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BMC Cancer

, 19:146 | Cite as

Sleep disorders associated with risk of prostate cancer: a population-based cohort study

  • Wei-Sheng ChungEmail author
  • Cheng-Li Lin
Open Access
Research article
Part of the following topical collections:
  1. Epidemiology, prevention and public health

Abstract

Background

Disrupted sleep rhythms may lead to cancer development. We conducted a population-based cohort study to evaluate the incidence and risk of prostate cancer in patients with sleep disorders (SDs).

Methods

Patients newly diagnosed with SDs between 2000 and 2010 were enrolled from the Taiwan Longitudinal Health Insurance Database. A non-SD cohort age-matched (5-y intervals), comorbidities, and medications was randomly sampled from the general population at a 1:1 ratio. The follow-up period extended from the index date of SDs to the diagnosis of prostate cancer, censoring, or the end of 2013. We used Cox proportional hazards models to calculate the risk of prostate cancer.

Results

In total, 41,444 patients were enrolled in each cohort. The mean age of the SD cohort was 48.0 years and that of the non-SD cohort was 47.8 years, with 58.2% of both cohorts aged younger than 50 years. The incidence of prostate cancer increased with age. The overall incidence of prostate cancer was higher in the SD cohort than in the non-SD cohort (9.56 vs 6.36 per 10,000 person-y), with an adjusted hazard ratio of 1.42 (95% CI = 1.20–1.69). Age-specific analysis revealed a 1.35-fold increased risk of prostate cancer in the patients aged ≥65 years in the SD cohort compared with the non-SD counterparts (95% CI = 1.10–1.65).

Conclusions

Patients with SDs are associated with increased risk of prostate cancer.

Keywords

Sleep disorders (SDs) Prostate cancer Cohort study 

Abbreviations

aHR

Adjusted hazard ratio

CIs

Confidence intervals

COPD

Chronic obstructive pulmonary disease

HRs

Hazard ratios

ICD-9-CM

International Classification of Diseases, Ninth Revision, Clinical Modification

IRB

Institutional review board

LHID

Longitudinal Health Insurance Database

NHI

National Health Insurance

NHIA

National Health Insurance Administration

NHIRD

National Health Insurance Research Database

PSA

Prostate specific antigen

SDs

Sleep disorders

Background

Sleep disorders (SDs) are one of the most common problems in the general population. The cause of SDs can be a primary disorder or secondary to various psychiatric and medical illnesses. The prevalence of SDs tends to increase with age. Approximately 41% of the elderly experienced difficulty initiating sleep onset insomnia, sleep maintaining insomnia, or early morning awakening insomnia. [1] Inadequate and nonrestorative sleep impairs quality of life and lead to future depression development and adverse health consequences. [2, 3, 4, 5]

Previous studies have suggested that sleep disruption and circadian dysrhythmia may increase the risk of breast cancer in women. [6, 7] Melatonin, a pineal hormone, is related to circadian rhythm and sleep. [8] Recent studies have indicated that melatonin carries potentially chemopreventive, oncostatic, and anticarcinogenic effects. [9, 10] Prostate cancer has become a major public health issue in men worldwide, though the etiology of the disease remains elucidative. Two studies have reported that short sleep duration is associated with increased risk of prostate cancer. [11, 12] However, Markt et al. [13] conducted a prospective study and did not find association between sleep duration and risk of prostate cancer.

Prostate cancer is a leading cancer in men and causes a considerable economic and public health burden. [14] The incidence of prostate cancer has rapidly increased from 26.2 per 100,000 population in 2002 to 47.9 per 100,000 population in 2012 in Taiwan. [15] Employment with high job strain and stress might contribute to excess risk of prostate cancer. [16] The residents in urban areas may be associated with prostate cancer. [17] Adult obesity in the epidemiologic study showed association with development of prostate cancer. [18] Urinary stones may lead to obstruction, infection, and further cancer development. [19] A nested case-control study indicated an association between SDs and cancer. [20] People use hypnotics, mainly benzodiazepines and nonbenzodiazepine agents, to aid sleep or treat anxiety. However, hypnotic use may be related to increased cancer risk. [21] Therefore, we conducted a large population-based cohort study to investigate the risk of prostate cancer in patients with SDs compared with people without SDs after controlling for hypnotic use and potential covariates.

