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Esophageal contraction pressures are not affected by normal menstrual cycles
GASTROENTEROLOGY
1984:87:867-71
Esophageal Contraction Pressures Are Not Affected by Normal Menstrual Cycles J. L. NELSON, III, J. E. RICHTER, D. N. JOHNS, D. 0. CASTELL, and G. M. CENTOLA Department of Medicine, Wake Forest University, Gynecology. Uniformed
Section on Gastroenterology. Bowman Gray School of Medicine Winston-Salem, North Carolina; Department of Obstetrics and Services Ilniversity of the Health Sciences, Bethesda, Marvland
Previous studies of lower esophageal sphincter pressures during the menstrual cycle and pregnant) have suggested that the smooth muscle relaxing effect of progesterone depresses sphincter tone. Results, however, have been contradictory and limited to a small number of patients. We studied lower esophageal sphincter and distal peristaltic pressures during the follicular [days 2-8) and Juteal [days ZO28) phases of the menstrual cycle. Twenty normal menstruating women (mean age 31 yr) not using oral contraceptives were evaluated. A low compliance pneumohydraulic infusion system was used for all studies. Lower esophageal sphincter pressure was determined by both rapid and station pull-through techniques. Distal peristaltic pressures were recorded 2 and 7 cm above the sphincter in response to 10 wet swallows [5 cc of H20). Mean amplitude and duration in the distal esophagus were evaluated. Plasma progesterone and estrogen concentrations were obtained and correlated with changes in esophageal pressures. The results were as follows: [a) unlike prior investigations, we found the menstrual cycle had no effect on lower esophageal sphincter pressure and (b) likewise, no change in esophageal contractions in the distal esophagus was found during the cycle. We concluded that changes in female sex hormone concentrations that characterize the menstrual cycle are not associated with
Received August 8, 1983. Accepted April 20. 1984. Address requests for reprints to: J. E. Richter, M.D., Section on Gastroenterology, Bowman Gray School of Medicine of Wake Forest University, 300 South Hawthorne Road, Winston-Salem. North Carolina 27103. The authors thank Harry M. Schey. Ph.D., Section on Community Medicine, Bowman Gray School of Medicine. for his assistance with statistical analysis. #P 1984 by the American Gastroenterological Association OOl&5085/84:$3.00
changes tion.
in parameters
of
of esophageal
motor func-
Resting tone of the lower esophageal sphincter (LES) has been described as the major barrier to acid reflux at the gastroesophageal junction (l-5). Pharmacologic doses of many hormones may alter sphincter pressure, but the physiologic role of these hormones in modulating LES tone is less well established (6). It has been proposed that physiologic increases in estrogen or progesterone, or both, may decrease resting LES tone (7-11). These changes may account for the fact that >50% of women complain of heartburn during the last trimester of pregnancy (12). However, many pregnant women with elevated levels of progesterone and estrogen have normal LES pressures (13). Furthermore, one investigator reported LES pressures greater than controls in asymptomatic pregnant women, but low LES pressures in pregnant women with heartburn (14). Heartburn in late pregnancy just as likely could be the result of mechanical alterations such as increased intraabdominal pressure, loss of an intraabdominal LES segment, alteration of anatomical structures surrounding the LES, and delayed gastric emptying secondary to the mass effect of the uterus (15). Studies in early pregnancy or the normal menstrual cycle might lend more support to the “female sex hormone hypothesis,” but current data are conflicting (9,13). Discrepancies among studies may reflect methodologic differences, limitations imposed by small sample sizes, or an incorrect hypothesis. The present study was initiated to reexamine the influence of sex hormones on parameters of esophageal motor function during the follicular and luteal phases of the menstrual cycle. Modern manometric equipment, multiple pressure measurements by sev-
868
GASTKOENTEROLOGY
NELSON ET AL.
era1 techniques, and a large subject sample size were previous study limitations. used to overcome
Subjects Twenty healthy female volunteers (mean age 31 yr, range 22-40 yr) known not to have been using oral contraceptives within a period of at least 6 mo before their participation in this study were evaluated. Each volunteer was interviewed and carefully followed by telephone to ensure normal menstrual cycling. Volunteers were excluded if there was any history of symptomatic heartburn or other gastrointestinal diseases. Additionally, no volunteer had a history of diabetes mellitus, alcoholism, collagen vascular disorders, or neurologic disorders. Written informed consent was obtained from the participants and the study was approved by the Human Research Review Committee of the Bowman Gray School of Medicine.
