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AAMJ, Vol. 10, N. 3, Sep, 2012, Suppl-1

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IMPACT OF SLEEP DEPRIVATION AND SLEEP RECOVERY

ON REPRODUCTIVE HORMONES AND TESTICULAR

OXIDATIVE STRESS IN ADULT MALE RATS

Ebtihal A. Abd El-Aziz And Dalia G. Mostafa

Department.of Physiology, faculty of Medicine, Assiut University

ABSTRACT

Objectives: sleep deprivation is a significant problem among adult men. It

is considered to be a risk factor that contributes to several disease. It has been

proposed that reactive oxygen species and the resulting oxidative stress may be

responsible for some of the effects of sleep deprivation. The present study was

performed to determine the impact of sleep deprivation for different periods on

serum testosterone, luteinizing hormone, corticosterone and whether sleep

deprivation causes oxidative stress indicated by measuring malondialdehyde

(MDA) level in testicular tissue as a direct evidence of cellular damage and

measuring glutathione (GSH) in testicular tissue to determine possibility of

reversible nature of oxidative stress by scavenger antioxidant system. We

studied also if sleep recovery after sleep loss could relieve these effects or not.

Material and methods: 42 adult male albino rats aged 12 weeks weighing about

200-250 gm were used in this study. They were divided into seven groups, six

animals in each group, a control group and six experimental groups. Three

experimental groups were used as sleep deprivation (SD) groups and another

three experimental groups were used as sleep recovery (SR) groups. The SR

groups were also sleep deprived and then returned to home-cages and were

allowed to undisturbed and spontaneous sleep. Group I: served as a control

group. Group II: rats were subjected to sleep deprivation for one day. Group

III: rats were subjected to sleep deprivation for three days. Group IV: rats were

subjected to sleep deprivation for five days. Group V: rats were subjected to

EBTIHAL A. ABD EL-AZIZ and DALIA G. MOSTAFA

161

sleep deprivation for three days followed by a period of sleep recovery for one

day. Group VI: rats were subjected to sleep deprivation for three days followed

by a period of sleep recovery for three days. Group VII: rats were subjected to

sleep deprivation for three days followed by a period of sleep recovery for five

days. After each planned SD and SR period, blood samples were collected for

hormonal assay. The rats were decapitated and the testes were dissected out

and used for the study of malondialdehyde and glutathione. The parameters

were measured then analyzed by using Student's t-test. Results: serum

testosterone level and luteinizing hormone (LH) showed significant decrease

after three days of deprivation. Serum corticosterone level increased

significantly from the first day of deprivation in comparison with the control

group. After five days of sleep recovery, serum testosterone level and

corticosterone returned to the level of the control group. Serum LH level

improved after three days of sleep recovery. Sleep deprivation increased the

testicular tissue MDA significantly and GSH was significantly decreased after

three day of sleep deprivation when comparing with the control. Sleep recovery

decreased testicular tissue MDA significantly and significant increase in GSH

after the fifth day as non-significant change noticed on comparing their levels

on that day with the control. Conclusions: The present study demonstrated the

sleep deprivation effects on testosterone, luteinizing hormone, corticosterone

levels in serum, malondialdehyde and glutathione in testicular tissue of rat.

Sleep recovery was associated with restoration of the serum hormone levels.

Also with sleep recovery MDA level was decreased and GSH content was

improved in testicular tissue.

Key words: sleep deprivation, sleep recovery, testosterone hormone ,

luteinizing hormone, corticosterone hormone , malondialdehyde and

glutathione


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INTRODUCTION

Sleep deprivation is a significant problem among adult men (Andersen et

al., 2005 and Andersen & Tufik, 2008). It is considered to be a risk factor that

contributes to several disease processes (Wu et al., 2011) via its ability to alter

behavioral (Andersen et al., 2000 & 2003), hormonal (Andersen et al., 2004 &

2005) and neurochemical pathways (Martins et al., 2004 and Pedrazzoli et al.,

2004). Sleep deprivation is one of the consequences of the pressure from society

on individuals, impacting their health and wellbeing (Tufik et al., 2009).

