Exploring the link between comorbid insomnia and sleep apnea (COMISA) and erectile dysfunction: implications for male sexual health

Abstract

Introduction

This review explores the interplay between comorbid insomnia and sleep apnea (COMISA) and erectile dysfunction (ED), 2 conditions that significantly impact men’s health. COMISA, a recently recognized condition characterized by the coexistence of insomnia and obstructive sleep apnea, has been shown to disrupt sleep architecture and cause intermittent hypoxia. These disturbances are increasingly linked to the exacerbation of ED, a prevalent issue among men. Understanding the connection between COMISA and ED is crucial for developing integrated treatment approaches that address both sleep and sexual health.

Objectives

We aim to explore the epidemiological, physiological, and potential therapeutic intersections of COMISA and ED. This review sets out to develop a better understanding of the relationship between these conditions and to emphasize the need for an integrated diagnostic and therapeutic approach that addresses both sleep and sexual health.

Methods

Through a comprehensive analysis, including a detailed examination of extant studies, we address the hormonal imbalances and alterations in neural pathways that collectively contribute to the complex pathophysiology of ED and how these are particularly susceptible to the concurrent presence of COMISA.

Results

Our analysis indicates that disruptions in sleep architecture and intermittent hypoxia associated with COMISA can exacerbate ED. Hormonal imbalances, endothelial dysfunction, autonomic imbalance, and increased inflammation and oxidative stress are key mechanisms through which COMISA influences ED. These factors collectively impair vascular health, reduce testosterone levels, disrupt neural control of erections, and contribute to the severity of ED.

Conclusions

This review underscores the necessity for an integrated approach to diagnosis and therapy that considers both sleep and sexual health to improve overall outcomes. These insights should foster a deeper understanding of the relationship between COMISA and ED, encourage further research in this area, and potentially lead to the development of innovative treatment strategies to manage these closely intertwined health concerns.

Introduction

Historically, our understanding of sleep disorders was largely based on personal experience and empirical reports until the year 1863 when Kohlschütter published the first paper on sleep as an experimental scientific study.¹ Since then, the knowledge on sleep disorders has significantly advanced, establishing Sleep Medicine as a critically important and recognized medical specialty² that enables expert evaluation and treatment of the large array of sleep diseases. Indeed, effective treatment of sleep disorders not only mitigates adverse clinical outcomes, but also significantly enhances quality of life.³

In recent years, the awareness to the co-existence of sleep disorders has emerged, and comorbid insomnia and sleep apnea (COMISA) has garnered particular attention, by virtue of the divergent phenotypic expression of this disease when compared to each of its constitutive elements. COMISA, which involves both difficulty in initiating and maintaining sleep (insomnia) and obstructive sleep apnea (OSA), can severely disrupt sleep architecture and impair sleep quality.⁴ The resulting sleep fragmentation and insufficiency along with the intermittent hypoxia that is characteristic of OSA can lead to physiological changes that exacerbate a number of health conditions, including erectile dysfunction (ED), a common disorder among men, especially those suffering from OSA.⁴ This potential relationship between COMISA, ED, and the broader health implications of such medical problems emphasizes the critical need for an integrated approach to diagnosing and treating sleep disorders with the aim of improving not just sleep, but overall male health and well-being.

In this review, we will explore in depth the relationship between COMISA and ED. We aim to elucidate the potential mechanisms that underlie these comorbidities, thereby enhancing our understanding and paving the way for future research and interventions. By exploring the pathways and physiological impact of COMISA and ED, this review seeks to highlight how these conditions influence one another and to explore potentially viable therapeutic strategies. The insights gained from this critical assessment could lead to more effective interventions and a broader perspective on managing these complex health issues, ultimately improving patient outcomes in both sleep and sexual health domains.

Methods

This literature review was conducted to explore the relationship between COMISA and ED. A systematic search was performed using electronic databases, such as PubMed, Scopus, and Google Scholar, covering publications from inception to the present. Keywords included “COMISA,” “erectile dysfunction,” “insomnia,” “sleep apnea,” “hypoxia,” and “sleep architecture.” Inclusion criteria were studies that focused on the pathophysiological mechanisms linking COMISA to ED, epidemiological data, and clinical trials evaluating treatment approaches. Exclusion criteria included studies not published in English, case reports, and studies solely focused on one of the conditions without addressing their comorbidity. Data extraction involved identifying key themes related to the physiological, neural, and hormonal pathways connecting COMISA and ED. The quality of the studies was assessed using a standardized checklist, ensuring that only high-quality evidence was included in the review. The findings were then synthesized to provide a comprehensive understanding of how COMISA exacerbates ED and to highlight areas requiring further research.

