Endometriosis & Pelvic pain

Department of Obstetrics/GynecologyUniversity of Ottawa

Base Camp Lecture Series

Learning Objectives

• After the completion of this program, students will be able to:• Review possible pathogenesis and distribution of

endometriosis• Describe gross and histological appearance of endometriosis.• Discuss impact of endometriosis, clinical presentations and

principles of treatment.• Review prevalence, risk factors, biopsychological impact of

pelvic pain.• Adenomyosis (not included, suggested reading provided)

2

Olive D.L. & Pritts E.A. NEJM 2001Bulun S.E. NEJM 2009

• Presence of endometrial glands and stroma outside the uterus

Features:

• Estrogen-dependent

• Inflammation

• Angiogenesis

• Cellular proliferation

COMMON LOCATIONS

A. Peritoneal endometriosis B. Ovarian endometriomas C. Deep endometriosis

• Affects 5-10% of the female population1,2

• Presentation:• Up to 20% are asymptomatic5

• 40-60% in women with dysmenorrhoea4

• 20-30% in women with subfertility4

• Global survey data indicate that 62% of women with endometriosis are under age 30 at onset of symptoms6

4

Epidemiology of Endometriosis

1. Mounsey AL et al. Am Fam Phys 2006;2. Eskenazi B & Warner ML. Obstet Gynecol Clin North Am 1997;3. Statistics Canada. Population statistics 2009. Available at: statcan.gc.ca 4. Farquhar C. BMJ 2007:334:249-535. SOGC. JSOGC May 1999.6. Global survey of women’s health, 2008-2009 (n=612). Data presented at the Symposium on Innovations in Endometriosis Therapy at the 14th World Congress on

Gynecological Endocrinology

Incidence of Endometriosis

• Risk is 3-10 X greater if 1st-degree relatives affected

• Also at increased risk:• Anomalous anatomy obstructing menstrual flow• Nulliparity• Subfertility• Prolonged interval since pregnancy

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• Significance of disease depends on the clinical presentation (pain and/or infertility)

• Typical pain symptoms:

• Dysmenorrhea

• Dyspareunia

• Diffuse chronic pelvic pain• Chronic, relapsing disorder

• Individual variation

• Requires long-term plan for management

Fraser IS. J Hum Reprod Sci 2008Mahutte NG, Kayisli U, Arici A. Endometriosis in Clinical Practice.2005SOGC Clinical Practice Guideline. Endometriosis: Diagnosis and management. J Obstet Gynecol Can 2010

Endometriosis

Life Long Plan

Earlier puberty

THE YOUNG

Individual impact Societal impact

Delay in diagnosis

• Dysmenorrhea

• Dyspareunia

• Chronic pelvic pain

• Medical costs

• Surgical costs

• Caregiver costs

• Absenteeism

• Reduced productivity at work

$1.8 Billion annual cost to Canadian Society

Levy A.R. et al. J Obstet Gynaecol Can 2011

Multifactorial Etiology

• Retrograde menstrual flow• Coelomic metaplasia• Lymphatic and/or

vascular metastasis • Transformation of

embryonic rests• Altered cellular immunity• Genetic• Hormonal• Environmental

Giudice & Kao. Lancet 2004; 364: 685-96. 8

Heterogeneity of Endometriosis

• Superficial implants

• Ovarian endometrioma

• Deep endometriosis

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Macroscopic appearance of endometriosis

black, red, vesicular POD obliteration Marked distorted anatomy

Endometriotic cysts

Adhesions Bowel endometriosis

Deep Endometriosis: A Different Disease?

Diagnosis

If only they could tell us…

• To explain the pain• Provide validation • Reduce feelings of isolation

• To provide earlier treatment

• To impact the natural history• Reduce risk of chronic pain• Reduce risk of associated pain syndromes• Reduce risk of infertility

We do know: • Persistent pain becomes chronic

–Nerve wind-up–Maladaptive response to pain

We don’t know:• Who will develop progressive disease• Who will regress• Who will develop infertility

Presentation of Pain Related To Endometriosis

• Dysmenorrhea• Dyspareunia• Dysuria• Dyschezia• Lower back or abdominal

discomfort• Pelvic or lower abdominal

pain • Chronic pelvic pain

(non-cyclic abdominal pain and pelvic pain ≥6 months)

• Atypical presentations: • Cyclic pain at other sites

(e.g., leg pain, sciatica)• Rectal bleeding or

hematuria• Cyclic dyspnea /

hemoptysis

Leyland et al. JOGC 2010; 32 (Suppl 2): S1-S32. 15

SOGC Clinical Practice Guideline. Endometriosis: Diagnosis and management. J Obstet Gynecol Can 2010

