Assessment of serum level of corticotropin-releasing factor in primary nocturnal enuresis

Twenty-nine children aged 8–14 years complaining of primary monosymptomatic NE (no urinary control since birth and no other urinary symptoms) attending the outpatient clinic at the National Research Centre were consecutively enrolled in this study (children coming from any part of the country with no specification to any area or social class, and fulfilling the inclusion and exclusion criteria). Exclusion criteria were children less than 6 years of age or more than 18 years, daytime incontinence or urinary symptoms, conditions causing secondary NE (neurological abnormalities, spinal, brain or pelvic surgery, and congenital anomalies of the urologic tract). Other exclusion criteria were urinary tract infection, diabetes mellitus, and diabetes insipidus. All cases had not received any enuresis-related medications for at least 1 year before inclusion in the study. Another 16 healthy children matched for age and sex with good toilet control day and night were recruited as controls.

All cases were subjected to history taking with special emphasis on sleep pattern and voiding history (to differentiate between monosymptomatic and non-monosymptomatic NE), anthropometric measurement (height, weight, and body mass index), clinical examination and investigations (urine, stool analysis, plain X-ray for lumbosacral spines (to exclude spina bifida), and ultrasonography (abdominal and pelvic to assess urinary tract abnormality). Serum CRF was assessed in all patients and controls in the morning and evening (2 mL of venous blood was withdrawn at 9 a.m. and 9 p.m. to test the circadian pattern of secretion (2 controls missed their night sampling). Samples were centrifuged and sera were stored at −20 °C until assayed using an enzyme-linked immunoassay kit (Assay Designs Inc., Ann Arbor, MI, USA).

The study was approved by the ethics committee of the National Research Centre; all patient guardians gave informed written consent.

Descriptive data and comparison between cases and controls are presented in Table 1. Both groups (patients and controls) were statistically matched.

Comparison between cases and controls regarding CRF serum levels (morning and evening) are presented in Table 2 and Fig. 1. Both morning and evening serum CRF levels were significantly lower in patients than in controls (p = 0.013 and p = <0.01 respectively).

Figure 1

Corticotropin-releasing factor serum levels in cases and controls (morning and evening).

 

No significant difference was detected regarding sex in either cases or controls.

The comparison between morning and evening CRF serum levels in each group is presented in Table 3. No statistical significant difference was found between morning and evening levels in either cases (p = 0.4) or controls (p = 0.57).

Correlation of CRF with age was statistically insignificant in both cases and controls (Table 4).

CRF is a neurotransmitter in Barrington's nucleus neurons. These neurons can coregulate the parasympathetic tone of the bladder [12] and brain noradrenergic activity [9] by targeting the preganglionic lumbosacral neurons [12] and projection into the locus ceruleus (LC), which is the major brain norepinephrine nucleus [9]. The LC norepinephrine system had long been implicated in arousal and attention [13]. LC neurons are activated by diverse stimuli including bladder and colon distension that is translated to forebrain electroencephalographic activation [14] and [15]. The CRF family may affect various body systems independently, stimulating peripheral CRF receptors via vagal and/or autocrine/paracrine pathways, but data supporting any clinical significance are still limited [16]. CRF was postulated to have an important role in coordinating both micturition and arousal [8]. We assumed that CRF has a role in primary NE.

CRF was deficient in our enuretic patients, which can draw attention to the possible pathophysiologic implications in primary NE (either at the level of loss of inhibitory effect on micturition or by lack of arousal in response to bladder distension). This is a preliminary study that cannot prove causation, but we think it is an important finding that needs further research.

Nocturnal enuresis (NE) refers to discrete episodes of urinary incontinence during sleep in children older than 5 years of age [1]. It can be primary or secondary. It is a stressful condition that needs treatment to relieve anxiety and prevent the accompanying stigma attached to it [2]. Various pathophysiologic mechanisms for primary NE have been discussed as maturational delay, genetic defect, disturbances in vasopressin secretion, bladder capacity defect, or sleep pattern [2], [3], [4], and [5].

Primary NE is considered to be one of the sleep-related phenomena “parasomnias” [6], characterized by disruption in the relationship between arousal and urination [7]. One factor that plays an important role in coordinating micturition and arousal is corticotropin-releasing factor (CRF) [8]. It is a neurohormone released from the paraventricular nucleus of the hypothalamus into the median eminence to elicit release of adrenocorticotrophin from the anterior pituitary, a hallmark of stress response [9]. CRF gives rise to divergently projecting pathways. It may act to modulate autonomic function and behavior in concert with its endocrine effect [10]. Conflicting animal results regarding the role of CRF in regulation of micturition have been raised: it could be a facilitator by decreasing the micturition threshold and increasing micturition frequency [11]. In contrast, CRF agonists were found to inhibit urination in the awake state and receptor antagonists had the opposite effect [7]. It was suggested to be a novel target for treatment of urinary disorders based on the finding that manipulation of CRF in the pontine micturition circuit could affect urodynamic function [7].

Twenty-nine children aged 8–14 years complaining of primary monosymptomatic NE (no urinary control since birth and no other urinary symptoms) attending the outpatient clinic at the National Research Centre were consecutively enrolled in this study (children coming from any part of the country with no specification to any area or social class, and fulfilling the inclusion and exclusion criteria). Exclusion criteria were children less than 6 years of age or more than 18 years, daytime incontinence or urinary symptoms, conditions causing secondary NE (neurological abnormalities, spinal, brain or pelvic surgery, and congenital anomalies of the urologic tract). Other exclusion criteria were urinary tract infection, diabetes mellitus, and diabetes insipidus. All cases had not received any enuresis-related medications for at least 1 year before inclusion in the study. Another 16 healthy children matched for age and sex with good toilet control day and night were recruited as controls.