Characteristics and prevalence of insomnia and OSA

Insomnia and sleep apnea are 2 highly prevalent sleep disorders that impact millions globally, each stemming from distinct physiological and neurobiological mechanisms.⁵ The International Classification of Sleep Disorders 3rd Edition defines insomnia as a common sleep disorder characterized by difficulty in falling or staying asleep, resulting in insufficient or non-restorative sleep with diurnal consequences.⁶ It is one of the most prevalent sleep disorders worldwide, affecting a significant portion of the world population across different ages and demographics.⁷ Studies suggest that about 8-18% of adults suffer from chronic insomnia, defined by a duration of at least 3 months, with a frequency of at least 3 times per week, with higher rates observed in older adults and women.⁸ The prevalence of insomnia can reach up to 50-60% when those individuals who experience occasional insomnia symptoms are included.⁸

Insomnia is often underdiagnosed or misdiagnosed, which can obscure its true impact on related health conditions, including ED.⁹ Accurately identifying insomnia is crucial, as failure to do so may weaken the observed associations between sleep disturbances and ED, potentially leading to less effective treatment strategies.¹⁰ Understanding these diagnostic challenges highlights the need for comprehensive assessment tools that can better capture the link between insomnia and ED.

Several factors contribute to the widespread nature of insomnia. Modern lifestyles often include elements that disrupt sleep, such as irregular work and sleep schedules, excessive screen time, and high stress levels.¹¹ Urban environments can also affect sleep due to persistent noise and light pollution.¹¹ Notwithstanding, the impact of insomnia is profound, not only affecting night-time rest, but also leading to a range of daytime problems. Individuals with insomnia often suffer from impaired cognitive functions, mood disturbances, reduced job performance, and a decreased quality of life.^11–13 Insomnia is frequently associated with various medical conditions, including cardiovascular diseases (CVDs), diabetes, and mental health disorders like depression and anxiety.^14–16

The physiological and neurobiological mechanisms behind insomnia are complex, involving multiple systems within the body.¹⁷ Many individuals with insomnia exhibit a heightened state of brain activity or hyperarousal, which can occur both during the day and at night.¹⁸ This state can include increased metabolic rates and higher levels of stress-related hormones, such as cortisol.¹⁸ This hyperarousal, often triggered by stress, anxiety, or other environmental factors, disrupts normal sleep patterns.¹⁸ Sleep and wakefulness are also influenced by several other neurotransmitters.¹⁹ Gamma-aminobutyric acid (GABA), a key neurotransmitter, promotes sleep and reduces neural activity.²⁰ However, in individuals with insomnia, an imbalance in excitatory and inhibitory neurotransmitters that promote arousal, e.g., norepinephrine and serotonin, and those neurotransmitters that promote sleep is present, leading to difficulties in sleep initiation and maintenance.²⁰ Moreover, cognitive processes, such as worrying about sleep or engaging in counterproductive behaviors, such as spending excessive time in bed without sleeping, can reinforce and consolidate insomnia.^11,21 Treatments for insomnia (eg, cognitive behavioral therapy for insomnia [CBT-I]) target these maladaptive behaviors and thought processes, alongside pharmacological treatments and lifestyle adjustments to promote better sleep hygiene and further align biological rhythms.^22,23

Obstructive sleep apnea (OSA) is the principal component of a spectrum of respiratory disorders that occurs during sleep and is characterized by complete (apneas) or partial (hypopneas) obstruction of the upper airway during sleep.²⁴ These events occur when the muscles in the oropharyngeal cavity undergo the characteristic relaxation that occurs during sleep, thereby facilitating the airway to partially or completely collapse in susceptible individuals. When apneas or hypopneas develop, significant drops in blood oxygen levels are likely to occur and trigger a set of arousal pathways that disrupt sleep architecture in an effort to resume ventilatory patterning.²⁴ These repeated arousals prevent deep, restorative sleep and lead to excessive daytime sleepiness and fatigue.²⁴

As indicated, the primary physiological event in OSA is the collapse or partial collapse of the upper airway, which can occur at several potential sites from the nasal level to the hypopharynx.²⁵ Several factors contribute to this collapse. First, anatomical vulnerabilities, such as enlarged tonsils, a large tongue, or a narrow airway predispose individuals to OSA.²⁵ Along with sleep onset, muscle tone in the upper airway dilators decreases, which can be further exacerbated by sleep stages, such as rapid eye movement (REM) sleep, in which muscle atonia is more pronounced.²⁵ In the event that upper airway obstruction takes place, it can last from a few seconds to over a minute.²⁵ The cessation of airflow leads to decreased oxygen saturation in the blood, known as hypoxemia, and increases in carbon dioxide levels, or hypercapnia.²⁶

The neurobiological responses to these events are multifaceted. First, the brain responds to the rising carbon dioxide levels and falling oxygen levels.^26,27 Chemoreceptors in the carotid body and medulla oblongata detect these changes and stimulate respiratory effort to overcome the obstruction.²⁷ This increased effort against a closed airway will trigger activation of mechanoreceptive, proprioceptive, and chemosensitive pathways along with recruitment of brain regions underlying the arousal response ultimately resulting in a respiratory effort-related arousal (RERA), usually lasting for only a few seconds before resumption of sleep.²⁸ These arousals are typically brief such that the individual does not have any recollection of these events, yet they are sufficient to restore muscle tone in the airway and promote its patency.²⁸ The repeated episodes of hypoxia and reoxygenation act as a stressor on the cardiovascular system.²⁹ They lead to increased sympathetic nervous system activity, which raises heart rate and blood pressure.²⁹ Over time, in addition to the emergence of persistent activation of sympathetic tone and withdrawal of parasympathetic activity, the protracted nature of this autonomic imbalance can contribute to cardiovascular problems like hypertension, heart failure, and atrial fibrillation.²⁹ At the molecular level, intermittent hypoxia also induces oxidative stress and inflammation.³⁰ Reactive oxygen species generated during reoxygenation periods can damage cellular structures and promote inflammatory pathways, which may contribute to the systemic consequences of OSA, including endothelial dysfunction and atherosclerosis potentially progressing to ischemic heart disease and cerebrovascular disease and stroke.^30,31