Methods

Data source

We conducted a retrospective population-based cohort study by using the Taiwan Longitudinal Health Insurance Database (LHID). The Taiwan government launched the National Health Insurance (NHI) program in 1995. Approximately 99% of the total population of approximately 23 million people, participate in the program. [22] The LHID is a sub-database of the National Health Insurance Research Database (NHIRD), which was established by the National Health Insurance Administration (NHIA) and is maintained by the National Health Research Institutes. The LHID contains the longitudinally linked data of 1,000,000 enrollees randomly sampled from the NHIRD. The LHID was released with de-identified data, rendering researchers unable to identify the study patients. Diseases in the database are coded according to the 2001 International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The institutional review board (IRB) of China Medical University Hospital approved this study (IRB ID number: CMUH104-REC2–115).

Sampled patients

To evaluate the risk of prostate cancer in patients with SDs, we compared a SD cohort with a non-SD cohort. From the LHID, we selected male patients who received a first diagnosis of SDs (ICD-9-CM codes 307.4 including nonorganic sleep disorders, insomnia, and circadian rhythm SD, 327 organic sleep disorders, and 780.5 indicating sleep disturbance) between January 1, 2000 and December 31, 2010, and set the first diagnosis day of SDs as the index date. We assembled the non-SD cohort by randomly selecting male patients without a diagnosis of SDs from the LHID, and frequency-matched them with the SD cohort patients by age (5-y intervals), occupation, urbanization level, comorbidities, and medications at a 1:1 ratio. We set the index date of the matched cases as the index date for the non-SD patients. We enrolled only patients who were aged more than 20 years and who did not have a history of prostate cancer (ICD-9-CM code 185) before the index date.

Outcomes, occupation, urbanization level, comorbidities, and medication

All patients were followed until a diagnosis of prostate cancer, withdrawal from the NHI, death, or the end of 2011. We categorized the occupation variable into white collar (working with long indoor work hours, such as business and administration personnel), blue collar (working with long outdoor work hours, such as farmers and laborers), and others (primarily retired, unemployed, and low-income groups). The urbanization variable for the patients’ residing area was categorized into four levels: level 1 being the highest urbanization and level 4 being the least urbanization. We examined pre-existing comorbidities including hyperlipidemia (ICD-9-CM code 272), diabetes (ICD-9-CM code 250), hypertension (ICD-9-CM codes 401–405), urinary stones (ICD-9-CM codes 592.0. 592.1, 594.0, and 594.1), urinary tract infection (ICD-9-CM codes 590 and 595), obesity (ICD-9-CM code 278), anxiety (ICD-9-CM code 300.00), depression (ICD-9-CM codes 296.2, 296.3, 300.4, and 311), chronic obstructive pulmonary disease (COPD, ICD-9-CM codes 491, 492, 496), and alcohol-related illness(ICD-9-CM codes 291, 303, 305, 571.0, 571.1, 571.2, 571.3, 790.3, and V11.3). A medication history of hypnotics and antihypertensive medication use was included in the analysis. In addition, we also evaluated prostate specific antigen (PSA) screening in the study.

Statistical analysis

The demographic and clinical characteristics of the SD and non-SD cohorts, including age (≤ 49, 50–64, and ≥ 65y), occupation category (white collar, blue collar, and others), urbanization level, comorbidities, and medication treatments, were compared using the chi-squared test. For continuous variables, we conducted the Student t test to compare the SD and non-SD cohorts. We computed the incidence rate (per 10,000 person-y) of follow-up for each cohort. To evaluate the risk of prostate cancer for the SD cohort compared with the non-SD cohort, hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using univariable and multivariable Cox proportional hazards models. The multivariable models were simultaneously adjusted for age; occupation category; urbanization level; comorbidities of hyperlipidemia, diabetes, hypertension, urinary stones, urinary tract infection, obesity, anxiety, and depression; and medication of hypnotics as well as antihypertensive medication, and PSA screening. The cumulative incidence of prostate cancer was calculated using the Kaplan–Meier method and the difference was evaluated using the log-rank test. All analyses were conducted using SAS statistical software (Version 9.4 for Windows; SAS Institute, Inc., Cary, NC, USA), with statistical significance set at P < .05 for a 2-tailed test.

