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ORIGINAL CONTRIBUTION

Obesity and Estrogen as Risk Factors


for Gastroesophageal Reflux Symptoms
Magnus Nilsson, MD Context Gastroesophageal reflux and obesity are both increasing in prevalence. The
Roar Johnsen, MD, PhD scientific evidence for an association between these conditions is sparse and contra-
dictory. A difference between sexes concerning this relation has been proposed.
Weimin Ye, MD
Objective To evaluate the relation between body mass and gastroesophageal re-
Kristian Hveem, MD, PhD flux symptoms and determine how this relation is influenced by female sex hormones.
Jesper Lagergren, MD, PhD Design Population-based, cross-sectional, case-control study.
Setting Two consecutive public health surveys within the county of Nord-

G
ASTROESOPHAGEAL REFLUX Trondelag, Norway, conducted in 1984-1986 and 1995-1997.
disease and obesity are both
Participants Among 65363 adult participants in the second survey, 3113 individuals
highly prevalent in West- who reported severe heartburn or regurgitation during the last 12 months were defined
ern societies, and the occur- as cases, whereas 39872 persons without reflux symptoms were defined as controls.
rence of these conditions is rapidly in-
Main Outcome Measure Risk of reflux, estimated using multivariate logistic re-
creasing.1-7 Reflux has an adverse impact
gression, with odds ratios (ORs) and 95% confidence intervals (CIs) as measures of
on quality of life,8 and the costs for long- association.
term antireflux medication are high.9
Reflux symptoms10-12 and obesity13,14 are Results There was a dose-response association between increasing body mass in-
dex (BMI) and reflux symptoms in both sexes (P for trend ⬍.001), with a significantly
strong and independent risk factors for stronger association in women (P⬍.001). Compared with those with a BMI less than
esophageal adenocarcinoma, a cancer 25, the risk of reflux was increased significantly among severely obese (BMI ⬎35) men
that has increased significantly in in- (OR, 3.3; 95% CI, 2.4-4.7) and women (OR, 6.3; 95% CI, 4.9-8.0). The association
cidence during recent decades.15,16 between BMI and reflux symptoms was stronger among premenopausal women com-
The relation between body mass and pared with postmenopausal women (P⬍.001), although use of postmenopausal hor-
gastroesophageal reflux symptoms re- mone therapy increased the strength of the association (P⬍.001). Reduction in BMI
mains uncertain, and valid data to as- was associated with decreased risk of reflux symptoms.
sess this proposed association are Conclusions There is a significant association between body mass and symptoms
limited. In our previous study, we dem- of gastroesophageal reflux. The association is stronger among women, especially pre-
onstrated a strong and dose-depen- menopausally, and use of hormone therapy strengthens the association, suggesting
dent association between increasing that estrogens may play an important role in the etiology of reflux disease.
body mass and endoscopically veri- JAMA. 2003;290:66-72 www.jama.com

fied esophagitis in women, but no as-


sociation was found in men.17 More- METHODS total of 47556 individuals, represent-
over, the positive association among The HUNT Public Health Surveys ing 72.8% of all persons included in
women seemed to be augmented by In the Norwegian County of Nord- HUNT 2, participated in both surveys.
postmenopausal hormone therapy, sug- Trondelag, 2 extensive public health
gesting a role of female sex hormones surveys have been conducted during re- Author Affiliations: Department of Surgery, Karolin-
in the etiology of reflux disease.17 To cent decades. The first, Helseunder- ska Institutet, Karolinska Hospital (Drs Nilsson and
Lagergren), and Department of Medical Epidemiol-
examine the relation between body sokelsen i Nord-Trondelag 1 (HUNT 1), ogy and Biostatistics, Karolinska Institutet (Drs Nils-
mass and reflux symptoms and evalu- was performed in 1984-1986 and in- son, Ye, and Lagergren), Stockholm, Sweden; De-
ate the influence of female sex hor- cluded 74 599 individuals, represent- partment of Community Medicine and General
Practice, Norwegian University of Science and Tech-
mones, we conducted a large popula- ing 88.1% of the entire adult popula- nology, Trondheim, Norway (Dr Johnsen); and De-
tion-based, cross-sectional, case- tion (from the year the patient turned partment of Medicine, Levanger Hospital, Levanger,
Norway, and HUNT Research Centre, Verdal, Nor-
control study of body mass index (BMI) 20 years or older). The second survey, way (Dr Hveem).
and hormone therapy with respect to HUNT 2, conducted in 1995-1997, in- Corresponding Author and Reprints: Magnus Nils-
son, MD, Department of Surgery, Karolinska Hospi-
the risk of reflux within a defined cluded 65 363 individuals, represent- tal, SE-171 76 Stockholm, Sweden (e-mail: magnus
cohort. ing 71.2% of the adult population. A .nilsson@ks.se).

