TOPICAL ISSUES OF PATHOPHYSIOLOGY

L.I. Kolesnikova, I.M. Madaev, N.V. Semenova, E.I. Solodova, L.A. Grebenkina, M.A. Daren

Scientific Center for Family Health and Human Reproduction, Irkutsk, Russian Federation

Assessment of the system "lipid peroxidation -

antioxidant protection"
in women with sleep disorders in the
perimenopausal period

Purpose of the study: to study lipid peroxidation processes and evaluate the antioxidant defense system with the determination of the oxidative stress coefficient (CBS) in women with
perimenopausal sleep disorders. Methods 45 women examined (average age
49.1 ± 0.32 years) of the perimenopausal period with sleep disturbances (n = 26) and without disturbances (n = 19). Evaluation of sleep disorders was carried out using a questionnaire
from the Stanford Sleep Research Center, a test to assess the subjective severity of insomnia, a questionnaire to quantify the risk of obstructive sleep apnea, a scale for quantifying the
degree of daytime sleepiness of Epworth. Spectrophotometric methods were used to study the system of “lipid peroxidation - antioxidant protection” (POL – AOZ). Intergroup differences
were evaluated by a nonparametric criterion. Results: in perimenopausal women, sleep disturbances are more often represented by difficulty falling asleep (93.3%) and morning
awakenings (78.8%). Complaints of snoring occurred in 33.3% of women. The insomnia severity index was 21.3 ± 0.54, the total score on the Epworth scale was 12.2 ± 0.42. Moreover,
these patients have a higher content of LPO intermediate products (ketodienes and conjugated trienes) 2.2 times (p <0.05), and CBS is 2 times higher. Conclusion: The obtained results
indicate the development of oxidative stress in patients with perimenopausal sleep disorders, which may serve as a pathogenetic justification for the inclusion of drugs that inhibit the
eleven
activation of lipoperoxidation processes in the complex therapy of these patients.

Key words: sleep disturbances, perimenopause, antioxidant defense, lipoperoxidation.

(Bulletin of the Russian Academy of Medical Sciences. 2014; 11–12: 11–16)

Justification hypoestrogenism, anovulation, which as a result leads to the onset of

In the life of every woman, a menopause occurs, which is considered as
a transitional period - from the heyday of the reproductive phase to the period
of extinction, and then the cessation of menstrual and reproductive functions.
During this long process, the follicular apparatus of the ovaries gradually
depletes, their functional activity decreases, hormonal relationships change,
development
menopause. In 60–80% of women, menopause occurs — a symptom complex
that complicates the physiological course of menopause and includes
vasomotor and psychoemotional disorders [1]. One of the leading signs of
neurovegetative changes in women during and after menopause is sleep
disturbance (25–50%) of menopause [2]. According to some researchers, an
inferior dream may have

LI Kolesnikova, IM Madaeva, NV Semenova, EI Solodova, LA Grebenkina, MA Darenskaya

Scienti fi c Center of the Family Health and Human Reproduction Problems, Irkutsk, Russian Federation

Evaluation of Lipid Peroxidation - Antioxidant protection in perimenopausal

Women with Sleep Disorders

Objective: Our aim was to assess lipid peroxidation - antioxidant protection with the definition of the oxidative stress coefficient in perimenopausal women with sleep disorders. Methods: 45
perimenopausal women (mean age 49.1 ± 0.32) were examined: 26 patients with sleep disorders, 19 - without sleep disorders. Evaluation of sleep disorders was conducted using a
questionnaire of Stanford Center for the Study of Sleep, test for assessment subjective severity of insomnia, the questionnaire for the quantitative assessment of the risks of sleep apnea,
the scale for quantifying the degree of daytime sleepiness Epworth. We used spectrophotometric methods for lipid peroxidation - antioxidant system investigation. Statistical analysis was
performed by non-parametric tests. Results: In perimenopausal women sleep disorders often presents falling asleep difficulties (93.3%) and morning awakening difficulties (78.8%).
Complaints of snoring detected in 33.3% of patients. Insomnia severity index was 21.3 ± 0.54, the total score on the Epworth scale - 12.2 ± 0.42. The study results showed increase of
secondary products of lipid peroxidation (ketodienes and coupled trienes) levels by

