Download The Link Between Estrogen and Gallbladder Disease

The Link Between Estrogen and Gallbladder Disease
Kelly Butler
March 1, 2008
PAS 655
Dr. William Grimes
Abstract
Gallbladder disease is prevalent in both men and women, in the United States and around
the world. There are many theories as to what exactly leads to the development of gallbladder
disease, however, a definitive etiology is unknown. These theories include a poor diet, rapid
weight loss, alcoholism, family history of gallbladder disease and pregnancy. The presence of
estrogen, endogenous or exogenous, is also being explored as a potential cause of gallbladder
disease.
Estrogen is the primary female sex hormone that regulates the menstrual cycle, among
other things. It is used as a treatment in many conditions including the prevention of pregnancy,
postmenopausal symptoms, prostate cancer and transsexual patients. There have been many
studies, old and recent, that have looked at the role of estrogen in the development of gallstones
which could ultimately lead to gallbladder disease. This paper analyzes those studies to attempt
to determine if in fact there is a link between the use of estrogen and gallstone formation.
The studies show that pregnancy, largely regulated by endogenous estrogen, can cause an
increase in the development of gallstones, which usually disappear after delivery when estrogen
levels return to normal circulating levels. In oral contraceptives, there is a correlation between
users and gallstone formation if they were predisposed in some way, such as a family history of
gallbladder disease. Not only estrogen in oral contraceptives, but also progestin could possibly
play a role by decreasing the motility of the gallbladder and thus increasing bile stasis so that
gallstones are more likely to form. In prostate cancer and male-to-female transsexuals, estrogen
decreases the amount of testosterone in the body and causes a feminizing effect. Estrogen also
increases the saturation of bile with cholesterol, a predisposing factor to developing gallstones.
Ultimately, estrogen seems to play a role in aiding the development of gallstones, but is not the
sole culprit.
Introduction
In the summer of 2005, I was awakened one early Sunday morning by this excruciating
pain in my right upper abdominal region. I felt as though it was on fire and I was extremely
nauseated and vomited up a viscous green substance. About four hours later, I vomited again
and the pain had not subsided so I decided to go to the hospital. I remember having to explain
everything to the triage nurse and then they took me back and got an intravenous access and I
was to have an ultrasound on my gallbladder. The ultrasound technician was very nice and I
remember her asking me why I had not come in sooner and I had responded that I had had these
attacks before and thought that this one, like the others, would subside eventually. As she did
what she needed to do, she began to palpate my abdomen and at one point I almost jumped up
off the gurney because I was in so much pain. She wheeled me out and immediately got on the
telephone saying “Definitely positive for Murphy’s.” I had no idea what that meant at the time,
but eventually I would learn that my gallbladder was infected, swollen, had a couple of stones
and ample sludge. After I had a round of intravenous Zosyn, I had to have a cholecystectomy.
Because I had waited so long to seek medical treatment and my gallbladder was very infected, it
took the surgeon an extra hour to remove it and I had a drainage tube for about a week. As a
result of my personal experience with gallbladder disease and the experiences of those close to
me, I have a vested interest in the cause and progression of biliary tract diseases.
The definitive underlying etiology of gallbladder disease is currently unknown; however,
doctors and researchers have made many hypotheses as to possible causes. These possible links
include: increased body weight, poor/unhealthy diet (one high in fat), rapid weight loss,
alcoholism, a family history of gallbladder disease and pregnancy. Another possible link cited in
the literature and the one that we will look at is the role of estrogen. This includes estrogen
produced by the body (endogenous) and estrogen taken as a supplement or as a medical
treatment (exogenous), such as in prostate cancer, postmenopausal therapy, or in transsexuals
(male-to-female).
Background
The Gallbladder
The gallbladder is a small anatomical sac located under the liver that functions as a
storage and concentrating unit for bile that is produced by the liver. The gallbladder contracts in
response to ingestion and digestion of food, especially foods high in fat content, and ejects bile
acid into the small intestine at the duodenum. It is connected to the liver and the pancreas via the
biliary tract (reason for gallbladder disease also being identified as biliary tract disease). If a
dysfunction occurs to slow or obstruct the flow of bile from the gallbladder, it results in
gallbladder disease (http://www.nlm.nih.gov/medlineplus/ency/article/001138.htm, accessed
Nov. 2007).
Estrogen
Estrogens are a group of steroid compounds that serve as the primary female sex
hormones. They are produced by the developing ovarian follicles, the corpus luteum and the
placenta during pregnancy. Estrogens play a vital role in the development of females by
regulating the development of secondary sex characteristics, such as breast growth, regulating
the menstrual cycle, by stimulating the uterine lining to thicken, and preparing the body for
fertilization.