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OBESITY, ESTROGEN, AND GASTROESOPHAGEAL REFLUX

Exposures and Definition of Reflux geal reflux disease, and the use of ques- tion (present use), diabetes mellitus
At their local health centers, all par- tionnaires to assess these symptoms is (known diagnosis), coffee use (cups per
ticipants completed extensive written well validated as a reliable measure- day), tea use (cups per day), table salt
questionnaires that covered a wide ment of the true occurrence of re- use (extra salt on regular meals), and
variety of exposures. A total of 813 flux.19-22 To further evaluate the out- dietary fiber intake (predominantly con-
variables were included in both sur- come among persons who reported sumed type of bread classified in terms
veys together. Data were collected on different levels of reflux symptoms in the of dietary fiber content) were con-
defined disorders and diseases, life- HUNT 2 survey, we conducted a sepa- trolled by introducing these variables
style factors, behavioral habits, work rate validation study. The question that individually into the model. For asthma
and employment information, use of covered reflux symptoms used in HUNT medication, antihypertensive medica-
medications, and aspects of psychoso- 2 was compared with a more exten- tion, coffee and tea use, and dietary fi-
cial well-being. Furthermore, all par- sive, validated questionnaire that cov- ber in bread, data were available from
ticipants underwent certain physical ered the frequency and duration of re- HUNT 2 only. For the other potential
examinations, including assessment of flux symptoms, the occurrence of nightly confounders, data were available from
body weight and height, and BMI18 reflux symptoms, the use and effect of both surveys. Whenever possible, data
(weight in kilograms divided by the specified antireflux medications, and the from HUNT 1 or HUNT 2 for lifetime
square of height in meters) was calcu- effect of the reflux symptoms on every- exposure were used rather than cross-
lated based on objective measure- day life. A total of 1102 outpatients at sectional HUNT 2 data to reduce the
ments. Information on other expo- general practices in Nord-Trondelag, the risk of reversed causality (ie, that the
sures of interest, including present or community hospital of Levanger in level of exposure is affected by the oc-
previous postmenopausal hormone Nord-Trondelag, and the Karolinska currence of reflux symptoms). More-
therapy, menstrual status, and previ- Hospital in Stockholm, Sweden, were in- over, nonspecific gastrointestinal symp-
ous hysterectomy, was gathered in the cluded in the validation study. toms, such as nausea (during last 12
questionnaire. months), constipation (minor or se-
Statistical Analyses vere during last 12 months), and diar-
Definition of Reflux Disease The cutoff points for BMI were prede- rhea (minor or severe during last 12
The outcome was defined as severe termined and based on the World months) were tested as outcome vari-
symptoms of reflux (eg, recurrent heart- Health Organization classification of ables in the logistic regression model
burn or regurgitation) and was as- overweight and obesity.23 A BMI value (ie, as control symptoms for reflux).
sessed in HUNT 2 only. Participants an- between 25 and 30 is defined as over- The potential interaction effect (ie,
swered a question regarding whether weight, a BMI greater than 30 as obe- effect modification) between body mass
they had experienced heartburn or re- sity, and a BMI greater than 35 as se- and hormone therapy was tested by in-
gurgitation during the past 12 months vere obesity. All persons with a BMI troducing a cross-product term, repre-
and, if so, if the symptoms were minor value less than 25 (normal) consti- senting the interaction between the 2
or severe. Among the 58 596 persons tuted the reference group in compari- variables, into the model. To avoid con-
(90%) in the HUNT 2 survey who an- sons between BMI levels. Odds ratios founding effects from pregnancy,
swered this question, 40210 (69%) re- (ORs) and their 95% confidence inter- women who reported that they were
ported that they had had no reflux vals (CIs), derived from uncondi- pregnant at the time of the HUNT 2 re-
symptoms, 15233 (26%) had had mi- tional logistic regression, were used to flux outcome assessment were ex-
nor symptoms, and 3153 (5%) had ex- assess the association between BMI and cluded from further analysis. To inves-
perienced severe symptoms of reflux. the risk of reflux.24 Linear trend of the tigate differences in the risk of reflux
The 3153 individuals who reported se- association was tested in a multivari- related to BMI between premeno-
vere symptoms were selected to repre- ate model by treating categorical vari- pausal and postmenopausal women, data
sent the case group and the 40210 per- ables as continuous. from female study participants were
sons without reflux symptoms were Potential confounding effects of age stratified according to menstrual status
selected as controls. The 15 233 per- (in 10-year intervals), tobacco smok- and then entered into the multivariate
sons with minor symptoms were ing (years of daily smoking subdi- model. The effects of weight loss and
analyzed separately, because the symp- vided into ⬍1 year, 1-10 years, and ⬎10 weight gain were assessed by entering
tom pattern in this group was consid- years), alcohol drinking (number of al- the net change in BMI between the
ered to be heterogeneous, with an in- coholic beverages consumed during the HUNT 1 and HUNT 2 surveys into the
creased risk of misclassification of the 2 weeks preceding data collection, sub- model, with adjustment for baseline
outcome, compared with the group re- divided into 0, 1-4 drinks, 5-10 drinks, BMI (ie, the BMI measured in the HUNT
porting severe symptoms. and ⬎10 drinks), asthma medication 1 survey). Informed consent was ob-
Heartburn and acid regurgitation are (months of daily use during the last 12 tained from all participants in the study.
the cardinal symptoms of gastroesopha- months), antihypertensive medica- The study was approved by the Re-
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OBESITY, ESTROGEN, AND GASTROESOPHAGEAL REFLUX

