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

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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

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Time (min)

%REMAINING

FEMALES

MALES

Distal Gastric Emptying Curves

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TIME (MIN)

%REMAINING

FEMALES

MALES

Visualization of Antral ContractilityUsing Dynamic Antral Scintigraphy

97

19

531

17151311

time (sec)

Data Analysis - DAS

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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

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Time (sec)

MALE SUBJECT

EFi = 100 x (MAX-MIN) / MAX

EF = EFi /n = 29%

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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

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60Dynamic Antral Scintigraphy

Time (min)1209060300-30-30

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4000Electrogastrography

Time (min) FEMALES

MALES

EF(%)

power

Frequency Analysis by Dynamic Antral Scintigraphy

Time (sec)

counts

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Raw Data

amplitude

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Frequency (cycles/minute)

fast Fourier transform

Examples of DAS data: Fourier Analysis

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Frequency (cycles/min)

FFT

FEMALE SUBJECT

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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

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0

200

400

600

800

1000

1200

Time (sec)

Raw Data

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20

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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

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Dynamic Antral Scintigraphy

Time (min)1209060300-30-30

0

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Electrogastrography

Time (min)FEMALES

MALES

DF(cpm)

DF(cpm)