In rodents, sleep interference causes alterations in several aspects of

physiological and behavioral functioning, such as sexual behavior (Alvarenga et

al., 2009 and Andersen et al., 2009), memory (Alvarenga et al., 2008), anxiety

(Suchecki et al., 2002), attention (Godoi et al., 2005), hormonal changes

(Antunes et al., 2006), and damage to the immune system (Zager et al., 2009).

Several studies have shown that sleep deprivation reduces circulating

androgens in healthy men including testosterone (Eacker et al., 2008 and Maia

et al., 2011). Decreased testosterone levels can impair gonadal and sexual

functions, and potentially result in decreased fertility (Luboshitzky et al., 2002).

Circulating testosterone levels are known to increase during sleep (Corts-

Gallegos et al., 1983).

The control of androgen production from the Leydig cell is dependent

upon the episodic secretion of LH hormone, which is released in pulses from the

anterior pituitary gland (Dufau et al., 1984).

Sleep deprivation involves some degree of stress which results in

stimulation of hypothalamicpituitaryadrenal axis (HPA axis). This stimulation

can result in an increase in the plasma level of corticosterone and a concomitant

change in testosterone (Suchecki and Tufik, 2000), mediated by a change in LH

(Demura et al., 1989).

Sleep deprivation per se causes changes in lipid peroxidation or in


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antioxidant defenses. Oxidative stress is a condition associated with an

increased rate of cellular damage induced by oxygen derived oxidants

commonly known as reactive oxygen species (ROS). ROS are reported to

damage almost all macromolecules of the cell, including polyunsaturated fatty

acids of membranes, thus causing impairment of cellular functions (Halliwell,

1996). Testicular membranes are extremely rich in polyunsaturated fatty acids

therefore; the organ is highly susceptible to oxidative stress (Manna et al.,

2003). Sleep after sleep deprivation is widely considered to have restorative

properties; free radicals accumulate during wakefulness and are removed during

sleep (Everson et al., 2005).

AIM OF THE STUDY

The present study was designed to determine the impact of sleep

deprivation for different periods on serum testosterone, luteinizing hormone,

corticosterone and whether sleep deprivation causes oxidative stress indicated

by measuring MDA level in testicular tissue as a direct evidence of cellular

damage and measuring GSH in testicular tissue to determine the possibility of

reversible nature of oxidative stress by scavenger antioxidant system and

whether sleep recovery after sleep loss could relieve these effects or not.

MATERIAL AND METHODS

Animals and groups:

42 adult male albino rats aged 12 weeks weighing about 200-250 gm were

used in this study. The rats were housed in animal house of Assiut University in

standard cages in normal room temperature with normal lightdark cycle. Food

and water were provided ad libitum. They were divided into seven groups, six

animals in each group, a control group and six experimental groups. The control

group was allowed to undisturbed, spontaneous sleep.

Rats were subjected to sleep deprivation according to Bergmann et al.

(1989) with slight modification by placing the animal on the top of a bottle


164

filled with water, the diameter of which is small relative to the animal's size.

The bottle is placed in a large tanks filled with water to be 5 cm less than the top

of the bottle. The animal is able to rest on the top of a bottle and if it began to

sleep, muscular relaxation occurred which result in either fall into the water

and clamber back to its site on the top of the bottle or get its nose wet enough to

awaken it. The water in the tanks was changed daily, throughout the SD period.

So the groups are classified as follows:

Group I: served a control group.

Group II: subjected to sleep deprivation for one day.

Group III: subjected to sleep deprivation for three days.

Group IV: subjected to sleep deprivation for five days.

Group V: subjected to sleep deprivation for three days then followed by a

period of sleep recovery for one day.

Group VI: subjected to sleep deprivation for three days then followed by a

period of sleep recovery for three days.

Group VII: subjected to sleep deprivation for three days then followed by a

period of sleep recovery for five days.

