Army Medical Research and Development Command (Ft. Detrick, Fredericksburg, MD) approved this study. The study design, recruitment methods, and primary outcomes of the parent study are published in detail elsewhere (33,35). Studies reporting repeated daily measures of HRV across a program of physical and psychological stress are also sparse (32). Furthermore, we aim to examine the effects of an exogenous treatment of testosterone on exercise HRV in the context of sleep deprivation, caloric deficit, and high-volume exercise. Exercise HRV metrics suggested parasympathetic hyperactivity despite concomitant increases in stress across the extended simulated military operations. POTS patients have variously been shown to have a partial neuropathic state with impaired lower extremity sympathetic innervations, abnormal venous pooling, a hypovolemic state with inadequate RAAS upregulation, cutaneous blood flow dysregulation, and also increased plasma Ang-II levels. In a larger study of 39 POTS patients refractory to conventional treatment, erythropoietin administration garnered no improvement in orthostatic tachycardia. The hormones estrogen, testosterone, and cortisol, as well as the neurotransmitters dopamine and serotonin, also affect how organisms react to stress. Huovinen et al. (61) suggested that the measurement of HRV during sympathetic activation (as in exercise) may be more sensitive to alterations in autonomic balance and may provide greater insight regarding response to stressful military service. The cumulative effects of chronic disrupted sleep, high-volume physical activity, and energy deficit on exercise HRV, and whether changes can be mitigated with exogenous testosterone administration, has not been previously explored. The purpose of this study was to assess exercise HRV as a marker of physiological and psychological stress and determine if testosterone administration maintains HRV during extended simulated military operations. As discussed in other sections, exogenous administration of estrogen decreased sympathetic nerve activity in postmenopausal women, therefore, it seems contradictory that estradiol supplementation would decrease pre-synaptic inhibition of norepinephrine release in the brain. How then do these various actions of estrogen on synthesis, uptake, and degradation of norepinephrine affect vasoconstrictor responses to sympathetic nerve activity? The sympathetic nervous system and testosterone are two critical components of the body’s response to stress and danger. While research directly examining the effects of testosterone boosters on the SNS is limited, studies have shown that testosterone can influence sympathetic activity. In a prospective study with 344 patients under treatment with SSRIs for psychiatric illness, a delay in ejaculatory time was found in 46 to 59% of cases (47). Dapoxetine is an Serotonin Selective Reuptake Inhibitor (SSRI) with fast onset of action and short duration (maximum blood levels reached after one hour and half and clearance of 95% ate 24 hours) comparing to other SSRIs (Table 5) (45). A further study could examine the effect of estradiol and progesterone on sound-induced vasoconstriction and its interaction with the effect of testosterone and cortisol by recruiting female participants and by examining the phase of their menstrual cycle on the day of the experiment. These results suggest that the testosterone/cortisol ratio can explain the cardiovascular activation induced by the approaching sound stimuli more efficiently than testosterone alone and cortisol alone. Taken together, the testosterone/cortisol ratio is an index of responsivity to environmental stimuli through the amygdala activity. Regardless of the complexity of the control of the HR, the sound stimuli used in this study induce HR reduction only (Ooishi and Kashino, 2012), which means that it is impossible to extract the effect of the sympathetic control of the HR. These results suggest that although sound-induced vasoconstriction is affected by testosterone within participants, the testosterone/cortisol ratio has the largest correlation with the sound-induced vasoconstriction both within participants and between participants. Interestingly, the correlation between sound-induced vasoconstriction and the salivary cortisol level, testosterone level, or testosterone/cortisol ratio is different for within-subject analysis and between-subject analysis. This is the first report demonstrating the relationship between the testosterone/cortisol ratio and the strength of sound-induced vasoconstriction.
