Clinical Expert Series

Clinical Management of Endometriosis

Tommaso Falcone, MD, FRCSC, and Dan I. Lebovic, MD

Endometriosis is a relatively common chronic gynecologic disorder that usually presents with
chronic pelvic pain or infertility. The societal effect of this disorder is enormous both in monetary
costs and in quality of life. The diagnosis of the disease can only be definitively made with
surgical intervention. Fertility may be enhanced with surgical intervention, but medical suppres-
sive therapy has no role apart from in vitro fertilization. Assisted reproductive technology is
associated with excellent outcomes. Management of endometriomas is particularly complex
because surgical intervention may reduce ovarian reserve. Both medical and surgical treatment
of endometriosis-associated chronic pelvic pain are effective in the short-term. Recurrence is
common with both modalities. Recurrence after surgical intervention can be decreased with the
use of postoperative suppressive medical therapy such as hormonal contraceptives. This article
presents the different types of peritoneal disease found in endometriosis patients. The technique
used to safely and completely remove the disease is discussed. The specific areas of involvement
include the pelvic side wall, the cul-de-sac, and bladder peritoneum.
(Obstet Gynecol 2011;118:691–705)
DOI: 10.1097/AOG.0b013e31822adfd1

T he presence of viable, estrogen-sensitive, endome-

trial-like glands and stroma associated with an
inflammatory response outside the uterus is globally
referred to as endometriosis. Three subtypes of endo-
metriosis are differentiated by gross and microscopic
inspection consisting of endometriomas (ovarian
cysts), superficial endometriotic implants (focus of
disease primarily on the peritoneum), and deeply
infiltrating endometriosis (rectovaginal nodules).
Each form may have its own etiology or share
origins with the other forms of this common
chronic gynecologic malady.1
From the Gynecology and Women’s Health Institute, Cleveland Clinic, Cleve-
land, Ohio; and the Division of Reproductive Endocrinology and Infertility,
Department of Obstetrics and Gynecology, University of Wisconsin-Madison,
Madison, Wisconsin.
Continuing medical education for this article is available at http://links.lww.com/
AOG/A253.
Corresponding author: Tommaso Falcone, MD, FRCSC, Professor and Chair
Obstetrics, Gynecology and Women’s Health Institute, Cleveland Clinic, 9500
Euclid Avenue, A81, Cleveland, OH 44195; e-mail: falcont@ccf.org.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2011 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/11
Incidence
This enigmatic disease affects 6 –10% of reproductive-
aged women2 and has been found in women between
the ages of 12 and 80 years. The average age at
diagnosis is approximately 28 years.3 Several condi-
tions show greater concordance with endometriosis:
21– 47% of women presenting with subfertility,4 71–
87% of those with chronic pelvic pain,5 and 69% of
adolescents with nonresponsive pelvic pain.6 Certain
phenotypes such as women with green or blue eyes or
a higher number of freckles may have greater preva-
lence of endometriosis.7,8 The significance of these
phenotypes is unclear and further confirmatory stud-
ies are required. Early menarche, short menstrual
cycles, low birth weight, and nulliparity are associated
with increased risk. Researchers have found that
endometriosis has a strong familial component; first-
degree relatives of individuals with endometriosis are
7- to 10-times more likely to have the disease de-
velop.9,10 Without noninvasive diagnostic testing, the
average time between onset of symptoms and a
definitive diagnosis is 7– 8 years. The diversity of
symptoms overlapping with other conditions contrib-
utes to this delay (Table 1). Surgery can confirm a
clinical diagnosis because it allows direct visual in-
spection of endometriotic lesions. When deeply infil-
trating peritoneal endometriosis is identified there is a

VOL. 118, NO. 3, SEPTEMBER 2011 OBSTETRICS & GYNECOLOGY 691

Table 1. Symptoms of Endometriosis12 this location would have a tendency to trap refluxed
Percentage of
endometrium in the right hypochondrium by the
Women With falciform ligament.14,15
Endometriosis A greater understanding of the molecular mech-
Presenting Confounding anisms associated with endometriosis has enhanced
Symptom With Symptom Disorders the traditional theories. Chronic inflammation with
Dysmenorrhea 79 Adenomyosis, primary increased cyclooxygenase-2 activity (and resultant
dysmenorrhea increased local aromatase activity), increased num-
Pelvic pain 69 Irritable bowel syndrome, bers of activated macrophages, and proinflammatory
neuropathic pain, cytokines are the predominant features of endometri-
adhesions
Dyspareunia 45 Psychosocial issues,
osis. Although most women have retrograde menses,
vaginal atrophy those who have endometriosis develop may have an
Bowel symptom 36 Hemorrhoids; constipation, inherent immune dysfunction that impairs normal
inflammatory bowel clearance yet promotes disease progression through
disease factors promoting adherence or invasion, angiogene-
Bowel pain 29 Anal fissures
Infertility 26 Unexplained subfertility
sis, and sensory, sympathetic, or parasympathetic
Ovarian mass 20 Hydrosalpinx, benign innervations (Fig. 2). Recent advances regarding the
or tumor ovarian cyst etiology of endometriosis must be applied judiciously
Dysuria 10 Cystitis in clinical practice to achieve optimal treatment
Other urinary 6 Interstitial cystitis outcomes.
problems
Mechanism of Pain
Many studies have noted the presence of increased
high likelihood of finding either superficial implants proinflammatory cytokines and growth factors in
(61%) or an endometrioma (51%).11,12 endometriosis that are closely related to pain sensa-
tion (ie, nerve growth factor, prostagladin, estradiol).16
Clinical Presentation and Importance This may explain why minimal endometriosis may
The majority present with a constellation of symp- still cause significant pain. Current evidence indicates
toms, including chronic pelvic pain, dysmenorrhea, that endometriosis is a hyperalgesic state that results
deep dyspareunia, dyschezia, and subfertility. Any of from augmented pain processing that is dictated by
these symptoms can negatively affect a woman’s the way the spinal cord and the brain process pain
physical, mental, and social well-being. Comorbid from the lesions and other sensory information. Pe-
ailments include asthma, fibromyalgia, irritable bowel ripheral nerve fibers supplying endometriotic lesions
syndrome, interstitial cystitis, temporomandibular could sensitize spinal segment neurons and eventually
disorder, melanoma, and migraines. The estimated lead to a central nervous system sensitization, result-
annual health care burden in the United States for ing in an exaggerated central nervous system re-
endometriosis exceeds $20 billion.13 This annual cost sponse or phantom-like endometriotic pain, or both,
actually supersedes that of Chron’s disease ($865 despite ablation of lesions.17–19 The multidimensional
million) or migraine care ($13–$17 billion). symptomology of endometriosis warrants multidisci-
plinary management strategies.20
Pathophysiology
Most experts would concur that the disease is multi- Mechanism of Subfertility
factorial in etiology (Fig. 1). Longstanding postulates Advanced cases of endometriosis often entail severe
include retrograde menstruation with refluxed men- adhesive disease that could pose an obvious impair-
struum implanting on pelvic structures, coelomic plu- ment to fertility by reducing tubo-ovarian motility,
ripotential mesothelial cells lining the peritoneum which ultimately impedes pick-up function. Whether
undergoing metaplasia into endometrial tissue, and milder forms of the disease even cause subfertility is
implantation of cells through hematogenous or lym- not certain. Infertile women with minimal to mild
phatic embolization. However, a conundrum persists: endometriosis had lower serum antimullerian hor-
why does the disease develop in some women and in mone levels on day 3 than infertile patients with tubal
others it does not? A study reporting a higher preva- obstruction.21 In a prospective study of therapeutic
lence of endometriosis in the right subphrenic region donor insemination (azoospermic partners), the
supports the retrograde menstruation theory because monthly fecundity was 0.13 in women without endo-

