effect of cyclic hormonal changes during normal menstrual cycle on esophageal motility

Effect of Cyclic Hormonal Changes

During Normal Menstrual Cycle on

Esophageal Motility

MUHAMMAD A. MOHIUDDIN, MD, KISHORE G. PURSNANI, MD, DAVID A. KATZKA, MD,

JUNE A. CASTELL, MS, and DONALD O. CASTELL, MD

Pregnancy has an inhibitory effect on motility of the gastrointe stinal tract most like ly relatedto increased leve ls of circulating female sex hormones. Similar ¯ uctuations of hormone s occurduring the normal menstrual cycle, but to a much lesser degree. We studied the effect of thesesequential hormonal changes on esophageal motility and acid exposure by performing anambulatory esophage al motility/pH study (AEM/pH) during the follicular (days 2± 4) andluteal phase s [days 4 ± 8 after the lute inizing hormone (LH) surge] of the menstrual cycle. Tennormal menstruating women aged 21± 39 years, (mean age 31) were studied with a Konigsbe rgcathe ter positione d such that the pH probe was 5 cm above and pressure transduce rs 7 and15 cm above the LES. Ovulation was predicted by LH detection kit, and serum proge steronelevels were obtained in the luteal phase . Each study was performed for 16 hr and includedmeal, upright, and supine periods. Peristaltic contractions increased during the meal periodsand decreased during supine periods. Simultane ous and isolated contractions increasedduring supine periods and decreased with meals. Number and amplitude of distal esophagealcontractions did not differ signi® cantly between follicular and luteal phase during meal,upright and supine periods. Median percentage of time of distal esophage al pH , 4 andmedian acid clearance were similar between the two phases. In conclusion, esophagealmotility and acid exposure , as measured by AEM/pH, are not affected by the hormonalchanges that occur during the menstrual cycle.

KEY WORDS: esophage al motility; pH; gastroesophage al re ¯ ux; menstrual cycle; progesterone.

Some of the symptoms commonly observed during

pregnancy, such as heartburn, abdominal bloating,

and constipation, may be related to alte ration in

gastrointe stinal motility secondary to physiological

hormonal changes (1). Both in vivo and in vitro studie s

have demonstrated the inhibitory effects of proge ster-

one on gastrointe stinal smooth muscle (2, 3). In ad-

dition, some studie s have shown a delay in the oro-

cecal transit time and in the emptying of the

gallbladde r during both the luteal phase of the men-

strual cycle and pregnancy (4, 5). However, othe r

studie s showed no effect of the menstrual cycle on

gastrointe stinal transit time (6) or on esophageal

emptying (7).

Many studies have focused on the effect of female

sex hormone s on the lower esophageal sphincte r.

However, studie s concerning the effect of sex hor-

mones on esophageal motility in humans have re-

sulted in some confusion. Previous studie s evaluating

the effect of female hormones on esophageal motility

were stationary manometric studie s utilizing water

perfusion or solid-state cathe ter systems (8, 9) .

Esophageal body contraction characte ristics were an-

Manuscript rece ived July 14, 1998; accepted Decembe r 15, 1998.From the Department of Medicine, The Graduate Hospital,

Philadelphia, Pennsylvania.Address for reprint requests: Dr. Donald O. Castell, Department

of Medicine, Suite 501, Pepper Pavilion, 1800 Lombard Street, TheGraduate Hospital, Philadelphia, Pennsylvania 19140.

Digestive Diseases and Sciences, Vol. 44, No. 7 (July 1999), pp. 1368 ± 1375

1368 Digestive Diseases and Sciences, Vol. 44, No. 7 (July 1999)

0163-2116/99/0700-1368$16.00/0 Ñ 1999 Plenum Publishing Corporation

alyzed with only a series of wet swallows and were

limited by the fact that conventional manometry pro-

vides a limited assessment of esophageal motor func-

tion unde r very standard conditions. The ambulatory

esophage al manometry/pH (AEM/pH) study over-

comes some of the limitations of standard manometry

by recording esophageal motility over a prolonge d

period of time unde r various physiological conditions.

