Endometriosis

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Endometriosis
Prof. Dr. Almahdy A, Apt Fakultas Farmasi
Unand. 2009
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What is endometriosis? Endometriosis is a common
cause of chronic pelvic pain in women and is also
associated with infertility. Characterized by the
presence of endometrial tissue (Endometrial cells
are the same cells that are shed each month
during menstruation) outside the uterus,
endometriosis is a chronic, recurring disease.
Therapy is targeted at relieving symptoms and
improving fertility.
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The cells of endometriosis attach themselves to
tissue outside the uterus and are called
endometriosis implants. These implants are most
commonly found on the ovaries, the Fallopian
tubes, outer surfaces of the uterus or
intestines, and on the surface lining of the
pelvic cavity.
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They can also be found in the vagina, cervix, and
bladder, although less commonly than other
locations in the pelvis. Rarely, endometriosis
implants can occur outside the pelvis, on the
liver, in old surgery scars, and even in or
around the lung or brain. Endometrial implants,
while they can cause problems, are benign (not
cancerous)
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Who is affected by endometriosis? Endometriosis
affects women in their reproductive years. The
exact prevalence of endometriosis is not known,
since many women may have the condition and have
no symptoms. Endometriosis is estimated to affect
over one million women (estimates range from 3
to 18 of women) in the United States. It is one
of the leading causes of pelvic pain and reasons
for laparoscopic surgery and hysterectomy in this
country.
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While most cases of endometriosis are diagnosed
in women aged around 25-35 years, endometriosis
has been reported in girls as young as 11 years
of age. Endometriosis is rare in postmenopausal
women. Endometriosis is more commonly found in
white women as compared with African American and
Asian women. Studies further suggest that
endometriosis is most common in taller, thin
women with a low body mass index (BMI). Delaying
pregnancy until an older age is also believed to
increase the risk of developing endometriosis.
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What causes endometriosis? The cause of
endometriosis is unknown. One theory is that the
endometrial tissue is deposited in unusual
locations by the backing up of menstrual flow
into the Fallopian tubes and the pelvic and
abdominal cavity during menstruation (termed
retrograde menstruation). The cause of retrograde
menstruation is not clearly understood. But
retrograde menstruation cannot be the sole cause
of endometriosis. Many women have retrograde
menstruation in varying degrees, yet not all of
them develop endometriosis.
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Another possibility is that areas lining the
pelvic organs possess primitive cells that are
able to grow into other forms of tissue, such as
endometrial cells. (This process is termed
coelomic metaplasia.)
It is also likely that direct transfer of
endometrial tissues during surgery may be
responsible for the endometriosis implants
sometimes seen in surgical scars (for example,
episiotomy or Cesarean section scars). Transfer
of endometrial cells via the bloodstream or
lymphatic system is the most likely explanation
for the rare cases of endometriosis that develop
in the brain and other organs distant from the
pelvis.
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Finally, some studies have shown alternations in
the immune response in women with endometriosis,
which may affect the body's natural ability to
recognize and destroy any misdirected growth of
endometrial tissue.
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Normal Pelvic Structures
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What are endometriosis symptoms? Most women who
have endometriosis, in fact, do not have
symptoms. Of those who do experience symptoms,
the common symptoms are pain (usually pelvic) and
infertility. Pelvic pain usually occurs during or
just before menstruation and lessens after
menstruation. Some women experience pain or
cramping with intercourse, bowel movements and/or
urination. Even pelvic examination by a doctor
can be painful. The pain intensity can change
from month to month, and vary greatly among
women. Some women experience progressive
worsening of symptoms, while others can have
resolution of pain without treatment. Pelvic
pain in women with endometriosis depends partly
on where the implants of endometriosis are
located. Deeper implants and implants in areas
with many pain-sensing nerves may be more likely
to produce pain. The implants may also produce
substances that circulate in the bloodstream and
cause pain.
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Other symptoms related to endometriosis
include lower abdominal pain, diarrhea and/or
constipation, low back pain, irregular or heavy
menstrual bleeding, or blood in the urine.
Rare symptoms of endometriosis include chest
pain or coughing blood due to endometriosis in
the lungs and headache and/or seizures due to
endometriosis in the brain.
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Endometriosis and cancer risk Women with
endometriosis have a mildly increased risk for
development of certain types of cancer of the
ovary, known as epithelial ovarian cancer (EOC).
This risk seems to be highest in women with
endometriosis and primary infertility (those who
have never borne a child), but the use of oral
contraceptive pills (OCPs), which are sometimes
used in the treatment of endometriosis, appears
to significantly reduce this risk. The reasons
for the association between endometriosis and
ovarian epithelial cancer are not clearly
understood. One theory is that the endometriosis
implants themselves undergo transformation to
cancer. Another possibility is that the presence
of endometriosis may be related to other genetic
or environmental factors that also increase a
women's risk of developing ovarian cancer
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How is endometriosis diagnosed? Endometriosis
can be suspected based on symptoms of pelvic pain
and findings during physical examinations in the
doctor's office. Occasionally, during a
rectovaginal exam (one finger in the vagina and