Results

The SD and non-SD cohorts each comprised 41,444 patients. The mean age of the SD cohort was 48.0 years and that of the non-SD cohort was 47.8 years, with 58.2% of both cohorts aged less than 50 years (Table 1). Most of the patients in both cohorts had white-collar jobs (54.3% vs 54.0%) and tended to reside in an urbanized area (59.6% vs 59.1%). The proportions of urinary tract infection and PSA screening in the SD cohort were significantly higher than those in the non-SD cohort.
Table 1

Comparison of Demographics and Comorbidities of Patients With and Without SDs

 

Sleep disorder (N = 41,444)

Control (N = 41,444)

P value

n

%

n

%

Age, year

    

0.58

  < 49

24,137

58.2

24,114

58.2

 

 50–64

9629

23.2

9597

23.2

 

  ≥ 65

7701

18.6

7710

18.6

 

Mean (SD) #

48.0

16.6

47.8

16.7

034

Occupation

    

0.65

 White collar

22,483

54.3

22,367

54.0

 

 Blue collar

14,250

34.4

14,377

34.7

 

 Others

4711

11.4

4700

11.3

 

Urbanization level

    

0.22

 1 (highest)

12,282

29.6

12,015

29.0

 

 2

12,417

30.0

12,472

30.1

 

 3

7350

17.7

7436

17.9

 

 4 (lowest)

9395

22.7

9521

23.0

 

Comorbidity

 Hyperlipidemia

7524

18.2

7630

18.4

0.34

 Diabetes

2187

5.28

2238

5.40

0.43

 Hypertension

12,345

29.8

12,459

30.1

0.39

 Urinary stones

2770

6.68

2868

6.92

0.18

 Urinary tract infection

3039

7.33

2796

6.75

0.001

Obesity

312

0.75

338

0.82

0.31

Anxiety

1775

4.28

1691

4.08

0.14

Depression

1187

2.86

1191

2.87

0.93

COPD

4939

11.9

5033

12.1

0.32

Alcohol-related illness

1573

3.80

1566

3.78

0.90

Medication

 Hypnotics

23,308

56.2

23,082

55.7

0.11

 Antihypertensives

11,657

28.1

11,748

28.4

0.48

PSA screening

5729

13.8

4523

10.9

< 0.001

Chi-square test compared to total SD; #:t test; COPD: Chronic obstructive pulmonary disease

: The urbanization level was categorized into 4 levels according to the population density of the residential area, with level 1 indicating the highest urbanization and level 4 indicating the lowest urbanization

The overall incidence of prostate cancer was 51% greater in the SD cohort than in the non-SD cohort (9.56 vs 6.36 per 10,000 person-years), with an adjusted HR (aHR) of 1.42 (95% CI = 1.20–1.69) (Table 2). The cumulative incidence of prostate cancer was greater in the SD cohort than in the non-SD cohort (Fig. 1). Age-specific analysis revealed a significantly higher risk of developing prostate cancer in the patients all aged group in the SD cohort compared with the same age group in the non-SD cohort. Occupation category-specific analyses showed that among the patients employed in white-collar positions, those with SDs had a significantly higher risk of prostate cancer than did those without SDs (aHR = 1.67, 95% CI = 1.28–2.18). The SD cohort again exhibited a significantly higher risk of prostate cancer compared with the non-SD cohort when only the patients living in the 2nd highest (aHR = 1.43, 95% CI = 1.03–1.98), 3rd highest (aHR = 1.79, 95% CI = 1.11–2.91), and lowest (aHR = 1.42, 95% CI = 1.03–1.95 for lowest) urbanization level areas were considered. In patients without comorbidities, the risk of prostate cancer was 2.26-fold higher in the SD cohort than in the non-SD cohort (95% CI = 1.46–3.51). Among the patients not prescribed the examined medications, those with SDs had a higher risk of prostate cancer than did those without SDs (aHR = 1.46, 95% CI = 1.07–1.99 for those not prescribed hypnotics; aHR = 1.66, 95% CI = 1.26–2.19 for those not prescribed antihypertensive medication). In patients without PSA screening, the risk of prostate cancer was 1.58-fold higher in the SD cohort than in the non-SD cohort (95% CI = 1.26–1.98).
Table 2

Comparison of Incidence Densities of Prostate Cancer Hazard Ratios of Men With and Without SDs Stratified by Demographic Characteristics and Comorbidities

 

Sleep disorder

  

Yes

No

  
 

Event

PY

Rate#

Event

PY

Rate#

Crude HR (95% CI)

Adjusted HR (95% CI)

