Abstract
Endometriosis is tissue which somewhat resembles the endometrium
lining the inside of the uterus, but which is found outside the
uterus where it doesn’t belong. The chief symptom is
pain. Symptomatic endometriosis
affects approximately 5% - 10% of women, although up to 40% of
asymptomatic women may harbor the disease, regardless of the indication
for surgery.1 This makes endometriosis one of the most common
human diseases on the face of the earth. Although endometriosis
has been a subject of the medical literature since the 19th century,
confusion has raged for decades regarding its origin and proper
treatment. Finally, at the dawn of the “1st century,
opinion is being replaced by facts which allow better diagnosis
and more rational treatment of the disease. Brief history of the
study of endometriosis. In the historical evolution of knowledge
of any disease, the most severe and therefore the most clinically
obviou manifestation may be identified earliest. This severe
form of disease may not be a good representation of the true nature
of the disease. A disease requiring surgery for diagnosis
and which is frequently misdiagnosed at surgery will undergo two
levels of diagnostic selection bias, further obscuring the true
nature of the disease.
A disease whose symptoms may be mimicked by other diseases will
be
inaccurately judged on its own true merit. All of these factors
together will lead to misunderstanding of the disease. As
a result, myths arise to
explain bewilderment, futile attempts at treatment are inevitable,
and a confused medical profession will follow false prophets into
an intellectual wilderness. This is exactly what has happened
for the last 85 years with endometriosis.
Among the earliest manifestations of endometriosis described in
individual case reports in the literature are included severe
nodular rectovaginal disease 2,4 and large ovarian “chocolate”
cysts.5
Nodules of endometriosis involving parenchymal structures, such
as the uterosacral ligaments or bowel wall, were noted to histologically
resemble the adenomyomas which were known to affect the uterine
myometrium. Thus, early manifestations of severe endometriotic
disease were termed “adenomyomas” and were identified
in the vagina, rectum, and the round ligament of the uterus as
it traversed the inguinal canal. In an early influential
paper, ovarian “chocolate” cysts in 23 women were
described, thus giving the impression that the ovaries were the
most common site of pelvic involvement by endometriosis, even
though most of the chocolate cysts described in that paper were
corpora lutea. Because no teenager or meno-pausal woman
was among those 23 women with chocolate cysts of the ovary, the
notion was born that endometriosis was a disease of reproductive
years and that menopause was protective of it. In that intellectually
naive era, natural fertility was assumed to approach 100%. Since
about 60% of married women with endometriosis in that study had
been pregnant, it was assumed that pregnancy was protective against
the disease and that endometriosis severely decreased fertility.
Due to the fact that some endome-triosis histologically resembled
endometrium, the simplistic idea of reflux menstruation was born
as the mechanism of origin of the disease and reigned as the most
widely-held theory of origin until recently. Sampson’s
theory of reflux menstruation6 alleged that endometriosis arises
because particles of endometrium which are shed during menses
travel from the uterine cavity in a retrograde fashion out the
fimbriated end of the fallopian tubes. These cells then attach
to peritoneal surfaces, proliferate, and invade to become the
disease called endometriosis. Endometriosis was long regarded
as an incurable disease since the pelvis should be re-seeded with
disease each month during menses. Since endometriosis was
declared to be an autotransplant identical to endometrium, it
was thought to bleed each month during menses. This would
give lesions a largely hemorrhagic visual manifestation and led
to the notion of the “black powderburn” lesion as
the most common visual manifestation of disease. It was not until
the mid-1980’s that clinical researchers aided in large
part by the magnification of laparoscopy documented the frequency
of early, subtle, non-hemorrhagic disease, thus completing the
morphologic spectrum of endometriosis.7,8 The visual manifestation
of endometriosis which had been long accepted as the most common
was found to be one of the least common, immediately calling into
question anything published before that time.
A paradigm collapse had begun. When it was realized that early
gynecological authors didn’t know what endometriosis looked
like, and that endometriosis is curable by conservative surgery,
and that endometriosis differs in dozens of profound ways from
endometrium, and that evidence of initial attachment and secondary
invasion had been sought but never found9 and when supporters
of the theory of reflux menstruation steadfastly refused to supply
what should be easily-obtainable photodocumentation of initial
attachment and secondary proliferation and invasion by refluxed
endometrial cells (which allegedly occurs by the billions), finally
Sampson’s theory was discarded by most experts. The
fact that this theory survived so long with so many fatal contradictions
and no confirming evidence is remarkable but speaks poorly of
the gynecological profession, which used it for decades as a convenient
explanation for all treatment failures instead of blaming the
ineffective medical and surgical treatments which are used to
this day by some.
