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The World Journal of Men's Health logoLink to The World Journal of Men's Health
. 2023 Jan 1;41(3):671–679. doi: 10.5534/wjmh.220130

Attenuation Effect of Recovery Sleep for Impaired Reproductive Function in Male Rats by Sleep Deprivation

Wei Zhang 1,*, Xiao Shi 2,*, Yuyang Zhang 1, Guodong Liu 1, Xu Wu 1, Houbao Huang 3, Hui Jiang 4,✉, Xiansheng Zhang 1,✉
PMCID: PMC10307645  PMID: 36593710

Abstract

Purpose

The aim of the present study was to test the hypothesis that recovery sleep could counteract the detrimental effects of sleep deprivation (SD) on male rats’ fertility.

Materials and Methods

Twenty-two rats were housed in groups of six per cage with unrestricted access to food and water in a room. The modified multiple platform method was used to induce SD in rats over a 96-hour period. We examined the effect of SD on semen quality, reproductive hormones, and testicular histology in adult male rats. Then, we investigated the effect of 7 days recovery sleep on impaired reproductive function induced by SD.

Results

After the acclimation period, 22 rats were randomly separated into three experimental groups (SD, recovery sleep, and the control groups). Ninety-six hours of SD resulted in a significant decrease in sperm motility (24.33±10.93 vs. 48.20±8.55, p<0.001) and the number of morphologically normal sperm (9.68±2.77 vs. 26.21±14.60, p<0.01) in rats, accompanied by a decrease in testosterone levels (1.53±0.55 vs. 4.44±0.56, p<0.001) and destruction of testicular tissue structure compared with control group. After 7 days of recovery sleep, semen quality, especially sperm motility, was improved and testosterone levels were significantly higher compared to post-SD (3.70±0.53 vs. 1.53±0.55, p<0.05), but remained low compared to the control group.

Conclusions

In conclusion, 96 hours of SD deteriorated the parameters of sperm motility and the number of morphologically normal sperm in rats, probably due to the decrease in serum testosterone levels and the disruption of testicular tissue structure when compared to the control group. After 7 days of recovery sleep, semen parameter, especially sperm motility and testosterone levels did not return to baseline levels compared to the control group.

Keywords: Semen analysis, Sleep deprivation, Testicular hormones

INTRODUCTION

Sleep deprivation (SD) is a state of sleep loss caused by various causes, including abnormal patterns, partial or total absence of sleep. As the pace of lifestyle accelerates and social pressure continues to increase, SD has become a prominent public health problem, and there is a noticeable increase in the incidence of SD in the last few years [1]. With the loss of sleep, it can produce various harmful health problems [2]. SD, as a harmful stress, in both humans and animals, may adversely affect the function of vital organs, including the brain, heart, liver, kidneys, testis, and epididymis [3,4,5,6]. Long-term SD may result in schizophrenia-like symptoms, which can lead to death in severe cases [7].

Currently, the effect of SD on the male reproductive system has raised concerns. It’s demonstrated that rats exposed to 96 hours of paradoxical sleep deprivation (PSD) displayed worse sexual performance [8]. In addition to the effects on sexual behavior, several studies suggest that sleep duration is related to serum testosterone levels in men [9]. Alvarenga et al [10] found that plasma testosterone levels were significantly lower in men who experienced SD ranging from 24 to 96 hours. There was a substantial inverse U-shaped association between sleep duration and two semen parameters (semen volume and total sperm number), and restrictive sleep can impair semen quality in human [11]. Continuous SD has been shown to cause pathological alterations in the testicular tissue of male rats to some extent, and these changes may be related to increased oxidative stress, decreased antioxidant capacity, and peroxidative damage in the testicular tissue of male rats [12].

Furthermore, the question of how reproductive functions are restored during recovery sleep (RS) is poorly explored. The extent and amount of RS required to reverse the consequences after SD is an area of evolving work and discussion. When, or if, recovery to baseline or in comparison to a control (CTRL) group occurs or if there is a critical point in the chronicity of detrimental changes, are important areas to investigate. In previous studies, subsequent RS after SD could restore some hormones to baseline levels, but other hormones such as testosterone and estrone remained reduced [13]. To date, there has been no systematic examination of the sperm parameters of recovery from SD.