Estrogens are also important in maintaining normal brain function and the development
of nerve cells. They are very important for healthy bones and overall health maintenance.
Because estrogens have such a huge role in the normal functioning of the body, they are being
used therapeutically for many things. Some of these therapeutic uses include oral contraceptives,
treatment of breast and prostate cancer, osteoporosis and to relieve the discomforts of
menopause, such as hot flashes, and in postmenopausal patients as hormone replacement therapy
(http://www.vitamins-supplements.org/hormones/estrogens.php).
The use of estrogen as hormone replacement therapy, or as therapy for any other medical
condition, is controversial. Although the benefits of estrogen therapy are many, there are also
many side effects. Some of these side effects include affecting the triglyceride levels and
increasing cardiovascular disease, may cause an increase in the risk of breast cancer if used over
a lifelong period of time. Recently studies have shown that estrogen therapy in postmenopausal
women may increase the risk of developing gallbladder disease 2 to 3 times more than in those
women not receiving hormone replacement therapy
(http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682922.html).
Epidemiology
Gallbladder disease is very common around the world and in the United States. Studies
show variation in gallstone prevalence between different ethnic populations. There are higher
rates of gallstone formation in western Caucasian, Hispanic, and Native American populations.
There appear to be lower rates in eastern European countries, African Americans, and Japanese
populations (http://patients.uptodate.com/print.asp?print=true&file=biliaryt/5497). Here in
Eastern Kentucky, there is an abnormally high incidence of gallbladder disease with gallstone
formation.
According to a study done in Rowan County by some local doctors back in the 1960’s
and 1970’s, gallbladder disease is a major cause of morbidity and mortality in Eastern Kentucky.
In this study, they reveal that the female to male ratio for the incidence of gallbladder disease is
14:1 in Rowan County, Kentucky compared to that of 5.4:1 and 6.3:1 in Framingham,
Massachusetts and the Pima Indians, respectively. There are also twice as many cases in the
rural areas as compared to the urban areas. This means that there are “pockets” of gallbladder
disease in the United States in groups other than the American Indians. They found that
gallbladder disease is primarily a disease of parous rural women of low socioeconomic status
(Richardson, J. David, et al, 1973).
Pathophysiology
Gallbladder disease, or biliary tract disease, includes inflammation, infection, stones,
sludge, or obstruction of the gallbladder or its duct (the cystic duct). The main types of
gallbladder disease are cholecystitis (acute or chronic), cholelithiasis, and gallbladder cancer.
Cholecystitis is inflammation of the gallbladder. Acute cholecystitis is most commonly caused
by cholelithiasis, the presence of gallstones. Bile becomes trapped in the gallbladder because of
obstruction, causing an increase in pressure and can lead to bacterial infection. Treatment of
acute cholecystitis is cholecystectomy (surgical removal of the gallbladder) as soon as possible.
If an infection is present, the infection must first be treated with antibiotics and then surgery can
be performed. Chronic cholecystitis is best managed through maintaining a healthy diet and
abstaining from those foods that produce biliary colic or other symptoms of gallbladder disease.
It can be treated with surgery, although this usually is not necessary (Medline Plus, 2007;
University of Maryland Medical Center, 2007).
There are two primary types of stones, which include cholesterol and pigmented stones or
they can be mixed stones. Most stones are mainly cholesterol or mixed. Gallstone formation is
thought to rely on three factors, which include: (1) supersaturation of biliary cholesterol from
liver oversecretion, (2) nucleation of cholesterol monohydrate crystals, and (3) gallbladder
hypomotility (Cirillo, 2005). Cholesterol formation is from the excess secretion of cholesterol in
bile in relation to the amount of bile salts present. Also, the bile salts can form micelles around
the cholesterol and intercalate with phospholipids to aid in the solubilization of cholesterol.
Pigmented stones are thought to be associated with bacteria, alcoholism or hemolytic anemia.
Pathogenesis, however, is not completely known.
The liver, which produces bile, has estrogen receptors present. Endogenous estrogens act
on these receptors to cause cholesterol saturation in the bile. Exogenous estrogens have been
shown to affect physiologic markers in a pattern that favors gallstone formation. Progestin’s,
which are often given in combination with estrogen for therapy, inhibit gallbladder contraction
which increases bile stasis and can decrease the gallbladders response to cholecystokinin (Cirillo,
2005).
Sludge, biliary sludge, or microlithiasis is the precursor to most gallstone formation. It is
a mixture of mucous, cholesterol microcrystals and calcium bilirubin molecules. It is associated
with pregnancy, early postpartum period, fasting, rapid weight loss, parenteral nutrition,
cirrhosis, and certain medications.
