Dr. Ron’s Research Review – April 22, 2020

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This week’s research review focuses on testosterone for Alzheimer’s disease in men.

Testosterone replacement as a treatment of Alzheimer’s disease in men is a novel concept.  (Fuller et al., 2007) (Drummond et al., 2009) (Henderson and Hogervorst, 2004)
Calculated free testosterone concentrations were lower in men who developed Alzheimer disease, and this difference occurred before diagnosis. (Moffat et al., 2004)
Testosterone does have an effect on brain metabolism in elderly male patients with Alzheimer's disease. PET scans of two subjects showed improvement in glucose uptake most consistently in the parietal lobe and brainstem; decreased glucose metabolism was observed in the temporal lobe, the limbic system and the insula. (Tan, 2013)

Transdermal Testosterone

A study investigated testosterone replacement therapy (TRT) in 44 older men (aged 61 ± 7.7 years) with subjective memory complaints using a double blind, randomized, crossover, placebo-controlled study.
Participants were randomized into 2 groups, one group received transdermal testosterone (50 mg) daily for 24 weeks, followed by a 4 week wash-out period, then 24 weeks of placebo; the other group received the reverse treatment. Blood evaluation revealed significant increases in total testosterone, free (calculated) testosterone, dihydrotestosterone, and a decrease in luteinizing hormone levels (p<0.001) following TRT.
Although there were significant increases in red blood cell counts, hemoglobin and prostate specific antigen levels following TRT, they remained within normal ranges. No significant differences in plasma amyloid beta, estradiol, sex hormone binding globulin, insulin levels, body fat percentage, or body mass index were detected.
TRT is safe and well-tolerated. (Asih et al., 2015)

AndroForte

A randomized, placebo-controlled, crossover study investigated whether testosterone treatment significantly improved performance on various measures of cognitive functioning in men with subjective memory complaint and low testosterone levels.
Forty-four men were administered a battery of neuropsychological tests to establish the baseline prior to being randomly divided into two groups. The first group (Group A) received 24 weeks of testosterone treatment (T treatment, 50 mg of AndroForte applied daily to the scrotum via transdermal route for a period of 24 weeks) followed by 4 weeks washout, and then 24 weeks of placebo (P); the second group (Group B) received the same treatments, in reverse order (Placebo, washout, and then T treatment).
In group A, compared to baseline, there was a modest (1 point) but significant improvement in general cognitive functioning as measured by the Mini Mental State Examination (MMSE) following testosterone treatment. This improvement from baseline was sustained following the washout period and crossover to placebo treatment. Similar Mini Mental State Examination (MMSE) scores were observed when comparing testosterone treatment with placebo. In group B, a significant increase was observed from baseline following testosterone treatment and a trend towards an increase when compared to placebo treatment. Improvements in baseline depression scores (assessed by Geriatric Depression Scale) were observed following testosterone/placebo treatment in both groups, and no difference was observed when comparing testosterone with placebo treatment.
These findings indicate a modest improvement on global cognition with testosterone treatment. (Wahjoepramono et al., 2016)

 

Dr. Ron

 


Articles

 

Testosterone replacement therapy in older male subjective memory complainers: double-blind randomized crossover placebo-controlled clinical trial of physiological assessment and safety.
            (Asih et al., 2015)  Download
Testosterone replacement therapy (TRT) has been investigated in older men as a preventative treatment against Alzheimer's disease and dementia. However, previous studies have been contradictory. We assessed TRT physiological effects in 44 older men (aged 61 ± 7.7 years) with subjective memory complaints using a double blind, randomized, crossover, placebo-controlled study. Participants were randomized into 2 groups, one group received transdermal testosterone (50 mg) daily for 24 weeks, followed by a 4 week wash-out period, then 24 weeks of placebo; the other group received the reverse treatment. Blood evaluation revealed significant increases in total testosterone, free (calculated) testosterone, dihydrotestosterone, and a decrease in luteinizing hormone levels (p<0.001) following TRT. Although there were significant increases in red blood cell counts, hemoglobin and prostate specific antigen levels following TRT, they remained within normal ranges. No significant differences in plasma amyloid beta, estradiol, sex hormone binding globulin, insulin levels, body fat percentage, or body mass index were detected. This is the first carefully controlled study that has investigated the influence of TRT in Indonesian men on blood biomarkers linked to dementia risk. Our study suggests TRT is safe and well-tolerated in this Indonesian cohort, yet longitudinal studies with larger cohorts are needed to assess TRT further, and to establish whether TRT reduces dementia risk.