All

327

342,189

9.56

222

349,060

6.36

1.51(1.28, 1.80)***

1.42(1.20, 1.69)***

Age

  < 49

14

208,908

0.67

4

214,073

0.19

3.82(1.26, 11.6)*

3.12(1.02, 9.58)*

 50–64

94

79,239

11.9

58

81,376

7.13

1.70(1.23, 2.36)**

1.50(1.08, 2.08)*

  ≥ 65

219

54,042

40.5

160

53,610

29.8

1.36(1.11, 1.67)**

1.35(1.10, 1.65)**

 P for trend

       

0.23

Occupation

 White collar

146

187,392

7.79

89

193,265

4.61

1.71(1.31, 2.23)***

1.67(1.28, 2.18)***

 Blue collar

118

118,498

9.96

96

118,302

8.11

1.23(0.94, 1.61)

1.14(0.87, 1.49)

 Others

63

36,300

17.4

37

37,493

9.87

1.77(1.18, 2.66)**

1.56(1.04, 2.36)*

 P for trend

       

0.06

Urbanization level

 1 (highest)

97

99,276

9.77

74

104,986

7.05

1.40(1.04, 1.90)*

1.30(0.96, 1.77)

 2

88

103,147

8.53

60

104,878

5.72

1.51(1.08, 2.09)*

1.43(1.03, 1.98)*

 3

46

61,671

7.46

26

61,550

4.22

1.78(1.10, 2.88)*

1.79(1.11, 2.91)*

 4 (lowest)

96

78,094

12.3

62

77,646

7.98

1.55(1.12, 2.13)**

1.42(1.03, 1.95)*

 P for trend

       

0.49

Comorbidity

 No

66

171,700

3.84

29

178,753

1.62

2.43(1.57, 3.76)***

2.26(1.46, 3.51)***

 Yes

261

170,489

15.3

193

170,307

11.3

1.36(1.13, 1.64)**

1.30(1.08, 1.56)**

 P for trend

       

0.02

Hyperlipidemia

 No

221

281,496

7.85

141

288,143

4.89

1.62(1.31, 2.00)***

1.52(1.23, 1.88)***

 Yes

106

60,693

17.5

81

60,918

13.3

1.32(0.99, 1.76)

1.24(0.93, 1.66)

 P for trend

       

0.27

Diabetes

 No

288

326,577

8.82

188

333,506

5.64

1.58(1.31, 1.90)***

1.47(1.22, 1.77)***

 Yes

39

15,611

25.0

34

15,555

21.9

1.14(0.72, 1.81)

1.15(0.72, 1.82)

 P for trend

       

0.21

Hypertension

 No

132

245,636

5.37

70

253,208

2.76

1.99(1.49, 2.65)***

1.79(1.34, 2.40)***

 Yes

195

96,553

20.2

152

95,853

15.9

1.27(1.03, 1.58)*

1.24(1.00, 1.54)*

 P for trend

       

0.58

Urinary stones

 No

302

319,449

9.45

203

326,940

6.21

1.54(1.29, 1.83)***

1.45(1.21, 1.73)***

 Yes

25

22,740

11.0

19

22,120

8.59

1.29(0.71, 2.34)

1.26(0.69, 2.31)

 P for trend

       

0.60

Urinary tract infection

 No

290

321,203

9.03

197

330,283

5.96

1.53(1.27, 1.83)***

1.44(1.20, 1.73)***

 Yes

37

20,986

17.6

25

18,777

13.3

1.33(0.80, 2.20)

1.32(0.79, 2.20)

 P for trend

       

0.60

Obesity

 No

222

346,734

6.40

323

339,663

9.51

1.50(1.26, 1.78)***

1.40(1.18, 1.66)***

 Yes

0

2326

0.00

4

2525

15.8

 P for trend

       

0.95

Anxiety

 No

310

329,242

9.42

217

335,558

6.47

1.47(1.23, 1.75)***

1.39(1.17, 1.65)***

 Yes

17

12,947

13.1

5

13,502

3.70

3.53(1.30, 9.58)*

2.72(0.99, 7.48)

 P for trend

       

0.09

Depression

 No

317

332,890

9.52

216

339,164

6.37

1.51(1.27, 1.79)***

1.43(1.20, 1.70)***

 Yes

10

9299

10.8

6

9897

6.06

1.82(0.66, 5.00)

