Hormonal Influences on the Gastrointestinal Tract and Irritable ...

TREATMENT OF IRRITABLE BOWEL SYNDROME, SERIES #7
Kevin W. Olden, M.D., Series Editor
Hormonal Influences on the
Gastrointestinal Tract and
Irritable Bowel Syndrome
by Sharmela Thevarajah, Margaret Polaneczky, Ellen J. Scherl and Christine L. Frissora
Irritable bowel syndrome (IBS) is a common disorder of gastrointestinal (GI) function
that affects more women than men in most Western countries. Often among women,
symptoms of IBS appear to be related to hormone status (e.g., menstruating, pregnant,
menopausal, taking oral contraceptives or hormone replacement therapy). In some
women, symptoms wax and wane in concert with their menstrual cycle. One potential
explanation for the observed variability in IBS symptoms is that sex hormones affect
GI motility and function. The purpose of this review is to describe the growing body of
evidence that supports a role for sex hormones in the pathophysiology and/or symptom
presentation of IBS.
IBS: CLINICAL SYMPTOMS
IBS: EPIDEMIOLOGY
IBS is a disorder in which abdominal pain or dis- Reported prevalence rates range from 3% to 20%, with
comfort is a primary symptom. It is accompanied by
most estimates concentrated between 10% and 15%
a change in bowel habit and abnormal stool fre-
(2). Although IBS affects individuals of all races and
quency (defined as >3 bowel movements per day
both sexes, women are more commonly affected than
[diarrhea] or <3 bowel movements per week [consti-
men in Western nations at a ratio of approximately 2:1,
pation]) (1). IBS patients also commonly report hard
a phenomenon that has yet to be completely explained
or loose/watery stools, a feeling of incomplete evacu-
(3–6). In North American studies, the female predom-
ation after bowel movement, bloating and/or abdomi-
inance is greater among individuals who seek medical
nal distension, and the passage of mucus.
attention (3–4:1) as compared with those who do not
(<2:1) (7); however, it is unclear if this reflects under-
reporting in men or a true predominance in women.
Sharmela Thevarajah, M.D., Resident; Margaret
Sex differences in presentation of symptoms have been
Polaneczky, M.D., Associate Professor of Clinical
described, including more IBS with diarrhea among
Medicine, Ellen J. Scherl, M.D., Associate Professor
men and more IBS with constipation and bloating
of Clinical Medicine; and Christine L. Frissora, M.D.,
among women (8). IBS is one of the most common
FACP, FACG, Associate Professor of Medicine; The
disorders seen in the primary care setting. Women
Weill Medical College of Cornell University, New York,
often present to their gynecologist first, as this may be
NY.
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Hormonal Influences on the Gastrointestinal Tract and IBS
TREATMENT OF IRRITABLE BOWEL SYNDROME, SERIES #7
the only physician they ever see. IBS accounts for 12%
their menstrual cycles and that flares occur in the per-
of diagnoses in the primary care setting (5) and is
imenstrual and perimenopausal phases (24–26). Alter-
responsible for 30% to 50% of referrals to gastroen-
ations in rectal sensitivity (27) (increased during
terologists (9).
menses) and GI transit, which is increased during the
follicular phase compared with the luteal phase
(28,29), also have been reported. Other studies showed
Coexistence of IBS and Other GI Disorders
that menses (a time of declining/minimal ovarian hor-
IBS often coexists with other GI disorders, both func-
mone levels) was associated with looser stools com-
tional (e.g., dyspepsia, chronic constipation) and
pared with the follicular and luteal phases (30,31). Fur-
organic (e.g., celiac disease, gastroesophageal reflux
thermore, IBS is diagnosed more often in women with
disease, inflammatory bowel disease [IBD]) (10). Fur-
dysmenorrhea than in those who cycle normally (32).
thermore, many patients with IBD are diagnosed ini-
It also has been proposed that hormonal disparities and
tially with IBS (11,12). However, once a diagnosis of
fluctuations may be responsible, at least in part, for
IBD is established, comorbid IBS tends to be under-
differences in prevalence and symptom presentation
diagnosed and undertreated. Studies have shown that
among women and between women and men (23,33).
more than 40% to 57% of Crohn’s disease patients and
Changes in hormone status associated with preg-
one third of ulcerative colitis patients who were in
nancy or menopause also may influence symptoms.
remission had comorbid IBS (11,13). IBS can con-
During pregnancy, a time during which estrogen and
tribute to symptoms of IBD, especially in quiescent
progesterone levels are high, GI symptoms increase
disease, if the symptoms of IBS are mistaken for an
and intestinal transit decreases (28). Reports of
IBD flare. This results in IBD overtreatment and IBS
abdominal bloating increase after menopause, primar-
undertreatment.
ily among women who are not receiving hormone
replacement therapy (HRT) (34).