Blood sampling and hormone determination:

After each planned SD and SR period, blood samples were collected from

the retro-orbital venous plexus before sacrifice. The whole blood was incubated

to clot for 30 minutes and serum was separated by centrifugation. The separated

serum was stored frozen at -20 oC until use. Samples were assayed for

testosterone, luteinizing hormone and corticosterone by ELISA method using

available Kits according to manufacture. Testosterone hormone levels in serum

were determined using ELISA kit Coate A count kit from diagnostic product

corporation Los Anglos (A 90045 5597 USA). Luteinizing hormone levels in

serum were determined using rat ELISA kit cattalloge No.E0830Rb according

to manufacture. Corticosterone hormone in serum was determined using Assay


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Max Corticosterone ELISA kit Catalloge No EC3001- 1 according to

manufacture.

Testicular tissue Collection

After each planned SD and SR period, the rats were decapitated; the testes

were dissected out and used for the study of lipid peroxidation and glutathione.

The tissues of testes of different groups were homogenized in ice-cold 100 mM

phosphate buffer (pH7.4). The obtained supernatants were used for estimation

of lipid peroxidation (malondialdehyde) and GSH. MDA was estimated by

method according to (El-Shahat et al., 2009). GSH was measured by following

the standard method (Ellman, 1959).

Statistical analysis

Data were expressed as mean SD for all parameters then analyzed using

Student's t-test. P values less than 0.05 were considered significant.

RESULTS

Serum testosterone (table 1 & 2, Fig. 1 & 2)

Serum testosterone level showed non-significant decrease after one day of

sleep deprivation (5.5 0.7 ng/ml) in comparing with the control (5.9 0.8

ng/ml). The level decreased significantly after three (4.6 0.5 ng/ml) and five

(2.9 0.7 ng/ml) days of deprivation.

After one day of sleep recovery, serum testosterone level (4.7 0.4 ng/ml)

still significantly lower than that of the control group (5.9 0.8 ng/ml) but non-

significant changes were noticed in comparison with the three days deprivation

(4.6 0.5 ng/ml) group.

After three days of sleep recovery, serum testosterone level (4.8 0.6

ng/ml) was still significantly lower than that of the control group (5.9 0.8

ng/ml) but non-significantly changed in comparison with the three days of sleep

deprivation (4.6 0.5 ng/ml) group.


166

After five days of sleep recovery, serum testosterone level (5.8 0.9

ng/ml) returned to the control group (5.9 0.8 ng/ml) and non-significantly

changed on comparing both. There was significant increase on comparing them

with the three days of deprivation (4.6 0.5 ng/ml).

Serum luteinizing hormone (table 1&2, Fig. 3&4)

Serum luteinizing hormone levels after sleep deprivation for one, three and

five days were 6.03 0.3 ng/ml, 4.2 0.5 ng/ml and 2.8 0.3 ng/ml,

respectively. The effect of sleep deprivation on serum luteinizing hormone

started from the third day onward. Significant decrease was reported on

comparing three and five days sleep deprivation with the control (6.5 0.5

ng/ml).

Serum luteinizing hormone level improved earlier from the third day of

recovery. After one day of sleep recovery, serum luteinizing hormone level (3.1

0.1 ng/ml) was non-significantly lower than that of three days sleep

deprivation (4.2 0.5 ng/ml), but significantly lower than that of the control

group (6.5 0.5 ng/ml).

After three days of sleep recovery, serum luteinizing hormone level (6.3

0.7 ng/ml) was significantly higher than that of the three days sleep deprivation

(4.2 0.5 ng/ml) but no significant changes in comparison with the control


After five days of sleep recovery, serum luteinizing hormone level (6.8

0.7 ng/ml) was significantly higher than that of the three days sleep deprivation

(4.2 0.5 ng/ml) but no significant changes on comparing with the control


Serum corticosterone (table 1&2, Fig. 5&6)

Sleep deprivation increased the serum corticosterone from the first day,

significant increase was reported on comparing the sleep deprivation groups of


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the three periods with that of the control (137.3 8.2 ng/ml) vs (147.5 5.3

ng/ml, 168.2 9.4 ng/ml and 192.4 6.1 ng/ml) respectively.