gional Committee for Medical Re- further analysis. Some general charac- mone therapy, whereas the correspond-
search Ethics, Region IV, Norway. teristics of the participants are pre- ing frequency was 9.6% among the fe-
sented in TABLE 1. The mean age of the male controls.
RESULTS participants was 52 years among the
Characteristics of 3113 cases and 48 years among the BMI and Reflux Symptoms
the Study Participants 39872 controls. The age differences be- Among men, a moderate and dose-
In total, the study evaluated 43363 sub- tween sexes were minor and not sig- dependent association between increas-
jects (20 369 men and 22 994 wom- nificant. Mean BMI was 28.1 among ing BMI and reflux symptoms was ob-
en). After excluding 378 pregnant cases and 25.8 among controls. Among served in the multivariate analysis (P
women, 22 616 women remained for female cases, 14.8% had ever used hor- for trend ⬍.001) (TABLE 2). Severely
obese men (BMI ⬎35) demonstrated a
Table 1. Characteristics of Participants With Reflux Symptoms (Cases) and Without Reflux more than 3-fold increase in risk of re-
Symptoms (Controls)* flux symptoms (OR, 3.3; 95% CI, 2.4-
Women 4.7) compared with men of normal
weight (BMI ⬍25). The correspond-
Men All Excluding Pregnant
ing analysis among severely obese (BMI
Characteristics Cases Controls Cases Controls Cases Controls ⬎35) women revealed a similarly dose-
No. 1555 18 814 1598 21 396 1558 21 058 dependent but stronger association
Age, mean (range), y 50 (19-101) 48 (19-99) 53 (20-92) 47 (19-95) 53 (20-92) 47 (19-95) compared with that observed in men
BMI (P⬍.001) (Table 2), with a more than
Mean 27.6 26.1 28.6 25.6 28.6 25.6
6-fold increase in risk of reflux symp-
Missing data, 75 (0.3) 205 (0.9) 204 (0.9) 280 (0.6)
No. (%) toms (OR, 6.3; 95% CI, 4.9-8.0) com-
Hormone therapy, No. pared with women of normal weight
Present 144 1424 (BMI ⬍25). Adjustment for age only re-
Previous 92 629 vealed no major differences compared
Never 904 14 534 with the multivariate analyses, indicat-
Missing data 5267 23 ing lack of important confounding by
*Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters using Helse- the variables that were tested (data not
undersokelsen i Nord-Trondelag 2 (HUNT 2) data.
shown).
Table 2. Association Between Obesity and Risk of Reflux Symptoms* Influence of Menopause
BMI† and Hormone Therapy
P Value
⬍25 25-30 ⬎30-35 ⬎35 for Trend The association between BMI and re-
Men flux symptoms was stronger in se-
No. of cases 317 916 271 46 verely obese premenopausal women
No. of controls 7378 9151 1926 289 than in severely obese postmeno-
OR (95% CI) 1.0 (Referent) 2.2 (2.0-2.6) 3.1 (2.6-3.6) 3.3 (2.4-4.7) ⬍.001 pausal women (P⬍.001) (Table 2) (OR,
Women 6.8; 95% CI, 4.7-9.7; and OR, 4.2; 95%
No. of cases 401 612 365 159 CI, 3.2-5.5; respectively) compared with
No. of controls 10 558 7402 2245 687 women of normal weight with the same
OR (95% CI) 1.0 (Referent) 2.0 (1.7-2.4) 3.9 (3.3-4.7) 6.3 (4.9-8.0) ⬍.001 menstrual status.
Premenopausal Women Among women who had ever (pres-
No. of cases 211 219 105 57 ently or previously) been treated with
No. of controls 6909 3579 878 232 hormone therapy, there was a strong
OR (95% CI) 1.0 (Referent) 2.0 (1.6-2.5) 3.9 (3.0-5.1) 6.8 (4.7-9.7) ⬍.001 and dose-dependent increase in the
Postmenopausal Women
risk of reflux symptoms, especially in
No. of cases 167 354 230 96
the highest BMI intervals, representing
No. of controls 3020 3335 1234 405
mainly an effect modification
OR (95% CI) 1.0 (Referent) 1.9 (1.6-2.3) 3.2 (2.6-4.0) 4.2 (3.2-5.5) ⬍.001 (P⬍.001) of the BMI effect on risk of
Abbreviations: BMI, body mass index; CI, confidence interval; OR, odds ratio. reflux symptoms (TABLE 3). The sepa-
*In the multivariate logistic regression model, adjustments were made for age, tobacco smoking, asthma medication, rate effect (independent of obesity) of
and postmenopausal hormone therapy in women. Alcohol use, antihypertensive medication, diabetes mellitus, cof-
fee and tea use, table salt use, and intake of dietary fibers in bread were tested in the model but omitted in this hormone therapy was tested among
presentation since they did not have any significant confounding effects. Pregnant women were excluded from analy-
sis. BMI data were missing in 280 participants. Menopause status data were missing in 1687 participants (7.3%).
women of normal weight (BMI ⬍25),
†BMI was calculated as weight in kilograms divided by the square of height in meters using Helseundersokelsen i Nord- and a tendency toward increased risk
Trondelag 2 (HUNT 2) data.
of reflux among women who ever
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OBESITY, ESTROGEN, AND GASTROESOPHAGEAL REFLUX