These thoughts are all intriguing, but exactly how
IBS: IMPACT
hormonal factors influence IBS remains unclear. There
IBS symptoms affect the lives of patients and their
also exists the question as to whether hormone differ-
families. Several studies have reported negative effects
ences are associated with specific symptoms (e.g.,
on quality of life (14–16), as well as on work-related
bloating) or with the wider spectrum of IBS symptoms.
and social activities (17–20). The direct costs associ-
ated with IBS are estimated to be as high as $10 billion
per year, and indirect costs as high as $20 billion annu-
Cycling Female Sex Hormones
ally (excluding prescription and over-the-counter drug
During the reproductive years in women, the normal
costs) (21,22).
menstrual cycle is characterized by predictable and
cyclic changes in estrogen and progesterone levels
(Figure 1) that may influence bowel activity. In the fol-
IBS: A ROLE FOR HORMONES?
licular phase, or immediate postmenstrual phase, estro-
A variety of observations support the hypothesis that
gen predominates and progesterone levels are low.
female sex hormones, and fluctuations thereof, may
Responding to follicle-stimulating hormone (FSH)
have an impact on IBS, including the simple fact that
secretion from the pituitary gland, the granulose cells
more women than men experience IBS. Men with IBS
of the ovarian follicles secrete gradually increasing lev-
have lower serum luteinizing hormone (LH) than men
els of estradiol, which peak around day 13, inducing the
without IBS, suggesting a potential protective effect of
pituitary LH surge that heralds ovulation. The intra-
this hormone (23).
ovarian events leading to ovulation involve estrogen-
Additional evidence comes from reports of men-
induced production of prostaglandins, primarily
strual cycle-related symptom fluctuations. Many
prostaglandin F2α (PGF2α), PGE2, and prostacyclin,
women with IBS report that symptoms fluctuate with
all of which are measurable in follicular fluid. The
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TREATMENT OF IRRITABLE BOWEL SYNDROME, SERIES #7
Figure 1. Hormonal, ovarian, endometrial, and basal body temperature changes and relationships throughout the normal men-
strual cycle. (Reprinted with permission from Carr BR, Bradshaw KD. Disorders of the ovary and female reproductive tract. In:
Braunwald E, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 15th ed. New York, NY: McGraw-Hill;
2001:2154-2172.) P = progesterone; E2 = estrogen; LH = luteinizing hormone; FSH = follicle-stimulating hormone.
release of this prostaglandin-rich fluid is thought to
prostaglandins, cytokines, and other lytic enzymes.
cause the pain that sometimes occurs with ovulation.
The endometrium also produces prostaglandins,
After ovulation, the corpus luteum secretes both
the predominant one being PGF2α, with lower levels
estrogen and progesterone. Progesterone levels peak 8 to
of PGE2 also produced. PGF2α release leads to
9 days after ovulation. Rising luteal phase estrogen levels
smooth muscle contraction, ischemia, and sensitiza-
are thought to induce luteolysis, mediated by PGF2α via
tion of nerve endings; PGE2 is a smooth muscle relax-
endoethelin-1 and tumor necrosis factor-alpha (TNF-α)
ant. Other molecules produced include endothelin-1,
in the corpus luteum. With the decline of the corpus
metalloproteinases, TNF-α, and cytokines. Endome-
luteum, estrogen and progesterone levels drop, triggering
trial prostaglandin levels are three times higher in the
the events in the uterine endometrium that lead to men-
luteal than in the follicular phase. Levels are highest
struation. These events involve complex interplay of
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Hormonal Influences on the Gastrointestinal Tract and IBS
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(continued from page 64)
during menstruation, when most PGF2α release from
these local chemical messengers play a vital role in
the endometrium occurs. Women who experience dys-
numerous functions, maintaining homeostasis. In the
menorrhea have greater endometrial prostaglandin lev-
gut, prostaglandins, particularly those of the E type,
els than do asymptomatic women, and they have
are implicated in the proper maintenance of mucosal
higher levels of PGF2α in their menstrual fluid (35).
blood flow, stimulation of the mucous secretion lining
Prostaglandin production has been thought to influ-
the gut surface, stimulation of GI motility, and secre-
ence diarrhea associated with menses by inhibiting
tion of bicarbonate to help neutralize acids (40).
transepithelial ion transport in the small intestine.
