Petri Haapalahti

Evidence for a role of hot flushes in vascular function in recently postmenopausal women.

OBJECTIVE: Observational studies indicate that postmenopausal hormone therapy (HT) prevents cardiovascular disease, but randomized clinical trials have not confirmed this effect. Hot flushes were more likely to be present in women starting HT in observational studies, whereas these symptoms were mild or absent among women attending randomized clinical trials. We hypothesized that vascular function may differ in women with and without vasomotor hot flushes. METHODS: One hundred forty-three recently postmenopausal women showing a broad range of variation in hot flushes were studied with radial artery tonometry. Pulse wave analyses were assessed at baseline and after nitroglycerin and salbutamol challenges. Wilcoxon signed rank test was used for paired comparisons after challenges with nitroglycerin and salbutamol. RESULTS: Neither baseline arterial stiffness nor endothelial function differed between women without or with mild, moderate, or severe hot flushes. However, after nitroglycerin challenge, the time to the onset of the reflected wave (dependent on pulse wave velocity) was 9.5% longer (P=.014), and the time to the first systolic peak (dependent on the rapid phase of ventricular ejection) was 13.9% longer (P=.025) in women with severe hot flushes as compared with asymptomatic women. CONCLUSION: Women with severe vasomotor hot flushes show greater vascular responsiveness to nitroglycerin than women without hot flushes. This may partially explain the conflicting data between observational and randomized HT studies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www. clinicaltrials.gov, NCT00668603 LEVEL OF EVIDENCE: II

Association between vasomotor hot flashes and heart rate variability in recently postmenopausal women.

Objective: The aim of this study was to investigate whether cardiovascular autonomic reactivity and risk profile are associated with the frequency and severity of hot flashes in recently postmenopausal women. Methods: A total of 150 postmenopausal women with varying degrees of severity of hot flashes (none, mild, moderate, or severe) underwent 24-hour electrocardiographic recording. The function of the autonomic nervous system was assessed via heart rate variability in time and frequency domains. The effects of hot flashes on cardiac autonomic function were studied by assessing heart rate variability in the presence and absence of symptoms. Results: There were no differences in mean heart rate, heart rate extremes, or total number of ectopic beats between women without and women with mild, moderate, or severe hot flashes. However, most women (14/17, 82%) with frequent ventricular ectopic beats and all women with ventricular runs belonged to the symptomatic groups. Although there were no differences in 24-hour or nighttime heart rate variability between the study groups, the very-low-frequency spectral component of heart rate variability increased by 72% (P < 0.001) during the hot flash period compared with the control period and was accompanied by an increase in heart rate (3%; P < 0.001). Conclusions: Cardiovascular risk markers based on heart rate variability failed to show an association with the frequency and severity of hot flashes in recently postmenopausal women. However, during a hot flash episode, there were signs of altered autonomic control of heart rate, which may be involved in the regulatory mechanisms of hot flashes.

Effect of Hot Flushes on Vascular Function: A Randomized Controlled Trial

OBJECTIVE: To compare the vascular responses to hormone therapy in women with and without hot flushes. METHODS: We randomly assigned 143 healthy, recently postmenopausal women (mean age 52.4±0.2 years, time since menopause 19.5±0.9 months) with intolerable hot flushes (more than seven moderate/severe episodes per day) or tolerable hot flushes (fewer than three mild episodes per day) to receive 1 mg of transdermal estradiol gel, oral estradiol (2 mg) with and without daily medroxyprogesterone acetate, or placebo for 6 months. Vascular function was assessed by pulse–wave analysis and endothelial function testing with nitroglycerin and salbutamol challenges. RESULTS: Hot flushes did not affect the changes in arterial or aortic stiffness or endothelial function in response to various forms of hormone therapy. However, in women with tolerable hot flushes, oral estrdiol caused a decrease of 13.2% (P=.028) in the time to the first systolic peak (dependent on the rapid phase of ventricular ejection) after nitroglycerin. In addition, the time to the reflected wave (dependent on pulse–wave velocity) after nitroglycerin was decreased by 8.4% (P=.018). These effects were not seen in women with intolerable hot flushes or with the other treatment regimens. CONCLUSION: Women without troublesome hot flushes are susceptible to unfavorable vascular effects after oral estrogen treatment, resulting in less compliant vasculature. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00668603. LEVEL OF EVIDENCE: I

Vasomotor hot flashes and heart rate variability: a placebo-controlled trial of postmenopausal hormone therapy.