2.2 times (p <0.05). Coefficient oxidative stress in women with sleep disorders is higher by 2 times than in group without sleep disorders. Conclusion:
In perimenopausal women sleep disorders are associated with oxidative stress, which is pathogenic rationale for inclusion in the complex therapy of these patients drugs that inhibit of
lipid peroxidation activation.
Key words: sleep disorders, perimenopause, antioxidant protection, lipid peroxidation.
(Vestnik Rossiiskoi Akademii Meditsinskikh Nauk - Annals of the Russian Academy of Medical Sciences. 2014; 11–12: 11–16)
 VESTNIK RAMS / 2014 / No 11-12
influence on the performance of the system “lipid peroxidation - antioxidant
protection” (LPO - AOD) and lead to the development of oxidative stress [3–5].
This, in turn, is dangerous for the surrounding tissues and can play an
important role in the development and maintenance of inflammatory and
destructive processes, increasing the severity of the manifestation of
menopausal syndrome [6]. Currently, in addition to determining individual
indicators of the LPO - AOD processes, it is possible to use integral indicators
of oxidative stress, which are more sensitive in assessing the balance of these
processes. This is due to the fact that the complexity and multicomponent
nature of the LP - AOD system complicates the quantitative assessment of
oxidative stress, which leads to difficulties not only in interpreting the results,
but also in the antioxidant therapy when it is difficult to predict the biological
response and therapeutic effect [5, 7]. In the available literature, there is no
information on the use of such indicators in assessing balance in the LP - AOD
system in women with sleep disturbances in the perimenopausal period, which
is why The present work was the study of lipid peroxidation processes and
assessment of the AOD system with determination of the oxidative stress
coefficient for this contingent.
12
Methods
Study design
In the case-control study, women from the perimenopausal period took
part, who, according to the results of the survey, were divided into 2 groups:
the main group (with sleep disorders) and the comparison group (without sleep
disorders). All women underwent a clinical and anamnestic examination
(questionnaire, general clinical examination), and a study of the LP - AOD
system.
Compliance criteria
The criteria for inclusion of women in the perimenopause group were:
• age 45–55 years;
• follicle-stimulating hormone concentration
> 20 mU / ml;
• change in the rhythm of menstruation according to the type of
oligomenorrhea or lack of menstrual function for 12 months;
• ultrasound parameters: mismatch of the structure and thickness of the
endometrium to the 1st and 2nd phase of the menstrual cycle;
• exhaustion of the follicular apparatus of the ovaries. Women were
questioned using special questionnaires, followed by the calculation of the
total points received: a specialized sleep questionnaire developed by the
Stanford Sleep Research Center (USA), a test to assess the subjective
severity of insomnia (ISI), a questionnaire to quantify the risk of obstructive
sleep apnea syndrome sleep (OSAS), Epworth Sleeppiness Scale (ESS).
Additional criteria for the selection of women in the main group were
complaints of sleep disturbance for 6 months, repeated at least 4 nights per
week or more in the form of difficulty falling asleep (more than 20 minutes
from the moment the lights are turned off) and frequent night awakenings (at
least 2-3 episodes per night).
The criteria for exclusion of patients from the study included:
• the use of hormone replacement therapy;
• decompensated mental, neurological, cardiovascular, endocrine diseases;
• exacerbation of chronic diseases;
• history of chronic sleep disturbances;
• the use of hypnotics in the last 2 weeks;
• surgical menopause;
• shift work schedule.
Conditions
Patients were examined at the somnological center, the center of
innovative medicine of the Scientific Center for Family Health and Human
Reproduction (Irkutsk, Russian Federation). Studies of the LPO-AOD system
were carried out in the laboratory of pathophysiology of reproduction of the
Scientific Center for Family Health and Human Reproduction.
Study duration
The study was conducted in the period 2012–2013.
Study Outcomes
The results of the study confirm the hypothesis about the association of
sleep disorders with the development of oxidative stress.
Outcome Registration Methods
As a material for biochemical studies used blood serum and hemolysate.
Spectrophotometric methods were used to determine the content of substrates
for LPO processes - compounds with isolated double bonds (conventional
units) and products of lipid peroxidation processes - diene conjugates (DC,
μmol / L), ketodienes and conjugated trienes (CD - CT, conventional units)
using method I.A. Volchegorsky et al. [8]. The content of active lipid
peroxidation products was determined in a reaction with thiobarbituric acid
(TBA-AP) by the method of B. B. Gavrilova et al. [9]. Antioxidant status was
evaluated by G.I. Klebanova et al. by the level of total antioxidant activity of
blood serum (AOA) [10]. The activity of the AOD system was also judged by
the content of α-tocopherol and retinol, determined by R.Ch. Chernyauskene
et al. [eleven],
PJ Hisin and R. Hilf [12]. Superoxide dismutase (SOD) activity was determined
by the dynamics of adrenaline autooxidation according to the HP Misra and I.
Fridivich method [13]. The measurements were carried out on a
SHIMADZU-1501 spectrofluorophotometer (Japan), which consists of two
units: a UV-1650PC spectrophotometer and an RF-1501 spectrofluorimeter.
The oxidative stress coefficient [7], which is the ratio of the prooxidant to
antioxidant link, was used as an integral indicator for characterizing disorders
in the LPO – AOD system:
CBS = (Double St.I / Double St.n) × (DKi / DKn) × (KD-STi /
KD-STn) × (TBK-APi / TBK-APn)
,
(SODi / SODn) × (GSHi / GSHn) × (retinol i / retinol n) ×
(α-tocopherol i / α-tocopherol n)
where dv.St. - isolated double bonds, i - indicators of the examined patient, n -
average group indicators of the control group.
 TOPICAL ISSUES OF PATHOPHYSIOLOGY

