American Journal of Gastroenterology ISSN 0002-9270


C 2008 by Am. Coll. of Gastroenterology doi: 10.1111/j.1572-0241.2007.01700.x
Published by Blackwell Publishing

Hormonal Replacement Therapy After Menopause

Is Protective of Disease Activity in Women
With Inflammatory Bowel Disease
Sunanda V. Kane, M.D., M.S.P.H., and Deepa Reddy, M.D.
Mayo Clinic, Rochester, Minnesota and University of Chicago, Chicago, Illinois

BACKGROUND The nature of inflammatory bowel disease (IBD) following menopause has not been previously
AND AIMS: studied. The aim of this study was to characterize the effect of menopause on disease activity and
identify possible modifiers of disease activity.
METHODS: This was a retrospective study of women followed at the University of Chicago IBD Clinic. Disease
activity was assessed using clinical scoring systems during the pre- and postmenstrual periods of
subjects. Variables of interest included: history of smoking, use of oral contraceptives (OCP) prior to
onset of menopause, and use of hormone replacement therapy (HRT).
RESULTS: Sixty-five women were included, 20 with ulcerative colitis and 45 with Crohn’s disease. The median
age of menopause was similar to historical controls. Twenty-three patients (35%) experienced active
symptoms in the premenopausal time period and 25 patients (38%) had disease indices consistent
with a flare within the first 2 yr after menopause (P > 0.05). There was no relation between those
who had a pre- versus postmenstrual flare as a group (P > 0.05). However, there was a significant
protective effect on disease activity with postmenopausal HRT use (hazard ratio [HR] 0.18, 95%
confidence interval [CI] 0.04–0.72). There was also a dose–response effect noted with an HR with
longer duration of use (0.20, 0.07–0.65).
CONCLUSIONS: The likelihood of having a flare postmenopause is not different from having it premenopause. HRT,
however, may provide a protective effect for disease activity in the postmenopausal period. The
anti-inflammatory effects of estrogen may be the mechanism for this observation.
(Am J Gastroenterol 2008;103:1193–1196)

INTRODUCTION provement in experimental models of vascular inflamma-

Inflammatory bowel disease (IBD) constitutes several
chronic diseases with a typical age of onset in the early re-
productive years. The effect of hormones and hormonal fluc-
tuation on the gastrointestinal tract has been documented in
human observational studies, including symptomatic wors-
ening of IBD symptoms during menses (1) and improvement
in irritable bowel syndrome symptoms after disruption of
menses through either medical (gonadotropin-releasing hor-
mone [GnRH] analogs) or surgical (2, 3) means.
The exact mechanism of how hormonal changes affect the
gastrointestinal tract and ultimately the symptomatology in
IBD has yet to be fully elucidated, but work at the cellu-
lar level has demonstrated estrogen’s effect in the control of
pathogenic inflammation. Estrogen receptors α and β are ex-
pressed in the gastrointestinal tract, as well as CD4+ and
CD8+ T cells, B cells, monocytes, and macrophages, and
thus are involved with the regulation of the immune sys-
tem (4). Monocyte chemoattractant protein-1 (MCP-1) stim-
ulates recruitment of leukocytes, and downregulation of this
molecule with 17-β-estrodiol has been associated with im-
tion, atherosclerosis, and autoimmune encephalitis (5). Es-
trogen has also been shown to reduce vascular cell adhesion
molecule-1 (VCAM-1) expression in cytokine- and tumor
necrosis factor (TNF)-stimulated endothelial cells (6).
If estrogen has potent anti-inflammatory effects, then
estrogen-deficient states should lead to an increased rate of
disease activity. Our hypothesis was that women in the post-
menopausal state would have a different disease activity pat-
tern compared with the those in premenopausal state. The
specific aim was to better quantify the effect of menopause
on disease symptoms in IBD, in order to make recommen-
dations regarding possible therapeutic changes and counsel
women regarding the potential risks and benefits of HRT.
METHODS
Patients
Female patients with IBD confirmed by prior endoscopic,
radiographic, and histologic criteria followed at the Uni-
versity of Chicago and registered in the IBD registry were

