Glycoprival diet – it is a principle similar to nutrition Kremlin diet and the Atkins diet. In order to achieve weight loss can benefit from this diet, the principle of which is passed to control enters the body of sugar and starch. The main rule glycoprival diet – 250 calories allowed, which can come in the form of carbohydrates.

When glycoprival diet is not controlled by eating fish, poultry, meat, cheese, cheese, and the most recommended foods are vegetables, root vegetables, citrus fruits and berries. Eating bread, flour, sugar, cereals, fruits (except citrus), dairy products, carrots, potatoes, maize and fat is severely restricted, however, as the alcohol and sugary drinks.

Rules glycoprival diet:
after eating forbidden to drink half an hour
permitted only when frying olive few
fractional eat – at least 5 times a day
at 20:00 on the power “today” should be completed

Glycoprival diet. Sample menu (optional):
1. Lean meat is cooked without salt (400 gr.) Divide into 4 portions and eat with vegetables (200-300 gr.) All day. Morning and evening, should drink a cup of tea or broth hips.
2. Lean cooked meat (250 gr.) + 2 cups of tea + 2 glasses of juice. All products are divided into 5 stages.

Presently available hypnotics are effective for the short-term treatment of insomnia.
The long-term indication for hypnotic drugs has been discouraged on the grounds
of risk of rebound insomnia, a withdrawal reaction, and/or dependence. Strictly,
this recommendation applies only to the older benzodiazepines. Notwithstanding
this, it has been extended to the recently introduced nonbenzodiazepine hypnotics,
which have a very low potential of causing rebound insomnia, dependence, or other
adverse effects on health [83, 84]. In this respect, evidence from accumulated clinical
practice and controlled studies indicates that long-term pharmacological treatment
of insomnia with zolpidem and eszopiclone is efficacious and safe [62, 66–68].
Sateia and Nowell [85] have proposed that long-term treatment with hypnotic
medication could be implemented in patients with persistent insomnia not related
to mental disorders, neurological diseases, medical conditions, or the effect of a
substance of abuse or medication. In addition, nonpharmacological approaches have
to be proven ineffective. Circumstances in which the long-term administration of
hypnotic drugs must be discontinued include the development of tolerance and dose
escalation, the occurrence of severe adverse events, and the diagnosis of newly developed
disabilities.
Non-nightly hypnotic administration has been proposed as an alternative option
to the nightly drug intake. To date, information on the efficacy and safety of nonnightly
intake of hypnotic medication is available only for zolpidem. Administration
of zolpidem (10 mg) for 5 nights followed by 2 nights of placebo per week for
2 weeks induced an improvement of sleep that was comparable to the nightly zolpidem
treatment in patients with chronic insomnia. Rebound insomnia did not occur
on the nights during which zolpidem was substituted by a placebo [86]. In another
study nightly and non-nightly zolpidem treatment were compared using the same
design except that the two placebo nights per week were randomly assigned. Again,
improvement of sleep was equivalent in the two groups of patients [87]. More recently,
zolpidem (10 mg) or placebo was administered for 12 weeks to patients with a
diagnosis of chronic primary insomnia. The patients were instructed to take no fewer
than three and no more than five pills per week. Sleep was evaluated daily with sleep
diaries. Patients receiving zolpidem exhibited an improvement of sleep induction
and maintenance that persisted over time. There was neither rebound insomnia nor
dose escalation [66]. Thus, presently available data tend to indicate that long-term
non-nightly administration of zolpidem (10 mg) is an appropriate alternative to the
nightly use of the hypnotic drug in patients with chronic primary insomnia.
In conclusion, sleep-related complaints are common in the general population.
Prevalence rates are significantly higher among women and the older age groups.
Primary insomnia results from the reaction to an emotional trigger or stressful event,
which leads to the further development of sleep-preventing associations. Secondary
insomnia is that related to another mental disorder, a neurological disease, another
sleep disorder, a general medical condition, the effect of a drug of abuse or a medication.
