Irina Virtanen

Effect of short-term transdermal estrogen replacement therapy on sleep: a randomized, double-blind crossover trial in postmenopausal women☆

Abstract Objective: To evaluate the effect of estrogen replacement therapy on sleep architecture, arousals, and body movements. Design: A 7-month, prospective, randomized, double-blind, placebo-controlled crossover trial. Setting: Departments of obstetrics and gynecology and a university sleep center in Turku, Finland. Patient(s): Seventy-one postmenopausal women, 4 of whom were excluded and 5 of whom withdrew from the study; the final study group consisted of 62 women. Intervention(s): Two periods of treatment with either estrogen or placebo. Main Outcome Measure(s): Polysomnography for measurement of sleep and arousals and a static charge–sensitive bed for monitoring of movements and breathing. Self-reports of climacteric symptoms for 14 days. Result(s): Estrogen effectively alleviated hot flashes, sweating, sleep complaints, and headaches. Estrogen decreased the total frequency of movement arousals but increased alpha-arousals, especially during light non–rapid eye movement sleep (stage 1). Sleep latency, distribution of sleep stages, sleep efficiency, and total sleep time were similar during treatment with estrogen and placebo. Changes in serum E 2 concentrations correlated with neither subjective nor objective sleep quality. Conclusion(s): Estrogen replacement therapy improves objective sleep quality by alleviating the frequency of nocturnal movement arousals. It also reduces climacteric symptoms, especially vasomotor symptoms. Estrogen replacement therapy does not seem to have any effect on sleep architecture.

Impact of menopause on the manifestation and severity of sleep‐disordered breathing

Background. Decreased production of female hormones might explain the increased prevalence of sleep‐disordered breathing in postmenopausal women. Objectives. We evaluated, whether menopause has an impact on the manifestation of sleep‐disordered breathing in terms of signs, symptoms, and breathing pattern. Methods. The study was a cross‐sectional study utilizing a patient database, hospital records, sleep studies, and questionnaires. The hospital records and sleep studies were reviewed in 601 consecutive women studied between 1994 and 1998 in a university hospital pulmonary clinic. The records were completed with questionnaires. Results. Nocturnal breathing abnormalities covered a greater proportion of the night in postmenopausal than in premenopausal women (68.1% versus 35.8% of time in bed, p<0.0001), and the prevalence of sleep‐disordered breathing tended to be higher (86.2% versus 79.4% of time in bed, p = 0.057). The body mass indices and the major symptoms of sleep‐disordered breathing were similar in pre‐ and postmenopausal women. Postmenopausal women had less nasal congestion (p<0.001) than premenopausal ones. Body mass index was a significant explanatory factor of daytime sleepiness. Conclusions. Post‐ and premenopausal women present with similar signs and symptoms when referred to sleep studies. However, sleep‐disordered breathing is more severe in postmenopausal than in premenopausal women.

The effect of estrogen replacement therapy on cardiac autonomic regulation

OBJECTIVE To study the effects of estrogen replacement therapy (ERT) and sleep stage on autonomic cardiac regulation. SRUDY DESIGN: Seventy-one healthy postmenopausal women received transdermal ERT and placebo separated by a washout in a randomized, placebo-controlled, double-blind, cross-over trial. Polysomnography was conducted at the end of each treatment. Heart rate variability (HRV) was assessed in epochs of the awake state, stage 2, slow wave and REM sleep. The effects of estradiol and sleep stages on HRV were analyzed. RESULTS ERT decreased heart rate in the awake state and quiet sleep, but not in REM sleep. ERT did not change the heart rate variability. Heart rate decreased and HRV increased during stage 2 and slow wave sleep compared with the awake state with placebo. In REM sleep, similarly, heart rate increased above awake values and the values of HRV parameters fell back to awake levels. CONCLUSIONS The results suggest that ERT increases vagal tone, but does not change cardiac vagal modulation. Changes in HRV suggest a strong vagal influence in non-REM and a sympathetic influence in REM sleep.

Climacteric vasomotor symptoms do not imply autonomic dysfunction

Objective To study whether oestrongen replacement therapy has an effect on autonomic haemodynamic control in postmenopausal women.