1.15(0.41, 3.28)

P for trend

       

0.74

COPD

 No

233

304,824

7.64

156

313,361

4.98

1.55(1.27, 1.90)***

1.44(1.17, 1.76)***

 Yes

94

37,365

25.2

66

35,699

18.5

1.36(0.99, 1.86)

1.35(0.99, 1.85)

P for trend

       

0.50

Alcohol-related illness

 No

318

331,360

9.60

217

338,475

6.41

1.51(1.27, 1.79)***

1.41(1.19, 1.68)***

 Yes

9

10,829

8.31

5

10,585

4.72

1.74(0.58, 5.20)

2.72(0.81, 9.11)

 P for trend

       

0.80

Medication

Hypnotics

 No

97

143,651

6.75

68

142,627

4.77

1.42(1.04, 1.93)*

1.46(1.07, 1.99)*

 Yes

230

198,538

11.6

154

206,434

7.46

1.57(1.28, 1.93)***

1.42(1.15, 1.74)***

 P for trend

       

0.59

Antihypertensives

 No

140

252,468

5.55

82

260,095

3.15

1.79(1.36, 2.35)***

1.66(1.26, 2.19)***

 Yes

187

89,721

20.8

140

88,966

15.7

1.33(1.07, 1.65)*

1.28(1.02, 1.59)*

 P for trend

       

0.11

PSA screening

 No

193

289,171

6.67

126

305,769

4.12

1.60(1.28, 2.01)***

1.58(1.26, 1.98)***

 Yes

134

53,018

25.3

96

43,292

22.2

1.18(0.91, 1.54)

1.20(0.92, 1.56)

 P for trend

       

0.047

Rate#, incidence rate per 10,000 person-years; Crude HR, relative hazard ratio

Adjusted HR: multivariable analysis with adjustment for age; occupation category; urbanization level; comorbidities of hyperlipidemia, diabetes, hypertension, urinary stones, urinary tract infection, obesity, anxiety, depression, chronic obstructive pulmonary disease, and alcohol-related illness, and medication of hypnotics as well as antihypertensive medication, and PSA screening; Comorbidity: Only one comorbidity (including hyperlipidemia, diabetes, hypertension, urinary stones, urinary tract infection, obesity, anxiety, and depression) classified as the comorbidity group

P < .05, **P < .01, ***P < .001

Fig. 1

Comparison of Kaplan-Meir analysis-determined cumulative incidence of Prostate cancer of SD and non-SD cohorts

The analysis of HRs for developing prostate cancer was stratified by follow-up time. The SD cohort exhibited a significantly increased risk of prostate cancer compared with the non-SD cohort in follow-up time of ≤1 year (aHR = 2.46, 95% CI = 1.40–4.33) and > 5 years (aHR = 1.36, 95% CI = 1.07–1.73) (Table 3).
Table 3

Trends of Prostate Cancer Risk Stratified by Follow-Up Years

 

Sleep disorder

  

Yes

No

  

Follow-up time, years

Event

PY

Rate#

Event

PY

Rate#

Crude HR (95% CI)

Adjusted HR

(95% CI)

≤1

42

41,067

10.2

17

41,066

4.14

2.47(1.41, 4.34)**

2.46(1.40, 4.33)**

2–3

58

79,920

7.26

42

79,951

5.25

1.38(0.93, 2.06)

1.37(0.92, 2.03)

4–5

65

72,438

8.97

52

72,465

7.18

1.25(0.87, 1.80)

1.20(0.83, 1.73)

> 5

162

148,765

10.9

111

155,578

7.13

1.54(1.21, 1.96)***

1.36(1.07, 1.73)***

Rate#, incidence rate per 10,000 person-years; Crude HR, relative hazard ratio

Adjusted HR: multivariable analysis with adjustment for age; occupation category; urbanization level; comorbidities of hyperlipidemia, diabetes, hypertension, urinary stones, urinary tract infection, obesity, anxiety, depression, chronic obstructive pulmonary disease, and alcohol-related illness,; and medication of hypnotics as well as antihypertensive medication, and PSA screening

