Hot flashes and sleep disruption in a randomized trial in menopausal women.

BACKGROUND: Hot flashes, common during menopause, affect up to 80% of the Western menopausal women and are reported to contribute to sleep disturbances in midlife. Few prospective data are available to confirm the specific role of hot flashes in disrupting sleep in midlife women, however, or confirm whether changes in hot flashes in response to clinical therapies result in improvement in sleep. OBJECTIVE: To examine the effects of continuous nitroglycerin therapy on sleep quality in perimenopausal and postmenopausal women with frequent hot flashes (pre-specified secondary trial endpoint) and to examine prospective associations between hot flashes and sleep disruption in this population. STUDY DESIGN: Sleep data were analyzed from a randomized, double-blinded, placebo-controlled trial of continuous transdermal nitroglycerin (NTG) therapy to suppress nitric oxide-mediated vasodilation in perimenopausal or postmenopausal women with hot flashes. Participants were randomized to uninterrupted use of transdermal NTG (0.2-0.6 mg/hour) or placebo for 12 weeks. Nocturnal hot flashes awakening participants from sleep were evaluated using 7-day symptom diaries at baseline, 5 weeks, and 12 weeks. Sleep disruption (wakefulness after sleep onset, WASO) was assessed using validated sleep diaries, and global sleep quality was assessed by the validated Pittsburgh Sleep Quality Index (PSQI: range 0 [best] 21 [worst]) questionnaire. Mixed linear models examined changes in sleep quality and disruption, as well as the strength of associations between nocturnal hot flash frequency and sleep outcomes, over 5 and 12 weeks, adjusting for baseline values, age, race, and ethnicity. RESULTS: Among the 141 participants (70 to NTG and 71 to placebo, mean age 54.6 [±3.9] years), the mean baseline hot flash frequency was 10.8 (±3.5) per day, including 2.6 (±1.7) nocturnal hot flashes awakening participants. At baseline, hot flashes were the most commonly reported reason for nocturnal awakening, with 62.6% of participants reporting waking due to hot flashes at least twice nightly. Over 5 and 12 weeks, mean frequency of nocturnal hot flashes causing awakenings decreased in both groups (NTG: -0.9 episodes/night, placebo: -1.0 episodes/night). Sleep disruption as measured by average nightly WASO also decreased (NTG: -10.1 minutes, placebo: -7.3 minutes), and mean PSQI score improved (NTG: -1.3 points, placebo: -1.2 points). No significant between-group differences in change in sleep outcomes were detected from baseline to 5 and 12 weeks, including PSQI sleep quality score as a prespecified secondary trial endpoint (P≥.05 for all). Greater improvement in nocturnal hot flash frequency over 5 and 12 weeks was associated with greater improvement in PSQI sleep quality score (ß= -0.30, P=.01) and sleep disruption reflected by WASO (ß= -1.88, P=.02) in the combined sample. CONCLUSION: Among menopausal women in a randomized trial of continuous NTG therapy for hot flashes, hot flashes were the most frequently reported cause of nocturnal awakenings. Compared to placebo, continuous NTG therapy did not result in greater improvements in sleep quality from baseline to 5 and 12 weeks. Based on night-by-night symptom diaries and questionnaires, however, greater improvement in nocturnal hot flash frequency in both groups was associated with greater improvement in sleep quality and disruption.

Beyond the bladder: poor sleep in women with overactive bladder syndrome.