On the basis of these considerations, the aim of the present study was to test the hypothesis that RS could counteract the detrimental effects of SD on male fertility. To achieve that, we examined the effect of RS on semen quality, reproductive hormones, and testicular histology in sleep-deprived adult male rats.

MATERIALS AND METHODS

1. Ethics statement

All procedures used in the present study were in accordance with the Guide for the Care and Use of Laboratory Animals and the experimental protocol was approved by the Animal Ethics Committee of Anhui Medical University (LLSC20200310).

2. Experimental animals and design

Male rats were provided and raised by the Experimental Animal Center of Anhui Medical University. For an acclimation period of at least 2 weeks, animals were housed in groups of six per cage with unrestricted access to food and water in a room. After the acclimation period, 22 rats were randomly separated into three experimental groups: PSD group (rats submitted to 96 h of PSD, n=6), RS group (7 days RS after PSD, n=6), and CTRL group (n=10). The overall diagram of study design was shown in Fig. 1.

Fig. 1. The overall diagram of study design. PSD: paradoxical sleep deprivation, RS: recovery sleep, CTRL: control.

Fig. 1

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3. Paradoxical sleep deprivation and recovery

The modified multiple platform method was used to induce PSD in rats over a 96-hour period [14]. Six rats were placed individually in a tiled water tank (100*50*40 cm) with eight circular platforms (each 6.5 cm in diameter) with the water level 1 cm below the platform surface. The rats can thus move within the tank by jumping from one platform to another. When they approached the paradoxical phase of sleep, muscle atonia caused them to fall into the water and awaken. Throughout the study, the experimental room was maintained at a controlled temperature (23℃±1℃) with a 12 h+12 h light/dark cycle (lights on from 7 AM to 7 PM). The rats had free access to food and water located on a grid at the top of the tank. The water in the tank was changed daily during the PSD period.

The RS protocol was based on the technique used for the PSD conditions. The difference in the RS protocol was that six rats were kept in a no-intervention environment for 7 days after PSD to study whether the effects of SD were reversible. After PSD, the RS group was maintained in the same room and conditions as the CTRL group and rats in RS group can sleep whenever it wants to without any interference.

4. Serum testosterone analysis

After the experiment on SD and RS, all the rats in the three groups were taken to an adjacent room and decapitated. Five mL of the blood sample from the abdominal aorta was centrifuged for 3,000 rpm, 15 minutes. Then the serum was aspirated into an eppendorf tube and stored individually. Enzyme-linked immunosorbent assay kits (ELISAs) were applied for the determination of serum testosterone levels. The manufacturer’s instruction manual was followed to determine. No significant cross-reactivity or interference was found in the assay. All samples were analyzed in duplicate.

5. Collection and analysis of sperm from epididymides

After the blood sample, both epididymides of the rat were removed and immediately immersed into 1 mL of saline at 37℃ and minced the epididymides tissue with scissors. The epididymis tissue releases sperm in the solution sufficiently to make a sperm suspension. Then, a Computer Assisted Semen Analyzer (CASA) system SQA-V (Medical Electronic Systems, Ltd, Tel Aviv, Israel) was applied to evaluate sperm parameters, including sperm concentration, motile sperm concentration, total motility, progressive motility, nonprogressive motility and morphologically normal sperm.

6. Testicular histomorphological observation

The testes of rats were carefully separated and removed, and fixed in animal testicular tissue fixative, dehydrated in ethanol after 24 hours, and paraffin-embedded. The tissue was then cut into 5 µm sections, fixed on the sections, de-paraffinized, and re-hydrated. Hematoxylin and eosin (H&E) staining was used to evaluate testicular histomorphological variations. Testicular tissue was magnified at 100× and 200× under a light microscope for observation.