Serum corticosterone of the animals that underwent sleep recovery for one

day (158.0 8.6 ng/ml), three days (150.3 5.1 ng/ml) and five days (138.5

2.0 ng/ml). Non-significant change was noticed only on comparing the five days

recovery with the control group (137.3 8.2 ng/ml). Highly significant decrease

in serum corticosterone level of the three and five days recovery groups on

comparing with the three days sleep deprivation group (168.2 9.4 ng/ml).

Testicular tissue MDA (table 3, Fig. 7)

Sleep deprivation increased the testicular tissue MDA from the first day.

Significant increase was reported after three and five day of sleep deprivation on

comparing with that of the control (8.62 0.7 mole/g tissue). One day sleep

deprivation was (8.97 0.8 mole/g tissue), three days sleep deprivation (9.55

0.8 mole/g tissue) and five days sleep deprivation (11.96 0.9 mole/g tissue).

Sleep recovery improved testicular tissue MDA after the fifth day as non-

significant change noticed on comparing its level with the control. One day

sleep recovery was (9.82 0.7 mole/g tissue), three days sleep deprivation

(9.59 0.5 mole/g tissue) and five days sleep deprivation (8.79 0.9 mole/g

tissue).

Testicular tissue glutathione (table 3, Fig. 8)

Sleep deprivation decreased the testicular tissue glutathione from the first

day. Significant decrease was reported after three and five days of sleep

deprivation on comparing with that of the control (310.0 13.2 nmol/mg

protein). One day sleep deprivation was (304.0 10.4 nmol/mg protein), three

days sleep deprivation (284.0 13.8 nmol/mg protein) and five days sleep

deprivation (270.0 17.1 nmol/mg protein). On the fifth day, sleep recovery

returned testicular tissue glutathione to control level as non-significant change

noticed on comparison with the control. One day sleep recovery was (285.0


168

20.6 nmol/mg protein), three days sleep deprivation (287.0 9.5 nmol/mg

protein) and five days sleep deprivation (305.0 19.4 nmol/mg protein).

Table (1): Serum testosterone, luteinizing hormone and corticosterone

concentrations of rats that underwent sleep deprivation (SD) for different

durations.

Testosterone

(ng/ml) P

(SDvC)

Luteinizing

hormone

(ng/ml)

P

(SDvC)

Corticosterone

(ng/ml) P

(SDvC)

Control 5.9 + 0.8 6.5+ 0.5 137.3+ 8.2

SD1 5.5 + 0.7 0.4ns 6.03+ 0.3 0.1ns 147.5+ 5.3 0.03*

SD3 4.6 + 0.5 0.02* 4.2+ 0.5 0.002** 168.2+ 9.4 0.002**

SD5 2.9 + 0.7 0.0001*** 2.8+ 0.3


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Table (3): Testicular Malondialdehyde level (MDA) and glutathione of rats

that underwent sleep deprivation (SD) and sleep recovery (SR) for different

durations.

MDA(moles/g

tissue) P

Glutathione

(nmol/mg protein) P

Control 8.62+ 0.7 310.0+ 13.2

SD1 8.97+ 0.8 (SD1vC) 0.1 ns 304.0+ 10.4 (SD1vC)0.2 ns

SD3 9.55+ 0.8 (SD3vC)0.03* 284.0+ 13.8 (SD3vC)0.02*

SD5 11.96+ 0.9 (SD5vC)0.002** 270.0+ 17.1 (SD5vC)0.006**

SR1 9.82+ 0.7 (SR1vC)0.04* 285.0+ 20.6 (SR1vC)0.03*

SR3 9.59+ 0.5 (SR3vC)0.03* 287.0+ 9.5 (SR3vC)0.03*

SR5 8.79+ 0.9 (SR5vC)0.8ns 305.0+ 19.4 (SR5vC)0.6ns

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AFATSOM .G AILAD dna ZIZA-LE DBA .A LAHITBE