All cases were subjected to history taking with special emphasis on sleep pattern and voiding history (to differentiate between monosymptomatic and non-monosymptomatic NE), anthropometric measurement (height, weight, and body mass index), clinical examination and investigations (urine, stool analysis, plain X-ray for lumbosacral spines (to exclude spina bifida), and ultrasonography (abdominal and pelvic to assess urinary tract abnormality). Serum CRF was assessed in all patients and controls in the morning and evening (2 mL of venous blood was withdrawn at 9 a.m. and 9 p.m. to test the circadian pattern of secretion (2 controls missed their night sampling). Samples were centrifuged and sera were stored at −20 °C until assayed using an enzyme-linked immunoassay kit (Assay Designs Inc., Ann Arbor, MI, USA).

The study was approved by the ethics committee of the National Research Centre; all patient guardians gave informed written consent.

Descriptive data and comparison between cases and controls are presented in Table 1. Both groups (patients and controls) were statistically matched.

Comparison between cases and controls regarding CRF serum levels (morning and evening) are presented in Table 2 and Fig. 1. Both morning and evening serum CRF levels were significantly lower in patients than in controls (p = 0.013 and p = <0.01 respectively).

Figure 1

Corticotropin-releasing factor serum levels in cases and controls (morning and evening).

 

No significant difference was detected regarding sex in either cases or controls.

The comparison between morning and evening CRF serum levels in each group is presented in Table 3. No statistical significant difference was found between morning and evening levels in either cases (p = 0.4) or controls (p = 0.57).

Correlation of CRF with age was statistically insignificant in both cases and controls (Table 4).

CRF is a neurotransmitter in Barrington's nucleus neurons. These neurons can coregulate the parasympathetic tone of the bladder [12] and brain noradrenergic activity [9] by targeting the preganglionic lumbosacral neurons [12] and projection into the locus ceruleus (LC), which is the major brain norepinephrine nucleus [9]. The LC norepinephrine system had long been implicated in arousal and attention [13]. LC neurons are activated by diverse stimuli including bladder and colon distension that is translated to forebrain electroencephalographic activation [14] and [15]. The CRF family may affect various body systems independently, stimulating peripheral CRF receptors via vagal and/or autocrine/paracrine pathways, but data supporting any clinical significance are still limited [16]. CRF was postulated to have an important role in coordinating both micturition and arousal [8]. We assumed that CRF has a role in primary NE.

CRF was deficient in our enuretic patients, which can draw attention to the possible pathophysiologic implications in primary NE (either at the level of loss of inhibitory effect on micturition or by lack of arousal in response to bladder distension). This is a preliminary study that cannot prove causation, but we think it is an important finding that needs further research.

Nocturnal enuresis (NE) refers to discrete episodes of urinary incontinence during sleep in children older than 5 years of age [1]. It can be primary or secondary. It is a stressful condition that needs treatment to relieve anxiety and prevent the accompanying stigma attached to it [2]. Various pathophysiologic mechanisms for primary NE have been discussed as maturational delay, genetic defect, disturbances in vasopressin secretion, bladder capacity defect, or sleep pattern [2], [3], [4], and [5].

Primary NE is considered to be one of the sleep-related phenomena “parasomnias” [6], characterized by disruption in the relationship between arousal and urination [7]. One factor that plays an important role in coordinating micturition and arousal is corticotropin-releasing factor (CRF) [8]. It is a neurohormone released from the paraventricular nucleus of the hypothalamus into the median eminence to elicit release of adrenocorticotrophin from the anterior pituitary, a hallmark of stress response [9]. CRF gives rise to divergently projecting pathways. It may act to modulate autonomic function and behavior in concert with its endocrine effect [10]. Conflicting animal results regarding the role of CRF in regulation of micturition have been raised: it could be a facilitator by decreasing the micturition threshold and increasing micturition frequency [11]. In contrast, CRF agonists were found to inhibit urination in the awake state and receptor antagonists had the opposite effect [7]. It was suggested to be a novel target for treatment of urinary disorders based on the finding that manipulation of CRF in the pontine micturition circuit could affect urodynamic function [7].

Twenty-nine children aged 8–14 years complaining of primary monosymptomatic NE (no urinary control since birth and no other urinary symptoms) attending the outpatient clinic at the National Research Centre were consecutively enrolled in this study (children coming from any part of the country with no specification to any area or social class, and fulfilling the inclusion and exclusion criteria). Exclusion criteria were children less than 6 years of age or more than 18 years, daytime incontinence or urinary symptoms, conditions causing secondary NE (neurological abnormalities, spinal, brain or pelvic surgery, and congenital anomalies of the urologic tract). Other exclusion criteria were urinary tract infection, diabetes mellitus, and diabetes insipidus. All cases had not received any enuresis-related medications for at least 1 year before inclusion in the study. Another 16 healthy children matched for age and sex with good toilet control day and night were recruited as controls.

All cases were subjected to history taking with special emphasis on sleep pattern and voiding history (to differentiate between monosymptomatic and non-monosymptomatic NE), anthropometric measurement (height, weight, and body mass index), clinical examination and investigations (urine, stool analysis, plain X-ray for lumbosacral spines (to exclude spina bifida), and ultrasonography (abdominal and pelvic to assess urinary tract abnormality). Serum CRF was assessed in all patients and controls in the morning and evening (2 mL of venous blood was withdrawn at 9 a.m. and 9 p.m. to test the circadian pattern of secretion (2 controls missed their night sampling). Samples were centrifuged and sera were stored at −20 °C until assayed using an enzyme-linked immunoassay kit (Assay Designs Inc., Ann Arbor, MI, USA).

The study was approved by the ethics committee of the National Research Centre; all patient guardians gave informed written consent.

Descriptive data and comparison between cases and controls are presented in Table 1. Both groups (patients and controls) were statistically matched.