Pressure
Measurements
Esophageal manometric studies were performed using a round &lumen polyvinyl catheter (diameter 4.5 mm; internal diameter 0.8 mm; Arndorfer Specialties, Inc., Greendale, Wis.). The distal four openings were located 1 cm apart at 90” angles and the four proximal openings were spaced at s-cm intervals. Each lumen was continuously perfused with distilled water at a rate of 0.5 mlimin using a low compliance pneumohydraulic capillary infusion system (Arndorfer Specialties, Inc.) The catheter was connected to external transducers (Beckman, model 4-327C, Norcross, Ga.) with output on a Beckman recorder (model R-612). The manometric system has a pressure rise rate of 400 mmHg/s. All volunteers were studied in a supine position after an overnight fast. The catheter was introduced through the nose into the stomach. Using the distal four openings, LES pressures were first recorded during midexpiration using the rapid pull-through technique (0.5 cm/s) with mean resting intragastric pressures used as zero reference [lS). This was repeated and the data were recorded in millimeters of mercury as an average of eight pressure recordings. The distal four openings were then repositioned into the stomach and the catheter was withdrawn slowly in l.O-cm increments using a standard station pull-through technique. Two separate station pull-throughs were performed and values were recorded at midexpiration. Lower esophageal sphincter pressure was recorded as the average of the eight values. Distal esophageal peristalsis was recorded at 2 and 7 cm above the LES in response to ~-CC wet swallows of water. Fifteen wet swallows were given at 30-s intervals. The last 10 swallows were analyzed and data from the two recording sites were combined to obtain a mean for amplitude and duration in the distal esophagus. Wave amplitude, in millimeters of mercury, was measured from the mean intraesophageal baseline pressure to the peak of the peristaltic wave. The duration of the individual peristaltic
was measured from to the end of the wave.
upstroke
Study
Method
IntraJuminaJ
wave, in seconds, major
Vol. 87. No. 4
the onset
of the
Design
Twelve volunteers were studied first during the follicular phase of their menstrual cycle (days 2-8 with day 1 being the first day of menstrual bleeding) and subsequently in their luteal phase (days 20-28). Eight volunteers were studied first in the luteal phase and
subsequently in the follicular phase. The order was determined randomly by the menstrual phase of the volunteer at the time of initial study.
Hormonal
Analysis
Blood for estrogen and progesterone determination was obtained from each fasting volunteer after each study. Plasma was immediately separated and stored at -20°C until assayed. Serum estradiol-l7p was measured using an anti-l 7/3-estradiol-6 bovine serum albumin (BSA) antiserum and a labeled isotope, [2,4,6,7-“Hlestradiol-17p. Values were expressed as picograms per milliliter. The minimal detectable concentration was 4.0 pgitube. Serum progesterone was assayed using anti-progesterone-11-BSA antiserum and [1,2,6,7,-3H]progesterone as the radiolabel. Values were expressed as nanograms per milliliter. The minimal detectable concentration was 30 pg/tube (10.11).
Interpretation
of Data
All manometric tracings and serum samples were coded and read or analyzed blindly after all studies were completed. A paired t-test was used for statistical analysis.
Results Individual mean LES pressures recorded during the follicular and luteal phases of the menstrual cycle using both station and rapid pull-through techniques are shown in Figures 1A and 1B. Mean LES pressure for the 20 women during the follicular phase was 29.9 ? 2.7 mmHg (?SEM) by the station pull-through technique and 31.7 + 2.8 mmHg by the rapid pull-through technique with a range of 10-54 mmHg and lo-60 mmHg, respectively. During the luteal phase, mean LES pressure was 29.5 t 2.2 mmHg by the station pull-through technique and 31.6 ? 2.2 mmHg by the rapid pull-through technique with a range of 11-50 mmHg and 17-52 mmHg, respectively. There was no significant difference in mean LES pressure measured by either technique between follicular and luteal phases of the menstrual cycle in the 20 women. Likewise, there was no consistent correlation between individual LES pressure measurements and individual progesterone concentrations or estrogen/progesterone ratios.