*P < .05, **P < .01

The risk of developing prostate cancer increased with age (aHR = 1.10, 95% CI = 1.09–1.11 every 1 y). Compared to patient of others occupation, patients of white collar occupation had a higher risk of developing prostate cancer (aHR = 1.36, 95% CI = 1.06–1.74). The risk of developing prostate cancer was greater for patients with comorbidities of hyperlipidemia (aHR = 1.36, 95% CI = 1.13–1.64), diabetes (aHR = 1.36, 95% CI = 1.06–1.76), and PSA screening (aHR = 1.99, 95% CI = 1.67–2.36) (Table 4).
Table 4

HR of Prostate Cancer in Association with Sex, Age, Occupation, Urbanization level, Comorbidities, and Medication in Univariable and Multivariable Cox Regression Models

Variable

Crude

Adjusted

HR

(95% CI)

HR

(95% CI)

Sleep disorder

1.51

(1.28, 1.80)***

1.42

(1.20, 1.69)***

Age, year

1.10

(1.09, 1.11)***

1.10

(1.09, 1.11)***

Occupation

 White collar

1.00

(Reference)

1.36

(1.06, 1.74)*

 Blue collar

1.46

(1.22, 1.76)***

1.28

(0.99, 1.65)

 Others

2.21

(1.75, 2.79)***

1.00

(Reference)

Urbanization level

 1 (highest)

1.43

(1.09, 1.89)*

1.31

(0.99,1 .72)

 2

1.22

(0.92, 1.61)

1.16

(0.88, 1.54)

 3

1.00

(Reference)

1.00

(Reference)

 4 (lowest)

1.73

(1.31, 2.29)***

1.25

(0.94, 1.66)

Comorbidity

 Hyperlipidemia

2.44

(2.05, 2.91)***

1.36

(1.13, 1.64)***

 Diabetes

3.32

(2.59, 4.24)***

1.36

(1.06, 1.76)*

 Hypertension

4.49

(3.77, 5.34)***

0.94

(0.75, 1.18)

 Urinary stones

1.28

(0.94, 1.74)

  

 Urinary tract infection

2.17

(1.66, 2.83)***

1.07

(0.82, 1.40)

 Obesity

1.07

(0.40, 2.87)

  

 Anxiety

1.07

(0.70, 1.65)

  

 Depression

1.05

(0.64, 1.73)

  

 COPD

3.54

(2.95, 4.26)***

1.03

(0.85, 1.25)

 Alcohol-related illness

0.85

(0.50, 1.45)

  

Medication

 Hypnotics

1.60

(1.33, 1.92)***

0.83

(0.69, 1.00)

 Antihypertensives

4.29

(3.61, 5.08)***

1.17

(0.94, 1.46)

 PSA screening

4.38

(3.69, 5.19)***

1.99

(1.67, 2.36)***

Crude HR, relative hazard ratio; Adjusted HR: multivariable analysis with adjustment for age; occupation category; urbanization level; comorbidities of hyperlipidemia, diabetes, hypertension, urinary stones, urinary tract infection, and COPD, and medication of hypnotics as well as antihypertensive medication, and PSA screening; COPD: chronic obstructive pulmonary disease

*p < 0.05, **p < 0.01, ***p < 0.001

Discussion

Previous studies have focused on the impact of night shift work and circadian rhythm disorders on cancer risks. [23, 24] We investigated the incidence and risk of prostate cancer in patients with SDs in an Asian population-based cohort study. Our study showed that the men with SDs displayed a greater incidence of prostate cancer than did the men without SDs (9.56 vs 6.36 per 10,000 person-y). The incidence of prostate cancer in our SD cohort was higher than that (4.79 per 10,000) in Taiwan Cancer Registry Database in 2012. [15] The possible reason may be related to considerable comorbidities and poor sleep quality in our SD cohort. [4, 5] Despite we assembled the non-SD cohort by randomly frequency-matched age, age (5-y intervals), occupation, urbanization level, comorbidities, and medications, the proportion of urinary tract infection and PSA screening were higher in the SD cohort than in the non-SD cohort. After adjustment for age, comorbidities, medication, and PSA screening, the men in the SD cohort still had a 1.42-fold increased risk of prostate cancer compared with the men in the non-SD cohort.

The incidence and risk of prostate cancer in our study were different from AGES-Reykjavik cohort study, which used questionnaires to investigate 2012 older men with sleep problems in Iceland and found that 135 of them (6.4%) were diagnosed with prostate cancer during follow-up. [12] However, Sigurdardottir et al. did not evaluate the effect of demographics, comorbidities, and hypnotic use.

