The age group typically examined for late onset hypogonadism extends into middle adulthood (age 50 years and older), and testosterone replacement therapy studies focused on older adult (≥65 years) hypogonadal patients are limited. Available studies of hypogonadal men ≥50 years old suggest that TRT may be effective in alleviating symptoms among patients in this age group.28
Among healthy men ≥60 years old, TRT has been associated with increased lean body mass, decreased fat mass, and increased muscle strength.33
Testim, the drug used in the current study, has previously been shown to be effective in two 90-day, randomized, placebo-controlled studies, demonstrating improvements in mean concentrations of testosterone, sexual function, lean body mass, and percentage of body fat among men 20–80 years old,36
which were maintained to 12 months.38
In the current study examining the effect of TRT in older men, we observed similar improvements after TRT, irrespective of age, suggesting that hypogonadal men ≥65 years may find benefit with careful monitoring.
In the current study, hypogonadal men ≥65 years old and enrolled in TRiUS comprised 16% of the registry participants. This percentage of patients could be seen as high given the debate about treating older adults with TD.18
Alternatively, the treatment rate appears quite low given that men ≥65 years attending primary care practices throughout the US were 1.2 times more likely to present with hypogonadism than men younger than 65 years.5
The current study findings demonstrated that men ≥65 years were similar to men <65 years in the duration of TD prior to study enrollment (a little longer than 1 year), prior use of TRT (10% and 14%, respectively), TT and FT levels at baseline, TT and FT levels at 12-month follow-up, and in their reported compliance with treatment. TRT dose was not controlled and TRT dose titration over the 12-month study period was unknown; thus, only baseline and 12-month TRT dose were reported. Patients ≥65 years were prescribed a lower dose of TRT at baseline significantly more often (95%) than patients <65 years (86%). Although the percentage of patients using 50 mg vs 100 mg testosterone dosing at 12-month follow-up did not significantly differ between age groups (100 mg: 26% of patients ≥65, 33% of patients <65), the lack of significant difference should be interpreted with caution given the small sample sizes. The data show that no patient was prescribed over 100 mg/day and suggest that older patients were more likely to continue to receive the lower TRT dose.
Both age groups showed a significant increase in TT levels at 12 months (which fell within the range suggested by the Endocrine Society),6
with mean TT at approximately 524 and 491 ng/dL (18.2 and 17.0 nmol/L), respectively, demonstrating a significant response to TRT independent of age. Thus, on average, older aged patients receiving 50 or 100 mg/day TRT attained a TT level within the physiological range that is considered optimal, between 400 and 800 ng/dL (13.9 and 27.8 nmol/L)6
following TRT. Importantly, treatment in older patients did not lead to attainment of sup-raphysiologic TT levels following TRT use of 50 mg or 100 mg/day. Although FT levels did increase over the 12-month treatment period, the increase was not significant in the group of patients ≥65. The lack of significance may be the result of a small sample size of patients undergoing FT testing at 12 months among the older patients, and the consequent lack of statistical power. Notably, the FT levels at 12 months did not significantly differ between patients ≥65 and <65 years.
The oldest participants (≥75 years) had similar duration of TD, similar TT and FT levels at baseline, and similar compliance with treatment when compared with participants who were 65–74 and <65 years. The current study was unable to compare responses to TRT at 12 months between participants ≥75 years and those younger due to limited number of participants in the ≥75 group with TT and FT testing at 12-month follow-up. Consequently, it is not known whether the response to TRT declined among the oldest patients. However, similar TT and FT levels at baseline and sustained high levels of treatment compliance across all of the age groups supports the likelihood of an adequate response to TRT among the oldest participants.