The frequent arousals and chronic intermittent hypoxia in OSA can affect neural function and structure.³² Neuroimaging studies have shown that individuals with OSA may have alterations in brain regions involved in cognitive functions, mood regulation, and sleep regulation.^33,34 These changes are thought to contribute to the cognitive deficits, emotional disturbances, and excessive daytime sleepiness commonly reported in OSA patients.³⁴

An earlier study using data from EPISONO estimated the prevalence of OSA in São Paulo and revealed previously unknown levels of the disease.³⁵ EPISONO used the latest clinical and epidemiological techniques, and involved 1042 participants who were randomly selected using a 3-stage cluster sampling method to reflect the population’s demographics. The study used in-lab polysomnography (PSG) along with a low non-participation rate.³⁵ The results indicated that OSA affected 32.9% of the population, with a higher prevalence among men (40.6%), obese individuals, and older age individuals.³⁵ Socio-economic status (SES) influenced OSA risk differently in men and women, with low SES status being protective for men but a risk factor for women.³⁵ This first large-scale metropolitan study in South America revealed a higher prevalence of OSA than that reported in previous studies. This can be attributed to the rigorous methodology used, particularly the use of PSG, and the fact that a population sample reflecting a broad age range and obesity factors was used.³⁵

COMISA: The intersection of insomnia and sleep apnea

It is not surprising that when to highly prevalent disorders are present in the population, co-occurrence of both diseases is likely to occur. The concept of COMISA has significantly advanced our understanding of sleep disorders by recognizing that sleep issues often do not occur in isolation.⁴ COMISA refers to the simultaneous presence of insomnia and OSA.⁴ The term and its clinical implications were first recognized by Christian Guilleminault and colleagues in 1973.³⁶ This early identification marked a critical juncture in Sleep Medicine, highlighting the interaction between 2 major sleep disorders that were previously treated and studied as separate entities.

In 2010, Luyster and colleagues conducted a comprehensive review of the co-occurrence of insomnia and OSA, highlighting the high prevalence of these conditions coexisting. Their analysis revealed that treating both conditions simultaneously with combination therapies, such as CBT-I and continuous positive airway pressure (CPAP) for OSA, led to better sleep outcomes than treating each condition alone. Despite these findings, the review concluded that the optimal treatment strategy for managing COMISA remains unclear, with a need for further research to understand the interplay between insomnia and OSA and to develop effective guidelines. The authors stressed the importance of a multidisciplinary approach for the effective management of these complex cases.³⁷

Luciano and colleagues conducted a longitudinal study within the EPISONO cohort in São Paulo, Brazil, to assess the prevalence and incidence of COMISA. Initially, in 2007, COMISA was found in 17.6% of the general population, with a lower prevalence of 2.5% for moderate to severe cases. By 2015, the overall prevalence increased to 22.9%, while the rate for moderate to severe cases remained stable at 2.6%. The study revealed a 16.7% overall incidence of COMISA, with a higher incidence among those with pre-existing insomnia or OSA. The study highlighted that prior insomnia significantly increased the risk of developing COMISA, more so than OSA alone, indicating that insomnia may play a more crucial role in COMISA development. The findings also showed that OSA diagnoses were more stable over time, while insomnia exhibited greater variability, underscoring the complexity of these co-occurring sleep disorders.³⁸

The relationship between insomnia and OSA is notably bidirectional, indicating that each condition can exacerbate the other, leading to more severe symptoms and health consequences.^4,39 Sleep fragmentation caused by insomnia can exacerbate the airway collapse characteristic of OSA during sleep, which in turn can disrupt sleep.³⁹ This mutual reinforcement can severely impact overall sleep quality and increase the risk of CVDs, cognitive impairments, metabolic disorders, and decreased quality of life.^39,40 The repeated awakenings and oxygen desaturation events that mark OSA can intensify insomnia symptoms by fragmenting sleep architecture and increasing night-time awakenings.³⁹ This interaction not only worsens sleep quality, but also heightens daytime sleepiness and fatigue, further impairing daily functioning.³⁹

COMISA has profound implications for an individual’s overall health, particularly affecting mental health, cardiovascular health, and metabolic functions.⁴¹ The interplay between insomnia and OSA not only disrupts sleep quality, but also leads to a cascade of negative health outcomes.⁴ Regarding mental health, individuals suffering from COMISA experience higher rates of depression and anxiety than those with either disorder alone.^42,43 The sleep disruption resulting from COMISA leads to excessive daytime sleepiness, mood disturbances, and heightened stress levels, all of which contribute to an increased risk of developing mental health issues.⁴² Cardiovascular health is at increased risk in patients with COMISA,⁴⁴ as the presence of OSA within this comorbid condition is associated with intermittent hypoxia and sleep fragmentation, both of which can lead to increased blood pressure, higher rates of arrhythmias, and a greater overall risk of heart disease.^44,45 Insomnia’s contribution to prolonged sympathetic activation exacerbates these risks, compounding the strain on the cardiovascular system.⁴⁴ Metabolic consequences are another critical aspect of COMISA’s impact on health.⁴⁴ Disrupted sleep patterns and the resultant poor sleep quality affect glucose metabolism and insulin sensitivity, increasing the risk of developing type 2 diabetes,⁴⁶ and the fatigue and disrupted sleep contribute to poor dietary choices and reduced physical activity, further impairing metabolic health.

