Prevalence of OSA among children with nocturia

Abstract

Objective We aimed the frequency of obstructive sleep apnea (OSA) and features among children
whom administered to child-adolescent clinic and pediatric urology clinic plaining of nocturia. In
addition to these , we measured the impact of adenotonsillectomy on nocturia.

Methods Questionnaires were used to assess EDS, nocturia and lower urinary tract symptoms in 34 URO

group patients and 49 age-matched SA group patients. We also compared these factors in the male
patients in

both groups and the male and female patients in the SA group. Significant SDB was diagnosed as a 3%
oxygen desaturation index (3%ODI) on pulse oximeter of >5/h. The treatment response was analyzed in
six

URO group patients treated with CPAP after not responding to the conventional medical treatment.

Results SDB was found in 91.8% of the SA group patients and 70.6% of the URO group patients. The

level of EDS and lower urinary tract symptoms were similar in both groups. The SA group showed higher

3%ODI values, while the frequency of urination during bedtime was higher in the URO group. The
frequency of nocturnal urination was reduced after CPAP in the subjects resistant to conventional
therapy.

Conclusion SDB is as prevalent in patients who visit a urology clinic complaining of nocturia as in those

who visit a sleep apnea clinic. Patients who complains of nocturia must be assessed for SDB before
starting

therapy for nocturia.

Key words: nocturia, urology clinic, sleep apnea clinic, sleep disordered breathing, Continuous Positive

Airway Pressure (CPAP)

Introduction
Nocturia is known to not only be associated with worsening sleep quality and daytime quality of life, but
it has also

been shown to increase the incidence of hip fractures (1, 2),

hypertension (3), coronary artery disease (4) and even mortality (5, 6). Recently, sleep disordered
breathing (SDB) has

been recognized as a cause of nocturia, along with benign

prostatic hypertrophy (BPH) and overactive bladder

(OAB) (7). As patients with nocturia usually visit urology

clinics rather than sleep clinics, even if they feel sleepiness,

SDB may be overlooked by many urologists, resulting in inadequate treatment for such patients. While
many studies

have examined the relationship between nocturia and

SDB (8-11), no studies have investigated the prevalence or

symptoms of SDB among patients visiting urology clinics

who complain of nocturia (URO group) compared with patients visiting sleep clinics who complain of
excessive daytime sleepiness, apnea or snoring (SA group).

Hence, the primary aim of this study was to assess the

prevalence of SDB among URO patients and determine the

differences in symptoms between the URO group and the

SA group. The secondary aim was to assess whether continuous positive airway pressure (CPAP) therapy
is effective

for nocturia in patients with SDB who are resistant to conventional medical therapy.

Materials and Methods

The participants were recruited from among the patients

who visited a urology outpatient clinic complaining of nocturia (URO group, n=34) and age-matched
patients who visited the sleep apnea clinic complaining of symptoms related

to SDB, such as excessive daytime sleepiness (EDS), sleep

apnea and snoring (SA group, n=49), at Saiseikai Futsukaichi Hospital.

The inclusion criteria for the participants were; 1) over 60

years of age for age matching and 2) no comorbidities with

severe organic lower urinary tract disease. The exclusion criteria were as follows; 1) receiving treatment
for SDB or

nocturia at the time of the study and 2) severe organic lower

urinary tract disease.

This study was approved by the ethics committee of

Saiseikai Futsukaichi Hospital, and we collected data for

consecutive patients analyzed retrospectively.

We examined EDS using the Japanese version of the Epworth sleepiness scale (JESS) questionnaire (12),
assessed

lower urinary tract symptoms (LUTS) using the international

prostate symptom score (IPSS: seven questions about symptoms and one question about quality of life),
evaluated the

degree of SDB using a pulse oximeter (Pulsox, TeijinMinolta, Tokyo, Japan) for one night at home and
counted

the frequency of nocturnal desaturation >=3% in one hour

[3% oxygen desaturation index (3%ODI)]. The frequency of

nocturnal urination was obtained using a questionnaire.

Patients with a 3% ODI of >5 were defined as having

SDB, as previously reported (13). The statistical analysis

was performed using JMP 9 (SAS Institute, Cary, USA),

and the data are presented as the mean ± standard deviation.

Comparisons between groups were performed using the Wilcoxon test, with a p value of <0.05
considered to be statistically significant.

We compared age, gender, body mass index (BMI), 3%

ODI, JESS, IPSS and nocturia between the URO group and
the SA group. We also compared these parameters in males

in the URO group (n=31) and males in the SA group (n=33)

to match the number of patients and gender and additionally

compared these parameters in males and females in the SA

group.

In the URO group (n=34), the patients were assessed for

SDB using a pulse oximeter after determining whether they

had urological problems, such as BPH or OAB. Patients

with SDB without any urological problems were treated

with CPAP if they accepted this treatment. For those with

urological problems, conventional urological medical treatment consisting of up to two different classes
of drugs was

offered first to improve urinary tract symptoms. When the

patients with SDB and urological problems did not respond

to the conventional treatment, they were offered CPAP treatment.

Results

SDB, defined as 3%ODI>5/h, was found in 91.8% (45/

49) of the SA group patients and 70.6% (24/34) of the URO

group patients. No significant differences were found in age

or BMI; however, the proportion of male patients was significantly higher in the URO group than in the
SA group

(Table). There were no significant differences in the severity

of daytime sleepiness or lower urinary tract symptoms between the two groups (JESS: 4.9±0.7 versus
6.0±0.6, p=0.2,

IPSS: 12.1±1.1 versus 10.4±0.9, p=0.1, respectively). The

3% ODI values were significantly higher in the SA group

(9.4±2.9/h versus 31.7±2.4/h, p<0.0001), while the frequency of nocturnal urination was significantly
higher in the

URO group (3.1±1.1 versus 1.9±1.3, p<0.0001).

We also analyzed age, BMI, 3% ODI, JESS, IPSS and

nocturia among each gender in both groups (Table). We

compared these parameters in males in the URO group (n=

31) and the SA group (n=33) (††† in Table). There were no

significant differences in the severity of daytime sleepiness

or lower urinary tract symptoms between the two groups

(JESS: 5.0±3.5 versus 5.5±4.1, p=0.72; IPSS 12.4±5.8,

11.5±6.9, p=0.46, respectively). The mean age of the participants was older in the URO group (68.6±6.2
years versus

64.9±4.4 years, p=0.01). Additionally, the 3% ODI values

were significantly higher in the SA group (9.6±8.5/h versus

38.4±18.9/h, p<0.0001), while the frequency of nocturnal

urination was significantly higher in the URO group (3.1±

1.1 versus 1.9±1.2, p=0.0001). In addition, we compared

these parameters between males (n=33) and females (n=16)

in the SA group (†† in Table). There were no significant

differences in the severity of daytime sleepiness or lower

urinary tract symptoms and nocturia between the two groups

(JESS: 5.5±4.1 versus 6.6±4.6, p=0.42; IPSS: 11.5±6.9,

8.3±4.8, p=0.12, nocturia: 1.9±1.2 versus 2.0±1.3, p=0.91,

respectively). Meanwhile, the mean age of the participants

was higher in females (64.9±4.4 years versus 72.3±4.7

years, p<0.0001). Additionally, the 3% ODI values were significantly higher in males (38.4±18.9/h versus
18.3±18.0/h,
p<0.0006) than in females in the URO group.

Although no significant correlations were observed between SDB and the frequency of nocturnal
urination, more

severe SDB was associated with severe nocturia (3 urinations per nights) in both groups (Fig. 1). No
significant correlations were found between the severity of daytime sleepiness assessed according to
the JESS score and the frequency

of nocturnal urination.

In the URO group, conventional treatments for nocturia

were offered to 17 patients with urological problems as well

as SDB and seven patients with urological problems without

SDB. Among these subjects, eight out of 17 patients with

SDB (47.1%) and six out of seven patients without SDB

(85.7%) showed an improvement in nocturia (Fig. 2).

Among the six patients with SDB who were treated with

CPAP, the mean frequency of nocturia was significantly reduced from 3.3 to 1.5 times.

Table. The Baseline Characteristics and Comparison of Each Urologic and Sleep Related Parameters.

URO group SA group

overall overall p value ᅤ

n 34 49

age 68.8±7.2 67.1±0.9 0.2

Male/Female 31/3 33/16 0.02᧦

Height(cm) 165.7±1.4 161.7±1.1 0.02᧦

Weight(kg) 70.0±20.3 65.9±11.0 0.24

BMI 25.4±0.9 25.1±0.7 0.78

3% ODI 9.4±2.4 31.7±2.4 <0.0001᧦

JESS 4.9±0.7 6.0±0.6 0.2

IPSS 12.1±1.1 10.4±0.9 0.1

nocturia 3.1±1.1 1.9±1.3 <0.0001᧦

male female male female p value ᅤᅤ p value ᅤᅤᅤ

n 31 3 33 16

age 68.6±6.2 70.7±2.5 64.9±4.4 72.3±4.7 <0.0001᧦ 0.01᧦

Height(cm) 167.0±5.7 152.3±5.0 166.0±5.0 151.9±5.2 <0.0001᧦ 0.73

Weight(kg) 70.9±2.8 61.3±16.0 69.5±2.7 57.9±12.4 0.0046᧦ 0.41

BMI 25.3±7.1 26.3±6.1 25.2±2.2 25.0±4.7 0.65 0.21

3% ODI 9.6±8.5 7.8±10.5 38.4±18.9 18.3±18.0 <0.0006᧦ ᧸0.0001᧦

JESS 5.0±3.5 3.3±2.9 5.5±4.1 6.6±4.6 0.42 0.72

IPSS 12.4±5.8 8.7±5.5 11.5±6.9 8.3±4.8 0.12 0.46

nocturia 3.1±1.1 3.3±1.5 1.9±1.2 2.0±1.3 0.91 0.0001᧦

ᅤ᧶ comparing URO group and SAS group

ᅤᅤ᧶ comparing males and females in SA group

ᅤᅤᅤ᧶ comparing males in both groups

ODI: oxygen desaturation index

JESS: Japanese version of the Epworth Sleepiness scale

IPSS: international prostate symptom score

Figure 1. Correlation between 3% ODI and frequency of nocturnal urinations. In each group, patients
with the severer SDB tended to have more frequent nocturia (>=3 times/night), though this did

not attain statistical significance.

Discussion
While many studies have examined the relationship between nocturia and SDB (8-11), no previous
studies have investigated the prevalence of SDB among patients specifically who visit urology clinics
complaining of nocturia, specifically from the standpoint of a comparison with nocturia

in those visiting sleep apnea clinics. Our study provides four

important findings in this context. First, approximately 70%

of the urology clinic patients complaining of nocturia had

more than mild SDB. Second, there were no significant differences between the SA group and the URO
group regarding symptoms of SDB and urological symptoms assessed

using the JESS and IPSS scales. Third, the patients with

more severe SDB tended to have more frequent nocturia.

Lastly, patients complaining of nocturia who do not respond

to conventional urological treatments are more likely to have

SDB complications and might receive more benefit from

therapy for SDB, such as CPAP.

Nocturia often develops after middle age (14). Nocturnal

urination of 1 times per night occurs in as many as 69% of

individuals in the general Japanese population and nocturnal

urination of 3 times per night is reportedly observed in

14% of the general Japanese population 40 years of

age (7). SDB, especially obstructive sleep apnea (OSA), has

been recognized to be an important cause of nocturia. The

mechanisms underlying the development of nocturia in OSA

patients are considered to be follows. Increased negative intrathoracic pressure generated by inspiration
against the obstructed upper airway stretches the atrial and ventricular

wall, resulting in the production of human atrial natriuretic

peptide (ANP) from the atrium and brain natriuretic peptide

(BNP) from the ventricle, both of which result in an increase in urine volume and consequent nocturia.
Additionally, the occurrence of hypoxia during apnea or hypopnea itself has been reported to result in
elevated BNP levels (15).

Furthermore, one report showed that elevated ANP production during nighttime among SDB patients is
likely due to

both the outward stretch of the atrial muscles and hypoxia (16). Krieger demonstrated that CPAP
therapy reduces

the nocturnal ANP levels in patients without OSA (17).

Therefore, changes in the natriuretic peptide level might be

the main cause of increased urine volume in patients with

SDB. In our study, approximately 70% of patients who visited the urology clinic complaining of nocturia
had various

degrees of SDB, whilst the prevalence of SDB, defined as

3% ODI >5, in the general Japanese population is reported

to be 25.6-40.4% (13, 18, 19). In this study, based on the

3%ODI assessment, the levels of SDB were higher in the

SA group than in the URO group, while the frequency of

nocturia was higher in the URO group versus the SA group.

The same results were indicated for males in the URO

group and males in the SA group.

These results are understandable considering that the different subjective complaints of the patients led
them to the

different departments. In contrast, it is an interesting finding

that there were no significant differences regarding the

symptoms of SDB or urological symptoms assessed according to the JESS and IPSS scales between the
two groups.

We consider one possible reason for the lack of observed

differences in the JESS and IPSS scores for the two groups
is that: first, as they age, patients become less aware of EDS

and LUTS (20), and, secondly, older persons have more

urological diseases, such as BPH or OAB manifesting as

LUTS (21, 22). It is also an interesting finding that there

were significant differences in age between males in the

URO and SA groups and in the prevalence of SDB between

males and females in the SA group, although the reasons for

this finding are not well explained.

The association between SDB and nocturia in the population under 50 years of age has been confirmed.
However, no

associations have been found between the frequency of nocturia and the symptoms of SDB in older
populations, as in

our patients (23). It was believed that an association between SDB and nocturia in the older population
has not

been confirmed due to the increased rate of urological

symptoms leading to LUTS in elderly patients. It is also

known that patients develop more symptoms of SDB as they

age. In this study, although we did not find any significant

relationships between SDB and the frequency of nocturia in

the patients, the results indicated an increase in the frequency of nocturia as the SDB levels increased,
as seen in

Fig. 1. Further studies should clarify the relationship between SDB and nocturia in older population.
However, as

described above, it is important to note that, in this study,

we found a high rate (70%) of SDB in the URO group (age

>60), whereas the rate of SDB among the general population in Japan is reported to be 25% to 40%
using the same

definition of 3% ODI>5.
Although the sample size was small, the current study

demonstrated a high success rate for CPAP treatment for

nocturia with comorbidities of SDB when conventional urology treatment fails. At present, only a limited
number of

urologists may recognize SDB as being an important cause

of nocturia and routinely look for this symptom in such patients. Our findings reinforce the importance
of considering

hidden SDB as a cause of nocturia, especially in those resistant to conventional urological therapy.
Therefore, asking the

patient whether they habitually snore or have apneic episodes when assessed at the outpatient clinic is
the simplest

and most important way to obtain the correct diagnosis and

provide proper treatment for nocturia. Additionally, we wish

to strongly recommend that urologists perform various simple but necessary tests, such as assessments
with a pulse oximeter, to identify hidden SDB.

