Clinical Management of Endometriosis Tommaso Falcone, MD, and Rebecca Flyckt, MD Endometriosis is a common and challenging condition of… [626627]

Clinical Expert Series
Clinical Management of Endometriosis
Tommaso Falcone, MD, and Rebecca Flyckt, MD
Endometriosis is a common and challenging condition of reproductive-aged women that carries
a high individual and societal cost. The many molecular dissimilarities between endometriosislesions and eutopic endometrium create difficulties in the development of new drug therapies
and treatments. Surgery remains the gold standard for definitive diagnosis, but it must be
weighed against the risks of surgical morbidity and potential decreases in ovarian reserve,especially in the case of endometriomas. Safe and effective surgical techniques are discussedwithin this article for various presentations of endometriosis. Medical therapy is suppressive
rather than curative, and regimens that are long-term and affordable with minimal side effects
are recommended. Recurrences are common and often rapid when medical therapy isdiscontinued. Endometriosis in the setting of infertility is reviewed and appropriate management
is discussed, including when and whether surgery is warranted in this at-risk population. In
patients with chronic pain, central sensitization and myofascial pain are integral components ofa multidisciplinary approach. Endometriosis is associated with an increased risk of epithelial
ovarian cancer; however, the risk is low and currently no preventive screening is recommended.
Hormone therapy for symptomatic women with postsurgical menopause should not be delayedas a result of concerns for malignancy or recurrence of endometriosis.
(Obstet Gynecol 2018;0:1–15)
DOI: 10.1097/AOG.0000000000002469
Endometriosis is diagnosed by the presence of via-
ble, estrogen-sensitive endometrial-like glands and
stroma outside the uterus. Although no clinical symp-toms are required, in many patients, endometriosis isa chronic inflammatory disorder that significantly de-
creases quality of life. The societal burden of endome-
triosis is estimated to be more than $49 billion in theUnited States with patients undergoing surgery esti-mated to incur higher direct and indirect costs andproductivity losses per woman that are twice as highas health care costs.
1The most common clinical pre-
sentations are adnexal masses, infertility, and dysmen-orrhea. Although the presence of ectopic endometrialtissue is the key pathologic feature, there are manymolecular differences that make endometriosis lesions
distinct from eutopic endometrium. These molecular
dissimilarities make the development of new drugtherapies and treatments challenging.
INCIDENCE AND EPIDEMIOLOGIC FACTORS
This enigmatic disease is influenced by multiplegenetic, environmental, and epidemiologic factors. Itaffects 6 –10% of reproductive-aged women and has
been found in premenarchal and postmenopausalwomen. The average age at diagnosis is approxi-
mately 28 years. Several conditions show greater
concordance with endometriosis. For example, endo-metriosis is present in 21 –47% of women presenting
with subfertility
2and 71 –87% of those with chronic
pelvic pain.3Early menarche, short menstrual cycle
length, heavy menstrual periods, and nulliparity areassociated with increased risk. Other factors associ-ated with increased prevalence are low body mass
index and alcohol use, as well as certain phenotypes
such as freckles and nevi. Exercise appears to beFrom the Obstetrics, Gynecology, and Women ’s Health Institute, Cleveland
Clinic, Cleveland, Ohio.
The authors thank acknowledge Ross Papalardo, C.M.I., for providing medical
illustrations for this manuscript.
Continuing medical education for this article is available at http://links.lww.
com/AOG/B59.
Each author has indicated that he or she has met the journal ’s requirements for
authorship.
Corresponding author: Tommaso Falcone, MD, Obstetrics, Gynecology, and
Women ’s Health Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland,
OH 44195; email: falcont@ccf.org.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2018 by American College of Obstetricians and Gynecologists. Published by
Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0029-7844/18
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VOL. 0, NO. 0, MONTH 2018 OBSTETRICS & GYNECOLOGY 1

protective. Oral contraceptive use is associated with
decreased prevalence of endometriosis and possiblylower prevalence of endometrioma at first laparoscopy.
4
Endometriosis has a strong familial component;
a first-degree relative with endometriosis increasesrisk 7- to 10-fold. A meta-analysis of genome-wideassociation studies has shown common genetic var-iants in seven risk loci.
5The genetic burden appears
to increase along with the severity of disease.
The long interval between presentation of symp-
toms and the definitive diagnosis of endometriosis is
7–8 years. This is attributed in part to the overlap
between symptoms associated with endometriosisand other pain-associated syndromes (Table 1). Clin-ical diagnosis can be confirmed surgically with directinspection and tissue biopsy of visible lesions. Endo-metriosis most likely does not have a single unifyingexplanation that accounts entirely for the varied clin-ical manifestations of the disease.
PATHOPHYSIOLOGY
An endometriotic lesion has the same histologicappearance as the endometrium with distinct endo-metrial glands and stroma. The etiology of endo-metriosis is still described in terms of implantationof eutopic endometrium from retrograde menstru-ation or metaplasia of coelomic pluripotential
mesothelial cells lining the peritoneum into endo-
metrial tissue at ectopic sites (Appendix 1, availableonline at http://links.lww.com/AOG/B60). Whyonly a minority of women develop endometriosisfrom a common phenomenon of retrograde men-struation is attributed in part to an inherent dys-function of the peritoneal immune system. A thirdtheory proposed to better describe endometriosis
infiltrating into the cul de sac and uterosacral
ligaments is the theory of müllerianosis, which pro-poses that at the time of fetal organogenesis, mis-
placed endometrial tissue such as what is observed
in the cul de sac develops into endometriosis (Appendix1, available online at http://links.lww.com/AOG/B60).Distant metastases and implantation of cells through
hematogenous or lymphatic embolization can explain
endometriosis observed in nontraditional locations.None of these theories is mutually exclusive. Further-more, all phenotypes of the disease can manifest within
the same patient. The challenge of implantation theories
is the fact that although ectopic endometriosis lesionsresemble eutopic endometrium histologically, they donot function physiologically in a similar manner. The
implication of this observation is that the response of
endometriosis lesions to medical therapy will probablybe unlike that of eutopic endometrium.
The multitude of abnormal molecular events in the
eutopic endometrium results in altered hormoneresponse and altered receptivity as well as enhanced
cellular survival and inflammation at ectopic sites. Cross-
talk between the ectopic lesions and the eutopic endo-metrium can influence gene expression in theendometrium. In endometriotic lesions it is postulatedthat defective methylation occurs in critical genes, whichinfluence downstream progesterone and estrogen recep-tor expression. This, in combination with increasedaromatase expression in the ectopic endometrium,
results in a higher concentration of local, more metabol-
ically active estradiol. These observed changes aresummarized as progesterone resistance (Appendix 2,available online at http://links.lww.com/AOG/B60).Relative progesterone resistance in the endometriumcan explain in part the dysregulated genes critical forimplantation.