Androgens and Alzheimer's disease.
            (Drummond et al., 2009)  Download
PURPOSE OF REVIEW:  To discuss the relationship between androgens, cognition and Alzheimer's disease. RECENT FINDINGS:  It has been found that low circulating levels of androgens are a risk factor for Alzheimer's disease. Decreased circulating androgens are also associated with declining cognitive performance, particularly in memory-related tasks. Conversely, androgen supplementation to hypogonadal men results in improved memory performance. It has therefore been hypothesized that androgen supplementation may be beneficial in Alzheimer's disease. In recent studies, animal models have been used to elucidate the molecular mechanism behind this relationship between androgens and Alzheimer's disease. These studies have shown that androgen depletion results in increased levels of beta amyloid and hyperphosphorylated tau, changes which are thought to be associated with subsequent neuronal death. SUMMARY:  Androgen depletion results in molecular changes associated with Alzheimer's disease. Further human trials are needed to determine whether androgen modulating therapy for Alzheimer's disease has clinical significance.

Testosterone and Alzheimer disease: is it men's turn now
            (Henderson and Hogervorst, 2004)  Download
The primary androgen is testosterone, which can be metabolized to the more potent androgen dihydrotestosterone. It is also converted to estradiol by aromatase, an enzyme found in brain and other tissues. Thus, for men and women, androgens can influence brain function directly through interactions with androgen receptors, or testosterone effects can be mediated indirectly through estradiol acting on estrogen receptors.  Is the testosterone hypothesis strong enough to justify long-term intervention? Is it men’s turn for clinical trials of hormone therapy for the primary prevention of AD? Perhaps someday it will be.

Free testosterone and risk for Alzheimer disease in older men.
            (Moffat et al., 2004)  Download
OBJECTIVE:  To investigate the relationships between age-associated decreases in endogenous serum total testosterone (T) and a free T index (FTI) in men and the subsequent development of Alzheimer disease (AD). METHOD:  The authors used a prospective, longitudinal design with follow-up in men since 1958. Participants were from the Baltimore Longitudinal Study of Aging, a community-dwelling volunteer sample with baseline ages of 32 to 87 years. All subjects were free of AD at baseline T assessment. Five hundred seventy-four men assessed at multiple time points were followed for a mean of 19.1 years (range, 4 to 37 years). Diagnoses of AD were based on biennial physical, neurologic, and neuropsychological evaluations. RESULTS:  Diagnosis of AD was associated inversely with FTI by itself and after adjustments for age, education, smoking status, body mass index, diabetes, any cancer diagnoses, and hormone supplements. In separate analyses, total T and sex hormone binding globulin were not significant predictors after adjustment with covariates. Increases in the FTI were associated with decreased risk of AD (hazard ratio = 0.74; 95% CI = 0.57 to 0.96), a 26% decrease for each 10-nmol/nmol FTI increase. CONCLUSIONS:  Calculated free testosterone concentrations were lower in men who developed Alzheimer disease, and this difference occurred before diagnosis. Future research may determine whether higher endogenous free testosterone levels offer protection against a diagnosis of Alzheimer disease in older men.


