Study Examines Links Between Sleep, Testosterone, and Cortisol in Aging Men

New research published in PLoS One suggests that fixing testosterone-cortisol balance in men could mitigate the metabolic harm caused by sleep loss without requiring patients to sleep more. Sleep serves multiple vital functions, including neurobehavioral performance, improving immune function, and conserving energy expenditure through metabolic processes.

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These benefits to metabolism, immunity, and cognition are crucial for healthy aging. However, the accumulation of sleep debt across the lifespan has negative impacts on all of these processes, which may be responsible for the development of diseases later in life.

Sleep debt accumulates throughout the lifespan as a result of insufficient sleep, misaligned sleep (such as with jetlag or night shiftwork), and disrupted sleep. Although individuals often try to “catch up” on sleep, this does not seem to completely reverse the adverse effects of sleep debt on multiple physiological processes, including psychomotor performance, metabolism, blood pressure regulation, and immune/adrenal response.

The accumulation of sleep debt is a widespread issue, with approximately 1 in 3 individuals getting insufficient sleep (<7 hours per night). Of those, an estimated 20% are shift workers with work schedules that misalign sleep. Additionally, 10% of men aged 30 to 49 years and 17% of men aged 50 to 70 years have at least moderate obstructive sleep apnea (OSA), which is a major cause of disrupted sleep. Insufficient, misaligned, and disrupted sleep is therefore likely to have major impacts on aging and the development of age-related diseases.

In their review, investigators primarily examined the effects of sleep disturbances on testosterone in the context of male gonadal aging. OSA and its interaction with testosterone is of particular importance because sleep architecture is disrupted and sleep duration is reduced.

Experts have long recommended that adults between the ages of 18 and 64 years require 7 to 9 hours of sleep per night, whereas adults over 65 years of age need 7 to 8 hours, including naps. Sleep needs decrease with age, but only up to age 60, after which sleep needs remain stable. Sleep architecture also changes with age, with rapid eye movement (REM) sleep decreasing and the proportion of stage 1 and 2 sleep increasing before age 60 and remaining stable afterward.

Like sleep, many longitudinal and cross-sectional studies of multiple populations have shown that testosterone declines with age in men. This decline is now recognized to be largely, although not exclusively, due to factors associated with aging, such as obesity and illness, rather than from aging itself.

A consistent relationship between sleep duration and testosterone has not been apparent in large cross-sectional studies of health community-dwelling older men. In their analysis of in-laboratory studies of sleep restriction on blood testosterone, only 1 study intensively sampled blood frequently enough to allow determination of pulse characteristics. Taken collectively, the studies showed that sleep restriction decreases testosterone, although importantly, most only assessed testosterone in the morning.

Only 1 study examined the effect of manipulating sleep in a cohort specifically including older men. In this study, 18 healthy older men and 17 healthy young men underwent total sleep deprivation and 8 hours of regular night sleep in random order. Although 24-hour, morning, and afternoon testosterone concentrations were all decreased by sleep restriction in both older and younger men, sleep restriction decreased the testosterone pulse frequency and pulsatile secretion only in older men.

Aging and sleep also intersect with cortisol. Multiple studies have shown that age is associated with higher late-afternoon and early-evening cortisol, and an advance in the timing of the cortisol rhythm. Notably, hypercortisolemia during the late afternoon and early evening is harmful and is believed to cause insulin resistance observed with advanced age, impaired physical performance, and neurocognitive deficits.

Some studies have suggested that sleep duration does not influence 24-hour or near 24-hour cortisol. However, recurrent self-reported short sleep duration is associated with higher late afternoon or bedtime salivary cortisol after 10 years of follow-up in a large occupational cohort of adults initially aged 35 to 55 years. These epidemiological data show that the effect of short sleep may be on a specific time of day in which higher cortisol levels result in metabolic harm, without any impact on 24-hour cortisol.

Finally, the investigators noted that cortisol and testosterone are, respectively, the major catabolic and anabolic signals in men. Changes in cortisol and testosterone signaling due to sleep restriction, specifically a reduction in testosterone and an increase in late-afternoon and early-evening cortisol, has long been suspected to be a mechanism by which sleep restriction induces insulin resistance. Randomized controlled trials have shown that testosterone treatment improves insulin sensitivity in men at risk for type 2 diabetes.

Based on all of the data analyzed, the researchers concluded that reciprocal changes in testosterone and cortisol as a result of sleep loss imbalance catabolic-anabolic signaling and is an important mechanism by which sleep loss induces insulin resistance.

By fixing the balance of testosterone and cortisol to prevent induced insulin resistance, the investigators said they provided the first proof-of-concept that the metabolic harm caused by sleep loss can potentially be mitigated by approaches that do not require more sleep. This could be particularly relevant for older men because the changes in testosterone-cortisol balance that occur in young men have been shown to also occur in older men.

Reference

Liu PY, Reddy RT. Sleep, testosterone and cortisol balance, and aging men. PLoS One. 2022;23(1323-1339). doi:10.1007/s11154-022-09755-4