Altered prostaglandin levels can result in abdominal
The perimenopausal transition is characterized by
pain, colonic contractions, and diarrhea.
its unpredictability and by wide fluctuations in estrogen
In women who experience dysmenorrhea, there is
levels throughout the cycle. Levels of estradiol may be
a significant increase in the uterine expression of
markedly increased because of ovarian follicular
PGF2α (41), which is the likely explanation for the
response to elevated FSH levels. There may be a rela-
increased pain associated with their menstruation.
tive progesterone deficiency due to lack of ovulation or
Nonsteroidal anti-inflammatory drugs (NSAIDs) are
luteal phase deficiencies as the quality of the ovarian
the most common treatment modality; however, use of
follicles diminish. This estrogen-dominant environ-
these agents can lead to GI depletion of prostaglandins
ment can occur even in the presence of hot flushes, and
(42). Medications to reduce acid production, neutralize
leads to irritability, breast tenderness, and bloating.
the acid, or coat the lining of the GI tract often are used
Bloating can occur when estrogen induces nitric oxide
as adjunctive therapies in patients taking NSAIDs for
synthetase, which relaxes the smooth muscle in the gut.
chronic conditions. Misoprostol (Cytotec®) is a syn-
This nitrogen oxide synthetase induced smooth muscle
thetic PGE1 analog that stimulates secretion of gastric
relaxation clinically results in bloating.
mucus and production of bicarbonate; prostaglandins
provide a protective effect for patients taking medica-
tions that inhibit GI COX enzymes. However, miso-
Potential Hormonal Influences on the GI Tract
prostol also invokes prostaglandin effects in the uterus
Estrogen, TNF-α, endothelin, and prostaglandins also
(uterine muscle contractions) that can lead to compli-
exert effects on the GI tract. Estrogen receptors are
cations in pregnancy, including premature labor and
found throughout the GI tract (36) in components of
abortion (Pfizer, data on file). Therefore, misoprostol
the pelvic floor (37) and in sensory neurons of the dor-
should not be used in women known or thought to be
sal root ganglia (38), suggesting that female sex hor-
pregnant. Alternatively, medications that inhibit pro-
mones may play a role in IBS symptomatology. Stud-
duction of gastric acid or coat the lining of the GI tract
ies have shown that estrogen and progesterone exert
can provide protection to patients on long-term
many effects on the GI tract (36). These hormones
NSAID therapy.
have a relaxing effect on the lower esophageal sphinc-
ter and decrease colonic transit. TNF-α induces
inflammation, delays gastric emptying, increases
Clinical Evidence Linking
colonic transit time, and induces flow of fluid into GI
Female Hormones to Bowel Function
tissues. Endothelin has potent effects on GI smooth
It has been postulated that cycling female sex hormones
muscle, leading to contraction of the esophagus, stom-
are related to changes in bowel habits. In the 1980s,
ach, and intestines, and has a modulatory effect on GI
alterations in GI transit (increased during the follicular
motility (39). It also is a potent stimulator of gallblad-
phase compared with the luteal phase) (28,29) were
der motility, stimulates sphincter of Oddi motility, and
reported. Heitkemper and colleagues (1988) reported
decreases trans-sphincteric flow (39).
that menses (a time of declining/minimal ovarian hor-
Prostaglandins are a diverse set of molecules
mone levels) was associated with looser stools com-
derived from the modification of essential fatty acids.