one finger in the rectum), the doctor can feel
nodules (endometrial implants) behind the uterus
and along the ligaments that attach to the pelvic
wall. At other times, no nodules are felt, but
the examination itself causes unusual pain or
discomfort.
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Unfortunately, neither the symptoms nor the
physical examinations can be relied upon to
conclusively establish the diagnosis of
endometriosis. Imaging studies, such as
ultrasound, can be helpful in ruling out other
pelvic diseases and may suggest the presence of
endometriosis in the vaginal and bladder areas,
but still cannot definitively diagnose
endometriosis. For an accurate diagnosis, a
direct visual inspection inside of the pelvis and
abdomen, as well as tissue biopsy of the implants
are necessary.
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As a result, the only accurate way of diagnosing
endometriosis is at the time of surgery, either
by opening the belly with large-incision
laparotomy or small-incision laparoscopy.
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How is endometriosis treated? Endometriosis can
be treated with medications and/or surgery. The
goals of endometriosis treatment may include pain
relief and/or enhancement of fertility.
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Medical treatment of endometriosis Nonsteroidal
anti-inflammatory drugs or NSAIDs (such as
ibuprofen or naproxen sodium) are commonly
prescribed to help relieve pelvic pain and
menstrual cramping. These pain-relieving
medications have no effect on the endometrial
implants. Since endometriosis occurs during the
reproductive years, many of the available medical
treatments for endometriosis rely on interruption
of the normal cyclical hormone production by the
ovaries. These medications include GnRH analogs,
oral contraceptive pills, and progestins.
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Gonadotropin-releasing hormone analogs (GnRH
analogs) Gonadotropin-releasing hormone analogs
(GnRH analogs) have been effectively used to
relieve pain and reduce the size of endometriosis
implants. These drugs suppress estrogen
production by the ovaries by inhibiting the
secretion of regulatory hormones from the
pituitary gland. As a result, menstrual periods
stop, mimicking menopause. Nasal and injection
forms of GnRH agonists are available.
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The side effects are a result of the lack of
estrogen, and include hot flashes, vaginal
dryness, irregular vaginal bleeding, mood
changes, fatigue, and loss of bone density
(osteoporosis). Fortunately, by adding back
small amounts of estrogen and progesterone in
pill form (similar to treatments sometimes used
for symptom relief in menopause) many of the
annoying side effects due to estrogen deficiency
can be avoided. "Add back therapy" is the term
that refers to this modern way of administering
GnRH agonists along with estrogen and
progesterone in a way to keep the treatment
successful, but avoid most of the unwanted side
effects.
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Oral contraceptive pills Oral contraceptive
pills (estrogen and progesterone in combination)
are also sometimes used to treat endometriosis.
The most common combination used is in the form
of the oral contraceptive pill (OCP). Sometimes
women who have severe menstrual pain are asked to
take the OCP continuously, meaning skipping the
placebo (sugar pill) portion of the cycle.
Continuous use in this manner will free a woman
of having any menstrual periods at all.
Occasionally, weight gain, breast tenderness,
nausea, and irregular bleeding are mild side
effects. Oral contraceptive pills are usually
well-tolerated in women with endometriosis.
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Progestins Progestins for example,
medroxyprogesterone acetate (Provera, Cycrin,
Amen), norethindrone acetate, norgestrel acetate
(Ovrette) are more potent than birth control
pills and are recommended for women who do not
obtain pain relief from or cannot take a birth
control pill. Side effects are more common and
include breast tenderness, bloating, weight
gain, irregular uterine bleeding, and
depression. Since the absence of menstruation
(amenorrhea) induced by high doses of progestins
can last many months after cessation of therapy,
these drugs are not recommended for women
planning pregnancy.
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Other drugs used to treat endometriosis Danazol
(Danocrine) Danazol (Danocrine) is a synthetic
drug that creates a high androgen (male type
hormone) and low estrogen hormonal environment by
interfering with ovulation and ovarian production
of estrogen. Eighty percent of women who take
this drug will have pain relief and shrinkage of
endometriosis implants, but up to 75 of women
develop side effects from the drug.
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Side effects can include weight gain, edema,
decreased breast size, acne, oily skin,
hirsutism (male pattern hair growth), deepening
of the voice, headache, hot flashes, changes
in libido, and mood changes.
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All of these changes are reversible, except for
voice changes but the return to normal may take
many months. Danazol should not be taken by women
with certain types of liver, kidney, and heart
conditions
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Aromatase inhibitors A newer approach to the
treatment of endometriosis has involved the
adminis tration of drugs known as aromatase
inhibi tors for example, anastrozole (Arimidex)
and letrozole (Femara). These drugs act by
interrupting local estrogen formation with in the
endometriosis implants themselves. They also
inhibit estrogen production in the ovary, brain,
and other sources, such as adipose tissue. .
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Medical Treatment
Progestin
Ovary
Estrogen
Endometriosis Tissue
Oral contraceptives Danazol GnRH agonists
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Role of Estrogen in Endometriosis
Estrogen
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Role of Estrogen in Endometriosis
Estrogen
Cell growth
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Role of Estrogen in Endometriosis
Aromatase
Estrogen
Cell growth
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Role of Estrogen in Endometriosis
Aromatase
PGE2 Cytokines
Estrogen
Cell growth
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Aromatase In Endometriosis