692 Falcone and Lebovic Clinical Management of Endometriosis OBSTETRICS & GYNECOLOGY
Fig. 1. Molecular predispositions to developing endometriosis. Retrograde menstruation deposited onto the peritoneal
surface is one of several pathophysiologic mechanisms purported to lead to endometriosis. Other theories are depicted in
this figure. Starting at the bottom and moving clockwise, these include: 1) candidate endometrial epithelial progenitor cells
and endometrial mesenchymal stromal or stem-like cells (eMSCs) may possess a greater propensity to avoid clearance,
attach, and invade ectopic locations; 2) and 3) metastatic spread of endometrial tissue through blood vasculature and
lymphatic channels; 4) altered immune cell population and functionality; 5) metaplastic differentiation of ovarian coelomic
epithelium; 6) refluxed endometrial tissue trapped between the pelvic sidewall and ovary that then colonizes a hemorrhagic
corpus luteum; 7) rectovaginal Mullerian remnant; and 8) Mullerianosis hypothesis of embryonic endometrial tissue
ectopically placed during organogenesis. Illustration: John Yanson.
Falcone. Clinical Management of Endometriosis. Obstet Gynecol 2011.

metriosis and 0.09 in those with minimal endometri- DIAGNOSIS

osis, although this study was underpowered to reveal
statistical significance.22 In minimal or mild endo-
metriosis, the biologic mechanism causing infertil-
ity remains elusive. Once again, an enhanced im-
mune response may be the culprit by impairing
fertility in early-stage disease.23 A hostile peritoneal
environment may lead to impaired sperm function
through increased sperm DNA damage24 and a
compromised oocyte cytoskeleton.25 Another the-
ory places the onus on an endometrial defect based
on reports of decreased expression for several
biomarkers of implantation.26 –30 Unfortunately, en-
dometriosis is associated with an increased risk
for preterm birth, antepartum complications, and
pre-eclampsia.31
Laparoscopy is considered the “gold” standard for the
diagnosis of endometriosis with visual identification
of classic endometriosis lesions. Histologic confirma-
tion is helpful because visual identification is associ-
ated with a high false-positive rate.32,33 The extent of
disease is usually staged by the American Society for
Reproductive Medicine scoring system, which differ-
entiates minimal and mild disease as stage I and stage
II, and moderate and severe disease as stage III and
stage IV.33 Although there is debate on the usefulness
of this classification for chronic pelvic pain associated
with endometriosis, it is helpful for disease quantifi-
cation. A noninvasive diagnostic test for endometrio-
sis may obviate the necessity to perform surgery.
However, none exists at this moment.32

VOL. 118, NO. 3, SEPTEMBER 2011 Falcone and Lebovic Clinical Management of Endometriosis 693