6In addition to epigenetic modification of
select genes, altered microRNA expression may influ-
ence gene transcription and posttranslational events asso-
ciated with proliferation or regulation of cell survival.7
Table 1. Symptoms of Endometriosis
Symptom Disorders With Similar Clinical Presentation
Dysmenorrhea Adenomyosis; primary dysmenorrhea; in adolescents—obstructed mu ¨llerian
anomalies
Nonmenstrual pelvic–abdominal pain Irritable bowel syndrome; neuropathic pain; adhesions; abdominal wall nerve
entrapment syndromes
Dyspareunia Psychosocial issues; pelvic floor disorders
Bowel symptoms (diarrhea, cramping,
constipation)Hemorrhoids; constipation; irritable bowel syndrome
Defecation pain (dyschezia) Anal fissures; pelvic floor disorders
Infertility Unexplained subfertility
Ovarian mass or tumor Benign ovarian cyst
Painful bladder symptoms and dysuria Painful bladder syndrome; interstitial cystitis; pelvic floor disorders
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2Falcone and Flyckt Clinical Management of Endometriosis OBSTETRICS & GYNECOLOGY

The resultant lesions are associated with chronic
inflammation and immune dysregulation (Appendix2, available online at http://links.lww.com/AOG/
B60). Excision of endometriosis has been shown to
decrease proinflammatory cytokines.
MECHANISM OF OVARIAN CYST
DEVELOPMENT (ENDOMETRIOMA)
Endometriomas are cysts within the ovary containing
“chocolate ”fluid (Appendix 3, available online at
http://links.lww.com/AOG/B60). Endometriosis
cysts are thought to arise from the surface, with super-ficial ovarian implants commonly observed at laparos-copy. Promoted by adhesions from the ovary to thesidewall, implants of endometrial glands and stromainvaginate or become entrapped within the cortex toprogressively form cystic lesions.
Another hypothesis of endometrioma formation
is that the peritoneal mesothelium covering of the
ovary can differentiate into endometrioid epitheliumand subsequently forms an invaginating cyst ina similar manner (metaplasia theory). Still anotherhypothesis suggests that müllerian epithelium fromthe tube or endometrium can implant on the surfaceof the ovary and lead to cyst formation. This latterconcept is similar to most surface epithelial tumors
and is supported by the recent association of ovarian
cancer with tubal tissue. The process of endometrio-ma formation is closely linked to ovulation becauseprevention of ovulation with cyclic oral contracep-tives reduces the risk of endometrioma recurrence.There may be seeding of endometriosis tissue intoa hemorrhagic corpus luteum with progression froma hemorrhagic corpus luteum to an endometrioma.
The inner surface of an endometrioma is lined by
endometriosis with variable penetration into thesurrounding fibrosis. The mean cyst wall thickness is1.2–1.6 mm. Endometriotic tissue covers approxi-
mately 60% of the inner surface of the cyst witha depth of penetration of 1.5 mm.
8This observation
is important if energy forms are used to ablate theendometriotic cysts rather than excisional strategies.
The unique features of endometriomas are intense
fibrosis and inflammation. Contrary to other cysts,endometriomas are firmly adherent to the cortex aswell as the underlying stroma (Appendix 3, availableonline at http://links.lww.com/AOG/B60). This dis-similarity can explain some differences in clinicalmanifestation from epithelial tumors such as the pres-ence of pain as well as the surgical observation that
excision is difficult and can result in the inadvertent
removal of normal ovarian tissue.MECHANISM OF PAIN
The chronic inflammation of endometriosis is charac-
terized by increased systemic and local proinflamma-
tory cytokines and growth factors that are closelyrelated to pain sensation including dyspareunia (ie,nerve growth factor, prostaglandin E
2). Long-term
exposure to these proinflammatory substances canlead to peripheral sensitization characterized by a hy-peralgesic state, central sensitization, and myofascialpain.
9The concept of central sensitization is critical to
understanding chronic pain and will help in avoiding
repetitive surgery. It is postulated that repetitive andpersistent noxious stimulation, chronic inflammation,and nerve injury will alter pain processing, resulting incentral sensitization. It is important to treat painsymptoms quickly to avert this condition. Surgicalintervention may actually increase central sensitiza-tion and these patients often report worsening of
symptoms after surgery. The recent observation of
altered brain chemistry in women with endometriosisis positively correlated with pain intensity.
10
MECHANISM OF SUBFERTILITY
The severe adhesive disease associated with advancedendometriosis is an obvious impairment to fertility.However, it is not obvious how a small lesion seen atlaparoscopy can cause infertility. There is strong
debate whether minimal endometriosis can cause
infertility different from idiopathic infertility.
The peritoneal environment of women with
endometriosis may lead to increased sperm DNAdamage as well as an abnormal oocyte cytoskeleton.
11
Monthly fecundity rates are lower in women withmild endometriosis undergoing therapeutic donorinsemination (azoospermic partners) compared with
women without endometriosis.
12However, implanta-
tion and clinical pregnancy rates were similar betweenwomen with and without disease in a donor egg pro-gram with the use of sibling oocytes in women withadvanced endometriosis and those without disease. Inanother study with a similar methodology, usingsibling oocytes from the same donor in recipientswith and without endometriosis resulted in lower
implantation and pregnancy rates in patients with
endometriosis.
13The authors suggested an endome-
trial defect as the explanation. This observation issupported by numerous studies showing decreasedexpression for several biomarkers of implantation. Itis difficult to ascertain whether lower implantationrates may also be explained by coexisting undiag-nosed adenomyosis.
Kitajima et al
14opine that women with endome-
triomas experience accelerated depletion of follicles
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from enhanced activation of granulosa cells leading to
dyssynchronous oocyte maturation and oocyte apo-ptosis. Women with endometriomas have lower base-
line antimüllerian hormone levels than their
unaffected counterparts; presurgical antimüllerianhormone levels in women with endometriomas were45% lower than in patients with no endometriosis and36% lower than in patients found to have only pelvicendometriosis.
15Other studies have shown a similar
effect on ovarian reserve, especially with bilateral en-dometriomas. It is not clear whether deeply infiltrat-
ing endometriosis is independently associated with
infertility.
NATURAL COURSE OF ENDOMETRIOSIS
Endometriosis should not be assumed to be pro-gressive. The short-term natural course of the diseasehas been demonstrated in randomized studies, whichinclude a placebo control group completing baselinediagnostic laparoscopy. In the pooled placebo group,162 patients reveal a disease in flux with nearly equaldistribution among deterioration (31%), no change(31%), and improvement (38%).
16It is unclear which
lesions recur and whether recurrence is associated
with symptoms. Some recurrences are persistent dis-ease that was not completely treated surgically. Thenatural course of recurrent symptoms may not neces-sarily reflect the recurrence of endometriosis lesions.Given the high rate of recurrent symptoms and reop-eration in women treated without suppressive postop-erative medical therapy, more women will likely have
their endometriosis track toward disease progression
rather than resolution. The mechanisms responsiblefor ongoing symptom expression are likely complexand multifactorial.
CLINICAL PRESENTATION AND DIAGNOSIS
Most women with endometriosis will present witha collection of symptoms, including dysmenorrhea,deep dyspareunia, dyschezia, and chronic abdomino-pelvic pain as well as subfertility. Each of thesesymptoms can significantly impair a woman ’s physi-
cal, mental, and socioemotional well-being. History-
taking should include a family history of endometri-osis as well as past surgeries known to increase the riskof local endometriosis such as cesarean delivery andmyomectomy. When considering endometriosis-associated pelvic pain, the clinician should bearin mind the extensive differential diagnosis and poten-tial contributors to the pain syndrome. These include
pelvic inflammatory disease, adhesions, abdominal
wall pain, irritable bowel syndrome, interstitial cysti-tis, myofascial pain and pelvic floor disorders, depres-
sion, and a history of sexual abuse.