The origin of endometriosis
To be considered rational, any theory of origin of endometriosis
must satisfy what is known about the disease, including the following
facts.
It occurs as early as age 1010 and as late as age 7811. Evidence
of possible endometriosis has been found in the cul de sac of
a female
infant dying of Sudden Infant Death Syndrome.12
Early endometriosis can be very subtle in appearance and easily
missed, but may become more obvious over time thus giving the
incorrect impression new disease has appeared.13
It occurs in elderly males with metastatic prostate cancer who
undergo estrogen therapy.14,16
Endometriosis is not an autotransplant since it differs so fundamentally
from eutopic endometrium. These differences include morphologic,
histologic, immunohistochemical, enzymatic, gene expression, and
chromosomal makeup. Autotransplants essentially remain identical
to the native tissue of origin.17
Endometriosis is associated with an increased incidence of associat
abnormalities, including immunologic differences18,19, genetic
differences,20,23 and fundamental differences of the endometrium.24,26
Endometriosis does not spread geographically throughout the pelvis
with advancing age27,29 although local invasion or fibromuscular
metaplasia may occur and give the impression of slight local spread.29
Most untreated patients do not have progression of their disease.30,33
Endometriosis is curable by excision in over 50% of patients by
a single surgery,34,35 and in another 50% of patients by a second
surgery.(unpublished data)
Sampson did not have all the facts we have today, so his theory
was based largely on speculation. Under those circumstances
existing in that era, there would be a very low probability that
his theory should be correct.
The facts above inevitably point toward an embryonic origin of
the
disease. At the moment of conception genetic, environmental
and chance factors combine to result in tracts of target tissue
being laid down across the posterior coelomic cavity during pelvic
organogenesis. Given the small size and plasticity of the
embryo, and the variability which is the hallmark of biology,
these tracts can sometimes be located outside the pelvis, such
as on the diaphragm, in the brain, or in the lower extremities. These
tracts are the result of abnormal differentiation and migration
of Mullerian duct precursors and may contain rests of actual endometriosis
or simply carry the potential to undergo metaplasia under the
influence of estrogen production at puberty. At first, the
rests are colorless and inconspicuous, or tracts of mesencyhmal
target substrate may be undifferentiated and therefore unidentifiable.
With rising estrogen levels, the glandular elements begin to secrete
an unidentied paracrine product which can irritate tissue and
cause pain. Nearby capillaries can be destabilized and bleed.
Epithelial growth factors, chemokines and cytokines associated
with tissue repair in response to chronic injury result in angiogenesis,
neovascularity, and overlying fibrosis. Mesenchymal tracts associated
with parenchymal structures such as the uterosacral ligaments,
or muscularis of the bowel or bladder may undergo fibromuscular
metaplasia around small rests of endometriosis.
Thus, lesions that were once colorless or clear may become reddish,
then yellow or whitish due to fibrosis, then blackish when trapped
blood degenerates. Parencymal structures may develop progressive
nodularity and appropriate adhesion formation results from the
chronicity of the irritative process. Not all of these embryologically-patterned
tracts or rests will have the same inherent level of potential
biologic activity, either in the same pelvis or from woman to
woman. It is possible to see innocuous-appearing endome-triosis
in one part of the pelvis and angry, aggressive disease in another. Also,
not all disease will change in appearance over time, and some
women will have only superficial, colorless disease forever.
By the time a woman is in her mid-twenties, she has probably formed
most of the endometriosis she will ever form in her lifetime,
leading to the possibility of cure following complete excision.
Symptoms
Endometriosis causes geographically precise pain but can sometimes
produce more widespread pain. The cul de sac is the pelvic
area most commonly involved, so disease in this site is impacted
by intercourse, bowel movements, or sitting, resulting in pain
with those actions, particularly just before or during menses.
