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GI Motility Disorders:Why are Women at Risk?
Henry P. Parkman, MD
Professor of Medicine
Director – Gastrointestinal Motility Laboratory
Temple University School of Medicine
Philadelphia, PA
Topics to Cover
GI Motility and Functional GI Disorders are common and are associated with poor quality of life.
GI Motility and Functional GI Disorders are
more common in women than in men.
Focus on gastric motility and gastroparesis to discuss gender effects on gastric motility.
Normal GI Tract Motility
Peristalsis: Involuntary wave-like muscular contractions that move materials through the gastrointestinal tract
EsophagusSwallowing initiates esophageal peristalsis and
relaxation of the lower esophageal sphincter, which propels food bolus into the stomach
StomachThe fundus relaxes to accommodate the ingested foodFood is broken down and mixed with gastric secretionsContents are slowly emptied into the small intestine
Small bowelFood is mixed, digested, and absorbed;
chyme is propelled by peristalsis
ColonWater and electrolytes are absorbed, and stool
is concentrated and stored until defecation
GI Motility and Functional GI DisordersPathophysiology
Dysmotility Disturbed regulation and coordination of the
muscles and nerves in the GI tract, leading to:► Decreased► Increased ► Chaotic motility
Altered sensationHypersensitivityHyposensitivity
GI Motility and Functional GI Disorders
Noncardiac chest pain (NCCP)
Dyspepsia
Biliarydyskinesia
Irritable bowelsyndrome (IBS)
Chronic constipation
Levator anisyndrome
Achalasia
Fecal incontinence
Gastroparesis
Gastroesophageal
Reflux Disease
Importance of GI Motility Disorders - 1
Gastrointestinal motility and its disorders are important areas for the health of the United States.
GI motility and functional bowel disorders affect up to 25% of the US population.
These disorders comprise about 40% of GI problems for which patients seek health care.
GI motility disorders pose a heavy burden of illness, decreased quality of life, and decreased work productivity.
Prevalence of Upper GI SymptomsIn the United States
Percent of US Population> 1 episode Clinically Relevant per month Symptoms (> 1-
2/week)
Heartburn 21.6% 6.3%Regurgitation 16.4% 2.9%Dysphagia 7.8% 4.6%Bloating 10.7% 4.5%Postprandial Fullness 20.9% 3.6%Early Satiety 23.0% 5.3%Nausea 9.5% 2.2%Vomiting 2.7% 0.4%Belching/Burping 6.3% 3.0%Abdominal Pain / Discomfort 4.8%
From: Camilleri, Dubois, et al. Clinical Gastroenterology and Hepatology 2005;3:543-552.
Effect of Gender on Upper GI SymptomsIn the United States
Percent of US Population With Clinically Relevant Symptoms
Total Males Females(n=17,484) (n=8,408) (n=9,076)
Heartburn 6.3% 5.7 6.9Regurgitation 2.9% 2.7 3.1Dysphagia 4.6% 4.4 4.7Bloating 4.5% 3.4 5.6Postprandial Fullness 3.6% 3.1 4.0Early Satiety 5.3% 3.7 6.7*Nausea 2.2% 1.4 3.0*Vomiting 0.4% 0.4 0.5Belching/Burping 3.0% 2.5 3.4
From: Camilleri, Dubois, et al. Clinical Gastroenterology and Hepatology 2005;3:543-552.
Prevalence of GI Motility and Functional GI Disorders Compared to Some Chronic Non-GI Disorders
Dyspepsia 20-25%Irritable bowel syndrome 10-25%Functional heartburn (GERD) 15.5%Chronic constipation 12-19%Gastroparesis 4%
Hypertension 28%Migraine Headache 6-18%Asthma 8%Diabetes 8%
The GI disorders, IBS, chronic constipation, and gastroparesisbut not dyspepsia, are more common in females than males.
Sources – several articles from 2000-2005
Motor Events During Gastric EmptyingHorowitz M, et al. Nature Clinical Practice 2005;2:454.
Gastric Emptying ScintigraphyThe Gold Standard Test to Measure Gastric Emptying
Normal Gastric Emptying Delayed Gastric Emptying
Clinical Characteristics of Patients With Gastroparesis
(146 Patients at Tertiary Motility Centers)
Gender: Female 82%
Male 18%
Onset of Symptoms: 34 years
Symptoms: Nausea 92% Vomiting 84% Abdominal bloating 75
%
Early Satiety60 %
Abdominal pain 46%
28%
8%
29%
14%
10%
4%4% 3%
Idiopathic
Postviral
Diabetic
Postsurgical
Parkinsons
Pseudoobstruction
Scleroderma
Miscellaneous
Cutaneous Electrogastrography (EGG) Measures Gastric Myoelectric Activity
Influence of Gender on the Electrogastrogram in Normal Subjects
Effect of Gender on EGG Dominant Frequency
Effect of the Female Menstrual Cycle on EGG Dominant Frequency
Parkman et al. AJG 1996;91: 127.