BACKGROUND: Nocturnal bladder symptoms and sleep disruption commonly coexist in middle-aged and older women. Although sleep disruption is often attributed to nocturnal bladder symptoms in women with overactive bladder syndrome, nonbladder factors also may influence sleep in this population. Many women with overactive bladder are eager to identify nonpharmacologic strategies for both bladder symptoms and sleep disruption, given the potential adverse effects of sedative and anticholinergic bladder medications in this population. OBJECTIVES: To provide greater insight into the complex relationship between nighttime overactive bladder symptoms and sleep disruption, and to evaluate the effects of a guided slow-paced respiration intervention on sleep outcomes in women with overactive bladder. STUDY DESIGN: We conducted an ancillary study within a randomized trial of slow-paced respiration in women with overactive bladder symptoms. Ambulatory community-dwelling women who reported ≥3 episodes/day of urgency-associated voiding or incontinence were randomized to use either a portable biofeedback device (RESPeRATE; Intercure, Ltd) to practice guided slow-paced respiration exercises daily for 12 weeks (N=79) or an identical-appearing device programmed to play nonrhythmic music without guiding breathing (N=82). At baseline and after 12 weeks, bladder symptoms were assessed by voiding diary, sleep duration, and disruption were assessed by sleep diary corroborated by wrist actigraphy, and poor sleep quality was determined by a Pittsburgh Sleep Quality Index global score >5. RESULTS: Of the 161 women randomized, 31% reported at least twice-nightly nocturia, 26% nocturnal incontinence, and 70% poor sleep quality at baseline. Of the 123 reporting any nighttime awakenings, 89% averaged 1 or more nighttime awakenings, and 83% attributed at least half of awakenings to using the bathroom. Self-reported wake time after sleep onset increased with increasing frequency of nocturnal bladder symptoms (P=.01 for linear trend). However, even among women without nocturia, average sleep quality was poor (Pittsburg Sleep Quality Index global score mean of 7.3; 95% confidence interval, 6.0-8.6). Over 12 weeks, women assigned to slow-paced respiration (N=79) experienced modest improvements in mean nocturnal voiding frequency (0.4 fewer voids/night), sleep quality (1.1 point score decrease), and sleep disruption (1.5% decreased wake time after sleep onset). However, similar improvements were detected in the music control group (N=81), without significant between-group differences. CONCLUSIONS: Many women with overactive bladder syndrome experience disrupted sleep, but not all nocturnal awakenings are attributable to bladder symptoms, and average sleep quality tends to be poor even in women without nocturia. Findings suggest that clinicians should not assume that poor sleep in women with overactive bladder syndrome is primarily caused by nocturnal bladder symptoms. Guided slow-paced respiration was associated with modest improvements in nocturia frequency and sleep quality in this trial, but the results do not support clinician recommendation to use this technique over other behavioral relaxation techniques for improving sleep.

A Randomized Controlled Trial of Device Guided, Slow-Paced Respiration in Women with Overactive Bladder Syndrome.

PURPOSE: We evaluated the effects of device guided, slow-paced respiration on urgency associated urinary symptoms, perceived stress and anxiety, and autonomic function in women with overactive bladder syndrome. MATERIALS AND METHODS: We performed a randomized, parallel group trial of slow-paced respiration to improve perceived stress and autonomic dysfunction as potential contributors to overactive bladder. Ambulatory women who reported at least 3 voiding or incontinence episodes per day associated with moderate to severe urgency were randomized to use a portable biofeedback device to practice daily, slow, guided breathing exercises or a control device which appeared identical and was reprogrammed to play music without guiding breathing. During 12 weeks we evaluated changes in urinary symptoms by voiding diaries, perceived stress and anxiety by validated questionnaires, and autonomic function by heart rate variability and impedance cardiography. RESULTS: In the 161 randomized participants, including 79 randomized to paced respiration and 82 randomized to the control group, the average ± SD baseline frequency of voiding or incontinence associated with moderate to severe urgency was 6.9 ± 3.4 episodes per day. Compared to controls the participants randomized to paced respiration demonstrated greater improvement in perceived stress (average Perceived Stress Scale score decrease 2.8 vs 1.1, p=0.03) but not in autonomic function markers. During 12 weeks the average frequency of voiding or incontinence associated with moderate to severe urgency, which was the study primary outcome, decreased by a mean of 0.9 ± 3.2 episodes per day but no significant between group difference was detected. CONCLUSIONS: Among women with overactive bladder slow-paced respiration was associated with a modest improvement in perceived stress during 12 weeks. However, it was not superior to a music listening control for reducing urinary symptoms or changing autonomic function.

DRD4 genotype predicts longevity in mouse and human.

Longevity is influenced by genetic and environmental factors. The brain's dopamine system may be particularly relevant, since it modulates traits (e.g., sensitivity to reward, incentive motivation, sustained effort) that impact behavioral responses to the environment. In particular, the dopamine D4 receptor (DRD4) has been shown to moderate the impact of environments on behavior and health. We tested the hypothesis that the DRD4 gene influences longevity and that its impact is mediated through environmental effects. Surviving participants of a 30-year-old population-based health survey (N = 310; age range, 90-109 years; the 90+ Study) were genotyped/resequenced at the DRD4 gene and compared with a European ancestry-matched younger population (N = 2902; age range, 7-45 years). We found that the oldest-old population had a 66% increase in individuals carrying the DRD4 7R allele relative to the younger sample (p = 3.5 × 10(-9)), and that this genotype was strongly correlated with increased levels of physical activity. Consistent with these results, DRD4 knock-out mice, when compared with wild-type and heterozygous mice, displayed a 7-9.7% decrease in lifespan, reduced spontaneous locomotor activity, and no lifespan increase when reared in an enriched environment. These results support the hypothesis that DRD4 gene variants contribute to longevity in humans and in mice, and suggest that this effect is mediated by shaping behavioral responses to the environment.

Adaptive statistical iterative reconstruction reduces patient radiation dose in neuroradiology CT studies.