In patients with primary insomnia nonpharmacological strategies and sleep
promoting medication are indicated. In patients with secondary insomnia the underlying
disorder needs to be treated appropriately. Notwithstanding, hypnotic medication
may be beneficial in secondary insomnias, as an adjunct to treatment of the
primary disorder. Currently used hypnotics include benzodiazepine derivatives, the
cyclopyrrolone zopiclone, the imidazopyridine zolpidem, and the pirazolopyrimidine
zaleplon. In patients with primary insomnia most hypnotics reduce sleep-onset
latency, decrease the number of nocturnal awakenings, and reduce the time spent
awake. The increase of total sleep time is related to greater amounts of non-REM
sleep. Sleep quality is also improved.

The commonly reported adverse effects of benzodiazepine hypnotics are drowsiness,
tiredness, dysarthria, ataxia, depression, and anterograde amnesia [20, 21]. Memory
impairment has been reported more often with benzodiazepines that have short halflives
and a high affinity for the GABAA α1 subunit-containing receptors, such as
triazolam and midazolam [74, 75]. Daytime functioning can be negatively affected,
as evidenced by the effects on measures of psychomotor performance in patients
taking long-acting derivatives. In addition, daytime anxiety can occur in individuals
receiving short-acting benzodiazepines [21, 76–78]. Increased daytime sleepiness, as
quantified by the polysomnographically measured disposition to fall asleep during
the day (multiple sleep latency test), can occur. This adverse effect is associated
with an increase in the rate of accidents on the road, in the home, and at work [79].
The elderly are particularly susceptible to the adverse effects of benzodiazepines,
due to age-related alterations in pharmacokinetics as a result of changes in hepatic
metabolism and renal excretion.
Zopiclone exhibits an adverse-effect profile similar to that of the shorter acting
benzodiazepines. Hence, poor quality of awakening, drowsiness, tiredness, nightmares,
and a dry or bitter taste in the mouth have been reported. The bitter taste is the
main reason for treatment discontinuation [80]. Zopiclone also impairs memory and
psychomotor performance within the first few hours after administration [77, 81].
The most common treatment-related adverse events during eszopiclone administration
are headache, nausea, vomiting and an unpleasant or bitter taste [61, 62].
The unpleasant or bitter taste is prevalent among patients, and constitutes the main
reason for treatment discontinuation.
Zolpidem does not impair the psychomotor performance of patients the morning
after administration. Adverse effects reported during its administration include
dizziness and lightheadedness, somnolence, headache, and gastrointestinal upset. At
doses of 10 mg there is no effect on anterograde memory [50, 82].
Adverse events occurring among zaleplon (5 or 10 mg)-treated patients include
abdominal pain, asthenia, headache, dyspepsia, nausea, dizziness, and somnolence

Insomnia is a complaint characterized by difficulty falling asleep (sleep latency of
more than 30 min), insufficient sleep (total sleep time of less than 5.5–6 h), numerous
nocturnal awakenings, an early morning awakening with inability to resume sleep,
or nonrestorative sleep. Common daytime complaints include somnolence, fatigue,
irritability, and difficulty concentrating and performing everyday tasks. In addition,
subjects with a diagnosis of insomnia are at risk for injury, drowsiness while driving,
and illness.
The International Classification of Sleep Disorders [11] considers severity criteria
as a guide to be applied in conjunction with consideration of the patient’s clinical
status. Mild insomnia refers to an almost nightly complaint of an insufficient amount
of sleep or not feeling rested after the habitual sleep episode. There is little or no
evidence of impairment of social or occupational functioning. Mild insomnia often is
associated with feelings of restlessness, irritability, mild anxiety, daytime fatigue, and
tiredness. Moderate and severe insomnia refer to a nightly complaint of an insufficient
amount of sleep or not being rested after the habitual sleep episode, accompanied by
moderate and severe impairment of social or occupational functioning, respectively.
No doubt, the severity criteria may help the clinician to more effectively treat the
complaint of insomnia.