Comparison between cases and controls regarding CRF serum levels (morning and evening) are presented in Table 2 and Fig. 1. Both morning and evening serum CRF levels were significantly lower in patients than in controls (p = 0.013 and p = <0.01 respectively).

Figure 1

Corticotropin-releasing factor serum levels in cases and controls (morning and evening).

 

No significant difference was detected regarding sex in either cases or controls.

The comparison between morning and evening CRF serum levels in each group is presented in Table 3. No statistical significant difference was found between morning and evening levels in either cases (p = 0.4) or controls (p = 0.57).

Correlation of CRF with age was statistically insignificant in both cases and controls (Table 4).

CRF is a neurotransmitter in Barrington's nucleus neurons. These neurons can coregulate the parasympathetic tone of the bladder [12] and brain noradrenergic activity [9] by targeting the preganglionic lumbosacral neurons [12] and projection into the locus ceruleus (LC), which is the major brain norepinephrine nucleus [9]. The LC norepinephrine system had long been implicated in arousal and attention [13]. LC neurons are activated by diverse stimuli including bladder and colon distension that is translated to forebrain electroencephalographic activation [14] and [15]. The CRF family may affect various body systems independently, stimulating peripheral CRF receptors via vagal and/or autocrine/paracrine pathways, but data supporting any clinical significance are still limited [16]. CRF was postulated to have an important role in coordinating both micturition and arousal [8]. We assumed that CRF has a role in primary NE.

CRF was deficient in our enuretic patients, which can draw attention to the possible pathophysiologic implications in primary NE (either at the level of loss of inhibitory effect on micturition or by lack of arousal in response to bladder distension). This is a preliminary study that cannot prove causation, but we think it is an important finding that needs further research.

Nocturnal enuresis (NE) refers to discrete episodes of urinary incontinence during sleep in children older than 5 years of age [1]. It can be primary or secondary. It is a stressful condition that needs treatment to relieve anxiety and prevent the accompanying stigma attached to it [2]. Various pathophysiologic mechanisms for primary NE have been discussed as maturational delay, genetic defect, disturbances in vasopressin secretion, bladder capacity defect, or sleep pattern [2], [3], [4], and [5].

Primary NE is considered to be one of the sleep-related phenomena “parasomnias” [6], characterized by disruption in the relationship between arousal and urination [7]. One factor that plays an important role in coordinating micturition and arousal is corticotropin-releasing factor (CRF) [8]. It is a neurohormone released from the paraventricular nucleus of the hypothalamus into the median eminence to elicit release of adrenocorticotrophin from the anterior pituitary, a hallmark of stress response [9]. CRF gives rise to divergently projecting pathways. It may act to modulate autonomic function and behavior in concert with its endocrine effect [10]. Conflicting animal results regarding the role of CRF in regulation of micturition have been raised: it could be a facilitator by decreasing the micturition threshold and increasing micturition frequency [11]. In contrast, CRF agonists were found to inhibit urination in the awake state and receptor antagonists had the opposite effect [7]. It was suggested to be a novel target for treatment of urinary disorders based on the finding that manipulation of CRF in the pontine micturition circuit could affect urodynamic function [7].

Twenty-nine children aged 8–14 years complaining of primary monosymptomatic NE (no urinary control since birth and no other urinary symptoms) attending the outpatient clinic at the National Research Centre were consecutively enrolled in this study (children coming from any part of the country with no specification to any area or social class, and fulfilling the inclusion and exclusion criteria). Exclusion criteria were children less than 6 years of age or more than 18 years, daytime incontinence or urinary symptoms, conditions causing secondary NE (neurological abnormalities, spinal, brain or pelvic surgery, and congenital anomalies of the urologic tract). Other exclusion criteria were urinary tract infection, diabetes mellitus, and diabetes insipidus. All cases had not received any enuresis-related medications for at least 1 year before inclusion in the study. Another 16 healthy children matched for age and sex with good toilet control day and night were recruited as controls.

All cases were subjected to history taking with special emphasis on sleep pattern and voiding history (to differentiate between monosymptomatic and non-monosymptomatic NE), anthropometric measurement (height, weight, and body mass index), clinical examination and investigations (urine, stool analysis, plain X-ray for lumbosacral spines (to exclude spina bifida), and ultrasonography (abdominal and pelvic to assess urinary tract abnormality). Serum CRF was assessed in all patients and controls in the morning and evening (2 mL of venous blood was withdrawn at 9 a.m. and 9 p.m. to test the circadian pattern of secretion (2 controls missed their night sampling). Samples were centrifuged and sera were stored at −20 °C until assayed using an enzyme-linked immunoassay kit (Assay Designs Inc., Ann Arbor, MI, USA).

The study was approved by the ethics committee of the National Research Centre; all patient guardians gave informed written consent.

Descriptive data and comparison between cases and controls are presented in Table 1. Both groups (patients and controls) were statistically matched.

Comparison between cases and controls regarding CRF serum levels (morning and evening) are presented in Table 2 and Fig. 1. Both morning and evening serum CRF levels were significantly lower in patients than in controls (p = 0.013 and p = <0.01 respectively).

Figure 1

Corticotropin-releasing factor serum levels in cases and controls (morning and evening).

 

No significant difference was detected regarding sex in either cases or controls.

The comparison between morning and evening CRF serum levels in each group is presented in Table 3. No statistical significant difference was found between morning and evening levels in either cases (p = 0.4) or controls (p = 0.57).

Correlation of CRF with age was statistically insignificant in both cases and controls (Table 4).