1193
1194 Kane and Reddy

eligible. Those women who were then found to be in a Table 1. Patient Characteristics
postmenopausal state were identified. Menopause was deter- Variable Value
mined by one of two scenarios: surgical menopause, defined
Median age at menopause (range) 48.2 (38–53)
as a history of hysterectomy and bilateral oophorectomy, or Type of menopause (N)
natural menopause, defined as sustained amenorrhea for more Natural 59
than 12 months along with elevated follicle stimulating hor- Surgical 6
mone (FSH). Diagnosis (N)
Crohn’s disease 40
Ulcerative colitis 25
Protocol HRT use (N) 20
Data were obtained from the medical records of subjects, and Symptoms 18
patient interviews were conducted when records were incom- Osteoporosis 2
plete. Each patient served as her own control, as disease activ- Experienced a flare premenopause (N) 23
Experienced a flare postmenopause (N) 25
ity in the 5 yr prior to the onset of menopause was compared
with the 5 yr postmenopause. A 2-yr phase of perimenopause
was assumed, and disease activity during this time was not
considered in the analysis. Disease activity was assessed by ing menopause. The indication for HRT use was symptomatic
the number of flare-ups and frequency of flare-ups (number hot flashes in 18 women and osteoporosis in 2 women. Fif-
of flares/patient-year), number of hospitalizations, need for teen patients were prescribed Premarin
(Wyeth, Philadel-
steroids (oral and IV), or initiation of other immunosuppres- phia, PA) at doses ranging from 0.3 mg to 0.625 mg and
sive therapies or surgery. Disease activity was measured using five were prescribed Prempro
(Wyeth, Philadelphia, PA),
either the modified Truelove and Witts score for patients with all at 0.625–2.5 mg. Follow-up for 5 yr after menopause was
ulcerative colitis (UC) or the Crohn’s Disease Activity Index complete for all patients. There was no significant difference
(CDAI) for patients with Crohn’s disease (CD) at each visit. between the number of office visits for any patient in the pre-
A flare of disease was defined as an increase in score of at menopausal period as compared with that in the menopausal
least two points in the Truelove and Witts score or a CDAI of period (average of 1.3 visits/yr for UC, 3 visits/yr for CD).
>150. Twenty-three patients (35%) experienced active symptoms
Patient data, including demographic characteristics, age at in the premenopausal time period and 25 patients (38%)
onset of IBD, and duration of disease, were collected. Infor- had disease indices consistent with a flare within the first
mation on potential confounding factors, including history 5 yr after menopause (P > 0.05). There was no apparent
of smoking (non- or exsmoker vs current), use of oral con- correlation between having a flare in the premenopausal
traceptives (OCP) prior to onset of menopause, and use and state and postmenopausal state in any individual (r = 0.32,
type of HRT following menopause, was also collected. P > 0.05).
Adjusted HR for disease activity during the menopause
Data Analysis are presented in Table 2. In the proportional hazards model,
Descriptive statistics were used to describe the cohort. The steroid use to treat a premenopause flare was significantly
frequencies of outcomes from the premenopausal state were associated with disease activity in menopause (HR 1.6, 95%
compared to those following menopause using χ 2 tests. The CI 1.1–2.3). In contrast, the use of HRT appeared to have
time of risk was during the postmenopause for both HRT a significant protective effect against a disease flare during
and non-HRT users. The number of flares per patient was the menopause. HRT therapy demonstrated an 82% reduc-
the outcome of interest and patients were not censored after tion in the likelihood of disease activity in the menopausal
their first flare. A Cox proportional hazard model was utilized period compared with that in women not taking any exoge-
to assess for disease activity, as this model assumes that the nous hormones (P = 0.001). The risk of disease activity was
underlying hazard rate (rather than survival time) is a function not increased by type of menopause, OCP use, diagnosis,
of independent variables (covariates), and as such it may be premenopause flare, or smoking.
considered to be a nonparametric method. A P value of 0.05
was used for statistical significance.
Approval from the University of Chicago institutional re- Table 2. Hazard Ratios for Disease Activity in the Menopause
view board was obtained prior to any data collection. Hazard Ratio
Variable With 95% CI P Value
Type of menopause 1.1 (0.56–1.72) 0.330
RESULTS Premenopause OCP use 1.2 (0.78–1.93) 0.210
Diagnosis of CD 0.99 (0.77–2.01) 0.710
Characteristics of the cohort are described in Table 1. A total Premenopause flare 1.4 (0.88–2.15) 0.320
of 65 women were studied, 25 with UC and 40 with CD. The Current smoker 1.3 (0.79–2.44) 0.440
median age of menopause was 48.2 yr (range 38–53). Twenty Postmenopause HRT use 0.18 (0.04–0.72) 0.001
Steroid use in premenopause flare 1.6 (1.1–2.3) 0.030
women (31%) in the cohort had a history of HRT use follow-
 Protective Effect of Postmenopausal HRT Use in Women With IBD
Table 3. Hazard Ratios for Disease Activity With HRT Use in
Women With IBD
Hazard Ratio
Variable With 95% CI P Value
+HRT use 0.18 (0.04–0.72) 0.001
+HRT and CD 0.22 (0.08–1.30) 0.070
+HRT and UC 0.16 (0.2–1.5) 0.060
<1-yr use 0.45 (0.12–1.70) 0.100
>1-yr use 0.20 (0.07–0.65) 0.030
Table 3 outlines a separate analysis with outcomes strati-
fied by HRT use. There also appeared to be a dose–response
relationship to the protective effect against disease activity.
The risk reduction was 55% with 1 yr of use, which increased
to 80% with use greater than 1 yr. When stratified by disease,
the odds ratios approached statistical significance, but the
number of patients in each group was small.
Of the 25 women who experienced a flare of disease in the