Normally, CBS tends to conditional 1. The value of CBS> 1 is considered Table. The structure of complaints of sleep disturbances in women of the

as an increase in the degree of oxidative stress. The higher the CBS value, the perimenopausal period

more intense the processes of lipid peroxidation and the less effective the Complaints n (% occurrence)
AOD system in the examined patient. Difficulty falling asleep 31 (93.3)
Frequent night awakenings 14 (42.4)
The difficulties of morning awakenings 26 (78.8)
Ethical expertise Snoring with respiratory arrest 8 (33.3)
The examination of patients was in accordance with the ethical standards Increased daytime sleepiness 8 (33.3)
of the Helsinki Declaration of the World Medical Association (World Medical
Association Declaration of Helsinki, 2008). All women signed written informed
consent. the average value of ISI was determined. So, in the main group, the value of
this index was 21.3 ± 0.54 (the norm is from 0 to 7), which corresponded to
severe sleep disturbances.
Statistical analysis
For the statistical analysis of the obtained data, the statistical package Moreover, 8 (33.3%) women of the main group complained of snoring and
STATISTICA v. 6.1 (StatSoft Inc, USA). Since the distribution of indicators in respiratory arrest during sleep - apnea (according to others), i.e. scored 4
the studied groups did not correspond to the normal, when analyzing points or more on the questionnaire for the primary diagnosis of OSAS, which
intergroup differences for independent samples, the nonparametric Mann – indicates the presence of this syndrome in these patients. When analyzing the
Whitney test was used. The critical level of significance was taken as 5% questionnaire data on the Epworth daytime sleepiness rating scale, it was
(0.05). Data are presented as mean (M) ± standard deviation (σ). revealed that the total score in patients of the main group was 12.2 ± 0.42
against standard values ​from 0 to 8 points.

When assessing the severity of menopausal syndrome in the examined

results
Study participants
45 women of the perimenopausal period were examined, the average age
of which was 49.2 ± 0.29 years. Based on the results of the questionnaire, 2
groups of patients were formed: the main one was women with sleep disorders
( n = 26), the average age of which was
women on the basis of a modified menopausal index, it was found that a mild thirteen
severity of menopausal disorders was recorded in 15 (57.7%) women of the
main group and in 16 (84.2%) comparison groups. Menopausal syndrome of
moderate severity was diagnosed in 11 (42.3%) women of the main group and
in 3 (15.8%) in the comparison group.

48.85 ± 0.55 years, body mass index - 27.09 ± 1.56 kg / m 2
and comparison group - women without sleep disturbances ( n = 19) with an
average age of 50.36 ± 0.53 years and a body mass index of 25.9 ± 4.73 kg /
m 2.
Key findings
In a detailed analysis of the questionnaire data of women in the main
group, it was found that 31 (93.3%) patients complained of difficulty falling
asleep (more than 20 minutes from the moment the lights turned off), 26
(78.8%) - of difficulties with morning awakenings. Nocturnal awakenings (2 or
more times during a night's sleep) were noted in 14 (42.4%) women (table).
Based on the results of an insomnia severity index (ISI) subjective
severity test
The results of the study, characterizing the processes of lipid
peroxidation and the AOD system in the studied patients, are presented in
Fig. 12.
In women with sleep disturbances in perimenopause, in contrast to the
comparison group, an increase in the content of CD - ST was found to be 2.2
times ( p < 0.05) (0.58 ±
0.33 versus 0.26 ± 0.12 conventional units, respectively, in the comparison
group), although the level of highly toxic TBA active LPO products did not
statistically differ from the values ​of the comparison group (1.30 ± 0.48 against
1.14 ± 0.52 ml mol / L, respectively). With respect to the AOD system, a
tendency toward a decrease in the content of molecular antioxidants and the
level of total serum AOA was noted (see Fig. 2).