CRF is a neurotransmitter in Barrington's nucleus neurons. These neurons can coregulate the parasympathetic tone of the bladder [12] and brain noradrenergic activity [9] by targeting the preganglionic lumbosacral neurons [12] and projection into the locus ceruleus (LC), which is the major brain norepinephrine nucleus [9]. The LC norepinephrine system had long been implicated in arousal and attention [13]. LC neurons are activated by diverse stimuli including bladder and colon distension that is translated to forebrain electroencephalographic activation [14] and [15]. The CRF family may affect various body systems independently, stimulating peripheral CRF receptors via vagal and/or autocrine/paracrine pathways, but data supporting any clinical significance are still limited [16]. CRF was postulated to have an important role in coordinating both micturition and arousal [8]. We assumed that CRF has a role in primary NE.

CRF was deficient in our enuretic patients, which can draw attention to the possible pathophysiologic implications in primary NE (either at the level of loss of inhibitory effect on micturition or by lack of arousal in response to bladder distension). This is a preliminary study that cannot prove causation, but we think it is an important finding that needs further research.

Nocturnal enuresis (NE) refers to discrete episodes of urinary incontinence during sleep in children older than 5 years of age [1]. It can be primary or secondary. It is a stressful condition that needs treatment to relieve anxiety and prevent the accompanying stigma attached to it [2]. Various pathophysiologic mechanisms for primary NE have been discussed as maturational delay, genetic defect, disturbances in vasopressin secretion, bladder capacity defect, or sleep pattern [2], [3], [4], and [5].

Primary NE is considered to be one of the sleep-related phenomena “parasomnias” [6], characterized by disruption in the relationship between arousal and urination [7]. One factor that plays an important role in coordinating micturition and arousal is corticotropin-releasing factor (CRF) [8]. It is a neurohormone released from the paraventricular nucleus of the hypothalamus into the median eminence to elicit release of adrenocorticotrophin from the anterior pituitary, a hallmark of stress response [9]. CRF gives rise to divergently projecting pathways. It may act to modulate autonomic function and behavior in concert with its endocrine effect [10]. Conflicting animal results regarding the role of CRF in regulation of micturition have been raised: it could be a facilitator by decreasing the micturition threshold and increasing micturition frequency [11]. In contrast, CRF agonists were found to inhibit urination in the awake state and receptor antagonists had the opposite effect [7]. It was suggested to be a novel target for treatment of urinary disorders based on the finding that manipulation of CRF in the pontine micturition circuit could affect urodynamic function [7].

Twenty-nine children aged 8–14 years complaining of primary monosymptomatic NE (no urinary control since birth and no other urinary symptoms) attending the outpatient clinic at the National Research Centre were consecutively enrolled in this study (children coming from any part of the country with no specification to any area or social class, and fulfilling the inclusion and exclusion criteria). Exclusion criteria were children less than 6 years of age or more than 18 years, daytime incontinence or urinary symptoms, conditions causing secondary NE (neurological abnormalities, spinal, brain or pelvic surgery, and congenital anomalies of the urologic tract). Other exclusion criteria were urinary tract infection, diabetes mellitus, and diabetes insipidus. All cases had not received any enuresis-related medications for at least 1 year before inclusion in the study. Another 16 healthy children matched for age and sex with good toilet control day and night were recruited as controls.

All cases were subjected to history taking with special emphasis on sleep pattern and voiding history (to differentiate between monosymptomatic and non-monosymptomatic NE), anthropometric measurement (height, weight, and body mass index), clinical examination and investigations (urine, stool analysis, plain X-ray for lumbosacral spines (to exclude spina bifida), and ultrasonography (abdominal and pelvic to assess urinary tract abnormality). Serum CRF was assessed in all patients and controls in the morning and evening (2 mL of venous blood was withdrawn at 9 a.m. and 9 p.m. to test the circadian pattern of secretion (2 controls missed their night sampling). Samples were centrifuged and sera were stored at −20 °C until assayed using an enzyme-linked immunoassay kit (Assay Designs Inc., Ann Arbor, MI, USA).

The study was approved by the ethics committee of the National Research Centre; all patient guardians gave informed written consent.

Descriptive data and comparison between cases and controls are presented in Table 1. Both groups (patients and controls) were statistically matched.

Comparison between cases and controls regarding CRF serum levels (morning and evening) are presented in Table 2 and Fig. 1. Both morning and evening serum CRF levels were significantly lower in patients than in controls (p = 0.013 and p = <0.01 respectively).

Figure 1

Corticotropin-releasing factor serum levels in cases and controls (morning and evening).

 

No significant difference was detected regarding sex in either cases or controls.

The comparison between morning and evening CRF serum levels in each group is presented in Table 3. No statistical significant difference was found between morning and evening levels in either cases (p = 0.4) or controls (p = 0.57).

Correlation of CRF with age was statistically insignificant in both cases and controls (Table 4).

CRF is a neurotransmitter in Barrington's nucleus neurons. These neurons can coregulate the parasympathetic tone of the bladder [12] and brain noradrenergic activity [9] by targeting the preganglionic lumbosacral neurons [12] and projection into the locus ceruleus (LC), which is the major brain norepinephrine nucleus [9]. The LC norepinephrine system had long been implicated in arousal and attention [13]. LC neurons are activated by diverse stimuli including bladder and colon distension that is translated to forebrain electroencephalographic activation [14] and [15]. The CRF family may affect various body systems independently, stimulating peripheral CRF receptors via vagal and/or autocrine/paracrine pathways, but data supporting any clinical significance are still limited [16]. CRF was postulated to have an important role in coordinating both micturition and arousal [8]. We assumed that CRF has a role in primary NE.

CRF was deficient in our enuretic patients, which can draw attention to the possible pathophysiologic implications in primary NE (either at the level of loss of inhibitory effect on micturition or by lack of arousal in response to bladder distension). This is a preliminary study that cannot prove causation, but we think it is an important finding that needs further research.