7. Statistical analyses

The data were analyzed by GraphPad Prism 4.00 (GraphPad Software, Inc., San Diego, CA, USA), and all the data are presented as mean±standard deviation. Shapiro–Wilk test was used to test the normality of data samples. ANOVA or Kruskal–Wallis test was applied to evaluate the effects of SD on serum testosterone and sperm parameters between groups. When the F value was significant, the post hoc comparison was done using the least-significant difference (LSD) test. Results were statistically significant when p<0.05. The significance level was also set at p<0.05.

RESULTS

1. Variations in behavior

All subject animals had completed the whole experiment, without death and escape. After 6 to 48 hours of SD, the PSD group behaved hyperactivity and the excitability to stimuli such as sound and light was increased compared to the CTRL group. After 72 to 96 hours of SD, the rats in the experimental group behaved exhibited frequent head down, reduced activity, depression, dull and scattered fur, decreased feeding, wasting, weakened response to external stimuli, and often occur “agitation” phenomenon. Rats behaved backward, escape, and scream in response to touching. The degree of fatigue and sleepiness of the rats gradually deepened with the extension of the experimental time, and the behavior of the rats gradually changed from excitement to inhibition.

2. Sperm parameters

After PSD and RS, we assessed sperm parameters such as sperm concentration, motile sperm concentration, total motility, progressive motility, nonprogressive motility, and morphologically normal sperm (Table 1). The results of the variance analysis revealed a significant difference among the means of motile sperm concentration, total motility, progressive motility, and morphologically normal sperm in different groups. Motile sperm concentration, total motility, progressive motility, and morphologically normal sperm all significantly decreased in rats under PSD. In order to investigate whether RS can reverse the impairment of sperm parameters, the LSD test was used to provide a post hoc comparison between the three groups (shown in Fig. 2). There was a significant decrease in the motile sperm concentration and morphologically normal sperm in the RS group when compared to the CTRL group (46.98±10.50 vs. 73.03±28.06, p<0.05; 12.85±3.67 vs. 26.21±14.60, p<0.05; Fig. 2B, 2D), while there was no significant increase in the RS group when compared to PSD group (46.98±10.50 vs. 33.13±10.15, p>0.05; 12.85±3.67 vs. 9.68±2.77, p>0.05; Fig. 2B, 2D). The results showed that RS did not significantly reverse the impairment of motile sperm concentration and morphologically normal sperm. However, the total sperm motility was significantly increased in the RS group when compared to the PSD group (39.00±6.87 vs. 24.33±10.93, p<0.05; Fig. 2C). The results showed that 7 days of RS can improve the total sperm motility of rats under PSD, which was mainly due to the significant improvement of progressive motility after RS (Fig. 2C).

Table 1. Comparison of sperm parameters and serum testosterone between PSD, RS, and control groups.

Group Sperm parameter Sex hormone
Sperm concentration (106/mL) Motile sperm concentration (106/mL) Sperm total motility (%) Progressive motility (%) Nonprogressive motility (%) Morphologically normal sperm (106/mL) Serum testosterone (ng/mL)
PSD 143.70±30.67 33.13±10.15** 24.33±10.93*** 14.33±8.69*** 10.00±2.28 9.68±2.77** 1.53±0.55***
RS 136.35±27.82 46.98±10.50** 39.00±6.87*** 26.33±6.12*** 12.67±1.37 12.85±3.67** 3.70±0.53***
CTRL 148.71±34.08 73.03±28.06** 48.20±8.55*** 37.20±9.20*** 11.00±1.76 26.21±14.60** 4.44±0.56***
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Values are presented as mean±standard deviation.

PSD: paradoxical sleep deprivation, RS: recovery sleep, CTRL: control.

ANOVA between groups. Significant differences between three groups, **p<0.01; ***p<0.001.

Fig. 2. Effect of paradoxical sleep deprivation (PSD) and recovery sleep (RS) on the sperm parameters. (A) Sperm concentration; (B) motile sperm concentration; (C) sperm total motility; (D) morphologically normal sperm. The LSD test was used to provide a post hoc comparison between three groups. Significant differences versus the control (CTRL) group, *p<0.05; **p<0.01; ***p<0.001. Significant differences versus the RS group, #p<0.05. ns: no significance.