?Hormonal Causes of GI Dysmotility
Progesterone Calcium Channels G proteins Nuclear transcription
Estrogen
Estrogen priming of Progesterone
Gender Effects on Gastric Emptying
Effects of gender on gastric emptying remain controversial. Some studies have reported delayed gastric emptying
in premenopausal women compared with men, especially in later phase of the menstrual cycle with progesterone and estrogen levels are high.
Other studies have reported no difference between women and men or between women in different phases of the menstrual cycle.
The majority of patients with symptoms of dyspepsia and gastroparesis are female. To evaluate these patients, it is important to determine the normal physiologic parameters of gastric emptying for women.
Gender Effects on Gastric Emptying
Linda C. Knight, Henry P. Parkman,
Jean-Luc Urbain, Alan H. Maurer, Robert S. Fisher
AIMSTo determine whether gender affects gastric emptying by
characterizing gastric emptying for normal women and age matched men.
To see if observed differences correlate with alterations in antral motility measured by dynamic antral scintigraphy (DAS) and cutaneous electrogastrography (EGG).
STUDY POPULATION 13 normal men age 27.5 ± 1.7 yr 9 normal women* age 27.9 ± 2.2 yr *studied in the first 10 days of the menstrual cycle
Gastric Emptying Curves - Whole Stomach
180150120906030000
20
40
60
80
100
Time (min)
Lag (F)T 1/2 (F)Mean: Lag (M)
T 1/2 (M)
%REMAINING
FEMALES
MALES
Gastric Emptying Parameters
MALE FEMALE0
30
60
90
120
150T 1/2
MALE FEMALE0.00
0.01
0.02
0.03
*
*
* P <0.05
T=0
Male Subject
Female Subject
T=60min
T=120min
T=90min
T=20min
Gender Affects Gastric Emptying
Proximal Gastric Emptying Curves
180150120906030000
20
40
60
80
100
Time (min)
%REMAINING
FEMALES
MALES
Distal Gastric Emptying Curves
18015012090603000
0
10
20
30
40
50
60
TIME (MIN)
%REMAINING
FEMALES
MALES
Visualization of Antral ContractilityUsing Dynamic Antral Scintigraphy
97
19
531
17151311
time (sec)
Data Analysis - DAS
2401801206000
400
600
800
1000
1200
Time (seconds)
CO
UN
TS
The oscillating data were analyzed:
• for dominant frequency by fast Fourier transform
• for mid-antral ejection fraction by determining the percentage of
basal content displaced by each contraction.
Examples of DAS Data: Ejection Fraction Analysis
24018012060000
20
40
60
80
100
120
Time (sec)
MALE SUBJECT
EFi = 100 x (MAX-MIN) / MAX
EF = EFi /n = 29%
24018012060000
20
40
60
80
100
120
Time (sec)
FEMALE SUBJECT
EFi = 100 x (MAX-MIN) / MAX
EF = EFi /n = 13%
Effect of Time Post Meal on Mid-Antral Ejection Fraction and EGG Power
1209060300-30-300
10
20
30
40
50
60Dynamic Antral Scintigraphy
Time (min)1209060300-30-30
0
1000
2000
3000
4000Electrogastrography
Time (min) FEMALES
MALES
EF(%)
power
Frequency Analysis by Dynamic Antral Scintigraphy
Time (sec)
counts
2401801206000
0
200
400
600
800
1000
1200
Raw Data
amplitude
1614121086420
0
5
10
15
20
25
30
Frequency (cycles/minute)
fast Fourier transform
Examples of DAS data: Fourier Analysis
16141210864200
1
2
3
4
Frequency (cycles/min)
FFT
FEMALE SUBJECT
16141210864200
5
10
15
20
25
30FFT
MALE SUBJECT
3.0 cycles/min 3.6 cycles/min
Frequency (cycles/min)
Summary of this Temple Study
• Gastric emptying of solid food in normal young women is slower than in age-matched men, even in the first 10 days of the menstrual cycle when estrogen and progesterone levels are low.
• Higher gastric retention in women was associated with normal proximal gastric emptying but a decreased rate of distal gastric emptying.
• Females had decreased antral contractility as recorded by dynamic antral scintigraphy.