October
ESOPHAGEAL
1984
CONTRACTIONS
75 c
7o
y
65
5g
60
= 2
55 50
‘;m 40-
E P
45 40
z
35-
“,
35
;
30-
*
25-
: -
2015-
E E
25 20
i
lo-
a 8 I”
15 10 : 30 5
r :
7065-
E = a’
605550-
s
45-
J
A Figure
50'
A
AND MENSTRUAL
CYCLE
869
k =X+SEM
n Follicular Phase of the Menstrual
Follicular
Luteal B
Cycle
1. Individual mean lower esophageal sphincter pressures (LESP) during the follicular recorded by station (A) and rapid (B) pull-through techniques in 20 healthy women. lower esophageal sphincter pressure between the phases of the menstrual cycle.
Individual mean distal esophageal peristaltic amplitudes recorded during the follicular and luteal phases of the menstrual cycle are shown in Figure 2. The mean distal amplitude for the 20 women during the follicular phase was 99.8 2 8.9 mmHg as compared with 109.0 t 8.3 mmHg during the luteal phase. This difference in distal peristaltic amplitude does not reach statistical significance. Mean duration was 3.8 2 0.2 s during the follicular phase and 3.7 k 0.2 s during the luteal phase. Again, the differences were not significant. All 20 women studied had normal menstrual cycles as documented by a significant rise in progesterone levels during the luteal phase (Table 1) and menstrual bleeding at appropriate times. Mean sampling during the luteal phase was at day 22 with a range from days 20 to 25.
Discussion Progesterone is a smooth muscle relaxant that requires the priming action of estrogen (17). It has been suggested that physiologic levels of progesterone found in pregnancy and during the menstrual cycle may result in reduced motility of the intestinal (18-20) and genitourinary systems (21). The esophagus, and particularly the LES, is probably the best studied portion of the gastrointestinal tract in relation to the “female sex hormone hypothesis.” The addition of sex hormones to isolated esophageal smooth muscle strips has been shown to depress the excitatory muscle response to pharmacologic agonists (22). Shulze and Christensen (23) observed a reduction in opossum LES pressure after administration of e&radio1 and methoxyprogesterone acetate.
Luteal
Phase of the Menstrual
Cycle
and luteal phases of the menstrual cycle No significant difference is noted in mean
Studies in humans have resulted in some confusion about the effect of sex hormones on esophageal muscle function. In 1961, Nagler and Spiro (7), using a noninfused catheter system, reported that LES pressures were reduced in 20% of asymptomatic pregnant women and in 55% of pregnant women with heartburn. Lind et al. used a similar manomet-
220210ol = : ; 2 “a
200190lBO170160150140-
5 .2 m
130120IIO-
5 5
loo90
T
1
60 70 60 50 40 30 20 10
k =KiSEM
1 Follicular Phase of the Menstrual
Figure
2
Luteal Cycle
Individual mean amplitudes of peristaltic contractions in the distal esophagus of 20 women measured during the follicular and luteal phases of the menstrual cycle. Again no significant difference is noted between the phases of the menstrual cycle.
870
NELSON
Table
GASTROENTEROLOGY
ET AL.
I. Plasma Estrogen and Progesterone
Volunteers Studied During the Two Phases of the Menstrual Cycle” Concentrations
Follicular Luteal a Results are expressed b p < 0.001 compared
in the
Estradiol
Progesterone
(pg/mll
(@ml)
74.9 f 8.1 109.3 -c 15.3
0.31 + 0.04 8.53 + 0.98”
as mean + SEM: n = 20 to each with the follicular phase.
group.
ric system to study women in the third trimester of pregnancy. They reported low LES pressures in pregnant women with heartburn, but LES pressures greater than control values in asymptomatic pregnant women (14). More recently, Ostick et al. (24) used an infused catheter system and found low LES pressures in asymptomatic as well as symptomatic women in the last trimester of pregnancy. In another study, Van Thiel and colleagues observed low LES pressures in 4 women during their third trimester of pregnancy. Pressures returned to normal after delivery (11). Investigation of LES function during the menstrual cycle and early pregnancy may be more relevant to our study. Van Thiel et al. (10) studied 7 women on sequential oral contraceptives. Sphincter pressures only decreased during the phase of the cycle when the women took the progestation agent. The same group observed in 10 women, a small, but significant reduction in LES pressure measured by the rapid pull-through technique during the luteal phase of the menstrual cycle (9). Fisher et al. studied LES function in 8 asymptomatic pregnant women who were scheduled for therapeutic abortion. Resting LES pressures were found to be in the normal range early in the second trimester of pregnancy and did not differ from values obtained 6 wk after abortion (13). Before abortion, however, sphincter responses to hormonal, pharmacologic, and physiologic stimuli were depressed. It is of interest that the progesterone concentrations in the pregnant women in Fisher’s study were similar to the values obtained for the women in the luteal phase of Van Thiel’s study. The present study suggests that hormonal fluctuations during the menstrual cycle have no significant effect on resting LES pressures as measured by either the rapid or station pull-through technique. Additionally, peristaltic pressures are not altered during the menstrual cycle. Serum estrogen and progesterone plasma concentrations were within the clinical range of accepted normal values for women in both the follicular and luteal phases of the menstrual cycle (25). In our current study, we have attempted to overcome limitations of previous investigations. This is
Vol.