Our study is associated with some limitations. First, we

used a pulse oximeter to assess SDB, rather than polysomnography (PSG). Compared to PSG, pulse
oximetry is not a

gold standard assessment tool; however, its benefits include

easy application, cost effectiveness (24) and the ability to be

used repeatedly. Since pulse oximeters have been used in

many studies to diagnose SDB (13, 18, 19, 25, 26), we believe that we were able to diagnose SDB as
accurately as

that using PSG. Using a pulse oximeter was particularly essential in this study, as the study required the
participation

of patients from a urology outpatient clinic who did not

have any self-awareness of their SDB symptoms. Therefore,

pulse oximetry made it possible for many patients to participate in this study without the need for
elaborate testing procedures. As our study was also quite small in size and retrospective, a larger scale
prospective trial with polysomnography is necessary to attain more accurate information about

this issue. Another limitation of the study includes the larger

male sample size in the URO group compared to the SDB

group at baseline. This may be attributed to the fact that

males were more likely to have LUTS among the elderly

population in this study (27), which is in contrast to the

findings of previous reports showing no gender differences

in the rate of perception of excessive daytime sleepiness in

middle-aged patients with AHI>5/h (28). A case control

study may be an alternative method to avoid this shortcoming.

In summary, this study indicated that approximately 70%

of patients who visit urology clinics complaining of nocturia

may also have SDB. Therefore, physicians in charge of taking care of patients with nocturia should
routinely take the

possibility of SDB into consideration in their practice, since

therapy for SDB, such as CPAP, is fundamental for improving nocturia in these patients and may highly
improve the

patient’s quality of life.

Author’s disclosure of potential Conflicts of Interest (COI).

Shin-ichi Ando: Research funding, Teijin Home Healthcare and

Philips Respironics.

References

1. Nakagawa H, Niu K, Hozawa A, et al. Impact of nocturia on bone

fracture and mortality in older individuals: a Japanese longitudinal

cohort study. J Urol 184: 1413-1418, 2010.

2. Asplund R. Hip fractures, nocturia, and nocturnal polyuria in the

elderly. Arch Gerontol Geriatr 43: 319-326, 2006.

3. Feldstein CA. Nocturia in arterial hypertension: a prevalent, underreported, and sometimes

underestimated association. J Am Soc

Hypertens 7: 75-84, 2013.

4. Lightner DJ, Krambeck AE, Jacobson DJ, et al. Nocturia is associated with an increased risk of coronary
heart disease and death.

BJU Int 110: 848-853, 2012.

5. Kupelian V, Fitzgerald MP, Kaplan SA, Norgaard JP, Chiu GR,

Rosen RC. Association of nocturia and mortality: results from the

third national health and nutrition examination survey. J Urol 185:

571-577, 2011.

6. Asplund R. Mortality in the elderly in relation to nocturnal micturition. BJU Int 84: 297-301, 1999.

7. Nishizawa O. Clinical guidelines for nocturia. Int J Urol 17: 397-

409, 2010.

8. Krieger J, Petiau C, Sforza E, Delanoe C, Hecht MT, Chamouard

V. Nocturnal pollakiuria is a symptom of obstructive sleep apnea.

Urol Int 50: 93-97, 1993.

9. Oztura I, Kaynak D, Kaynak HC. Nocturia in sleep-disordered

breathing. Sleep Med 7: 362-367, 2006.

10. Endeshaw YW, Johnson TM, Kutner MH, Ouslander JG, Bliwise

DL. Sleep-disordered breathing and nocturia in older adults. J Am

Geriatr Soc 52: 957-960, 2004.

11. Hajduk IA, Strollo PJ Jr, Jasani RR, Atwood CW Jr, Houck PR,

Sanders MH. Prevalence and predictors of nocturia in obstructive

sleep apnea-hypopnea syndrome: a retrospective study. Sleep 26:

61-64, 2003.

12. Takegami M, Suzukamo Y, Wakita T, et al. Development of a

Japanese version of the Epworth Sleepiness Scale (JESS) based on

item response theory. Sleep Med 10: 556-565, 2009.

13. Tanigawa T, Tachibana N, Yamagishi K, et al. Relationship between sleep-disordered breathing and
blood pressure levels in

community-based samples of Japanese men. Hypertens Res 27:

479-484, 2004.

14. Schatzl G, Temml C, Schmidbauer J, Dolezal B, Haidinger G,

Madersbacher S. Cross-sectional study of nocturia in both sexes:

analysis of a voluntary health screening project. Urology 56: 71-

75, 2000.

15. Gottlieb JD, Schwartz AR, Marshall J, et al. Hypoxia, not the frequency of sleep apnea, induces acute
hemodynamic stress in patients with chronic heart failure. J Am Coll Cardiol 54: 1706-

1712, 2009.

16. Umlauf MG, Chasens ER, Greevy RA, Arnold J, Burgio KL,

Pillion DJ. Obstructive sleep apnea, nocturia and polyuria in older

adults. Sleep 27: 139-144, 2004.

17. Krieger J, Follenius M, Sforza E, Brandenberger G, Peter JD. Effects of treatment with nasal
continuous positive airway pressure

on atrial natriuretic peptide and arginine vasopressin release during sleep in patients with obstructive
sleep apnoea. Clin Sci 80:

443-449, 1991.

18. Cui R, Tanigawa T, Sakurai S, Yamagishi K, Iso H. Relationships

between sleep-disordered breathing and blood pressure and excessive daytime sleepiness among truck
drivers. Hypertens Res 29:

605-610, 2006.
19. Cui R, Tanigawa T, Sakurai S, et al. Associations of sleepdisordered breathing with excessive daytime
sleepiness and blood

pressure in Japanese women. Hypertens Res 31: 501-506, 2008.

20. Onen F, Moreau T, Gooneratne NS, Petit C, Falissard B, Onen

SH. Limits of the Epworth Sleepiness Scale in older adults. Sleep

Breath 17: 343-350, 2013.

21. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of

human benign prostatic hyperplasia with age. J Urol 132: 474-

479, 1984.

22. Resnick NM, Yalla SV, Laurino E. The pathophysiology of urinary incontinence among
institutionalized elderly persons. N Engl

J Med 320: 1-7, 1989.

23. Moriyama Y, Miwa K, Tanaka H, Fujihiro S, Nishino Y, Deguchi

T. Nocturia in men less than 50 years of age may be associated

with obstructive sleep apnea syndrome. Urology 71: 1096-1098,

2008.

24. Epstein LJ, Dorlac GR. Cost-effectiveness analysis of nocturnal

oximetry as a method of screening for sleep apnea-hypopnea syndrome. Chest 113: 97-103, 1998.

25. Dohi T, Narui K, Kasai T, et al. Effects of olmesartan on blood

pressure and insulin resistance in hypertensive patients with sleepdisordered breathing. Heart Vessels
26: 603-608, 2011.

26. Lévy P, Pépin JL, Deschaux-Blanc C, Paramelle B, Brambilla C.

Accuracy of oximetry for detection of respiratory disturbances in

sleep apnea syndrome. Chest 109: 395-399, 1996.

27. Boyle P, Robertson C, Mazzetta C, et al. The prevalence of lower

urinary tract symptoms in men and women in four centres. The

UrEpik study. BJU Int 92: 409-414, 2003.

28. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The

occurrence of sleep-disordered breathing among middle-aged

adults. N Engl J Med 328: 1230-1235, 1993.

Figure 2. Flow diagram of treatment and the results in patients who visited urology clinic complaining of
nocturia.

Among these patients, of 70.3 % (26/37) had SDB and frequency of patients who were resistant to
urological conventional

therapy was higher in patients with SDB (9/18) than those without SDB (1/7).

Efficacy of nasal continuous positive airway pressure on patients with

OSA with erectile dysfunction and low sex hormone levels

abstract

Purpose: This study aimed to test the hypothesis that erectile dysfunction (ED) is common in men with

obstructive sleep apnea (OSA). We also assessed the efficacy of continuous positive airway pressure

(CPAP) treatment for ED and sex hormone levels in patients with severe OSA and ED.

Methods: A total of 153 OSA patients and 60 healthy controls were enrolled in this study. The Interna-

tional Index of Erectile Dysfunction-5 (IIEF-5) score was obtained, and blood samples were collected for

analysis of sex hormones after polysomnography. The IIEF-5 score, sex hormone levels, and poly-

somnographic parameters were re-evaluated in 32 patients with severe OSA and ED after 1 month of

CPAP treatment.
Results: The present study showed that the prevalence of ED was 47.1% in all cases and only 13.3% in

controls, and a lower sex hormone levels was presented in OSA patients. OSA patients with ED had

greater severity of disease, and lower serum levels of follicle stimulating hormone (FSH) and
testosterone

than OSA patients without ED (p < 0.05). After CPAP therapy, there was a significant increase in the IIEF-
5

score, and serum levels of FSH, luteinizing hormone, and testosterone, were elevated compared with

baseline levels (p < 0.05). Multivariate regression analysis indicated the serum level of testosterone had

impact on the ED.

Conclusions: OSA patients had lower sex hormone levels and a higher occurrence of ED than controls,

and serum level of testosterone had effect on ED. CPAP treatment ameliorated the symptoms of ED and

elevated serum levels of FSH, luteinizing hormone, and testosterone.

© 2016 Elsevier Ltd. All rights reserved.

1. Introduction

Obstructive sleep apnea (OSA) is a common disorder caused by

partial or complete obstruction of the upper airway. OSA is char-

acterized by recurrent reductions in oxygen saturation and sleep

fragmentation during sleep. Additionally, OSA significantly in-

creases the risk of several pathophysiological disorders, such as

hypertension, metabolic syndrome, coronary artery disease, stroke,

and sudden cardiac fatality [1e3]. With changing lifestyle and di-

etary habits, the global burden of OSA has become relatively high,

and is estimated to affect up to 9% of middle-aged women and 17%

of middle-aged men [4].

Erectile dysfunction (ED) is defined as an inability to achieve or

maintain an erection sufficient to permit satisfactory sexual per-

formance. ED is a simultaneous phenomenon of OSA and was first

described in 1977 [5]. ED may be caused by psychological, neuro-

logical, endocrinological, and vascular system impairment, or by a

combination of these factors. Among the several common compli-

cations of OSA, sexual disorders remain the least studied, but their

prevalence is remarkable. Previous studies have reported that

sexual disorders, especially ED, are a highly prevalent condition in

patients with OSA [6]. The frequency and severity of ED appear to

have a positive association with the severity of disease, with up to

80% of patients with OSA having ED [7]. The underlying mechanism

of ED in patients with OSA might be associated with nocturnal

hypoxemia [8], sleep fragmentation, low sex hormone levels [9],

and endothelial disorders [10].

Continuous positive airway pressure (CPAP) is widely accepted

as an effective treatment choice for OSA. CPAP improves night

chronic intermittent hypoxemia and sleep disturbance, and has

beneficial effects on the pathophysiological process of patients with

OSA. The efficacy of CPAP has also been extensively investigated in

patients with OSA and ED [11e14]. However, the results of these

reports on the efficacy of CPAP are still controversial. Some studies

have demonstrated that CPAP elevates sex hormone levels and

improves sexual performance [11,12]. However, other studies have

made a different conclusion. Hoekema et al. showed that male

patients with OSA showed more sexual dysfunction compared with

age-matched control subjects [13]. However, there was no signifi-

cant improvement in sexual function after CPAP treatment [13].

Additionally, Shin et al. suggested that CPAP did not improve ED in

male patients with OSA [14].

Therefore, this study aimed to determine to what extent un-

treated male patients with OSA experience ED. We also aimed to

evaluate the results of CPAP therapy on ED and sex hormone levels.

2. Subjects and methods

2.1. Study subjects

A total of 153 patients with OSA (mild [n ¼ 38], moderate

[n ¼ 48], and severe OSA [n ¼ 67]) and 60 healthy controls were

consecutively recruited in the study. The patients were examined at

the sleep laboratory of the Respiratory Department of Zhejiang

Hospital from January 2013 to August 2015. Written informed

consent was obtained from all individuals. The research was con-

ducted according to the World Medical Association Declaration of

Helsinki and approved by the Ethics Committee of Zhejiang

Hospital.

The diagnosis of OSA was performed according to clinical

snoring during sleep and day time sleepiness, upper airway nar-

rowing, and overnight polysomnography examination (Alice LE;

Philips Respironics, Inc., Murrysville, PA). The following parameters

were measured. A baseline examination comprised assessment of

oxyhemoglobin saturation, awakening reactions, electrophysio-

logical signals, chest and abdominal movement, and airflow

detection via a thermocouple and nasal pressure. Two sleep spe-

cialists (Jianzong Du and Liang Gu) reviewed the recordings inde-

pendently. Apnea was defined as continuous cessation of airflow

for >10 s. Hypopnea was defined as a 30% reduction in airflow for

>10 s with oxygen desaturation of 4%, or a 50% decrease in

airflow for >10 s associated with 3% oxygen desaturation. The

ApneaeHypopnea Index (AHI) was calculated as the sum of apneas

and hypopneas per hour of sleep. An event was defined as

obstructive when chest and abdominal respiratory movement was

identified and oronasal airflow ceased during apnea. Arousal was

defined according to the American Academy of Sleep Medicine

Scoring Manual [15]. The oxygen desaturation index (ODI) was

defined as 4% oxygen desaturation per hour during sleep. Patients

with OSA were divided into the mild group (AHI: 5e15 events/h),

moderate group (AHI: 15e30 events/h), and severe group (AHI >30

events/h) [16]. Individuals with an AHI <5 events/h were included

in the study as healthy controls. The exclusion criteria of subjects

were as follows: (1) patients were excluded in case of previous

treatment of OSA by CPAP, oral appliance, or upper airway surgery;

(2) ED patients before the enrollment of the current sudy treated

with medications; (3) patients had already undergone therapy with

sexual hormone replacement or with a disease known to poten-

tially influence serum levels of sexual hormones; (4) asthma,

chronic obstructive pulmonary disease, interstitial lung disease,

and respiratory disorders caused by others; (5) a history of drug or

alcohol abuse, or intaking other medications that could affect

erection; (6) depression, or psychological disorders without toler-

ance of PSG examination or CPAP treatment; (7) cardiovascular,

endocrine, and other disorders that could lead to hypoxemia.