• Aromatase is key for the biosynthesis of estrogen
• In patients aromatase expression is higher in
  endometriosis tissue than in normal endometrium
• In endometriosis tissue aromatase activity is
  stimulated by prostaglandin
• Estrogen synthesized by endometriotic tissue
  stimulates growth of lesions

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Role of Estrogen in Endometriosis
Aromatase Inhibitors

• Letrozole
• Exemestane
• Anastrozole

Aromatase
PGE2 Cytokines
Estrogen
Cell growth
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Role of Estrogen in Endometriosis
Aromatase Inhibitors

• Letrozole
• Exemestane
• Anastrozole
• Danazol

Aromatase
PGE2 Cytokines
Estrogen
Cell growth
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Research is still ongoing to characterize the
effectiveness of aromatase inhibitors in the
management of endometriosis. Aromatase inhibitors
cause significant bone loss with prolonged use
and cannot be used alone without other
medications in premenopausal women because they
stimulate development of multiple follicles at
ovulation
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Endometriosis At A Glance Endometriosis is the
growth of endometrial tissue but in a location
outside of the uterus. Endometriosis is most
commonly found on other organs of the
pelvis. The exact cause of endometriosis has not
been identified.
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Endometriosis is more common in women who are
experiencing infertility than in fertile women,
but the condition does not fully prevent
conception. Pelvic pain during menstruation or
ovulation can be a symptom of endometriosis, but
may also occur in normal women.
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Endometriosis can be suspected by definite
diagnosis by surgery, usually laparoscopy.
Treatment of endometriosis includes medication
and surgery for both pain relief and treatment of
infertility if pregnancy is desired.
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