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Women have smaller cortisol responses to psychological stress than men do, and women taking hormonal contraceptives (HC+) have smaller responses than HC- women. Cortisol secretion undergoes substantial diurnal variation, with elevated levels in the morning and lower levels in the afternoon, and these variations are accompanied by differences in response to acute stress. However, the impact of HC use on these diurnal relationships has not been examined. We tested saliva cortisol values in 744 healthy young adults, 351 men and 393 women, 254 HC- and 139 HC+, who were assigned to morning (9:00 am) or afternoon (1:00 pm) test sessions that were held both on a rest day and on a stress day that included public speaking and mental arithmetic challenges. Saliva cortisol responses to stress were largest in men and progressively smaller in HC- and in HC+ women (F = 23.26, p < .0001). In the morning test sessions, HC+ women had significantly elevated rest day cortisol levels (t = 5.99, p ≪ .0001, Cohen's d = 0.95) along with a complete absence of response on the stress day. In the afternoon sessions, both HC+ and HC- women had normal rest-day cortisol levels and normal responses to the stressors. Heart rates at rest and during stress did not vary by time of day or HC status. Cortisol stress responses in HC+ women are absent in the morning and normal in size by early afternoon. Studies of stress reactivity should account for time of day in evaluating cortisol responses in women using hormonal contraceptives.

Early life adversity (ELA) contributes to behavioral impulsivity along with risk for substance use disorders, both accompanied by blunted stress-axis reactivity. However, the biological contributors to blunted stress reactivity are not known. We took advantage of the fact that women have significant opioid inhibition of cortisol output by using the opioid antagonist, naltrexone, to unmask opioid interactions due to ELA. We administered 50 mg of naltrexone or placebo to 72 healthy women (23 years of age) in a double-blind crossover study and observed deviations in cortisol secretion from placebo over the next 180 minutes. ELA was assessed by reported exposure to physical and sexual abuse or neglect and low socioeconomic status and scored as Low, Medium, or High (0, 1-2, and 3+). The ELA groups all had identical placebo-day cortisol secretion, indicating normal basal regulation of the hypothalamic-pituitary-adrenocortical axis. Cortisol rises to naltrexone were largest in the Low-ELA group and strongly blunted in the High-ELA group (F = 3.51, p = 0.035), indicating a lack of opioid function in women with high degrees of ELA. The Low-ELA women reported dysphoric responses to naltrexone (F = 4.05, p = .022) indicating a mild opioid withdrawal, an effect that was absent in the High-ELA group. Women exposed to ELA have blunted cortisol responses to naltrexone, indicating reduced opioid regulation of the stress axis. Central opioid changes may be one pathway linking ELA to blunted stress reactivity in adulthood., Competing Interests: The authors have declared that no competing interest exists.

Objective: Exposure to stress during critical periods of development can diminish stress reactivity by the hypothalamic-pituitary-adrenocortical axis. Genetic characteristics may further modify this effect of early adversity, leading to a gene by environment (G × E) interaction on stress reactivity in adulthood. Val-allele carriers of a common polymorphism of the COMT gene (Val158Met, rs4680) have rapid removal of catecholamines in the prefrontal cortex, limbic system, and reward centers. Carriers of the Val and Met alleles may therefore respond differently to the environment and differ in the long-term impact of exposure to early life adversity (ELA)., Methods: We measured saliva cortisol reactivity to public speaking and mental arithmetic stress in 252 healthy young adults exposed to low, medium, and high levels of ELA and who were genotyped for the Val158Met polymorphism., Results: Cortisol responses showed a G × E interaction (F(4,243) = 2.78, p = .028); simple effects tests showed that Met/Met carriers had progressively smaller cortisol responses with greater levels of ELA. In comparison, Val/Val homozygotes had blunted responses that did not vary with ELA exposure., Conclusions: Met/Met homozygotes seem sensitive to stressful events in childhood and adolescence, leading to environmental programming of the stress axis. Glucocorticoid responsivity may represent a common pathway revealing targeted genetic vulnerabilities to the long-term effects of early life stress. The results suggest that further G × E studies of ELA are warranted in relation to health behaviors and health outcomes in adulthood.

