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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.
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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 • Esophagus • Swallowing initiates esophageal peristalsis and relaxation of the lower esophageal sphincter, which propels food bolus into the stomach • Stomach • The fundus relaxes to accommodate the ingested food • Food is broken down and mixed with gastric secretions • Contents are slowly emptied into the small intestine • Small bowel • Food is mixed, digested, and absorbed;chyme is propelled by peristalsis • Colon • Water and electrolytes are absorbed, and stoolis 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 sensation • Hypersensitivity • Hyposensitivity
GI Motility and Functional GI Disorders Noncardiac chest pain (NCCP) Achalasia Gastroesophageal Reflux Disease Dyspepsia Gastroparesis Irritable bowelsyndrome (IBS) Biliarydyskinesia Chronic constipation Levator anisyndrome Fecal incontinence
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 6.9 Regurgitation 2.9% 2.7 3.1 Dysphagia 4.6% 4.4 4.7 Bloating 4.5% 3.4 5.6 Postprandial Fullness 3.6% 3.1 4.0 Early Satiety 5.3% 3.7 6.7* Nausea 2.2% 1.4 3.0* Vomiting 0.4% 0.4 0.5 Belching/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 DisordersCompared 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 gastroparesis but not dyspepsia, are more common in females than males. Sources – several articles from 2000-2005
Motor Events During Gastric Emptying Horowitz 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 Satiety 60 % Abdominal pain 46%
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 EmptyingLinda C. Knight, Henry P. Parkman, Jean-Luc Urbain, Alan H. Maurer, Robert S. Fisher AIMS To 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
FEMALES 100 % R E M A I N I N G MALES 80 60 40 Lag (F) T 1/2 (M) 20 T 1/2 (F) Mean: Lag (M) 0 0 0 30 60 90 120 150 180 Time (min) Gastric Emptying Curves - Whole Stomach
150 0.03 120 0.02 90 60 0.01 30 0.00 0 MALE FEMALE MALE FEMALE Gastric Emptying Parameters T 1/2 * P <0.05 * *
Gender Affects Gastric Emptying Male Subject Female Subject T=20 min T=60 min T=90 min T=120 min T=0
FEMALES 100 MALES % R E M A I N I N G 80 60 40 20 0 0 0 30 60 90 120 150 180 Time (min) Proximal Gastric Emptying Curves
60 FEMALES MALES % R E M A I N I N G 50 40 30 20 10 0 0 0 30 60 90 120 150 180 TIME (MIN) Distal Gastric Emptying Curves
1 3 5 7 9 11 13 15 17 19 Visualization of Antral ContractilityUsing Dynamic Antral Scintigraphy time (sec)
1200 1000 COUNTS 800 600 400 0 0 60 120 180 240 Time (seconds) Data Analysis - DAS 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.
FEMALES MALES Effect of Time Post Meal on Mid-Antral Ejection Fraction and EGG Power p o w e r EF (%)
Raw Data fast Fourier transform 30 1200 a m p l i t u d e 25 1000 c o u n t s 20 800 15 600 10 400 5 200 0 0 0 0 60 120 180 240 0 2 4 6 8 10 12 14 16 Frequency (cycles/minute) Frequency Analysis by Dynamic Antral Scintigraphy Time (sec)
30 4 25 3 20 15 2 10 1 5 0 0 0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16 Examples of DAS data: Fourier Analysis MALE SUBJECT FEMALE SUBJECT FFT FFT 3.0 cycles/min 3.6 cycles/min Frequency (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 Illness Higher prevalence of symptoms in females • Different Physiology Neural pathways – Gastrocolonic reflex Sensory pain pathways and neurotransmission • Evaluation of the Patient Different Normal Values – Gastric Emptying, Colonic Transit • Prevalence of GI Motility Disorders and Functional GI Disorders Higher prevalence in females • Response to Treatment Different Response to Therapy IBS: Allosetron, Tegaserod
Importance of GI Motility Disorders Relates to Other FunctionsDo 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 decreased The 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.
200 ß % R E T E N T I O N 100 50 -slope = Lag = ( ln ß) / 20 T1/2 10 0 30 60 90 120 150 180 TIME (MIN) Data Analysis - GES Geometric mean counts were fit to a modified power exponential function: %Retention = 100(1-(1-e-t)ß)
Raw Data Normalized Data 1200 120 1000 100 c o u n t s 800 80 600 60 EFi = MAX-MIN / MAX 400 40 = 29% EF = average EFi 200 20 0 0 0 0 60 120 180 240 0 0 60 120 180 240 Time (sec) Time (sec) Ejection Fraction Analysis by Dynamic Antral Scintigraphy
Data Analysis-EGG EGG signals were analyzed using fast Fourier transformation • during 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.
FEMALES MALES Frequency of Contractions vs time post meal DF (cpm) DF (cpm)