The present study was undertaken to clarify the

effect of female sex hormone change s occurring dur-

ing the normal menstrual cycle on esophage al motility

and acid exposure using AEM/pH. We hypothe sized

that since proge sterone decreases the LESP and has

an inhibitory effect on esophageal motility, female s in

the luteal phase of the menstrual cycle might be

expected to demonstrate decreased esophageal con-

tractions and possibly increased episode s of re¯ ux

and abnormal esophage al acid clearance as compared

to the follicular phase .

MATERIALS AND METHODS

Ten normal female volunteers aged 21± 39 years (meanage 31 years) were included in the study. These subjects hadno symptoms suggestive of abnormal gastroesophageal re-¯ ux (heartburn, regurgitation, odynophagia). None of thesesubjects were using medications (anticholinergics, nitrates,calcium antagonists) or had systemic illness (collagen vas-cular disease, endocrine disease , nervous system disease)that could affect the upper gastrointestinal tract.

Subjects were not included if they were pregnant, hadmissed their last menstrual period, had a history of irregularcycles or gynecological diseases, were in menopause, or ifthey were taking birth control pills or practicing any otherhormonal method of contraception.

All volunteers gave informed consent for participation inthe study. They were randomly assigned to two groups.Volunteers in group A were studied ® rst during the follic-ular phase of their menstrual cycle (days 2± 8 with day 1being the ® rst day of menstrual bleeding) and subsequentlyin their luteal [days 4 ± 8 after their luteinizing hormone(LH) surge]. Those in group B were studied ® rst in theluteal phase and then in the follicular phase.

For the purpose of predicting ovulation, subjects weregiven a urinary LH surge measuring kit, One-Step Clear-plan Easy, (Whitehall Labs, Madison, New Jersey) . Clear-plan Easy detects the amount of LH in the urine. Normally,during the mid-cycle, the leve l of this hormone will sud-denly increase (LH surge) causing ovulation to occur within24 ± 36 hr. Subjects were instructed to begin using the kit(depending on the cycle length) according to the calendarprovided with the kit and continue using it until LH surgewas detected. The date of the LH surge was noted. Also onthe study day in the luteal phase, venous blood was obtainedfrom each subject for the determination of serum proges-terone leve ls.

A 16-hr monitoring period from 4:30 PM until 8:30 AMwas used in all studies. On the day of the manometric and

pH studies, subjects were instructed to observe a 3-hr fast

prior to intubation. For proper placement of the ambula-

tory catheter, lower esophageal sphincter (LES) locationwas determined by stationary manometry using a station

pull-through technique. Afte r proper placement of the am-

bulatory catheter, subjects performed their normal daily

routine during the monitoring period. No speci® c schedulewas imposed on mealtime, and there were no restrictions on

diet. However, maximum supine time allowed was 8 hr.

Subjects were instructed to keep a complete diary andidentify meal contents and beginning and end of prandialand supine periods. They were told to follow the same mealmenu, meal times, and supine times on both study days.

Monitoring Apparatus. The recording system containedintraluminal transducers and a portable digital data re-corder. The pressure signals were recorded from two min-iature transducers located at 2 and 10 cm from the distal tip.Esophageal pH was monitored by an electrode at the distaltip (Konigsberg Instrument Inc., Pasadena, California). Themotility/pH catheter was introduced through the nose, andpositioned with the pH electrode 5 cm above the proximalborder of the LES, the distal pressure transducer 7 cmabove the proximal border of the LES, and the secondtransducer 15 cm above the proximal border of the LES.