pared with the follicular and luteal phases (30). In con-
When present at the proper time, place, and amount,
trast, high levels of estradiol and progesterone during
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Hormonal Influences on the Gastrointestinal Tract and IBS
TREATMENT OF IRRITABLE BOWEL SYNDROME, SERIES #7
the luteal phase were reported to be associated with
transit, it did not appear to affect rectal motility or sen-
delayed GI transit (28), which may account for firmer
sitivity in 20 healthy women (31). However, in their
stools during this phase of the menstrual cycle. Healthy
later study of 29 female patients with IBS, they found
women describe changes in bowel habits during their
that, in contrast to healthy women, women with IBS
menstrual cycle, and women with IBD experience an
had increasing levels of rectal sensitivity at the time of
even higher prevalence of GI symptom–related fluctu-
menses compared with all other phases of the men-
ations. A suggestive physiologic mechanism may be
strual cycle (27). This increase in rectal sensitivity was
the increased intestinal prostaglandin production that
not related to changes in rectal compliance or wall ten-
causes contraction of colonic smooth muscle or the
sion. The authors considered the possibility that,
increased intestinal secretions related to variation in
because acute episodes of diarrhea are associated with
progesterone levels (43).
increases in rectal sensitivity in women (but not men)
Whereas other early clinical studies failed to show
and IBS patients are more susceptible to sensitizing
a relationship between female hormones and bowel
events, this may be an explanation for the increased
function, a growing body of evidence suggests that
rectal sensitivity noted in IBS patients at menses. The
such a relationship exists. Kamm and colleagues
authors also posed a second explanation—that
(1989) reported that, under normal physiologic condi-
prostaglandin release during menses may play a role in
tions, sex hormones have no major effect on bowel
rectal sensitivity. Because the GI system of IBS
function (44). They based this conclusion on their
patients may already be sensitive, the release of
observation that mean transit times (whole gut transit)
prostaglandins, known to induce afferent nerve sensiti-
and stool weights were not significantly different dur-
zation, may be enough to trigger a further increase in
ing the follicular versus the luteal phase of the men-
this sensitivity. The authors also noted that anxiety and
strual cycle in 18 healthy women. Furthermore, self-
depression remained unaltered throughout the men-
reported bowel frequency and stool consistency were
strual cycle—a finding that was consistent with past
not significantly different during the menstrual, follic-
studies demonstrating that psychological traits are not
ular, or luteal phase.
associated with perimenstrual bowel-related symp-
However, Wald and colleagues (1981) described
toms (25,45). Similar to past studies, Houghton, et al
different findings in a more recent report of their study
(2002) reported a significant worsening of abdominal
of hormone levels and GI transit times in 15 normally
pain and bloating and more frequent bowel movements
menstruating women (28). They measured serum
during menses (27). They also reported firmer consis-
estradiol and progesterone levels and GI transit times
tency of the stool during the luteal phase. Houghton
at 2 points during the menstrual cycle, once in the fol-
and colleagues concluded that women with IBS are
licular phase (days 8–10) when progesterone levels are
predisposed to fluctuations in visceral sensitivity asso-
low, and once in the luteal phase (days 18–20) when
ciated with the menstrual cycle.
progesterone levels are elevated. GI transit was deter-
Further evidence for a role of female hormones in
mined via monitoring of breath hydrogen levels at
bowel function comes from studies conducted in
10-minute intervals after the ingestion of lactulose (to
women in the perimenopausal and postmenopausal
determine time from ingestion until delivery to the
states. Triadafilopoulos and colleagues (1998)
cecum). The authors reported that progesterone levels
prospectively studied 228 women (170 post-
did increase during the luteal phase, as expected, and
menopausal and 58 premenopausal) who presented for
that GI transit time was significantly (P < 0.01) pro-
evaluation at a primary care practice facility; investi-
longed during this phase as compared with the follicu-
gators used a previously validated GI symptom ques-
lar phase. Based on these findings, they concluded that
tionnaire designed to evaluate symptoms consistent
the menstrual cycle plays a role in determining GI
with IBS (46). (At the time of their participation in the
transit time in normally menstruating women.