Sleep stage dependent patterns of nonlinear heart rate dynamics in postmenopausal women

OBJECTIVE To study the effects of sleep stage changes on nocturnal nonlinear heart rate variability (HRV) in postmenopausal women. DESIGN A prospective study. POPULATION Seventy-one healthy postmenopausal women. METHODS The women underwent two separate sleep studies four months apart. One steady state epoch per night of the awake state, stage 2 (light) non-REM sleep, stage 3-4 (deep) non-REM sleep and REM sleep were extracted. From the ECG, the fractal scaling exponents alpha(1) and alpha(2), approximate entropy (ApEn), the Poincaré plot variability coefficients SD1 and SD2, along with the low (LF) and high frequency (HF) bands of linear HRV as well as the LF/HF ratio were calculated. RESULTS None of the spectral measures of HRV changed significantly during the non-REM sleep compared to awake state. However, in non-REM sleep, alpha(2) (p<0.001) decreased significantly compared to the awake state, while alpha(1) and ApEn remained unchanged. SD1 was slightly increased in stage 2 sleep (p<0.05), while SD2 decreased in slow wave sleep (p<0.001). In REM sleep, alpha(2) values returned to the awake values, while ApEn and alpha(1) increased above the awake levels (p<0.01 for all variables), and SD1 decreased (p<0.01). HF spectral component decreased slightly (p<0.05 compared to stage 2 sleep) and LF/HF ratio increased during REM sleep (p<0.001). ApEn and alpha(2) had no correlations with any of the spectral measures of HRV, and alpha(1) had a modest correlation with the LF/HF ratio only during sleep. CONCLUSIONS We found that nonlinear indices of HRV describe specific features in HR dynamics during various sleep stages that are not detected by traditional spectral HRV indices.

Cardiac autonomic changes after 40 hours of total sleep deprivation in women

OBJECTIVES The effect of total sleep deprivation on heart rate variability (HRV) in groups of postmenopausal women on oral hormone therapy (HT) (on-HT, n = 10, 64.2 (1.4) years), postmenopausal women without HT (off-HT, n = 10, 64.6 (1.4) years) and young women (n = 11, 23.1 (0.5) years) was studied using a prospective case-control setup. METHODS Polysomnography was performed over an adaptation night, a baseline night, and a recovery night after 40 h of total sleep deprivation. Time and frequency domain and nonlinear HRV from overnight electrocardiogram recordings were compared between groups during baseline and recovery nights. Further, the changes in HRV from baseline to recovery were analysed and compared between groups. Finally, correlations of HRV to percentages of sleep stages and measures of sleep fragmentation were analysed during baseline and recovery. RESULTS Young women had higher HRV than older women; the most marked difference was between young and on-HT postmenopausal women. Sleep deprivation induced a decrease in frequency domain HRV in young and in off-HT women, an increase in α2 in off-HT women, and an increase in mean heart rate in on-HT women. The sleep deprivation effect was mainly uncorrelated to changes in sleep parameters. CONCLUSIONS Acute total sleep deprivation has a deleterious effect on the autonomic nervous system in young women, but an even more pronounced effect in postmenopausal women. Hormone therapy use in late postmenopause does not give protection against these changes. These harmful effects may partly explain the increased cardiovascular morbidity and overall mortality associated with sleep loss.

Postmenopausal estrogen therapy modulates nocturnal nonlinear heart rate dynamics.

Objective:To study the effects of postmenopausal estrogen therapy (ET) on nocturnal nonlinear heart rate variability (HRV). Design:In this prospective, randomized, double-blind, placebo-controlled study, 71 healthy hysterectomized postmenopausal women received either transdermal estradiol or placebo for 3 months. After a washout period of 1 month, the treatments were reversed. Sleep studies were performed after both treatment periods. One steady-state epoch per night of the awake state, stage 2 (light) non-rapid eye movement (REM) sleep, stage 3-4 (deep) non-REM sleep, also known as slow-wave sleep, and REM sleep was extracted. From the electrocardiogram, nonlinear HRV was analyzed as the fractal scaling exponents &agr;1 and &agr;2, approximate entropy (ApEn), and the Poincaré plot variability coefficients SD1 and SD2. These were correlated to ET use in both different sleep stages and averaged across all sleep stages. Results:During ET, the nocturnal ApEn decreased from 0.80 ± 0.01 to 0.74 ± 0.02 (P < 0.05), the most marked reduction occurring during slow-wave sleep (from 0.77 ± 0.05 to 0.63 ± 0.06, P < 0.05). In addition, SD2 decreased in slow-wave sleep and REM sleep during ET (P < 0.05 for both). In light non-REM sleep, &agr;1 slightly increased during ET (P < 0.05). Conclusions:ET has a slightly but distinctively attenuating effect on some nocturnal nonlinear measures of HRV, especially on complexity of heart rate dynamics. This implies that ET may have potentially deleterious effects on cardiovascular health during sleep.

Recurrent sinus arrest and asystole due to breath-holding spell in a toddler; recovery with levetiracetam-therapy.