General Endometriosis

SOGC Clinical Practice Guideline. Endometriosis: Diagnosis and management. J Obstet Gynecol Can 2010

Uterine Primary dysmenorrhea Adenomyosis

Bowel Irritable bowel syndrome Inflammatory bowel disease Chronic constipation

Bladder Interstitial cystitis Urinary tract infection Urinary tract calculi

Ovarian Mittelschmerz (ovulation pain) Ovarian cysts (rupture, torsion, etc.) Ovarian remnant syndrome

Fallopian tube Ectopic pregnancy (acute or chronic) Pelvic inflammatory disease Hematosalpinx (after sterilization or endometrial ablation)

General Endometriosis Myofascial pain Neuropathic pain Pelvic congestion Adhesions

No correlation between pain scores, types of pain, and various aspects of anatomy and biochemistry of the implants

Surgical removal of the ectopic implants alleviates pain symptoms in many women, but…

Surgery can fail to alleviate the pain and/or pain may recur even without evidence of residual or recurrent disease or any other identifiable

visceral or somatic pathology

What Causes The Pain?

Berkley. Science 2005;308:1587-9. Gruppo Italiano per lo Studio dell’Endometriosi. Hum Reprod 2001; 16: 2668-71.

Abbott et al. Hum Reprod 2003; 18: 1922. 18

Screening & Diagnosis of Pelvic Pain

• Investigation of suspected endometriosis :• History• Physical examination• Imaging assessments (e.g., ultrasound)

• Ancillary tests for deeply invasive endometriosis:• Colonoscopy, cystoscopy, rectal ultrasonography, MRI

• Direct visualization at laparoscopy and histologic study is the gold standard for definitive diagnosis

Leyland et al. JOGC 2010; 32 (Suppl 2): S1-S32. 19

Step 1: The History

• “Listen to your patient, (s)he is telling you the diagnosis”

Sir William Osler (July 12, 1849 – December 29, 1919)

Pelvic Pain only6.5%

Dyspareunia only0.7%

Pelvic Pain +Dysmenorrhea

25.2%

Dysmenorrhea +Dyspareunia

6.5%

Pelvic Pain +Dyspareunia

3.3%

*Pelvic Pain + Dysmenorrhea +

Dyspareunia34.4%

Sinaii N. et al. Fertil Steril 2008

Dysmenorrhea only

12.7%

Step 2: Physical Exam

• Essential to be thorough and do full exam of pelvic floor and internal anatomy

• Recto-vaginal exam may be necessary

• Exam during menses is helpful

Image for educational purposes only.

Deep Endometriosis

Rectovaginal Nodules

STEP 3: Get the RIGHT imaging

• GUIDED by your exam

• Ultrasound is ONLY a tool• Negative scan does

not mean anything if your exam was positive

• Expert Guided US

• CHECK THE KIDNEYS

“The common belief that a preliminary laparoscopy must always be performed in order to definitely diagnose the disease should

be challenged, as the nonsurgical diagnosis of endometriosis has been demonstrated to be highly reliable”

Vercellini P. et al. Endometriosis: current and future medical therapies. Best Pract Res Clin Obstet Gynaecol 2008;22(2):275–306

Suggestive history even with a negative exam should be considered adequate for a

presumptive diagnosis

SOGC Clinical Practice Guideline. Endometriosis: Diagnosis and management. J Obstet Gynecol Can 2010

When could laparoscopy be considered?

• When history is consistent with endometriosis and:• Other causes of pain ruled out• First-line medical management is ineffective• Atypical pain (i.e., not cyclic)

• Surgeon should be prepared to vaporize or excise lesions that are discovered

• Good evidence that laparoscopy provides long-term pain relief in up to 50% of patients

Leyland et al. JOGC 2010; 32 (Suppl 2): S1-S32. 27

Medical Management of Pain

The “Pragmatic Approach” to treatment of endometriosis

Treat the Patient

NOT THE LESIONS

Vercellini P. et al. Endometriosis: current and future medical therapies. Best Pract Res Clin Obstet Gynaecol 2008

SOGC GuidelinesManagement of Pain Alone with Suspected Endometriosis

Figure adapted from: SOGC Clinical Practice Guideline. Endometriosis: Diagnosis and management. J Obstet Gynecol Can 2010

Suspected Endometriosis

CHC therapy, continuous or cyclic

1. Reconsider diagnosisadditional testing ± non-gynaecologic referrals2. Chronic pain managementand multidisciplinarysupport

Failure of CHC therapy

Failure of surgical ormedical therapy

Laparoscopy fordiagnosis and treatment

Medical therapy1. Progestins2. GnRH agonist with addback3. Progestin IUS4. Danazol

CHC, combined hormonal contraceptiveIUS, intrauterine system

SOGC Recommendations (Evidence Level I-A)

• 1st-line agents:• CHC, ideally administered continuously• Progestin alone orally or intramuscularly

• 2nd-line agents:• GnRH agonist with combined HT add-back• LNG-IUS

• GnRH treatment with combined HT add-back may be considered for long-term use• Prudent to follow bone mineral density

Leyland et al. JOGC 2010; 32 (Suppl 2): S1-S32.