Traditionally insomnia has been classified into sleep-onset insomnia, sleep-maintaining
insomnia and insomnia with early morning awakening. However, such a
categorization could be misleading because the respective patterns are not stable over
the course of time. In this respect, Hohagen et al. [12] found that only 51% of 2512
patients who complained of sleep-onset insomnia at the beginning of the study still
reported exclusively problems in initiating sleep 4 months later. The stability of sleepmaintaining
insomnia and of insomnia with early morning awakeningwas even lower
(17% and 45 %, respectively). The low stability of the different patterns of insomnia
must be taken into consideration when selecting the most appropriate hypnotic drug
for treatment of the sleep disorder. Thus, after a relatively short period of time, ultrashort-
acting hypnotics would no longer be effective in numerous patients with an
initial diagnosis of sleep-onset insomnia.
The duration of insomnia has been considered an important guide to its evaluation
and treatment. Individuals with transient insomnia are normal sleepers who
experience an acute stress or situation for a few days (e.g., air travel to a new time
zone, hospitalization for elective surgery) that disrupts their sleep. The use of sleeppromoting
medication (short-acting agent) and good sleep hygiene tend to resolve
the problem. Short-term insomnia is usually associated with a situational stress, often
related to work or family life or serious medical illness. This type of insomnia
may last up to 3 weeks. However, in some cases short-term insomnia may evolve
into a chronic condition. Proper sleep hygiene and other nonpharmacological approaches
are appropriate for treating short-term insomnia. However, adjunctive use
of hypnotic medication, while providing nonpharmacological interventions, could
be necessary. Conventionally, long-term or chronic insomnia has been considered to
be that lasting for at least 21–30 nights. Usually, it persists for months or years, and
its onset may or may not be associated with an identifiable stressor. When there is
no other diagnosable condition directly associated with the chronic insomnia, it is
diagnosed as a primary insomnia.
If the insomnia is precipitated or aggravated by another sleep disorder or mental
disorder, or if it is due to the direct physiological effects of a substance of abuse
or a general medical condition, then the other disorder is termed primary and the
insomnia secondary [13, 14].
Primary insomnia includes a number of insomnia diagnoses according to the
International Classification of Sleep Disorders, including psychophysiological insomnia
and idiopathic insomnia [11]. Psychophysiological insomnia most closely
resembles primary insomnia. Individuals with idiopathic or childhood-onset insomnia
show a lifelong inability to obtain adequate sleep; there is no evidence of medical
or psychiatric disorders that could account for the sleep disturbance. In sleep disor
ders centers, about 15% of all insomniacs are diagnosed with psychophysiological
insomnia. The prevalence of idiopathic insomnia in its pure form is not known.
Secondary insomnia is the most frequent form of insomnia. The determinants
of secondary insomnia can be grouped into the following categories: (1) mental
disorders; (2) neurological diseases; (3) medical conditions; and (4) abuse of drugor
medication-induced sleep disorder [15]. A list of major factors is included as

Drugs that influence the circadian apparatus are often referred as chronobiotics [34].
The prototype of this type of drugs is melatonin. Melatonin secretion is an ‘arm’ of
the biological clock in the sense that it responds to signals from the SCN, and in that
the timing of the melatonin rhythm indicates the status of the clock, both in terms
of phase (i.e. , internal clock time relative to external clock time) and amplitude.
From another point of view, melatonin is also a chemical code of night: the longer
the night, the longer the duration of its secretion. In many species, this pattern of
secretion serves as a time cue for seasonal rhythms [35].
Like the effects induced by the external Zeitgeber light, effects by the internal
Zeitgeber melatonin are also time dependent. Entraining free-running circadian
rhythms by administering melatonin is only possible if the SCN is intact. Daily timed
administration of melatonin to rats shifts the phase of the circadian clock, and this
phase shifting may partly explain melatonin effect on sleep in humans, or ‘chronobiotic
effect’ [34]. Indirect support for such a physiological role derived from clinical
studies on blind subjects, who show free running of their circadian rhythms, while a
more direct support for this hypothesis was provided by the demonstration that the
phase response curve for melatonin was opposite (i.e. , 180 degrees out of phase) to
that of light [36, 37].