The pressure and pH signals were both sampled at 4 Hzand registered into a three-channel recorder (Microdigi-trapper Synectics Medical, Inc.). This portable solid-statedigital recording device has the ability to store data over anextended period with memory capacity of 2 megabyte s.After completion of the study, the data were transferredfrom the portable data recorder to a personal computer.Gastrosoft Multigram software (Synectics Medical, Inc.)was used for the automate d analysis of motility and pHdata.

Motility Analysis. The reading and analysis of the ambu-latory motility and pH data was performed entirely by thecomputer program to eliminate subjectivity. The entirepressure tracing was reviewed visually only to ensure ade-quate recording. The total recording time was divided intothree distinct periodsÐ meal, upright and supineÐ whichwere analyzed separate ly by the automate d data analysis.Both the characterization and classi® cation of esophagealcontractions were performed for each of these prede® nedperiods.

An algorithm was developed for computer analysis forautomated detection and characterization of contractionevents. In order to differentiate artifacts from true contrac-tions, two criteria must be ful® lled. The pressure event mustreach an amplitude threshold of 15 mm Hg, and last for 1sec to be considered a valid contraction. Pressure eventsbelow this level were discarded, and those exceeding thisleve l but with a duration of less than 1 sec were de ® ned asartifacts. The automate d analysis recorded the total num-ber, amplitude, and duration of contractions sampled byonly the most distal e lectrode for each period and expressedthese as mean values. In addition, analysis recorded threedifferent types of contractions, ie, peristaltic, simultaneous,and isolated, based on the time interval between onset ofcontraction from the two transducers. Propagation wasclassi® ed as peristaltic when the time interval was between0.8 and 8 sec (propagation ve locity of 1± 10 cm/sec). If thetime interval was between 2 0.8 and 0.8 sec, the contrac-

HORMONES AND ESOPHAGEAL MOTILITY

1369Digestive Diseases and Sciences, Vol. 44, No. 7 (July 1999)

tions were registered as simultaneous. Isolated contractionswere de ® ned when the time interval did not fall within thesepreviously de ® ned intervals. The distribution between thesethree types of propagation were expressed in percentage s.

The pH electrode at the catheter tip was placed 5 cmabove the proximal border of the LES. Re¯ ux of acid fromthe stomach was de® ned by a decrease in pH to less than 4.The total number of episodes and the percentage of timepH remained less than 4 were calculated for meal, upright(nonmeal) , and supine periods, and automate d analysis wasperformed by the computer.

Statis tical Analysis. The motility characteristics and pHparameters for each subject were determined for meal,upright, and supine periods in both the follicular and lutealphases. Mean or median values for the 10 subjects werethen compared using either a paired Student’s t test orWilcoxon signed rank test as appropriate . Results wereconsidered as signi® cant at P , 0.05.

RESULTS

All 10 subje cts tole rated the AEM/pH cathe ter and

completed the study without any complications . None

of the subje cts reported any heartburn, chest pain, or

dysphagia during the study. The mean duration of the

ambulatory manometric recording period was 16 hr,

11 min.

Figure 1 compare s the individual (and mean) num-

ber of distal esophageal contractions for the 10 sub-

jects, divide d into meal, upright, and supine periods

during follicular and luteal phase s. Mean ( 6 SEM)

value s during follicular and luteal phase s were 105 ( 613) and 105 ( 6 16) for the meal period, 808 ( 6 89)

and 684 ( 6 42) upright, and 222 ( 6 36) and 274 ( 656) supine , respectively. There were no signi® cant

differences in the number of contractions during any

period between the two phase s of the cycle .

Individual and mean distal esophage al amplitude

of contractions during the two phases are shown in

Figure 2. Mean amplitude during the follicular and

luteal phases was 51 ( 6 4) and 53 ( 6 5) mm Hg

during meals, 42 ( 6 3) mm Hg and 44.5 ( 6 4.5) mm

Hg upright, and 43 ( 6 4) mm Hg and 48 ( 6 4) mm Hg

supine . The differences between the two phase s were

not signi® cant.