Conclusions of this Temple Study
• The delay in gastric emptying of solids in women appears to be primarily due to altered distal gastric motor function.
• One explanation may be that less vigorous antral contractions may contribute to slower breakdown of food particles and thus delay the rate of emptying.
• This hypothesis was corroborated by finding decreased antral contractility as recorded by DAS.
• This study emphasizes the need to evaluate symptomatic females using gastric emptying parameters derived in normal women.
Gender Affects Many Aspects of Health Care in Gastroenterology
Presentation of IllnessHigher prevalence of symptoms in females
Different PhysiologyNeural pathways – Gastrocolonic reflexSensory pain pathways and neurotransmission
Evaluation of the PatientDifferent Normal Values – Gastric Emptying, Colonic
Transit
Prevalence of GI Motility Disorders and Functional GI DisordersHigher prevalence in females
Response to TreatmentDifferent Response to Therapy
IBS: Allosetron, Tegaserod
Importance of GI Motility Disorders Relates to Other Functions
Do These Areas Also Have Gender-Related Effects?
GI motility also plays an important role in issues outside of traditional gastroenterology. Examples of this include nutrition, obesity, and drug delivery.
Nutrition depends on the controlled delivery of food for optimal assimilation from the gastrointestinal tract.
Signaling of satiety is dependent on proper control of GI motility and release of GI hormones. Obesity can result when satiety and GI motility are altered.
Bioavailability of orally administered drugs is controlled in large part by GI motility.
Decreased Electromechanical Activity of Guinea Pig Circular Muscle During Pregnancy
During the third trimester of pregnancy in guinea pigs,The force of both spontaneous and bethanechol-induced
antral circular muscle contractions is decreasedThe electrical slow waves displayed decreased upstroke
amplitude, plateau amplitude, and number of spikes during the plateau potential.
The diminished gastric contractility during pregnancy is due to a change in electromechanical activity of the gastric muscle.
(Parkman, Wang, Ryan. Gastroenterology 1993;105:1306.)
Delayed Gastric Emptying in Normal Women is Associated with
Decreased Antral Contractility
Linda C. Knight, Henry P. Parkman,
Jean-Luc Urbain, Alan H. Maurer, Robert S. Fisher
Gastroenterology Section; Department of Medicine
Nuclear Medicine Section; Department of Radiology
Temple University School of Medicine
Philadelphia, PA
PROTOCOL
• Study starts at 7:30 AM after an overnight fast.
• Fasting EGG recording for 1 hour.
• Ingest standard test meal:99mTc egg sandwich (2mCi 99mTc-SC in 2 eggs) and 300 ml nonlabeled water.
• Perform the following tests for 3 hr:Gastric Emptying Scintigraphy (GES):
Anterior/posterior images every 10-15 minutes.
Dynamic Antral Scintigraphy (DAS): 256 images of 1 sec each, every 10-15 minutes.
Cutaneous Electrogastrography (EGG): Continuous recordings with time stamp at start of DAS
DATA ANALYSIS
GES:
Geometric mean counts were fit to a modified power exponential function: %Retention = 100(1-(1-e-kt)ß)
DAS:
A region was drawn across the mid-antrum and a time-activity curve was generated. The oscillating data were analyzed for dominant frequency by fast Fourier transform and for mid-antral ejection fraction by determining the percentage of basal content displaced by each contraction.
EGG:
The signals were analyzed during the fasting period and during the postprandial period at time periods corresponding to DAS recordings, using fast Fourier transform to determine dominant frequency (DF) of contractions and the power of DF.
Data Analysis - GES
Geometric mean counts were fit to a modified power exponential function: %Retention = 100(1-(1-e-t)ß)
1801501209060300
10
100
TIME (MIN)
50
20
200
%RETENTION
ß
Lag =( ln ß) /
T1/2
-slope =
Ejection Fraction Analysis by Dynamic Antral Scintigraphy
counts
2401801206000
0
200
400
600
800
1000
1200
Time (sec)
Raw Data
2401801206000
0
20
40
60
80
100
120
Time (sec)
Normalized Data
EFi = MAX-MIN / MAX
EF = average EFi = 29%
Data Analysis-EGG
EGG signals were analyzed using fast Fourier transformationduring the fasting period and during the postprandial period at time
periods corresponding to DAS recordings
Parameters determined: dominant frequency (DF) of contractions the power of DF.
Frequency of Contractions vs time post meal
1209060300-30-300
1
2
3
4
Dynamic Antral Scintigraphy
Time (min)1209060300-30-30
0
1
2
3
4
Electrogastrography
Time (min)FEMALES
MALES
DF(cpm)
DF(cpm)