Primary cancer of the gallbladder is a rare occurrence. Cancer of the gallbladder is
usually seen in those patients with gallbladders that are nonfunctioning and have stones.
Gallbladder cancer is commonly found incidentally during surgery for the removal of the
gallbladder (Sander, G., 2007). However, when cancer of the gallbladder is found and
diagnosed, there is a poor prognosis because about half of all gallbladder cancers are metastatic
and advanced at presentation (Bateson, M., 1999).
Main Ideas
Gallstones and Pregnancy
As previously stated, gallbladder disease, especially in the form of cholelithiasis, occurs
more frequently in women than in men. Many epidemiologic studies have shown a positive
correlation between the development of gallstones and pregnancy. Biliary sludge is often found
in the gallbladders of pregnant women however, this usually disappears during the first months
after delivery (see Figure 1 in appendix; Maringhini, A., 1993). The role of pregnancy in
gallstone formation is uncertain, however, alterations in cholesterol metabolism and decreased
gallbladder motility are observed during pregnancy. There is also an association between
number of pregnancies and disease such that with increasing pregnancies, there is an increased
risk of developing gallbladder disease (Richardson, J. David, 1973).
A group at the Rotunda Hospital in Dublin Ireland studied 512 healthy, pregnant women
to determine the prevalence of gallstones. Most of the women were asked to complete
questionnaires and had a pelvic area examination and examination of the upper part of the
abdomen. Ultrasound was used to determine the presence of gallstones. They found that 4.5 %
of the women had gallstones. However, 30.4% had previously experienced cholecystectomy and
8.7% had already been diagnosed with gallstones. Women who were found to have gallstones
were more likely to experience irregular, painful menses than the controls. A higher parity
among symptomatic mothers was observed as compared with asymptomatic mothers. They
concluded that pregnancy may increase the prospect of symptoms in women who were unaware
of the gallstones. Researches also found a positive correlation of gallstones in women who
breast fed and in women with a positive family history of gallstones (Basso, 1992).
Oral Contraceptives in Women of Childbearing Age and Gallstone Formation
Oral contraceptives are the most widely used hormonal method worldwide for
contraception. They are effective, convenient and seemingly safe. There are more than 100
million users in the United States and worldwide today in married and unmarried women (see
Figure 2 in appendix). The major risks involved with using oral contraceptives remains
increased risk of cardiovascular and cerebrovascular incidents, however, other health risks
include gallbladder disease in women who are already susceptible and rare noncancerous liver
tumors are among those side effects worth mentioning. Oral contraceptives probably do not
cause gallbladder disease, but may accelerate the development of cholesterol gallstones in
women who are already susceptible because cholesterol saturation is higher in persons using oral
contraceptives as compared to nonusers (http://www.infoforhealth.org/pr/a9/a9chap4_2.shtml).
A Medical University in Bangladesh studied 340 women to determine if there was any
significance between oral contraceptive use and the development of gallstones. Out of the 340,
184 had a previous history of taking or were currently taking oral contraceptives and 154 had no
history of use. The women were broken up into four age groups: 21-30, 31-40, 41-50, 51+.
They found a significantly higher incidence of gallstones in younger patients taking oral
contraceptives than without contraceptives. In the older age groups, incidence of gallstones
occurred more in those who were not taking oral contraceptives. They concluded that oral
contraceptives increase the incidence of gallstones in younger women, especially in the early
stages of their use of oral contraceptives (Khan, 2007).
Estrogen Therapy in Postmenopausal Women
The decision to use postmenopausal hormone replacement therapy is a difficult one to
make. The physician and patient must together discuss the benefits versus the risks for such
treatment to make an informed decision about their health care needs. Of the postmenopausal
women in the United States, approximately 38% of them use hormone replacement therapy. A
fairly recent article in The New England Journal of Medicine discussed the benefits and risks, or
probably risks of hormone replacement therapy in postmenopausal women. It lists gallbladder
disease as a probable risk based on other studies that have been conducted such as the Women’s
Health Initiative. They have determined that the risk for gallstones or cholecystectomy is
increased by a factor of 2-3 in postmenopausal women receiving estrogen (Manson, 2001).
The risk of gallbladder disease is 38% higher (from the Heart and Estrogen/progestin
Replacement Study) among women receiving estrogen-progestin therapy than those receiving
placebo (Cirillo, 2005).
