madman
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Although the sole unequivocal indication for testosterone treatment is replacement therapy for male hypogonadism, off-label testosterone prescribing for aging men without pathologic hypogonadism rose dramatically (100-fold) over recent decades including 10-fold increases in the USA and 40-fold in Canada over the first decade of this century (1). Without new approved indication or prospective safety data for high-volume off-label testosterone treatment, the FDA mandated an industry-funded cardiovascular safety study (TRAVERSE). Recently this well-designed study reported recruiting 5204 men over 45 years7 of age with a low circulating testosterone (<10.4 nmol/L, 300 ng/dl) plus one or more non-specific symptom(s) with the participants mostly having pre-existing cardiovascular disease and high rates of obesity, diabetes, hypertension, and dyslipidemia. Randomized to daily testosterone or placebo transdermal gel for a median of 22 months and followed for a median of 33 months, major CV events were not increased but there were unexpected increases in arrhythmias, venous thromboembolism, renal injury, and bone fractures, and with >60% discontinuing treatment from both arms (2). Beyond primary cardiovascular safety objective, TRAVERSE investigators and commercial sponsors report side benefits of testosterone treatment on hemoglobin, bone density, and sexual function, all expected effects of testosterone treatment for any men but each alone insufficient to warrant initiating testosterone treatment in aging men without reproductive pathology.
A recent secondary analysis of the TRAVERSE data reports the impact of testosterone treatment on depressive symptoms in aging men with “age-related hypogonadism” but not pathologic hypogonadism (3). This study focussed on “late-life-onset, low-grade persistent depressive disorder” (LG-PDD), once known as dysthymia, and on depressive symptoms in the whole study population or those having mild or higher (PHQ-9 >4, 35%) depression scores. The primary outcome measure, PHQ-9 questionnaire, was supported by another depression scale (GDS-15) and the mood scale of a disease-specific quality of life measure (HIS-Q). LG-PDD was both rare (1.5% prevalence) and unresponsive to testosterone treatment whereas among those with mild or more PHQ-9 depression scores (>4), or all participants, there was a statistically significant improvement in depressive scores (mean <1 point). This improvement was less than that expected of an effective antidepressant and consistent with the finding that, for men with severe depression (PHQ-9>15), testosterone treatment was ineffective. In the middle category of modest depressive scores (PHQ-9 of 5-14), testosterone produced a statistically significant improvement in HIS-Q29 mood score, a difference comparable with that between very mild or more and no symptoms (4). There were no benefits of testosterone for cognition or sleep nor in number of suicides or new psychiatric diagnoses. A modest lift in depressive symptoms rediscovers the mood-elevating effects of testosterone described 75 years ago and patented as a forerunner of modern antidepressants. Generic mood elevation does not necessarily signify treatable depression. It places mood improvement alongside the 2 other expected small side benefits of testosterone treatment but not as an indication for initiating treatment where more effective therapeutics are available.
On treatment, median serum testosterone rose from 7.8 nmol/L (227 ng/dl) at baseline to 14.7 nmol/L (424 ng/dl) on treatment, substantially below the mid-normal range (19.0 nmol/L, 550 ng/dl) reflecting the low serum SHBG of obesity and probable suboptimal compliance with daily gel application given the study’s high dropout rate. Whether higher on-treatment testosterone concentrations would have better effects remains speculative.
In wider context, the TRAVERSE study originated after the failure of the NIH-funded T Trials to meet the IOM (now National Academy of Science) 2004 mandate of sufficient short-term efficacy evidence to warrant public funding of a large, randomized placebo-controlled study of testosterone for “age-related hypogonadism”. The FDA regards that ill-defined entity as neither a disease nor justification for testosterone treatment (5). However, the high rates of off-label testosterone prescribing without prospective safety data, the FDA to mandate an industry-funded study (TRAVERSE) (6), remarkably as a safety study is rarely justified for a non-approved indication. While TRAVERSE provides sound evidence for short-term cardiovascular safety of testosterone treatment of aging men with pre-existing cardiovascular disease, longer-term safety beyond 2 years remains to be established. Nor did TRAVERSE provide reassurance on the unprecedented T-Trials finding that 12 months of testosterone treatment increased non-calcified coronary plaque(7).