ObjectiveThe aim of the study was to compare the responses of heart rate variability (HRV) with hormone therapy in recently postmenopausal women with and without vasomotor hot flashes. MethodsSeventy-two women with and 78 women without hot flashes were randomized to receive transdermal estradiol gel (1 g/day), oral estradiol alone (2 mg/day), oral estradiol combined with medroxyprogesterone acetate (MPA; 5 mg/day), or placebo for 6 months. Time- and frequency-domain measures of HRV were assessed using 24-hour electrocardiographic recordings at baseline and after hormone therapy. ResultsAt baseline, the cardiac variables were similar in women with and without hot flashes. In women with hot flashes, the mean 24-hour heart rate and nighttime heart rate showed a tendency toward reduction in estradiol-only users compared with those taking placebo and those taking estradiol combined with MPA. In women with hot flashes, oral estradiol versus transdermal estradiol reduced nighttime HRV in the time domain (triangular index, −27 ± 36 vs +8 ± 36, P = 0.042). In women without hot flashes, the use of oral estradiol with MPA reduced time-domain HRV (SD of all normal-to-normal intervals; −11 ± 13 ms, P = 0.048, and square root of the mean of the sum of the squares of differences between adjacent normal-to-normal intervals; −6 ± 8 ms, P = 0.036). The women with hot flashes had more supraventricular ectopic beats when using oral estradiol with MPA than when using oral estradiol only (71 ± 128 vs 12 ± 11, P = 0.018). ConclusionsOral estrogen, especially when combined with MPA, may have adverse effects on HRV in women with and without hot flashes, whereas transdermal estradiol showed no such effects. Furthermore, women with hot flashes receiving oral estrogen combined with MPA are possibly more prone to cardiac arrhythmias than are women using estrogen only.

Magnetic-Stimulation-Related Physiological Artifacts in Hemodynamic Near-Infrared Spectroscopy Signals

Hemodynamic responses evoked by transcranial magnetic stimulation (TMS) can be measured with near-infrared spectroscopy (NIRS). This study demonstrates that cerebral neuronal activity is not their sole contributor. We compared bilateral NIRS responses following brain stimulation to those from the shoulders evoked by shoulder stimulation and contrasted them with changes in circulatory parameters. The left primary motor cortex of ten subjects was stimulated with 8-s repetitive TMS trains at 0.5, 1, and 2 Hz at an intensity of 75% of the resting motor threshold. Hemoglobin concentration changes were measured with NIRS on the stimulated and contralateral hemispheres. The photoplethysmograph (PPG) amplitude and heart rate were recorded as well. The left shoulder of ten other subjects was stimulated with the same protocol while the hemoglobin concentration changes in both shoulders were measured. In addition to PPG amplitude and heart rate, the pulse transit time was recorded. The brain stimulation reduced the total hemoglobin concentration (HbT) on the stimulated and contralateral hemispheres. The shoulder stimulation reduced HbT on the stimulated shoulder but increased it contralaterally. The waveforms of the HbT responses on the stimulated hemisphere and shoulder correlated strongly with each other (r = 0.65–0.87). All circulatory parameters were also affected. The results suggest that the TMS-evoked NIRS signal includes components that do not result directly from cerebral neuronal activity. These components arise from local effects of TMS on the vasculature. Also global circulatory effects due to arousal may affect the responses. Thus, studies involving TMS-evoked NIRS responses should be carefully controlled for physiological artifacts and effective artifact removal methods are needed to draw inferences about TMS-evoked brain activity.