2.2. Blood collection and analysis

A venous blood sample was collected from each subject on the

next morning after polysomnography. Chemiluminescence

methods were used for detecting serum levels of sex hormones,

including follicle-stimulating hormone (FSH), luteinizing hormone

(LH), prolactin, estradiol, progesterone, and testosterone, according

to the manufacturer's instructions. We used the International Index

of Erectile Dysfunction-5 (IIEF-5) score [17], which focuses on the

relevant domains of male sexual function (erectile function,

orgasmic function, sexual desire, intercourse satisfaction, and

overall satisfaction). The IIEF-5 is a good diagnostic test for ED. An

IIEF-5 score < 21 indicates ED.

2.3. Treatment protocol

Patients with severe OSA and ED received CPAP titration to

determine the best pressure on the second night. Good adherence

to CPAP was defined as using CPAP for a minimum of 70% of days for

at least 4 h. Serum sex hormone levels, IIEF-5 score, and poly-

somnography testing were re-examined after completing 1 month

of CPAP treatment.

2.4. Statistical analysis

Continuous variables are expressed as the mean ± standard

deviation. Comparisons were performed using the rank-sum test or

paired t-test depending on data differences among groups. A

multivariate regression analysis was performed to evaluate the role

of confounding factors on IIEF-5. All statistical analysis were two-

sided, and a p value < 0.05 was considered as significance. Statis-

tical power was calculated using the software Statistical Package for

Social Sciences, version 17.0.0 (SPSS, Chicago, IL).

3. Results

3.1. General characteristics of the study

The clinical, polysomnographic, and biochemical characteristics

of study subjects are shown in Table 1. The mean age in patients

with OSA and controls was 46.6 ± 10.4 years and 47.7 ± 9.5 years,

respectively. In terms of body mass index, neck circumference,

abdominal circumference, AHI and arousal index, the value of pa-

tients with OSA was more higher than controls (all p < 0.05).

Similarly, serum levels of FSH, progesterone, and testosterone of

patients were more lower than controls (all p < 0.05). However,

there were no significant differences in LH, prolactin, and estradiol

between the groups (all p > 0.05).

3.2. Characteristics of OSA patients with ED or without ED

The IIEF-5 score was used to determine erectile disorders. The

prevalence of ED (IIEF-5 score <21) was 47.1% in all of the patients

with OSA. In patients with mild, moderate, and severe OSA, nine

(23.6%), 23 (47.9%), and 40 (59.7%) had ED, respectively. However, in

controls, only eight (13.3%) subjects had ED, resulting in a lower

occurrence (p ¼ 0.002) compared with patients with OSA (Table 1).

According to the IIEF-5 score, patients were divided into two

groups: 72 patients had OSA with ED and 81 had OSA without ED.

We compared these two groups, and found that patients who had

OSA with ED had greater severity of this disease, and lower serum

FSH and testosterone levels compared with patients who had OSA

without ED (p ¼ 0.01 and p ¼ 0.042, respectively). There were no

differences in any other parameters between these two groups

(Table 2).

Four patients refused to further participate in the intervention

study and accept any form of therapy, and four patients did not visit

during the treatment period (see Table 3). Therefore, the remaining

32 patients with severe OSA and ED completed 1 month of CPAP

treatment. The median CPAP pressure was 10.4 cmH2O mmHg, and

mean CPAP use was 5.8 h/day and 5.2 days/week. A significant

improvement (p ¼ 0.043) in the IIEF-5 score was observed after

CPAP (19.2 ± 3.0) therapy compared with before CPAP (14.2 ± 2.9).

The lowest saturation of oxygen, and serum levels of FSH, LH, and

testosterone were elevated compared with baseline levels

(p ¼ 0.017, p ¼ 0.002, p ¼ 0.041 and p ¼ 0.018, respectively). In

addition, a remarkable decrease in the AHI was observed after CPAP

intervention compared with before intervention (51.6 ± 16.3 vs.

4.4 ± 1.2, p ¼ 0.002). There were no significant changes in prolactin,

progesterone, and estradiol levels (p ¼ 0.29, p ¼ 0.21 and p ¼ 0.42,

respectively).

Multivariate regression analysis were used to determine the role

of possible factors to IIEF-5. The result of analysis showed that the

serum level of testosterone had a significant impact on the IIEF-5

(p < 0.05). However, other variables were not observed (p > 0.05)

(Table 4)

4. Discussion

Our study showed that patients with OSA had lower serum sex

hormone levels than did controls and 47.1% experienced a poor

Table 1

Demographic data of the OSA and control group.

Table 2

Comparison of various index between OSA with or without ED

Table 3

Comparison of various index in 32 severe OSA with ED pre- and post-CPAP

Table 4

The effect of confounding factor on IIEF-5.

erectile performance. A significant increase in the IIEF-5 score was

observed after 1 month of CPAP treatment. Furthermore, CPAP

treatment elevated serum levels of FSH, LH, and testosterone.

However, CPAP treatment had no effect on prolactin, estradiol, and

progesterone levels. The serum level of testosterone had a signifi-

cant effect on OSA patients with ED.

Many studies have indicated that patients with OSA have lower

sex hormone levels and experience erectile disorders [9,13]. A

previous study reported abnormal levels of sex hormones in pa-

tients with OSA, as well as a correlation between ED and OSA [9].

Zhang et al. showed that patients with severe OSA had significantly

lower testosterone levels and IIEF-5 score compared with the

simple snoring group [9], which is in line with our findings. The

current study showed that serum levels of sex hormones, including

FSH, LH, progesterone, and testosterone, in patients with OSA were

significantly lower than those in controls. A variety of sex hormones

are synthesized and secreted from the hypothalamus, pituitary and

gonads, including gonadotropin-releasing hormone, FSH, LH, and

testosterone. Therefore, hypothalamic abnormality and dysfunc-

tion of the pituitaryegonadal axis have been implicated in sup-

pression of secretion of sex hormones. Notably, nocturnal

hypoxemia and sleep disorder characteristics of OSA contribute to

impairing function of the hypothalamusepituitaryegonadal axis,

which may lead to relatively low levels of serum sex hormones in

these patients.

Previous studies have shown a high prevalence of sexual dis-

orders in male patients with OSA, with approximately 10e80% of

patients with OSA experiencing ED [6e8,18]. Recently, a clinical

study by Budweiser et al. showed that ED and overall sexual dis-

orders were highly frequent in patients with suspected OSA, with

up to 69% of patients with OSA experiencing ED [8]. Hirshkowitz

et al. also reported that up to 43.8% of patients with ED had OSA

[18]. Our finding that 47.1% of patients with OSA had ED is consis-

tent with these reports. Furthermore, a higher AHI was found in

patients with OSA and ED. This finding suggests that there is a

positive association between the occurrence of ED and severity of

OSA. In addition, the current study showed that OSA patients with

ED had lower serum levels of FSH and testosterone compared with

those with OSA without ED, and serum level of testosterone had a

significant effect on the OSA patients with ED. Serum testosterone

levels, regulated by FSH levels, appear to play an important part in

sexual performance. The European Male Aging study demonstrated

that sexual activity was the most specific symptom associated with

low levels of testosterone [19]. Accumulating evidence has shown

that testosterone levels are suppressed in patients with OSA, and

supplementary testosterone therapy increases sexual desire in

male patients with OSA [20]. Another randomized controlled trial

by Hackett et al. showed that after testosterone replacement

therapy, a significant improvement was observed in erectile func-

tion, intercourse satisfaction, sexual desire, overall satisfaction, and

orgasms in men [21].

Several studies have addressed the efficacy of CPAP in patients

with OSA and ED, but the results are conflicting [11e14]. However,

the present study showed that erectile disorders were improved

after CPAP treatment. In addition, CPAP led to elevated serum levels

of FSH, LH, and testosterone, as well as a decrease in the AHI in

patients with OSA and ED. These results are in line with previous

studies [9,11,12,22,23]. Margel et al. reported that CPAP treatment

has a positive effect on erectile function by improving apnea and

hypopnea, and elevating oxygen saturation during sleep [22].

Studies by Zhang et al. [9], Taskin et al. [11], Budweiser et al. [12],

and Gonçalves et al. [23] showed that long-term CPAP treatment

could improve or preserve erectile activity in male patients with

OSA. However, Zhang et al. [9] demonstrated that completing 3

months of CPAP treatment did not elevate the levels of serum FSH,

LH, and testosterone. The differences between the present study

and Zhang et al. research may be primarily attributed to more se-

vere OSA patients were enrolled in their study, with AHI

63.45 ± 12.03 vs 51.6 ± 16.3 in our study. As previously described,

endothelial disorders maybe the underlying mechanism of ED in

OSA patients [10]. Ciccone et al. [24,25] studies demonstrated that

such as flow-mediated vasodilation and intima-media thickness

values, a hallmark of endothelial dysfunction, had association with

severity of OSA, and endothelial disorder was improved after 3

month of CPAP therapy. But the association of endothelial

dysfunction and ED was not evaluated in their research. Therefore

further studies should be needed to explore the efficacy of CPAP

treatment on OSA patients with ED and endothelial dysfunction.

Taken together, these studies and our results show that the efficacy

of CPAP for ED in patients with OSA may be associated with

improving apnea, hypopnea, and nocturnal hypoxemia, and

elevating serum levels of sex hormones.

There are several limitations of the current study. First, the study

was not a clinical randomized controlled trial, and only ED and sex
hormone levels in patients with severe OSA were observed be-

tween pre- and post-CPAP treatment. Second, comparison between

groups was conducted after only 1 month of CPAP therapy, which

might have not have been representative of the efficacy of CPAP.

Therefore, a longer period of CPAP treatment needs to be conducted

in a future study. Third, the sample size of the intervention study

was relatively small, with only 32 patients with severe OSA and ED.

Finally, IIEF-5 testing has a certain degree of subjectivity, which can

be influenced by age, educational level, and psychological factors.

All of these limitations could have affected the power of the con-

clusions. In the future, we intend to conduct an analysis of a larger

sample size and a randomized controlled trial, which will include

these risk factors.

In conclusion, our study shows that male patients with OSA

have lower serum sex hormone levels and a higher prevalence of

ED than control subjects, and the serum of testosterone level had

effect on the ED. One month of CPAP therapy improves ED and el-

evates serum levels of sex hormones. Based on our results, we

speculate that poor erectile function has a positive association with

the severity of OSA and the serum level of testosterone, and CPAP

treatment reverses erectile disorder to a certain extent.

Conflict of interest

All authors certify that they have no conflict of interest.

Funding

This study was supported by the Medical and Health Science

and Technology Plan of Zhejiang Province (2014KYA001), and TCM

Science and Technology Plan of Zhejiang Province (2015ZB002).

Acknowledgements

We thank Mr. Wei Cai's team for his excellent technical support.

References

[1] P.E. Peppard, T. Young, M. Palta, J. Skatrud, Prospective study of the association

between sleep-disordered breathing and hypertension, N. Engl. J. Med. 342

(2000) 1378e1384.

[2] S. Xu, Y. Wan, M. Xu, J. Ming, Y. Xing, F. An, et al., The association between

obstructive sleep apnea and metabolic syndrome: a systematic review and

meta-analysis, BMC. Pulm. Med. 15 (2015) 105.

[3] P. Rajan, H. Greenberg, Obstructive sleep apnea as a risk factor for type 2

diabetes mellitus, Nat. Sci. Sleep. 7 (2015) 113e125.

[4] P.E. Peppard, T. Young, J.H. Barnet, M. Palta, E.W. Hagen, K.M. Hla, Increased

prevalence of sleep-disordered breathing in adults, Am. J. Epidemiol. 177

(2013) 1006e1014.

[5] C. Guilleminault, A. Tilkian, F.L. Eldridge, Sleep apnea syndrome due to upper

airway obstruction: a review of 25 cases, Arch. Intern. Med. 137 (1977)

296e300.

[6] T. Santos, M. Drummond, F. Botelho, Erectile dysfunction in obstructive sleep

apnea syndrome prevalence and determinants, Rev. Port. Pneumol. 18 (2012)

64e71.

[7] P.E. Teloken, E.B. Smith, C. Lodowsky, T. Freedom, J.P. Mulhall, Defining as-

sociation between sleep apnea syndrome and erectile dysfunction, Urology 67

(2006) 1033e1037.
[8] S. Budweiser, S. Enderlein, R.A. J€orres, A.P. Hitzl, W.F. Wieland, M. Pfeifer, et al.,

Sleep apnea is an independent correlate of erectile and sexual dysfunction,

J. Sex. Med. 6 (2009) 3147e3157.

[9] X.B. Zhang, Q.C. Lin, H.Q. Zeng, X.T. Jiang, B. Chen, X. Chen, Erectile dysfunction

and sexual hormone levels in men with obstructive sleep apnea: efficacy of

continuous positive airway pressure, Arch. Sex. Behav. 45 (2016) 235e240.

[10] G.K. Soukhova-O'Hare, Z.A. Shah, Z. Lei, A.D. Nozdrachev, C.V. Rao, D. Gozal,

Erectile dysfunction in a murine model of sleep apnea, Am. J. Respir. Crit. Care

Med. 178 (2008) 644e650.

[11] U. Taskin, Q. Yigit, E. Acioglu, M. Aricigil, G. Toktas, Y. Guzelhan, Erectile

dysfunction in severe sleep apnea patients and response to CPAP, Int. J. Impot.

Res. 22 (2010) 134e139.

[12] S. Budweiser, R. Luigart, R.A. J€orres, F. Kollert, Y. Kleemann, W.F. Wieland, et

al., Long-term changes of sexual function in men with obstructive sleep apnea

after initiation of continuous positive airway pressure, J. Sex. Med. 10 (2013)

524e531.

[13] A. Hoekema, A.L. Stel, B. Stegenga, J.H. van der Hoeven, P.J. Wijkstra, M.F. van

Driel, et al., Sexual function and obstructive sleep apneaehypopnea: a ran-

domized clinical trial evaluating the effects of oral-appliance and continuous

positive airway pressure therapy, J. Sex. Med. 4 (2007) 1153e1162.