Nocturnal enuresis (NE) refers to discrete episodes of urinary incontinence during sleep in children older than 5 years of age [1]. It can be primary or secondary. It is a stressful condition that needs treatment to relieve anxiety and prevent the accompanying stigma attached to it [2]. Various pathophysiologic mechanisms for primary NE have been discussed as maturational delay, genetic defect, disturbances in vasopressin secretion, bladder capacity defect, or sleep pattern [2], [3], [4], and [5].

Primary NE is considered to be one of the sleep-related phenomena “parasomnias” [6], characterized by disruption in the relationship between arousal and urination [7]. One factor that plays an important role in coordinating micturition and arousal is corticotropin-releasing factor (CRF) [8]. It is a neurohormone released from the paraventricular nucleus of the hypothalamus into the median eminence to elicit release of adrenocorticotrophin from the anterior pituitary, a hallmark of stress response [9]. CRF gives rise to divergently projecting pathways. It may act to modulate autonomic function and behavior in concert with its endocrine effect [10]. Conflicting animal results regarding the role of CRF in regulation of micturition have been raised: it could be a facilitator by decreasing the micturition threshold and increasing micturition frequency [11]. In contrast, CRF agonists were found to inhibit urination in the awake state and receptor antagonists had the opposite effect [7]. It was suggested to be a novel target for treatment of urinary disorders based on the finding that manipulation of CRF in the pontine micturition circuit could affect urodynamic function [7].

Twenty-nine children aged 8–14 years complaining of primary monosymptomatic NE (no urinary control since birth and no other urinary symptoms) attending the outpatient clinic at the National Research Centre were consecutively enrolled in this study (children coming from any part of the country with no specification to any area or social class, and fulfilling the inclusion and exclusion criteria). Exclusion criteria were children less than 6 years of age or more than 18 years, daytime incontinence or urinary symptoms, conditions causing secondary NE (neurological abnormalities, spinal, brain or pelvic surgery, and congenital anomalies of the urologic tract). Other exclusion criteria were urinary tract infection, diabetes mellitus, and diabetes insipidus. All cases had not received any enuresis-related medications for at least 1 year before inclusion in the study. Another 16 healthy children matched for age and sex with good toilet control day and night were recruited as controls.

All cases were subjected to history taking with special emphasis on sleep pattern and voiding history (to differentiate between monosymptomatic and non-monosymptomatic NE), anthropometric measurement (height, weight, and body mass index), clinical examination and investigations (urine, stool analysis, plain X-ray for lumbosacral spines (to exclude spina bifida), and ultrasonography (abdominal and pelvic to assess urinary tract abnormality). Serum CRF was assessed in all patients and controls in the morning and evening (2 mL of venous blood was withdrawn at 9 a.m. and 9 p.m. to test the circadian pattern of secretion (2 controls missed their night sampling). Samples were centrifuged and sera were stored at −20 °C until assayed using an enzyme-linked immunoassay kit (Assay Designs Inc., Ann Arbor, MI, USA).

The study was approved by the ethics committee of the National Research Centre; all patient guardians gave informed written consent.

Descriptive data and comparison between cases and controls are presented in Table 1. Both groups (patients and controls) were statistically matched.

Comparison between cases and controls regarding CRF serum levels (morning and evening) are presented in Table 2 and Fig. 1. Both morning and evening serum CRF levels were significantly lower in patients than in controls (p = 0.013 and p = <0.01 respectively).

Figure 1

Corticotropin-releasing factor serum levels in cases and controls (morning and evening).

 

No significant difference was detected regarding sex in either cases or controls.

The comparison between morning and evening CRF serum levels in each group is presented in Table 3. No statistical significant difference was found between morning and evening levels in either cases (p = 0.4) or controls (p = 0.57).

Correlation of CRF with age was statistically insignificant in both cases and controls (Table 4).

CRF is a neurotransmitter in Barrington's nucleus neurons. These neurons can coregulate the parasympathetic tone of the bladder [12] and brain noradrenergic activity [9] by targeting the preganglionic lumbosacral neurons [12] and projection into the locus ceruleus (LC), which is the major brain norepinephrine nucleus [9]. The LC norepinephrine system had long been implicated in arousal and attention [13]. LC neurons are activated by diverse stimuli including bladder and colon distension that is translated to forebrain electroencephalographic activation [14] and [15]. The CRF family may affect various body systems independently, stimulating peripheral CRF receptors via vagal and/or autocrine/paracrine pathways, but data supporting any clinical significance are still limited [16]. CRF was postulated to have an important role in coordinating both micturition and arousal [8]. We assumed that CRF has a role in primary NE.

CRF was deficient in our enuretic patients, which can draw attention to the possible pathophysiologic implications in primary NE (either at the level of loss of inhibitory effect on micturition or by lack of arousal in response to bladder distension). This is a preliminary study that cannot prove causation, but we think it is an important finding that needs further research.

Nocturnal enuresis (NE) refers to discrete episodes of urinary incontinence during sleep in children older than 5 years of age [1]. It can be primary or secondary. It is a stressful condition that needs treatment to relieve anxiety and prevent the accompanying stigma attached to it [2]. Various pathophysiologic mechanisms for primary NE have been discussed as maturational delay, genetic defect, disturbances in vasopressin secretion, bladder capacity defect, or sleep pattern [2], [3], [4], and [5].

Primary NE is considered to be one of the sleep-related phenomena “parasomnias” [6], characterized by disruption in the relationship between arousal and urination [7]. One factor that plays an important role in coordinating micturition and arousal is corticotropin-releasing factor (CRF) [8]. It is a neurohormone released from the paraventricular nucleus of the hypothalamus into the median eminence to elicit release of adrenocorticotrophin from the anterior pituitary, a hallmark of stress response [9]. CRF gives rise to divergently projecting pathways. It may act to modulate autonomic function and behavior in concert with its endocrine effect [10]. Conflicting animal results regarding the role of CRF in regulation of micturition have been raised: it could be a facilitator by decreasing the micturition threshold and increasing micturition frequency [11]. In contrast, CRF agonists were found to inhibit urination in the awake state and receptor antagonists had the opposite effect [7]. It was suggested to be a novel target for treatment of urinary disorders based on the finding that manipulation of CRF in the pontine micturition circuit could affect urodynamic function [7].