 

Testosterone effect on brain metabolism in elderly patients with Alzheimer's disease: comparing two cases at different disease stages.
            (Tan, 2013)  Download
OBJECTIVE:  To describe the effect of testosterone replacement therapy (TRT) on the brain activity of two demented, hypogonadal male patients with early and late-stage Alzheimer's disease (AD), respectively. METHODS:  We describe the clinical and positron emission tomography (PET) findings for two individuals, one with early stage and the other with late-stage Alzheimer's disease, before and after treatment with a topical testosterone gel. Both patients were hypogonadal at baseline. We assessed cerebral glucose metabolism (CGM) via (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET). We investigated whether there are testosterone-susceptible areas within cerebral structures in patients with Alzheimer's disease. RESULTS:  Under testosterone replacement therapy, changes in cerebral glucose metabolism were observed in both patients. Improvement in glucose uptake was observed most consistently in the parietal lobe and brainstem; decreased glucose metabolism was observed in the temporal lobe, the limbic system and the insula for these two subjects. DISCUSSION:  These case reports demonstrate the potential for PET scanning to detect changes in cerebral glucose metabolism in hypogonadal men with Alzheimer's disease who are treated with testosterone. Further study will be needed to investigate the consistency and significance of these changes in terms of magnitude and brain region, and the correlation with functional changes.

The Effects of Testosterone Supplementation on Cognitive Functioning in Older Men.
            (Wahjoepramono et al., 2016)  Download
Reduction in testosterone levels in men during aging is associated with cognitive decline and risk of dementia. Animal studies have shown benefits for testosterone supplementation in improving cognition and reducing Alzheimer's disease pathology. In a randomized, placebo-controlled, crossover study of men with subjective memory complaint and low testosterone levels, we investigated whether testosterone treatment significantly improved performance on various measures of cognitive functioning. Forty-four men were administered a battery of neuropsychological tests to establish the baseline prior to being randomly divided into two groups. The first group (Group A) received 24 weeks of testosterone treatment (T treatment) followed by 4 weeks washout, and then 24 weeks of placebo (P); the second group (Group B) received the same treatments, in reverse order (Placebo, washout, and then T treatment). In group A (TèP), compared to baseline, there was a modest (1 point) but significant improvement in general cognitive functioning as measured by the Mini Mental State Examination (MMSE) following testosterone treatment. This improvement from baseline was sustained following the washout period and crossover to placebo treatment. Similar Mini Mental State Examination (MMSE) scores were observed when comparing testosterone treatment with placebo. In group B (PèT) a significant increase was observed from baseline following testosterone treatment and a trend towards an increase when compared to placebo treatment. Improvements in baseline depression scores (assessed by Geriatric Depression Scale) were observed following testosterone/placebo treatment in both groups, and no difference was observed when comparing testosterone with placebo treatment. Our findings indicate a modest improvement on global cognition with testosterone treatment. Larger clinical trials with a longer follow- up and with the inclusion of blood and brain imaging markers are now needed to conclusively determine the significance of testosterone treatment.

 

References

Asih, PR, et al. (2015), ‘Testosterone replacement therapy in older male subjective memory complainers: double-blind randomized crossover placebo-controlled clinical trial of physiological assessment and safety.’, CNS Neurol Disord Drug Targets, 14 (5), 576-86. PubMed: 25921747
Drummond, ES, AR Harvey, and RN Martins (2009), ‘Androgens and Alzheimer’s disease.’, Curr Opin Endocrinol Diabetes Obes, 16 (3), 254-59. PubMed: 19373081
Fuller, S. J., R. S. Tan, and R. N. Martins (2007), ‘Androgens in the etiology of Alzheimer’s disease in aging men and possible therapeutic interventions’, J Alzheimers Dis, 12 (2), 129-42. PubMed: 17917157
Henderson, VW and E Hogervorst (2004), ‘Testosterone and Alzheimer disease: is it men’s turn now’, Neurology, 62 (2), 170-71. PubMed: 14745046
Moffat, SD, et al. (2004), ‘Free testosterone and risk for Alzheimer disease in older men.’, Neurology, 62 (2), 188-93. PubMed: 14745052
Tan, RS (2013), ‘Testosterone effect on brain metabolism in elderly patients with Alzheimer’s disease: comparing two cases at different disease stages.’, Aging Clin Exp Res, 25 (3), 343-47. PubMed: 23740590
Wahjoepramono, EJ, et al. (2016), ‘The Effects of Testosterone Supplementation on Cognitive Functioning in Older Men.’, CNS Neurol Disord Drug Targets, 15 (3), 337-43. PubMed: 26553159