Androgen Supplementation During Aging: Development of a Physiologically Appropriate Protocol

Abstract

Men show an age-related decline in the circulating levels of testosterone (T) and dehydroepiandrosterone sulfate (DHEAS). Consequently, there is interest in developing androgen supplementation paradigms for old men that replicate the hormone profiles of young adults. In the present study, we used old (21-26 years old) male rhesus monkeys as a model to examine the efficacy of an androgen supplementation paradigm that comprised oral T administration (12 mg/kg body weight, dissolved in sesame oil/chocolate) in the evening, and two oral DHEA administrations, 3 hr apart (0.04 mg/kg body weight, dissolved in sesame oil/chocolate) in the morning. After 5 days of repeated hormone supplementation, serial blood samples were remotely collected from each animal hourly across the 24-hr day, and assayed for cortisol, DHEAS, T, 5α-dihydrotestosterone (DHT), estrone (E1), and 17β-estradiol (E2). Following androgen supplementation, T levels were significantly elevated and this was associated with a more sustained nocturnal elevation of T's primary bioactive metabolites, DHT and E1 and E2. Plasma DHEAS levels were also significantly elevated after androgen supplementation; DHEAS levels rose in the early morning and gradually declined during the course of the day, closely mimicking the profiles observed in young adults (7-12 years old); in contrast, cortisol levels were unaltered by the supplementation. Together the data demonstrate a non-invasive androgen supplementation paradigm that restores youthful circulating androgen levels in old male primates. Because this paradigm preserves the natural circulating circadian hormone patterns, we predict that it will produce fewer adverse side effects, such as perturbed sleep or cognitive impairment.

Effect of androgen supplementation on 24-hour activity-rest patterns of aged male rhesus macaques

“…At the end of the study, the mean (± SEM) body weights of the young (n=6), old controls (n=6), and old supplemented animals (n=6) were 9.5 ± 0.8 kg, 10.9 ± 0.6 kg and 12.1 ± 1.1 kg, respectively, and their mean testis weights were 26.1 ± 2.6, 28.4 ± 2.4 and 21.3 ± 2.5 g; there were no significant ( p >0.05) between-group differences for either body weight or testis weight (Kuskal-Wallis 1-way ANOVA). As expected, mean (± SEM) plasma DHEAS concentrations were significantly ( p <0.05) lower in the old controls (43.7 ± 12.7 ng/ml) than in the young animals (126.8 ± 18.1 ng/ml) (Urbanski et al, 2014), but significantly ( p <0.01) elevated (359.2 ± 50.8 ng/ml) in the old animals ∼3 hours after DHEA supplementation (Mann-Whitney U -tests).…”

“…Half of the old animals (n=6) received daily androgen supplementation, as previously described (Urbanski et al, 2014), while the other half (n=6) served as age-matched controls. The androgen supplementation comprised oral T administration (12 mg/kg body weight, at 1900 h) and two oral DHEA administrations (0.04 mg/kg body weight, at 0700 and 1000 h).…”

“…Although men and male rhesus macaques show less dramatic age-related decreases in the circulating levels of DHEAS and testosterone (T), these androgens have well-defined circadian rhythms. Consequently, their decrease during aging contributes to attenuation of circadian signaling throughout the body, which in turn may play a key role in the etiology of perturbed activity-sleep patterns that are so prevalent in the elderly (Downs et al, 2007; 2008; Sitzmann et al, 2014; Sorwell and Urbanski, 2013; Urbanski and Sorwell, 2012; Urbanski et al, 2014). …”

“…The daily androgen supplementation paradigm that we employed was previously developed in the same old rhesus macaques, and was shown to recapitulate mean youthful circulating levels of DHEAS, estradiol, estrone, 5α-dihydrotestosterone and T, while preserving their characteristic circadian profiles but not the underlying pusatile patterns (Urbanski et al, 2014). …”

Cognition in aged rhesus monkeys: effect of DHEA and correlation with steroidogenic gene expression

“…First, the duration of the DHEA treatment in the current study may have been too short to elicit a significant effect, although previously we observed cognitive improvements in ovariectomized macaques after only 2 months of treatment with E 2 (Kohama et al 2016). It’s also possible that the 5-mg oral dose of DHEA that we administered daily was suboptimal at maintaining elevated circulating levels of DHEAS throughout the entire day (Urbanski et al 2014). Another possible cause for the negative results is that our old females were still able to maintain elevated E 2 levels in their cognitive brain centers, despite showing perimenopausal hormonal changes in the circulation.…”