Twenty-nine children aged 8–14 years complaining of primary monosymptomatic NE (no urinary control since birth and no other urinary symptoms) attending the outpatient clinic at the National Research Centre were consecutively enrolled in this study (children coming from any part of the country with no specification to any area or social class, and fulfilling the inclusion and exclusion criteria). Exclusion criteria were children less than 6 years of age or more than 18 years, daytime incontinence or urinary symptoms, conditions causing secondary NE (neurological abnormalities, spinal, brain or pelvic surgery, and congenital anomalies of the urologic tract). Other exclusion criteria were urinary tract infection, diabetes mellitus, and diabetes insipidus. All cases had not received any enuresis-related medications for at least 1 year before inclusion in the study. Another 16 healthy children matched for age and sex with good toilet control day and night were recruited as controls.

All cases were subjected to history taking with special emphasis on sleep pattern and voiding history (to differentiate between monosymptomatic and non-monosymptomatic NE), anthropometric measurement (height, weight, and body mass index), clinical examination and investigations (urine, stool analysis, plain X-ray for lumbosacral spines (to exclude spina bifida), and ultrasonography (abdominal and pelvic to assess urinary tract abnormality). Serum CRF was assessed in all patients and controls in the morning and evening (2 mL of venous blood was withdrawn at 9 a.m. and 9 p.m. to test the circadian pattern of secretion (2 controls missed their night sampling). Samples were centrifuged and sera were stored at −20 °C until assayed using an enzyme-linked immunoassay kit (Assay Designs Inc., Ann Arbor, MI, USA).

The study was approved by the ethics committee of the National Research Centre; all patient guardians gave informed written consent.

Descriptive data and comparison between cases and controls are presented in Table 1. Both groups (patients and controls) were statistically matched.

Comparison between cases and controls regarding CRF serum levels (morning and evening) are presented in Table 2 and Fig. 1. Both morning and evening serum CRF levels were significantly lower in patients than in controls (p = 0.013 and p = <0.01 respectively).

Figure 1

Corticotropin-releasing factor serum levels in cases and controls (morning and evening).

 

No significant difference was detected regarding sex in either cases or controls.

The comparison between morning and evening CRF serum levels in each group is presented in Table 3. No statistical significant difference was found between morning and evening levels in either cases (p = 0.4) or controls (p = 0.57).

Correlation of CRF with age was statistically insignificant in both cases and controls (Table 4).

CRF is a neurotransmitter in Barrington's nucleus neurons. These neurons can coregulate the parasympathetic tone of the bladder [12] and brain noradrenergic activity [9] by targeting the preganglionic lumbosacral neurons [12] and projection into the locus ceruleus (LC), which is the major brain norepinephrine nucleus [9]. The LC norepinephrine system had long been implicated in arousal and attention [13]. LC neurons are activated by diverse stimuli including bladder and colon distension that is translated to forebrain electroencephalographic activation [14] and [15]. The CRF family may affect various body systems independently, stimulating peripheral CRF receptors via vagal and/or autocrine/paracrine pathways, but data supporting any clinical significance are still limited [16]. CRF was postulated to have an important role in coordinating both micturition and arousal [8]. We assumed that CRF has a role in primary NE.

CRF was deficient in our enuretic patients, which can draw attention to the possible pathophysiologic implications in primary NE (either at the level of loss of inhibitory effect on micturition or by lack of arousal in response to bladder distension). This is a preliminary study that cannot prove causation, but we think it is an important finding that needs further research.

Nocturnal enuresis (NE) refers to discrete episodes of urinary incontinence during sleep in children older than 5 years of age [1]. It can be primary or secondary. It is a stressful condition that needs treatment to relieve anxiety and prevent the accompanying stigma attached to it [2]. Various pathophysiologic mechanisms for primary NE have been discussed as maturational delay, genetic defect, disturbances in vasopressin secretion, bladder capacity defect, or sleep pattern [2], [3], [4], and [5].

Primary NE is considered to be one of the sleep-related phenomena “parasomnias” [6], characterized by disruption in the relationship between arousal and urination [7]. One factor that plays an important role in coordinating micturition and arousal is corticotropin-releasing factor (CRF) [8]. It is a neurohormone released from the paraventricular nucleus of the hypothalamus into the median eminence to elicit release of adrenocorticotrophin from the anterior pituitary, a hallmark of stress response [9]. CRF gives rise to divergently projecting pathways. It may act to modulate autonomic function and behavior in concert with its endocrine effect [10]. Conflicting animal results regarding the role of CRF in regulation of micturition have been raised: it could be a facilitator by decreasing the micturition threshold and increasing micturition frequency [11]. In contrast, CRF agonists were found to inhibit urination in the awake state and receptor antagonists had the opposite effect [7]. It was suggested to be a novel target for treatment of urinary disorders based on the finding that manipulation of CRF in the pontine micturition circuit could affect urodynamic function [7].

Twenty-nine children aged 8–14 years complaining of primary monosymptomatic NE (no urinary control since birth and no other urinary symptoms) attending the outpatient clinic at the National Research Centre were consecutively enrolled in this study (children coming from any part of the country with no specification to any area or social class, and fulfilling the inclusion and exclusion criteria). Exclusion criteria were children less than 6 years of age or more than 18 years, daytime incontinence or urinary symptoms, conditions causing secondary NE (neurological abnormalities, spinal, brain or pelvic surgery, and congenital anomalies of the urologic tract). Other exclusion criteria were urinary tract infection, diabetes mellitus, and diabetes insipidus. All cases had not received any enuresis-related medications for at least 1 year before inclusion in the study. Another 16 healthy children matched for age and sex with good toilet control day and night were recruited as controls.