87. No. 4
the largest group of women studied to date using a high fidelity, low compliance infusion system. Technical variations in LES pressure measurements were minimized by using both station and rapid pullthrough techniques (26). All studies were read blindly by an investigator unaware of the phases of the menstrual cycle. Progesterone plasma concentrations observed during our study were less than values obtained by Van Thiel et al. at similar stages in the menstrual cycle. Peak progesterone concentration occurs about day 22 in the cycle and, therefore. our lower values might represent sampling later in the luteal phase. We do not believe this is the case. In our series, mean luteal sampling was obtained at day 22 with a range from days 20 to 25. Studies in our laboratory have correlated similar progesterone plasma concentrations with endometrial biopsy specimens obtained during this period of the menstrual cycle (27). Differences in progesterone concentrations between studies, therefore. more likely represent methodologic variations in the steroid determinations. Although the “female sex hormone hypothesis” may ultimately be shown to be correct, it appears that for the esophagus, at least, there may be variable responses dependent on magnitude and duration of hormonal exposure. Our study suggests that plasma concentrations of progesterone and estrogen in the normal menstrual cycle may not be sufficiently high or may lack adequate exposure time to have any significant effect on esophageal smooth muscle function.
References 1 2
3 4
5, 6. 7.
8. 9.
10.
11.
Winans CS. Harris LD. Quantitation 01 lo\vc!r esophageal sphincter competence. Gastroenterology 1967;52:773-8. Haddad Jk. Relation of gastroesophageal rrflux to yield sphincter pressures. Gastroenterology 1970:58:175~84. Cohen S, Harris LD. The lower esophageal sphincter. Gastroenterology 1972:63:1066-73. Dodds WJ. Dent J. Hogan \VJ. et al. Mechanisms of gastroesophageal reflux in patients with retlux esophagitis. N Engl J Med 19&?;307:1547-52. Richter JE, Caste11 DO. Gastroesophageal reflux. Ann Intern Med 1982:97:9%103. Caste11 DO. The lower esophageal sphincter. Ann Intern Med 1975;83:390-401. Nagler R. Spiro HM. Heartburn in late pregnanLq, manometric: studies of esophageal motor function. I (:lin Invest 1961: 40:954-70. Castro LP. Reflux esophagitis as the pause of heartburn in pregnancy. Am J Obst Gynecol 1967:98:1-10. Van Thiel DH. Gravaler JS. Stremple 1. Lower esophageal sphincter pressure during the normal menstrual cycle. Am J Obst Gynecol 1979:134:64-7. Van Thiel DH. Gravaler JS. Stremplr I. Lowrr esophagrl sphincter pressure in women using sequential oral contraceptives. Gastroenterology 1976;71:232-4. Van Thiel DH, Gravaler JS. Shobha AB. loshi SN. Sara Kk;.
October
1984
Stremple
ESOPHAGEAL
j. Heartburn
of pregnancy.
Gastroenterology
1977:
72:666--8. 12.
13.
14.
15. 16.
17. 18.
Nebel CT, Fornes MF. Caste11 DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Dig Dis Sci 1976;21:963-6. Fisher KS. Roberts GS, Grabowski CJ, Cohen S. Altered lower esophageal sphincter function during early pregnancy. Gastroenterology 1978;74:1233-7. Lind JF. Smith AM, McIver DK. Coopland AT, Crispen JS. Heartburn in pregnancy, a manometric study. Can Med Assoc J 1968:98:571-4. Dodds WJ. Dent J, Hogan WJ. Pregnancy and the lower esophageal sphincter. Gastroenterology 1978:74:1334-6. Dodds WJ. Stef JJ, Hogan WJ. Factors determining pressure measurement accuracy by intraluminal esophageal manometry. Gastroenterology 1976:70:117-23. Hytten FE. Leitch 1. The physiology of human pregnancy. 2nd ed. Oxford: Blackwell Scientific, 1971.