received hormone therapy was found from the estimates from multivariate pared with those with a BMI less than
but was not statistically significant models (data not shown). 25. Overweight nonpregnant women
(OR, 1.3; 95% CI, 0.9-1.8). In the (BMI 25-30) had an increased risk of
group of women treated with hor- BMI Data From the HUNT 1 Survey reflux symptoms compared with par-
mone therapy after hysterectomy (ie, and Analysis of Weight Changes ticipants with a BMI less than 25 (OR,
women without an endometrium to For the 72.8% of the individuals who 2.1; 95% CI, 1.7-2.4). In obese women
protect who hence received estrogens participated in both surveys, we re- (BMI 30-35) the risk of reflux symp-
only [without gestagens]), the risk of peated the analyses using BMI data from toms was increased compared with
reflux in normal-weight women was the first survey (ie, approximately a de- women of normal weight (OR, 3.2; 95%
increased significantly (OR, 2.3; 95% cade before the assessment of reflux CI, 2.5-4.1), and the corresponding risk
CI, 1.1-4.8) (Table 3). symptoms). A weak association be- was similarly increased in severely obese
The risk of reflux symptoms was tween increasing body mass and re- women (BMI ⬎35) (OR, 2.5; 95% CI,
increased among women with BMI flux symptoms was found among mod- 1.7-4.0). The analyses concerning ex-
greater than 35 currently using hor- erately obese men (BMI 30-35), with a posure to hormone therapy based on
mone therapy and among women in 40% increase in risk of reflux symp- data from HUNT 1 are similar to the re-
the same BMI category with previous toms (OR, 1.4; 95% CI, 1.1-1.9) com- sults from HUNT 2, although the
hormone therapy. The highest risk of pared with men of normal weight (BMI strength of the associations are some-
reflux symptoms observed in our ⬍25). Among severely obese men (BMI what diluted. Both analyses show strong
study was among women treated with ⬎35), the association was not statisti- and dose-dependent increases in risk of
estrogen-only hormone therapy (ie, cally significant (OR, 1.8; 95% CI, reflux symptoms among hormone
previous hysterectomy) with a BMI 0.9-3.5). therapy users. Similar to the results
greater than 35, although the number In women, the association was stron- from HUNT 2, the strongest associa-
of women in these groups was small ger, with a significant increase in the tion was among severely obese women
(Table 3). In general, the age-adjusted risk of reflux symptoms in all 3 catego- (BMI ⬎35) taking estrogen-only hor-
estimates did not differ importantly ries of overweight and obesity com- mone therapy.

