ISSUES IN CHRONIC PELVIC PAIN AND ENDOMETRIOSIS
| ENDOMETRIOSIS: IS IT ALWAYS BENIGN ?—Marcelle I. Cedars, MD, Professor and Director, Division of Reproductive
Endocrinology, University of California, San Francisco, School of Medicine
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| Introduction: ovaries common site for endometrial implants; different histologic features can be found on same
cyst; endometrioma can spread as result of invasion of functional cyst, may originate in cyst wall and undergo coelomic
metaplasia, or simple implant can become more aggressive
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| Diagnostic imaging: computed tomography (CT)—no benefit in diagnosing abnormality involving cystic structures;
pelvic ultrasonography (US)— better option than CT; cannot differentiate between benign and malignant;
minimal improvement in sensitivity and specificity with B-mode plus color Doppler, compared to B-mode without
color Doppler; magnetic resonance imaging (MRI)—recommended if US unclear or with high degree of suspicion
(eg, areas of calcification, nonhomogenous asymmetrical pattern); cancer antigen (CA)-125—elevated in some
patients with endometriosis; reassure patient that moderately elevated CA-125 not necessarily indicative of cancer
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| Risks associated with endometriosis: data show prevalence of endometriosis in patients with endometrioid or
clear cell ovarian cancer 21% to 26%; in serous or mucinous ovarian cancer, 3% to 5%; synchronous incidence of
endometriosis with clear cell and endometrioid ovarian carcinoma suggests malignant transformation; several studies
show 2.4% relative risk for malignant transformation and ovarian malignancy in women with endometriosis,
compared to women without endometriosis; with addition of infertility (risk factor for ovarian cancer), relative risk
≈4.2%; studies in United States and United Kingdom show significantly increased risk for ovarian cancer, non-
Hodgkin’s lymphoma, and breast cancer (controversial) in women with endometriosis; studies also show association
between dysplastic nevi and malignant melanoma
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| Inflammation and hormonal interaction in cancer
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 | Role of inflammation: state of chronic inflammation increases oxidative stress; oxidative stress causes cell necrosis,
resulting in compensatory increased cell division, and increasing risk for DNA replicative errors; in inflammatory
environment, release of cytokines and growth factors leads to imbalance between immunosuppressant and immunostimulant
cytokines; chronic inflammation associated with potential local and systemic effect on immune system,
oxidative stress, and cell DNA repair; studies suggest nonsteroidal anti-inflammatory drugs (NSAIDs) reduce
breast and ovarian cancer risks; key processes for tumor growth—proinflammatory cytokines upregulate cyclooxygenase-2
(COX-2) and increase synthesis of prostaglandins; increased prostaglandins inhibit cell differentiation
and apoptosis, increase tumor cell proliferation in vitro, and induce angiogenesis, leading to greater likelihood of
malignancy and tumor growth; tumor necrosis factor-α (TNF-α)—elevated in patients with ovarian cancer; levels
of TNF-α appear to correlate with stage of ovarian cancer; stimulates in vitro cell lines to have more invasive properties;
studies suggest endometriosis associated with increased immune suppression
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| Hormonal interaction: effect of estrogen on breast cancer clearly shown; progestins and androgens may enhance
breast cancer risk; unopposed estrogens and androgens may influence ovarian cancer risk (association with polycystic
ovary syndrome [PCOS] and increased risk for cancers other than endometrial yet to be studied); altered
immune function associated with endometriosis; increased local estrogen and aromatase activity in endometrial
implants in peritoneal cavity (local estrogen levels might exceed levels in systemic circulation); presence of endometriosis
causes inhibition of cytotoxicity, which perpetuates growth of endometriosis (self-perpetuating system);
activity of natural killer cells inhibited by transforming growth factor (TGF)- β TGF- β and TNF-α
investigated for role in endometriosis
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| Breast cancer: data suggest inflammatory mediators regulate estrogen synthesis in breast tissue; even without systemically