Imaging modalities are typically used in the in-
vestigation of chronic pain or in the preoperative
assessment of patients who will undergo surgery for
known endometriosis. The sensitivity of imaging is
dependent on the phenotype of the endometriosis
lesion (ie, ovarian cysts, peritoneal disease, or deeply
infiltrating endometriosis). Pelvic ultrasonography is
the modality of choice for the investigation of women
with chronic pain thought to be endometriosis-related
as well as for the assessment of adnexal masses and
deep endometriosis. Ultrasonography has high sensi-
tivity (84 –100%) and specificity (90 –100%) in identi-
fying ovarian endometriomas with their characteristic
low-level, homogeneous, internal echoes.32
Deeply infiltrating endometriosis is typically found
in the area of the utero-sacral ligaments, vagina,
rectum, or bladder. Transvaginal and transrectal ul-
trasonography and magnetic resonance imaging are
the most commonly used modalities. Transvaginal
ultrasonography has a diagnostic accuracy similar to
magnetic resonance imaging 32 for most deeply infil-
trating disease and should be the modality of choice
when it is suspected. Magnetic resonance imaging has
higher diagnostic accuracy for vaginal and bladder
694 Falcone and Lebovic Clinical Management of Endometriosis
Fig. 2. Molecular predispositions to
developing endometriosis. Illustra-
tion: John Yanson.
Falcone. Clinical Management of
Endometriosis. Obstet Gynecol 2011.
endometriosis and should be considered in cases in
which transvaginal ultrasonography is equivocal.
Transvaginal ultrasonography with water contrast in
the rectum may improve accuracy of this modality for
detecting colorectal endometriosis.
There is no imaging modality that has a high
diagnostic accuracy for peritoneal endometriosis or
adhesions. CA 125 has poor diagnostic accuracy and
has no value in the investigation of a patient with
chronic pelvic pain.33 In the diagnostic approach to
endometriosis-associated pelvic pain, the clinician
should always consider the extensive differential di-
agnosis and possible contributors to the pain syn-
drome. These include pelvic inflammatory disease,
adhesions, irritable bowel syndrome, interstitial cysti-
tis, myofascial pain, depression, and a history of
sexual abuse.
Natural Course of Endometriosis
A priori medical therapy is not a diagnostic tool but is
a reasonable option, especially if it mitigates symp-
toms. Nevertheless, it is vitally important to develop a
long-term treatment approach because of the chronic
relapsing nature of endometriosis. A window into the
OBSTETRICS & GYNECOLOGY
short-term natural course of the disease is gleaned endometriotic implants may not be adequate to pre-
from randomized studies wherein one treatment arm dict disease progression or regression.35 One must
consisted of a placebo control group undergoing a remember that the follow-up was rather short; in 75%
baseline diagnostic laparoscopy followed by a 6- to of these studies, the subsequent laparoscopy occurred
39-month follow-up laparoscopy. Combining all the after less than 1 year. Given the known recurrence
placebo participants provides a total of 162 women rate for endometriosis over time, without medical
who revealed a disease in flux, with nearly equal therapy, more women will likely have their endome-
distribution between deterioration (31%), unchanged triosis track toward disease progression rather than
endometrial disease (31%), and improvement (38%). resolution.36,37 In addition, pain sensation does not
In fact, all but two studies noted the number of necessarily correlate with identification of lesions.14
placebo patients who had complete disease regres- The mechanisms responsible for ongoing symptom
sion, and this occurred in approximately one-quarter expression likely are complex and multifactorial.
of the women (Table 2). One caveat to this group,
however, is that 11–25% of biopsy samples of grossly SUBFERTILITY
normal peritoneum in endometriosis patients are his- Even though the causes of endometriosis-associated
tologically positive for endometriosis.4,34 The clinical subfertility remain obscure, one thing is certain, sub-
implication of this observation is unclear. Another fertile women have endometriosis at a greater preva-
shortcoming is that the current system used to score lence, 20 –50%, than reproductive-aged women not
seeking fertility treatment.38 In one study of infertile
women, the incidence distribution was surprisingly
Table 2. Natural Course of Endometriosis robust for minimal-to-mild cases at 68%, whereas
Increase Decrease in women with moderate-to-severe disease constituted
in No Disease the remaining 32%.39 The current classification scheme
Study Disease Change 关Elimination兴* is not useful in predicting spontaneous pregnancy
rates.40 The monthly fecundity rate for those with endo-
Thomas EJ, 1987†120
Stage I–III (n⫽17) 47 (8) 24 (4) 29 (5) 关18 (3)兴 metriosis is 0.02– 0.10 compared with 0.15– 0.20 in
6-mo follow-up L/S fertile couples,41 although the rate is not necessarily
Telimaa S, 1987†121 lower than in those patients with unexplained subfertil-
Stage I–II (n⫽17) 25 (4) 63 (10) 19 (3) 关13 (2)兴 ity.42 There is no evidence of an association with recur-
6-mo follow-up L/S rent pregnancy loss.43
Cooke ID, 1989†122
Stage I–II (n⫽17) 47 (8) 24 (4) 29 (5) 关18 (3)兴 Donor egg in vitro fertilization (IVF) programs
6-mo follow-up L/S offer some insight on possible deleterious effects of
Mahmood TA, 1990†123 this disease. The salient points from these retrospec-
Stage I–III (n⫽11) 64 (7) 9 (1) 27 (3) 关9 (1)兴 tive studies are that implantation and clinical preg-
9–18-mo follow-up nancy rates were similar between those with and
L/S
Overton CE, 1994†124 those without disease when donor eggs from women
Stage I–II (n⫽15) 27 (4) 20 (3) 53 (8) 关NR兴 without endometriosis were used, and oocytes origi-
6–9-mo follow-up nating from women with endometriotic ovaries and
L/S donated to disease-free women led to reduced im-
Sutton CJ, 1997125 plantation rates.45 In the former situation, recipients
Stage I–III (n⫽24) 29 (7) 42 (10) 29 (7) 关4 (1)兴
6–39-mo follow-up with endometriosis may not have experienced dimin-
L/S ished clinical pregnancy rates because they all first
Harrison RF, 2000†126 underwent pituitary suppression with leuprolide ace-
All stages (n⫽43) 9 (4) 28 (12) 63 (27) 关44 (19)兴 tate, which has the potential to normalize the immune
4–6-mo follow-up deficiencies that could otherwise adversely affect clin-
L/S
Abbott J, 200483 ical pregnancy rates.
All stages (n⫽18) 44 (8) 33 (6) 22 (4) 关(NR)兴
6-mo follow-up L/S MEDICAL THERAPY TO AID FERTILITY
Total (n⫽162) 31 (50) 31 (50) 38 (62) 关22 (29)兴 Using medical therapy in the form of ovarian suppres-
L/S, laparoscopy; NR, not reported. sion for stage I or II endometriosis does not improve
Data are % (n) unless otherwise specified. fecundity rates and should not be offered.46 Supple-
* Data in brackets in this column signify total elimination of
disease on second-look laparoscopy. menting treatment after operative laparoscopy for
†
Infertile patients. stage III or IV endometriosis with a gonadotropin-