Table 3. Risk of Reflux Symptoms Among Women in Different BMI Categories, Including Status of HT*
BMI†
All BMI
⬍25 25-30 ⬎30-35 ⬎35 Categories
Never HT
No. of cases 253 347 200 92 892
No. of controls 7613 4941 1458 441 14 453
OR (95% CI) 1.0 (Referent‡) 2.0 (1.7-2.4) 3.8 (3.1-4.6) 5.5 (4.2-7.2) 1.0 (Referent§)
Ever HT
No. of cases 45 101 58 32 236
No. of controls 967 826 198 55 2046
OR (95% CI) 1.3 (0.9-1.8) 3.3 (2.5-4.2) 7.9 (5.7-11.0) 16.0 (10.0-25.6) 1.7 (1.5-2.0)
Present HT
No. of cases 32 57 34 21 144
No. of controls 681 570 128 41 1420
OR (95% CI) 1.3 (0.9-1.9) 2.7 (1.9-3.6) 7.4 (4.9-11.1) 14.4 (8.2-25.1) 1.5 (1.3-1.9)
Previous HT
No. of cases 13 44 24 11 92
No of controls 286 256 70 14 626
OR (95% CI) 1.3 (0.7-2.3) 4.5 (3.2-6.5) 8.7 (5.3-14.3) 20.2 (8.9-46.1) 2.1 (1.7-2.7)
Ever HT, posthysterectomy㛳
No. of cases 8 15 10 8 41
No. of controls 103 117 38 7 265
OR (95% CI) 2.3 (1.1-4.8) 3.2 (1.8-5.6) 6.8 (3.3-14.0) 33.3 (11.8-94.4) 2.1 (1.4-2.9)
Abbreviations: BMI, body mass index; CI, confidence interval; HT, hormone therapy; OR, odds ratio.
*In the multivariate logistic regression model, adjustments were made for age, tobacco smoking, and asthma medication. Alcohol use, antihypertensive medication, diabetes melli-
tus, coffee and tea use, table salt use, and intake of dietary fibers in bread were tested in the model but omitted in this presentation since they did not have any significant
confounding effects. The far right column was, in addition to the adjustments mentioned herein, also adjusted to BMI. P value for interaction term between BMI and HT never-ever
status was ⬍.001.
†BMI was calculated as weight in kilograms divided by the square of height in meters using Helseundersokelsen i Nord-Trondelag 2 (HUNT 2) data.
‡Referent for all ORs presented in the table except for last column (concerning all BMI categories).
§Referent for ORs presented in the last column.
㛳Posthysterectomy status indicates HT with estrogens only (no gestagens).