Pain levels should be documented using a visual
analog scale (usually 0 –10). Although there is a poor
correlation between level of pain and disease severity,deeply infiltrating endometriosis is associated withincreased severity of pain. Implants do not localizewell to subjective pain locations with the exceptionof deeply infiltrating endometriosis. In patients withendometriomas, severe pain is often associated withthe presence of deeply infiltrating disease rather than
the size of the cyst.
17Therefore, surgical treatment of
an endometrioma requires concomitant treatment ofdeeply infiltrating endometriosis if present to obtainoptimal pain relief.
The physical examination should be detailed,
looking for multiple causes of pain such as nerveentrapment, myofascial pain, and pelvic floor disor-ders. On pelvic examination, signs of advanced
disease are tenderness or nodules of the cul de sac
or uterosacral ligaments, tenderness of the adnexa,rectovaginal septum induration, and the presence ofa fixed retroverted uterus.
Three phenotypes of endometriosis can be dis-
cerned at surgery: endometriomas (ovarian cysts),superficial endometriotic implants (primarily on theperitoneum), and deeply infiltrating endometriosis,
which is defined as a nodule extending more than
5 mm beneath the peritoneum (Fig. 1). When theselesions occur near the uterine ligaments or the bowel,proliferation of the indigenous smooth muscle of thesestructures creates a mass-like effect and fibrosis thatfill the rectovaginal space. Ovarian disease can occursuperficially on the cortex but is still associated withinflammation and fibrosis.
Imaging is often used in the investigation of chronic
pelvic pain and can also be informative in the pre-operative assessment of patients preparing for endome-triosis surgery. Imaging sensitivity varies depending onthe particular phenotype of lesion (ie, endometrioma,peritoneal disease, or deeply in filtrating endometriosis).
For chronic pelvic pain, pelvic ultrasonography remainsthe modality of choice because it can detect other causes
of pelvic pain such as adenomyosis. Transvaginal
ultrasonography has the highest sensitivity and specific-ity in identifying ovarian endometriomas. Classic ultra-sonographic features are a unilocular cyst withhomogeneous low-level echogenicity of the fluid(ground glass appearance) and poor or mild vascularflow (Fig. 2). If small papilla are present, there should beno flow noted within this area.
Pelvic ultrasonography for deeply infiltrating
endometriosis is more challenging. Accurate
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4Falcone and Flyckt Clinical Management of Endometriosis OBSTETRICS & GYNECOLOGY

preoperative mapping of deeply infiltrating endome-
triosis will allow more thorough counseling of surgicalrisks as well as the potential need for bowel or bladderresection; preoperative detection of deeply infiltratingendometriosis will also allow the surgeon to refera patient to a center skilled in managing advanceddisease if necessary. Ultrasonography performed for
deeply infiltrating endometriosis should be a dynamic
process; dense adhesions and cul de sac obliterationcan be detected while moving the ovaries, uterus, orbowel during the examination. A recent consensusreport on ultrasonographic terminology for deeplyinfiltrating endometriosis has been proposed to prop-erly communicate the extent of disease.
18There are
currently no data to establish that preoperative imag-ing results in improved patient outcomes for endome-
triosis surgery.
In this report there are four ultrasonographic
steps to the evaluation of the pelvis with suspected
endometriosis. The first step is the traditional evalu-ation of the uterus and adnexa for adenomyosis orendometriomas. Adenomyosis is observed more fre-quently in women with deep endometriosis lesionscompared with those with superficial lesions. In steptwo, the ultrasound probe is used to determine thelocation of specific tender spots that may reflect
disease-specific sites to be investigated at the time of
surgery. Step three evaluates the cul de sac (pouch ofDouglas) to determine whether there is deeply infil-trating disease or obliteration by the “sliding sign, ”in
which pressure is placed on the cervix with the probeto see whether the anterior rectum moves freelyacross the area of the vagina next to the posteriorcervix and upper uterus. The final step is evaluation
for nodules of the anterior compartment (bladder) and
posterior compartment. The posterior compartmentincludes the uterosacral ligaments, which are not seenby ultrasonography unless there is a nodule, the rec-tovaginal septum, vaginal wall, and rectum. Fluid con-trast in the vagina or rectum can improve visualizationof bowel or bladder involvement.
The predictive value of this ultrasound approach
depends on the experience of the center performing
the ultrasonography and is very highly operator-dependent. In experienced centers, the sensitivityand specificity of finding disease at the rectocervicalor rectosigmoid levels is higher than 95%.
19The sen-
sitivity for deeply infiltrating endometriosis overalland the uterosacral ligaments in particular is less(80% and 75%, respectively).
20Magnetic resonance
imaging has also been found to have high diagnostic
accuracy with similar sensitivity and specificity toultrasonography in the diagnosis of deep endometri-osis of the uterosacral ligaments (85% and 88%), vag-inal endometriosis (77% and 70%), and colorectalendometriosis (88% and 92%).
21Magnetic resonance
imaging with an enema compared with rectal watercontrast transvaginal ultrasonography in the diagno-
sis of rectosigmoid endometriosis has shown similar
sensitivity and specificity, reported at higher than90%. The use of magnetic resonance imaging seemslogical for equivocal ultrasound findings, especially ifsurgery is planned for excision of deeply infiltratingendometriosis, possibly requiring rectal or bladderresection.
There are no diagnostic markers with adequate
reliability for clinical use. Research has focused on
molecular markers in the eutopic endometrium as
Fig. 1. Deeply infiltrating endometriosis. In this image, the
lesion infiltrates the rectum and the rectovaginal space at
the level of the cervix.
Falcone and Flyckt. Clinical Management of Endometriosis. Obstet
Gynecol 2018.
Fig. 2. Endometrioma. The typical ultrasonographic
appearance is shown of a unilocular cyst with homoge-
neous low-level echogenicity and minimal vascular flow.
Falcone and Flyckt. Clinical Management of Endometriosis. Obstet
Gynecol 2018.
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VOL. 0, NO. 0, MONTH 2018 Falcone and Flyckt Clinical Management of Endometriosis 5

well as noncoding RNA in tissue and blood.7,22A
2016 Cochrane review concluded that none of thepublished biomarkers could be evaluated in a mean-
ingful way and that laparoscopy remains the gold
standard.
23The CA 125 test has poor diagnostic accu-
racy and has minimal value in the investigation ofa patient with chronic pelvic pain. It is often mildlyelevated in women with endometrioma. Althougha noninvasive diagnostic test for endometriosis isdesirable and could help avoid the need for surgeryin establishing a definitive diagnosis, there is currently
no such test available.