The possible biological mechanism of SDs being associated with increased prostate cancer risk remains unclear. Men with reported sleep problems had lower morning levels of urinary 6-sulfatoxymelatonin, which are associated with increased risk of prostate cancer. [25] The 6-sulfatoxymelatonin in urine is the major enzymatic metabolite of melatonin. Melatonin has been observed to inhibit cancer development and growth in both in vitro and in vivo experimental models. [10, 26] Kao et al. indicated that hypnotics may relate to risk of prostate cancer. [27] We found the incidence of prostate cancer higher in patients with hypnotic use than that in patients without hypnotic use. However, the use of hypnotics was not an independent risk factor of prostate cancer in the multivariable Cox regression model.

A reciprocal interaction and regulation between sleep and the immune system exists. A lack of sleep can lead to immune suppression and activate cancer-stimulatory cytokines. [28, 29, 30] Studies have reported that patients with SDs are associated with unhealthy habits including excessive alcohol consumption and smoking, which are related to prostate cancer risk. [31, 32, 33, 34] COPD is strongly correlated with smoking. [35] We used COPD and alcohol-related illness to evaluate smoking and alcohol consumption habits. The SD cohort exhibited significantly higher proportion of COPD and alcohol-related illness than did the non-SD cohort.

The incidence and risk of prostate cancer increased exponentially with age, which finding was consistent with previous reports. [36] Among men in white-collar employment, those with SDs exhibited a substantially higher risk of developing prostate cancer compared with those without SDs. Insomnia may be considered as a clinical marker of high job strain for white-collar workers. [37] White-collar workers experiencing occupational stress may present SDs. High job strain and stress might contribute to excess risk of prostate cancer. [38] The men who resided in the highest urbanization areas exhibited significantly increased risks of prostate cancer compared with the controls residing in the lowest urbanization areas. These epiphenomena may be associated with stress-related insomnia implicated in cancer development and progression. [16, 39, 40]

Several limitations should be considered when interpreting our results. First, the LHID does not provide detailed patient information such as smoking and alcohol consumption, which may be potential confounding factors for this study. Evidence shows that hypertension, diabetes, and COPD are associated with smoking. [41, 42] Therefore, we adjusted for hypertension, diabetes, and COPD to minimize the smoking confounder. Second, lack of time-varying approach may result in misclassification of exposure. The effect of SD on the risk of prostate cancer may be underestimated because non-SD controls may experience SD before diagnosis of prostate cancer.

The strength of the study lies in the use of a large population-based sample with a longitudinal cohort design. The diagnoses of SDs were made by physicians instead of self-reported in a questionnaire survey. Researchers using the LHID can track patients throughout a study period because the NHIA is the single payer for the NHI program in Taiwan and all beneficiaries are assigned unique identification numbers. The NHIA routinely examines the validity of the reimbursement claims data through administrative and peer-review processes.

Conclusion

We found that patients with SDs are associated with increased prostate cancer risk, which increases with age. Therefore, appropriately managing sleep problems is a crucial healthcare concern, particularly as the number of people with SDs is increasing.

Notes

Acknowledgements

We acknowledged Sunny Chung for providing novel idea and editing this manuscript.

Funding

This work was partly supported by grants from the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center for Excellence (MOHW104-TDU-B-212-113002). The funders did not have a role in study design, data collection and analysis, preparation of the manuscript, and publication.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request

Authors’ contributions

All authors have contributed significantly, and that all authors are in agreement with the content of the manuscript: Conception/Design: WSC; Collection and data assembly: all authors; Data analysis and interpretation: all authors; Manuscript writing: all authors; Final approval of manuscript: all authors.

Ethics approval and consent to participate

The institutional review board (IRB) of China Medical University Hospital approved this study (IRB ID number: CMUH104-REC2–115). Informed consent for the study participants were waived by the IRB because the study participants were deidentified in the Taiwan Longitudinal Health Insurance Database.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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© The Author(s). 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  1. 1.Department of Internal Medicine, Taichung Hospital, Ministry of Health and WelfareTaichung CityTaiwan
  2. 2.Department of Health Services AdministrationChina Medical UniversityTaichungTaiwan
  3. 3.Department of Healthcare AdministrationCentral Taiwan University of Science and TechnologyTaichungTaiwan
  4. 4.Management Office for Health Data, China Medical University HospitalTaichungTaiwan
  5. 5.College of Medicine, China Medical UniversityTaichungTaiwan

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