Hein and colleagues conducted a study based on data from 471 type 2 diabetic patients from the Erasme Hospital sleep laboratory, focusing on the CVD risks associated with COMISA in this subgroup.⁴⁴ The study uncovered that 32.9% of the type 2 diabetics analyzed were at high risk of CVD, as indicated by a SCORE index ≥5%.⁴⁴ Using multivariate logistic regression analysis and adjusting for the main cardiovascular risk factors, the findings revealed that unlike the presence of either OSAS or insomnia alone, it was only COMISA that was associated with a higher risk of CVD among these patients.⁴⁴ This outcome underscores the significant negative synergistic effect of COMISA on cardiovascular outcomes in type 2 diabetics, highlighting the necessity for more systematic research and adequate therapeutic management of COMISA to enhance cardiovascular and metabolic prevention in this particular subpopulation.⁴⁴ Another study investigated the 10-year risk for CVD associated with COMISA in hypertensive subjects.⁴⁵ Clinical data from 1009 hypertensive subjects from the Sleep Laboratory database were analyzed.⁴⁵ A Framingham Risk Score ≥ 10% was used as a cutoff to identify subjects with a high 10-year risk for CVD.⁴⁵ The association between the 10-year risk for CVD and COMISA was explored using logistic regression analyses.⁴⁵ The study found that 65.3% of the hypertensive subjects in the sample presented a high 10-year risk for CVD.⁴⁵ After adjusting for major confounding factors, multivariate logistic regression analyses revealed that, unlike when its insomnia or OSA are present separately, COMISA was significantly associated with a high 10-year risk for CVD in hypertensive subjects (OR 1.88, 95% CI 1.01-3.51).⁴⁵ This study demonstrated that the negative synergy between OSAS and insomnia disorder plays a central role in the 10-year risk for CVD among hypertensive subjects.⁴⁵

Data from the Wisconsin Sleep Cohort was analyzed to investigate the association between COMISA symptoms and all-cause mortality.⁴⁷ This study defined nocturnal insomnia symptoms as difficulties in initiating sleep, maintaining sleep, and/or early morning awakenings “often” or “almost always”, as well as regular use of sedative-hypnotic medication.⁴⁷ OSA was identified with an AHI of ≥5/h of sleep.⁴⁷ Participants were categorized into 4 groups: those with neither insomnia symptoms nor OSA, those with only insomnia symptoms, those with OSA alone, and those exhibiting symptoms of COMISA.⁴⁷ The relationship between these groups and all-cause mortality over a 20-year follow-up was examined using multivariable adjusted Cox regression models.⁴⁷ Among the 1115 adult participants (mean ± SD age 55 ± 8 years, 53% male), 19.1% had symptoms of COMISA.⁴⁷ After adjusting for sociodemographic and behavioral factors, COMISA symptoms were associated with an increased risk of all-cause mortality (HR [95% CI]; 1.71 [1.00-2.93]), compared to participants without insomnia symptoms or OSA.⁴⁷ Neither OSA alone (0.91 [0.53, 1.57]) nor insomnia symptoms alone (1.04 [0.55, 1.97]) were linked with an increased risk of mortality.⁴⁷ The study concluded that symptoms of COMISA are associated with an increased risk of all-cause mortality.⁴⁷ These findings emphasize the critical need for further research to understand the underlying mechanisms and to evaluate effective treatment strategies for reducing mortality risk in individuals with COMISA.

Treatment strategies for COMISA are complex and require multi-faceted approaches. CPAP is the standard treatment for OSA and can also alleviate some symptoms of insomnia by stabilizing breathing during sleep.⁴⁸ CBT-I is recommended for managing insomnia and may also aid in improving adherence to CPAP treatment by reducing the cognitive and physiological hyperarousal associated with insomnia.⁴⁸ A study assessed the impact of depression, anxiety, and stress on the effectiveness of CBT-I in patients with COMISA.⁴⁹ The research involved 145 patients who were randomized into a CBT-I group and a no-treatment control group.⁴⁹ Assessments included sleep diaries and questionnaires on insomnia, depression, anxiety, and stress, conducted before and after treatment.⁴⁹ Results indicated that approximately half of the patients reported symptoms of depression (57%), anxiety (53%), and stress (48%).⁴⁹ Despite these initial psychological symptoms, improvements in insomnia following CBT-I were not significantly affected by the severity of depression, anxiety, or stress.⁴⁹ The study concluded that CBT-I is effective in treating insomnia in patients with COMISA, regardless of the presence of comorbid depression, anxiety, or stress symptoms.⁴⁹ This suggests that CBT-I should be recommended for these patients to help manage their sleep conditions effectively.