SURGICAL DIAGNOSIS
Surgery remains a fundamental tool in the diagnosis
and treatment of endometriosis and allows directvisual identification of disease. Excision and confir-mation by histology is highly recommended as a result
of the low reliability of visual inspection alone. The
typical histologic appearance of endometriosis con-sists of endometrial glands, stroma, and hemosiderin-laden macrophages.
Staging of endometriosis follows the American
Society for Reproductive Medicine system, whichassigns a score to designate minimal and mild disease(stage I and II) and moderate and severe disease (stage
III and IV).
24The model is not without limitations in
clinical utility because there is poor correlation withquality-of-life indicators. Although initially developedfor the assessment of fertility, the American Societyfor Reproductive Medicine staging score is commonlyused to quantify disease burden and facilitate unifor-mity in both research and patient care. Other surgicaltaxonomies exist such as the Enzian classification,
which reports the depth of deep infiltrating endome-
triosis, and the Endometriosis Fertility Index, whichpredicts fertility outcomes based on surgical findings.
The most common sites for endometriosis are the
ovaries, pelvic peritoneum (the broad ligament andcul de sac), and uterosacral ligaments. A systematicapproach to the pelvis will ensure no lesions aremissed during surgery.
25Photographing each area
will assist in communication with the patient and
other physicians.
MEDICAL MANAGEMENT
Medical Therapies for Endometriosis Pain
Accurate clinical diagnosis is important, because
many societies including the American College ofObstetricians and Gynecologists and the American
Society for Reproductive Medicine endorse empiric
therapy before definitive surgical diagnosis.
24,26Response to empiric therapy does not confirm thediagnosis of endometriosis.
There are numerous current medical treatments
for the management of endometriosis symptoms. All
of these treatments should be considered suppressiverather than curative. Medical therapy will not increasefecundity or resolve endometriomas or deeply infil-trating disease. Because the effectiveness of medicaloptions for reducing symptoms is comparable, selec-tion of an optimal regimen is based on multiple factorsincluding patient age, patient preference, reproductive
plans, pain severity, and degree of disease. Additional
factors include treatment cost and intended durationas well as treatment risks, side effect profiles, andaccessibility. The main objective of medical manage-ment is to prevent recurrence and reduce symptoms,thereby eliminating the need for repeat surgery orprolonging the time between surgeries.
Endometriosis is a chronic disease requiring
sustained treatment; this key educational point must
be reinforced in discussions with patients both beforeand after surgery. Although patients may desirea single operative procedure to permanently removeendometriosis lesions and provide enduring painrelief, ongoing hormonal suppression after endome-triosis surgery is necessary. It is clear that withouthormonal suppression, pain symptoms will recur and
they often recur rapidly with a recurrence risk of 50%
at 5 years.
27Because hormonal management is by
necessity long-term, the ideal regimen should becost-effective, well-tolerated, and without significantrisk to the patient. Medical therapies for endometri-osis are summarized in Table 2.
For decades, the mainstays of conventional endo-
metriosis treatment have been nonsteroidal antiin-
flammatory drugs and combined oral contraceptives
followed closely by gonadotropin-releasing hormone(GnRH) agonists and oral progestins. This strategyhas been endorsed by several professional socie-ties.
24,26Despite their widespread use, nonsteroidal
antiinflammatory drugs alone are probablyof minimal effectiveness in patients with endometri-osis. A placebo-controlled, double-blind, randomized
trial confirms improvement of dysmenorrhea and
reduction in the size of endometriomas greater than3 cm in women with endometriosis taking combinedoral contraceptives compared with placebo.
28The
goal of hormonal treatments is to induce a localhypoestrogenic state by suppressing ovulation. Fur-thermore, the resulting amenorrhea or hypomenor-rhea reduces the conversion of arachidonic acid to
prostaglandins with menses and subsequently lessens
dysmenorrhea and pelvic pain. Continuous rather
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Table 2. Medical Therapies for Endometriosis
ClassMechanism of Pain
Relief Drug Dose Side Effects
Estrogen–
progestin
combinations/C15Ovulation inhibition
/C15Decidualization or
atrophy of lesions/C15Monophasic
estrogen–progestin*Continuous orally daily Breakthrough bleeding,
breast tenderness, nausea,
headaches, mood changes
Progestins /C15Decidualization or
atrophy of lesions
/C15Inhibition of
angiogenesis
/C15Suppression of matrix
metalloproteinase-
facilitated growth and
implantation of
ectopic endometrium/C15Depo Provera*
/C15Etonogestrel-releasing
implant
/C15Norethindrone
acetate*
/C15Levonorgestrel-
releasing IUS
/C15Medroxyprogesterone
acetate
/C15Dienogest†/C15104 mg SC every 3 mo
/C151 for 3 y
/C155 mg daily
/C151 for 5 y
/C1530 mg orally for 6 mo,
then 100 mg IM every22
wk for 2 mo, then 200
mg IM monthly for 4 mo
/C152 mg dailyAcne, weight gain, mood
changes, headache,
breakthrough bleeding,
breast tenderness, lipidabnormalities
(norethindrone)
GnRH agonists Inhibition of
gonadotropinsecretion and
subsequent
downregulation ofovarian
steroidogenesis/C15Leuprolide depot*
‡
/C15Goserelin*‡
/C15Nafarelin*‡/C153.75 mg IM monthly
(11.25 mg IM every
3 mo)
/C153.6 mg SC monthly
(10.8 mg IM
every 3 mo)
/C15200 micrograms
intranasally twice dailyDecreased bone density,
atrophic vaginitis, hotflashes, headache, joint
pain
Androgenic
steroids/C15Inhibition of
pituitary gonadotropinsecretion/C15Danazol* 100–400 mg orally twice
dailyHair loss, weight gain, acne,
hirsutism
/C15Local growth inhibitor
/C15Inhibition of
estrogenic enzymes100 mg vaginally daily
Antiandrogens Competitively
inhibition of the
androgen receptor/C15Cyproterone
acetate
†12.5 mg orally daily Hair loss, breast tenderness,
weight gain
GnRH
antagonistsInhibition of
gonadotropinsecretion andsubsequent
downregulation of
ovariansteroidogenesis/C15Elagolix 150 mg orally daily Hot flushes, lipid
abnormalities, decreasedbone density
Aromatase
inhibitorsLocal blockade of
enzymatic
(aromatase) conver-
sion of androgens toestrogens/C15Letrozole
/C15Anastrozole/C152.5 mg orally daily
/C151 mg orally dailyHot flushes, headaches,
decreased bone density
Selective
progesteronereceptor
modulatorsInhibition of
ovulation, agonist orantagonist at proges-
terone receptor/C15Mifepristone
/C15Ulipristal acetate/C1550 mg orally daily
/C1515 mg orally every
other daySpotting, cramping,
dizziness, headache,nausea
SC, subcutaneously; IUS, intrauterine system; IM, intramuscularly; GnRH, gonadotropin-releasing hormone.
* U.S. Food and Drug Administration–approved for endometriosis.
†Used as monotherapy outside the United States.
‡With add-back, that is, 5 mg norethindrone acetate daily plus 800 international units vitamin D daily plus 1.25 g calcium daily.
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than cyclic administration appears to be more effec-
tive in reducing the recurrence of dysmenorrhea butnot noncyclic pelvic pain or dyspareunia.