Fig. 2

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3. Serum testosterone levels

The results of the variance analysis revealed a significant difference in the serum testosterone level in the three groups (Table 1). After SD, there was a significant decrease in serum testosterone levels in rats. Further pairwise comparison showed that serum testosterone levels were significantly increased in the RS group when compared to the PSD group (3.70±0.53 vs. 1.53±0.55, p<0.05; Fig. 3); while serum testosterone levels remained decreased in the RS group rats when compared to the CTRL group (3.70±0.53 vs. 4.44±0.56, p<0.05; Fig. 3). This indicated that 7 days of sleep recovery can partially reverse the damage of PSD in serum testosterone.

Fig. 3. Effect of paradoxical sleep deprivation (PSD) and recovery sleep (RS) on the serum testosterone levels. The LSD test was used to provide a post hoc comparison between three groups. Significant differences versus the control (CTRL) group, *p<0.05; ***p<0.001. Significant differences versus the RS group, #p<0.05. ns: no significance.

Fig. 3

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4. Testicular histology

Testicular histology changes were shown in Fig. 4. Compared with the CTRL group, the RS group had increased interstitial mass and partial congestion, whereas the PSD group had lax germinal tubules with increased interstitial mass and more pronounced congestion and edema. The wall of the testicular seminiferous tubules in the experimental group became thinner, the spermatogenic cells at all levels were loosely arranged and disorganized, and the number of mature spermatozoa in the tube lumen was reduced, when compared with the CTRL group (Fig. 4B, 4C). Under high magnification, the basement membrane of the wall of the testicular seminiferous tubules in high concentration group was broken and the spermatogonia were shed to the lumen (Fig. 4E, 4F).

Fig. 4. The morphological changes of testis tissue through H&E staining between three groups. Normal morphology of seminiferous tubules is seen in the control group. Abnormal morphology of seminiferous tubules is seen in the PSD and RS groups. (A, D) Control group. (B, E) RS group. (C, F) PSD group. (A-C) Magnification, ×100. (D-F) Magnification, ×200.

Fig. 4

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DISCUSSION

With the development of society, various factors leading to sleep disorders are gradually increasing, such as cell phone use on the pillow, car noise on the road, and being briefly awakened from work during the night shift [15,16]. Exposure to this environmental stressor may cause damage to male reproductive function and even eventually lead to male infertility [17]. In the meantime, the RS required to reverse impaired reproductive function after sleep restriction is an area that deserves further work and discussion. The study of the mechanisms of SD and RS effects on reproductive function may help us accomplish significant progress in the treatment of infertility.

In the current study, 96 hours of SD resulted in a significant decrease in sperm motility and the number of morphologically normal sperm in rats, accompanied by a decrease in testosterone levels and destruction of testicular tissue structure when compared to the CTRL group. These findings confirm previous observations that SD can reduce semen quality and impair male reproductive function, which may be caused by several factors, including a decreased testosterone level [13], oxidative stress in the testes [18], and a disruption of the blood-testis barrier [19].

The exact mechanism of altered testosterone levels associated with SD is not fully clarified. However, a couple of relevant pathways have been revealed so far. The increased levels of corticosteroids caused by stressful stimuli such as sleep disorders may depress the hypothalamic-pituitary-gonadal axis, and lead to a decrease in testosterone secretion [20,21]. In addition, a decrease in testosterone levels can impair reproductive function by affecting spermatogenesis and the growth of spermatogenic tissues [22].