[14] H.W. Shin, J.H. Park, J.W. Park, C.S. Rhee, C.H. Lee, Y.G. Min, et al., Effects of

surgical vs. nonsurgical therapy on erectile dysfunction and quality of life in

obstructive sleep apnea syndrome: a pilot study, J. Sex. Med. 10 (2013)

2053e2059.

[15] American Sleep Disorders Association, EEG arousals: scoring rules and ex-
amples: a preliminary report from the sleep disorders atlas task force of the

American Sleep Disorders Association, Sleep 15 (1992) 173e184.

[16] Sleep-related breathing disorders in adults, Recommendations for syndrome

definition and measurement techniques in clinical research. The Report of an

American Academy of Sleep Medicine Task Force, Sleep 22 (1999) 667e689.

[17] R.C. Rosen, A. Riley, G. Wagner, I.H. Osterloh, J. Kirkpatrick, A. Mishra, The

international index of erectile function (IIEF): a multidimensional scale for

assessment of erectile dysfunction, Urology 49 (1997) 822e830.

[18] M. Hirshkowitz, I. Karacan, M.O. Arcasoy, G. Acik, E.M. Narter, R.L. Williams,

Prevalence of sleep apnea in men with erectile dysfunction, Urology 36 (1990)

232e234.

[19] F.C. Wu, A. Tajar, J.M. Beynon, S.R. Pye, A.J. Silman, J.D. Finn, et al., Identifi-

cation of late-onset hypogonadism in middle-aged and elderly men, N. Engl. J.

Med. 363 (2010) 123e135.

[20] K.L. Melehan, C.M. Hoyos, B.J. Yee, K.K. Wong, P.R. Buchanan, R.R. Grunstein, et

al., Increased sexual desire with exogenous testosterone administration in

men with obstructive sleep apnea: a randomized placebo-controlled study,

Andrology 4 (2016) 55e61.

[21] G. Hackett, N. Cole, M. Bhartia, D. Kennedy, J. Raju, P. Wilkinson, Testosterone

replacement therapy with long-acting testosterone undecanoate improves

sexual function and quality-of-life parameters vs. placebo in a population of

men with type 2 diabetes, J. Sex. Med. 10 (2013) 1612e1627.

[22] D. Margel, R. Tal, P.M. Livne, G. Pillar, Predictors of erectile function

improvement in obstructive sleep apnea patients with long-term CPAP

treatment, Int. J. Impot. Res. 17 (2005) 186e190.

[23] M.A. Gonçalves, C. Guilleminault, E. Ramos, A. Palha, T. Paiva, Erectile

dysfunction, obstructive sleep apnea syndrome and nasal CPAP treatment,

Sleep. Med. 6 (2005) 333e339.

[24] M.M. Ciccone, S. Favale, P. Scicchitano, F. Mangini, G. Mitacchione, F. Gadaleta,

et al., Reversibility of the endothelial dysfunction after CPAP therapy in OSAS

patients, Int. J. Cardiol. 158 (2012) 383e386.

[25] M.M. Ciccone, P. Scicchitano, G. Mitacchione, A. Zito, M. Gesualdo, P. Caputo, et

al., Is there a correlation between OSAS duration/severity and carotid intima-

media thickness? Respir. Med. 106 (2012) 740e746.

Z. Li et al. / Respiratory Medicine 119 (2016) 130e134134

To ED or not to ED – Is erectile dysfunction in obstructive sleep apnea related to endothelial

dysfunction? RSS Download PDF

Camilla M. Hoyos, Kerri L. Melehan, Craig L. Phillips, Ronald R. Grunstein and Peter Y. Liu

Sleep Medicine Reviews, 2015-04-01, Volume 20, Pages 5-14, Copyright © 2014

Open reading mode

Summary
Both obstructive sleep apnea (OSA) and erectile dysfunction (ErectD) are highly prevalent and largely
under diagnosed medical conditions. These disorders often co-exist, with about half of the male OSA
population having ErectD and vice versa. OSA is strongly associated with an increased risk of
cardiovascular mortality while ErectD has been proposed as a phenotypic marker of cardiovascular
disease. This implies that the two conditions may be linked by a common pathophysiological
mechanism. In this review we provide evidence supporting the hypothesis that endothelial dysfunction
(EndoD) may be the common pathophysiological mechanism linking OSA with both ErectD and
cardiovascular complications. EndoD is one of the earliest markers of cardiovascular disease and
substantial evidence suggests that OSA independently causes EndoD. There is also strong evidence that
causally links EndoD with organic ErectD. Further research should be directed at determining the value
of simultaneously assessing both ErectD and OSA in patients presenting with symptoms of either
condition. In both ErectD and OSA clinics, identifying both conditions could improve overall
cardiovascular risk stratification whilst treatment of OSA could reduce both ErectD and cardiovascular
risk.

Abbreviations

ADMA

asymmetric dimethylarginine

AHI

apnea hypopnea index

CVD

cardiovascular disease

ErectD

erectile dysfunction

EndoD

endothelial dysfunction
FMD

flow mediated dilatation

IIEF

international index of erectile function

NPT

nocturnal penile tumescence monitoring

OSA

obstructive sleep apnea

PDE5

phosphodiesterase type 5

PSG

polysomnography

REM

rapid eye movement

Introduction

Erectile dysfunction (ErectD) is the inability to obtain and maintain a penile erection sufficient for
penetration [1] and is both highly prevalent and inadequately treated. In 1995, 150 million men
reported some degree of ErectD and this prevalence is predicted to increase to 322 million by 2025 [2] .
ErectD is now recognized as an important sentinel event for cardiovascular disease (CVD) which requires
more aggressive CVD risk reduction strategies [34] . It has been proposed that the link between ErectD
and CVD is endothelial dysfunction (EndoD) which may manifest early in the smallest vessels of the
body. EndoD is the earliest sign of vascular damage and has been shown to have prognostic value in
regards to the likelihood of future cardiovascular events [56] .

Untreated obstructive sleep apnea (OSA) is independently associated with increased all-cause mortality
789 , cardiovascular mortality 8910 and cardiovascular events [1011] . The cardiometabolic
consequences of OSA such as hypertension [12] , insulin resistance [13] and diabetes [1415] are all well
recognized. The link between OSA and obesity, particularly visceral abdominal fat which is one of the
central components of the metabolic syndrome, is also well known [1617] . OSA is also associated with
ErectD, low libido and biochemical androgen deficiency; however these relationships are not commonly
assessed and are therefore far less recognized. This is despite cross-sectional studies showing that
ErectD occurs in half of all men with OSA independent of obesity [1819] and that OSA treatment with
continuous positive airway pressure (CPAP) improves ErectD [20] and possibly reproductive hormones
[2122] . OSA is also strongly associated with EndoD, with evidence of a causal relationship through a
number of mechanistic pathways ( Fig. 1 ) [2324] . Thus the resulting EndoD in OSA may explain the
increased rate of ErectD in this population. Consequently the independent association between OSA
[25] and ErectD [26] with worsened cardiovascular outcome may be through EndoD. Men with both OSA
and ErectD are likely to have markedly impaired endothelial function and thus be at substantially
increased CVD risk. This review will examine the evidence suggesting that OSA causes ErectD by
promoting EndoD ( Fig. 1 ). Previous reviews have examined the relationship between testosterone and
sexual function with obesity [27] and sleep [28] , and we have previously reviewed the relationship
between testosterone, obesity and OSA [29] hence this review will not examine hormonal relationships.

Open full size image

Fig. 1

Different causes of endothelial dysfunction and in turn erectile dysfunction which is a silent early marker
of cardiovascular disease. The plausible mechanisms in which OSA may directly cause both endothelial
dysfunction and erectile dysfunction are shown in the circles. REM = rapid eye movement.

ErectD – measurement and prevalence

ErectD is the most common cause of sexual dissatisfaction, surpassing loss of sexual desire (libido) and
ejaculatory dysfunction. ErectD is highly prevalent, with approximately 20% of men in Australia [3031]
reporting the condition. Rates are similar in North and South America 3233343536 with 10–17% overall,
increasing to 50–60% in older age groups. The underlying cause of ErectD can be organic, psychogenic or
a combination of the two. Organic ErectD represents 60–80% of all cases and is caused by underlying
chronic diseases such as Parkinson's disease, stroke, diabetes, obesity, hypertension and atherosclerosis
[137] . The remaining cases are due to psychogenic causes including performance anxiety, lack of sexual
excitement, depression and schizophrenia [1] . Traditionally, the differentiation between psychogenic
and organic was evaluated by the measurement of sleep related erections normally associated with
rapid eye movement (REM) sleep using nocturnal penile tumescence monitoring (NPT). Patients with
psychogenic ErectD typically have preserved erections during REM sleep. However because more
recently both forms of the condition are generally treated similarly, NPT testing is not always clinically
necessary. The international index of erectile function (IIEF) questionnaire is currently the gold standard
assessment tool for ErectD [38] . There are, however, numerous other validated ErectD measurements
that have been used in the research setting 3940414243444546 .

ErectD and CVD

Most of the traditional risk factors for CVD including older age, obesity, cigarette smoking, diabetes,
hyperlipidemia and hypertension have been causally associated with ErectD [447] ( Fig. 1 ). Indeed, two
large prospective longitudinal studies have shown that age, smoking and being overweight are
associated with the subsequent development of ErectD after 8–10 [36] and 25 [48] years of follow-up.
However the presence of ErectD is increasingly being recognized as an early warning sign of CVD prior to
developing overt cardiovascular symptoms [4] . In support of this, prospective studies 49505152 and a
retrospective study [53] suggest that ErectD can predict subsequent CVD. Additionally, a recent large
population-based longitudinal study found that self-reported ErectD was associated with both
cardiovasular-mortality and all-cause mortality after adjusting for known risk factors [54] . The presence
of ErectD has been shown to be comparable to smoking or a familial history of myocardial infarct as a
marker for developing cardiovascular disease [495354] . Therefore, ErectD may have important
prognostic value for CVD development which suggests that those men who present with ErectD should
be screened for CVD and other associated risk factors [49] .

EndoD – definition, measurement and role in CVD

The vascular endothelium is critical for many functions including the maintenance of vascular tone,
platelet activity, vessel wall inflammation, smooth muscle proliferation and cellular adhesion. The
healthy endothelium secretes nitric oxide, which combats atherosclerosis through local vasodilation as
well as inhibition of platelet aggregation, monocyte adhesion and vascular smooth muscle proliferation.
Clinically EndoD is assessed by measuring the vasodilator response to an increase in blood flow or to
infusion of a vasodilator (e.g., acetylcholine) [55] . EndoD is well known to be exacerbated by traditional
cardiovascular risk factors including smoking, age and dyslipidemia and has been implicated as one of
the earliest detectable abnormalities initiating atherosclerosis and the development of CVD.

EndoD as a cause for ErectD

It has been demonstrated that EndoD is a root cause of ErectD. EndoD therefore represents the
pathophysiological link between ErectD and this increased cardiovascular risk [56] ( Fig. 1 ). This is
because EndoD impairs the endothelial cells ability to release nitric oxide which can cause the inability of
the smooth muscle to relax. This in turn results in inadequate endothelial vasodilatation and lack of
blood flow to the corpora cavernosa can lead to ErectD. This has been demonstrated in vitro with both
neurogenic and endothelium-dependant relaxation being impaired in isolated corpus cavernosum strips
from patients with ErectD [57] . Since the diameter of the penile artery is smaller than that of the
coronary artery, it has been hypothesized that generalized atheromatous disease which arises from
EndoD, manifests as ErectD first.

Penile endothelial function, measured by the change in blood flow through the penis as determined by
plethysmography, has been shown to be impaired in men with ErectD [58] . However peripheral
endothelial function, measured at the forearm, has been studied more commonly and these measures
are more generalizable to clinical populations. Studies have repeatedly found EndoD, as measured by
flow mediated dilatation (FMD) in the brachial artery, to be impaired in ErectD patients compared to
healthy controls 596061 . In contrast EndoD using a different method, venous occlusion
plethysmography, found no difference between patients and controls [58] . This discrepancy may be
because FMD measures vasodilatation of the larger brachial artery whereas venous plethysmography
measures this in the microvasculature. Furthermore asymmetric dimethylarginine (ADMA) levels, which
interfere with the production of nitric oxide, are elevated in men with ErectD compared to healthy men
or men with coronary artery disease and are predictive of ErectD severity [62] . Similar results have been
reported in men with other conditions such as metabolic syndrome [63] . Additionally endothelium-
independent vasodilatation has been shown to be impaired in men with ErectD and vascular risk factors
compared to healthy controls 596061 and also patients with vascular risk factors but not ErectD [61] .
This suggests that men with ErectD have impaired endothelium-dependent vasodilatation as well as
smooth muscle dysfunction in the artery wall which supports the findings that ErectD predicts CVD.

Effect of phosphodiesterase type 5 (PDE5) inhibitors on EndoD and ErectD and CVD

Phosphodiesterase type 5 (PDE5) inhibitors have been investigated for treatment and possible
prevention of some cardiovascular conditions, specifically through the improvement in EndoD [6465] .
Phosphodiesterases type 5 catalyze the degradation of cGMP, and are metabolized by PDE5 inhibitors.
PDE5 is the isoform generally expressed in the penile corpus cavernosum however it is also found in
other areas of the body including the pulmonary and systemic vasculature. In this context PDE5
inhibitors specifically prevent the breakdown of cGMP in the penis, thereby promoting vascular smooth
muscle relaxation, arterial dilatation and venous constriction which results in an erection [66] .
Therefore PDE5 inhibitors have been marketed as first line oral pharmacotherapy for men with ErectD,
even though they were originally developed as an angina treatment [64] . Since PDE5 is also present in
the vascular smooth muscle of the lung these inhibitors have also been used for treatment of pulmonary
hypertension as well as other diseases [67] . Decreased EndoD is therefore a potential mechanism in
which PDE5 inhibitors can improve cardiovascular conditions.