Current treatments for COMISA may include several additional approaches.^50,51 Mandibular advancement devices (MADs), positional training, and surgery are effective for certain OSA cases and can also improve insomnia symptoms.^51,52 Benzodiazepines, although generally not recommended for OSA patients, have shown some benefits in specific cases but should be used cautiously.^53,54 Newer non-benzodiazepine sedative-hypnotics like zolpidem and eszopiclone have fewer negative effects on the airways and can improve sleep duration and efficiency.^55,56 Antidepressants (eg, ramelteon and mirtazapine) can help improve sleep quality without worsening OSA.^57,58 Furthermore, specific approaches to endotypic phenotypes may further enable better stratification of combinatorial pharmaceutical approaches to OSA that may concurrently benefit the insomnia elements in patients with COMISA.^59–62 Sleep hygiene education, which focuses on lifestyle changes, such as managing caffeine and alcohol intake and maintaining a proper sleep environment, can alleviate symptoms of both insomnia and mild to moderate OSA.^63,64 Melatonin and herbal therapies using valerian, chamomile, among other herbs, have shown limited effectiveness, but melatonin might be useful for those with circadian rhythm sleep–wake disorders.^65,66

Overall, the most researched and effective treatments for COMISA are CPAP and CBT-I. These methods have demonstrated substantial improvements in both OSA and insomnia symptoms, making them the primary recommendations for managing COMISA.⁶⁷

COMISA and ED: A possible relationship?

Erectile dysfunction (ED) is a prevalent condition characterized by the inability to achieve or maintain an erection sufficient for satisfactory sexual performance.⁶⁸ The pathophysiology of ED involves vascular, neurological, hormonal, and psychological factors.⁶⁸ Vascular integrity is critical for ED, as an erection requires a significant increase in blood flow to the penile arteries, which fills the erectile tissues.⁶⁹ Conditions, such as atherosclerosis can impair this blood flow, leading to ED.⁷⁰ The neurological aspects are equally important, and both the central and peripheral nervous systems are involved in initiating the physiological processes that trigger an erection.⁷¹ Neurological disorders like Parkinson’s disease, multiple sclerosis, and spinal cord injuries can disrupt these nerve signals.⁷² Hormonal regulation also plays a vital role in sexual function, with testosterone being particularly significant.⁷³ Low levels of this hormone can lead to decreased libido and ED.⁷⁴ Recently, it has been suggested that the microbiome may also have an important role in ED.⁷⁵ Andersen and colleagues conducted an extensive literature review on the relationships among ED, the gut microbiota, and OSA,⁷⁵ and found that poor sleep quality from OSA can impair reproductive function and lead to ED, while also causing changes in the gut microbiota that further exacerbate health issues.⁷⁵ Thus, the use of probiotics and prebiotics may help prevent and treat OSA by reducing inflammation and improving gut health. Moreover, a healthy diet and lifestyle are crucial for managing these conditions and enhancing overall health.⁷⁵ Additionally, psychological factors like stress, anxiety, and depression can influence the ability to initiate the nerve impulses necessary for an erection, further complicating the condition.⁷⁶

The scientific study of ED has evolved over centuries, with early references in ancient texts suggesting various remedies.⁶⁸ However, it was not until the late 20th century that a more scientific understanding emerged, especially with the discovery of the cardiovascular implications of penile blood flow.⁷⁷ This led to the development of pharmacological treatments involving increased generation of nitric oxide, such as sildenafil in the late 1990s, which revolutionized the clinical approach to ED.^78,79 These treatments primarily manipulate the bioavailability of nitric oxide and downstream pathways, which are essential for the relaxation of penis muscles and increased blood flow.⁷⁸ Today, the treatment of ED involves a holistic approach that includes lifestyle changes, psychological counseling, and medical interventions, reflecting its multifactorial nature.⁸⁰ This comprehensive approach helps address the various underlying causes and improve the quality of life for affected individuals.

A good night’s sleep plays a crucial role in overall health and well-being, and has a significant impact on various bodily functions, including sexual health.⁸¹ Sleep is essential for balancing hormone levels, supporting cardiovascular health, and managing stress and anxiety, all factors that are intricately linked to erectile function.⁷³ Consequently, disturbances in sleep can have a profound effect on ED.