Cardiovascular autonomic responsiveness in postmenopausal women with and without hot flushes

OBJECTIVES During menopausal transition autonomic balance is known to shift towards sympathetic dominance, but the role of vasomotor hot flushes in this phenomenon is not understood. We compared cardiovascular autonomic responsiveness between women with and without hot flushes. STUDY DESIGN AND MAIN OUTCOME MEASURES One hundred fifty recently postmenopausal healthy women with varying degree of hot flushes (none, mild, moderate, severe) underwent comprehensive cardiovascular autonomic nervous testing (controlled and deep breathing, active orthostatic test, Valsalva manoeuvre and handgrip test) assessing both sympathetic and parasympathetic activity. The responses of heart rate, heart rate variability and blood pressure in these tests were evaluated. RESULTS Responses in heart rate showed differences between the study groups only in the Valsalva manoeuvre where the tachycardia ratio in all symptomatic women was lower (p=0.041) than in women without hot flushes. Neither change in the heart rate variability analyses nor the blood pressure responses were affected by hot flush status. However, there was a non-significantly higher maximum systolic (140 (112-182)mmHg vs. 135 (102-208)mmHg) and diastolic blood pressure (94 (72-112)mmHg vs. 90 (66-122)mmHg) following the handgrip test in women without hot flushes vs. all the symptomatic women. CONCLUSIONS Menopausal hot flushes seem to be associated with a possibly increased sympathetic preponderance without an effect on parasympathetic activity in cardiovascular autonomic responses. This may imply a potentially negative impact on cardiovascular health in women experiencing hot flushes.

Vasomotor hot flushes and 24-hour ambulatory blood pressure in recently post-menopausal women

Abstract Background. Menopausal hot flushes may be a marker for a difference in vascular function. We studied the associations between hot flushes of varying severity and ambulatory blood pressure (BP) and heart rate (HR). Methods. A total of 147 women with onset of menopause within the preceding 6–36 months reported no hot flushes (n = 23) or mild (n = 33), moderate (n = 30), or severe (n = 61). Ambulatory BP and HR were registered for 24 hours. The variables, analyzed separately for day-time and night-time, were compared among the four study groups. Results. Hot flushes failed to show any relationship to mean day- or night-time BP, nocturnal dipping of BP, or HR. However, severe night-time hot flushes were accompanied by elevations in systolic BP (4.1 ± 10.5 mmHg, P = 0.061), diastolic BP (3.1 ± 6.8 mmHg, P = 0.032), and heart rate (3.0 ± 7.2 beats/minute, P = 0.043). Conclusion. Hot flushes are not associated with ambulatory BP or heart rate in normotensive, recently post-menopausal women, although severe night-time hot flush episodes are followed by significant elevations in BP and heart rate. The latter may be of clinical significance.

Vasomotor hot flushes and 24-hour ambulatory blood pressure in normotensive women: A placebo-controlled trial on post-menopausal hormone therapy.

Abstract Background. Blood pressure (BP) is one of the most powerful determinants of cardiovascular risk in women. This risk may differ between post-menopausal women with and without vasomotor hot flushes, possibly indicating different vascular responses to hormone therapy (HT). Thus, we compared in a clinical trial the effect of HT on ambulatory BP in normotensive, recently post-menopausal women with or without severe hot flushes. Methods. A total of 147 women recorded prospectively their hot flushes for 2 weeks; 70 women were symptomatic (≥7 moderate/severe hot flush episodes/day), whereas 77 women were defined as asymptomatic (≤3 mild hot flush episodes/day). Women were treated for 6 months with either transdermal estradiol, oral estradiol with or without medroxyprogesterone acetate, or placebo. Results. In symptomatic women decreases in BPs were seen during estradiol use. In contrast, in asymptomatic women receiving oral but not transdermal estradiol, increases in 24-h and day-time systolic and diastolic BPs were encountered. Conclusion. Hot flushes modify the HT-mediated responses in ambulatory BP. In asymptomatic women oral but not transdermal estradiol show potentially harmful cardiovascular effect by increasing BP. Our results give additional justification to prescribing HT primarily for the treatment of troublesome hot flushes and avoiding HT in women without vasomotor symptoms.