high levels of estrogen, there may be high local estrogen in breast tissue stimulated by inflammatory
mediators; interleukin (IL)-6 with or without TGF-α increases local aromatase activity in breast cancer
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| Ovarian cancer: steroid hormones modulate T helper (TH )1 and TH 2 cytokines and TGF- β cytokines and growth
factors stimulate steroidogenesis; endometriosis local process of malignant transformation to ovarian cancer (not
factor with breast cancer); in summary, possible explanation for association between endometriosis and reproductive
cancers may be local and systemic enhancement of aberrant inflammatory and hormonal mediators
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| Detection of early malignancy: important; patient with endometriomas should have annual history and physical
examination, pelvic US, and appropriate laboratory tests; if changes observed on US, follow with MRI; CA-125
used as marker for progression (if normal) of endometriomas; promote health maintenance; avoid alarming patient
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| Summary: can have long delay before diagnosis of endometriosis; treatment should be targeted toward goals of patient
(eg, pain control vs fertility); associated disorders should be evaluated for early detection and treatment; future
therapies—selective estrogen receptor modulators (SERMs), selective progesterone receptor modulators
(SPRMs), aromatase inhibitors (may be important because of enhanced local aromatase activity in endometrial implant,
breast, and ovary), antiangiogenic factors, immunosuppressants, and antioxidants
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| DIAGNOSIS AND MANAGEMENT OF CHRONIC PELVIC PAIN AND ENDOMETRIOSIS —Carl Della Badia,
DO, Assistant Professor, and Director, Clinical Division, Department of Obstetrics and Gynecology, Drexel University
College of Medicine, Philadelphia, PA
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| Chronic pelvic pain (CPP): management holistic; often different entities involved; endometriosis small part of
CPP; prevalence—12% to 39% of reproductive-age women; indication for 10% of hysterectomies; health care costs
related to CPP >$2.8 billion annually; gynecologic causes—endometriosis, adenomyosis, chronic pelvic inflammatory
disease (PID), pelvic congestion syndrome, adnexal masses, and fibroids; controversial whether fibroids cause
pain; pain most likely caused by degeneration of fibroid
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| Diagnosing endometriosis: histologic diagnosis (visual diagnosis not adequate); most commonly found in ovaries,
ovarian fossa, posterior cul-de-sac, vesicouterine fold, uterosacral ligaments, uterine serosa, and broad ligaments;
laparoscopy—optical magnification 5 times; perform close visualization of tissues; look under ovary; trace
uterosacral ligaments; inspect bladder flap and upper abdomen; CO2 irritates peritoneal lining, causing breakage of
small capillaries; irritation of capillaries (seen as small red dots) mistaken for endometriosis; establish areas of endometriosis
and document after entering pelvis; pain associated with endometriosis demonstrated 3 to 4 mm away
from implant; speaker performs wide local excision with needle tip cautery (achieves same results without high
cost of laser and associated laser precautions); in sensitive areas (eg, ureter), speaker injects 5 to 10 mL of saline
between peritoneum and vital structure (absorbs some electrical energy); address adhesions, using caution not to
distort normal anatomy; although peritoneal stripping reduces pain, speaker concerned about effects on fertility;
adhesion barriers—lack of good clinical data showing definitive benefit in laparoscopic surgery
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| Medical treatment options: pseudopregnancy—oral contraceptives (OCs) cyclical or continuous dosing;
danazol—older drug with many male hormone side effects; gonadotropin-releasing hormone (GnRH) with add-
back therapy—norethindrone 2.5 mg to 5 mg; gestrinone— progestin; not approved for use in United States;
SPRMs—clinical trials showed beneficial results with asoprisnil, but trial stopped because of endometrial hyperplasia
observed at 2-yr mark; pulse dosing being considered; recurrence rates—after surgery, ≈20% annually
(40% at 5 yr); after GnRH therapy, 37% at 5 yr (with severe disease, 74% at 5 yr); total abdominal hysterectomy