The Women’s Health Initiative (like the HERS study only on a grand scale) was a
postmenopausal hormone trial consisting of 2 randomized groups of women with and without
hysterectomies. Those with hysterectomy would receive either estrogen alone or placebo. Those
without hysterectomy would receive a combination of estrogen and progestin or placebo. A total
of 22,579 women were analyzed, 8,376 receiving estrogen only or placebo and 14,203 receiving
estrogen and progestin or placebo. The estrogen alone trial was stopped in February 2004 and
the combination estrogen and progestin group was halted early in July 2002 after a
recommendation from the data and safety monitoring board concluded that the overall harm
outweighed the potential benefits of the combination drug. Overall, the results provide strong
evidence of a causal relationship between estrogen therapy and gallstones and risk of surgical
procedure among women using estrogen alone or a combination of estrogen and progestin
(Cirillo, 2005).
Gallstones in Prostate Cancer Patients Receiving Estrogen Therapy
After sexual maturation, both androgens (e.g. testosterone) and estrogens are important
for maintenance of the structure and integrity of the prostate gland. Prostate cancer occurs when
the cells of the prostate are growing uncontrollably because of a disruption in the cell cycle.
Testosterone serves as a fuel for the cancerous cells to grow and therefore it is targeted in
treating prostate cancer. Hormone therapy, also known as androgen deprivation therapy, is used
to stop testosterone from being released or prevent it from acting on the prostate gland. Estrogen
is used as a final option hormone therapy (Prostate Cancer Foundation, 2007).
A university study in Australia looked at the effects of estrogen on the human prostate
gland by studying male-to-female transsexuals who had been exposed to high doses of estrogens
for a median of 9 years. All were using at least one estrogen and most also used an antiandrogen. All prostate dimensions were measured via ultrasound and compared to healthy
eugonadal controls and found to be significantly reduced. Blood total and free testosterone was
also markedly reduced and PSA was decreased by over 90% (Turner, 1996).
Another university hospital study in Sweden looked at the development of gallstones in
men with prostate cancer who received estrogen therapy as compared to those patients who had
undergone orchidectomy. Thirty-five patients underwent orchidectomy and 37 patients were
assigned to the estrogen group. Before treatment, gallbladder disease affected a quarter of the
patients equally distributed between the groups. After one year of therapy with estrogen or after
orchidectomy, five patients previously without gallstones before treatment in the estrogen group
developed new gallstones. No patients in the orchidectomy group developed new gallstones.
Four patients in the estrogen group with previous gallstones had an increase in the number or
size of gallstones compared to one in the orchidectomy group. A biliary lipids analysis showed
an increase in the concentration of cholesterol and cholesterol saturation of bile during estrogen
treatment. There was also an increase in the amount of HDL and decrease in the amount of LDL
cholesterol levels. It is hypothesized that the inflow of lipoprotein cholesterol is a major
criterion for the increased cholesterol concentration in the bile. The catabolism of LDL
cholesterol explains the increased cholesterol secretion into bile during estrogen therapy. Due to
these study results, overall there was an increase in gallstone formation correlated to treatment
with exogenous estrogen in prostate cancer patients (Henriksson, 1989).
Gallstones in Transsexuals Receiving Hormone Therapy
A transsexual is a person who is biologically one gender but identifies him or herself as a
member of the other gender. Transgender is a more broad term used to describe those
individuals who are transsexual, cross-dressers, biologically intersexed, or who otherwise
challenge gender roles. Many of these patients may seek medical advice for hormone
replacement therapy in their quest to become more like the other gender, the gender that they
identify with. The goal of hormonal reassignment therapy is to: (1) reduce the hormonally
induced secondary sex characteristic of the original sex and (2) induce secondary sex
characteristics of the new sex (Gooren, 2005). In this situation, the primary care provider needs
to determine any medical contraindication to hormones once a mental health professional has
determined that the patient is psychologically ready to change their gender identity. Being aware
of contraindications also includes knowing the side effects that can occur with taking hormone
replacement therapy. Males who want to become females will be given estrogens to feminize
them and there are many side effects seen with estrogen use (Oriel, 2000).
Those who choose to pursue hormone replacement therapy take different doses for
varying lengths of time. The average dose of estrogen is 0.625-2.5 milligrams per day. In the
male-to-female transsexual patient, there are many changes that are expected to take place
(www.ohio.edu/lgbt/resources/transoptions.cfm).
Change to Expect
*Softer skin and body appearance
*Breast growth and lessening of body hair
*Loss of strength
*Increased emotional sensitivity, especially to
stress – depression is not uncommon
*Diminished ability to achieve erections and to
ejaculate
*Redistibution of body fat from stomach to
breasts, hips, and thighs
Traits That Will Not Change
*Voice
*Height
*Size of hands and feet
*Presence of facial hair (may grow finer.)