29No single
route of administration (oral, transdermal, or transva-
ginal) has been shown to provide superior pain relief.Breakthrough bleeding can typically be managed bya brief interruption in treatment with regimens resum-ing within 7 days.
Progestin monotherapy has historically been
favored in women who fail combined hormone ther-apy, smokers older than 35 years, and women with
predisposing risk factors for myocardial infarction,
stroke, or thrombolic events. However, some authorssuggest that progestin-only methods such as the 19-nortestosterone derivatives norethindrone acetate anddienogest may be superior to combined oral contra-ceptives and can be considered first-line, especially inwomen with rectovaginal and extrapelvic endometri-osis.
30The argument for progestin monotherapy is
based on a similar combination of ovulation inhibition
and amenorrhea but with potentially fewer unfavorableestrogenic effects and equivalent improvements in dys-menorrhea and pelvic pain symptoms when comparedwith combined oral contraceptives and GnRH ago-nists. Dienogest has shown benefit in controlling endo-metriosis pain; however, like cyproterone acetate, it isnot currently available as a single agent in the United
States. In contrast, norethindrone acetate has a lower
cost and is approved for the treatment of endometriosisin the United States by the U.S. Food and DrugAdministration (FDA). Furthermore, comparative clin-ical trials comparing norethindrone acetate with dieno-gest have not shown superior results for either agent.
31
The dose of norethindrone acetate can be increased asneeded from 5 to 15 mg daily as needed. Lipid profiles
should be serially monitored while on higher doses and
longer durations of norethindrone acetate.
Progestin-only methods can be administered by
oral, intrauterine, parenteral, or implantable routes andall have breakthrough bleeding as their most commonside effect. Breakthrough bleeding can be amelioratedwith a 7- to 14-day course of oral estrogen. Thelevonorgestrel-releasing intrauterine device, although
not FDA-approved for this purpose, has also been
shown to be effective in decreasing endometriosis-related pain. Depot medroxyprogesterone acetate is anFDA-approved treatment for endometriosis and hasbeen shown to be as effective as GnRH agonist ina multicenter randomized comparison
32;h o w e v e r ,
bone density loss is a concern with long-term use.
Gonadotropin-releasing hormone agonists have
been considered second or even third line as a result
of higher cost, limited accessibility, patient preferencefor nonparenteral administration, and presence of
hypoestrogenic side effects. They are effective ininhibiting ovarian steroidogenesis through central sup-
pression of gonadotropin release. A Cochrane review
from 2010 examined 41 studies and demonstrated thatGnRH agonist treatment is superior to placebo and aseffective as other combined and progestin-only regi-mens.
33Furthermore, a randomized comparison of
combined oral contraceptives compared with GnRHagonist therapy demonstrated that although both treat-ments were effective in reducing pain, the GnRH ago-
nist group reported more significant improvements in
dyspareunia.
34Gonadotropin-releasing hormone ago-
nist treatment alone has also been shown to be as effec-
tive as surgical management or combined treatment ina prospective randomized trial; however, recurrence riskwas lower with combined management.
35Reductions in
pain symptoms expected with GnRH agonist therapyrange from 50% to 90% and GnRH is considered
to be a particularly good agent for suppression of deeply
infiltrating endometriosis and extrapelvic endometriosis.
Long-term GnRH agonist use leads to loss of
bone density as well as increasingly bothersome hotflushes, vaginal dryness, headaches, and moodchanges; GnRH agonist monotherapy should notextend beyond 6 months ’duration. Adverse effects
can be mitigated by add-back therapy such as 5 mg
norethindrone acetate daily or combined hormone
treatment with estrogen and progestin, and this canallow longer treatment courses. Despite this, GnRHagonist use is not practical as a long-term strategy forthe management of endometriosis. Calcium and vita-min D may also provide some bone protection. Add-back therapy can be initiated concomitantly withGnRH agonist treatment; there is no documented
benefit in pain relief with a delayed start.
The ideal method is one that can be used long-
term. Therefore, we recommend initial selection ofcontinuous combined oral contraceptives orprogestin-only methods such as norethindrone acetateor the levonorgestrel-releasing intrauterine device formedical management of endometriosis symptoms.
Alternative Therapeutic Agents
Danazol is an established and effective endometriosistreatment; however, it is seldom used as a result ofundesirable androgenic side effects. Aromatase inhib-itors are successfully used in refractory cases to decreaseendometriosis-associated pain. Aromatase inhibitorsinduce hypoestrogenemia by decreasing local enzymaticconversion of androgens to estrogens. Although the
target is largely ovarian, aromatase inhibitors block
aromatase activity within adipocytes as well as ectopic
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8Falcone and Flyckt Clinical Management of Endometriosis OBSTETRICS & GYNECOLOGY

aromatase that provides self-s ustaining estradiol within
endometriotic lesions. Aromatase inhibitors are notFDA-approved, may induce bone loss, and must be
combined with combined oral contraceptives, proges-
tins, or GnRH agonists to avoid unwanted ovarian cystdevelopment.
Given the limitations of currently available treat-
ments, new therapeutic options for endometriosis aredesirable. Oral GnRH antagonists and selective pro-gesterone receptor modulators have shown potentialin investigational settings. The efficacy of oral daily
GnRH antagonist therapy for endometriosis pain was
established with a multicenter, double-blind, random-ized, placebo-controlled phase 3 clinical trial; how-ever, hypoestrogenic side effects were noted.
36
Improvements were most notable for dysmenorrhearather than nonmenstrual pain or dyspareunia.
Selective progesterone receptor modulators have
been prospectively studied, but randomized placebo-
controlled studies are lacking. Further opportunities
for development include immunomodulators andantiangiogenic agents; however, these agents remainhighly experimental in the setting of endometriosistreatment.
SURGICAL MANAGEMENT
Surgical management of endometriosis for the man-
agement of infertility, chronic pain, or ovarian cysts is
effective but has several controversial features. Surgi-cal management is indicated after failure of empirictherapy, failure, or intolerance of medical manage-ment or for purposes of diagnosis and immediatetreatment. It is also indicated for diagnosis andtreatment of an adnexal mass and treatment ofinfertility in some patients.
The surgical approach can be conservative with
treatment of endometriosis or definitive with hyster-ectomy with or without removal of the ovaries. Themanagement of peritoneal disease can involve abla-tion of the lesion with an energy form or excision. Arecent systematic review of three randomized trialsreported no clear statistical difference in pain scores,although there was a trend that favored excision.
37
Ablation should not be attempted when endometri-osis is located near critical structures such as the ure-ter, bowel, or bladder because lateral spread of anenergy form can damage underlying structures. Fur-thermore, it is difficult with any energy form to ablatedeeply infiltrating disease because the risk of injury tounderlying structures is high without proper dissec-tion. Therefore, excision is usually required for the
most effective and complete surgical management of
endometriosis.Surgical Outcome in Women With Chronic
Pelvic Pain
A recent Cochrane review reported that laparoscopic
surgery for endometriosis clearly decreased overallpain at 6 and 12 months compared with diagnosticlaparoscopy alone (odds ratio [OR] 10.00, CI 3.21 –
31.17).