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OBESITY, ESTROGEN, AND GASTROESOPHAGEAL REFLUX

Table 4. Association of Weight Change Between the 1984-1986 and 1995-1997 Surveys and Risk of Gastroesophageal Reflux Symptoms*
Weight Loss, BMI Units† Weight Gain, BMI Units†

No Weight Change 0.5-1.5 ⬎1.5-3.5 ⬎3.5 0.5-1.5 ⬎1.5-3.5 ⬎3.5


No. of cases 290 98 81 69 399 805 636
No. of controls 4628 1684 1097 928 5792 9287 4394
OR (95% CI) 1.0 (Referent) 0.8 (0.7-1.1) 0.9 (0.7-1.2) 0.6 (0.4-0.9) 1.2 (1.0-1.4) 1.6 (1.4-1.8) 2.7 (2.3-3.2)
Abbreviations: BMI, body mass index; CI, confidence interval; OR, odds ratio.
*In the multivariate logistic regression model, adjustments were made for baseline (1984-1986) BMI, age, and sex.
†BMI was calculated as weight in kilograms divided by the square of height in meters using Helseundersokelsen i Nord-Trondelag 1 (HUNT 1) and HUNT 2 data.

Participants in both surveys were (9.6%) reported severe reflux symp- that hormone therapy is an effect modi-
evaluated for the association between toms of heartburn or regurgitation dur- fier of the association between body
weight change, identified during the ing the past 12 months. In this group mass and reflux. The study also re-
time interval between the 2 surveys, and (which corresponded to our case group veals that weight loss is associated with
risk of reflux (TABLE 4). The risk of re- with severe reflux symptoms), 72% re- reduced risk of reflux symptoms.
flux was dose-dependently greater with ported heartburn or regurgitation that Strengths of the study include the
increasing net BMI gain. In the group occurred at least daily or were taking population-based design with high par-
that gained more than 3.5 BMI units, antireflux medication daily, 23% had ticipation rates, reducing the risk of se-
the risk of reflux symptoms was in- heartburn or regurgitation one or sev- lection bias. The large sample size de-
creased (OR, 2.7; 95% CI, 2.3-3.2) com- eral times per week, and 5% had symp- creased the risk of chance findings and
pared with persons with stable BMI, toms less frequently than once weekly. facilitated extensive subgroup analy-
whereas the risk of reflux symptoms Hence, 95% of the group correspond- ses. The wide range of exposure data
was decreased among persons who lost ing to our case group had experienced made it possible to adjust for potential
more than 3.5 BMI units (OR, 0.6; 95% reflux symptoms at least once per week. confounding variables.
CI, 0.4-0.9). Among the 280 participants (25.4%) A weakness of the study is that re-
who reported minor symptoms of heart- flux was assessed only in the HUNT 2
Additional Analyses burn or acid regurgitation during the survey, which prevented us from as-
Sex-stratified analyses of the relation be- past 12 months (corresponding to sessing new cases of reflux that oc-
tween BMI and reflux symptoms and the group excluded from the main curred between the 2 surveys (ie, truly
analyses of the influence of hormone analyses), 15% had daily symptoms or incident cases). This cross-sectional de-
therapy were also performed using the had used antireflux medication on a sign theoretically opens the field for re-
15 233 study participants who re- daily basis, 10% had symptoms at least versed causality. However, the consis-
ported minor reflux symptoms (omit- once per week, and 75% had symp- tently strong and dose-dependent
ted from the main analyses because of toms less frequently than once a week. associations among body mass, hor-
suspected heterogeneity of symp- Among those reporting severe reflux mone therapy, and reflux symptoms, to-
toms) as the case group, instead of per- symptoms (corresponding to the case gether with the biological implausibil-
sons who reported severe symptoms. group in the main analyses), the speci- ity of reflux causing obesity and the use
The results of these analyses were simi- ficity for symptoms that occurred at of hormone therapy, provide reassur-
lar, except with lower point estimates least once per week was 99.5% and the ance against reversed causality.
and weaker trends, compared with the corresponding sensitivity was 58.3%. Another possible weakness is that re-
analyses using severe reflux outcome flux was assessed by reflux symptoms
for case classification (data not shown). COMMENT only, with a potential risk of misclas-
In analyses of the association between This study demonstrates a strong and sification of the outcome. This is of less
BMI and hormone therapy and con- dose-dependent association between in- concern, however, because the symp-
trol symptoms for reflux, the risks of creasing body mass and symptomatic toms used for outcome assessment,
nausea, constipation, and diarrhea were reflux in women and a moderate asso- heartburn and regurgitation, are well
not significantly affected by either varia- ciation among men. The association validated as representing true reflux dis-
tions in BMI or use of hormone therapy was stronger among premenopausal ease.19-22 Furthermore, we validated our
(data not shown). women. There was a weak association question concerning reflux symptoms
between hormone therapy and reflux against a more extensive, previously
Validation Study in women of normal weight. With in- used reflux symptom questionnaire.11
of Reflux Symptoms creasing body mass, the association be- The usual definition of reflux disease,
In the validation study, which com- tween hormone therapy and reflux be- based on symptom evaluation, is a fre-
prises a total of 1102 participants, 103 came increasingly stronger, suggesting quency of symptoms of once per week
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OBESITY, ESTROGEN, AND GASTROESOPHAGEAL REFLUX