All cases were subjected to history taking with special emphasis on sleep pattern and voiding history (to differentiate between monosymptomatic and non-monosymptomatic NE), anthropometric measurement (height, weight, and body mass index), clinical examination and investigations (urine, stool analysis, plain X-ray for lumbosacral spines (to exclude spina bifida), and ultrasonography (abdominal and pelvic to assess urinary tract abnormality). Serum CRF was assessed in all patients and controls in the morning and evening (2 mL of venous blood was withdrawn at 9 a.m. and 9 p.m. to test the circadian pattern of secretion (2 controls missed their night sampling). Samples were centrifuged and sera were stored at −20 °C until assayed using an enzyme-linked immunoassay kit (Assay Designs Inc., Ann Arbor, MI, USA).

The study was approved by the ethics committee of the National Research Centre; all patient guardians gave informed written consent.

Descriptive data and comparison between cases and controls are presented in Table 1. Both groups (patients and controls) were statistically matched.

Comparison between cases and controls regarding CRF serum levels (morning and evening) are presented in Table 2 and Fig. 1. Both morning and evening serum CRF levels were significantly lower in patients than in controls (p = 0.013 and p = <0.01 respectively).

Figure 1

Corticotropin-releasing factor serum levels in cases and controls (morning and evening).

 

No significant difference was detected regarding sex in either cases or controls.

The comparison between morning and evening CRF serum levels in each group is presented in Table 3. No statistical significant difference was found between morning and evening levels in either cases (p = 0.4) or controls (p = 0.57).

Correlation of CRF with age was statistically insignificant in both cases and controls (Table 4).

CRF is a neurotransmitter in Barrington's nucleus neurons. These neurons can coregulate the parasympathetic tone of the bladder [12] and brain noradrenergic activity [9] by targeting the preganglionic lumbosacral neurons [12] and projection into the locus ceruleus (LC), which is the major brain norepinephrine nucleus [9]. The LC norepinephrine system had long been implicated in arousal and attention [13]. LC neurons are activated by diverse stimuli including bladder and colon distension that is translated to forebrain electroencephalographic activation [14] and [15]. The CRF family may affect various body systems independently, stimulating peripheral CRF receptors via vagal and/or autocrine/paracrine pathways, but data supporting any clinical significance are still limited [16]. CRF was postulated to have an important role in coordinating both micturition and arousal [8]. We assumed that CRF has a role in primary NE.

CRF was deficient in our enuretic patients, which can draw attention to the possible pathophysiologic implications in primary NE (either at the level of loss of inhibitory effect on micturition or by lack of arousal in response to bladder distension). This is a preliminary study that cannot prove causation, but we think it is an important finding that needs further research.

Nocturnal enuresis (NE) refers to discrete episodes of urinary incontinence during sleep in children older than 5 years of age [1]. It can be primary or secondary. It is a stressful condition that needs treatment to relieve anxiety and prevent the accompanying stigma attached to it [2]. Various pathophysiologic mechanisms for primary NE have been discussed as maturational delay, genetic defect, disturbances in vasopressin secretion, bladder capacity defect, or sleep pattern [2], [3], [4], and [5].

Primary NE is considered to be one of the sleep-related phenomena “parasomnias” [6], characterized by disruption in the relationship between arousal and urination [7]. One factor that plays an important role in coordinating micturition and arousal is corticotropin-releasing factor (CRF) [8]. It is a neurohormone released from the paraventricular nucleus of the hypothalamus into the median eminence to elicit release of adrenocorticotrophin from the anterior pituitary, a hallmark of stress response [9]. CRF gives rise to divergently projecting pathways. It may act to modulate autonomic function and behavior in concert with its endocrine effect [10]. Conflicting animal results regarding the role of CRF in regulation of micturition have been raised: it could be a facilitator by decreasing the micturition threshold and increasing micturition frequency [11]. In contrast, CRF agonists were found to inhibit urination in the awake state and receptor antagonists had the opposite effect [7]. It was suggested to be a novel target for treatment of urinary disorders based on the finding that manipulation of CRF in the pontine micturition circuit could affect urodynamic function [7].

Twenty-nine children aged 8–14 years complaining of primary monosymptomatic NE (no urinary control since birth and no other urinary symptoms) attending the outpatient clinic at the National Research Centre were consecutively enrolled in this study (children coming from any part of the country with no specification to any area or social class, and fulfilling the inclusion and exclusion criteria). Exclusion criteria were children less than 6 years of age or more than 18 years, daytime incontinence or urinary symptoms, conditions causing secondary NE (neurological abnormalities, spinal, brain or pelvic surgery, and congenital anomalies of the urologic tract). Other exclusion criteria were urinary tract infection, diabetes mellitus, and diabetes insipidus. All cases had not received any enuresis-related medications for at least 1 year before inclusion in the study. Another 16 healthy children matched for age and sex with good toilet control day and night were recruited as controls.

All cases were subjected to history taking with special emphasis on sleep pattern and voiding history (to differentiate between monosymptomatic and non-monosymptomatic NE), anthropometric measurement (height, weight, and body mass index), clinical examination and investigations (urine, stool analysis, plain X-ray for lumbosacral spines (to exclude spina bifida), and ultrasonography (abdominal and pelvic to assess urinary tract abnormality). Serum CRF was assessed in all patients and controls in the morning and evening (2 mL of venous blood was withdrawn at 9 a.m. and 9 p.m. to test the circadian pattern of secretion (2 controls missed their night sampling). Samples were centrifuged and sera were stored at −20 °C until assayed using an enzyme-linked immunoassay kit (Assay Designs Inc., Ann Arbor, MI, USA).