38Furthermore, laparoscopic surgery was supe-
rior to diagnostic laparoscopy followed by medicaltherapy with a GnRH agonist. The recurrence ofsymptoms is estimated to be approximately 10% at
1 year to as high as 40 –50% at 5 –7 years.
39Many
surgical trials have not consistently used long-termpostoperative medical suppressive therapy. The useof immediate postoperative long-term hormonal sup-pressive medical therapy can reduce the recurrence ofsymptoms and repeat surgery, an approach that isfavored by society guidelines.
24,26The ideal duration
of suppression is a minimum of 6 –24 months.
There have been several suggested approaches to
improve surgical outcome . The first concept is to
improve visualization of endometriosis at surgery, forexample with the use of indocyanine green, a fluorescentdye. There are no high-quality studies to support the useof this product in the surgical management of endome-triosis. Although robotic surgery adds another dimensionto the visualization and treatment of endometriosis,
a recent randomized multicenter clinical trial comparing
robotic surgery with conven tional laparoscopy showed
no advantage in short-term postoperative parameters orimprovement in pain scores or other quality-of-lifeindicators.
40Second, uterine denervation or nerve tran-
section procedures have also been performed to improvesurgical outcome. Numerous studies have shown thatnone has improved outcomes with the exception of pre-
sacral neurectomy. The presacral neurectomy can help
reduce midline pain such as dysmenorrhea, but it isassociated with the possible consequences of bowel andbladder denervation with re ported increased frequency
of constipation and bladder dysfunction.
Management of Endometriomas
Clinical management of an endometrioma requiresa clear understanding of the goals of surgery because
surgical intervention can clearly cause ovarian dam-age and decrease ovarian reserve. If surgery is meant
to obtain a tissue diagnosis and relieve symptoms,
complete excision will accomplish this task mosteffectively with decreased recurrence. As summarized
in a Cochrane review that included two randomized
clinical trials, excision of a cyst is associated witha reduced rate of recurrence, reduced symptomrecurrence, and increased spontaneous pregnancy
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VOL. 0, NO. 0, MONTH 2018 Falcone and Flyckt Clinical Management of Endometriosis 9

rates (OR 5.1, CI 2.04 –13.29) compared with ablative
surgery.41
Despite these favorable observations, there have
also been many recent reports of decreased ovarian
reserve from cystectomy. Numerous studies haveshown a decrease in ovarian reserve with the exci-sional technique with up to a 30% decrease inantimüllerian hormone after unilateral cystectomyand a 44% decrease after bilateral cystectomy.
15This
ovarian damage can occur at several steps during theexcision process including removing normal cortex
containing follicles during the dissection and damage
incurred while obtaining hemostasis. The excessiveuse of electrosurgery for hemostasis can cause injury,either directly to the follicles or indirectly to the bloodvessels. It is possible that newer energy forms such asplasma energy could cause less ovarian damage thanexcision. In patients with low potential for spontane-ous pregnancy as a result of extensive adhesions, for
example, those who will need assisted reproductive
technology, ablation rather than excision may bemore advantageous to maintain ovarian reserve.
Repetitive surgery for recurrent endometriomas
is associated with increased harm as evaluated byantral follicle count and ovarian volume. Prospectiverandomized trials have shown long-term cyclic andcontinuous oral contraceptives can reduce recurrence
of endometriomas. Although the levonorgestrel-
releasing intrauterine device is effective for decreasingrecurrence of dysmenorrhea, it has not been showneffective in reducing endometrioma recurrence.
Cystectomy Technique
Preoperative imaging is important to determinewhether the cyst is bilateral. Dissection of the adher-
ent ovarian cyst complex from the pelvic side wall
requires knowledge of the course of the ureter and theovarian blood supply. As shown in (Appendix 3available online at http://links.lww.com/AOG/B60),the ovarian blood supply has two primary sources: theovarian vessels that course through the suspensoryligament and the vessels that course through the ute-roovarian ligament.
There are several critical steps during surgery.
Peritoneal washings should be obtained at the time of
the diagnostic laparoscopy if there is any suspicion ofmalignancy. After this, adhesions are lysed to restorenormal anatomy. Endometriomas can then be excised orablated. Bipolar electrosurgery is the most commonenergy form used for cyst ablation; however, depth ofpenetration can be up to 12 mm so careful technique is
advised. If cystectomy (exc ision) is performed, dilute
vasopressin can be injected to decrease bleeding and anincision must be made to identify a cleavage plane,
although this drug is not approved for this indication.Traction –countertraction is applied to carefully peel the
cyst wall from the ovarian co rtex. Excessive traction
risks the removal of normal tissu e. In difficult dissections,
extra caution should be taken at the hilum wherebleeding commonly occurs. Precise bipolar electrosur-gery, suturing, or the use he mostatic sealant agents can
be considered in this event. If the cleavage plane cannot
be identified, a small portion of tissue can be obtainedfor histology and the remaining cyst wall can be ablated.
Management of Deeply Invasive and
Extrapelvic Endometriosis
Deeply infiltrating endometriosis often involves non-
gynecologic organs. It can involve the urinary tract,ureter and bladder, bowel, uterosacral ligaments, andrectovaginal septum. Excision of deeply infiltratingendometriosis requires detailed knowledge of the
retroperitoneal space.
42Simple ablation will not effec-
tively treat deep lesions because they typically involvethe anatomic area of the ureter, bladder, or rectal areabehind the cervix. Although suppressive medical ther-apy improves pain in women with deeply infiltratingendometriosis, it has not been shown to improvefertility outcomes.
43
Colorectal Endometriosis
Symptoms suggesting bowel involvement of endome-triosis overlap with mild or deeply infiltrating endo-metriosis found in nonbowel sites. Cyclic defecationpain or cyclic constipation is reported in the majorityof women with rectal endometriosis (between 55%and 65%), but is also found in between 25% and 40%of women with minimal endometriosis or deeply
infiltrating disease at nonbowel sites. In patients with
rectal disease, most patients report more frequent andsevere symptoms of bloating, constipation, diarrhea,cramping, and defecation pain, but they are notuniquely associated with bowel endometriosis.
The most common site of gastrointestinal tract
endometriosis is the rectosigmoid (85%) followed bythe appendix, distal ileum, and cecum. Endometriosis
involving the bowel usually occurs at the level of the
rectocervix rather than the rectovaginal septum. Inmost cases the septum is spared and dissection underthe lesion can be achieved. Pelvic ultrasonographycan identify the presence of rectal nodules, althoughthe ability to reliably predict bowel penetration is stillunclear.
21Accurate determination of this clinical fea-
ture is important for surgical management.
Excision of disease of the peritoneum overlying
the rectum is straightforward and is not considered
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10 Falcone and Flyckt Clinical Management of Endometriosis OBSTETRICS & GYNECOLOGY

within the context of deeply infiltrating endometriosis.
There are three approaches to removing deeplyinfiltrating endometriosis of the rectum: rectal shaving
(refers to excision of disease from the bowel without
entering the lumen); discoid excision of the diseasewith primary closure of the rectal opening; andsegmental resection. The choice of surgical approachis not clearly defined, but expert opinions have beenpublished.