study, none of these women presented for evaluation
Jackson and colleagues (1994) reported that,
of abdominal or genitourinary symptoms.) The authors
although the phase of the menstrual cycle may affect
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(continued from page 68)
found that 38% of postmenopausal women reported
identified via history and physical examination, was
altered bowel function, as opposed to 14% of pre-
present in 19.8% of patients. Functional bowel disor-
menopausal women (P < 0.001). However, the two
der, defined as abdominal pain with altered bowel
groups did not differ in occurrence of abdominal pain,
function, was diagnosed in 61% of patients with dys-
diarrhea, and constipation, which are symptoms sug-
menorrhea compared with 20% of patients without
gestive of IBS. The prevalence of IBS-type complaints
dysmenorrhea (P < 0.05). A relationship between
peaked at a high of 36% among the 40- to 49-year-old
bowel symptoms (bowel symptom inventory [25]) and
age group. Laxative usage, gaseousness/excessive flat-
menstrual symptoms (Moos’ Menstrual Distress Ques-
ulence, and heartburn/acid regurgitation were also
tionnaire [47]) was evident throughout the study and
more common among postmenopausal women than
was independent of psychological differences (i.e.,
premenopausal women, with prevalence rates of 9.4%
neuroticism, as measured using the NEO Personality
vs 3.4%, 48% vs 27%, and 34% vs 18%, respectively.
Inventory [48]). Prostaglandin levels were measured in
Interestingly, estrogen use did not affect GI symptoms
vaginal dialysate on the first day of menses in a subset
in either group. The authors concluded that there is a
of subjects (n = 44) and were elevated in women with
high prevalence of altered bowel function and IBS-like
dysmenorrhea regardless of bowel symptoms. The
GI complaints among women in the perimenopausal
authors concluded that the observed relationship
and postmenopausal periods.
between menstrual and bowel symptoms and the over-
Copas and colleagues (2001) attempted to explain
lap in diagnoses of dysmenorrhea and functional
various pelvic floor disorders, including fecal inconti-
bowel disease were evidence of a common physiologic
nence, by evaluating hormone receptor expression in the
basis for many of the symptoms characteristic of these
levator ani muscle and fascia, which make up the pelvic
disorders.
floor (37). The study looked at 55 women undergoing
Data from an earlier study conducted by Heitkem-
surgery for asymptomatic gynecological (n = 10) or
per and colleagues (1992) also suggested a relationship
symptomatic urogynecological (n = 45) conditions.
between symptoms and the menstrual cycle in women
Twenty-four of the women, all of whom were sympto-
with FBD. In this study, patterns of GI symptoms and
matic, were receiving HRT. Estrogen receptor (ER)
select mood and somatic symptoms were evaluated
expression in the levator ani fascia was increased
across two menstrual cycles in a group of 19 women
significantly (P < 0.03) in symptomatic women not
with and 39 women without FBD (45). Each day,
receiving HRT when compared with asymptomatic,
women rated their GI, perimenstrual, and other symp-
age-matched women, but was significantly lower
toms and recorded stool frequency and consistency.
(P < 0.001) in symptomatic women receiving long-term
Serum estrogen and progesterone concentrations were
HRT when compared with age-matched women without
measured during menses and during the follicular and
HRT. The authors concluded that ER expression is sig-
luteal phases. The group with FBD rated stomach pain,
nificantly higher in symptomatic women when com-
nausea, and diarrhea higher at menses than did the
pared with asymptomatic women of the same age, but
group without FBD. Stomach pain was higher during
that long-term use of estrogen leads to a significant
the remaining days as well. The group with FBD also
decrease in ER expression. This may explain why long-
reported higher levels of perimenstrual symptoms on
term HRT does not appear to favorably impact pelvic
six of the eight Menstrual Distress Questionnaire-T
floor disorders and suggests that down-regulation of
subscales (P < 0.01). Interestingly, the authors reported
receptors or relative tissue dominance of the progestin
no significant group differences in ovarian hormone
component of therapy is the cause.
levels or stool consistency/frequency scores. This is in
Crowell and colleagues (1994) noted an overlap in
agreement with what is known about premenstrual syn-
diagnoses of dysmenorrhea and functional bowel dis-
drome—those who suffer from this condition do not
orders (FBDs) in their 12-month evaluation of 383
exhibit differences in ovarian hormone levels compared
women (aged 20 to 40 years) who presented to a sin-
with healthy individuals; rather, they differ in their
gle Planned Parenthood clinic (32). Dysmenorrhea, as
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(continued from page 70)
responses to normal hormonal fluctuations, in this case,
argued against a significant role for menstrual cycle-
in the central nervous system and other target organs.