INTRODUCTION: Adaptive statistical iterative reconstruction (ASIR) can decrease image noise, thereby generating CT images of comparable diagnostic quality with less radiation. The purpose of this study is to quantify the effect of systematic use of ASIR versus filtered back projection (FBP) for neuroradiology CT protocols on patients' radiation dose and image quality. METHODS: We evaluated the effect of ASIR on six types of neuroradiologic CT studies: adult and pediatric unenhanced head CT, adult cervical spine CT, adult cervical and intracranial CT angiography, adult soft tissue neck CT with contrast, and adult lumbar spine CT. For each type of CT study, two groups of 100 consecutive studies were retrospectively reviewed: 100 studies performed with FBP and 100 studies performed with ASIR/FBP blending factor of 40 %/60 % with appropriate noise indices. The weighted volume CT dose index (CTDIvol), dose-length product (DLP) and noise were recorded. Each study was also reviewed for image quality by two reviewers. Continuous and categorical variables were compared by t test and free permutation test, respectively. RESULTS: For adult unenhanced brain CT, CT cervical myelography, cervical and intracranial CT angiography and lumbar spine CT both CTDIvol and DLP were lowered by up to 10.9 % (p < 0.001), 17.9 % (p = 0.005), 20.9 % (p < 0.001), and 21.7 % (p = 0.001), respectively, by using ASIR compared with FBP alone. Image quality and noise were similar for both FBP and ASIR. CONCLUSION: We recommend routine use of iterative reconstruction for neuroradiology CT examinations because this approach affords a significant dose reduction while preserving image quality.

Efficacy of Continuous Transdermal Nitroglycerin for Treating Hot Flashes by Inducing Nitrate Cross-tolerance in Perimenopausal and Postmenopausal Women: A Randomized Clinical Trial.

Importance: Due to the potential risks of long-term systemic estrogen therapy, many menopausal women are interested in nonhormonal treatments for vasomotor symptoms. Physiologic studies indicate that nitric oxide plays a key role in mediating hot flash-related vasodilation, suggesting that nonhormonal medications that induce nitrate tolerance in the vasculature may offer therapeutic benefit for vasomotor symptoms. Objective: To determine whether uninterrupted administration of transdermal nitroglycerin (NTG) to induce nitrate cross-tolerance decreased the frequency or severity of menopause-related hot flashes. Design, Setting, and Participants: This randomized, double-blinded, placebo-controlled clinical trial included perimenopausal or postmenopausal women reporting 7 or more hot flashes per day who were recruited from northern California by study personnel at a single academic center. Patients were randomized between July 2017 and December 2021, and the trial ended in April 2022 when the last randomized participant completed follow-up. Interventions: Uninterrupted daily use of transdermal NTG (participant-directed dose titration from 0.2-0.6 mg/h) or identical placebo patches. Main Outcome Measures: Validated symptom diaries assessing changes in any hot flash frequency (primary outcome) and moderate-to-severe hot flash frequency over 5 and 12 weeks. Results: Among the 141 randomized participants (70 NTG [49.6%], 71 placebo [50.4%]; 12 [85.8%] Asian, 16 [11.3%] Black or African American, 15 [10.6%] Hispanic or Latina, 3 [2.1%] multiracial, 1 [0.7%] Native Hawaiian or Pacific Islander, and 100 [70.9%] White or Caucasian individuals), a mean (SD) of 10.8 (3.5) hot flashes and 8.4 (3.6) moderate-to-severe hot flashes daily was reported at baseline. Sixty-five participants assigned to NTG (92.9%) and 69 assigned to placebo (97.2%) completed 12-week follow-up (P = .27). Over 5 weeks, the estimated change in any hot flash frequency associated with NTG vs placebo was -0.9 (95% CI, -2.1 to 0.3) episodes per day (P = .10), and change in moderate-to-severe hot flash frequency with NTG vs placebo was -1.1 (95% CI, -2.2 to 0) episodes per day (P = .05). At 12 weeks, treatment with NTG did not significantly decrease the frequency of any hot flashes (-0.1 episodes per day; 95% CI, -1.2 to 0.4) or moderate-to-severe hot flashes (-0.5 episodes per day; 95% CI, -1.6 to 0.7) relative to placebo. In analyses combining 5-week and 12-week data, no significant differences in change in the frequency of any hot flashes (-0.5 episodes per day; 95% CI, -1.6 to 0.6; P = .25) or moderate-to-severe hot flashes (-0.8 episodes per day; 95% CI, -1.9 to 0.2; P = .12) were detected with NTG vs placebo. At 1 week, 47 NTG (67.1%) and 4 placebo participants (5.6%) reported headache (P < .001), but only 1 participant in each group reported headache at 12 weeks. Conclusions and Relevance: This randomized clinical trial found that continuous use of NTG did not result in sustained improvements in hot flash frequency or severity relative to placebo and was associated with more early but not persistent headache. Trial Registration: Clinicaltrials.gov Identifier: NCT02714205.