44Generally, in severely symptomatic
women with multiple deeply infiltrating skip lesions,deeply infiltrating lesions more than 3 cm, more than
40% of the circumference of the bowel involved, or
depth of invasion into the inner muscularis layer, seg-mental bowel resection is recommended. In patientswith a less than 3-cm nodule and no other criterialisted, a nodule resection only can be performed. Inpatients with a greater than 3-cm nodule and no othercriteria listed, a shaving technique can be used. Afterresection, pain symptoms have been reported to
improve by at least 70% with rate of pain symptoms
recurrence ranging from 0% to 34%.
45The complica-
tions of bowel resection for endometriosis occur in theshort term, and these include anastomosis leak, pelvicabscess and fistula as well as bladder and bowel dys-function and stricture. Long-term complicationsinclude a higher frequency of new bowel symptomssuch as incomplete bowel movements or unreliable
sensations of bowel urgency, but not a higher fre-
quency of worse constipation or fecal incontinence.
Improvements in pain after rectal nodule excision,
shaving, and segmental bowel resection appear similar.Consideration should be given to routine removal ofa normal-appearing appendix during planned laparo-scopic surgery for pelvic endometriosis. Pregnancy ratesafter excision (shaving technique) have been reported to
be 65% at 3 years; 59% conceived spontaneously.
46
Most authors report similar pain, fertility, and quality-
of-life outcomes of the shaving technique with segmen-tal and discoid resection of the lesions; however, someauthors report higher rates of symptom recurrence andreintervention with the shaving technique.
Urinary Tract Endometriosis
Like with gastrointestinal symptoms, urinary symp-toms can occur even without direct bladder involve-ment. Clinical symptoms associated with urinary tractinvolvement are voiding dysfunction, dysuria,urgency, pain with a full bladder, and hematuria.Urodynamic testing demonstrates neurogenic dys-function. Patients with direct bladder endometriosismore frequently report urinary symptoms, especially
painful bladder filling and voiding dysfunction such as
dysuria and frequency. Hematuria is infrequent.Ureter involvement does not typically present
with unique symptoms but is considered part of thepain syndrome. Rarely ureteral endometriosis can
present with flank pain and hematuria. Most endo-
metriosis of the urinary tract involves solely theperitoneum overlying the bladder or ureter in thepelvis. Deeply infiltrating endometriosis of the blad-der involves the muscularis and rarely the submucosaand mucosa and can be diagnosed by transvaginalultrasonography with variable sensitivity and specific-ity depending on the technique and experience of the
ultrasonographer.
Deeply infiltrating endometriosis of the pelvic
ureter can be diagnosed by pelvic or abdominalultrasonography, which demonstrates a nodular lesionor dilated ureter. Medical treatment of bladderendometriosis can be attempted using combined oralcontraceptives or GnRH agonist therapy. Surgicalremoval is indicated if symptoms persist despite
treatment. Ureter involvement with endometriosis is
typically from extrinsic compression with markedfibrosis of the muscularis of the ureter. Because ofthe severe fibrosis, which encases the ureter, medicaltreatment is unsuccessful and surgery will be neces-sary in these instances.
Hysterectomy
Hysterectomy is effective in treating women withsevere pain associated with endometriosis.
39Long-
term follow-up reported a reoperation-free rate at 2,5, and 7 years of 96%, 92%, and 92% in women withhysterectomy bilateral oophorectomy, respectively,and 96%, 87%, and 77% in women with hysterectomyalone, respectively. The risk of reoperation is 2.44
times higher with conservation of the ovaries. How-
ever, in a subgroup analysis of women younger than40 years of age who underwent hysterectomy withexcision of endometriosis but retention of normal ova-ries, the risk of reoperation at 7 years was the same asin those patients with removal of normal ovaries. Werecommend conservation of normal ovaries in womenyounger than 40 years of age. Ultimately the patient
must choose between an increased risk of recurrence
compared with surgical menopause.
ENDOMETRIOSIS IN THE INFERTILE PATIENT
Surgical Considerations
Once regarded as a fundamental step in the evaluation
and management of the infertile patient, diagnosticlaparoscopy for possible endometriosis is now a morerestricted procedure. In patients with stage I –II dis-
ease, four randomized controlled trials (RCTs) have
shed light on the utility of this intervention.
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VOL. 0, NO. 0, MONTH 2018 Falcone and Flyckt Clinical Management of Endometriosis 11

Combined data from the two largest trials demon-
strate an increased clinical pregnancy rate after exci-sion or ablation of stage I –II endometriosis; however,
the number needed to treat is approximately 40 if an
endometriosis prevalence of 30% at the time of lapa-roscopy is assumed.
47There are no RCTs to deter-
mine whether clinical pregnancy rates are improvedafter surgery in patients with stage III –IV disease.
Observational studies indicate that surgical interven-tion results in a 30% pregnancy rate in women with anobliterated cul de sac and a 50 –60% pregnancy rate in
women after endometrioma excision.
48Given these
data, women with advanced disease can be counseledtoward surgery to optimize fertility if they are youngor have significant pain symptoms, large endometrio-mas, or constriction of the ureter or bowel. Potentialbenefits of surgery, especially endometrioma excision,must be considered against reductions in ovarianreserve as well as potential surgical risks. Multiple
surgeries to improve fertility should not be attempted.
Patients with advanced maternal age, low ovarianreserve, male factor, or a combination of these shouldconsider immediate in vitro fertilization (IVF) ratherthan surgical intervention.
Fertility Treatments and Assisted
Reproductive Technology
Women with known endometriosis are often pre-
scribed a combination of oral or injectable fertility
agents and intrauterine insemination. The utility ofintrauterine insemination in patients with endometri-osis is not documented and there is a single RCT tosupport its use.
49Intrauterine insemination may not
ameliorate the impairments in follicular development,oocyte competency, endometrial receptivity, andtubal function theorized to play a role in the subfer-tility of endometriosis. Treatment with intrauterineinsemination may actually expose women with stageIII–IV disease to a greater recurrence risk than those
treated with IVF.
It is unclear whether treatment with GnRH
agonists or excision of endometriomas and deeply
infiltrating endometriosis improves clinical outcomeswith assisted reproductive technology. Althougha meta-analysis of three RCTs did demonstratea positive OR of 4.28 (95% CI 2.00 –9.15) for clinical
pregnancy after 2 –6 months of GnRH agonist pre-
treatment, more recent data have not shown a signifi-cant difference (Rodriguez-Tarrega E, Monzo A,Quiroga R, Romeu M, Polo P, Garcia-Gimeno T,et al. Randomized controlled trial to evaluate the use-fulness of GnRH agonist versus placebo on the out-come of IVF in infertile patients with endometriosis
[abstract P-322]. Hum Reprod 2016;31(suppl 1)).
Endometrioma excision is similarly controversial.
For small endometriomas, there is no evidence that
excision is indicated because a small endometriomawill not compromise access to the ovary and spillagerisk is minimal. Data from meta-analyses, includingrandomized controlled studies, suggest no differencein clinical pregnancy or livebirth rates when anendometrioma was excised before initiating an IVFcycle.