VOL. 118, NO. 3, SEPTEMBER 2011 Falcone and Lebovic Clinical Management of Endometriosis 695
releasing hormone agonist (GnRH) does not appear
to be superior to expectant management in terms of
natural conception rates during a 5-year follow-up
period in a randomized controlled trial.47 Moreover,
this therapy delays conception. In a Cochrane Review
of three randomized controlled trials, 3 to 6 months of
ovarian suppression with a GnRH agonist before IVF
in women with stage II–IV endometriosis led to a
fourfold increase in clinical pregnancy rates.48
If ovarian suppression before fertility treatment is
of no value except before IVF, then would the use of
fertility medicine for controlled ovarian stimulation
assist in the treatment of endometriosis-associated infer-
tility? Several studies do reveal a benefit to utilizing
superovulation drugs such as clomiphene citrate or
gonadotropins along with intrauterine inseminations.49
However, these conservative methods are not recom-
mended in women with advanced endometriosis who
have a distorted pelvic anatomy, but only in those with
mild peritoneal disease.
Although assisted reproductive technology can cer-
tainly improve pregnancy rates for women with endo-
metriosis, there is debate as to whether a suboptimal
outcome is obtained compared with other groups such
as tubal factor patients undergoing in vitro fertilization.
A meta-analysis concluded that there was a significant
diminution of success rate for stage III or IV (13.8%) as
opposed to the control group (27.7%).50 In contrast, the
2008 Centers for Disease Control and Prevention U.S.
National Assisted Reproductive Technology Registry
showed live birth rates to be similar for endometriosis
patients and those with tubal factor (33.4%).51 Unfortu-
nately, the Centers for Disease Control and Prevention
database does not differentiate by disease stage. Further-
more, administrative registries are not designed for
research because of diagnostic misclassification. Given
the potential benefits of GnRH agonist downregulation
observed for endometriosis recipients of donor embryos
and with 3 to 6 months of pre-IVF therapy, it is
conceivable that conventional short-term GnRH agonist
suppression during IVF cycles also may normalize the
milieu such that success rates would be comparable to
women without endometriosis. On a related and reas-
suring note, the cumulative endometriosis recurrence
rates do not seem to be increased after IVF.52–54
SURGICAL THERAPY TO AID FERTILITY
Despite the aforementioned theories explaining why
stage I or II may lead to subfertility, there is no convinc-
ing evidence to date. Surgery can eradicate visualized
lesions but may not fully resolve the biomolecular
alterations associated with chronic inflammation that
could adversely affect fertility. Augmentation of fertility
696 Falcone and Lebovic Clinical Management of Endometriosis
by laparoscopic endometriosis surgery for stage I or II is
based on two randomized trials that revealed a modest
benefit with a number needed to treat of 12.55 In other
words, one additional pregnancy would be gained from
performing the surgery for every 12 patients. Because
the a priori diagnosis of endometriosis is not absolute,
the number undergoing surgery to meet this additional
pregnancy is most likely more than 12. When counsel-
ing a patient seeking fertility treatment and weighing
surgery, one should consider the degree of pain to help
decide if ablative surgery might improve fertility and
ameliorate pain. There is no randomized fertility trial
assessing the value of surgery with stage III or IV
disease. In a nonrandomized trial, surgery for rectovagi-
nal endometriosis did not improve fertility rates.41 In this
study, pregnancy rates were similar but the surgery did
benefit pain control and recurrence. The reported preg-
nancy rate is between 40% and 50% after surgery for
advanced endometriosis.56
There are two studies that suggest removing deeply
infiltrating endometriosis may help IVF outcomes.57,58
These studies were not randomized controlled trials. In
the study by Bianchi et al,57 the group treated surgically
before IVF had a higher pregnancy rate but required
more gonadotropins and obtained fewer oocytes in the
IVF cycle. In patients with previous surgery for ad-
vanced endometriosis, repeat surgery was inferior to
IVF regarding pregnancy rates.59 However, if surgery is
performed for pain, the pregnancy rates are approxi-
mately 20 –25% over a 9-month period.59 There is no
controlled study to determine if surgical excision of
moderate-to-severe endometriosis enhances fecundity
with IVF, and it is generally not recommended unless
performed for pain relief as well.
Endometriomas
Endometriomas represent the most significant challenge
for the practicing clinician. The overall weighted mean
pregnancy rate reported after laparoscopic cystectomy is
approximately 50%.56 These uncontrolled studies prob-
ably overestimate the spontaneous pregnancy rate
because some of the included trials did not indicate if
IVF was utilized postoperatively. Even if we estimate
half this pregnancy rate, the number needed to treat
would be four. Because endometriomas are easily
detected preoperatively, the number of laparoscopies
needed to achieve these pregnancies would be simi-
lar. Two randomized clinical trials have shown that
cyst excision is associated with higher spontaneous
pregnancy rates than other techniques.60,61 Systematic
reviews have concluded that surgical management of
endometriomas 3 cm or larger has no benefit over
expectant management on assisted reproductive tech-
OBSTETRICS & GYNECOLOGY
nology pregnancy rates.62,63 In general, surgery may
diminish the responsiveness to gonadotropins and
thus adversely affect the number of retrieved oocytes,
yet there does not seem to be a significant effect on
pregnancy outcomes64 – 66 Because a contralateral in-
tact ovary can adequately compensate for the dimin-
ished function of the operated side, the ultimate
concern would be for bilateral disease or for the effect
on numbers of frozen embryos. If the overall oocyte
yield is lower in IVF cycles, then it should follow that
there may be fewer supernumerary embryos or that
they may be of lesser quality.
Antimullerian hormone and antral follicle count
are extensively used to measure ovarian reserve. In a
study comparing endometrioma to nonendometri-
oma cystectomy, antimullerian hormone decreased
postoperatively to lower levels in the endometrioma