Within the SCN, melatonin reduces neuronal activity in a time-dependent manner.
In rodents, the effects of melatonin on SCN activity are mediated by at least two
different receptors. They are insensitive during the day, but sensitive at dusk and
dawn (MT2; causes phase shifts) and during early night period (MT1; decreases
neuronal firing rate) [38]. Melatonin secreted during nighttime provides enough
inertia to resist minor perturbations of the circadian timing system.
The evening increase in melatonin secretion is associated with an increase in the
propensity for sleep [39]. This results from the antagonistic action of melatonin on
SCN electrical activity mediated by MT1 receptors. Since SCN plays an important
role during late evening to counteract sleep propensity derived from the accumulation
of the “sleep debt” (possibly adenosine at the anterior hypothalamus) [40], inhibition
by melatonin is instrumental in the “opening of the sleep gates” [39]. A new family
of hypnotics (melatonin agonists acting mainly on MT1/MT2 receptors at the SCN)
is now being tested in the market [41]. It is interesting that ramelteon (TAK-375),
one of these MT1/MT2-selective receptor agonists,was able (as melatonin) to induce
sleep and to accelerate resynchronization without affecting learning or memory in rats
tested by thewater maze task or the delayed match to position task, although diazepam
and triazolam impaired both tasks. Neither ramelteon nor melatonin demonstrated a
rewarding property in the conditioned place-preference test, implying that MT1/MT2
receptor agonists have no abuse potential. In contrast, benzodiazepines and morphine
showed rewarding properties in this test [41].
In blind subjects with free-running rhythms, it has been possible to stabilize, or
entrain, the sleep/wake cycle to a 24-hour period by giving melatonin, with resulting
improvements in sleep and mood [42]. In normal aged subjects [43].and in demented
patients with desynchronization of sleep/wake cycle [44] melatonin administration is
helpful in reducing the variation of onset time of sleep. The phase-shifting effects of
melatonin were also sufficient to explain its effectiveness as a treatment for circadianrelated
sleep disorders such as jet lag or the delayed phase sleep syndrome.
A compelling amount of evidence indicates that melatonin is useful for ameliorating
jet-lag symptoms in air travelers (see meta-analysis at Cochrane Data Base
[45]). We examined the timely use of three factors (melatonin treatment, exposure
to light, physical exercise) to hasten the resynchronization of in a group of elite
sports competitors after a transmeridian flight comprising 12 time zones [46]. More
recently, we published a retrospective analysis of the data obtained from normal volunteers
flying from Buenos Aires to Sydney, or from Sydney to Buenos Aires, by
a transpolar route in the last 9 years [47]. Mean resynchronization rate was about
2–3 days. It should be noted that the expected minimal resynchronization rate after
a 13-h flight across several time zones without any treatment is 7–9 days.
Alzheimer’s disease (AD) patients show a greater breakdown of the circadian
sleep/wake cycle compared to similarly aged, non-demented controls. Demented
patients spend their nights in a state of frequent restlessness and their days in a state
of frequent sleepiness. These sleep/wake disturbances became increasingly more
marked with progression of the disease. In AD patients with disturbed sleep/wake
rhythms there is a higher degree of irregularities in melatonin secretion [48]. The
impairment of melatonin secretion present is related to both age and severity of
mental impairment [49]. Loss or damage of neurons in the hypothalamic SCN and
other parts of the circadian timing system have been implicated in the circadian
disturbances of demented patients [50].
The efficacy of melatonin as a chronobiotic inADpatients is supported by several
studies [51–59]. The effect of melatonin was seen regardless of any concomitant
medication employed to treat cognitive or behavioral signs of disease [44]. In a
double-blind study to examine the effects of melatonin on the sleep/wake rhythm,
cognitive and non-cognitive functions inAD type of dementia, it was observed that a
3-mg melatonin dose for 4 weeks significantly prolonged actigraphically evaluated
sleep time, decreased activity at the night and improved cognitive function

Several diseases with established oscillatory rhythm in their pathogenesis have been
identified. In the case of asthma, chronotherapy has been extensively studied [9,
10]. Airway resistance increases progressively at night in asthmatic patients [11].