10-month-old girl was referred to our institution forevaluation of recurrent loss of consciousness that oc-curred for 30 seconds 1 to 3 times a day. The seizuresoccurred after crying, pain, or frustration. Because of tonic-like seizures before the loss of consciousness, the girl wasinitially remitted to pediatric neurology, where a movie-assisted electroencephalography was registered (Movie I ofthe online-only Data Supplement). When the girl was crying,she held breath, stiffened, and the recording showed asignificant bradycardia and a 30s asystole followed by flat-tening of assisted electroencephalography activity and loss ofconsciousness consistent with anoxia. Consciousness returnedrapidly after her cardiac function normalized. Between theseizures she was otherwise healthy and cardiac ultrasound andelectrocardiogram (ECG) were normal. Girl was diagnosed tosuffer from severe breath-holding spells.Ambulatory ECG demonstrated similar episodes daily anda treatment with atropine (8 g/kg, orally 3 times a day) wasinitiated by a pediatric cardiologist. Atropine did not signif-icantly affect the occurrence of the spells and pharmacolog-ical treatment was changed two months later to propranolol(0.4 mg/kg 3 times a day) without any significant improve-ment in the incidence of the spells. Since the girl wasoccasionally hurt by the falls caused by loss of consciousness,an off-label treatment with levetiracetam (8 mg/kg twice aday) was started. Levetiracetam did not affect the occurrenceof the breath-holding seizures, but after the treatment wasinitiated, breath-holding did not result in unconsciousness.Ambulatory ECG showed that her heart rate still slightlydecelerated during breath-holding, but no asystole was rec-orded. After the girl had been spell-free for 1 month,levetiracetam was discontinued and the symptoms reappearedwithin few days. Levetiracetam therapy was resumed and thesymptoms disappeared. However, because of the side-effects(hyperreactivity, aggressive behavior, and loss of appetite)the drug was eventually discontinued. As the symptoms weresevere, implantation of permanent pacemaker was warranted.Breath-holding spells is a relatively common disorder inyoungchildrenthatusuallyspontaneouslyresolvesandneedsnotreatment. The pathogenesis is incompletely understood, but animbalance between sympathetic and parasympathetic nervoussystem has been proposed.

First-Night Effect on Sleep in Different Female Reproductive States

ABSTRACT Objectives: In sleep laboratory studies, the new environment is generally considered to disturb sleep during the first night. However, older women have rarely been studied. Although menopause and hormone therapy affect sleep, their impact on the first-night effect is virtually unknown. Participants: Four groups of women with no sleep laboratory experience: young on hormonal contraceptives (n = 11, 23.1 [0.5] years), perimenopausal (n = 15, 48.0 [0.4] years), postmenopausal without hormone therapy (HT; off-HT, n = 22, 63.4 [0.8] years) and postmenopausal with HT (n = 16, 63.1 [0.9] years). Procedure: A cross-sectional study. Methods: Polysomnography was performed over two consecutive nights and the first-night effect and group differences were evaluated. Questionnaire-based insomnia and sleepiness scores were correlated to sleep variables and their between-night changes. Results: Although sleep in young women was deeper and less fragmented than in the other groups, first-night effect was similar in all study groups. Total sleep time, sleep efficiency, and S1 and S2 sleep increased, and wake after sleep onset, awakenings per hour of sleep, S2 and REM latencies, and percentage of SWS decreased from the first to the second night. Perimenopausal women had more insomnia complaints than other women. Insomnia complaints were associated with more disturbed sleep but not with the first-night effect. Conclusions: A first night in a sleep laboratory elicits a marked interference of sleep architecture in women of all ages, with a carryover effect of lighter sleep on the second study night. Menopausal state, HT use, or insomnia complaints do not modify this effect.

First-night effect on cardiac autonomic function in different female reproductive states

Decreases in heart rate variability, a marker of autonomic nervous system function, are associated with increased cardiovascular mortality. Heart rate variability increases in non‐rapid eye movement sleep, peaking in slow‐wave sleep. Therefore, decreasing the amount of deep sleep, for example, by introducing patients to a sleep laboratory environment, could decrease heart rate variability, increasing cardiovascular risk. We studied four groups of women with no previous sleep laboratory experience: young [n = 11, 23.1 (0.5) years]; perimenopausal [n = 15, 48.0 (0.4) years]; postmenopausal without hormone therapy [n = 22, 63.4 (0.8) years]; and postmenopausal on hormone therapy [n = 16, 63.1 (0.9) years], using a cross‐sectional design. Polysomnography including electrocardiogram was performed over two consecutive nights. Heart rate variability was assessed overnight, and the first‐night effect on heart rate variability was analysed. Furthermore, correlations between heart rate variability and sleep variables were analysed. Using combined groups, only minor changes were observed in non‐linear heart rate variability, indicating increased parasympathetic tone from the first to the second night. No group differences in first‐night effect were seen. Heart rate variability and sleep variables were not significantly correlated. Heart rate variability decreased with increasing age, and it was lowest in the postmenopausal women on hormone therapy. We conclude that a first night in a sleep laboratory elicits only minimal changes in overnight vagally mediated non‐linear heart rate variability in women irrespective of reproductive state. This finding warrants further analyses in different sleep stages, but suggests that changes in sleep architecture per se do not predict the autonomic strain of a poor night.