*Hair loss stops, but what has been lost will
not grow back
*Adam’s apple
There are some pre-existing health problems that could disqualify a person for hormone
replacement therapy. There is a problem, however, in prescribing these drugs to patients because
there hasn’t been much research to determine all of the health risks involved. These health risks
also depend on the route of administration, for example, oral, patch, or injection and how long
you take the medicine: long term or short term. However, one known health risk seen is that
estrogen can cause male-to-female transsexual patients to be at a higher risk for gallbladder
disease, among other things, which include pituitary tumors and hypertension. Also, oral
estrogens have been reported to cause more problems with the liver, but they are cheaper
(http://www.ohio.edu/lgbt/resources/transoptions.cfm).
One study from the Erlangen University Hospital in Germany used a combination of
ethinyl estradiol and cyproterone acetate as hormone replacement therapy. The mortality and
morbidity rates with this regimen have been documented in over 800 patients. The typical side
effects reported included elevated liver enzymes and symptomatic gallstones, among others
(Dittrick, 2005).
Review of Literature
Sources used were ACP Medicine, a text book available online that is updated monthly.
Other sources used were peer reviewed medical journals, either in paper form or online. I also
used my personal experience with gallbladder disease and the experiences of others that I know
who have had their own bouts with gallbladder disease.
Summary/Synthesis
Sometimes, the presence of gallbladder disease is seen with pregnancy. In older and
recent studies, it has been shown that sludge and inflammation occurs with pregnancy.
However, the symptoms associated with each often disappear after delivery. This could be due
to the levels of estrogen returning to normal cycling after delivery. There is also an increased
incidence of gallbladder disease with an increased number of pregnancies, especially in the
younger female population.
Oral contraceptives are used by many women in the United States and around the world
as the primary pregnancy prevention method. They are very effective, convenient and safe for
most. The use of oral contraceptives has been correlated with an increased risk in developing
gallstones due to saturation of bile with cholesterol and should not be used in those women who
have a pre-existing or predisposition to gallbladder disease.
One treatment of postmenopausal women is hormone replacement therapy with
estrogens, which are sometimes given in combination with progestin. Studies show that in
healthy postmenopausal women receiving hormone replacement therapy, there is an increase in
the number of hospitalizations associated with gallbladder disease or gallbladder related disease
and procedures. There is also an increased risk of surgical procedure, where women receiving
estrogen therapy are more likely to have cholecystectomy performed.
Hormone therapy is also instituted for the treatment of prostate cancer. There are many
side effects in the use of estrogen for this. One side effect is the increased risk of developing
gallbladder disease with an increased risk for surgery to have the gallbladder removed.
Transsexuals (male-to-female) use estrogen as a feminizing tool. There are many risks
that are associated with estrogen therapy, some of which are reversible after hormone therapy
has been stopped and other effects which are irreversible even after cessation of therapy. One
risk associated with hormone therapy in the male-to-female gender change category is
gallbladder disease. In the female-to-male change category taking hormone replacement
testosterone and decreased estrogen, there is no increase in the incidence or risk of developing
gallbladder disease.
Conclusions/Recommendation
Gallbladder disease is a worldwide problem with some persons being at an increased risk
to develop gallstones more so than others. The link between pregnancy and the use of oral
contraceptives has been studied but not completely elucidated and further research needs to be
performed. Postmenopausal women who seek estrogen therapy should be aware of the side
effects shown for the Women’s Health Initiative study and should be looking forward to the
results of the Women’s International Study of Long Duration Estrogen after Menopause in 14
countries, which are expected in 2012 (Manson, 2001). The risks of estrogen in males suffering
from prostate cancer and in transsexuals have been shown to be the same as in women taking
hormone replacement therapy. From the current data, both groups of males (prostate cancer and
transsexuals) would be better off to have an orchidectomy to reduce testosterone amounts as
compared to the risks of estrogen use. However, the ultimate decision to use estrogen is up to
the patient and the provider should be a fountain of knowledge for the patient’s use by providing
them with the most up to date side effects available, especially if they are at an increased risk for
gallstones either from diet, weight loss, or family history.
Appendix
Figure 1: Levels of various hormones as pregnancy progress. The dotted lines represent what
they would normally be without implantation and subsequent growth of fetus.
(http://www.lifeissues.net/writers/kah/images/chap6-6A.gif)
Figure 2: The menstrual cycle in human females and female rats. They are relatively similar with similar
levels of all hormones. As we can see, estrogen peaks twice in the human cycle which can lead to the
exacerbation of nausea and vomiting often associated with gallbladder disease. (Google images.)
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