group. Bilateral cystectomy was associated with even
lower antimullerian hormone.67 In 53 women with
endometriomas, the ovary that contained a cyst had a
lower antral follicle count than the contralateral
ovary.68 A retrospective study among 93 women
reported a 13% rate of complete unresponsiveness to
gonadotropin stimulation in the ovary that had an
excised endometrioma.69 We have insufficient evi-
dence to assess whether there are endometrioma-
related adverse effects on ovarian responsiveness that
antedate or follow surgery. A nonrandomized retro-
spective study in 28 infertile patients provided a
window into this issue; laparoscopic cystectomy for
small endometriotic cysts smaller than 4 cm led to a
diminished ovulatory rate in the operated ovary from
41% to 19%.70 If controlled ovarian stimulation or
assisted reproductive technology is going to be uti-
lized after surgery for an endometrioma, then there is
insufficient evidence to favor cystectomy over aspira-
tion at the time of surgery.63,71
The technique of endometrioma removal may be
critical to preserving ovarian function. Involvement
of the ovary is often associated with deeply infiltrating
endometriosis, which requires extensive surgical re-
section. The fertility outcomes of a laparoscopic ap-
proach are similar to those of laparotomy with a faster
recovery. Excision of the cyst is the treatment of
choice. It is imperative to use techniques that reduce
ovarian damage such as cautious use of electrocautery
especially at the hilus. Preliminary experience with a
matrix hemostatic sealant has been shown to be
effective.72 In a prospective randomized clinical trial,
the use of intraovarian suturing to achieve hemostasis
was associated with fewer adhesions at second-look
laparoscopy compared with the exclusive use of elec-
trocautery.73 Excision of the cyst requires identifying
VOL. 118, NO. 3, SEPTEMBER 2011 Falcone and Lebovic
the correct plane of cleavage, which is challenging.
Evidence shows that normal ovarian tissue is commonly
removed with the endometrioma wall.74 Furthermore,
the larger the cyst diameter, the more normal ovarian
tissue is removed.74,75
Cystectomy often is started by lysing adhesions
between the ovary and the broad ligament. At this
time, the cyst commonly ruptures. Cystectomy can be
performed by finding a cleavage plane between the
ovarian cortex and the cyst wall and simply stripping
the cyst after incision. The endometriosis tissue typi-
cally penetrates the cyst wall less than 2 mm. Where
the cyst wall is very adherent to cortex, the area
should be cut rather than simply pulled to not remove
ovarian tissue.74,75 The use of preoperative medical
suppressive therapy was shown in one study to be a
risk factor for removal of normal ovarian tissue.76 A
recent technique involves stripping away most of the
cyst and then ablating the remaining cyst wall at the
hilus, a procedure that seems to be associated with
decreased ovarian trauma, as demonstrated by post-
operative antral follicle count.77 Further research is
required before adopting this technique because recur-
rence rates may be higher from other less experienced
centers. Recurrence of endometriomas has been re-
ported to be between 6% and 17%.60,61 In patients not
desiring immediate fertility, cyst recurrence was reduced
from 29% to 15% in cyclic oral contraceptive users and
to 8% in continuous oral contraceptive users.78
Overall, surgery seems to improve spontaneous
pregnancy rates. Because the monthly fecundity rate
after surgery is low, ample time should be available to
achieve pregnancy in women who are younger than
35 years, typically 9 –12 months before proceeding to
further infertility treatment. The evidence suggests
that surgery for endometriosis is not required before
IVF, except in patients who require pain management
or excision of a large endometrioma. In general, if an
endometrioma is at least 4 cm in diameter, consider-
ation should be given to removal of the cyst before
IVF because of a question of malignancy (approxi-
mately 2% risk), improved transvaginal access to
ovarian follicles, and the fact that endometriomas do
not regress.79 Removal of an endometrioma may
affect ovarian reserve, especially with bilateral cysts.
MANAGEMENT OF CHRONIC PELVIC PAIN
ASSOCIATED WITH ENDOMETRIOSIS
Generally, most chronic pelvic pain symptoms are
treated with analgesics and the birth control pill after
a thorough history, physical examination, and appro-
priate imaging. Empiric therapy with a GnRH agonist
or an injectable progestin also can be considered. If
Clinical Management of Endometriosis 697
these fail, then diagnostic laparoscopy is usually per-
formed to confirm the diagnosis and extirpate as
much endometriosis as possible. What is clear is that
most of these approaches are ineffective long-term. A
recent Canadian study80 of more than 53,000 admis-
sions showed that 25% of patients who had an initial
surgical treatment for endometriosis required addi-
tional surgery within 4 years and that 10% required a
hysterectomy. Continual medical management is pre-
ferred over serial surgeries. Surgical management of
endometriosis-associated pain is provided online (see
video at http://links.lww.com/AOG/A254).
A Cochrane database analysis concluded that lapa-
roscopic surgery for endometriosis is superior to diag-
nostic laparoscopy alone.81 The odds ratio was 7.72
(95% confidence interval 2.97–20.06). There are sev-
eral observations that can be gleaned from the ran-
domized clinical trials. First, not all patients respond
to surgical removal of endometriosis.82,83 The re-
sponse rate at 6 months ranges between 66% and
80%. This variable response rate can be attributed to
the fact that there were fewer patients with stage I
disease in the study with the higher response rate.
Second, both studies reported a placebo effect rang-
ing between 22% and 32%.
A large number of case series have been pub-
lished on pain recurrence or reoperation for pain
recurrence after an initial surgical procedure.84 Publi-
cations on surgical outcomes are dependent on sur-
geon experience and they contain a large number of
unreported confounding variables such as operator
experience, use of postoperative suppressive therapy,
the duration of follow-up, and publication bias. All
published studies have reported symptom recurrence
after an index surgery. Recurrence of symptoms after
surgery requiring reoperation is progressive with time