PDE5 inhibitor use has the potential to benefit several cardiovascular disease categories such as
pulmonary hypertension, coronary artery disease and heart failure [6869] . A prospective study showed
PDE5 inhibitor use protected against incident cardiovascular events in men with diabetes and coronary
artery disease [70] . Although the authors did acknowledge reduction of EndoD as a potential cause for
the finding, this was not directly measured. Studies examining the effects of PDE5 inhibitors directly on
EndoD have repeatedly shown significant improvements in several different populations [68] . It has
been stated that although PDE5 inhibitors do show potential value in the treatment and protection
against CVD this should only be secondary to reducing traditional risk factors [71] . Despite the value of
PDE5 inhibitors in term of endothelial health, their long-term safety is an ongoing concern as they are a
relatively new drug.

Population-based studies of ErectD in OSA

Although the association between ErectD and OSA has been recognized for over three decades [72] ,
population-based studies showing the joint prevalence of OSA and ErectD in the community using gold
standard methods assessing OSA by overnight attended in-laboratory polysomnography (PSG) and
erectile function by the IIEF questionnaire [38] , are not available. Several other validated ErectD
instruments have been applied in the research setting, including objective measurements of sleep
related erections, as well as a variety of subjective questionnaires 3940414243444546 . The only
community based study to use a well-validated assessment of ErectD [73] and PSG found men with OSA
were at two times greater risk of having ErectD [35] however did not report a joint prevalence of the
two conditions. Other community based studies have reported inconsistent results which have been due
to the reduced sensitivity of the subjective questionnaires which have been used to assess sleep
disordered breathing rather than PSG [7475] : Table 1 .

Table 1

Population studies investigating the association between ErectD and OSA.

First author N Age (y) ErectD measureOSA measure Results

Andersen (2010) [35] 467 Range: 20–80 MMAS single question PSG Odds ratio 2.75** of
having OSA (AHI > 15) if have ErectD compared to no OSA (AHI < 5).
Hanak (2007) [75] 827 64 (51, 90) BMSFI Snoring questionnaire Heavy snorers twice as
likely to have lower sexual satisfaction compared to mild/non-snorers, after adjustment for potential
confounders.

No association between degree of snoring and erectile function.

Schiavi (1991) [118] 70 Range: 45–75 NPT & psychosexual interview Partial PSG (no SaO 2 or
respiratory effort) No correlation between sleep disordered breathing parameters and NPT/sexual
behavior parameters once age was accounted for.

Heruti (2005) [74] 3363 36 ± 7 IIEF-5 Sleep quality questionnaire Correlation between
IIEF-5 and SQ ( r = −029**). SQ not specific to sleep apnea.

View full size

Data are mean ± standard deviation or median (25th, 75th percentiles) unless otherwise stated, ** p <
0.01. AHI = apnea hypopnea index, BMSFI = brief male sexual functioning inventory, ErectD = erectile
dysfunction, IIEF-5 = 5-item international index of erectile function, MMAS = Massachusetts male aging
study, NPT = nocturnal penile tumescence, PSG = polysomnography, SaO 2 = blood oxygen saturation,
SQ = sleep quality.

Case-controlled and clinic-based studies of ErectD in OSA

In contrast to population-based studies, clinic-based studies using gold standard methods (IIEF and PSG),
have found 40–70% of men who attended a sleep disorders clinic also had ErectD: Table 2 . These data
are consistent with the joint prevalence rates of 30–70% reported in other studies using PSG with other
validated measures of ErectD: Table 2 . In contrast to sleep clinic populations, there are no studies using
both gold standard methods that have examined the proportion of men presenting for ErectD
investigations with OSA: Table 3 . However, studies using PSG do exist, in conjunction with NPT
monitoring. The largest study ( n = 1025) reported that 44% of men presenting with self-reported ErectD
for further investigation also had OSA [76] . Similarly, two smaller studies ( n < 40) have reported
comparable prevalence rates in these clinic populations [7778] . Studies have reported that OSA
severity, particularly parameters measuring hypoxia, predicts the presence of ErectD [1819798081 . One
study showed in multivariate analysis that the mean nocturnal oxygen saturation was independently
associated with ErectD [18] . Although common risk factors, including increasing age, past prostate
surgery and vascular disease, also predicted ErectD, mean nocturnal oxygen maintained significance in
the final adjusted model. This suggests that despite many common risk factors, intermittent hypoxia is a
key underlying mechanism of the association between OSA and ErectD and points to a possible causal
relationship however this cannot be deducted from these studies. Several studies have not shown an
association between OSA severity and ErectD however this was using the apnea hypopnea index (AHI) as
the severity parameter and even though this measure somewhat represents intermittent hypoxia it may
be less sensitive [8283] . Interestingly, excessive daytime sleepiness may also be predictive of ErectD. A
study of men attending a sleep clinic found 80% of those who reported excessive sleepiness (Epworth
sleepiness scale >10) were diagnosed with ErectD compared to only 20% of those without sleepiness
[84] . Excessive sleepiness however may be a marker of many conditions associated with ErectD
including obesity and therefore is an unreliable marker of OSA.

Table 2

Prevalence of ErectD in a sleep clinic population.

First author N OSA definition (events/h) Age (y) ErectD measureOSA measure Joint
prevalence (%) Comments

Budweiser (2009) [18] 401 AHI > 5 ( n = 369)

AHI < 5 (controls, n = 32) 62 (54, 70) (ErectD)

50 (42, 55) (No ErectD) IIEF-15 PSG 69 34% of controls had ErectD. Different to OSA group**.

Erectile function decreased with worsening quartiles of AHI**, MinSaO 2 ∗∗ and meanSaO 2 **.

MVA: meanSaO 2 ** predicted erectile function after adjustment for other risk factors.

Cruz (2012) [94]98 AHI > 20 55 ± 11 Single question Limited channel PSG 26

Fanfulla (2000) [119] 25 AHI > 10 48 ± 12 Self-reported PSG 72

Goncalves (2005) [80] 98 AHI > 10 47 ± 10 Sexologist Interview PSG 29 MVA:

MinSaO 2 * and age* not AHI, BMI or SaO 2 predicted ErectD.

Sub-group analysis:

MinSaO 2 >80%: 15% with ErectD

MinSaO 2 ≤80%: 40% with ErectD. Different between groups**.

Guilleminault (1977) [72] 25 NR 44 (25–65) Self-reported impotence PSG

48 Impotence defined as ErectD and/or reduced sexual drive.

Guilleminault (1981) [120] 49 NR 47 (12–66) Self-reported PSG NR 44%

had erectile or ejaculatory difficulties

Hoekema (2007) [103] 96 AHI > 5 ( n = 48)

ND (controls, n = 48) 49 ± 9

48 ± 8 GRISS PSG NR More ErectD* in OSA than controls.

Margel (2004) [79] 209 AHI 5–20 ( n = 80)

AHI 20–40 ( n = 60)

AHI > 40 ( n = 46)

AHI < 5 (controls, n = 23) 44 ± 12

44 ± 12

50 ± 10

50 ± 8 IIEF-5 PSG NR All aspects of erectile function declined with increased OSA severity*.
Severe OSA (AHI > 40) had increased ErectD compared to all other groups*. Those with severe ErectD
had the greatest AHI.

Petersen (2010) [82] 308

1185 AHI > 5

ND (controls, collected separately) 51 ± 10 BMSFI LiSat PSG NR BMSFI and LiSat

outcomes worse in OSA compared to controls. AHI not associated with any outcomes.

Shin (2008) [19] 59 AHI > 10 ( n = 32)

AHI < 10 (controls, n = 27) 45 ± 10

43 ± 10 IIEF-5 PSG 59 30% of controls had ErectD. Different to OSA group*. ErectD correlated
with MinSaO 2 ( r = 0.34**) but not AHI ( r = 0.06 NS).

Stannek (2009) [83] 186 AHI > 5 ( n = 131)

AHI < 5 (controls, n = 55) 51 ± 11 Single question from IIEF PSG NR More ErectD in
OSA than controls*

AHI not associated with ErectD.

Zhuravlev (2009) [121] 72 NR 44 (32–56) IIEF-5

NPT PSG 44

View full size

Data are mean ± standard deviation, mean (range) or median (25th, 75th percentiles). *p < 0.05, **p <
0.01.

AHI = apnea hypopnea index, BMI = body mass index, BMSFI = brief male sexual functioning inventory,
ErectD = erectile dysfunction, GRISS = Golombok Rust inventory of sexual function questionnaire, IIEF =
international index of erectile function, LiSat = Fugl-Meyer life satisfaction checklist, MinSaO 2 =
minimum desaturation level, MVA = multi-variate analysis, ND = not done, NPT = nocturnal penile
tumescence, NR = not reported, OSA = obstructive sleep apnea, PSG = polysomnography, RDI =
respiratory disturbance index, SaO 2 = blood oxygen saturation, TST = total sleep time.

Table 3

Prevalence of OSA in an ErectD population.

First author N Study population Age (y) ErectD measureOSA definition (events/h)
OSA measure Joint prevalence (%) Comments

Chediak (1996) [78] 37 NPT clinic 52 ± 14 NPT AHI > 10 PSG 49 PSG
confirmed on two nights

Foreman (1986) [122] 30 NPT clinic NR NPT NR Limited PSG 17

Hirshkowitz (1990) [76] 1025 NPT clinic 54 (NR) NPT Apnea Index ≥ 5 PSG 44

Pressman (1986) [77] 31 NPT clinic 58 ± 6.8NPT AHI ≥ 5 PSG 32

Seftel (2002) [123] 285 Urology surgeons clinic 53 ± 13 Self-reported NR Cleveland sleep
habits questionnaire 28 (at high risk of OSA) 63% had ErectD ( n = 168)

View full size

Data are mean ± standard deviation.

AHI = apnea hypopnea index, ErectD = erectile dysfunction, ESS = Epworth sleepiness scale, IIEF =
international index of erectile function, NPT = nocturnal penile tumescence, OSA = obstructive sleep
apnea, PSG = polysomnography.

As previously discussed, EndoD has been proposed as the underlying cause of ErectD ( Fig. 1 ). OSA has
been causatively linked with EndoD through a number of mechanistic pathways and thus it is
conceivable that OSA would in turn lead to ErectD. On the other hand OSA has been proposed as a
direct potential causal factor for ErectD through apnea-related disruption of REM sleep. During REM
related nocturnal penile tumescence [20] the penile blood engorgement is thought to increase corporeal
oxygenation and protect the morphological integrity of the penis [2085] . Although it is conceivable that
some ErectD in OSA is directly caused by REM sleep disturbance, we would argue that the majority
would result from the promotion of EndoD (discussed further on).

Overall, the evidence shows an increased joint prevalence of ErectD and OSA despite several limitations
including studies being conducted in varying and/or small populations and the use of different outcome
measurement tools: Tables 1–3 .
Treatment studies of ErectD in OSA

As there are currently no longitudinal studies in the literature regarding the relationship between the
development of OSA and ErectD, direction of causality is yet to be determined. OSA treatment studies
should help answer this question, however to date, most interventional studies have failed to
definitively support OSA as a causal factor in ErectD.

Although a recent review concluded that CPAP improves ErectD in men with both erectile dysfunction
and OSA, it was based on theoretical mechanisms combined with observational and uncontrolled clinical
studies [20] . Importantly, a pivotal randomized sham-controlled study showing that CPAP improves
ErectD has yet to be performed. Sham-control is essential, because the primary outcome of therapy is
self-reported [86] , but none of the available studies are sham-controlled: see Table 4 . The only
randomized no-treatment controlled study (comparing CPAP with a non-treated control group) showed
a significant improvement in ErectD after 1 mo of CPAP in 27 men [87] , but considerable residual
disease persisted even in those randomized to CPAP therapy and the duration of therapy was relatively
short.

Table 4

CPAP treatment and erectile dysfunction.

First author N Age (y) AHI (events/h) Duration Erectile function measure Change
in erectile function with CPAP Comments

Randomized controlled studies

Li (2004) [87] 27

CPAP ( n = 15)

Control ( n = 12) NR 45 ± 11

42 ± 14 1 mo IIEF-5 ↑* compared to controls (non-English text)

Observational studies

Cruz (2012) [94]98 55 ± 11 52.2 ± 21.4 6 mo Likert scale 12%↑ (NS from baseline)

5%↓ (NS from baseline)

Goncalves (2005) [80] 17 48 ± 9 71.4 ± 26.8 1 mo Sexologist Interview ErectD resolved

in 76%* (13 out of 17 patients). OSA parameters did not predict ErectD change
Karacan and Karatas (1995) [88] 22 54 (27–73) 49.2 ± 28 1 night NPT 33% ↑
abnormal NPT

Karkoulias (2007) [89] 15 56 ± 4 7.3 ± 1.2 3 mo IIEF

SIA ↑*

Margel (2005) [92] 60 54 ± 10 (↔)

54 ± 11 (↑)

59 ± 10 (↓) 40.6 ± 18.1 (↔)

53.7 ± 15.2 (↑)

38.4 ± 18.9 (↓) 17 mo (range 12–26) IIEF-5 20% ↑ (**from baseline)

18% ↓ (**from baseline) UCA: ΔIIEF vs Baseline MinSaO 2 ( r = −0.37**), CPAP adherence ( r =
0.69*). ΔIIEF not correlated with RDI (NS).

Perimenis (2007) [93] 48 COPD + OSA 53 ± 10 28.3 ± 23.2 6 mo ErectD Intensity Score ↑**
AHI greater in patients who ↑**.

ΔIIEF positively correlated with age, AHI.

Petersen (2012) [91] 146 52 ± 10 43.3 ± 26.3 12 mo BMSFI ↑*

View full size

↑ denotes an improvement, ↓denotes a worsening, ↔ denotes not change. Data are mean ± standard
deviation or mean (range). * p < 0.05, ** p < 0.01.

AHI = apnea hypopnea index, CPAP = continuous positive airway pressure, BMSFI = brief male sexual
functioning questionnaire, COPD = chronic obstructive pulmonary disease, ErectD = erectile dysfunction,
EF = erectile function, IIEF = international index of erectile function, IIEF-5 = 5-item international index of
erectile function, GRISS = Golombok Rust inventory of sexual function, LiSat11 = Life satisfaction 11, MAS
= mandibular advancement splint, MinSaO 2 = minimum desaturation level, NPT = nocturnal penile
tumescence, OSA = obstructive sleep apnea, RDI = respiratory disturbance index, SIA = successful
intercourse attempts, UCA = univariate correlational analysis.