Besides, 96 hours of PSD in male rats can cause an abnormal increase in inducible nitric oxide synthase (iNOS) gene expression [23], induce oxidative stress and increase NO levels [18]. NO can be involved in spermatogenesis and apoptosis of spermatogenic cells [24], which can damage the reproductive system. The excessive accumulation of NO inhibits the mitochondrial electron transport chain and various enzymes related to the citric acid cycle, leading to mitochondrial dysfunction, increasing oxygen radical production, and promoting oxygen radical release [25], which in turn promotes high-level oxidative stress, thereby causing atrophy of the germinal tubules and reducing germinal cell and sperm survival [26]. SD also alters antioxidant defense systems and increases cellular energy metabolism [27], all of which promote the production of oxidative stress. Sleep restriction increased the barrier permeability to low and high-molecular-weight tracers, decreased the expression of tight junction proteins, actin, and disrupts blood-testis and blood–epididymis barriers [19]. In a combination of these pathological factors, SD may be one of the factors of impaired semen quality in male rats. The adverse effects of SD on male reproductive function were further confirmed by abnormal testicular histopathologic findings. Our results of H&E staining showed that the spermatogenic tubules of the testes were lax, with increased interstitial and visible congestion and edema after SD compared to the CTRL group.

In our study, we have observed that after 7 days of RS, semen quality, especially sperm motility, was improved and testosterone levels were significantly higher compared to post-SD, but remained low compared to the CTRL group. Thus, there may be other factors and mechanisms behind the significant reduction in testosterone. The mechanism responsible for the failure to restore testosterone to its basal levels is unknown. It is speculated that prolonged SD may have caused some irreversible damage to the reproductive system. Previous studies on sleep recovery had similar results [28], SD induced a significant increase in white blood cell (WBC) counts and altered subpopulation distribution, and subsequent RS had an overall reversal effect on diurnal changes in WBC subpopulations compared to SD. However, even after 7 days of RS, not all blood counts return to baseline.

SD causes a decrease in semen quality, but does not destroy the spermatogenic tubules and other structures of the testis completely, nor damage all the sperm in the transit cycle, so there may be normal sperm in transit cycle ready to enter caput epididymides. Therefore, we do not consider the complete cycle of the sperm (3 wk or longer). After acute SD or sleep restriction (night shift work, etc.), semen quality may be negatively affected, while a short sleep recovery (within a week) does not fully restore semen quality, it may take a longer time. Although RS does not reverse the damage completely, these results further emphasize the importance of longer periods of RS after sleep restriction and suggest that the adaptive mechanisms established after variations in sleep quantity take time to stabilize [29]. For individuals who work night shifts, rest and sleep recovery after work are essential.

One limitation of our study may be the small sample size. Our experimental platform can only sleep deprive six rats at a time, so we only selected one group for 7 days recovery after SD. The other limitation of this study is that we do not know the baseline of all the rats. In addition, this is a short-term experimental study, different recovery time groups (different number of days and weeks) need to be designed to determine when and what extent recovery occurs. Despite these limitations, our studies do illustrate the changes that occur with increased RS after sleep restriction. More systematic experiments are required to properly understand how RS improves the pathological process.

CONCLUSIONS

In conclusion, these experiments showed that 96 hours of SD deteriorated the parameters of sperm motility and the number of morphologically normal sperm in rats, probably due to the decrease in serum testosterone levels and the disruption of testicular tissue structure. Interestingly, semen parameter, especially sperm motility and testosterone levels did not return to baseline levels compared to the CTRL group even after 7 days of RS.

Footnotes

Conflict of Interest: The authors have nothing to disclose.

Funding: The National Natural Science Foundation of China (Grant No. 82071637).

Author Contribution:
  • Conceptualization: WZ, XS.
  • Data curation: YZ, XW, GL.
  • Formal analysis: WZ, XS.
  • Funding acquisition: HJ, XZ.
  • Investigation: YZ, XW, GL, HH.
  • Methodology: WZ, XS.
  • Project administration: HJ, XZ.
  • Resources: HJ, XZ.
  • Software: WZ, XS.
  • Supervision: WZ, XS.
  • Validation: WZ, XS.
  • Visualization: WZ, XS.
  • Writing – original draft: WZ, XS.
  • Writing – review & editing: WZ, XS, HJ, XZ.

Data Sharing Statement

The data required to reproduce these findings cannot be shared at this time due to legal and ethical reasons.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data required to reproduce these findings cannot be shared at this time due to legal and ethical reasons.

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