Gssg
*
twenty
140 -
SOD GSH
120
-4
100
%

-6
80
%

-8
60 Total AOA Retinol
40
- 10
α –Tocopherol
0 20 - 12
Double bond DK KD-ST TBK-active
- 20 - 14
substrates products
-sixteen

Fig. 1. Relative values ​of indicators of lipid peroxidation processes in women with sleep Fig. 2. The relative values ​of the indicators of the AOD system in women with sleep
disturbances in perimenopause. disorders in perimenopause.
Note. 0% - comparison group; * - significant differences with the comparison group ( p < 0.05). Note. 0% - comparison group.

Total AOA - total antioxidant activity of blood, SOD - superoxide dismutase, GSH -
DK - diene conjugates, KD-ST - ketodienes and conjugated trienes, TBA-active products - reduced glutathione, GSSG - oxidized glutathione.
active products of thiobarbituric acid.
 VESTNIK RAMS / 2014 / No 11-12
When calculating CBS, it was revealed that in women of the
perimenopausal period with sleep disorders, CBS is equal to
2.2, which indicates the presence of initial manifestations of oxidative stress in
them. It should be noted that in 78% of patients the values ​of the prooxidant
link were
> 1, and the values ​of the AOD system <1, which indicates the activation of the
prooxidant and depletion of the antioxidant link of the LPO - AOD system in
patients with sleep disorders.
Discussion
Normally, lipid peroxidation, although at a very low rate, continuously
proceeds in the tissues of a living organism with the formation of active
products, which leads to radical polymerization. To control free radical
processes and further possible damage to cellular structures, there is a
multicomponent AOD system that allows maintaining the intensity of free
radical processes at an optimal level. The ratio of the activity of oxidative
processes and antioxidant protection not only reflects, but also largely
determines the metabolic rate, the adaptive capacity of the body and the risk
of oxidative stress [14].
14
Currently, menopause is considered as a risk factor for oxidative stress,
which is associated with hypoestrogenia, which is one of the characteristic
endocrine disorders in the development of menopause and leads to
atherogenic disorders in the blood serum and, as a consequence, the
intensification of LPO processes [15, 16]. Studies conducted in recent years
have shown that oxidative stress has pathogenetic significance in the
development of disorders and the extinction of a woman’s reproductive
function and is more pronounced in postmenopausal women than in the
perimenopausal period [17]. The activity of free radical oxidation of body lipids
in women with a deficiency of sex steroids largely depends on the variant of its
development. With the physiological course of menopause, the activity of free
radical lipid oxidation is within the age norm due to the fact that LPO
processes and the antioxidant supply of the body are balanced. In the
pathological course of menopause, there is a significant activation of lipid
peroxidation processes, which is the result, on the one hand, of an increase in
the true level of lipid peroxidation products, and, on the other, of a decrease in
the total antioxidant activity.
According to the theory of E. Reimund (1994), during sleep, the removal
of free radicals that accumulate in the body during wakefulness occurs. In this
regard, insomnia, which is one of the most common disorders that accompany
menopause in women, leads to the accumulation of free radicals in the body
[18]. However, the results of experimental studies concerning the study of
these aspects are highly controversial [19, 20]. The data obtained in the
studies of M. Gulec et al. Demonstrate that in patients with insomnia, the
activity of glutathione peroxidase is reduced and the content of end-products
of lipid peroxidation is increased [4]. An increase in the level of TBA-active
products was also detected in patients with postmenopausal insomnia [3].
According to our results, in women in perimenopause with sleep disorders, an
increase in the concentration of secondary lipoperoxidation products was
noted.
no significant differences were found, but there was a tendency to a decrease
in the content of important bioantioxidants: α-tocopherol and retinol. The fact of
the development of oxidative stress in patients with sleep disorders is
indicated by an integral indicator of the balance of the LPO - AOD system, the
magnitude of which this condition can be interpreted as the initial
manifestations of oxidative stress. Our results are to some extent consistent
with the data of B. Liang et al. (2013), the study of which showed a decrease
in the overall antioxidant status and an increase in oxidative link and oxidative
stress coefficient. In contrast to our work, their studied groups included both
women and men. According to the researchers, a decrease in the activity of
the antioxidant enzyme paraoxanase can play a role in the development of
oxidative stress with insomnia [21].
The development of oxidative stress in women with sleep disturbances in
perimenopause can also be associated with a decrease in the level of
melatonin in their body, which, in addition to a variety of biological regulatory
effects, also has antioxidant activity. In addition to the direct effect on free
radicals, melatonin affects the activation of AOD system enzymes, such as
SOD, catalase, glutathione peroxidase, glutathione reductase and
glucose-6-phosphate dehydrogenase, and its deficiency in the body
contributes to the development of oxidative stress [22]. To date, it is known
that this hormone is one of the main regulators of circadian biorhythms, and a
violation of its secretion during the onset and development of menopause in
women leads to a change in metabolic processes and the formation of various
diseases, including and sleep disturbances [23–25]. So shown that in
menopausal women with insomnia, a decrease in the content of melatonin in
the blood serum occurs [23]. According to other authors, the combination of
menopausal syndrome and sleep disturbances occurs with increased
excretion of 6-sulfato-simelatonin in the urine of middle-aged patients. In older
women, an increase in its excretion level is associated with sleep disturbances
and does not depend on the presence of menopausal syndrome [25]. Our
previous studies showed a change in the circadian rhythm of melatonin
secretion in women with perimenopausal sleep disturbances, characterized by
a shift in the peak of secretion from nighttime to early morning hours. In
addition, a significant decrease in its content in salivary fluid was found in
women with sleep disorders [26].
According to the literature, oxidative stress can also occur with OSAS.
Hypoxia occurring in this pathological condition, as a stressor, causes changes
in free radical homeostasis, manifested in the form of a deficiency of reactive
oxygen species and activation of LPO processes [27]. The combination of
OSA with insomnia was observed in 33.3% of women in our country. a study
that can also play a role in the development of oxidative stress in the main
group of patients.
Thus, oxidative stress in women with sleep disturbances in
perimenopause may be due to the insufficiency of various parts of the AOD
system, as well as hypoxia that occurs during OSAS. The fact of the
development of oxidative stress in this study is consistent with the hypothesis
of E. Reimund about the protective function of sleep from oxidative damage
[18]. Given the relationship of insomnia with impaired carbohydrate
metabolism [28], obesity [29] and cardiovascular disease