The durations of esophage al contractions were sim-

ilar between the two phase s except while supine ,

when mean contraction duration was 2.4 ( 6 0.1) sec

during the follicular phase compared to 2.7 ( 6 0.13)

sec in luteal phase (P , 0.01) .

Fig 1. Number of contractions in the distal esophagus for each individual subject during meal,upright, and supine periods comparing follicular phase (F) and luteal phase (L). Small bars indicate

mean for each period. There was no signi® cant difference in number of contractions between the twophases of the menstrual cycle; P . 0.05.

MOHIUDDIN ET AL


Esophage al contraction characteristics are shown

as percentage s between the two phase s of the men-

strual cycle in Tables 1± 3. The peristaltic contractions

were highe st during meals and lowest during the

supine period for both phase s. Conversely both simul-

taneous and isolated waves were lowest during meals

and highest when the subjects were supine . However,

there was no signi® cant difference for any of the types

of contraction between the two phases.

The number of acid re¯ ux episode s for the 10

subje cts in the distal esophagus for upright and supine

is shown in Figure 3. Figure 4 illustrate s individual

value s for the percentage of time esophageal pH was

below 4 during each of the time periods. There was no

signi® cant difference for any of these value s compar-

ing the follicular or luteal phases.

Overall esophage al acid clearance de ® ned as total

minute s of acid re¯ ux divide d by the total number of

re¯ ux episode s is shown in Figure 5 for each individ-

ual subje ct. Again, the differences were not signi® cant

between the two phase s of the cycle .

All subje cts had normal menstrual cycle s as docu-

Fig 2. Amplitude of contraction in the distal esophagus for each individual subject during meal, upright, andsupine periods comparing follicular phase (F) and luteal phase (L). Small bars denote mean for each period.

There was no signi ® cant difference in amplitude of contractions between the two phases of the menstrual cycle;P . 0.05.

TABLE 1. MEDIAN (RANGE) PERCENT PERISTALTIC CONTRACTIONS

DURING MEAL, UPRIGHT, AND SUPINE PERIODS DURING TWO

PHASES OF MENSTRUAL CYCLE

Meal Upright Supine

Follicular 64 (50± 85) 60 (40± 85) 43 (26± 89)Luteal 73 (53± 85) 69 (34± 87) 48 (17± 70)

P 0.1 0.3 0.4

TABLE 2. MEDIAN (RANGE) PERCENT SIMULTANEOUS

CONTRACTIONS DURING MEAL, UPRIGHT, AND SUPINE PERIODS

DURING TWO PHASES OF MENSTRUAL CYCLE

Meal Upright Supine

Follicular 13 (4± 37) 17 (8± 34) 21 (3± 37)

Luteal 18 (3± 27) 14 (8± 44) 19 (8± 29)P 0.4 0.5 0.1

TABLE 3. MEDIAN (RANGE) PERCENT ISOLATED CONTRACTIONS

DURING MEAL, UPRIGHT, AND SUPINE PERIODS DURING TWO

PHASES OF MENSTRUAL CYCLE

Meal Upright Supine

Follicular 14 (7± 32) 15 (7± 31) 21 (8± 63)

Luteal 15 (3± 27) 16 (3± 26) 37 (8± 63)P 0.2 0.3 0.3



mented by rise in serum proge sterone in the luteal

phase and detection of LH surge by the ovulation

predictor kit. Mean serum progesterone level in the

luteal phase for the 10 subje cts was 8.7 ng/ml (normal

luteal phase levels 2.5± 28 ng/ml) .

DISCUSSION

Increased leve ls of female sex steroids, particularly

proge sterone , that occur during pregnancy decrease

the motility of the gastrointe stinal tract. Such alte r-

ations in hormonal leve ls are implicate d as a cause of

nausea, vomiting, constipation, and heartburn in

pregnancy (1). In vitro studie s with animals and hu-

man tissue show inhibitory effects of progesterone on

gastrointe stinal smooth muscle . Contractile activity in

esophage al, antral, and colonic muscle excised from

proge sterone pretreated male rats is decreased com-

pared to nontre ated male s (2). Proge sterone also has

a marked inhibitory effect on spontane ous contractil-

ity of smooth muscle strips of human large bowe l and

stomach (3).