or more. In the validation study, 95% based study examining the relation be- significant effect of hormone therapy on
of the group corresponding to our case tween body mass and endoscopically reflux risk among normal-weight
group had reflux symptoms that ful- verified that reflux esophagitis demon- women (BMI ⬍25) and the strongest
filled this definition, confirming our strated a strong and dose-dependent as- effect among severely obese women
outcome assessment to have high speci- sociation between increasing body mass (BMI ⬎35) suggests that the hormone
ficity (99.5%). Moreover, any misclas- and reflux esophagitis in women, aug- therapy effect is mediated by estro-
sification of reflux would dilute the as- mented by hormone therapy, whereas gens and not gestagens.
sociations and could not explain the no association was found in men.17 The Stratification between present and
positive associations. The fact that the difference between our previous study previous use of hormone therapy re-
analyses of the participants who re- and the present study, concerning the veals a stronger effect modification of the
ported minor reflux symptoms re- association among men, might be ex- BMI effect on reflux symptoms among
vealed similar but weaker patterns of plained by lack of precision in the pre- previous hormone therapy users than
associations compared with the main vious study. among present users. This finding might
analyses of persons with severe reflux The findings of our previous re- be explained by selection bias in that in-
symptoms further supports the cred- port17 led us to formulate the hypoth- dividuals who had reflux symptoms be-
ibility of our results. esis that estrogens might be involved fore hormone therapy might have had
All analyses used BMI data from the in the pathogenesis of reflux disease exacerbation of symptoms during
HUNT 1 and HUNT 2 surveys. Re- among obese women. The concentra- present hormone therapy and there-
sults were similar, revealing the same tion of sex hormone–binding globulin fore may have stopped treatment. Such
patterns of associations, but in data is lower among obese women than nor- bias does not affect the “ever hormone
from HUNT 1 the point estimates were mal-weight women, resulting in a larger therapy” group as a whole, because it
generally weaker. This difference be- proportion of unbound, active estra- only affects the distribution between the
tween the surveys is probably because diol. Moreover, obese women also have present and previous groups. The find-
the relation between BMI and reflux is increased synthesis of estrone in the ing that weight loss, manifested as a re-
more dependent on current than pre- fatty tissue.27-29 Reflux symptoms dur- duction in BMI between the 2 surveys,
vious BMI. In this respect, current, ing pregnancy usually commence dur- was associated with a significantly de-
cross-sectional BMI data may be more ing the first trimester30-33 because of a creased risk of reflux symptoms when
relevant to reflux outcome than previ- predominantly hormonally mediated compared with individuals with stable
ous BMI. pathogenesis, and women taking se- BMI supports the role of weight loss in
Previous scientific evidence concern- quential oral contraceptives have re- the clinical management of patients with
ing the relation between body mass and duced lower esophageal sphincter tone, reflux symptoms.
reflux is ambiguous. Three population- facilitating reflux.34 Moreover, estro- In conclusion, our large, population-
based, epidemiological studies9,25,26 have gen increases nitric oxide synthesis, the based study provides evidence of a
evaluated the association between body predominant relaxing transmitter sub- dose-dependent association between in-
mass and reflux symptoms. In our pre- stance of the lower esophageal sphinc- creasing body mass and the risk of gas-
vious cross-sectional study of reflux ter,35-39 resulting in smooth muscle troesophageal reflux symptoms. Hor-
symptoms,25 we found no association. relaxation in animal models40 and hu- mone therapy was a weak risk factor for
In light of the data presented herein, mans.41 Therefore, we hypothesize that reflux symptoms but increased the
that might be explained by the low per- the association between estrogens and strength of the association between body
centage (17%) of women included and reflux might be conveyed by a nitric ox- mass and reflux, an effect that was more
that BMI was assessed retrospectively ide–mediated reduction of smooth pronounced with estrogen-only treat-
at least 20 years before the collection muscle tone in the lower esophageal ment. Weight reduction is associated
of data. Previous (as opposed to pres- sphincter. Findings from a random- with reduced risk of reflux.
ent) exposure to high BMI levels di- ized, double-blind, crossover, placebo-
Author Contributions: Drs Nilsson, Ye, and Lager-
luted the results in the present study, controlled study42 showing that nitric gren had full access to all the data in the study and
particularly among men. This could ex- oxide synthesis increased with increas- take responsibility for the integrity of the data and the
accuracy of the data analysis.
plain the negative result in our previ- ing BMI in postmenopausal women Study concept and design: Nilsson, Johnsen, Ye,
ous study.25 In a cross-sectional study, with estrogen treatment support this Hveem, Lagergren.
Locke et al9 identified a moderate as- hypothesis. Our finding that hormone Acquisition of data: Nilsson, Johnsen, Hveem.
Analysis and interpretation of data: Nilsson, Johnsen,
sociation, but no separate analysis of therapy increases the risk of reflux with Ye, Hveem, Lagergren.
men and women was presented. In a co- increasing degrees of obesity supports Drafting of the manuscript: Nilsson, Johnsen, Hveem,
Lagergren.
hort design, Ruhl and Everhart26 dem- a role of female sex hormones in the eti- Critical revision of the manuscript for important in-
onstrated a weak association between ology of reflux disease. Furthermore, tellectual content: Nilsson, Johnsen, Ye, Hveem,
Lagergren.
BMI and hospitalization for reflux di- the finding that stratification for estro- Statistical expertise: Nilsson, Johnsen, Ye.
agnoses. Our previous population- gen-only hormone therapy is the only Obtained funding: Nilsson, Lagergren.