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172

DISCUSSION

Sleep deprivation is a known physiological stressor and considered as a

major problem for in males (Wu et al., 2011 and Meerlo et al., 2008). The

activation of hypothalamo-pituitary-adrenocortical system and the sympatho-

adrenomedullary system was considered to be the main regulators of the stress

response (Reeder and Kramer, 2005, Joels et al., 2007 and McEwen et al.,

2007). So, the current study tried to focus on the effects of sleep deprivation and

recovery of different durations on changes of male reproductive hormones;

serum testosterone, luteinizing hormone and corticosterone levels in adult male

rats.

Our model for sleep deprivation was described as a good physiological

stressor as it produces alterations in almost all studied hormones (Knutson et al.,

2007). We compared our results of sleep recovery with sleep deprivation of the

third day because at that day we get establish socially stable group animals,

thereby obviating other possible stress variables (Suchecki & Tufik, 2000 and

Suchecki et al., 2002).

We studied the effect of SD from the 1st day up to the 5th day as Andersen

et al. (2002 & 2004), Andersen and Tufik (2008) and Eacker et al. (2008)

reported that testosterone concentrations were decreased following one to four

days of SD and this reduction was further enhanced with longer durations of

SD.

The present study estimated the serum levels of testosterone, luteinizing

hormone and corticosterone after recovery period from the 1st day up to the 5th

day trying to estimate the time elapsed to return to the resting level.

Our study revealed reduction in serum testosterone levels after SD and the

level decreased significantly after three to five days of deprivation. The same

results were reported by Amikishieva et al., 2001 and Dong et al., 2004 (for

mice), Almedia et al., 2000 and Manna et al., 2004 (for rats), and Oltmanns et


173

al., 2005 (humans). The reduction was explained according to Rajaratnam &

Arendt (2001) and Mazaro & Lamano-Carvalho (2006) by stress. The synthesis

of testosterone is dependent on endocrine (Rajaratnam & Arendt, 2001) and

neuronal (Roman et al. 2006) signals which in turn are influenced by

physiological conditions such as stress. Stress in fact results in secretion of

several hormones such as, CRH (Rivest and Rivier, 1991), ACTH (Ishikawa et

al., 1992 and Monder et al., 1994), and corticosterone (Suchecki & Tufik, 2000

and Machado et al., 2010) on HPG axis function. Although the mechanism(s)

for these effects on reproductive function are not fully elucidated, possible sites

of action include: (1) a centrally mediated inhibition of gonadotropin releasing

hormone (GnRH) release by CRH, opioids and glucocorticoids (MacLusky et

al., 1988; ); (2) glucocorticoid-induced tissue resistance to gonadal sex steroids

(Rabin et al., 1990), decreasing the sensitivity of Leydig cells to LH, or

decreasing testicular receptors to this hormone (Payne & Youngblood, 1995);

(3) direct gonadal effects of glucocorticoids with subsequent alterations in sex

steroid output (Hardy and Ganjam, 1997), corticosterone reduce testosterone

production in Leydig cells and to induce apoptosis in these cells (Gao et al.,

2002, Retana-Mrquez et al., 2003 and) (4) a glucocorticoid-mediated decrease

in pituitary responsiveness to GnRH, resulting in decreased LH secretion

(Chichinadze & Chichinadze, 2008).

The decreased testosterone levels associated with SD may be in part due to

serotonin-related inhibition of testosterone production (Gao et al., 2002 and

Meerlo et al., 2008). In addition, both serotonin and serotonin receptors have

been localized in Leydig cells isolated from the testes of golden hamsters and

serotonin has also been demonstrated to inhibit testosterone production

(Frungieri et al., 2002).

Kraut et al. (2004), Hones & Marin, (2006) and McEwen (2007) explained

the decrease in testosterone level during SD by decrease in the blood flow to


174

the testicles (less vital organs) leading to suppression of its activity during stress

in order to maximally increase the resources supplied to organs critically

important for adaptation.