Endometrioma cysts of the ovary can cause ipsilateral pain, especially
if periovarian adhesions are stretched by cyst growth. Leakage
of cyst contents can cause acute severe pain lasting
several hours, with a more widespread pelvic and lower abdominal
discomfort lasting several days until the irritative liquid is
reabsorbed. Intestinal endometriosis may be asymptomatic
if it is superficial, while rectal nodules associated with complete
obliteration of the cul de sac will cause painful bowel movements
even away from menses. Invasive endometriosis of a uterosacral
ligament may involve the adjacent ureter with surrounding fibrosis
or rarely invade the ureter, resulting in symptoms of hydroureter
and hydronephrosis. If ureteral stricture is gradual, silent
permanent loss of kidney function may occur. Large nodules
of the terminal ileum may cause symptoms of partial bowel obstruction.
Right chest and shoulder pain associated with menses will be caused
by diaphragmatic endometriosis.
figure 1
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figure
1
Symptomatic endometriosis of the diaphragm (arrows) is usually
located on the posterior portion of the right hemidiaphragm. This
area cannot be seen easily with a laparoscope placed through
the umbilicus, but is always visible through a 5 mm laparoscope
advanced through a sheath placed beneath the right costal
margin, as seen in this frame.
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It is important to try to distinguish pelvic pain which may not
be due to endometriosis, otherwise diagnostic confusion will result
and outcome following treatment will be confounded. As one
important example, uterine cramping with menses is a symptom which
may not be due to endometriosis but which can be caused by adenomyosis
uterii, uterine leiomyomata, or primary dysmenorrhea.
Physical examination
Tenderness or nodularity of the cul de sac and uterosacral ligaments
during gentle stroking of these areas is pathognomonic of endo-metriosis.
Enlargement of an ovary may or may not be due to endometriosis.
Occasionally a patient may have endometriosis of the posterior
vaginal fornix figure 2 eroding through from a nodule of the uterosacral
ligament or rectum. This will be visible on office pelvic exam
if the speculum is directed posteriorly. Endometriosis of a cesarean
section scar or of the round ligament as it exits the inguinal
canal will manifest as a painful lump which may enlarge during
menses.
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figure
2
Endometriosis of the posterior vaginal fornix has caused
epithelial piling (within the circle). Vaginal endometriosis
may be associated with obliteration of the cul de sac and
results from extension of invasive disease of the uterosacral
ligaments or from a rectal nodule.
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Diagnosis
Since endometriosis is the leading cause of pelvic pain in women
of reproductive years, it should always be the first on the list
of differential diagnoses. In most patients, a presumptive
diagnosis of endometriosis can be made on the basis of a typical
history of pain combined with findings on pelvic exam. Imaging
tests are usually negative since most patients do not have ovarian
cysts or severe intestinal involvement.
Negative imaging tests in the face of significant symptoms will
not eliminate the need for surgical evaluation. When imaging
tests are positive, the patient usually has flagrant findings
on pelvic exam, such as tenderness and nodularity of the posterior
pelvis or ovarian enlargement.
In obese patients or patients with uterine cramping, imaging tests
may help augment findings on pelvic exam or suggest a non-endomtriotic
uterine pathology which would not respond to endometriosis surgery.
Given the
multi-organ system involvement possible with endometriosis, expert
surgical management will always include the capability of treating
pelvic, bowel, bladder, diaphragmatic or ureteral disease regardless
of imaging test results. For this reason, not all experts
in surgical treatment obtain any pre-operative imaging tests.
Surgery is the most accurate diagnostic test for endometriosis,
but the surgeon must be familiar with the all the possible appearances
of
endometriosis, ranging from the subtle to the extreme. figures
3-7
Medical treatment of symptoms
The historical observations that pregnancy might be protective
against endomeriosis and that the disease was rarely symptomatic
after menopause led to the development of medicines to mimic these
presumed beneficial hormonal states. Thus, birth control pill
or progesterone therapy mimicked pregnancy, while danazol and
gonadotropin-releasing hormone agonists mimicked menopause.
When these drugs were introduced, it was firmly believed that
endometriosis could be physically eradicated and cured by mimicking
the naturally occurring hormonal states which were assumed to
cure the disease.
Since no one had done the simple studies to prove that pregnancy
or menopause cured endometriosis, these hopes were unfounded and
were based on observations of symptom response rather than disease
response, a basic epidemiologic error. The only indication
for medical therapy of endometriosis is for temporary reduction
of symptoms. Since medical therapy has been shown not to
improve fertility, it is contraindicated for the treatment of
infertility associated with endometriosis.