studies [30], in the pathogenesis of which there is oxidative stress, the study of
all stages of the multi-stage LPO process in sleep disorders requires close
attention of researchers to develop recommendations for preventive and
therapeutic measures in order to improve the quality of life of patients.
Conclusion
In women of the perimenopausal period, sleep disorders are more often
represented by press and postcommunic disorders and are associated with
the development of oxidative stress, as evidenced by the value of the integral
indicator. The results of this work confirm the position that, for a complete
picture of the character
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CONTACT INFORMATION
Kolesnikova Lyubov Ilinichna, Doctor of Medical Sciences, Corresponding Member of the Russian Academy of Sciences, Professor, Director of the NCHPCH

The address: 664003, Irkutsk, st. Timiryazev, d. 16, tel .: + 7 (3952) 20-76-36, e-mail: iphr@sbamsr.irk.ru
Madaeva Irina Mikhailovna, Doctor of Medical Sciences, Head of the Somnological Center
The address: 664003, Irkutsk, st. Timiryazev, d. 16, tel .: + 7 (3952) 20-76-36, e-mail: iphr@sbamsr.irk.ru
Semenova Natalya Viktorovna, Candidate of Biological Sciences, Researcher, Laboratory of Pathophysiology of Reproduction

The address: 664003, Irkutsk, st. Timiryazev, d. 16, tel .: + 7 (3952) 20-76-36, e-mail: natkor_84@mail.ru
Solodova Elena Igorevna, obstetrician-gynecologist of the clinic
The address: 664003, Irkutsk, st. Timiryazev, d. 16, tel .: + 7 (3952) 20-76-36, e-mail: iphr@sbamsr.irk.ru
Grebenkina Lyudmila Anatolyevna, Candidate of Biological Sciences, Senior Researcher, Laboratory of Pathophysiology of Reproduction

The address: 664003, Irkutsk, st. Timiryazev, d. 16, tel .: + 7 (3952) 20-76-36, e-mail: iphr@sbamsr.irk.ru
Darenskaya Marina Alexandrovna, Candidate of Biological Sciences, Senior Researcher, Laboratory of Pathophysiology of Reproduction

The address: 664003, Irkutsk, st. Timiryazev, d. 16, tel .: + 7 (3952) 20-76-36, e-mail: iphr@sbamsr.irk.ru
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