TRT in older hypogonadal men requires consideration of the risks and benefits of TRT6
and in particular the possibility of an increased risk in rate of prostate events, such as PSA levels >4 ng/mL (>4 μg/L), prostate biopsies, and prostate cancer.39
In the current study, the oldest group of patients (≥75) showed the highest PSA levels at baseline, and patients ≥65 had a significantly higher mean PSA level than the <65 group at baseline and at 12-month follow-up. However, the ≥65 group did not show signifi-cantly increased PSA at 12 months compared with baseline, whereas the <65 group did. The mean increase in PSA level among patients ≥65 years in the current study was 0.33 ng/mL (0.33 μg/L) and among patients <65 years was 0.17 ng/mL (0.17 μg/L). These mean increases are consistent with what has been previously found in PSA level change following TRT; approximately 0.30 ng/mL (0.30 μg/L) overall and 0.43 ng/mL (0.43 μg/L) among older men on average.40
PSA level increases associated with TRT typically occur during the initial 6 months of treatment,27
and further PSA level changes are considered age-related changes in PSA levels.40
The mean PSA level of 2.18 ng/mL (2.18 μg/L) at 12-month follow-up among the patients ≥65 years is consistent with a study examining age-stratified normal values for PSA level; mean PSA levels increased with aging from 1.1 to 2.5 ng/mL (1.1 to 2.5 μg/L) among community-dwelling men 50–80 years old.41
Consistent with the prostate saturation theory in which PSA and prostate tissue growth are sensitive to changes in serum testosterone only when serum testosterone levels are low, clinicians may expect an initial increase in PSA in hypogonadal men following TRT during the first few months.27
Increases in PSA levels during the first year of TRT that are > 1.4 ng/mL (1.4 μg/L)6
or PSA levels > 4 ng/mL (4 μg/L)40
may be unusual and suggest the need for a urological consultation as per the Endocrine Society guidelines.6
In the current study, a small number of patients (eleven patients ≥65 years; six patients <65 years) had a PSA level > 4 ng/mL (4 μg/L) or an increase in PSA > 1.4 ng/mL (1.4 μg/L) at some time during the 12-month study period.
Although the TRiUS registry was not specifically designed to assess safety, adverse event reporting suggests TRT was well tolerated in both age groups. Additionally, study findings suggest that cardiovascular risk factors did not worsen during 12 months of TRT in men ≥65 years. This was a concern given the results of a recent trial examining the effect of Testim on muscle strength and physical performance in a population of community-dwelling men ≥65 years old with limitations in mobility and a high prevalence of cardiovascular risk factors (ie, hypertension, diabetes, hyperlipidemia, and obesity).18
The trial was halted due to a higher rate of cardiovascular-related adverse events in the TRT group compared with placebo. However, the trial design limits generalizing these findings to a larger population, given the small size of the trial, the initial high dose of TRT used, and the unique mobility-limited population. A recent review examining the cardiovascular risk of TRT in elderly males concluded that TRT does not increase cardiovascular risk or adversely affect the cardiovascular profile in older men.42
The current study found associations between lower TT levels and cardiovascular risk factors of greater weight, BMI, waist and hip circumference, diastolic BP, and plasma glucose levels at baseline, independent of age. TT levels at baseline were not associated with total cholesterol, HDL, LDL, or triglycerides. Lower FT levels at baseline were associated with greater plasma glucose levels independent of age but not with anthropometric or cardiovascular factors. Average BMI at baseline did not significantly differ between age groups and was in the obese range. Whether obesity may serve as a potential indicator of TD in older men is not yet known, and no published study as yet, has specifically addressed differences in BMI in older men without TD compared with older men with TD.
Over the 12 months of the study, increase in TT level was associated with decreased waist circumference and plasma glucose levels and increase in FT level was associated with decreased total and LDL cholesterol, independent of age. Notably, the percentage of patients completing follow-up assessments was similar between men ≥65 and men <65 at 12 months, indicating there was not a disproportionate loss to follow-up based on age.
It has been suggested that aging of men in the US will cause a large increase in the burden of TD, with an estimated prevalence of symptomatic TD of 6.5 million by the year 2025 among American men 30–79 years of age.4
The primary care setting seems an ideal place for testosterone level testing and TD screening. However, in the primary care setting, barriers to diagnosis of TD and referral to treatment include lack of physician–patient communication, inadequate provider knowledge or assessment tools, as well as personal, cultural, or gender influences.43
Increased clinician awareness that older men with TD may present with symptoms that are easily misinterpreted as signs of aging or chronic disease is needed as well as an understanding that older men with TD show benefit from TRT. Prior studies have shown the benefits of TRT on visceral fat, total body fat-free mass, and total body and thigh skeletal muscle mass among healthy older hypogonadal men;30
benefits have also been shown on insulin resistance, improved glycemic control, and improved visceral adiposity among older hypogonadal men with type 2 diabetes,45
on symptoms of metabolic syndrome,28
and on symptoms of depression among older hypogonadal men with dysthymia or minor depression.32
However, these positive results must be tempered by the lack of long-term efficacy and safety studies of TRT in hypogonadal men of all ages; while older men with TD may expect benefit from TRT, they must be carefully monitored during treatment.
The limitations to our study are characteristic of patient registries where, unlike placebo-controlled studies, physician and patient behavior are not directed. There was a high degree of variability in inter-patient data collection, no standardized definition of TD, no testosterone washout period before enrollment, no centralized laboratory testing facility, and no standardized time of testosterone draw. The differences between the primary age groups in enrollment sample size, although expected given that the study is not a controlled trial, may have influenced statistical analyses. Also, patient-supplied records were the evidence used for drug compliance.