A key issue in the TRAVERSE and related studies is their population recruited based on the definition of “hypogonadism” as a low circulating testosterone plus any non-specific symptom(s). This definition systematically disregards underlying pathologic causes of, or even causality between, those two features which may equally be linked by reverse causality or both being due to an independent third factor (eg systemic illness, non-pathologic conditions). Widening the definition of “hypogonadism” inevitably fosters more drug prescribing (“disease mongering”). While understandably attractive to enthusiasts, single-issue clinics, and testosterone suppliers, this widened definition erodes sound medical practice. By disregarding the underlying pathologic causes of a low testosterone, it encourages testosterone treatment for functional states associated with lowered circulating testosterone, a dynamic and reversible hypothalamic response to systemic illness and/or non-pathologic conditions. These are more appropriately called sick eugonadal or non-gonadal illness syndrome, evoking the analogous terms for reduced circulating thyroxine in the absence of thyroidal disease, rather than “hypogonadism”. This includes the pseudo-hypogonadism of obesity where obesity-related reduced serum SHBG produces a reduced serum testosterone but with normal serum LH and FSH, operating as tissue androgen sensors and signifying a eugonadal state. In such states, medical management is more logically directed toward the unglamorous and demanding pursuits of reducing smoking, weight, increasing physical activity, and rectifying sleep apnea. The lack of a firm nexus between the symptoms (all non-specific and nondiscriminatory) and “low” testosterone is an illogical unidirectional assumption leading to a misdirected leap of therapeutic faith in fostering misguided over-treatment. In effect, the permissive redefinition endorses testosterone treatment for virtually any cause of a low testosterone, making it a substantial contributor to the massive, unjustified increase in testosterone prescribing in recent decades (1). Had such a loose definition prevailed in thyroidology, there would have been an equivalent flood of unjustified prescribing of thyroxine, a hormone lacking the charisma of testosterone perceived as an elixir of youthful vigor. Furthermore, prolonged testosterone treatment in men without pathologic hypogonadism also risks androgen dependence (8).
Overall, the high rate of discontinuation in TRAVERSE confirms the minimal efficacy of testosterone treatment over placebo according to the participants, and congruent with the FDA’s concerns, while also showing that testosterone treatment can be reasonably safe, with small side benefits, for up to 2 years without achieving anything decisive therapeutically, rather than demanding but cost-effective lifestyle interventions.
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A recent secondary analysis of the TRAVERSE data reports the impact of testosterone treatment on depressive symptoms in aging men with “age-related hypogonadism” but not pathologic hypogonadism (3). This study focussed on “late-life-onset, low-grade persistent depressive disorder” (LG-PDD), once known as dysthymia, and on depressive symptoms in the whole study population or those having mild or higher (PHQ-9 >4, 35%) depression scores. The primary outcome measure, PHQ-9 questionnaire, was supported by another depression scale (GDS-15) and the mood scale of a disease-specific quality of life measure (HIS-Q). LG-PDD was both rare (1.5% prevalence) and unresponsive to testosterone treatment whereas among those with mild or more PHQ-9 depression scores (>4), or all participants, there was a statistically significant improvement in depressive scores (mean <1 point). This improvement was less than that expected of an effective antidepressant and consistent with the finding that, for men with severe depression (PHQ-9>15), testosterone treatment was ineffective. In the middle category of modest depressive scores (PHQ-9 of 5-14), testosterone produced a statistically significant improvement in HIS-Q29 mood score, a difference comparable with that between very mild or more and no symptoms (4). There were no benefits of testosterone for cognition or sleep nor in number of suicides or new psychiatric diagnoses. A modest lift in depressive symptoms rediscovers the mood-elevating effects of testosterone described 75 years ago and patented as a forerunner of modern antidepressants. Generic mood elevation does not necessarily signify treatable depression. It places mood improvement alongside the 2 other expected small side benefits of testosterone treatment but not as an indication for initiating treatment where more effective therapeutics are available.