and is generally reported to be approximately 15% at
1 year, 36% at 5 years, and 50% by 7 years.84 – 86 The
cause could be incomplete resection of disease at the
index surgery (persistent disease) or true disease
recurrence. Endometriosis is often not identified in
follow-up reoperation studies of patients with chronic
pelvic pain associated with endometriosis.
Prevention of recurrent pain symptoms after sur-
gery with suppressive therapy such as progestins or
oral contraceptives is effective.87 However, symptoms
rapidly recur after medical therapy is discontinued.
Recurrence of endometriomas also can be prevented
with the use of postoperative oral contraceptives.87 Sim-
ilarly, GnRH agonists or danazol are effective as sup-
pressive therapy in prevention of recurrence of pain
symptoms, but side effects preclude their long-term use.
Although not approved for endometriosis by the U.S.
698 Falcone and Lebovic Clinical Management of Endometriosis
Food and Drug Administration, the levonorgestrel-re-
leasing intrauterine system was shown to be effective in
reducing chronic pain after conservative surgery.88
Surgical technique for treatment of endometriosis
is often dependent on surgeon preference. At laparos-
copy, surgeons should clearly document the location
and extent of disease. They should consider using the
American Society of Reproductive Medicine classifi-
cation system or photo documentation. There is de-
bate on whether excision or ablation of endometriosis
is best. A recent randomized controlled trial seems to
shows equal benefit to excision and ablation for early-
stage superficial disease.89 Caution should be used when
ablating near the ureter. More advanced disease and
deeply infiltrating disease as well as endometriomas will
require excision.
Although presacral neurectomy is effective in treat-
ing midline pain for the short-term, laparoscopic utero-
sacral nerve ablation does not improve pain symp-
toms.90 A presacral neurectomy is associated with
increased frequency of postoperative constipation and
urinary urgency. Adhesion prevention is an important
concept of pelvic surgery. Surgical technique that limits
tissue damage is imperative. No energy modalities
have proven to be risk-free and the general goal is to
minimize thermal damage. There is insufficient high-
quality evidence to support the routine use of phar-
macologic agents, icodextrin 4% (Adept, Baxter), or
dextran in adhesion prevention after surgery.91 Ico-
dextrin 4% was shown to reduce but not eliminate
adhesion scores (reformation) when used during lapa-
roscopic surgery for endometriosis.92 Although not
approved for laparoscopy, one study found that oxi-
dized regenerated cellulose (Interceed, Ethicon)
seemed effective in preventing reformation of adhe-
sions if the conditions were ideal, such as excellent
hemostasis and no extra irrigating fluid.93
Definitive surgical therapy for endometriosis-as-
sociated pain is clearly successful in alleviating symp-
toms.86 The main debate is whether the ovaries should
be removed. Recent data with a median 7-year fol-
low-up have shown that in women undergoing hys-
terectomy with ovarian preservation, the reoperation-
free percentages at 2, 5, and 7 years were 95%, 86%,
and 77%, respectively, compared with 96%, 91%, and
91% in those without ovarian preservation. A subset
analysis showed that the differences were not statisti-
cally significant in the 30- to 39-year age group.
Therefore, removal of normal ovaries at definitive
surgery for endometriosis-associated pain should be
decided on a case-by-case basis with a full discussion
of the risks associated with oophorectomy. We rec-
ommend a conservative approach with normal ova-
OBSTETRICS & GYNECOLOGY
ries, but excision of all visible disease should be
undertaken at the time of hysterectomy.
Medical Management of Endometriosis-
Associated Pain
Conservative surgical intervention is associated with
recurrence of pain. Therefore, medical management
is commonly used to alleviate the symptoms of this
chronic disorder. There are many randomized place-
bo-controlled studies showing the superiority of these
drugs over placebo.87 As with surgery, there is a
significant “placebo effect” and recurrence of pain
after discontinuing the medication is high. Medical
suppressive therapy does not influence fertility.
The most important principal to remember is that
medical management is effective but that symptoms
tend to recur rapidly after therapy is stopped. There-
fore, first-line medical therapy should focus on drugs
that can be used in the long-term (Table 3). Nonsteroi-
dal anti-inflammatory drugs may be used to control
pain; however, if these fail, suppressive medical ther-
apy is commonly used. The general principal is to
induce amenorrhea. As a first-line treatment, oral
contraceptives or progestins are the treatment of
choice.87 Dysmenorrhea recurrence rates are lower
with continuous oral contraceptives than with cyclic
administration, although there was no difference in
dyspareunia and nonmenstrual pelvic pain.78 It seems
logical that a regimen that reduces menstrual bleeding
would be the treatment of choice. Oral contraceptives
are well-tolerated, cost-effective, and are as clinically
effective as danazol and GnRH agonist.87
Oral progestins have been used for endometriosis
with excellent pain relief. The C21 steroids such as
medroxyprogesterone acetate are only effective orally
at high doses, with significant side effects and possible
untoward effects on high-density lipoprotein.87 Nor-
ethindrone acetate, a Food and Drug Administration-
approved drug for endometriosis, is a 19-nortestoster-
one progestin. It has been shown to be effective even
with rectovaginal endometriosis.94 Subcutaneous de-
pot medroxyprogesterone acetate, approved by the
Food and Drug Administration, also has been shown
to be effective in controlling endometriosis-associated
pain.87 These drugs are appealing because they can be
used for long-term treatment. Breakthrough bleeding
is the most common side effect that leads to discon-
tinuing therapy.
Gonadotropin-releasing hormone agonist ther-
apy has been shown to be effective in many clinical
trials and several drugs are approved by the Food and
Drug Administration.95 There is no oral form. The
main limitations for this class of drugs are the adverse
effects and cost. These drugs induce a hypogonadal or
hypoestrogenic state. The use of this drug class in
postmenopausal women is not logical. The adverse