Circadian changes are seen in normal lung function, which reaches a low point in
the early morning hours. This dip is particularly pronounced in people with asthma.
Chronotherapies that have been employed for asthma include oral corticosteroids,
theophylline and β2-adrenergic agonists [10].
The chronobiology, chronopharmacology and chronotherapeutics of osteoarticular
pain have also been extensively reviewed (e.g. , [12]). Patients with osteoarthritis
tend to have less pain in the morning and more at night; while those with rheumatoid
arthritis, have pain that usually peaks in the morning and decreases throughout
the day. In addition, a number of drugs used to treat rheumatic diseases have varying
therapeutic and toxic effects based on the time of day of administration [13].
Chronotherapy for all forms of arthritis should be timed to ensure that the highest
blood levels of the drug coincide with peak pain. For osteoarthritis sufferers, the
optimal time for a nonsteroidal anti-inflammatory drug such as ibuprofen would be
around noon or mid-afternoon. The same drug would be more effective for people
with rheumatoid arthritis when taken after the evening meal.
Many of the functions of the gastrointestinal tract exhibit circadian rhythms
[14, 15]. Gastric acid secretion is highest at night, while gastric and small bowel
motility and gastric emptying are all slower at night [16, 17]. These 24-h rhythms
have important implications in the pharmacokinetics of orally administered drugs:
at nighttime, when gastric motility and emptying are slower, drug disintegration,
dissolution, and absorption may be slower [18]. Suppression of nocturnal acid is
an important factor in duodenal ulcer healing. Therefore, for an active duodenal
ulcer, the recommended dosage regimen for H2-antagonists is once daily at bedtime
[19, 20].
Cardiac events occur with a circadian pattern. Numerous studies have shown
an increase in the incidence of early-morning myocardial infarction, sudden cardiac
death, stroke and episodes of ischemia (e.g. , [21]). This is because several functions
in the cardiovascular system [blood pressure (BP), heart rate, stroke volume, cardiac
output, blood flow] show circadian rhythmicity. For example, the ability of platelet
to aggregate increases and fibrinolytic activity decreases in the morning, leading to
a state of relative hypercoagulability of the blood [21]. BP is at its lowest during
the sleep cycle and rises steeply during the early morning awakening period [22].
In addition, circadian changes in lipid fractions in patients and normal subjects may
contribute. A circadian rhythm of hepatic cholesterol synthesis occurs [23], and
studies with HMG CoA reductase inhibitors indicated that evening dosing was more
effective than morning dosing [24]. The circadian variations of glucose and insulin
in diabetes have been also extensively studied, and their clinical importance in the
case of insulin substitution has been discussed [25].
In the case of cancer, human and animal studies suggest that chemotherapy may
be more effective and less toxic if cancer drugs are administered at carefully selected
times that take advantage of tumor cell cycles, while being less toxic to normal
tissue [26]. The blood flow to tumors and tumor growth rate are both up to threefold
greater during each daily activity phase of the circadian cycle than during the daily
rest phase. The chronotherapy concept offers further promise for improving current
cancer-treatment options, as well as for optimizing the development of newanticancer
or supportive agents
As far as drugs that affect theCNSare concerned, information on their chronopharmacology
has been available for a long time. Several chronopharmacological studies
were performed on the effects of antipsychotic drugs like reserpine, chloropromazine,
haloperidol, tetrabenazine, spiperone and pimozide (for a recent review see [28]).
The timing of drug efficacy along the circadian cycle differed among drugs, even
when the same endpoints were compared. Moreover, the peak time often varied with
the variable measured for a given drug.
Human sleep, its duration and organization depend on its circadian phase [29].