In our study we observed that a decrease of LH levels were associated with

a decrease of testosterone levels in SD. This was in agreement with Almeida et

al., 2000 and Manna et al., 2004 (in rat), Stackpole et al., 2003 & Wingfield &

Sapolsky, 2003 (in farm animals) and Oltmanns et al., 2005 (humans). Rivest &

Rivier (1995) explained that by inhibiting LHRH synthesis and release from the

hypothalamus.

We found an increase of corticosterone levels during SD from the first day

to the fifth day which was associated with decreased levels of testosterone.

These findings are confirmed by the previous studies in rats and men. In rats

Gonzlez-Quijano et al., 1991 (stress by immobilization), Watanabe et al., 1991

(stress by prolonged exercise), Ishikawa et al., 1992 (stress by intermittent

electric foot shocks), Bidzinska et al., 1993 (stress by forced swimming in cold

water), Novati et al., 2008; Tiba et al., 2008; Tartar et al., 2009 (stress by

plateform). In men Opstad, 1994 (prolonged physical stress due to military

training).

In the present study, there was an increased level of testicular MDA level

(the product of lipid peroxidation) significantly after three to five days of

deprivation. These findings are confirmed by Ramanathan et al (2002) who

found that with sleep deprivation there was increase in lipid peroxidation in the

hippocampal region of the brain in wistar rats. Sleep deprivation could enhance

metabolic rate and in turn increase oxidative stress. An increase in MDA level is

related to an increase in the levels of lipid peroxidation in cell membrane. ROS

can cause cytotoxicity, one of the manifestations of which can be observed

through lipid peroxidations (Jana and Samanta, 2006).


175

The current study revealed a decrease of GSH level in testicular tissue

during SD, the level decreased significantly after three to five days of

deprivation. This was in agreement with Everson et al (2005) who found a

decrease in glutathione activity in liver after 5 days of sleep deprivation and this

decrease was sustained or worsened by prolongation of sleep deprivation. GSH

plays multiple roles as a cellular antioxidant defense because its main function

is to remove hydrogen peroxide and organic peroxides (Chainy et al., 1997).

Therefore, any decline in the level of GSH indicates the increased production of

free radicals (Debnath and Mandal., 2000). In contrast, Singh et al (2008)

noticed that sleep deprivation did not affect oxidative stress parameters in the

striatum; and the activity of glutathione peroxidase was not affected in any of

the studied brain regions.

During the recovery period, the preset study showed that the testosterone

and corticosterone reached the control level at the fifth day of recovery. While

the LH level reached the control level at the third day of recovery. This is may

be due to the ability of the rats in recovery period to accommodate the HPA axis

derangements that accompany SD and allowing them to return to a normally

functioning HPA axis during periods of SR.

The present results of corticosterone were in agreement with that reported

by Leenaars et al. (2011). In contrast, Andersen et al. (2005) found that

testosterone did not return to basal values during the recovery periods after 96 h

of SD and they suggested that long periods of SD lead to long-term effects that

may become harmful.

During the recovery period, we found that the level of MDA decreased and

level of glutathione increased and reached the basal level at the fifth day of

recovery. The decrease in lipid peroxidation following restorative sleep

indicates that there is decrease in free radical production. The other possibility is

that the free radicals are scavenged by the antioxidant mechanism. This is well


176

correlated by increase in glutathione level following restorative sleep. These

results were in accordance with the results of Mallik et al. (1995). The present

study provides evidence that sleep recovery restores or accentuates antioxidants

and antioxidant activities in the testes. Sleep recovery resulted in dramatic

returns toward normal testicular glutathione(Everson et al., 2005).

In conclusion, the present study demonstrates that sleep deprivation is a

type of stress induces changes in testosterone, luteinizing hormone and

corticosterone levels in serum and biochemical effects in rat testes. The

increased oxidative stress resulted from SD in testicular tissue might be

responsible, at least in part, for the changes occurred. SR had restoration effect

evidenced by reduction of MDA and increase of GSH in testicular tissue.


177

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