Table 3. Drugs Used for the Treatment of Endometriosis

Class Drug Dosage

Androgen Danazol* 100–400 mg orally twice a day

100 mg per vagina daily
Aromatase inhibitor Anastrozole† 1 mg orally daily
Letrozole† 2.5 mg orally daily
Estrogen-progestin combinations Monophasic Low ethinyl estradiol dose continuously
Estrogen-progestin*
Gonadotropin-releasing hormone Goserelin*† 3.6 mg SC monthly (10.8 mg IM every 3 mo)
agonist Leuprolide depot*† 3.75 mg IM monthly (11.25 mg IM every 3 mo)
Nafarelin*† 200 micrograms intranasally twice a day
Gonadotropin-releasing hormone Cetrorelix 3 mg SC weekly
antagonist
Progestin Depo-subQ Provera 104* 104 mg/0.65 mL SC every 3 mo
Dienogest 2 mg daily‡
Etonogestrel-releasing implant 1 for 3 y
Levonorgestrel-releasing IUS 1 for 5 y
Medroxyprogesterone acetate 30 mg orally daily for 6 mo, then 100 mg IM
every 2 wk for 2 mo, then 200 mg IM
Monthly for 4 mo
Norethindrone acetate* 5 mg daily
SC, subcutaneously; IM, intramuscularly; IUS, intrauterine system.
* FDA-approved for endometriosis.
†
With add-back, ie, norethindrone acetate 5 mg daily plus vitamin D 800 international units daily plus calcium 1.25 gm daily.
‡
Dienogest is a 19-nortestosterone derivative that is approved in the European Union for treatment of endometriosis. It is not available
in the United States as a separate drug. It is available only in the oral contraceptive Natazia (Bayer HealthCare Pharmaceuticals;
estradiol valerate/dienogest), which is a newer, four-phasic pack that contains dienogest.