If endoge nous progesterone were to have an inhib-

itory effect on the gastrointe stinal tract, then one

would expect slowing in inte stinal contractility with

resulting increased orocecal transit time. However,

studie s measuring gastrointe stinal motility in humans

by comparing orocecal transit times in pregnant fe-

male s vs nonpregnant females or between the two

phase s of the menstrual cycle have had controversial

results. Orocecal transit times measured by breath

hydrogen test after administration of a lactulose meal

were signi® cantly decreased in the third trimester of

pregnancy as compared to ® ve to six weeks after

de livery (4). In one study, gastrointe stinal transit

times were decreased in the luteal phase , when the

leve ls of proge sterone and estrogens are high, com-

pared to the follicular phase (5). However, in a late r

study Bovo et al refuted this by observing that the

menstrual cycle has no effect on gastrointe stinal tran-

sit time when evaluated by means of lactulose hydro-

gen breath test (6).

The role of sex steroids on esophageal transit times

and clearance is less well known. A study of esopha-

geal emptying by scintigraphy during the menstrual

Fig 3. Number of re¯ ux episodes with pH , 4 in the distal esophagus for each individual subject during meal,

upright, and supine periods comparing follicular phase (F) and luteal phase (L). Meals were excluded from theanalysis. Small bars denote median for each period. There was no signi® cant difference in the number of re¯ ux

episodes of between the two phases of the menstrual cycle; P . 0.05.

MOHIUDDIN ET AL


cycle showed that esophage al emptying was unaf-

fected by the phases of the cycle (7). Ulmsten and

Sundstrom used an infusion system to measure veloc-

ity and amplitude of esophageal contractions in preg-

nant and nonpregnant females (8). The recording was

performed in the supine and standing positions, at

rest, and during water swallows. This study showed

that both the peristaltic speed and amplitude s were

decreased in the lower portion of the esophagus in

pregnant females. Nelson et al studied the effect of

normal menstrual cycle on distal esophage al peristal-

tic pressures and LESP. Using a water infusion sys-

tem, they recorded distal esophageal pressures at 2

and 7 cm above the LES in response to wet swallows.

They found no signi® cant difference in LES pressure

measurements and distal esophage al amplitude and

duration between the phase s of the cycle (9).

In our study we have attempted to overcome the

limitations of stationary manometry by conducting an

ambulatory manome tric study to provide a more

physiological assessment of esophage al motility. Our

results agree with the study by Nelson et al. The mean

proge sterone leve ls during the luteal phase in our

study were 8.7 ng/ml compared to 8.5 ng/ml in Nel-

son’s study. The distal esophageal amplitude and du-

ration were not signi® cantly different between the two

phase s in our study, with the exception that the mean

duration of contractions during supine periods was

signi® cantly longer during the luteal phase . Ulmsten

and Sundstrom had reported that peristaltic wave

speed was decreased in pregnant women compared to

nonpregnant women when supine (8).

Results of ambulatory motility recordings per-

formed on healthy individuals have revealed that

these subje cts have a background of nonpe ristaltic

activity during the day (10) . Furthe rmore, both con-

traction features and propagation patterns are char-

acterized by diurnal variation. The esophage al con-

tractile patte rn is different during meals compared to

nonmeal periods and also during supine periods com-

pared to upright periods. Therefore three distinct

periods (meal, upright and supine ) must be consid-

ered separate ly for a complete analysis of AEM. Our

study speci® cally analyze d the different contractile

patterns during these periods and compared these

patterns between the two phases of menstrual cycle.