The study was approved by the ethics committee of the National Research Centre; all patient guardians gave informed written consent.

Descriptive data and comparison between cases and controls are presented in Table 1. Both groups (patients and controls) were statistically matched.

Comparison between cases and controls regarding CRF serum levels (morning and evening) are presented in Table 2 and Fig. 1. Both morning and evening serum CRF levels were significantly lower in patients than in controls (p = 0.013 and p = <0.01 respectively).

Figure 1

Corticotropin-releasing factor serum levels in cases and controls (morning and evening).

 

No significant difference was detected regarding sex in either cases or controls.

The comparison between morning and evening CRF serum levels in each group is presented in Table 3. No statistical significant difference was found between morning and evening levels in either cases (p = 0.4) or controls (p = 0.57).

Correlation of CRF with age was statistically insignificant in both cases and controls (Table 4).

CRF is a neurotransmitter in Barrington's nucleus neurons. These neurons can coregulate the parasympathetic tone of the bladder [12] and brain noradrenergic activity [9] by targeting the preganglionic lumbosacral neurons [12] and projection into the locus ceruleus (LC), which is the major brain norepinephrine nucleus [9]. The LC norepinephrine system had long been implicated in arousal and attention [13]. LC neurons are activated by diverse stimuli including bladder and colon distension that is translated to forebrain electroencephalographic activation [14] and [15]. The CRF family may affect various body systems independently, stimulating peripheral CRF receptors via vagal and/or autocrine/paracrine pathways, but data supporting any clinical significance are still limited [16]. CRF was postulated to have an important role in coordinating both micturition and arousal [8]. We assumed that CRF has a role in primary NE.

CRF was deficient in our enuretic patients, which can draw attention to the possible pathophysiologic implications in primary NE (either at the level of loss of inhibitory effect on micturition or by lack of arousal in response to bladder distension). This is a preliminary study that cannot prove causation, but we think it is an important finding that needs further research.

Nocturnal enuresis (NE) refers to discrete episodes of urinary incontinence during sleep in children older than 5 years of age [1]. It can be primary or secondary. It is a stressful condition that needs treatment to relieve anxiety and prevent the accompanying stigma attached to it [2]. Various pathophysiologic mechanisms for primary NE have been discussed as maturational delay, genetic defect, disturbances in vasopressin secretion, bladder capacity defect, or sleep pattern [2], [3], [4], and [5].

Primary NE is considered to be one of the sleep-related phenomena “parasomnias” [6], characterized by disruption in the relationship between arousal and urination [7]. One factor that plays an important role in coordinating micturition and arousal is corticotropin-releasing factor (CRF) [8]. It is a neurohormone released from the paraventricular nucleus of the hypothalamus into the median eminence to elicit release of adrenocorticotrophin from the anterior pituitary, a hallmark of stress response [9]. CRF gives rise to divergently projecting pathways. It may act to modulate autonomic function and behavior in concert with its endocrine effect [10]. Conflicting animal results regarding the role of CRF in regulation of micturition have been raised: it could be a facilitator by decreasing the micturition threshold and increasing micturition frequency [11]. In contrast, CRF agonists were found to inhibit urination in the awake state and receptor antagonists had the opposite effect [7]. It was suggested to be a novel target for treatment of urinary disorders based on the finding that manipulation of CRF in the pontine micturition circuit could affect urodynamic function [7].

Twenty-nine children aged 8–14 years complaining of primary monosymptomatic NE (no urinary control since birth and no other urinary symptoms) attending the outpatient clinic at the National Research Centre were consecutively enrolled in this study (children coming from any part of the country with no specification to any area or social class, and fulfilling the inclusion and exclusion criteria). Exclusion criteria were children less than 6 years of age or more than 18 years, daytime incontinence or urinary symptoms, conditions causing secondary NE (neurological abnormalities, spinal, brain or pelvic surgery, and congenital anomalies of the urologic tract). Other exclusion criteria were urinary tract infection, diabetes mellitus, and diabetes insipidus. All cases had not received any enuresis-related medications for at least 1 year before inclusion in the study. Another 16 healthy children matched for age and sex with good toilet control day and night were recruited as controls.

All cases were subjected to history taking with special emphasis on sleep pattern and voiding history (to differentiate between monosymptomatic and non-monosymptomatic NE), anthropometric measurement (height, weight, and body mass index), clinical examination and investigations (urine, stool analysis, plain X-ray for lumbosacral spines (to exclude spina bifida), and ultrasonography (abdominal and pelvic to assess urinary tract abnormality). Serum CRF was assessed in all patients and controls in the morning and evening (2 mL of venous blood was withdrawn at 9 a.m. and 9 p.m. to test the circadian pattern of secretion (2 controls missed their night sampling). Samples were centrifuged and sera were stored at −20 °C until assayed using an enzyme-linked immunoassay kit (Assay Designs Inc., Ann Arbor, MI, USA).

The study was approved by the ethics committee of the National Research Centre; all patient guardians gave informed written consent.

Descriptive data and comparison between cases and controls are presented in Table 1. Both groups (patients and controls) were statistically matched.

Comparison between cases and controls regarding CRF serum levels (morning and evening) are presented in Table 2 and Fig. 1. Both morning and evening serum CRF levels were significantly lower in patients than in controls (p = 0.013 and p = <0.01 respectively).

Figure 1

Corticotropin-releasing factor serum levels in cases and controls (morning and evening).

 

No significant difference was detected regarding sex in either cases or controls.

The comparison between morning and evening CRF serum levels in each group is presented in Table 3. No statistical significant difference was found between morning and evening levels in either cases (p = 0.4) or controls (p = 0.57).

Correlation of CRF with age was statistically insignificant in both cases and controls (Table 4).