21.
Wald A, Van Thiel DH, Hoechstetter transit: the effect of the menstrual
26.
L, et al. Gastrointestinal cycle. Gastroenterology
1981;80:1497-1500. 19. Wald A, Van Thiel DH, Hoechstetter pregnancy on gastrointestinal transit. 20.
L. et al. Effect of Dig Dis Sci 1982;27:
1015-8. Everson GT. McKinley C, Lawson M. Johnson M, Kern F. Gallbladder function in the human female: effect of the
22.
23.
24.
25.
27.
CONTRACTIONS
AND
MENSTRUAL
CYCLE
871
ovulatory cycle, pregnancy. and contraceptive steroids. Gastroenterology 1982:82:711-g. Bruce NW. Gestational adaption: major systems. In: Ifffy L, Kaminetzky HA. eds. Principles and practice of obstetrics and perinatology. New York: John Wiley & Sons, 1981:691. Pope CE. Reflux esophagitis. In: Sleisinger IMH, Fortran JS, eds. Gastrointestinal disease. Philadelphia: WB Saunders. 1973:432. Schulze K, Christensen J. Lower sphincter of the opossum esophagus in pseudopregnancy. Gastroenterology 1977;73: 1082-5. Ostick DG. Cowley DJ, Hey VM, et al. A study of gastrointestinal reflux in late pregnancy. In: Proceedings of the Fifth International Symposium on Gastrointestinal Motility. Leuven. Belgium: Typoff Press. 1976:358-62. Ross GT, Vande Wiele RL. The ovaries. In: William RH. ed. Textbook of endocrinology. Philadelphia: WB Saunders, 1974:388. Welch RW. Drake JT. Normal lower esophageal sphincter pressure: a comparison of rapid vs. slow pull-through techniques. Gastroenterology 1980;78:1446-51. Centola GM, Chaleraborty PK, Damaska G. Knab DR. Human endometrial estrogen, progesterone receptors. and plasma steroid concentrations during the menstrual cycle. hyperplasia and adenocarcinoma (abstr). Proceedings of the 65th Annual Meeting of the Endocrine Society, 1983353; abstract 1090.
1984:87:867-71
Esophageal Contraction Pressures Are Not Affected by Normal Menstrual Cycles J. L. NELSON, III, J. E. RICHTER, D. N. JOHNS, D. 0. CASTELL, and G. M. CENTOLA Department of Medicine, Wake Forest University, Gynecology. Uniformed
Section on Gastroenterology. Bowman Gray School of Medicine Winston-Salem, North Carolina; Department of Obstetrics and Services Ilniversity of the Health Sciences, Bethesda, Marvland
Previous studies of lower esophageal sphincter pressures during the menstrual cycle and pregnant) have suggested that the smooth muscle relaxing effect of progesterone depresses sphincter tone. Results, however, have been contradictory and limited to a small number of patients. We studied lower esophageal sphincter and distal peristaltic pressures during the follicular [days 2-8) and Juteal [days ZO28) phases of the menstrual cycle. Twenty normal menstruating women (mean age 31 yr) not using oral contraceptives were evaluated. A low compliance pneumohydraulic infusion system was used for all studies. Lower esophageal sphincter pressure was determined by both rapid and station pull-through techniques. Distal peristaltic pressures were recorded 2 and 7 cm above the sphincter in response to 10 wet swallows [5 cc of H20). Mean amplitude and duration in the distal esophagus were evaluated. Plasma progesterone and estrogen concentrations were obtained and correlated with changes in esophageal pressures. The results were as follows: [a) unlike prior investigations, we found the menstrual cycle had no effect on lower esophageal sphincter pressure and (b) likewise, no change in esophageal contractions in the distal esophagus was found during the cycle. We concluded that changes in female sex hormone concentrations that characterize the menstrual cycle are not associated with
Received August 8, 1983. Accepted April 20. 1984. Address requests for reprints to: J. E. Richter, M.D., Section on Gastroenterology, Bowman Gray School of Medicine of Wake Forest University, 300 South Hawthorne Road, Winston-Salem. North Carolina 27103. The authors thank Harry M. Schey. Ph.D., Section on Community Medicine, Bowman Gray School of Medicine. for his assistance with statistical analysis. #P 1984 by the American Gastroenterological Association OOl&5085/84:$3.00
changes tion.