Within-individual, before and after studies are also presented in Table 4 . Improvements in sexual
function have been reported after 1–3 mo of CPAP treatment [8088899091 . Longer term (6–12 mo)
uncontrolled studies also show maintenance of these improvements with continued CPAP treatment at
least in those with severe disease [9293] . Another study found one in three men had resolution of their
ErectD after 6 mo of CPAP use but the percent of men with ErectD at 6 mo (17%) was not significantly
different from that at baseline (25%) [94] . One longer term (3 y) observational study ( n = 91) found that
in men with OSA and poor sexual function, overall satisfaction and sexual desire was better in those who
chose to use CPAP ( n = 56) compared to non-CPAP users ( n = 35). This was due to CPAP preventing a
decline in sexual function that occurred in non-CPAP users. A similar trend was seen for erectile function
but the difference did not reach significance. In those men who had moderate-severe ErectD, between
group differences were seen in overall sexual function, orgasmic function, sexual desire and overall
satisfaction but not erectile function. In contrast, erectile function improved only in men with both
moderate-severe ErectD and low nocturnal oxygen saturation levels [95] . This suggests that those with
intermittent hypoxia have greater response to treatment most likely because they have greater
impairment to begin with.

Other randomized comparison studies have also been conducted however they have not included
control groups without treatment: Table 5 . Studies comparing sildenafil (a PDE5 inhibitor) to CPAP
[899697] or sildenafil with CPAP [98] have shown significant improvements in the IIEF after 1–3 mo of
CPAP treatment in men however adverse event information regarding the effects of sildenafil on OSA
were not reported. PDE5 inhibitors have been previously shown to worsen sleep disordered breathing
[99] and therefore their effect on OSA needs to be documented. Another study compared CPAP to an
anti-depressant and showed the IIEF-5 to improve significantly after CPAP but not the anti-depressant,
however the between-group difference was not reported [100] . In an observational study using either
CPAP, mandibular advancement splint, or surgery (uvulopalatopharyngoplasty), as selected by the
patient, only those who had surgery were found to have improvements in the IIEF, however despite
surgery improving but not resolving OSA [101] . Similarly, a study showed both surgery (in people who
were CPAP non-compliant) and CPAP in a separate group of men had an overall improvement in both
subjective and objective (NPT) measurements of ErectD, however the improvements per treatment
were not reported [102] . Finally a study comparing CPAP to mandibular advancement splint showed no
changes in erectile function after either treatment but did not assess ErectD by IIEF, and did not exclude
men without ErectD [103] .

Table 5

Studies of CPAP with comparator arm.

First author N Age (y) AHI (events/h) Duration, design Erectile function measure
Erectile function changes Comments

Randomized controlled studies

Hoekema (2007) [66] 48

CPAP ( n = 27)

MAS ( n = 21) 51 ± 9
48 ± 8 46.7 (10–64.4)

20.6 (9.5–31.1) 2–3 mo, parallel GRISS ↔CPAP, ↔MAS. Between-group NR.

Perimenis (2004) [96] 30

CPAP ( n = 15)

Sildenafil ( n = 15) 56 ± 4

56 ± 6 7.3 ± 1.2

7.4 ± 1.4 3 mo, parallel IIEF-5

SIA ↑ (NR) Sildenafil, ↑CPAP (NR) but Sildenafil was superior**.

Perimenis (2007) [98] 40

CPAP ( n = 20)

CPAP + Sildenafil ( n = 20) 56 ± 5 15.1 ± 3.9 6 wk, CO ND

SIA SIA greater with Sildenafil that CPAP**.

Perimenis (2007) [97] 40

CPAP ( n = 20)

Sildenafil ( n = 20) 56 (48–62)

55 (42–64) 8.9 (6–25)

9.9 (6–24) 12 wk, parallel IIEF

SIA ↑** CPAP, ↑** Sildenafil but Sildenafil was superior* SIA greater with Sildenafil that CPAP**.

Taskin (2010) [100] 40

CPAP ( n = 20)

Anti-Depressant ( n = 20) 51 ± 7

53 ± 7 35 ± 19.3

33 ± 21.7 1 mo, parallel IIEF-5 ↑** CPAP, ↔ (NS) anti-depressant Stratifying by MinSaO 2
(80%) did not show correlation with ΔIIEF.

Observational studies

Budweiser (2013) [95] 91

CPAP users (any use, n = 56)

Non-CPAP users ( n = 35) 55 (48, 62)

58 (45, 69) 28.1 (18.0, 40.0)

14.7 (6.8, 23.7) 3 y IIEF-15 ↔CPAP users, ↓ non-users. Between-group NS.

Sub-analysis: 1): No difference in those with moderate/severe ErectD. 2): CPAP↑* compared to non-
users in those with both moderate-severe ErectD and mean nocturnal SaO 2 <93%. 61.5% had
ErectD

Ceylan (2013) [124] 23

CPAP ( n = 16)

Surgery ( n = 7) 46 ± 11 48.8 ± 32.5 3 mo IIEF-5 ↑* Results combined for both treatments

Khafagy (2012) [102] 80

CPAP ( n = 57)

Surgery ( n = 23) 42 ± 9 33.4 ± 1.7

37.0 ± 7.6 3 mo NPT + IIEF-5 ↑** ErectD resolved in 22.5% (IIEF-5)

↑* Percentage rigidity (NPT) Results combined for both treatments

Commonly reported NPT parameters not reported.

Shin (2013) [101] 56

UPPP ( n = 30)

CPAP ( n = 16)

MAS ( n = 10) 44 ± 10

53 ± 8

49 ± 9 29.6 ± 21.6

51.6 ± 17.1

29.3 ± 10.6 7 (4, 15) mo IIEF-5 ↑UPPP (*from baseline)

↔CPAP (NS)

↔MAS (NS) No comparisons between groups

View full size

↑ denotes an improvement, ↔ denotes no change. Data are mean ± standard deviation, mean (range) or
median (25th, 75th percentile). * p < 0.05, ** p < 0.01. AHI = apnea hypopnea index, CO = cross-over,
CPAP = continuous positive airway pressure, ErectD = erectile dysfunction, IIEF = international index of
erectile function, IIEF-15 = 15-item international index of erectile function, IIEF-5 = 5-item international
index of erectile function, GRISS = Golombok Rust inventory of sexual function, MAS = mandibular
advancement splint, MinSaO 2 = minimum desaturation level, ND = not done, NPT = nocturnal penile
tumescence, NR = not reported, SaO 2 = oxygen saturation levels, SIA = successful intercourse attempts,
UPPP = uvulopalatopharyngoplasty.

Effects of PDE5 inhibitors in OSA

As previously established ErectD is common in men with OSA and thus it is predicted that treatment
with PDE5 inhibitors may be warranted in these men in order to restore erectile function. Furthermore
as previously shown PDE5 inhibitors have the potential to reverse EndoD which may be beneficial in
patients that refuse or cannot use CPAP, which has been estimated as high as 50% of users [104] . The
safety of using PDE5 inhibitors in men with OSA has however been questioned [105] . PDE5 inhibitors
reduce subjective and objective nasal patency which has led to the suggestion that their use may
promote OSA in susceptible individuals by facilitating airway occlusion [106107] . However in the only
randomized controlled trial, despite an increase in subjective and objective nasal patency after the
administration of a PDE5 inhibitor, between group comparisons between the placebo and active
treatment were not reported [107] . The first safety study conducted in an OSA population was a
randomized order placebo-controlled crossover trial. This study showed that a single mid-range 50 mg
dose of sildenafil increased the AHI, desaturation index, and amount of time hypoxic in 13 men with
severe OSA [99] . The same study also showed a worsening in the arousal index and heart rate variability
in REM sleep [108] . However efficacy studies which have used PDE5 inhibitors in men with ErectD and
OSA have not reported safety outcomes specifically in terms of sleep disordered parameters [9698109] .
As OSA and ErectD commonly co-exist the safety of PDE5 inhibitors in these patients, does need to be
explored further in larger groups with higher exposure. This is of importance as there is a high chance
that men with untreated or undiagnosed OSA will be prescribed these drugs for erectile issues.

It is generally believed that EndoD is the underlying cause of ErectD and this is confirmed by clinical
studies showing the two conditions occur together. Furthermore ErectD is an established risk factor for
CVD most likely due to underlying EndoD. Therefore it is conceivable that EndoD promotes the
manifestation of ErectD in OSA patients. EndoD is strongly associated with OSA and the increasing
evidence from randomized controlled trials of CPAP suggest that OSA can cause EndoD (see below)
strengthens this hypothesis.

EndoD and ErectD in OSA

Substantial evidence supports OSA as a causal factor in the promotion of EndoD. Most studies have
concluded that OSA independently impairs endothelial function, although it is beyond the scope of this
review to detail studies which support this [24110] and the relationship is through a variety of
mechanisms ( Fig. 1 ) [23111112] . The strongest evidence comes from recent randomized controlled
trials which have demonstrated reversal of EndoD with CPAP 113114115116 . These randomized trials
have specifically confirmed that CPAP improves endothelium-dependant vasodilatation. The
improvement is most consistent for measures in larger conduit vessels which may have direct relevance
to ErectD in this group (see below). The effects on endothelium-dependant vasodilatation of the smaller
vessels as well as endothelium-independent vasodilatation requires the conduction of larger and
possibly longer randomized controlled trials [116117] . In addition, since approximately 50% of CPAP
users do not use their machine adequately or stop using it completely [104] other treatments that can
reverse EndoD should also be explored.

Hence overall, the current evidence supports independent associations between OSA and ErectD as well
as between OSA and EndoD however the complex inter-relationships between all three conditions
cannot be truly determined by the current literature. To our knowledge there are no current
observational data from clinical or population studies nor interventional studies available which examine
all three conditions simultaneously. Nevertheless, the data presented in this review provides a unifying
hypothesis to explain how OSA may cause ErectD through worsening of EndoD. Studies recruiting men
with both OSA and ErectD are a priority as these men could be at a heightened risk for future
cardiovascular events. Controlled studies in this population should explore the effect of not only CPAP
on both EndoD and ErectD but also the effect of PDE5 inhibitors on these outcomes while specifically
examining OSA safety. There is potential for the use for PDE5 inhibitors in OSA to promote EndoD
improvement as CPAP withdrawal rates are high. Furthermore, in a man with both OSA and Erect and
therefore most likely EndoD, the use of CPAP plus a PDE5 inhibitor may provide a synergistic effect on
ErectD and EndoD. Further studies are required to investigate these interactive effects.

Conclusion

There is substantial evidence that EndoD is a strong contender as the mechanism linking ErectD and
OSA. Both erectile function and endothelial function are worsened in those with OSA, with growing
evidence that both improve with CPAP. The use of PDE5 inhibitors can improve endothelial function;
however they may have some detrimental effects in regard to OSA. Well-designed randomized
controlled studies are needed to further solidify EndoD as the pathophysiological link between OSA and
ErectD. Clinical application of this evidence is warranted, through screening of OSA and ErectD patients
for the presence of the alternate condition, and identification of the increased cardiovascular risk for
these patients.

Conflict of interests
None to declare.

1 Co-first authors.

References ∗

∗ The most important references are denoted by an asterisk.

1. Lue T.F.: Erectile dysfunction. N Engl J Med 2000; 342: pp. 1802-1813.

View In Article

2. Ayta I.A., McKinlay J.B., Krane R.J.: The likely worldwide increase in erectile dysfunction between 1995
and 2025 and some possible policy consequences. BJU Int 1999; 84: pp. 50-56.

View In ArticleCross Ref

3. Gandaglia G., Briganti A., Jackson G., Kloner R.A., Montorsi F., Montorsi P., et. al.: A systematic review of
the association between erectile dysfunction and cardiovascular disease. Eur Urol 2014; 65: pp. 968-978.

View In ArticleCross Ref

4. Jackson G.: Prevention of cardiovascular disease by the early identification of erectile dysfunction. Int J
Impot Res 2008; 20: pp. S9-S14.

View In ArticleCross Ref

5. Yeboah J., Crouse J.R., Hsu F.C., Burke G.L., Herrington D.M.: Brachial flow-mediated dilation predicts
incident cardiovascular events in older adults: the Cardiovascular Health Study. Circulation 2007; 115:
pp. 2390-2397.

View In Article

6. Rossi R., Nuzzo A., Origliani G., Modena M.G.: Prognostic role of flow-mediated dilation and cardiac risk
factors in post-menopausal women. J Am Coll Cardiol 2008; 51: pp. 997-1002.

View In ArticleCross Ref

7. Marshall N.S., Wong K.K., Liu P.Y., Cullen S.R., Knuiman M.W., Grunstein R.R.: Sleep apnea as an
independent risk factor for all-cause mortality: the Busselton Health Study. Sleep 2008; 31: pp. 1079-
1085.

View In Article
8. Young T., Finn L., Peppard P.E., Szklo-Coxe M., Austin D., Nieto F.J., et. al.: Sleep disordered breathing
and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008; 31: pp. 1071-1078.

View In Article

9. Punjabi N.M., Caffo B.S., Goodwin J.L., Gottlieb D.J., Newman A.B., O'Connor G.T., et. al.: Sleep-
disordered breathing and mortality: a prospective cohort study. PLoS Med 2009; 6: pp. e1000132.

View In ArticleCross Ref

10. Marin J.M., Carrizo S.J., Vicente E., Agusti A.G.: Long-term cardiovascular outcomes in men with
obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway
pressure: an observational study. Lancet 2005; 365: pp. 1046-1053.

View In Article

11. Shah N.A., Yaggi H.K., Concato J., Mohsenin V.: Obstructive sleep apnea as a risk factor for coronary
events or cardiovascular death. Sleep Breath 2010; 14: pp. 131-136.

View In ArticleCross Ref

12. Bazzano L.A., Khan Z., Reynolds K., He J.: Effect of nocturnal nasal continuous positive airway pressure
on blood pressure in obstructive sleep apnea. Hypertension 2007; 50: pp. 417-423.

View In Article

13. Levy P., Bonsignore M.R., Eckel J.: Sleep, sleep-disordered breathing and metabolic consequences. Eur
Respir J 2009; 34: pp. 243-260.

View In ArticleCross Ref

14. Marshall N.S., Wong K.K., Phillips C.L., Liu P.Y., Knuiman M.W., Grunstein R.R.: Is sleep apnea an
independent risk factor for prevalent and incident diabetes in the Busselton Health Study?. J Clin Sleep
Med 2009; 5: pp. 15-20.

View In ArticleCross Ref

15. Tasali E., Mokhlesi B., Van Cauter E.: Obstructive sleep apnea and type 2 diabetes: interacting
epidemics. Chest 2008; 133: pp. 496-506.