A breakthrough chronopharmaceutical formulation against insomnia that plagues
many people would be one that addresses the entire oscillatory cycle of human sleeping
process. Anti-histamine preparations (with or without mild analgesics), benzodiazepine
receptor agonists, sedating antidepressants, neuroleptics, melatonin, and
herbal remedies such as valerian are used for treatment of insomnia. Indeed, pharmacological
treatment of insomnia has remained the most widely used for decades,
despite concerns about long-term effectiveness, habituation, tolerance, and potential
complications, especially in elderly people. Chronic hypnotic exposure can also
carry additional risks of physical or behavioral dependence, withdrawal, rebound
insomnia, and increased mortality [30].
Since efforts should be made to use drugs with fast onset and short half-lives
for sleep onset problems, to reduce adverse daytime effects, chronopharmacological
data become important. Many animal studies on the effects on sleep duration of
pentobarbital and hexobarbital have been performed [28]. Most of them indicated
maximal effects after administration in the latter half of the light span or early dark
span. Mortality after librium was higher in mice injected during daily dark period
(18:00 to 06:00 h) than during light period, with a peak usually at 24:00 h [28]. This
circadian peak in susceptibility has a timing similar to other susceptibility rhythms
(e.g. , ethanol, valproic acid or audiogenic seizures) in that all fall into a period of
increased electrical activity of CNS. The results of rotarod tests in mice after administration
of lorazepam indicated a peak at late scotophase. Differences in acrophase
and in amplitude as well as age and dose effects, in the presence of unvaried serum
levels indicated that peak efficacy was not due to pharmacokinetics (e.g. , drug absorption,
pharmacodynamics) [28].Among patients whose insomnia difficulties were
mostly at sleep onset, short-acting drugs like zaleplon and triazolam might be more
suitable, whereas zolpidem, zopiclone, eszopiclone and temazepam can be helpful
for wakefulness after sleep onset because of their longer duration of activity.
The time-related variations in drug effects have also been clinically applied to
the use of antidepressants. Lofepramine had greater antidepressant effect during a
3-week course of therapy when administered at 24:00 h than when administered at
08:00 or 06:00 h [31]. Likewise, the antidepressant effects of clomipramine during a
4-week therapy varied depending on the time of administration, being more effective
at noon than after administration in the morning or evening [32]. In animal studies,
fluoxetine suppressed the intake of carbohydrates only when administered in the
early dark span but not at other time intervals examined. The timing of food, notably
on a diet restricted in calories, can play a critical role in this context and must be
taken into consideration both in laboratory and clinical studies

Medical chronobiology is concerned with the mechanisms of periodic influences on
health and disease. Chronopathology is the study of biological rhythms in disease
processes and in morbid and mortal events; most medical conditions are affected
by circadian rhythms. Chronopharmacology is the discipline that investigates the effects
of a drug as a function of biological time. Traditionally, drug delivery has meant
getting a simple chemical absorbed predictably from the gut or from the site of injection.
A second-generation drug delivery goal has been the perfection of continuous
constant rate (zero-order) delivery of drugs. However, living organisms are not ‘zeroorder’
in their response to drugs.As above mentioned, they are predictable resonating
dynamic systems, which require different amounts of drug at predictably different
times within the circadian cycle to maximize desired and minimize undesired drug
effects (chronotoxicity).
Two concepts must be considered when dealing with day-related changes of drug
efficacy: (a) circadian changes in drug bioavailability (chronokinetics); (b) circadian
changes in the susceptibility to the drug (chronesthesy). Clinical chronopharmacology
(or chronotherapeutics) is the purposeful alteration of drug level to match
rhythms to optimize therapeutic outcomes and minimize size effects.
Within the past few years it has become apparent that the liver is a biological
clock capable of generating its own diurnal rhythms. As the body’s primary defense
against metabolic poisoning, and the target of many toxic substances, the liver is
continuously exposed to relatively high amounts of ingested drugs or toxins. Being
a major organ of metabolism and detoxification of drugs, knowledge of circadian
effects on transcriptional activities that govern daily biochemical and physiological
processes in the liver is key for pharmacological and toxicological studies. In a recent
study, out of 3906 genes evaluated, about 4%of hepatic genes were found to display
a significant effect in their expression levels during the day [8]. Among these genes,
a circadian variation in relative expression levels of cytochrome P-450 4a3 and Nacetyltransferase
of phase I and phase II categories of drug metabolism was found.