Sleep disorders, such as insomnia, OSA, and restless leg syndrome, can disrupt the quality and quantity of sleep, leading to hormonal imbalances that may affect libido and erectile function.^73,82 Specifically, sleep disorders often lead to reduced levels of testosterone, which is critical for sexual desire and for maintaining erections.^74,83,84 Poor sleep quality is associated with increased stress and anxiety levels, which can further exacerbate issues related to ED.⁸⁴ Sleep apnea, in particular, is directly linked to an increased risk of ED. This condition can lead to chronic sleep deprivation and a reduction in the oxygen saturation of the blood, and therefore compromise the proper functioning of all organs, including those involved in sexual response.⁸⁴

Andersen and colleagues analyzed the EPISONO sample to determine the prevalence of ED and its association with various factors, including sleep disturbances, testosterone levels, age, body mass index (BMI), and comorbid conditions in a population-based sample from São Paulo.⁸⁵ The study included 467 men aged 20 to 80 years, utilizing questionnaires, polysomnography, and fasting blood samples. The overall prevalence of ED complaints was 17.1%, with a significant increase in prevalence with age, 7.3% among younger men (20-29 years) compared to 63.3% in men over 50 years old (OR = 21.65).⁸⁵ Critically, the study found that sleep disturbances, such as reduced REM sleep (OR = 1.77) and sleep fragmentation (indicated by an increased number of arousals per hour, OR = 1.61), were strongly associated with an increased risk of ED.⁸⁵ Comorbid conditions like obesity (OR = 1.89), low testosterone levels (OR = 3.94), and OSA (OR = 2.12) were significant risk factors.⁸⁵ These findings underscore the importance of addressing sleep quality and related disorders as part of managing ED, particularly in older men with comorbidities.⁸⁵

However, the potential influence of COMISA on ED is still a neglected risk factor in the study of sexual health. As discussed in previous sections, COMISA combines 2 significant sleep disorders, insomnia and OSA, each being capable of individually impacting erectile function, and together, they may significantly exacerbate both the risk and severity of ED.^86,87

The pathophysiological mechanisms linking COMISA to ED can occur through various pathways (Table 1). Firstly, the recurrent hypoxemia and fragmented sleep associated with OSA contribute to endothelial dysfunction, a condition where the endothelial layer of blood vessels fails to perform its normal regulatory functions, including the modulation of vascular tone.^32,88,89 Endothelial dysfunction is a critical factor in the pathogenesis of ED as it impairs the nitric oxide-mediated vasodilation necessary for achieving and maintaining an erection.^89,90 Secondly, the sympathetic hyperactivity resulting from frequent nocturnal awakenings associated with COMISA can lead to an imbalance in the autonomic nervous system, favoring sympathetic over parasympathetic activity.^91–93 This autonomic imbalance reduces the physiological ability to initiate and maintain penile erection, as penile tumescence is primarily under parasympathetic control.^94,95 Moreover, poor sleep quality and chronic sleep deprivation, common in individuals with COMISA, have been linked to decreased serum testosterone levels.^73,84,85,96 Testosterone plays a crucial role in sexual function, and its deficiency is a known risk factor for ED.⁷³ The chronic stress and fatigue associated with COMISA can exacerbate psychological components of ED, including reduced sexual desire and performance anxiety.^74,76,82,97 Emerging research suggests a role for inflammation and oxidative stress, both of which are elevated in OSA, in the development of ED.^29,90,98,99 The systemic inflammatory response and oxidative stress can further impair endothelial function and contribute to the vascular abnormalities associated with ED.^29,100 Erythrocytosis, a condition characterized by an abnormal increase in red blood cell mass, is a known consequence of OSA due to chronic intermittent hypoxia.¹⁰¹ This elevated red blood cell count increases blood viscosity, which can impair microvascular circulation, including the blood flow critical for penile erection.¹⁰² The resultant reduction in oxygen delivery to penile tissues may contribute to endothelial dysfunction.¹⁰² The increased blood viscosity and associated hypercoagulability elevate the risk of thrombosis, further compromising vascular health and potentially leading to a higher incidence of ED in patients with OSA-induced erythrocytosis.¹⁰² This interplay between erythrocytosis and vascular impairment underscores the importance of managing OSA to mitigate its impact on sexual health.¹⁰² In this context, testosterone replacement therapy (TRT), often used to treat hypogonadism, can complicate the clinical picture.¹⁰³ TRT is known to exacerbate erythrocytosis by further increasing red blood cell production, potentially worsening the hyperviscosity and associated risks.¹⁰³ Therefore, careful monitoring of hematocrit levels and cardiovascular status is essential when considering TRT in patients with OSA, as the interplay between erythrocytosis and vascular impairment could significantly impact sexual health outcomes.¹⁰³

Table 1.

Key mechanisms linking COMISA to ED.

Mechanism	Description
Endothelial dysfunction	Recurrent hypoxemia and fragmented sleep impair endothelial function, reducing nitric oxide availability, which is crucial for vascular health and erections.89
Autonomic imbalance	Increased sympathetic activity due to sleep disturbances disrupts the balance with parasympathetic activity, impairing the physiological process of erection.104
Hormonal disruptions	Chronic sleep deprivation and poor sleep quality lead to decreased testosterone levels, a critical hormone for sexual function.84
Inflammation and oxidative stress	COMISA elevates systemic inflammation and oxidative stress, further damaging vascular health and contributing to ED.75,100

Abbreviations: COMISA, comorbid insomnia and sleep apnea; ED, erectile dysfunction.

