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.
Abkürzungen
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. [2‐5]
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.
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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.
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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.
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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. [28‐30] 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. [31‐34] 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.
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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.
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
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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.
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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.
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