VOL. 118, NO. 3, SEPTEMBER 2011 Falcone and Lebovic Clinical Management of Endometriosis 699
effects include vasomotor symptoms, insomnia, mem-
ory impairment, mood disorders, urogential atrophy,
and loss of bone mineral density. The loss of bone
density is approximately 6% per year and may take
years to reverse. Although there is no fracture data to
correlate this with, it is concerning given that there is
a bone mineral density loss of 3.3% annually within
the first 2 years after the final menstrual period.96
To minimize these adverse effects, “add-back”
steroid therapy is recommended.97 The use of add-
back therapy has been shown to increase compliance
with treatment.98 Norethindrone acetate 5 mg alone
or oral conjugated estrogens 0.625 mg with norethin-
drone 5.0 mg daily has been shown to effectively
reduce vasomotor symptoms, preserve bone mineral
density, yet maintain pain relief similar to patients on
an agonist without add-back. Norethindrone may be
more effective than other progestins in preventing
bone loss because of its estrogenic metabolites.99 If
women cannot tolerate the high doses of norethin-
drone, then transdermal estradiol 25 micrograms per
day with medroxyprogesterone acetate 5.0 mg orally
daily was shown to diminish vasomotor symptoms.100
The only Food and Drug Administration-approved
add-back drug is norethindrone acetate 5 mg daily.
We suggest starting add-back therapy immediately
with the start of the GnRH agonist. Treatment is
usually for 6 months. If retreatment is required, then
the GnRH agonist should only be used with add-back
therapy. Higher doses of estrogen or the use of oral
contraceptives seems to prevent hyopestroegnic side
effects but are less effective in reducing pain symp-
toms and are not recommended.101 We advise daily
supplemental calcium 1,200 mg and vitamin D 800
international units.
A 6-month course of GnRH agonist is recom-
mended with a 6-month retreatment for recurrent
pain. Use of a GnRH agonist for more than 1 year is
not Food and Drug Administration-approved. If after
discussion with the patient it is decided to extend the
use of the GnRH agonist, then we recommend a bone
density scan. If the results show any osteopenia, then
estrogen should be added to the regimen. We recom-
mend immediately starting the patient on a hormonal
contraceptive agent once the agonist is stopped. If the
combined oral contraceptives are unacceptable for
medical or personal reasons, then an equally effective
option would be an oral progestin, such as norethin-
drone 5 mg, or a long-acting one, such as depotme-
droxyprogesterone acetate 104 mg subcutaneous or
the progestin intrauterine system.
Danazol is an oral medication with androgenic
properties that has been shown to be effective in
700 Falcone and Lebovic Clinical Management of Endometriosis
controlling pain symptoms. However, its side effect
profile of weight gain, acne, and hirsutism make it
unacceptable. The drug originally was administered
in doses that induced amenorrhea. New approaches
to deliver this medication, such as vaginally in lower
doses or in an intrauterine system may make this drug
more appealing.102
Several drugs without Food and Drug Administra-
tion approval have been used to treat chronic pain
associated with endometriosis. The levonorgestrel-con-
taining intrauterine system (Mirena, Bayer HealthCare
Pharmaceuticals) has been shown to be effective in
several studies for treating endometriosis-associated
pain.87 Letrozole and anastrozole are aromatase inhibi-
tors that have been used with some success in case
series. In premenopausal women they must be used
with drugs that suppress gonadotropins to prevent be-
nign ovarian cyst production. Letrozole combined with
norethindrone acetate was shown to be more effective
than norethindrone alone, but with more side effects.103
As with other drugs, symptoms recur after the medica-
tion is stopped.103 Some patients with deeply infiltrating
disease may not respond sufficiently to anastrozole.104
In summary, both medical and surgical treatment
of chronic pelvic pain associated with endometriosis
are associated with recurrence, probably as a result of
peripheral and central nervous system sensitization as
well as myofascial dysfunction. In these patients, a
multidisciplinary approach is required that includes
not only therapy directed specifically at the endome-
triosis lesion but also specific management of pain.
This involves the a comprehensive pain management
team and physical therapy.
Management of Intestinal, Urinary Tract, and
Extrapelvic Endometriosis
Endometriosis involving the bowel usually occurs in
the area of the rectovaginal septum and is associated
with typical endometriosis symptoms (eg, dysmenor-
rhea and dyspareunia) and also dyschezia and, less
commonly, blood loss. Excision of this disease is the
most challenging surgery for endometriosis. Excision
of all disease and, occasionally, bowel resection is
necessary. Bowel resection has been reported in
numerous trials.56,105 After resection, pain symptoms
have been reported to improve by at least 70%, with
rate of pain symptoms recurrence ranging from 0% to
34%.106 All large case series report complications. The
complications of bowel resection for endometriosis
occur in the short-term, and these include anastomo-
sis leak, pelvic abscess and fistula, as well as bladder
and bowel dysfunction and stricture.106 The indica-
tions for bowel resection have not been consistently
OBSTETRICS & GYNECOLOGY
reported but are generally related to the size of the
lesion (more than 2–3 cm), the percent of the circum-
ference involved (one-third the rectal circumference),
and the depth of invasion into the inner muscularis
layer. Recent literature supports a primarily laparo-
scopic approach. Pregnancy rates range between 34%
and 57% in small case series.107–109 Pain outcomes
from rectal nodule excision without segmental bowel
resection seem to be similar.77,110,111 Regardless of the
type of bowel excision performed, it will be necessary
to remove endometriosis on the posterior vaginal
fornix. Typically, pelvic sidewall surgery also will be
required with extensive dissection of the ureter. Other
areas of bowel involvement are sigmoid colon, appen-
dix, cecum, and terminal ileum. These areas should
be carefully evaluated at laparoscopy and treatment
should be determined by the visual identification of
the lesion. Routine removal of a normal-appearing
appendix at the time of laparoscopic surgery for
pelvic endometriosis should be considered. As dis-
cussed, the use of postoperative oral contraceptive or
other long-term suppressive therapy will prevent re-
currence of postoperative pain.111
Most endometriosis that envelopes the urinary
tract involves the part of the peritoneum that is
located over the ureter and bladder. Invasion of
deeper structures such as the bladder muscularis or
extrinsic ureteral compression is less common. Clin-
ical manifestations of bladder involvement include
nonspecific urinary symptoms that may occur during
menstruation. Ultrasonography and cystoscopy are
the first diagnostic procedures. Magnetic resonance
imaging is recommended if no lesion can be identified
by test or if further delineation of the extent of
involvement is required for surgical planning. Med-
ical treatment with oral contraceptives or GnRH
agonist can be tried.112 If symptoms persist, then
surgical removal is indicated. Ureter involvement
with endometriosis is usually at the distal third.
Extrinsic compression is usually caused by marked
fibrosis starting on the peritoneum. Intrinsic com-
pression most likely occurs as a result of an implant
in the muscularis of the ureter. Flank pain and
hematuria can be present, but most patients present
as part of a syndrome of chronic pain. Ureteral
obstruction is diagnosed on preoperative imaging
when hydronephrosis is seen or at the time of
laparoscopy. Medical treatment is ineffective be-
cause of the severe fibrosis seen and surgery is
required. If hydronephrosis is present, then ureteral
resection will most likely be necessary.
Diaphragmatic endometriosis can be visualized at
laparoscopy. Symptoms are menstruation-associated
VOL. 118, NO. 3, SEPTEMBER 2011 Falcone and Lebovic
right-side chest pain or shoulder pain with occasional
radiation into the neck or arm and dyspnea. Symptom-
atic patients can be treated with GnRH agonists. Surgery
is associated with a high rate of pleural space penetra-
tion. Asymptomatic patients do not require treatment.
Thoracic endometriosis most commonly presents as a
right-sided catamenial pneumothorax but can also be
manifest as hemothorax, hemoptysis, or pulmonary
nodules. The typical symptoms are chest pain and
dyspnea. Referral to a thoracic surgeon is recom-
mended.
Patients with endometriosis of the sciatic nerve can
present with hip pain, which is usually localized to the
buttock. Usually the pain radiates down the back of
the leg, and numbness occurs in areas innervated by the
sciatic nerve. Magnetic resonance imaging typically
shows a lesion infiltrating the sciatic nerve. CT-guided
biopsy can be used to confirm the diagnosis. Treatment
with a GnRH agonist has been shown to reverse the
neurologic abnormalities in some patients.
Long-Term Follow-up
Hormone therapy after hysterectomy with bilateral sal-
pingo-oophorectomy is not contraindicated and should
be considered in young women who have undergone
definitive surgery.15 According to a recent Cochrane
analysis, there may be a low probability (3.5%) of
recurrence associated with hormone replacement ther-
apy.113 The observation did not reach statistical signifi-
cance in the analysis. A review of the cases that had
recurrence suggests patients had residual disease. A
decision should be made on a case-by-case basis with
proper evaluation of individual risk. Premenopausal
women with surgically induced menopause or symp-
tomatic postmenopausal women should be offered hor-
mone replacement therapy. There is no compelling
datum to support a delay in implementing treatment.
The most controversial aspect of hormone ther-
apy is whether to include a progestin with estrogen
therapy in women with endometriosis after hysterec-
tomy with bilateral salpingo-oophorectomy.114 In one
retrospective study, 31 patients had cancer develop
from endometriosis, but only nine patients were using
unopposed estrogen. There was a higher risk for
cancer only in patients using unopposed estrogen and
with a body mass index higher than 27 compared
with controls.115 There is no datum to support the
concept that the addition of progestins to estrogen
replacement therapy will reduce the risk of malignant
transformation in endometriosis lesions from unop-
posed estrogen.113 This theoretical benefit needs to be
weighed against the fact that progestin supplementa-
tion is associated with an increased risk for breast
Clinical Management of Endometriosis 701
cancer.116,117 In women with surgical or spontaneous
menopause with an intact uterus, progestine therapy
is required if estrogen is administered.
There appears to be an increased risk of ovarian
cancer in endometriosis patients, although it is not
clear by what magnitude. It recently has been re-
ported to have a rate ratio of 1.6 (95% confidence
interval 1.12–2.09).118 However, precursors such as
cytologic or histologic atypia are uncommon.119
SUMMARY
Endometriosis is a complex gynecologic disorder re-
flected in all of the preceding categories, ranging from its
pathophysiology to the utility of surgery and medical
therapy. We have presented an up-to-date summary of
salient findings gleaned from evidence-based data when
available. The management of endometriosis-related
subfertility is typically with surgery, which has a modest
effect, or assisted reproductive technology. Excision of
endometriomas improves spontaneous fertility but is
associated with removal of normal ovarian tissue that
may decrease ovarian reserve. Surgical and medical
management of chronic pelvic pain associated with
endometriosis are effective but associated with high
recurrence rates that can be diminished with the use of
chronic administration of hormonal contraception. Fu-
ture studies utilizing improved models of endometriosis
in concert with major advances in the molecular science
of endometriosis may provide greater clarity on the
etiology, which would then be followed-up with more
efficacious treatment.
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