A systematic review and meta-analysis investigated the association between OSA and ED.¹⁰⁵ The search utilized various keywords including OSA, sleep apnea syndromes, ED, sleep-disordered breathing, snoring, sexual function, and impotence.¹⁰⁵ The analysis excluded review articles, case reports, commentaries, and studies solely assessing treatment efficacy for OSA or ED.¹⁰⁵ The review identified 28 observational studies, of which 19 were cross-sectional, 7 were case-control, and 2 were cohort studies.¹⁰⁵ From these, an OR with a 95% confidence interval was calculated based on data from 10 studies. The combined OR of 0.45 (95% CI: 0.18-0.71) indicated that individuals without OSA have a significantly lower risk of ED compared to those with OSA.¹⁰⁵ This suggests a strong association between OSA and an increased risk of ED, highlighting the need for further well-designed controlled clinical trials and longitudinal prospective studies to explore this relationship further. Interestingly, in a study assessing sleep architecture and daytime sleepiness in 280 patients with suspected OSA, 107 were found to have ED.¹⁰⁶ These patients with ED exhibited higher scores on the Epworth Sleepiness Scale, prolonged N1 sleep phase duration, and lower mean and minimal oxygen saturation levels compared to the 173 patients in the control group who did not have ED. These findings suggest that patients with ED who also have OSA experience significant alterations in sleep architecture and increased daytime sleepiness.¹⁰⁶ However, it’s important to note that these alterations are likely associated with the severity of OSA and related comorbidities, rather than being directly caused by ED itself.

Another study explored the link between sleep quality and ED in university students at the Universidad Ricardo Palma in Lima, Peru.¹⁰⁷ The survey involved 381 men aged 18-30, and used various indices to measure erectile function and sleep quality.¹⁰⁷ The study found that 50.9% of the participants had poor sleep quality, and those with poor sleep were significantly more likely to experience ED (adjusted PR = 6.48) compared to those with good sleep.¹⁰⁷ Sleep apnea was linked to a higher prevalence of ED, whereas overweight and obesity were associated with a lower prevalence.¹⁰⁷ The study highlighted that poor sleep quality was a significant risk factor for ED among young men, underlining the potential impact of lifestyle and health factors on sexual health.¹⁰⁷

Xiong and colleagues conducted a comprehensive study to clarify the causal associations between 42 modifiable risk factors and ED using univariate Mendelian Randomization (MR), multivariate MR, and mediation MR analyses.¹⁰⁸ The study pooled results from 2 independent ED genome-wide association studies to verify the findings.¹⁰⁸ Several factors were identified that significantly increase the risk of ED, including genetically predicted BMI, waist circumference, trunk fat mass, whole body fat mass, poor overall health rating, type 2 diabetes, basal metabolic rate, adiponectin, cigarette consumption, insomnia, snoring, hypertension, and various CVDs, such as stroke and coronary heart disease, as well as major depressive disorder. The study particularly highlighted the significant impact of sleep-related factors, such as insomnia and snoring, on the risk of ED.¹⁰⁸ The multivariate MR analysis confirmed that these sleep disturbances were strongly associated with an increased risk of ED, independent of other factors.¹⁰⁸ This underscores the critical role that sleep quality plays in sexual health, emphasizing the need for targeted interventions to address these specific risk factors.¹⁰⁸ The study found also that a higher genetic predisposition to sex hormone-binding globulin levels was associated with a decreased risk of ED, further contributing to the understanding of the complex interplay between these variables and ED. This research supports the causal role of several modifiable risk factors in the onset and development of ED, highlighting the importance of addressing these factors in the prevention and management of ED.

Another recent study utilizing the TriNetX Diamond database has demonstrated significant associations between ED, testosterone deficiency, and various sleep disorders in a large cohort of US men aged 40-70 years.¹⁰⁹ Conducted in June 2022, the research assessed the links between ED and testosterone deficiency with conditions, such as insomnia, OSA, and circadian rhythm sleep disorder.¹⁰⁹ The findings revealed that testosterone deficiency was significantly more likely in men diagnosed with OSA (odds ratio (OR) = 1.66), insomnia (OR = 1.74), and circadian rhythm dysfunction (OR = 2.63) compared to matched controls without these sleep disorders.¹⁰⁹ Similarly, ED was more prevalent among men with OSA (OR = 1.02), insomnia (OR = 1.30), and circadian rhythm dysfunction (OR = 1.54).¹⁰⁹ The study, which used propensity score matching to control for variables like age, hypertension, hyperlipidemia, diabetes, ischemic heart disease, tobacco usage, and obesity, underscores the considerable impact of poor sleep on the male genitourinary health.¹⁰⁹

Regarding insomnia, a recent study investigated its association with ED among patients treated for insomnia, using the IBM MarketScan databases from 2007 to 2016.¹¹⁰ The authors suggested that the higher rates of ED treatment in the treated group might be due to these men being more proactive in seeking care, leading to a higher likelihood of ED diagnosis and subsequent treatment.¹¹⁰ Furthermore, age differences between the treated and non-treated groups may have contributed to the observed differences, as older men tend to seek treatment more frequently.¹¹⁰ This highlights the importance of considering patient characteristics when interpreting these findings.¹¹⁰ The study emphasized that insomnia was significantly associated with a higher incidence of ED, suggesting that effective management of insomnia might be crucial for preventing or mitigating ED. Further research is warranted to explore the long-term impacts of insomnia treatment on erectile function, given the commonality of insomnia and its profound impact on quality of life.

