific BMI between study periods, with no discernible trend (data not shown). We therefore suggest that the observed testosterone decline is not likely to be explained by obesity trends.
In two of the previous observational reports (2, 4) adjustment to body mass index (BMI) led to a nullification of the period-related changes in testosterone. However, in the other two observational reports (1, 3) the age-specific testosterone decline remained significant after adjustment to BMI. Additionally, an US longitudinal study (9)of 991 men have shown that a between the years 1982–2002 testosterone decreased more than expected by aging. Decline was evident also in men who did not gain weight during the study. Thus, it cannot be concluded based on previous studies that the secular testosterone decline can be explained by a concurrent secular increase in body weight.
All the patients observed in this study were referred to a testosterone blood test by a physician while the indication for the referral was not available in study. While this is an obvious limitation of the study, particularly of its external validity, there is no reason to believe it affect internal validity, as the indications for the test have not been changed through the observation period. However, there still may be a concern that the observed trend can be explained by a growth in the size of the subpopulation of referred patients that end up having a below-norm level of testosterone in the serum, i.e. that the trend is due to a growth in the number of patients with a discernible problem rather than a decline of testosterone levels in the general healthy population. In order to address this concern, we repeated the analysis only for the samples which were within the normal range with similar results (data not shown).
It should also be noted regarding the external validity that the particularly large sample size in this study leads us to believe that in spite the aforementioned limitation the results can still be reasonably generalized to the general population, especially as most patients referred to this test eventually are not diagnosed with a discernible medical problem affecting the level of testosterone in the serum. Moreover, the age-specific levels of circulating testosterone are comparable with previous reports, including a study on 58,162 consecutive results in men from a single large pathology laboratory in Australia(10).