Autonomic function in women across the menopausal transition
Date
2025
Authors
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Publisher
University of Delaware
Abstract
Women experience an accelerated rise in blood pressure (BP) and cardiovascular (CV) disease risk with age compared to men, an interaction which appears to occur around the time of the menopausal transition. The autonomic nervous system tightly controls CV function, in part through the arterial baroreflex and sympathetic nervous system activity (SNA). SNA is generated in the medulla oblongata but is also influenced by higher brain regions, such as the insula, amygdala, and prefrontal cortex. SNA directly increases BP and age-related elevations in SNA contribute to elevations in BP. Interestingly, resting SNA increases more sharply with age in women than in men, mirroring the sex difference in the age-related increase in BP. The acute increases in both BP and SNA with handgrip exercise are greater in postmenopausal (POST) women compared to premenopausal women (PRE). This exaggerated pressor response is associated with increased risk of CV events and is therefore clinically relevant. However, no studies measuring autonomic CV regulation have included women just prior to menopause (perimenopausal women; PERI). Accordingly, the central hypothesis was that the menopausal transition promotes activity in central sympathetic brain regions which mediate augmented BP reactivity, SNA reactivity, and sympathetic baroreflex sensitivity as well as a reduction in cardiovagal baroreflex sensitivity. Methods: The central hypothesis was tested using 2 protocols; one in the laboratory for measurement of BP reactivity, SNA reactivity, and baroreflex sensitivity, and one in the MRI for measurement of central autonomic activity in autonomic brain regions using BOLD fMRI. In the laboratory study, we measured beat-to-beat BP and MSNA in response to sympathetic perturbations including handgrip exercise, post-exercise ischemia, the cold pressor test, and the Valsalva maneuver in PRE and PERI. In the MRI study, we used blood oxygen level dependent (BOLD) functional MRI (fMRI) to measure the BOLD signal intensity change in central autonomic brain regions in response to handgrip exercise in PRE, PERI, and POST. Results: Changes in mean arterial pressure in response to handgrip exercise (PRE 11 ± 5 vs. PERI 13 ± 8 mm Hg, P = 0.43), post-exercise ischemia (PRE 10 ± 5 vs. PERI 12 ± 8 mm Hg, P = 0.45), and the cold pressor test (PRE 18 ± 8 vs. PERI 18 ± 11 mm Hg, P = 0.95) did not significantly differ between PRE and PERI. Resting MSNA burst frequency was significantly higher in PERI compared to PRE (PRE 12 ± 5 vs. PERI 19 ± 9 bursts/min, P < 0.05). There was a significantly greater increase in MSNA burst frequency (PRE 5 ± 4 vs. PERI 14 ± 6 bursts/min, P < 0.01) in response to handgrip exercise in PERI relative to PRE, while responses to post-exercise ischemia (PRE 5 ± 3 vs. PERI 4 ± 5 bursts/min, P = 0.91) and the cold pressor test (PRE 12 ± 12 vs. PERI 14 ± 9 bursts/min, P = 0.80) did not differ between groups. Spontaneous cardiovagal baroreflex sensitivity (PRE 27 ± 10 vs. PERI 13 ± 5 ms/mm Hg, P < 0.0001) and cardiovagal baroreflex sensitivity during phase IV of the Valsalva maneuver (PRE 14 ± 7 vs. PERI 7 ± 4 ms/mm Hg, P < 0.05) were significantly lower in PERI compared to PRE, whereas cardiovagal baroreflex sensitivity during phase II of the Valsalva maneuver (PRE 8 ± 3 vs. PERI 6 ± 5 ms/mm Hg, P = 0.13) did not significantly differ between groups. Spontaneous sympathetic baroreflex sensitivity (PRE -4.0 ± 2.7 vs. PERI -3.8 ± 1.5 bursts/100 heart beats/mm Hg, P = 0.85), as well as sympathetic baroreflex sensitivity during the Valsalva maneuver (PRE -0.4 ± 0.2 vs. PERI -0.6 ± 0.3 bursts/15 sec/mm Hg, P = 0.13), did not significantly differ between PRE and PERI. During BOLD fMRI, handgrip exercise elicited significant increases in BOLD signal intensity change in the bilateral supramedullary autonomic regions of the amygdala, insula, and vmPFC, as well as in medullary autonomic regions of the NTS and RVLM, in PRE, PERI, and POST. Significant interactions between the main effects of time and menopausal group were found with the BOLD signal intensity changes in the left amygdala (Interaction: P < 0.05), left insula (Interaction: P < 0.05), and left RVLM (Interaction: P < 0.01). Post-hoc tests revealed greater left insula BOLD signal intensity changes at 90 and 100 seconds of HG in POST relative to PERI, while no significant post-hoc tests were observed with the left amygdala or left RVLM. Lastly, the average BOLD signal intensity change in the left insula during the last minute of handgrip exercise significantly differed across menopausal groups (Interaction: P < 0.05), although no significant post-hoc tests were found. Conclusion: These data demonstrate that PERI exhibit exaggerated sympathetic reactivity to HG relative to PRE, extending the timeframe for augmented sympathetic reactivity to earlier in the menopausal transition and/or aging process, with no apparent group difference in BP reactivity. PERI also exhibit attenuated cvBRS relative to PRE with no apparent difference in sBRS. These findings extend the decline in cvBRS to earlier in the menopausal transition and/or aging process than previously described, but suggest that the decline in sBRS in women may not be apparent until postmenopause. Finally, evidence for differential BOLD responses to handgrip exercise across menopausal groups was observed in the left amygdala, left insula, and left RVLM. These findings suggest that the menopausal transition and/or aging may alter both supramedullary and medullary central autonomic regulation during sympathoexcitation in women.
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Keywords
Autonomic, Cardiovascular, Menopause, Sympathetic