Comparison of salivary cortisol, amylase, and chromogranin A diurnal profiles in healthy volunteers

Salivary chromogranin A is often used in stress research as a marker of the sympathetic-adrenal-medullary activity as it is co-released with epinephrine or norepinephrine upon sympathetic stimulation (Kanno et al., 2000). Its level was also correlated with norepinephrine release rate (Dimsdale et al., 1992). Moreover, norepinephrine (as well as acetylcholine) was able to induce chromogranin A release in rats (Kanno et al., 1999). Many studies on various models of both physical and psychological stress have detected increased levels of chromogranin A in response to stress especially in studies detecting only chromogranin A alone (Kanamaru et al., 2006, Lihala et al., 2019, Miyakawa et al., 2006, Nakamura et al., 2009, Nakane et al., 1998) and that its level decreased with interventions to reduce stress such as music therapy, aromatherapy, laughter, medication, or tea consumption (Kanamaru et al., 2008, Matsumoto et al., 2014, Suzuki et al., 2004, Toda and Ichikawa, 2012, Yoto et al., 2018). Hence, the general understanding that chromogranin A is a representative of the sympathetic system.

However, with more studies especially in comparison with other biomarkers such as salivary alpha-amylase and salivary cortisol, some conflicting results emerge. A large number of studies have consistently found increased amylase levels in response to a variety of stress models as reviewed elsewhere (Nater & Rohleder, 2009). While cortisol is regarded as a gold standard marker of stress as it represents the activity of the hypothalamic-pituitary-adrenal axis (Hellhammer et al., 2009). Since amylase and cortisol represent a different system of stress response, they don’t always react in a similar manner. For example, amylase reacts faster to stress rising within 5 min after the onset and the level declines soon after the stress ceases. While cortisol usually displays a delayed response rising in 20 min and declines much later (Schumacher et al., 2013, Takai et al., 2004).

Typically, it would be expected that even if chromogranin A does not react in the same way as that of cortisol, at least it should with that of amylase since both are expected to represent the sympathetic activity. Current evidence provides inconsistent results. Some studies found chromogranin A and amylase or cortisol to increase in social stress test and in oral presentation (Gallina et al., 2011, Hua et al., 2014, Nakane et al., 1998), or in sporting competition (Diaz et al., 2012). Some found cortisol or amylase to increase but not chromogranin A in response to physical stress in athletes (Chennaoui et al., 2016, Leicht et al., 2017), upon giving lectures among professors (Filaire et al., 2009), in academic stress (Ng et al., 2003). While others found chromogranin A level to change but not cortisol or amylase in periodontal disease (Haririan et al., 2012), after back massage (Noto et al., 2010), or after examination (Takatsuji et al., 2008). A previous study by our group found cortisol and amylase to respond much more robustly than that of chromogranin A to academic oral presentation (Tammayan et al., 2021). Clearly, more studies are needed to gain more understanding in the nature of chromogranin A reactivity.

Surprisingly, current literature provides little information regarding the physiological nature of chromogranin A. We have found only two studies on diurnal profile of salivary chromogranin A. One was performed with 40 male college students (Den et al., 2007) and the other was performed in 35 females (Hong et al., 2009). More studies are needed to gain more understanding of the physiological profile of chromogranin A. This study aimed to compare the diurnal patterns of two well-known salivary biomarkers (cortisol and amylase) with chromogranin A to gain more understanding of these markers and on choosing the optimal biomarker and optimal time to do the experiment as well as the factors affecting their levels.

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