Effect of hot flushes on cardiovascular autonomic responsiveness: A randomized controlled trial on hormone therapy

OBJECTIVES To compare the responses of heart rate and blood pressure to various autonomic tests in women with and without pre-treatment hot flushes during estradiol and estradiol+medroxyprogesterone acetate (MPA) use. STUDY DESIGN AND MAIN OUTCOME MEASURES Hundred and fifty recently postmenopausal women (72 with and 78 without hot flushes) were randomized to receive transdermal estradiol (1mg/day), oral estradiol (2 mg/day) alone or in combination with MPA (5mg/day), or placebo for six months. Cardiovascular responsiveness was comprehensively assessed with controlled and deep breathing, active orthostatic test, Valsalva maneuver and handgrip test. RESULTS Hot flushes were accompanied with a significant reduction (-2.2±0.7 vs. 1.3±1.1 beats/min, p=0.03) in resting heart rate during estradiol-only treatment; the route of estradiol administration was no factor in this regard. This effect was attenuated by the addition of MPA to oral estradiol. Hot flushes were also associated with reduced maximal heart rate in response to handgrip during the use of estradiol-only therapy (-2.2±1.3 vs. 2.8±1.5 beats/min, p=0.038); again, the MPA addition eliminated this effect. Hot flushes were accompanied with lowered resting but augmented blood pressure responses to handgrip test during all hormone regimens, whereas in women without hot flushes estradiol-only regimen tended to elevate diastolic resting blood pressure. CONCLUSIONS Hot flushes appear as determinants for cardiovascular responses to hormone therapy. Estradiol-only therapy causes beneficial changes in cardiovascular regulation in flushing women, and these are blunted, in part, by the addition of MPA.

Premenstrual symptoms in fertile age are associated with impaired quality of life, but not hot flashes, in recently postmenopausal women.

ObjectiveBecause premenstrual symptoms in fertile age resemble menopausal symptoms, many women with premenstrual symptoms fear that they have an increased risk for developing vasomotor symptoms in menopause. We investigated the impact of premenstrual symptoms on the occurrence and severity of menopausal vasomotor symptoms and quality of life. MethodsOne hundred fifty recently postmenopausal healthy women recorded hot flashes prospectively (23, none; 34, mild; 30, moderate; 63, severe), and their quality of life was assessed using the Women’s Health Questionnaire. We measured the occurrence of premenstrual symptoms in fertile age using the Premenstrual Symptoms Screening Tool and calculated a premenstrual score reflecting symptom severity. ResultsOne hundred seven women (89.2%) reported premenstrual symptoms (median score, 7.0; range, 0-38), which had impaired work efficiency or social relations in 64 women (53.3%). The occurrence of premenstrual symptoms was similar in women with and without hot flashes of different magnitudes, as the mean (SEM) premenstrual score was 7.8 (1.4) for no hot flashes, 5.0 (1.0) for mild hot flashes, 7.7 (1.3) for moderate hot flashes, and 9.4 (1.2) for severe hot flashes (P = 0.10). The severity of premenstrual symptoms failed to correlate with the severity of postmenopausal hot flashes (r = 0.087, P = 0.346). A history of premenstrual symptoms was associated with impaired memory and concentration capacity (r = −0.448, P < 0.001), depressive mood (r = −0.263, P = 0.02), sleep problems (r = −0.282, P = 0.01), and feeling less attractive (r = −0.260, P = 0.02) during the first menopausal years. ConclusionsThe occurrence of premenstrual symptoms in fertile age is associated with impaired quality of life, but not hot flashes, in recently postmenopausal women.