Therefore, it is essential to consider time of day effects on drug administration and
animal sacrifice when designing and interpreting toxicology studies.

Since the origin of the sleep disturbance and the contributing factors involved are
often complex, solving or alleviating those problems is also demanding. In women
with climacteric vasomotor symptoms, the first line treatment for insomnia should
be HT. Additionally, women whose insomnia is indispensably related to mood symptoms,
benefit from HT [48].A subset of vasomotorically asymptomatic women may
also gain an advantage from HT [48], but among them careful screening for other
underlying reasons for sleep problems is crucial. Inwomen over 60 years the vascular
side effects of HT may surpass the favorable effects on sleep [47], and thus starting
treatment should be considered carefully. In case of contraindications or fears for
HT other treatment alternatives, such as antidepressants, selective serotonin reuptake
inhibitor (SSRI), gabapentin, dietary isofavones and soy foods, as well as relaxation
therapies and improvement of sleep hygiene should be considered, although the effectiveness
and safeness of these treatments at least in a long run are still unanswered.
In sleep-disordered breathing, nasal continuous positive airway pressure (CPAP) remains
the treatment of choice until more information about HT, especially about
progesterone, is available.

Although menopause is an important initiator for sleeping problems, sleep disturbances
may just coincide with the menopausal period. Thus other explanatory factors
behind should not be dismissed but evaluated with similar intensity at different periods
around menopause. The most important reasons embrace depressive mood,
stress, behavioral factors, as well as restless leg syndrome (RLS) and periodic limb
movement syndrome (PLMS).
Mood symptoms, especially depression, anxiety and lack of initiative occur more
frequently in women than in men [73, 74]. The influence of hormonal fluctuations is
plausible, as mood symptoms have been connected to the female reproductive cycle
(premenstrual tension syndrome, postpartum depression or climacteric depression).
Anderson et al. [38] reported that among climacteric women seeking treatment, the
occurrence of depressive symptoms was as high as 70–90 %. Several studied have
suggested an association between mood symptoms and sleep disturbance in peri- and
postmenopausal women [37, 75]. Sleep quality is sensitive to mood disturbances and
in a number of cases it may be the first sign of affected mood. Especially awakening
too early in the morning originates typically from a depressive mood.
RLS and PLMS are regarded as elements of the similar clinical features with a
difference in timing. Whereas RLS takes place during wakefulness, PLMS occurs
during sleep. Characteristics of RLS are unpleasant sensations, typically in the lower
extremities, urging movement. In PLMS abrupt and repetitive movements usually
last 0.5–5 s with the interval of 5–90 s. There is no consistent gender difference in
either syndrome. RLS occurs in 5–15% of the adult population and PLMS in 30%
between 50 and 65 years, and in 45% over the age of 65 years. Etiologies include
idiopathic with highly genetic basis and secondary forms, like iron, magnesium or
folate deficiency, renal failure, peripheral neuropathies and use of drugs, especially
CNS stimulants and dopamine antagonists [76]. Because of the antidopaminergic
action of estrogen, an effect of estrogen on these syndromes is plausible. However,
in a study of 62 postmenopausal women, estrogen therapy showed no effect on the
frequency of PLM during sleep [77]. Thus, aging with related degenerative processes
in CNS are more plausible in increasing the prevalence of these syndromes than the
menopausal state per se or female sex hormone levels.
For good sleep quality appropriate sleep hygiene is crucial. A dark, quiet room
together with comfortable (often low) temperature and bed is essential.Also avoiding
daytime napping, especially long ones, may contribute to improvement of sleep.
Behavioral factors, such as refreshing drugs (tea, coffee, some soft drinks and herbal
drinks), smoking and alcohol intake may interfere with or cause sleep disruption [78].