Differences in stress reactivity may affect long-term health outcomes, but there is little information on how these differences arise. The stress axis is regulated by, in part, the endogenous opioid, beta-endorphin, acting on mu-opioid receptors. Persons carrying one or two copies of the G allele of the mu-opioid receptor gene (OPRM1 A118G) may have higher receptor binding for beta-endorphin compared with AA homozygotes that may contribute to individual differences in cortisol reactivity to stress, leading to a relative blunting of cortisol stress reactivity in G allele genotypes. We measured cortisol in 251 young adults (69 GA/GG vs 182 AA genotypes) exposed to mental arithmetic plus public speaking stress relative to a resting control day. Women had smaller cortisol responses than men (F=10.2, p=0.002), and women with GA or GG genotypes (N=39) had an absence of cortisol response relative to AA carriers (N=110) (F=18.4, p<0.0001). Male genotypes had no such difference in response (F=0.29). Cortisol response following mu-opioid receptor blockade using naltrexone in 119 of these subjects unmasked a greater tonic opioid inhibition of cortisol secretion in women (N=64), consistent with their blunted stress reactivity. Compared with men, women may have cortisol stress responses that are more heavily regulated by endogenous opioid mechanisms, and the OPRM1 GA/GG genotypes may affect females differentially relative to males. Diminished cortisol responses to stress may have consequences for health behaviors in women with GA/GG genotypes.

Naltrexone evokes a cortisol response through its blockade of central opioid receptors on the hypothalamic-pituitary-adrenocortical axis (HPA). The magnitude of this cortisol response may be useful as a probe for central opioid activity in different groups of subjects. Accordingly, the present study examined the effect of opioid blockade on the HPA in 70 women and 58 men with (N=41) and without (N=87) a family history of alcoholism, using a randomized, placebo-controlled, double blind administration of oral naltrexone (50mg). Saliva cortisol was sampled at baseline prior to placebo or naltrexone and again every 30 min over the next 180 min. Women had significantly larger cortisol responses to naltrexone than did the men, F=6.88, p<0.0001. There were no significant differences in cortisol response between groups differing in family history of alcoholism, F=0.65, p>0.69. The present results confirm that women have much greater central opioid restraint on the HPA than men do and that this endogenous restraint is unmasked by opioid blockade. However the results provide no evidence of a differential central opioid tonus in persons with a family history of alcoholism at this dose of naltrexone. The cortisol response to naltrexone may be a useful probe for central opioid activity in women and to a lesser degree in men., (Published by Elsevier Ltd.)

In laboratory studies of individual differences in stress reactivity, cortisol responses are typically measured by comparing a prestress baseline with values obtained at the end of the stressor. In the present study, we measured cortisol in this manner on a stress day, but we also took samples on a second day when the volunteers rested in the lab at the same time of day and for the same duration. We compared stress responses as the difference from pre- to poststress and also poststress vs. rest day control. The latter method allowed a greater appreciation of how stress perturbed the underlying diurnal baseline. Although the effect of stress was statistically significant when measured as the change from pre- to poststress, the magnitude of the effect was 54% larger when measured against the time-of-day control from the rest day. In particular the diurnal control method provided a wider range of stress values that potentially provide a greater range of response values in carrying out analyses of individual differences., (Published by Elsevier Ltd.)

