تفاوت های جنسیتی در تغییرات وابسته به سن در محور HPA واکنش پذیری

Abstract Possible differences between men and women in age-related patterns of hypothalamic–pituitary–adrenal (HPA) axis response to challenge were examined to test the hypothesis that women show greater age-related increase in HPA axis reactivity to challenge. Twenty-six younger subjects, 9 men and 17 women, ages 22–26 and 14 older subjects, 7 men and 7 women, ages 67–88 participated in the study. Patterns of change in salivary “free” cortisol were measured in response to a standardized, 30-minute cognitive challenge, administered individually to each subject beginning at 1600 h. Consistent with previous research, there was a significant main effect for age with respect to baseline cortisol: older age was associated with higher baseline cortisol (P=<0.001). Results also provide support for the hypothesized age-by-gender interaction with respect to patterns of response to challenge. There was a significant interaction with respect to maximum percentage increase over baseline (P<0.002): among younger adults, the men exhibited greater increases whereas among the older adults, the women exhibited greater increases. A similar, though only marginally significant pattern was seen for total area under the response curve (P=0.07). Repeated measures ANOVA confirmed the gender-by-age differences in the patterns of response (P=0.01 for time*age*gender interaction).

. Introduction Gender differences in morbidity and mortality remain a topic of considerable research interest. Although women enjoy greater longevity (Verbrugge and Wingard, 1987), their relative protection against major causes of morbidity and mortality such as heart disease is greatly reduced post-menopause (Greendale et al., 1999). Though there has been considerable research directed towards understanding the sources of observed gender differences in health and longevity, much remains to be elucidated. Here, we examine the question of possible gender differences in age-related changes in hypothalamic–pituitary–adrenal (HPA) axis reactivity to challenge. Such gender differences are of interest as potential contributors to gender differences in health risks and, in particular, to the known reduction in women's relative protection against heart disease and stroke post-menopause. Specifically, we examine the hypothesis that women exhibit greater age-related increase in HPA axis reactivity, resulting in greater exposure to elevated levels of cortisol. Data on patterns of diurnal, plasma cortisol activity suggest an age-related increase in basal cortisol secretion (Deuschle et al., 1997 and van Cauter et al., 1996). Significantly, recent analyses comparing age-related changes for men versus women have suggested that women experience larger age-related increases in cortisol secretion, with postmenopausal women exhibiting shorter nocturnal nadirs, higher morning acrophase and higher overall mean 24-hr cortisols (van Cauter et al., 1996). Studies also suggest that women may experience greater age-related increase in HPA axis response to challenge. At younger ages, studies show either greater cortisol response among men (Collins and Frankenhaeuser, 1978 and Kirschbaum et al., 1992b) or no significant gender differences (Gallucci et al., 1993, Stoney et al., 1987 and Streeten et al., 1984). A number of studies of older men and postmenopausal women, however, show intriguing patterns of greater HPA axis reactivity among women in response to CRH challenge (Greenspan et al., 1993, Heuser et al., 1994 and Luisi et al., 1998) and a trend towards greater response to physostigmine, a centrally active cholinesterase inhibitor (Peskind et al., 1995). Wilkinson et al. (1997) have also reported that postmenopausal women exhibit less feedback inhibition (i.e., blunted ACTH decline) in response to cortisol infusion, post-metyrapone administration, compared with younger, pre-menopausal women and with older men. Patterns of response to psychological challenge have to date shown a more mixed picture. One study has reported greater ACTH and cortisol response among men in response to a public-speaking challenge (Kudielka et al., 1998). By contrast, we found a pattern of greater ACTH and cortisol in older women as compared with older men in response to a “driving simulation” challenge (Seeman et al., 1995). Several lines of evidence suggest the possible role of reproductive hormones such as estrogen in this apparent age-related shift towards greater relative HPA axis reactivity among postmenopausal women. First, variations in estrogen have been linked to altered reactivity — periods of higher estrogen being associated with reduced