©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, July 2, 2003—Vol 290, No. 1 71

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OBESITY, ESTROGEN, AND GASTROESOPHAGEAL REFLUX

Administrative, technical, or material support: Nils- Symptomatic gastroesophageal reflux as a risk factor serum binding of oestradiol: relationship to cancer.
son, Lagergren. for esophageal adenocarcinoma. N Engl J Med. 1999; J Endocrinol. 1981;89(suppl):119P-129P.
Study supervision: Johnsen, Ye, Hveem, Lagergren. 340:825-831. 28. Hautanen A. Synthesis and regulation of sex hor-
Funding/Support: AstraZeneca, Sodertalje, Swe- 12. Ye W, Chow WH, Lagergren J, Yin L, Nyren O. mone-binding globulin in obesity. Int J Obes Relat
den, and the Swedish Medical Society, Stockholm, Swe- Risk of adenocarcinomas of the esophagus and gas- Metab Disord. 2000;24(suppl 2):S64-S70.
den, provided financial support. tric cardia in patients with gastroesophageal reflux dis- 29. Bray GA. Obesity and reproduction. Hum Re-
Acknowledgment: We thank the Norwegian Insti- eases and after antireflux surgery. Gastroenterology. prod. 1997;12(suppl 1):26-32.
tute of Public Health and the HUNT Research Cen- 2001;121:1286-1293. 30. Castro Lde P. Reflux esophagitis as the cause of
tre, Verdal, Norway for performing the 2 HUNT sur- 13. Chow WH, Blot WJ, Vaughan TL, et al. Body mass heartburn in pregnancy. Am J Obstet Gynecol. 1967;
veys and the HUNT Research Centre, Verdal, Norway, index and risk of adenocarcinomas of the esophagus and 98:1-10.
and the medical faculty of the Norwegian University gastric cardia. J Natl Cancer Inst. 1998;90:150-155. 31. Van Thiel DH, Gavaler JS, Joshi SN, Sara RK,
of Science and Technology, Trondheim, Norway, for 14. Lagergren J, Bergstrom R, Nyren O. Association Stremple J. Heartburn of pregnancy. Gastroenterol-
allowing access to the database. between body mass and adenocarcinoma of the ogy. 1977;72(4 pt 1):666-668.
esophagus and gastric cardia. Ann Intern Med. 1999; 32. Day JP, Richter JE. Medical and surgical condi-
130:883-890. tions predisposing to gastroesophageal reflux dis-
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