Caffeine elevates cortisol secretion, and caffeine is often consumed in conjunction with exercise or mental stress. The interactions of caffeine and stress on cortisol secretion have not been explored adequately in women. We measured cortisol levels at eight times on days when healthy men and women consumed caffeine (250 mg x 3) and underwent either mental stress or dynamic exercise protocols, followed by a midday meal, in a double blind, placebo-controlled, crossover design. Men and women had similar cortisol levels at the predrug baselines, but they responded differently to mental stress and exercise. The cortisol response to mental stress was smaller in women than in men (p=.003). Caffeine acted in concert with mental stress to further increase cortisol levels (p=.011), the effect was similar in men and women. Exercise alone did not increase cortisol, but caffeine taken before exercise elevated cortisol in both men and women (ps<.05). After a postexercise meal, the women had a larger cortisol response than the men, and this effect was greater after caffeine (p<.01). Cortisol release in response to stress and caffeine therefore appears to be a function of the type of stressor and the sex of the subject. However, repeated caffeine doses increased cortisol levels across the test day without regard to the sex of the subject or type of stressor employed (p<.00001). Caffeine may elevate cortisol by stimulating the central nervous system in men but may interact with peripheral metabolic mechanisms in women.

Objective: Caffeine increases cortisol secretion in people at rest or undergoing mental stress. It is not known whether tolerance develops in this response with daily intake of caffeine in the diet. We therefore tested the cortisol response to caffeine challenge after controlled levels of caffeine intake., Methods: Men (N = 48) and women (N = 48) completed a double-blind, crossover trial conducted over 4 weeks. On each week, subjects abstained for 5 days from dietary caffeine and instead took capsules totaling 0 mg, 300 mg, and 600 mg/day in 3 divided doses. On day 6, they took capsules with either 0 mg or 250 mg at 9:00 AM, 1:00 PM, and 6:00 PM, and cortisol was sampled from saliva collected at 8 times from 7:30 AM to 7:00 PM., Results: After 5 days of caffeine abstinence, caffeine challenge doses caused a robust increase in cortisol across the test day (p < .0001). In contrast, 5 days of caffeine intake at 300 mg/day and 600 mg/day abolished the cortisol response to the initial 9:00 AM caffeine dose, although cortisol levels were again elevated between 1:00 PM and 7:00 PM (p = .02 to .002) after the second caffeine dose taken at 1:00 PM. Cortisol levels declined to control levels during the evening sampling period., Conclusion: Cortisol responses to caffeine are reduced, but not eliminated, in healthy young men and women who consume caffeine on a daily basis.

Women have smaller cortisol responses to psychological stress than men do, and women taking hormonal contraceptives (HC+) have smaller responses than HC− women. Cortisol secretion undergoes substantial diurnal variation, with elevated levels in the morning and lower levels in the afternoon, and these variations are accompanied by differences in response to acute stress. However, the impact of HC use on these diurnal relationships has not been examined. We tested saliva cortisol values in 744 healthy young adults, 351 men and 393 women, 254 HC− and 139 HC+, who were assigned to morning (9:00 am) or afternoon (1:00 pm) test sessions that were held both on a rest day and on a stress day that included public speaking and mental arithmetic challenges. Saliva cortisol responses to stress were largest in men and progressively smaller in HC− and in HC+ women (F = 23.26, p <.0001). In the morning test sessions, HC+ women had significantly elevated rest day cortisol levels (t = 5.99, p ≪.0001, Cohen's d = 0.95) along with a complete absence of response on the stress day. In the afternoon sessions, both HC+ and HC− women had normal rest-day cortisol levels and normal responses to the stressors. Heart rates at rest and during stress did not vary by time of day or HC status. Cortisol stress responses in HC+ women are absent in the morning and normal in size by early afternoon. Studies of stress reactivity should account for time of day in evaluating cortisol responses in women using hormonal contraceptives. [ABSTRACT FROM AUTHOR]