blood pressure (von Eiff et al., 1971), cardiovascular (Sita and Miller, 1996) and HPA reactivity (Bonen et al., 1991 and Marinari et al., 1976) though there are also data suggesting that this reduced reactivity may be lost in the presence of higher progesterone levels (Kirschbaum et al., 1999). Second, and more important for the postulated age-related increase in HPA reactivity in postmenopausal women, hormone replacement therapy (HRT) has been associated with reductions in blood pressure responses to challenge (Stoney, 1992) and with a blunting of cortisol responses to cognitive and physical stress tests in postmenopausal women exposed short-term (six weeks) to 17β-estradiol (Lindheim et al., 1992 and Lindheim et al., 1994). To date, however, no study has directly tested for a gender difference in age-related changes in patterns of HPA reactivity. Rather, studies have generally examined gender differences either in older adults or in younger subjects but rarely have such differences been examined for both age groups simultaneously. Also, no studies have directly tested for an age-by-gender interaction with respect to patterns of HPA axis reactivity to challenge. The study reported here was designed to assess age and gender differences in patterns of HPA axis response to a single, structured cognitive challenge. Specifically, we sought to test the hypothesis that there would be an interaction such that among younger adults the men would be more reactive while among the older adults the reverse would be true with women exhibiting greater cortisol reactivity to the cognitive challenge.

. Results Twenty-six younger subjects, 9 men and 17 women, ages 22–36 (Full-size image (<1 K)=26.1, SD=3.8), and 14 older adults, 7 men and 7 women, ages 67–88 (Full-size image (<1 K)=77.5, SD=6.1) participated in the study. Due to the strict selection criteria, there were no group differences on possible correlates of cortisol activity such as medication use or relative weight (body mass index), and no pre-existing health conditions such as diabetes or CVD in either group. There were no differences in educational attainment (Full-size image (<1 K)=16 years in both younger and older subjects; P=0.44) so education was not considered further as a covariate. Likewise, analyses of possible differences in cortisol activity by OC status did not reveal any differences so OC-use was not considered further as a covariate. The younger subjects were marginally more likely to be classified as being depressed (31% [n=8] of the young subjects vs. 7.1% [n=1] of the older subjects; χ2=2.91, P=0.09). Those classified as depressed exhibited higher baseline cortisol (Full-size image (<1 K)=0.13 ug/dl vs. Full-size image (<1 K)=0.09 ug/dl among those classified as non-depressed, t=2.17, P=0.04) and less relative increases in response to the challenge (Full-size image (<1 K)=1.31 ug/dl vs. Full-size image (<1 K)=2.03 ug/dl among those classified as non-depressed, t=2.38, P=0.02 for maximum increase). Depression was included as a control variable in subsequent analyses. All analyses were also examined with those scoring 16+ on the CESD excluded from the analyses; all results reported here were unchanged from the analyses including all subjects and controlling for depression. For baseline salivary cortisol, there was a significant main effect for age [F(1,33)=19.14, P=0.0001; with significantly higher levels seen among the older subjects (Full-size image (<1 K)=0.20 μg/dl among older subjects vs. Full-size image (<1 K)=0.11 μg/dl among the younger subjects, P<0.001). There was also a marginal age-by-gender interaction [F(1,33)=3.79, P=0.06], suggesting that this relationship deserves further exploration with larger data sets. As shown in Fig. 1, there was no significant gender difference among the younger subjects (P=0.99). However among the older subjects, the men had significantly higher baseline cortisols (Full-size image (<1 K)=0.23 μg/dl vs. 0.16 μg/dl among the women, P=0.02). Comparisons of baseline salivary cortisol levels across age and gender groupings ... Fig. 1. Comparisons of baseline salivary cortisol levels across age and gender groupings (group differences are indicated by paired symbols; ***P<0.001; +P<0.05; ∼P=0.10). Figure options With respect to cortisol reactivity to the cognitive challenge, a significant age-by-gender difference was seen for maximum increase over baseline [F(1,32)=11.70; P=0.002]. As shown in Fig. 2, planned comparisons for this interaction revealed that among the younger subjects, men exhibited a greater relative percentage increase over baseline (i.e., maximum increase/baseline) as compared with the women (Full-size image (<1 K)=264% for men vs. 112% for women, P=0.004). The reverse pattern was seen in the older group where older women exhibited greater relative increase compared with older men (Full-size image (<1 K)=228% for women vs. 88% for men, P=0.05). Comparisons of maximum increase in cortisol during the challenge session across ... Fig. 2. Comparisons of maximum increase in cortisol during the challenge session across age and gender groupings (group differences are indicated by paired symbols: *P<0.005; ∼P<0.05). Figure options Analyses of total AUC adjusted for baseline revealed a similar pattern, though the age-by-gender interaction achieves only marginal statistical significance [F(1,33)=3.52, P=0.07]. As shown in Fig. 3, younger men had greater overall response (17.5 vs. 7.8 for young women, P=0.05) whereas older women tended to show greater overall response compared with older men, though the differences in this case were not statistical significance (21.7 for the women vs. 16.2 for the men, P=0.41). There was also a non-significant trend towards greater AUC among older adults (18.9 AUC among older adults vs. 12.6 for the younger group, P=0.14). Analyses of the unadjusted AUC data (i.e., total cortisol exposure including baseline levels plus challenge responses) revealed a significant age effect [F(1,33)=7.29, P=0.01] with older adults showing a total AUC 64% larger than that seen among the younger subjects: 35.8 vs. 21.9. This latter finding is consistent with the previous findings of higher baseline cortisols among the older adults as well as marginally greater adjusted AUCs among the older adults. Comparisons of total area under the response curve across age and gender ... Fig. 3. Comparisons of total area under the response curve across age and gender groupings (group difference are indicated by paired symbols: *P=0.05; @P=0.02). Figure options Actual patterns of response were examined initially through repeated measures ANOVA. A significant time effect was found [F(8,232)=5.09, P=0.015, ε=0.20] reflecting the fact that our challenge protocol successfully elicited increases in cortisol activity. A significant time*sex*age interaction was also found [F(8,232)=5.14; P=0.01, ε=0.20]. The time trends in cortisol response underlying this interaction were further examined by plotting cortisol responses over the seven time-points beyond the baseline, defined as deviations from the baseline level for each individual. Fig. 4 shows the mean responses by gender and category of trajectory — i.e. responder or non-responder — for the young and old groups separately. Simultaneous 90% confidence intervals are shown for all groups ( Miller, 1981). Most notable is the fact that among the younger subjects, it is the men “responders” who exhibit the largest responses while among the older subjects, it is the women “responders” who exhibit the larger responses. For both age groups, the high responders — young men and older women — lie on trajectories that are separated from the non-responder trajectories from time 15 c (i.e. first challenge sample) through to time 120 r (i.e., 120 minutes after the end of challenge and the end of recovery period). The young female responders are significantly above both non responder groups from time 15 c through to time 60 r (i.e., 60 minutes into the recovery period). The older male responders are significantly above the non-responders only at times 30 r and 60 r (i.e., 30 and 60 minutes respectively into the recovery period after the conclusion of the challenge). The individual trajectories of these men show a time delay in response to challenge relative to the rapid high cortisol response of the older women who are classified as responders. (A) Salivary cortisol response to the cognitive challenge by age and gender ... Fig. 4. (A) Salivary cortisol response to the cognitive challenge by age and gender groups: deviations from baseline among younger men and women. (B) Salivary cortisol response to the cognitive challenge by age and gender groups: deviations from baseline among older men and women. Figure options Examination of the age-by-gender-specific distributions of these patterns of response vs. non-response to the challenge indicates that among the younger subjects, the men were more likely to be responders (3/4 men versus 1/9 women; χ2=5.3, P=0.02). By contrast, among the older subjects, the men and women are more comparable in their propensity to show a response to the challenge (2/6 men and 2/5 women; χ2=0.052, P=0.82). As illustrated in Fig. 4, however, the female responders among these older subjects exhibit considerably larger elevations in response to the challenge than do the male responders.