in parameters
of
of esophageal
motor func-
Resting tone of the lower esophageal sphincter (LES) has been described as the major barrier to acid reflux at the gastroesophageal junction (l-5). Pharmacologic doses of many hormones may alter sphincter pressure, but the physiologic role of these hormones in modulating LES tone is less well established (6). It has been proposed that physiologic increases in estrogen or progesterone, or both, may decrease resting LES tone (7-11). These changes may account for the fact that >50% of women complain of heartburn during the last trimester of pregnancy (12). However, many pregnant women with elevated levels of progesterone and estrogen have normal LES pressures (13). Furthermore, one investigator reported LES pressures greater than controls in asymptomatic pregnant women, but low LES pressures in pregnant women with heartburn (14). Heartburn in late pregnancy just as likely could be the result of mechanical alterations such as increased intraabdominal pressure, loss of an intraabdominal LES segment, alteration of anatomical structures surrounding the LES, and delayed gastric emptying secondary to the mass effect of the uterus (15). Studies in early pregnancy or the normal menstrual cycle might lend more support to the “female sex hormone hypothesis,” but current data are conflicting (9,13). Discrepancies among studies may reflect methodologic differences, limitations imposed by small sample sizes, or an incorrect hypothesis. The present study was initiated to reexamine the influence of sex hormones on parameters of esophageal motor function during the follicular and luteal phases of the menstrual cycle. Modern manometric equipment, multiple pressure measurements by sev-
868
GASTKOENTEROLOGY
NELSON ET AL.
era1 techniques, and a large subject sample size were previous study limitations. used to overcome
Subjects Twenty healthy female volunteers (mean age 31 yr, range 22-40 yr) known not to have been using oral contraceptives within a period of at least 6 mo before their participation in this study were evaluated. Each volunteer was interviewed and carefully followed by telephone to ensure normal menstrual cycling. Volunteers were excluded if there was any history of symptomatic heartburn or other gastrointestinal diseases. Additionally, no volunteer had a history of diabetes mellitus, alcoholism, collagen vascular disorders, or neurologic disorders. Written informed consent was obtained from the participants and the study was approved by the Human Research Review Committee of the Bowman Gray School of Medicine.
Pressure
Measurements
Esophageal manometric studies were performed using a round &lumen polyvinyl catheter (diameter 4.5 mm; internal diameter 0.8 mm; Arndorfer Specialties, Inc., Greendale, Wis.). The distal four openings were located 1 cm apart at 90” angles and the four proximal openings were spaced at s-cm intervals. Each lumen was continuously perfused with distilled water at a rate of 0.5 mlimin using a low compliance pneumohydraulic capillary infusion system (Arndorfer Specialties, Inc.) The catheter was connected to external transducers (Beckman, model 4-327C, Norcross, Ga.) with output on a Beckman recorder (model R-612). The manometric system has a pressure rise rate of 400 mmHg/s. All volunteers were studied in a supine position after an overnight fast. The catheter was introduced through the nose into the stomach. Using the distal four openings, LES pressures were first recorded during midexpiration using the rapid pull-through technique (0.5 cm/s) with mean resting intragastric pressures used as zero reference [lS). This was repeated and the data were recorded in millimeters of mercury as an average of eight pressure recordings. The distal four openings were then repositioned into the stomach and the catheter was withdrawn slowly in l.O-cm increments using a standard station pull-through technique. Two separate station pull-throughs were performed and values were recorded at midexpiration. Lower esophageal sphincter pressure was recorded as the average of the eight values. Distal esophageal peristalsis was recorded at 2 and 7 cm above the LES in response to ~-CC wet swallows of water. Fifteen wet swallows were given at 30-s intervals. The last 10 swallows were analyzed and data from the two recording sites were combined to obtain a mean for amplitude and duration in the distal esophagus. Wave amplitude, in millimeters of mercury, was measured from the mean intraesophageal baseline pressure to the peak of the peristaltic wave. The duration of the individual peristaltic
was measured from to the end of the wave.
upstroke
Study
Method
IntraJuminaJ
wave, in seconds, major
Vol. 87. No. 4
the onset
of the
Design
Twelve volunteers were studied first during the follicular phase of their menstrual cycle (days 2-8 with day 1 being the first day of menstrual bleeding) and subsequently in their luteal phase (days 20-28). Eight volunteers were studied first in the luteal phase and
subsequently in the follicular phase. The order was determined randomly by the menstrual phase of the volunteer at the time of initial study.