related hormone fluctuations in causing symptom differ-
GI symptoms also appear to be influenced by the
ences. First, when premenopausal women with IBS were
menstrual cycle in women with IBS. Whitehead, et al
compared with postmenopausal women, there was no
(1990) assessed differences in GI complaints between
significant difference in bowel habit predominance (i.e.,
female patients at a family planning clinic and women
constipation, diarrhea, or alternating constipation and
with IBS or FBD who were referred to a gastroen-
diarrhea). Furthermore, when postmenopausal women
terology clinic (25). (Criteria for diagnosis of IBS
were compared with a group of age-matched men, the
were abdominal pain plus altered bowel habits, but
same difference as in the total male and female samples
restrictive criteria for IBS were not satisfied.) All
was observed, highlighting the concept that menstrual
patients were asked whether gas, diarrhea, or constipa-
status does not affect bowel habit predominance. The
tion occurred during menstruation. One third of
authors did report, however, that premenstrual women
patients who denied symptoms of IBS or FBD reported
were two times more likely to complain of nausea than
that menstruation was associated with one or more
were postmenopausal women with IBS.
bowel symptoms; however, patients with IBS were
significantly more likely to experience exacerbations
of each of these bowel symptoms, especially increased
Hormonal Influences on Serotonin Activity?
bowel gas. The authors noted also that reports of
Serotonin (5-hydroxtryptamine [5-HT]), which is pro-
bowel symptoms during menstruation were not associ-
duced mainly by and stored in enterochromaffin cells in
ated with psychological traits or with menses-related
the GI tract, is vital to normal gut function. It is respon-
changes in mood.
sible for initiating and maintaining peristalsis, mediat-
Similarly, Heitkemper, et al (2003) reported in
ing secretion in the GI tract, and modulating the sensa-
another study that women with IBS had higher symp-
tion of pain (51,52). Recent research has uncovered a
tom severity, in terms of somatic, psychological, and
potential role for abnormal serotonin expression and/or
GI symptoms, than did women in a control group (49).
signaling in IBS and other GI disorders (53). The
Compared with controls, women with IBS had signifi-
potential effect of sex hormones such as estrogen and
cantly more severe GI symptoms, including abdominal
progesterone on serotonin remains to be elucidated.
pain, gas, and bloating, and also reported a higher per-
However, the importance of serotonin and its receptors,
centage of days with hard and with loose stools. GI
as well as serotonin polymorphisms, in predicting
symptoms were significantly affected by the menstrual
response to treatment is an area of interest. A recent
cycle phase, with complaints worse during menses.
study has shown that estrogen and progesterone influ-
Among women with IBS, oral contraceptive users
ence the level of 5-HT type 3 (5-HT3) receptor mRNA
reported fewer symptoms of abdominal pain than did
(54). In ovariectomized rats, lower levels of PGE2 and
nonusers; however, there were no significant differ-
progesterone resulted in significantly higher amounts
ences between the two groups with respect to gas,
of 5-HT3 receptor mRNA. When ovariectomized ani-
bloating, constipation, and diarrhea. In a subsequent
mals were treated with estradiol and progesterone,
study of women with IBS, Heitkemper and colleagues
5-HT3 receptor transcript levels returned to normal.
(2004) described a specific relationship between bloat-
Additional studies highlight the importance of the
ing and menses-associated symptoms such as uterine
serotonin reuptake transporter in IBS as polymor-
cramping and breast tenderness (50).
phisms in this gene resulted in a differential response
In a study of 477 female patients with IBS, Lee, et al
to alosetron, a 5-HT3 receptor antagonist that is used to
(2001) reported that 40% of all female patients with IBS
treat diarrhea-predominant IBS (55,56). Collectively,
reported menstrual cycle-related worsening of symptoms
these results suggest that 5-HT3 receptor activity,
(8). Of women younger than age 45, 50.8% reported
which is a target of pharmacologic intervention in
experiencing menstrual cycle-related worsening of
patients with diarrhea-predominant IBS, also is regu-
symptoms. However, based on two findings, the authors
lated by female sex hormones.
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TREATMENT OF IRRITABLE BOWEL SYNDROME, SERIES #7
IBS SYMPTOMS IN PATIENTS
Acknowledgment
USING ORAL CONTRACEPTIVES
The authors would like to acknowledge the editorial
Oral contraceptive use should be investigated among
assistance of Maribeth Bogush, PhD, in preparation of
patients seeking relief from GI symptoms. Because
this manuscript.
estrogen excess can cause nausea, bloating, and cyclic
weight gain, patients taking preparations high in estro-
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