with bilateral salpingo-oophorectomy (TAHBSO) only definitive treatment; if ovaries left, 37% require second surgery,
with recurrence rate of 50%; speaker considers chance of recurrence and patient’s age when counseling about
hysterectomy for treatment of endometriosis
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| Prolonged medical treatment: GnRH with add-back therapy—norethindrone 2.5 to 5 mg daily; medroxyprogesterone
acetate (Depo-Provera)—not as effective as prolonged medical treatment; less expensive than
GnRH therapy; all patients on long-term therapy should have bone density monitoring
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| Treatment algorithm: if childbearing desired—determine reason for treatment (infertility or pain); perform laparoscopy
to determine disease stage; excise as many lesions as possible; laparoscopic light source delivering blue
light demonstrated to enable visualization of nonvisible endometriosis and makes other visible lesions easier to identify;
speaker counsels patient not to delay pregnancy too long; if no response after 3 mo of attempting pregnancy,
speaker recommends assisted reproduction; if childbearing finished—consider definitive surgery (depending on
how close patient to menopause); in most instances, speaker performs laparoscopic hysterectomy (and bilateral salpingo-oophprectimy,
depending on patient’s age); do not perform supracervical hysterectomy in woman with endometriosis
(may leave some endometrial implants behind); spillage and implantation of viable endometrial tissue
might occur during uterine morcellation; laparoscopic oophorectomy recommended if patient continues to have
symptoms after hysterectomy; if childbearing not immediately desired—implants excised laparoscopically and patient
placed on suppression (eg, continuous-dose pills, Depo-Provera); do not perform laparoscopy and do nothing
afterwards (another laparoscopy required 2 to 3 yr after); speaker has had beneficial results with 3 or 6 mo of continuous
dose etonogestrel/ethinyl estradiol (NuvaRing)
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| Other causes of CPP: gastrointestinal—chronic appendicitis (speaker recommends including appendectomy
with consent for laparoscopy); inflammatory bowel disease, diverticulitis, irritable bowel syndrome; urologic—
interstitial cystitis; speaker always performs intravesical potassium sensitivity test (PST) before performing laparoscopy;
musculoskeletal and myofascial—evaluate for sports hernia; palpate rectus muscle from origin to insertion
(especially where it articulates into pubic rami); have patient do half sit-up; exert pressure on flexed rectus
muscles; evaluate whether pain superficial; check for inguinal hernia; psychologic—difficult type of patient to
treat; speaker cautions against performing hysterectomy on patient suspected of having psychologic cause of pain
(concern about malpractice)
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| History: ask about history of abuse (common cause of CPP; gain patient’s trust before asking about abuse); ask about
urine leakage and pain as it relates to sexual intercourse; ask about location, duration, severity, and what worsens
the pain (with sports hernia, sit-up motion or twisting motion); ask whether pain related to sexual intercourse, menstrual
cycle, urination, bowel movement, diet, or stress; 85% of diagnosis made by history
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| Physical examination: musculoskeletal—observe patient’s posture (whether patient hunched over); abdomen—
check for hernia, guarding, and rebound; check rectus and oblique muscles (patient may have chronically aggravated
muscle); pelvic examination— inspect introitus for tender areas; with cotton-tip applicator, touch different
gland openings; if pain elicited, may be associated with vestibulitis; extreme discomfort with gentle push on lateral
side walls of vagina indicates pelvic floor spasm; speaker has elicited pain from episiotomy sites and has had
good results with trigger-point injections at site; assess for cervical motion tenderness, signs of PID, and cervical
lesions; assess uterus (eg, enlarged, tender, mobile); adherence of uterus to anterior abdominal wall possible in
women who have had cesarean delivery; speaker recommends lysis of adhesions using harmonic scalpel and absorbable
adhesion barrier (Interceed) on raw surface of uterus; perform rectal examination