Hormonal
Analysis
Blood for estrogen and progesterone determination was obtained from each fasting volunteer after each study. Plasma was immediately separated and stored at -20°C until assayed. Serum estradiol-l7p was measured using an anti-l 7/3-estradiol-6 bovine serum albumin (BSA) antiserum and a labeled isotope, [2,4,6,7-“Hlestradiol-17p. Values were expressed as picograms per milliliter. The minimal detectable concentration was 4.0 pgitube. Serum progesterone was assayed using anti-progesterone-11-BSA antiserum and [1,2,6,7,-3H]progesterone as the radiolabel. Values were expressed as nanograms per milliliter. The minimal detectable concentration was 30 pg/tube (10.11).
Interpretation
of Data
All manometric tracings and serum samples were coded and read or analyzed blindly after all studies were completed. A paired t-test was used for statistical analysis.
Results Individual mean LES pressures recorded during the follicular and luteal phases of the menstrual cycle using both station and rapid pull-through techniques are shown in Figures 1A and 1B. Mean LES pressure for the 20 women during the follicular phase was 29.9 ? 2.7 mmHg (?SEM) by the station pull-through technique and 31.7 + 2.8 mmHg by the rapid pull-through technique with a range of 10-54 mmHg and lo-60 mmHg, respectively. During the luteal phase, mean LES pressure was 29.5 t 2.2 mmHg by the station pull-through technique and 31.6 ? 2.2 mmHg by the rapid pull-through technique with a range of 11-50 mmHg and 17-52 mmHg, respectively. There was no significant difference in mean LES pressure measured by either technique between follicular and luteal phases of the menstrual cycle in the 20 women. Likewise, there was no consistent correlation between individual LES pressure measurements and individual progesterone concentrations or estrogen/progesterone ratios.
October
ESOPHAGEAL
1984
CONTRACTIONS
75 c
7o
y
65
5g
60
= 2
55 50
‘;m 40-
E P
45 40
z
35-
“,
35
;
30-
*
25-
: -
2015-
E E
25 20
i
lo-
a 8 I”
15 10 : 30 5
r :
7065-
E = a’
605550-
s
45-
J
A Figure
50'
A
AND MENSTRUAL
CYCLE
869
k =X+SEM
n Follicular Phase of the Menstrual
Follicular
Luteal B
Cycle
1. Individual mean lower esophageal sphincter pressures (LESP) during the follicular recorded by station (A) and rapid (B) pull-through techniques in 20 healthy women. lower esophageal sphincter pressure between the phases of the menstrual cycle.
Individual mean distal esophageal peristaltic amplitudes recorded during the follicular and luteal phases of the menstrual cycle are shown in Figure 2. The mean distal amplitude for the 20 women during the follicular phase was 99.8 2 8.9 mmHg as compared with 109.0 t 8.3 mmHg during the luteal phase. This difference in distal peristaltic amplitude does not reach statistical significance. Mean duration was 3.8 2 0.2 s during the follicular phase and 3.7 k 0.2 s during the luteal phase. Again, the differences were not significant. All 20 women studied had normal menstrual cycles as documented by a significant rise in progesterone levels during the luteal phase (Table 1) and menstrual bleeding at appropriate times. Mean sampling during the luteal phase was at day 22 with a range from days 20 to 25.
Discussion Progesterone is a smooth muscle relaxant that requires the priming action of estrogen (17). It has been suggested that physiologic levels of progesterone found in pregnancy and during the menstrual cycle may result in reduced motility of the intestinal (18-20) and genitourinary systems (21). The esophagus, and particularly the LES, is probably the best studied portion of the gastrointestinal tract in relation to the “female sex hormone hypothesis.” The addition of sex hormones to isolated esophageal smooth muscle strips has been shown to depress the excitatory muscle response to pharmacologic agonists (22). Shulze and Christensen (23) observed a reduction in opossum LES pressure after administration of e&radio1 and methoxyprogesterone acetate.