On treatment, median serum testosterone rose from 7.8 nmol/L (227 ng/dl) at baseline to 14.7 nmol/L (424 ng/dl) on treatment, substantially below the mid-normal range (19.0 nmol/L, 550 ng/dl) reflecting the low serum SHBG of obesity and probable suboptimal compliance with daily gel application given the study’s high dropout rate. Whether higher on-treatment testosterone concentrations would have better effects remains speculative.
In wider context, the TRAVERSE study originated after the failure of the NIH-funded T Trials to meet the IOM (now National Academy of Science) 2004 mandate of sufficient short-term efficacy evidence to warrant public funding of a large, randomized placebo-controlled study of testosterone for “age-related hypogonadism”. The FDA regards that ill-defined entity as neither a disease nor justification for testosterone treatment (5). However, the high rates of off-label testosterone prescribing without prospective safety data, the FDA to mandate an industry-funded study (TRAVERSE) (6), remarkably as a safety study is rarely justified for a non-approved indication. While TRAVERSE provides sound evidence for short-term cardiovascular safety of testosterone treatment of aging men with pre-existing cardiovascular disease, longer-term safety beyond 2 years remains to be established. Nor did TRAVERSE provide reassurance on the unprecedented T-Trials finding that 12 months of testosterone treatment increased non-calcified coronary plaque(7).
A key issue in the TRAVERSE and related studies is their population recruited based on the definition of “hypogonadism” as a low circulating testosterone plus any non-specific symptom(s). This definition systematically disregards underlying pathologic causes of, or even causality between, those two features which may equally be linked by reverse causality or both being due to an independent third factor (eg systemic illness, non-pathologic conditions). Widening the definition of “hypogonadism” inevitably fosters more drug prescribing (“disease mongering”). While understandably attractive to enthusiasts, single-issue clinics, and testosterone suppliers, this widened definition erodes sound medical practice. By disregarding the underlying pathologic causes of a low testosterone, it encourages testosterone treatment for functional states associated with lowered circulating testosterone, a dynamic and reversible hypothalamic response to systemic illness and/or non-pathologic conditions. These are more appropriately called sick eugonadal or non-gonadal illness syndrome, evoking the analogous terms for reduced circulating thyroxine in the absence of thyroidal disease, rather than “hypogonadism”. This includes the pseudo-hypogonadism of obesity where obesity-related reduced serum SHBG produces a reduced serum testosterone but with normal serum LH and FSH, operating as tissue androgen sensors and signifying a eugonadal state. In such states, medical management is more logically directed toward the unglamorous and demanding pursuits of reducing smoking, weight, increasing physical activity, and rectifying sleep apnea. The lack of a firm nexus between the symptoms (all non-specific and nondiscriminatory) and “low” testosterone is an illogical unidirectional assumption leading to a misdirected leap of therapeutic faith in fostering misguided over-treatment. In effect, the permissive redefinition endorses testosterone treatment for virtually any cause of a low testosterone, making it a substantial contributor to the massive, unjustified increase in testosterone prescribing in recent decades (1). Had such a loose definition prevailed in thyroidology, there would have been an equivalent flood of unjustified prescribing of thyroxine, a hormone lacking the charisma of testosterone perceived as an elixir of youthful vigor. Furthermore, prolonged testosterone treatment in men without pathologic hypogonadism also risks androgen dependence (8).
Overall, the high rate of discontinuation in TRAVERSE confirms the minimal efficacy of testosterone treatment over placebo according to the participants, and congruent with the FDA’s concerns, while also showing that testosterone treatment can be reasonably safe, with small side benefits, for up to 2 years without achieving anything decisive therapeutically, rather than demanding but cost-effective lifestyle interventions.
Testosterone and Depression Symptoms in Aging Men
Although the sole unequivocal indication for testosterone treatment is replacement therapy for male hypogonadism, off-label testosterone prescribing for ag
academic.oup.com
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