View In ArticleCross Ref

16. Young T., Peppard P.E., Taheri S.: Excess weight and sleep-disordered breathing. J Appl Physiol 2005;
99: pp. 1592-1599.

View In ArticleCross Ref

17. Vgontzas A.N., Papanicolaou D.A., Bixler E.O., Hopper K., Lotsikas A., Lin H.M., et. al.: Sleep apnea and
daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J
Clin Endocrinol Metab 2000; 85: pp. 1151-1158.

View In ArticleCross Ref

Budweiser S., Enderlein S., Jorres R.A., Hitzl A.P., Wieland W.F., Pfeifer M., et. al.: Sleep apnea is an
independent correlate of erectile and sexual dysfunction. J Sex Med 2009; 6: pp. 3147-3157.

View In ArticleCross Ref

19. Shin H.W., Rha Y.C., Han D.H., Chung S., Yoon I.Y., Rhee C.S., et. al.: Erectile dysfunction and disease-
specific quality of life in patients with obstructive sleep apnea. Int J Impot Res 2008; 20: pp. 549-553.

View In ArticleCross Ref

20. Jankowski J.T., Seftel A.D., Strohl K.P.: Erectile dysfunction and sleep related disorders. J Urol 2008;
179: pp. 837-841.

View In ArticleCross Ref

21. Grunstein R.R., Handelsman D.J., Lawrence S.J., Blackwell C., Caterson I.D., Sullivan C.E.:
Neuroendocrine dysfunction in sleep apnea: reversal by continuous positive airways pressure therapy. J
Clin Endocrinol Metab 1989; 68: pp. 352-358.

View In ArticleCross Ref

22. Luboshitzky R., Lavie L., Shen-Orr Z., Lavie P.: Pituitary-gonadal function in men with obstructive sleep
apnea. The effect of continuous positive airways pressure treatment. Neuro Endocrinol Lett 2003; 24: pp.
463-467.

View In Article

23. Kohler M., Stradling J.R.: Mechanisms of vascular damage in obstructive sleep apnea. Nat Rev Cardiol
2010; 7: pp. 677-685.

View In ArticleCross Ref

24. Atkeson A., Yeh S.Y., Malhotra A., Jelic S.: Endothelial function in obstructive sleep apnea. Prog
Cardiovasc Dis 2009; 51: pp. 351-362.

View In ArticleCross Ref

25. Bradley T.D., Floras J.S.: Obstructive sleep apnoea and its cardiovascular consequences. Lancet 2009;
373: pp. 82-93.

View In Article
26. Zias N., Bezwada V., Gilman S., Chroneou A.: Obstructive sleep apnea and erectile dysfunction: still a
neglected risk factor?. Sleep Breath 2009; 13: pp. 3-10.

View In ArticleCross Ref

27. Corona G., Mannucci E., Forti G., Maggi M.: Hypogonadism, ED, metabolic syndrome and obesity: a
pathological link supporting cardiovascular diseases. Int J Androl 2009; 32: pp. 587-598.

View In ArticleCross Ref

28. Andersen M.L., Alvarenga T.F., Mazaro-Costa R., Hachul H.C., Tufik S.: The association of testosterone,
sleep, and sexual function in men and women. Brain Res 2011; 1416: pp. 80-104.

View In ArticleCross Ref

29. Liu P.Y., Caterson I.D., Grunstein R.R., Handelsman D.J.: Androgens, obesity, and sleep-disordered
breathing in men. Endocrinol Metab Clin North Am 2007; 36: pp. 349-363.

View In ArticleCross Ref

30. Holden C.A., McLachlan R.I., Pitts M., Cumming R., Wittert G., Agius P.A., et. al.: Men in Australia
Telephone Survey (MATeS): a national survey of the reproductive health and concerns of middle-aged
and older Australian men. Lancet 2005; 366: pp. 218-224.

View In Article

31. Moreira E.D., Glasser D.B., King R., Duarte F.G., Gingell C., Group G.I.: Sexual difficulties and help-
seeking among mature adults in Australia: results from the Global Study of Sexual Attitudes and
Behaviours. Sex Health 2008; 5: pp. 227-234.

View In Article

32. Rosen R.C., Fisher W.A., Eardley I., Niederberger C., Nadel A., Sand M.: The multinational Men's
Attitudes to Life Events and Sexuality (MALES) study: I. Prevalence of erectile dysfunction and related
health concerns in the general population. Curr Med Res Opin 2004; 20: pp. 607-617.

View In ArticleCross Ref

Laumann E.O., Paik A., Rosen R.C.: Sexual dysfunction in the United States: prevalence and predictors. J
Am Med Assoc 1999; 281: pp. 537-544.

View In ArticleCross Ref

34. Bacon C.G., Mittleman M.A., Kawachi I., Giovannucci E., Glasser D.B., Rimm E.B.: Sexual function in
men older than 50 years of age: results from the health professionals follow-up study. Ann Intern Med
2003; 139: pp. 161-168.

View In ArticleCross Ref

Andersen M.L., Santos-Silva R., Bittencourt L.R., Tufik S.: Prevalence of erectile dysfunction complaints
associated with sleep disturbances in Sao Paulo, Brazil: a population-based survey. Sleep Med 2010; 11:
pp. 1019-1024.

View In ArticleCross Ref

36. Feldman H.A., Johannes C.B., Derby C.A., Kleinman K.P., Mohr B.A., Araujo A.B., et. al.: Erectile
dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study. Prev
Med 2000; 30: pp. 328-338.

View In ArticleCross Ref

37. Shamloul R., Ghanem H.: Erectile dysfunction. Lancet 2013; 381: pp. 153-165.

View In Article

38. Rosen R.C., Riley A., Wagner G., Osterloh I.H., Kirkpatrick J., Mishra A.: The international index of
erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;
49: pp. 822-830.

View In Article

39. Rosen R.C., Cappelleri J.C., Smith M.D., Lipsky J., Pena B.M.: Development and evaluation of an
abridged, 5-item version of the international index of erectile function (IIEF-5) as a diagnostic tool for
erectile dysfunction. Int J Impot Res 1999; 11: pp. 319-326.

View In ArticleCross Ref

40. Mulhall J.P., Goldstein I., Bushmakin A.G., Cappelleri J.C., Hvidsten K.: Validation of the erection
hardness score. J Sex Med 2007; 4: pp. 1626-1634.

View In ArticleCross Ref

41. Mulhall J.P., King R., Kirby M., Hvidsten K., Symonds T., Bushmakin A.G., et. al.: Evaluating the sexual
experience in men: validation of the sexual experience questionnaire. J Sex Med 2008; 5: pp. 365-376.

View In ArticleCross Ref

42. Mulhall J.P., Levine L.A., Junemann K.P.: Erection hardness: a unifying factor for defining response in
the treatment of erectile dysfunction. Urology 2006; 68: pp. 17-25.

View In ArticleCross Ref

43. O'Leary M.P., Fowler F.J., Lenderking W.R., Barber B., Sagnier P.P., Guess H.A., et. al.: A brief male
sexual function inventory for urology. Urology 1995; 46: pp. 697-706.

View In Article
44. Porst H., Gilbert C., Collins S., Huang X., Symonds T., Stecher V., et. al.: Development and validation of
the quality of erection questionnaire. J Sex Med 2007; 4: pp. 372-381.

View In ArticleCross Ref

45. Lowy M., Collins S., Bloch M., Gillman M., Lording D., Sutherland P., et. al.: Quality of erection
questionnaire correlates: change in erection quality with erectile function, hardness, and psychosocial
measures in men treated with sildenafil for erectile dysfunction. J Sex Med 2007; 4: pp. 83-92.

View In ArticleCross Ref

46. Rust J., Golombok S.: The Golombok-Rust inventory of sexual satisfaction (GRISS). Br J Clin Psychol
1985; 24: pp. 63-64.

View In ArticleCross Ref

47. Montorsi F., Briganti A., Salonia A., Rigatti P., Margonato A., Macchi A., et. al.: Erectile dysfunction
prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest
pain and angiographically documented coronary artery disease. Eur Urol 2003; 44: pp. 360-364.
[discussion 4–5]

View In Article

48. Barrett-Connor E.: Heart disease risk factors predict erectile dysfunction 25 years later (the Rancho
Bernardo Study). Am J Cardiol 2005; 96: pp. 3M-7M.

View In Article

Thompson I.M., Tangen C.M., Goodman P.J., Probstfield J.L., Moinpour C.M., Coltman C.A.: Erectile
dysfunction and subsequent cardiovascular disease. J Am Med Assoc 2005; 294: pp. 2996-3002.

View In ArticleCross Ref

50. Inman B.A., Sauver J.L., Jacobson D.J., McGree M.E., Nehra A., Lieber M.M., et. al.: A population-based,
longitudinal study of erectile dysfunction and future coronary artery disease. Mayo Clin Proc 2009; 84:
pp. 108-113.

View In ArticleCross Ref

51. Schouten B.W., Bohnen A.M., Bosch J.L., Bernsen R.M., Deckers J.W., Dohle G.R., et. al.: Erectile
dysfunction prospectively associated with cardiovascular disease in the Dutch general population:
results from the Krimpen Study. Int J Impot Res 2008; 20: pp. 92-99.

View In ArticleCross Ref

52. Ma R.C., So W.Y., Yang X., Yu L.W., Kong A.P., Ko G.T., et. al.: Erectile dysfunction predicts coronary
heart disease in type 2 diabetes. J Am Coll Cardiol 2008; 51: pp. 2045-2050.
View In ArticleCross Ref

53. Chew K.K., Finn J., Stuckey B., Gibson N., Sanfilippo F., Bremner A., et. al.: Erectile dysfunction as a
predictor for subsequent atherosclerotic cardiovascular events: findings from a linked-data study. J Sex
Med 2010; 7: pp. 192-202.

View In ArticleCross Ref

54. Araujo A.B., Travison T.G., Ganz P., Chiu G.R., Kupelian V., Rosen R.C., et. al.: Erectile dysfunction and
mortality. J Sex Med 2009; 6: pp. 2445-2454.

View In ArticleCross Ref

55. Deanfield J.E., Halcox J.P., Rabelink T.J.: Endothelial function and dysfunction: testing and clinical
relevance. Circulation 2007; 115: pp. 1285-1295.

View In ArticleCross Ref

56. Solomon H., Man J.W., Jackson G.: Erectile dysfunction and the cardiovascular patient: endothelial
dysfunction is the common denominator. Heart 2003; 89: pp. 251-253.

View In ArticleCross Ref

57. Saenz de Tejada I., Goldstein I., Azadzoi K., Krane R.J., Cohen R.A.: Impaired neurogenic and
endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J
Med 1989; 320: pp. 1025-1030.

View In Article

58. Vardi Y., Dayan L., Apple B., Gruenwald I., Ofer Y., Jacob G.: Penile and systemic endothelial function in
men with and without erectile dysfunction. Eur Urol 2009; 55: pp. 979-985.

View In ArticleCross Ref

Kaiser D.R., Billups K., Mason C., Wetterling R., Lundberg J.L., Bank A.J.: Impaired brachial artery
endothelium-dependent and -independent vasodilation in men with erectile dysfunction and no other
clinical cardiovascular disease. J Am Coll Cardiol 2004; 43: pp. 179-184.

View In ArticleCross Ref

60. Kaya C., Uslu Z., Karaman I.: Is endothelial function impaired in erectile dysfunction patients?. Int J
Impot Res 2006; 18: pp. 55-60.

View In ArticleCross Ref

61. Yavuzgil O., Altay B., Zoghi M., Gurgun C., Kayikcioglu M., Kultursay H.: Endothelial function in patients
with vasculogenic erectile dysfunction. Int J Cardiol 2005; 103: pp. 19-26.
View In ArticleCross Ref

62. Aktoz T., Aktoz M., Tatli E., Kaplan M., Turan F.N., Barutcu A., et. al.: Assessment of the relationship
between asymmetric dimethylarginine and severity of erectile dysfunction and coronary artery disease.
Int Urol Nephrol 2010; 42: pp. 873-879.

View In ArticleCross Ref

63. Esposito K., Giugliano F., Martedi E., Feola G., Marfella R., D'Armiento M., et. al.: High proportions of
erectile dysfunction in men with the metabolic syndrome. Diabetes Care 2005; 28: pp. 1201-1203.

View In ArticleCross Ref

64. Schwartz B.G., Jackson G., Stecher V.J., Campoli-Richards D.M., Kloner R.A.: Phosphodiesterase type 5
inhibitors improve endothelial function and may benefit cardiovascular conditions. Am J Med 2013; 126:
pp. 192-199.

View In ArticleCross Ref

65. Schwartz B.G., Levine L.A., Comstock G., Stecher V.J., Kloner R.A.: Cardiac uses of phosphodiesterase-5
inhibitors. J Am Coll Cardiol 2012; 59: pp. 9-15.

View In ArticleCross Ref

66. Corbin J.D.: Mechanisms of action of PDE5 inhibition in erectile dysfunction. Int J Impot Res 2004; 16:
pp. S4-S7.

View In ArticleCross Ref

67. Sandner P., Hutter J., Tinel H., Ziegelbauer K., Bischoff E.: PDE5 inhibitors beyond erectile dysfunction.
Int J Impot Res 2007; 19: pp. 533-543.

View In ArticleCross Ref

68. Vlachopoulos C., Ioakeimidis N., Rokkas K., Stefanadis C.: Cardiovascular effects of phosphodiesterase
type 5 inhibitors. J Sex Med 2009; 6: pp. 658-674.

View In ArticleCross Ref

69. Aversa A., Caprio M., Rosano G.M., Spera G.: Endothelial effects of drugs designed to treat erectile
dysfunction. Curr Pharm Des 2008; 14: pp. 3768-3778.

View In ArticleCross Ref

70. Gazzaruso C., Solerte S.B., Pujia A., Coppola A., Vezzoli M., Salvucci F., et. al.: Erectile dysfunction as a
predictor of cardiovascular events and death in diabetic patients with angiographically proven
asymptomatic coronary artery disease: a potential protective role for statins and 5-phosphodiesterase
inhibitors. J Am Coll Cardiol 2008; 51: pp. 2040-2044.
View In ArticleCross Ref

71. Nehra A., Jackson G., Miner M., Billups K.L., Burnett A.L., Buvat J., et. al.: Diagnosis and treatment of
erectile dysfunction for reduction of cardiovascular risk. J Urol 2013; 189: pp. 2031-2038.