Background: Risk for alcoholism may be enhanced by exposure to early‐life adversity (ELA) in persons with genetic vulnerabilities. We examined ELA in the presence of a common variant of the gene for the enzyme catechol‐O‐methyltransferase (COMT, Val158Met, rs4680) in relation to cortisol reactivity, the onset of early drinking, and experimentation with drugs. Methods: Saliva cortisol reactivity to speech and mental arithmetic stress was measured in 480 healthy young adults (23.5 years of age, 50% females) who experienced either 0, 1, or ≥ 2 forms of ELA during childhood and adolescence, provided information on use of alcohol and recreational drugs, and were genotyped for the Val158Met polymorphism. Results: ELA led to progressively smaller cortisol responses in the Met/Met and Val/Met allele groups but to progressively larger responses in Val homozygotes, F = 3.29, p = 0.011. ELA independently predicted earlier age at first drink, F = 14.2, p < 0.0001, with a larger effect in Met‐allele carriers, F = 13.95, p < 0.00001, and a smaller effect in Val homozygotes, F = 4.14, p = 0.02. Similar effects were seen in recreational drug use. Cortisol reactivity was unrelated to drinking behavior or drug experimentation. Conclusions: ELA leads to blunted stress reactivity and, independently, contributes to potentially risky drinking and drug‐use behaviors in persons carrying 1 or 2 copies of the COMT 158Met allele. The results reinforce the impact of early experience on the stress axis and on risky behaviors, and they point to the 158Met allele as conveying a vulnerability to the early environment. [ABSTRACT FROM AUTHOR]

Background and aims: People with blunted stress reactivity have poor impulse control and also show increased risk for alcoholism. Exposure to early life adversity (ELA) contributes to blunted reactivity, but individual differences in susceptibility to ELA are not well understood. This study aimed to determine whether exposure to ELA has a greater impact on stress reactivity in young adults with a family history of alcoholism (FH+) compared with young adults with no family history of alcoholism (FH–). Design Observational study using linear modeling. Setting: Oklahoma, USA. Participants: Seven hundred and nine young adults (398 females) recruited through community advertisement. Measurements We obtained heart rates and cortisol levels in subjects while undergoing public speaking and mental arithmetic stress compared with a resting control day (1418 test sessions). ELA was quantified as 0, 1 or > 1 adverse events experienced by age 15 years. FH+ people had one or two parents with an alcohol use disorder, and FH– controls had no such history for two generations. Findings Increasing levels of ELA predicted progressive blunting of cortisol and heart rate reactivity for the whole sample (Fs = 4.57 and 4.70, Ps ≤ 0.011), but examination by FH status showed that the effect of ELA was significant only among FH+ (Fs ≥ 3.5, Ps < 0.05) and absent in FH– (Ps > 0.40). This difference in ELA impact was not explained by the cortisol diurnal cycle or subjective evaluation of the stressors. Conclusions: People with a family history of alcoholism appear to be vulnerable, in terms of changes to physiological stress response, to the impact of exposure to early life adversity while people with no family history of alcoholism appear to be resilient. Blunted stress reactivity may reflect differential vulnerability to early life adversity in young adults with a family history of alcoholism. [ABSTRACT FROM AUTHOR]

Abstract: Abstinent alcoholics show a blunted stress cortisol response that may be a consequence of drinking or a preexisting risk marker. We tested cortisol responses to psychological stress in 186 18–30 year-old, healthy social drinkers having no personal history of alcohol or drug dependence, 91 of whom had one or two alcoholic parents (FH+) and 95 having no family alcoholism for two generations (FH−). We predicted that, similar to alcoholic patients, the FH+ would have reduced stress cortisol responses that would be partially determined by their temperament characteristics, specifically antisocial tendencies as measured by the California Psychological Inventory. On a stress day, subjects performed continuous simulated public speaking and mental arithmetic tasks for 45 min, and on a control day they sat and rested for the same time period. The FH+ who were low in sociability had smaller cortisol responses than FH−, high-sociability persons (t =2.27, p =.02). These two groups were not different in diurnal cortisol secretion patterns or affective responses to the stressors. Persons with a familial risk for alcoholism who have more antisocial tendencies may have altered central nervous system responses to emotionally relevant social challenges. Disrupted cortisol stress responses may serve as a risk marker for the development of substance use disorders. [Copyright &y& Elsevier]