Luteal
Phase of the Menstrual
Cycle
and luteal phases of the menstrual cycle No significant difference is noted in mean
Studies in humans have resulted in some confusion about the effect of sex hormones on esophageal muscle function. In 1961, Nagler and Spiro (7), using a noninfused catheter system, reported that LES pressures were reduced in 20% of asymptomatic pregnant women and in 55% of pregnant women with heartburn. Lind et al. used a similar manomet-
220210ol = : ; 2 “a
200190lBO170160150140-
5 .2 m
130120IIO-
5 5
loo90
T
1
60 70 60 50 40 30 20 10
k =KiSEM
1 Follicular Phase of the Menstrual
Figure
2
Luteal Cycle
Individual mean amplitudes of peristaltic contractions in the distal esophagus of 20 women measured during the follicular and luteal phases of the menstrual cycle. Again no significant difference is noted between the phases of the menstrual cycle.
870
NELSON
Table
GASTROENTEROLOGY
ET AL.
I. Plasma Estrogen and Progesterone
Volunteers Studied During the Two Phases of the Menstrual Cycle” Concentrations
Follicular Luteal a Results are expressed b p < 0.001 compared
in the
Estradiol
Progesterone
(pg/mll
(@ml)
74.9 f 8.1 109.3 -c 15.3
0.31 + 0.04 8.53 + 0.98”
as mean + SEM: n = 20 to each with the follicular phase.
group.
ric system to study women in the third trimester of pregnancy. They reported low LES pressures in pregnant women with heartburn, but LES pressures greater than control values in asymptomatic pregnant women (14). More recently, Ostick et al. (24) used an infused catheter system and found low LES pressures in asymptomatic as well as symptomatic women in the last trimester of pregnancy. In another study, Van Thiel and colleagues observed low LES pressures in 4 women during their third trimester of pregnancy. Pressures returned to normal after delivery (11). Investigation of LES function during the menstrual cycle and early pregnancy may be more relevant to our study. Van Thiel et al. (10) studied 7 women on sequential oral contraceptives. Sphincter pressures only decreased during the phase of the cycle when the women took the progestation agent. The same group observed in 10 women, a small, but significant reduction in LES pressure measured by the rapid pull-through technique during the luteal phase of the menstrual cycle (9). Fisher et al. studied LES function in 8 asymptomatic pregnant women who were scheduled for therapeutic abortion. Resting LES pressures were found to be in the normal range early in the second trimester of pregnancy and did not differ from values obtained 6 wk after abortion (13). Before abortion, however, sphincter responses to hormonal, pharmacologic, and physiologic stimuli were depressed. It is of interest that the progesterone concentrations in the pregnant women in Fisher’s study were similar to the values obtained for the women in the luteal phase of Van Thiel’s study. The present study suggests that hormonal fluctuations during the menstrual cycle have no significant effect on resting LES pressures as measured by either the rapid or station pull-through technique. Additionally, peristaltic pressures are not altered during the menstrual cycle. Serum estrogen and progesterone plasma concentrations were within the clinical range of accepted normal values for women in both the follicular and luteal phases of the menstrual cycle (25). In our current study, we have attempted to overcome limitations of previous investigations. This is
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the largest group of women studied to date using a high fidelity, low compliance infusion system. Technical variations in LES pressure measurements were minimized by using both station and rapid pullthrough techniques (26). All studies were read blindly by an investigator unaware of the phases of the menstrual cycle. Progesterone plasma concentrations observed during our study were less than values obtained by Van Thiel et al. at similar stages in the menstrual cycle. Peak progesterone concentration occurs about day 22 in the cycle and, therefore. our lower values might represent sampling later in the luteal phase. We do not believe this is the case. In our series, mean luteal sampling was obtained at day 22 with a range from days 20 to 25. Studies in our laboratory have correlated similar progesterone plasma concentrations with endometrial biopsy specimens obtained during this period of the menstrual cycle (27). Differences in progesterone concentrations between studies, therefore. more likely represent methodologic variations in the steroid determinations. Although the “female sex hormone hypothesis” may ultimately be shown to be correct, it appears that for the esophagus, at least, there may be variable responses dependent on magnitude and duration of hormonal exposure. Our study suggests that plasma concentrations of progesterone and estrogen in the normal menstrual cycle may not be sufficiently high or may lack adequate exposure time to have any significant effect on esophageal smooth muscle function.
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