50
Although a prospective study reported higher
implantation and pregnancy rates after laparoscopicexcision of deeply infiltrating endometriosis, there areno RCTs comparing fertility outcomes after surgicalexcision of deeply infiltrating endometriosis with IVF.In patients with untreated colorectal endometriosisundergoing IVF, the cumulative pregnancy rates afterone, two, and three cycles were 29%, 52%, and 68%,
respectively.
51There is evidence that the presence of
deeply infiltrating endometriosis has a negative effecton IVF outcome and excising the disease mayimprove outcome. However, excision must be bal-anced with the risks of surgery associated with exci-sion of advanced endometriosis. There is a generalconsensus that IVF rather than surgery should bethe first approach in women who are solely interested
in fertility.
44
Fertility Preservation in Patients
With Endometriosis
As awareness and methods for early detection of
endometriosis improve, women with endometriosismay be increasingly identified as candidates for
fertility preservation. Suggested techniques include
oocyte and embryo cryopreservation as well asovarian tissue freezing. Women who have the greatestpotential risk are those who pursue recurrent surgicalinterventions and women with bilateral endometrio-mas. Despite growing interest in fertility preservationin this population, there are little data availableregarding the cost-effectiveness or feasibility of such
an approach.
CHRONIC PELVIC PAIN APPROACH
Not all pelvic pain is endometriosis, even if the
disease is found at the time of laparoscopy. Patientsmay have chronic pain syndromes in the absence ofendometriosis and, conversely, patients with endome-triosis of all stages may or may not develop chronicpain.
Medical and surgical management is often incom-
plete in addressing the multiple contributors to
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12 Falcone and Flyckt Clinical Management of Endometriosis OBSTETRICS & GYNECOLOGY

endometriosis symptoms. Endometriosis is recog-
nized as a syndrome of chronic abdominopelvic pain(ie, pain lasting more than 6 months), and the
necessity of a chronic care approach for optimal
results is clear. Specialized centers with multidisci-plinary care can combine medical and surgicalinterventions with pelvic physical therapy, pain man-agement, biofeedback, nutrition, and psychologicsupport. Understanding central sensitization (ie,heightened activation of pain pathways within thecentral nervous system) and myofascial pain is inte-
gral to the chronic pain approach (Appendix 4,
available online at http://links.lww.com/AOG/B60).
10The hallmarks of central sensitization are allo-
dynia, hyperalgesia, and referred pain. When painremains after maximizing medical and surgical treat-ments, it should prompt evaluation for central sensiti-zation and myofascial pain.
Central sensitization fo llows peripheral nervous
system activation. The mechanism of pain is thought to
be inflammatory, neuropathic, and nociceptive. Althoughperipheral nociceptive input may remit with treatment,sensory nerve fibers from established lesions synapse inthe sacral spine with centra l afferent neurons; their
repetitive and protracted activation can propagate centralsensitization that persists l ong beyond the initial stimu-
lus.
10Structural and functional alterations to spinal cord
neurons underlie tonic activation and also confer an
exaggerated response to peripheral stimuli.
Myofascial pain, characterized by the presence of
myofascial trigger points, can both arise from andfurther sustain centralized pain. Pelvic trigger pointsare tender, palpable contracted nodules in the musculo-skeletal tissues of the pelvis. Typical symptoms aredyspareunia, dyschezia, and dysuria. A complete his-
tory, systematic pelvic examination, and detailed neu-
romuscular evaluation will identify the problem. Triggerpoints are amenable to pelvic physical therapy andtrigger point injection, either with a dry needle or withinjection of local anesthetic or botulinum toxin.
10Phys-
ical therapists specifically trained in the management ofpelvic floor disorders are an integral part of the team.Opioids should not be prescribed because they are not
feasible for long-term pain management and may in fact
augment the central phenomenon. Instead, medicaltherapy that targets the central nervous system is pre-ferred. Pain psychologists can also be useful in the long-term management of chronic endometriosis pain.
ASSOCIATIONS WITH MALIGNANCY
Although endometriosis is a benign disease, it bearsmany similarities to cancer. Even in nonmalignantlesions, exome-wide sequencing reveals somatic mu-
tations in cancer-promoting genes.
52Malignant trans-
formation of endometriosis lesions is possible and
there is consistent evidence that women with endome-
triosis have an increased risk of epithelial ovarianmalignancy, mainly clear cell and endometrioid car-cinomas. Furthermore, atypical endometriosis mayrepresent a precursor lesion with characteristic fea-tures. Although women with endometriosis may haveas high as a fourfold increased risk of developing epi-thelial ovarian cancer, this remains a tiny fraction of
women with endometriosis.
53Preventive screening is
not currently recommended. It is uncertain whetherovarian cancer risk reduction is achieved withextended use of combined oral contraceptives, as isreported in the general population. Possible associa-tions between endometriosis and endometrial andbreast cancers are of uncertain validity.
MANAGEMENT OF THE POSTMENOPAUSAL
WOMAN WITH ENDOMETRIOSIS
The main concerns in managing symptomatic meno-
pausal women with a history of endometriosis are
malignant transformation of endometriotic lesionsand reactivation of the disease. The available datado not support delaying treatment with hormone
replacement therapy in symptomatic women. Recur-
rence is low at 2.3%.
54If a patient enters menopause
spontaneously with her uterus in situ, she can be man-
aged similar to other women with combined estrogen
and progesterone treatment to prevent endometrialcancer. The same concepts apply to a patient with
surgical menopause and an intact uterus; however,
the duration of treatment may be longer if this occursat a young age.
A controversial area is the management of the
posthysterectomy young menopausal patient.
Whether the menopause is spontaneous or surgical,
these patients may require a longer duration of
hormone therapy. The challenge is balancing the riskof malignant transformation of endometriotic residual
foci with estrogen alone and the known association of
increased risk of breast cancer with the use of long-term use of progestins. Although the risk of malignanttransformation appears low, no high-quality data exist
to advise patients with any degree of accuracy.
54
There are currently only 25 cases in the entire world
literature in postmenopausal women with a history of
endometriosis on hormone replacement. Discussion
of therapy must take into account individualizedbreast cancer risk and family history.
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VOL. 0, NO. 0, MONTH 2018 Falcone and Flyckt Clinical Management of Endometriosis 13

DISCUSSION
Managing patients with endometriosis is a complex
endeavor. Assembled here are the most up-to-date,
evidence-based strategies for treating patients withpain, pelvic dysfunction, and subfertility related totheir disease. As our appreciation of the molecularunderpinnings of endometriosis deepens, we maybetter select noninvasive diagnostic strategies andnew therapeutic targets and therefore avoid surgicalmorbidity and diminished ovarian reserve, which
occurs with ovarian surgery. A key element in
counseling patients is the necessity of prolongedsuppressive therapy to avert undesirable recurrencesand additional surgery. Special consideration shouldbe given to the patient with chronic pain withincreased recognition of the role of central sensitiza-tion, myofascial pain, and a multidisciplinary chronicpain approach. Despite a known increased small
risk of epithelial ovarian cancer in patients with
endometriosis, hormone therapy for symptomaticreproductive-aged women with postsurgical meno-pause is recommended.
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