Fig 4. Percent of time pH , 4 in the distal esophagus for each individual subject during upright period, supine period,

and total of these periods. Meals were excluded from the analysis. Small bars denote median for each period. F indicatesfollicular phase and L indicates luteal. There was no signi ® cant difference in the percent of time pH , 4 between the

two phases of the menstrual cycle ; P . 0.05.



Langevin et al (11) reported that there was a prepon-

derance of peristaltic contractions and increased am-

plitude during meals compared to other periods. They

also obse rved that during supine periods esophage al

activity was reduced, and there were increased simul-

taneous and isolate d contractions while peristaltic

contractions decreased. Our study con® rms this pat-

tern; however, there was no difference in contractile

pattern between the two phase s, as might have been

expected from the inhibitory effects of female hor-

mones.

The LES pressures during the menstrual cycle and

during pregnancy has been more extensive ly studied.

Basal resting LESP is reduced during the luteal phase

as compared to the follicular phase of the menstrual

cycle (12) . LES pressure decreases after administra-

tion of estradiol and proge sterone (13). During early

pregnancy and six weeks after elective abortion, the

LES pressure was unchange d from the pre- to post-

abortion period but the response to hormonal and

physiological stimulation was decreased prior to abor-

tion (14) . A progre ssive decrease in LESP throughout

pregnancy, reaching its nadir at 36 weeks and return-

ing to normal postpartum, has been demonstrated

(15) . These changes were associate d with increased

plasma proge sterone leve ls. Normal menstruating

women taking sequential oral contraceptive s have

shown no signi® cant change in baseline LES pressure

after estrogen administrat ion. However, sphincte r

pressure decreased during the administration of both

estrogen and proge sterone . It was postulate d that

proge sterone is a smooth muscle relaxant and is the

mediator of LES relaxation, with estrogen perhaps

acting as a cofactor needed for this action (13) .

There are , however, con¯ icting data as to whether

the decrease in LES pressure is due to estrogens,

proge sterone , or both. Filipone addressed this issue

by studying ® ve transsexual males during a control

period without hormonal stimulation, followe d by

periods of estrogen, proge sterone , or both. Resting

Fig 5. Acid clearance in the distal esophagus for each individual subject during upright

period, supine period, and the total of these periods. Meals were excluded from the analysis.Small bars denote median for each period. F indicates follicular phase and L indicates

luteal. There was no signi ® cant difference in acid clearance between the two phases of themenstrual cycle; P . 0.05.

MOHIUDDIN ET AL


LESP was signi® cantly decreased during combination

hormonal therapy when compared with the control

period (16) . No decrease in sphincte r pressure was

obse rved during eithe r proge sterone or estrogen ad-

ministration alone .

Our ambulatory technology did not permit LES

pressure monitoring, but continuous pH recording

was performed. The pH data did not reveal any

signi® cant difference in the mean number of re¯ ux

episodes or mean percentage of time of pH , 4

comparing luteal and follicular phases in normal vol-

unteers having no history of re¯ ux symptoms. The

current be lie f is that transient LES relaxations play a

more important role than resting LES pressure in the

pathoge nesis of re¯ ux (17) . Therefore, a decrease in

LESP caused by proge sterone as previously observed

may not be the only factor responsible for re¯ ux

during pregnancy or potentially in the luteal phase of

the menstrual cycle. In addition, we found no signif-

icant difference in esophageal acid clearance between

the two phases.

Our study group consisted of 10 subje cts and beta

error is, therefore , a possible explanation for lack of

change s in esophageal function during normal men-

ses. Despite this limitation, prolonge d ambulatory

e sophage al pre ssure and pH monitoring in the

present study suggests that hormonal change s during

the menstrual cycle do not in¯ uence eithe r the esoph-

ageal contraction characte ristics or distal acid expo-

sure in healthy controls.

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effect of cyclic hormonal changes during normal menstrual cycle on esophageal motility

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