In the clinical setting, physicians must be vigilant in recognizing the interconnectedness of ED and low testosterone levels. These conditions often coexist, and their overlapping mechanisms can complicate diagnosis and treatment. Metabolic disorders, such as obesity and diabetes contribute to chronic inflammation, further disrupting the hypothalamic pituitary gonadal axis (HPG) and resulting in decreased testosterone levels. This hormonal imbalance can not only reduce libido but also worsen erectile difficulties, making early identification and comprehensive management essential. Clinicians should consider the bidirectional relationship between ED and low testosterone levels when developing treatment plans. TRT has been shown to improve erectile function, particularly when used alongside phosphodiesterase type 5 inhibitors (PDE5is). However, not all patients respond equally to TRT, underscoring the importance of a thorough evaluation of cardiovascular health, metabolic conditions, and the potential for erythrocytosis before initiating therapy.^103,111 As mentioned above, erythrocytosis, which can be exacerbated by TRT, increases blood viscosity and can impair microvascular circulation, potentially worsening ED and increasing the risk of thrombosis.¹⁰³ Therefore, while the association between ED and low testosterone levels is well-supported by clinical data, personalized treatment approaches are crucial to addressing the multifaceted nature of these interrelated conditions effectively.¹⁰³

In conclusion, COMISA and ED share common pathophysiological pathways, primarily involving endothelial dysfunction, autonomic imbalance, hormonal disruptions, and psychological factors. Understanding these interconnected pathways is crucial for developing targeted therapeutic strategies that address both the respiratory and erectile functions in affected individuals. This approach promises to enhance the overall quality of life and sexual health of men suffering from these comorbid conditions.

Future perspectives

Future research into the relationship between COMISA and ED is critical for developing more effective treatment strategies and understanding the underlying mechanisms that connect sleep disorders with sexual health. Despite increasing recognition of the interconnectedness of these conditions, several key areas remain underexplored.

1. Longitudinal studies: There is a significant need for long-term, prospective studies to better understand the causal relationships between COMISA and ED. Such studies could help determine whether early intervention in sleep disorders can prevent or alleviate the development of ED, and vice versa. Professionals dealing with insomnia, OSA, and/or COMISA should keep in mind the interface these disorders and sexual outcomes.

2. Mechanistic research: Exploring the biological pathways and physiological interactions between sleep disorders and erectile function is crucial. Research should focus on how disruptions in sleep architecture, hypoxia related to OSA, and hormonal imbalances associated with both conditions, particularly testosterone levels, contribute to ED.

3. Impact of treatment efficacy: Investigating how the treatment of sleep disorders affects the outcomes of ED is essential. This includes clinical trials on the efficacy of CPAP therapy for OSA in patients with ED and the effects of pharmacological treatments for insomnia or OSA on erectile function. Identification of the synergistic effects of treating both conditions simultaneously could lead to more holistic treatment approaches.

4. Subgroup analyses: Future research should also consider the impact of demographic variables, such as age, comorbidities, and lifestyle factors on the relationship between COMISA and ED. Tailoring research and treatments to specific populations could enhance therapeutic outcomes.

5. Technological innovations: The development of new diagnostic tools and therapeutic technologies holds promise for better management of COMISA and ED. Wearable devices that monitor sleep and new pharmacological agents could offer more precise and personalized treatment options.

6. Psychological and social dimensions: Given the psychological impact of both ED and sleep disorders, further studies on the psychological interventions and social dynamics associated with these conditions are warranted. This includes exploring the role of mental health in the onset and management of COMISA and ED, and how patient education and support systems can be improved.

By addressing these future research areas, the scientific community can move closer to a comprehensive understanding of COMISA and ED, potentially leading to more effective treatments and improved quality of life for patients suffering from these complexes, recent, and still under investigated conditions.

Conclusions

This review emphasizes the complex relationship COMISA and ED, underlining the necessity for a combined diagnostic and therapeutic approach that considers both sleep and sexual health. The evidence presented shows that sleep disturbances associated with COMISA, such as disrupted sleep patterns and intermittent hypoxia, significantly contribute to the worsening of ED. These sleep-related issues lead to physiological changes, including endothelial dysfunction, autonomic imbalances, and hormonal alterations, which are key mechanisms by which COMISA impacts erectile function. The review also identifies the importance of treating both COMISA and ED together, as addressing only one condition may not fully resolve the patient’s health issues. By integrating treatment strategies that target both sleep disorders and ED, healthcare providers can achieve better outcomes, improving both sleep quality and sexual function. Further research is needed to explore the long-term effects of such integrated treatments, particularly through studies that examine the impact of early intervention in sleep disorders on the progression of ED. In summary, managing COMISA and ED together is essential for improving the overall health and quality of life of patients. This approach requires collaboration across various medical disciplines, including sleep medicine, endocrinology, cardiology, and urology, to ensure that both sleep and sexual health are adequately addressed.

Funding

This work was supported by the Associação Fundo de Incentivo à Pesquisa and grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, recipient M.L.A.: 2020/13467-8), and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, recipient: M.L.A. and S.T.). D.G. is supported in part by National Institutes of Health grant HL166617.

Conflicts of interest

None declared.