Initial medical treatment of symptoms includes pain pills or birth
control pills. When the diagnosis of endometriosis is finally
suspected or confirmed by surgery, medicines more specific for
the treatment of endometriosis are begun. These include
gonadotropin-releasing hormone agonists, danazol, or gestrinone. Many
patients who do not respond to an initial round of medical therapy
are subjected to repeated medical therapy, which is obviously
nonsensical: if a therapy did not work the first or second time,
why would it work on the third or fourth attempt?
Pharmaceutical companies have observed that most gynecologists
do a poor job of treating endometriosis surgically and have promoted
medical therapy as a treatment choice for those clinicians who
are not expert at surgical
treatment. Thus, medical therapy is the hallmark of those
who are not experts in treating endometriosis.
Surgical treatment of endometriosis
Since medicines treat only symptoms, surgery is the only treatment
for endometriosis. The question then becomes: which form
of surgery will most completely eradicate endometriosis from the
body? Given the invasive nature of the disease, all experts
are in agreement that excision is the treatment of choice for
endometriosis. Excision is the only form of treatment which
has been documented to be able cure endometriosis by findings
at repeat surgery. Although thermal ablation by laser vaporization
and electrocoagulation are frequently used to treat endometriosis,
frequently these methods don’t burn deeply enough to destroy
all disease figures 8,9, and surgeons will be understandably hesitant
to burn over or on vital
structures invaded by the disease. Neither of these thermal
ablation treatments has documentation of efficacy as assessed
by repeat operation and electrocoagulation of endometriosis has
not been described in sufficient detail in the literature to be
used rationally in human females.
Techniques for excision of endome-triosis have been developed
which can treat any form of the disease anywhere in the body,
usually by laparoscopy. figures 10,11
Gynecological cancer is far less prevalent than endometriosis,
and surgery for advanced endometriosis is universally acknowledged
as being the most difficult in the gynecological repetoire.
For this reason, three levels of endometriosis care are recognized.
At the first level, symptoms may be treated medically by a general
practitioner or gynecologist. At the second level, a general
gynecologist diagnoses the disease surgically and treats by a
single attempt at superficial thermal ablation which should not
be repeated if unsuccessful. At the third level, an endometriosis
expert treats the disease by aggressive and complete surgical
excision, with the aid of urologists or general surgeons as needed.
figure 12 Relief of symptoms caused by endometriosis is predictable
and highly successful following aggressive excision of endometriosis.
Symptoms caused by other gynecological conditions will not be
affected by excision of endometriosis, and hysterectomy may be
indicated in some patients for treatment of uterine pathology
figure 13.
It is popular in some areas to treat endometriosis surgically
by removing something else, such as the uterus, tubes and ovaries.
The hope is that endometriosis will wither away in the absence
of estrogen. Since endometriosis occurs primarily on peritoneal
surfaces away from the female pelvic organs, this surgical strategy
will leave disease behind in most patients. Some 10% to 20%
of women will remain symptomatic because of their retained disease.
This may be explained in part by the fact that many lesions of
endometriosis contain aromatase enzyme, which is able to convert
circulating androstenedione into estrogen. So even in the
absence of endogenous or exogenous estrogen, endometriosis can
continue to produce its own estrogen and remain symptomatic.
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13
The posterior uterine fundus exhibits several darkly hemorrhagic
spots representing either adenomyosis or endometeriosis,
with adjacent neovascularity. Excision of endometriosis
will not treat uterine symptoms caused by such findings.
The cul de sac is completely obliterated, but the rectal
wall is flat, indicating that there is little or no rectal
involvement by endometriosis. The left ovary is cystic
and hidden beneath peritoneal folds which are adherent to
the left uterosacral ligament. Superficial glandular lesions
of endometriosis with faint fibrosis are seen on the right
broad ligament.
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The future
Research is being conducted into novel medical treatments directed
against aromatase enzyme or against the angiogenesis which accompanies
the development of some (but not all) lesions of endometriosis.
Since the origin of endometriosis is so closely tied to embyrological
and genetic factors, true prevention of the disease is likely
to require some type of gene therapy.
While there is still much to learn about endometriosis, it is
clear that throughout the world most women suffering from the
disease do not receive the most effective current treatment, which
is complete excision.
More good could be done more quickly for more women if excision
were adopted by more practitioners, with difficult cases quickly
referred to superspecialists in endometriosis surgery at select
centes of excellence around the world.
Dr. David B. Redwine
Head of the Endometriosis Treatment
Program at St. Charles Medical Center
Bend, Oregon
USA