postmenopause, the three on HRT did not require escalation
of therapy to an immunomodulator, but rather an increase
in mesalamine dosing; this was compared with only 23%
(5/22) who could be treated without escalation of therapy to
an immunomodulator.
DISCUSSION
We found that overall the percentage of women experiencing
a flare of their disease during menopause was not significantly
higher than that prior to menopause. This may be secondary
to factors that we could not account for or the variable nature
of the disease. However, when taking into account the use of
HRT, we found a significant protective effect of HRT use in
women with IBD. Women who were taking HRT were about
80% less likely to experience a flare of their disease in the
first 2 yr following the onset of menopause compared with
those who did not. In addition, for those who did experience
a flare, medical management was much more conservative.
We also found that the average age of the onset of
menopause was similar to that of the accepted standard. This
is in distinction from a previous study that reported a mean
age at menopause of 47.6 yr in women with CD, which was
significantly lower than the surrounding population (7). At
this time, it is unclear why these two studies are disparate in
their findings.
There are some weaknesses to our study. This was a rela-
tively small study of women followed at a single tertiary care
institution. We did examine a number of possible factors for
disease activity, and thus the strength of the associations may
be biased by the small number of subjects. However, each
patient was used as her own internal control as the disease
course pre- and postmenopause was the outcome of interest.
The small number of women included makes it difficult to
account for all possible factors that lead to disease activity,
but this is the first time that a study has specifically examined
the potential role of HRT in disease activity.
1195
There is biologic plausibility to our findings. Estrogen in
the form of 17-β-estradiol suppresses the transcription of in-
terleukin (IL)-2 from activated peripheral blood T cells and
CD4+ T-cell lines through the suppression of transcription
factors, including nuclear factor (NF)-kB. In multiple scle-
rosis, another autoimmune condition, exogenous estriol, has
been found to inhibit activity (8). Further, identification of
pathway-selective estrogen receptor ligands that inhibit NF-
kB transcriptional activity have been identified and tested on
transgenic rat models of IBD (9–11).
In human trials, estrogen has been shown to disrupt the im-
balance of proinflammatory cytokines in systemic lupus ery-
thematosus (12). Dehydroepiandrosterone (DHEA) inhibits
the activation of NF-kB and the secretion of IL-6 and IL-12
(13), and has been shown to be effective in patients with lu-
pus erythematosus (14). In a small phase II pilot trial in IBD,
six of seven patients with CD and 8 of 13 patients with UC
responded to treatment with 200 mg DHEA per day orally
for 56 days (15). More specific to HRT use, plasma levels
of MCP-1 have been reported to be lower in postmenopausal
women receiving hormone replacement compared with those
not on replacement (16).
The use of HRT has recently become more controversial
with the findings that such agents increase the risk for cer-
tain cancers and do not carry as high a protective effect for
cardiovascular events as once believed. The indications for
use and duration are now individualized, with each woman’s
personal and family history taken into account. While we also
noted that the apparent protective effect is strengthened by
the dose–response effect seen with extended versus limited
use, it is important to understand the indications for HRT
use.
In conclusion, we found that the use of HRT was protec-
tive against disease activity in the short-term postmenopausal
state. Whether to protect against disease activity or temper
a flare, women on short-term HRT either were less likely to
experience a flare or require escalation of therapy compared
with those women not on HRT. These findings were neither
specific to surgical or natural menopause nor to either diag-
nosis. A biologic mechanism could potentially explain these
findings. Studies with larger numbers of women observed
for longer periods of time need to be done to verify this
association.
STUDY HIGHLIGHTS
What Is Current Knowledge
r We know that hormones can play a role in disease activ-
ity of women with inflammatory bowel disease (IBD).
r We know that some women take hormone replacement
therapy (HRT) for symptomatic hot flashes or other
indications.
r We know that estrogens have anti-inflammatory prop-
erties.
1196 Kane and Reddy
What Is New Here
r What we did not know was the effect of menopause on
disease symptoms, nor the impact that HRT could play.
r We have demonstrated that HRT use is associated with
a protective effect for disease activity, as well as a dose–
response effect.
Reprint requests and correspondence: Sunanda V. Kane, M.D.,
M.S.P.H., Mayo Clinic, Miles and Shirley Fiterman Division of Gas-
troenterology and Hepatology, 200 First Street SW, Rochester, MN
55905.
Received July 27, 2007; accepted November 2, 2007.
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CONFLICT OF INTEREST
Guarantor of the article: Dr. Sunanda V. Kane, M.D.,
M.S.P.H.
Specific author contributions: Dr. Kane is responsible for
the design of the study, data collection and analysis, and
preparation of the manuscript. Dr. Deepa Reddy aided in the
study design and data collection.
Financial support: Research support was provided by a
grant from Procter and Gamble Pharmaceuticals, and by
the National Institute of Diabetes and Digestive and Kid-
ney (NIDDK) P30DK42086, as well as the David and Reva
Logan Center for Inflammatory Bowel Disease Research at
the University of Chicago.
Potential competing interests: Dr. Kane receives honoraria
from Procter and Gamble as a Consultant.