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| Imaging: obtain pelvic US and assess for fibroids or adnexal masses; MRI if adenomyosis suspected (eg, menstrual
cramps that do not decrease in severity as period progresses); obtain appropriate laboratory tests
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| Laparoscopy vs empiric treatment with GnRH therapy: Ling recommends treating patient with trial of GnRH for 3
mo; assume endometriosis if patient improves, and treat for 6 mo; speaker performs laparoscopy first (believes it
provides definitive histologic diagnosis), then follows with leuprolide acetate (eg, Lupron)
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| Other considerations: irritable bowel syndrome—can be psychosocially related; urethral syndrome—most likely
if pain elicited when urethra touched or rubbed; treat with conjugated estrogens (Premarin cream) daily for 2 wk; intravesical
PST—speaker performs before laparoscopy; potassium chloride instilled into bladder using 50-mL syringe
and pediatric catheter; bladder component interstitial cystitis when pain and severe discomfort; speaker uses
rescue solution of lidocaine, bicarbonate, and heparin; trigger-point injections—effective as treatment for side wall
spasms when physical therapy ineffective; laparoscopic uterine nerve ablation (LUNA)—ineffective and no longer
performed; presacral neurectomy—reserve for patient refractory to other treatments; dangerous because of large
blood vessels in area; uterine suspension—speaker reserves for patient with collision dyspareunia; laparoscopic uplift
surgery short procedure providing for more comfortable sexual intercourse; lysis of adhesions—in most cases,
adhesions not source of pain; ovarian embolization for chronic pelvic congestion—speaker has achieved good results
treating ovarian and uterine varicose veins with baby aspirin
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Suggested Readings
Gambone JC et al: Consensus statement for the management of chronic pelvic pain and endometriosis: proceedings
of an expert-panel consensus process. Fertil Steril 78:961, 2002; Ling FW: Randomized controlled trial of depot
leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group.
Obstet Gynecol 93:51, 1999; Martin DC et al: Endometriosis and pain. Clin Obstet Gynecol 42:664, 1999; Ness
RB et al: Endometriosis as a model for inflammation-hormone interactions in ovarian and breast cancers. Eur J Cancer
42:691, 2006; Swiersz LM: Role of endometriosis in cancer and tumor development. Ann N Y Acad Sci
955:281, 2002; Sepilian V et al: Iatrogenic endometriosis caused by uterine morcellation during a supracervical
hysterectomy. Obstet Gynecol 102:1125, 2003; Van Gorp T et al: Endometriosis and the development of malignant
tumors of the pelvis. A review of literature. Best Pract Res Clin Obstet Gynaecol 18:349, 2004.
Educational Objectives
| The goal of this program is to improve the diagnosis and management of chronic pelvic pain and inform the clinician
about research on the link between endometriosis and ovarian cancer. After hearing and assimilating this program, the
clinician will be better able to:
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| 1. Advise the patient about the health risks associated with endometriosis.
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| 2. Explain the role of inflammation and hormones in malignant transformation of endometriosis.
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| 3. Diagnose and choose the appropriate medical and surgical treatment options for endometriosis.
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| 4. Utilize the treatment algorithm for endometriosis depending on the patient’s childbearing status.
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| 5. Determine causes of chronic pelvic pain other than endometriosis.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Della Badia is on the
Speaker’s Bureaus for Wyeth, Apple Medical, American Medical, Ethicon, Gynecare and Proctor and Gamble and has
received a research grant from Apple Medical.
Acknowledgements
Dr. Cedars was recorded at Reproductive Endocrinology and Infertility, sponsored by the University of California, San
Francisco, School of Medicine, and held April 6-7, 2006, in San Francisco, CA. Dr. Della Badia was recorded at the 6th
Annual Women’s Health Symposium, sponsored by the University of Medicine and Dentistry of New Jersey, School of
Osteopathic Medicine and held on September 16-17, 2006, in Cape May, NJ.
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