View In ArticleCross Ref

72. Guilleminault C., Eldridge F.L., Tilkian A., Simmons F.B., Dement W.C.: Sleep apnea syndrome due to
upper airway obstruction: a review of 25 cases. Arch Intern Med 1977; 137: pp. 296-300.

View In ArticleCross Ref

73. O'Donnell A.B., Araujo A.B., Goldstein I., McKinlay J.B.: The validity of a single-question self-report of
erectile dysfunction. Results from the Massachusetts Male Aging Study. J Gen Intern Med 2005; 20: pp.
515-519.

View In ArticleCross Ref

74. Heruti R., Shochat T., Tekes-Manova D., Ashkenazi I., Justo D.: Association between erectile
dysfunction and sleep disorders measured by self-assessment questionnaires in adult men. J Sex Med
2005; 2: pp. 543-550.

View In ArticleCross Ref

75. Hanak V., Jacobson D.J., McGree M.E., Sauver J.S., Lieber M.M., Olson E.J., et. al.: Snoring as a risk
factor for sexual dysfunction in community men. J Sex Med 2008; 5: pp. 898-908.

View In ArticleCross Ref

Hirshkowitz M., Karacan I., Arcasoy M.O., Acik G., Narter E.M., Williams R.L.: Prevalence of sleep apnea in
men with erectile dysfunction. Urology 1990; 36: pp. 232-234.

View In Article

77. Pressman M.R., DiPhillipo M.A., Kendrick J.I., Conroy K., Fry J.M.: Problems in the interpretation of
nocturnal penile tumescence studies: disruption of sleep by occult sleep disorders. J Urol 1986; 136: pp.
595-598.

View In Article

78. Chediak A.D., Acevedo-Crespo J.C., Seiden D.J., Kim H.H., Kiel M.H.: Nightly variability in the indices of
sleep-disordered breathing in men being evaluated for impotence with consecutive night
polysomnograms. Sleep 1996; 19: pp. 589-592.

View In ArticleCross Ref

79. Margel D., Cohen M., Livne P.M., Pillar G.: Severe, but not mild, obstructive sleep apnea syndrome is
associated with erectile dysfunction. Urology 2004; 63: pp. 545-549.
View In ArticleCross Ref

80. Goncalves M.A., Guilleminault C., Ramos E., Palha A., Paiva T.: Erectile dysfunction, obstructive sleep
apnea syndrome and nasal CPAP treatment. Sleep Med 2005; 6: pp. 333-339.

View In ArticleCross Ref

81. Schmidt H.S., Wise H.A.: Significance of impaired penile tumescence and associated
polysomnographic abnormalities in the impotent patient. J Urol 1981; 126: pp. 348-352.

View In Article

Petersen M., Kristensen E., Berg S., Midgren B.: Sexual function in male patients with obstructive sleep
apnoea. Clin Respir J 2010; 4: pp. 186-191.

View In Article

83. Stannek T., Hurny C., Schoch O.D., Bucher T., Munzer T.: Factors affecting self-reported sexuality in
men with obstructive sleep apnea syndrome. J Sex Med 2009; 6: pp. 3415-3424.

View In ArticleCross Ref

84. Teloken P.E., Smith E.B., Lodowsky C., Freedom T., Mulhall J.P.: Defining association between sleep
apnea syndrome and erectile dysfunction. Urology 2006; 67: pp. 1033-1037.

View In ArticleCross Ref

85. Moreland R.B.: Is there a role of hypoxemia in penile fibrosis: a viewpoint presented to the Society
for the Study of Impotence. Int J Impot Res 1998; 10: pp. 113-120.

View In ArticleCross Ref

86. Cappelleri J.C., Stecher V.J.: An assessment of patient-reported outcomes for men with erectile
dysfunction: Pfizer's perspective. Int J Impot Res 2008; 20: pp. 343-357.

View In ArticleCross Ref

87. Li F., Feng Q., Zhang X., Liu Q.: Treatment for erectile dysfunction patients with obstructive sleep
apnea syndrome by nasal continual positive airway pressure. Zhonghua Nan Ke Xue 2004; 10: pp. 355-
357.

View In ArticleCross Ref

88. Karacan I., Karatas M.: Erectile dysfunction in sleep apnea and response to CPAP. J Sex Marital Ther
1995; 21: pp. 239-247.

View In ArticleCross Ref

89. Karkoulias K., Perimenis P., Charokopos N., Efremidis G., Sampsonas F., Kaparianos A., et. al.: Does
CPAP therapy improve erectile dysfunction in patients with obstructive sleep apnea syndrome?. Clin Ter
2007; 158: pp. 515-518.

View In Article

90. Reishtein J.L., Maislin G., Weaver T.E.: Outcome of CPAP treatment on intimate and sexual
relationships in men with obstructive sleep apnea. J Clin Sleep Med 2010; 6: pp. 221-226.

View In ArticleCross Ref

91. Petersen M., Kristensen E., Berg S., Midgren B.: Sexual function in male patients with obstructive
sleep apnoea after 1 year of CPAP treatment. Clin Respir J 2012;

View In Article

92. Margel D., Tal R., Livne P.M., Pillar G.: Predictors of erectile function improvement in obstructive sleep
apnea patients with long-term CPAP treatment. Int J Impot Res 2005; 17: pp. 186-190.

View In ArticleCross Ref

93. Perimenis P., Karkoulias K., Konstantinopoulos A., Alchanatis M., Perimeni P.P., Athanasopoulos A., et.
al.: The impact of long-term conventional treatment for overlap syndrome (obstructive sleep apnea and
chronic obstructive pulmonary disease) on concurrent erectile dysfunction. Respir Med 2007; 101: pp.
210-216.

View In ArticleCross Ref

94. Cruz I.A., Drummond M., Winck J.C.: Obstructive sleep apnea symptoms beyond sleepiness and
snoring: effects of nasal APAP therapy. Sleep Breath 2012; 16: pp. 361-366.

View In ArticleCross Ref

Budweiser S., Luigart R., Jorres R.A., Kollert F., Kleemann Y., Wieland W.F., et. al.: Long-term changes of
sexual function in men with obstructive sleep apnea after initiation of continuous positive airway
pressure. J Sex Med 2013; 10: pp. 524-531.

View In ArticleCross Ref

96. Perimenis P., Karkoulias K., Markou S., Gyftopoulos K., Athanasopoulos A., Barbalias G., et. al.: Erectile
dysfunction in men with obstructive sleep apnea syndrome: a randomized study of the efficacy of
sildenafil and continuous positive airway pressure. Int J Impot Res 2004; 16: pp. 256-260.

View In ArticleCross Ref

97. Perimenis P., Karkoulias K., Konstantinopoulos A., Perimeni P.P., Katsenis G., Athanasopoulos A., et. al.:
Sildenafil versus continuous positive airway pressure for erectile dysfunction in men with obstructive
sleep apnea: a comparative study of their efficacy and safety and the patient's satisfaction with
treatment. Asian J Androl 2007; 9: pp. 259-264.

View In ArticleCross Ref

98. Perimenis P., Konstantinopoulos A., Karkoulias K., Markou S., Perimeni P., Spyropoulos K.: Sildenafil
combined with continuous positive airway pressure for treatment of erectile dysfunction in men with
obstructive sleep apnea. Int Urol Nephrol 2007; 39: pp. 547-552.

View In ArticleCross Ref

Roizenblatt S., Guilleminault C., Poyares D., Cintra F., Kauati A., Tufik S.: A double-blind, placebo-
controlled, crossover study of sildenafil in obstructive sleep apnea. Arch Intern Med 2006; 166: pp. 1763-
1767.

View In ArticleCross Ref

100. Taskin U., Yigit O., Acioglu E., Aricigil M., Toktas G., Guzelhan Y.: Erectile dysfunction in severe sleep
apnea patients and response to CPAP. Int J Impot Res 2010; 22: pp. 134-139.

View In ArticleCross Ref

101. Shin H.W., Park J.H., Park J.W., Rhee C.S., Lee C.H., Min Y.G., et. al.: Effects of surgical vs. nonsurgical
therapy on erectile dysfunction and quality of life in obstructive sleep apnea syndrome: a pilot study. J
Sex Med 2013; 10: pp. 2053-2059.

View In ArticleCross Ref

102. Khafagy A.H., Khafagy A.H.: Treatment of obstructive sleep apnoea as a therapeutic modality for
associated erectile dysfunction. Int J Clin Pract 2012; 66: pp. 1204-1208.

View In ArticleCross Ref

103. Hoekema A., Stel A.L., Stegenga B., van der Hoeven J.H., Wijkstra P.J., van Driel M.F., et. al.: Sexual
function and obstructive sleep apnea-hypopnea: a randomized clinical trial evaluating the effects of oral-
appliance and continuous positive airway pressure therapy. J Sex Med 2007; 4: pp. 1153-1162.

View In ArticleCross Ref

104. Weaver T.E., Grunstein R.R.: Adherence to continuous positive airway pressure therapy: the
challenge to effective treatment. Proc Am Thorac Soc 2008; 5: pp. 173-178.

View In ArticleCross Ref

105. Perimenis P., Giannitsas K.: Safety of sildenafil in the treatment of erectile dysfunction in patients
with obstructive sleep apnoea. Expert Opin Drug Saf 2007; 6: pp. 423-430.

View In ArticleCross Ref

106. Motamed M., Sandhu D., Murty G.E.: Sildenafil and nasal obstruction. J Otolaryngol 2003; 32: pp.
259-261.

View In ArticleCross Ref

107. Aydin E., Hizal E., Onay O., Ozgen B., Turhan B., Zaimoglu M., et. al.: A double-blind, placebo-
controlled, randomized clinical study of the effects of vardenafil on human nasal patency. Am J Rhinol
2008; 22: pp. 276-279.

View In ArticleCross Ref

108. Neves C., Tufik S., Monteiro M.A., Chediek F., Jose F.F., Roizenblatt S.: The effect of sildenafil on sleep
respiratory parameters and heart rate variability in obstructive sleep apnea. Sleep Med 2010; 11: pp.
545-551.

View In ArticleCross Ref

109. Li X., Dong Z., Wan Y., Wang Z.: Sildenafil versus continuous positive airway pressure for erectile
dysfunction in men with obstructive sleep apnea: a meta-analysis. Aging Male 2010; 13: pp. 82-86.

View In ArticleCross Ref

110. Budhiraja R., Parthasarathy S., Quan S.F.: Endothelial dysfunction in obstructive sleep apnea. J Clin
Sleep Med 2007; 3: pp. 409-415.

View In ArticleCross Ref

111. Atkeson A., Jelic S.: Mechanisms of endothelial dysfunction in obstructive sleep apnea. Vasc Health
Risk Manag 2008; 4: pp. 1327-1335.

View In ArticleCross Ref

112. Feng J., Zhang D., Chen B.: Endothelial mechanisms of endothelial dysfunction in patients with
obstructive sleep apnea. Sleep Breath 2012; 16: pp. 283-294.

View In ArticleCross Ref

Kohler M., Stoewhas A.C., Ayers L., Senn O., Bloch K.E., Russi E.W., et. al.: Effects of continuous positive
airway pressure therapy withdrawal in patients with obstructive sleep apnea: a randomized controlled
trial. Am J Respir Crit Care Med 2011; 184: pp. 1192-1199.

View In Article

114. Kohler M., Craig S., Pepperell J.C., Nicoll D., Bratton D.J., Nunn A.J., et. al.: CPAP improves endothelial
function in patients with minimally symptomatic OSA: results from a subset study of the MOSAIC trial.
Chest 2013; 144: pp. 896-902.

View In ArticleCross Ref

115. Ip M.S., Tse H.F., Lam B., Tsang K.W., Lam W.K.: Endothelial function in obstructive sleep apnea and
response to treatment. Am J Respir Crit Care Med 2004; 169: pp. 348-353.

View In Article

116. Cross M.D., Mills N.L., Al-Abri M., Riha R., Vennelle M., Mackay T.W., et. al.: Continuous positive
airway pressure improves vascular function in obstructive sleep apnoea/hypopnoea syndrome: a
randomised controlled trial. Thorax 2008; 63: pp. 578-583.

View In ArticleCross Ref

117. Simpson P.J., Hoyos C.M., Celermajer D., Liu P.Y., Ng M.K.: Effects of continuous positive airway
pressure on endothelial function and circulating progenitor cells in obstructive sleep apnoea: a
randomised sham-controlled study. Int J Cardiol 2013; 168: pp. 2042-2048.

View In ArticleCross Ref

118. Schiavi R.C., Mandeli J., Schreiner-Engel P., Chambers A.: Aging, sleep disorders, and male sexual
function. Biol Psychiatry 1991; 30: pp. 15-24.

View In Article

119. Fanfulla F., Malaguti S., Montagna T., Salvini S., Bruschi C., Crotti P., et. al.: Erectile dysfunction in
men with obstructive sleep apnea: an early sign of nerve involvement. Sleep 2000; 23: pp. 775-781.

View In Article

120. Guilleminault C., Simmons F.B., Motta J., Cummiskey J., Rosekind M., Schroeder J.S., et. al.:
Obstructive sleep apnea syndrome and tracheostomy. Long-term follow-up experience. Arch Intern Med
1981; 141: pp. 985-988.

View In ArticleCross Ref

121. Zhuravlev V.N., Frank M.A., Gomzhin A.I.: Sexual functions of men with obstructive sleep apnoea
syndrome and hypogonadism may improve upon testosterone administration: a pilot study. Andrologia
2009; 41: pp. 193-195.

View In ArticleCross Ref

122. Foreman P.J., Stahl J., Hobbins T.E., Paskewitz D.A., Gross H.S.: Sleep apnea in five patients evaluated
for nocturnal penile tumescence. Md Med J 1986; 35: pp. 46-48.

View In Article

123. Seftel A.D., Strohl K.P., Loye T.L., Bayard D., Kress J., Netzer N.C.: Erectile dysfunction and symptoms
of sleep disorders. Sleep 2002; 25: pp. 643-647.

View In Article
124. Ceylan C., Odabas O., Yigman M., Dogan S., Yuksel S.: Does the treatment of sleep apnea improve the
sexual performance in men with obstructive sleep apnea syndrome?. J Clin Anal Med 2013; 4: pp. 9-12.

View In ArticleCross Ref