In addition to poor sleep hygiene, social issues, such as low income, low education
or living alone also predispose for sleep complaints

Hormone therapy (HT) has widely been used to control climacteric symptoms for
decades [24, 45]. In addition, it has been found to have preventive action at least for
osteoporosis [46]. Because of the side-effects and complications associated particularly
with long duration of the treatment and in older women [47], such as increased
risk for breast cancer and venous thromboembolic events, the consensus today recommends
the use of HT only for alleviation of climacteric symptoms and for as short
a time as possible. HT has also been found to be an effective treatment to control
menopausal sleeping complaints [24, 45, 47, 48]. In a multicenter study with over
200 women, estrogen (patches twice a week for 6 months) abolished sleeping problems
for 95%of women with complaints [24]. In another study, 4 weeks of treatment
(2 weeks of estrogen followed by estrogen+progestagen for the next 2 weeks) led
to a significant reduction of sleep disturbance. The duration of the study was 1 year.
Alleviation of the vasomotor symptoms were strongly associated with improvement
in sleep quality in that study
In a study with both vasomotorically symptomatic and asymptomatic postmenopausal
women [48], estrogen facilitated falling asleep, decreased nocturnal restlessness
and awakenings, and decreased tiredness in the morning and during the daytime.
The degree of improvement in vasomotor symptoms was an important predictor for
the degree of improvement in sleep disturbance. However, the subset of women with
at least some degree of insomnia in the absence of vasomotor symptoms, also reported
improved sleep quality during HT. The same was also evident in a recent
large randomized, placebo-controlled study of Women’s Health Initiative (WHI),
evaluating the long-term effects of HT on the quality of life, where enrolment of the
participants excluded climacterically moderate or high symptomatic women [47].
The beneficial results of HT on subjective sleep quality are easily explained in vasomotorically
symptomatic women, in whom sleeping problems can be regarded
secondary to vasomotor symptoms. As for asymptomatic women, two types of explanation
could address these findings. Firstly, women may underestimate or not
recognize their symptoms. In that case alleviation of the vasomotor symptoms again
plays an important role in improving sleep quality. Secondly, decreased hormone
levels associated with menopause may interfere with sleep regulation in the CNS
causing sleeping disturbance. By replenishing hormone levels by HT, at least some
of these symptoms may be abolished.
The findings about the effects of HT on objective sleep quality have not been as
unanimous as subjectively measured sleep quality. The main outcomes in previous
studies with healthy women are presented in the Table 1. The two most common
findings have been an increase in REM sleep [49–51] and reduction of awakenings
[42, 49, 52, 53] during HT. In addition, a decrease in nocturnal wakefulness during
the entire night [49, 54] or in the first sleep circles [51] has been reported. Moreover,
a shortening of sleep latency [50, 55], an improvement in sleep efficiency [52, 54]
and a reduction of the rate of cyclic alternating patterns of sleep [52] have also
been reported. In some studies no improvement what so ever have been found [56–
58]. In the largest study to date, although observational without the placebo group,
the postmenopausal women with HT had worse sleep quality compared to their
counterparts without HT, as they had less SWS, more S1 sleep and their sleep was
more fragmentized [10].
Because of differences in study design, subject enrolment and administration of
the treatment (form, dose and duration) in previous HT studies, the conclusion about
the effect HT on objectively measured sleep quality is debatable. The results may
be influenced by the inclusion of perimenopausal women instead of postmenopausal
women [49]. Also, recruiting both naturally and surgically menopausal women to the
same sleep study [50] may cause significant bias not only because of wide age range
but because in natural menopause biological changes and clinical symptoms occur
gradually, while in surgical menopause a sudden decrease in female sex-hormone
production leads to major changes in physiological functions and generally to more
severe symptoms [59]. The duration of all prospective studies has been short, from
4 weeks to 7 months, and thus the possible long-term effects of HT remain unanswered.
In observational studies [10, 55], which also have gained conflicting results,
self-chosen use of HT might have influenced the outcomes. Taken together, women
in general feel marked improvement in their sleep during HT. However, not all data
obtained from polysomnographic sleep studies support this improvement.