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Any treatment trial should be administered for a minimum of 3 months, with evaluation of efficacy at the end of the

trial

Non-Hormonal TreatmentsTreating the Pain Alone

• NSAIDs / acetaminophen• Opioids• Increase patient comfort until primary medical management

(hormonal treatment) becomes effective• Treat associated conditions (e.g., depression, IBS)

Leyland et al. JOGC 2010; 32 (Suppl 2): S1-S32. 32

Drug Administration Limited Use Side Effects

Dienogest (Visanne) Oral – 2mg/day None Irregular bleeding

Norethindrone acetate (Norlutate)

Oral – 5mg/day to 15mg/day

6-9 months Irregular bleeding

MPA (Depo Provera) IM – 50mg/week or 100mg/2weeks

BMD >2 years – monitor

BMD, weight gain, depression, irregular bleeding

Leuprolide Acetate (Lupron)

IM – 3.75mg/mos or 11.25mg/mos + add back (5mg NA)

6 mos* BMD, Menopausal symptoms*

Triptorelin (Trelstar) IM – 3.75mg/mos 6 mos BMD, Menopausal symptoms

Goserelin (Zoladex) SC – 3.6mg/mos or 10.8mg/3 mos

6 mos BMD, Menopausal symptoms

Nafarelin (Syneral)Burserlin (Suprefact)

Nasal – 200mcg BIDNasal – 400 mcg TID

6 mos BMD, Menopausal symptoms

Danazol (Cyclomen) Oral – 200-800mg/day 6 mos androgenic

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Medications Available in Canada 2012

Recipes for Combined Add-back Hormone Therapy

Add-back regimens

Ethinyl estradiol

1mg

Ethinyl estradiol

2.5mg

Estradiol-17ß (micronized)

0,5 mg

Estradiol-17ß (micronized)

1mg

Conjugated equine estrogens 0,625 mg

Micronor 0.35mg(Norethindrone Tablets)

Provera 2.5mg(medroxyprogesterone acetate)

Prometrium 100mg (progesterone capsule)

Norethindrone Acetate 0.5mg

Norlutate(Norethindrone Acetate 5mg tablets)

Pro

gest

in

Estrogen

34(1)Activelle; (2)FemHRT

(1) (2)

Surgical Management of Pain

An asymptomatic patient with an incidental finding of endometriosis does not require any medical

or surgical intervention

Decision for surgery should be based on clinical evaluation, imaging, and effectiveness of medical management

Clinical Tips

Leyland et al. JOGC 2010; 32 (Suppl 2): S1-S32. 36

Indications For Surgery

• Patients with pelvic pain • Not responding or with contraindications to medical therapy• With an acute adnexal event (torsion, rupture)• With severe invasive disease involving bowel, bladder, ureters or

pelvic nerves (having failed medical management)• Patients who have a known or suspected ovarian

endometrioma• Uncertainty of diagnosis affects management (as with chronic

pelvic pain)• With infertility and associated factors (e.g., pain, pelvic mass)

Leyland et al. JOGC 2010; 32 (Suppl 2): S1-S32. 37

Conservative vs. Definitive Approach

Conservative Definitive

Restore normal anatomy and relieve pain Induction of menopause

Women of reproductive age who wish to conceive in the future or avoid induction of early menopause

Women with significant pain and symptoms despite conservative treatment, do not desire future pregnancies and have severe disease, or undergoing hysterectomy due to other pelvic conditions (e.g., abnormal cervix confirmed by colposcopy)

Direct ablation, lysis or excision, removal of ovarian endometriomas, interruption of nerve pathways, excision of lesions involving adjacent organs

Bilateral oophorectomy May also include removal of uterus and fallopian tubes and ideally excision of all visible endometriotic nodules and lesions

Leyland et al. JOGC 2010; 32 (Suppl 2): S1-S32. 38

“Laparoscopic surgery reduces pelvic pain caused by endometriosis”

Does Surgery Reduce Pain?

Cochrane Library:

Jacobson et al. Cochrane Database Syst Rev 2009 Oct 7; (4): CD001300. 39

Laparoscopic surgery for endometriosis is effective for

reducing pain......

• Three studies report an improvement at pain 6 months

• RCT: comparing surgery with GnRHa showed similar reduction in pain

• One study reports improvement 12 months • Recurrence of pain in 30-60% of women with 6-12

months

OR=5.7(3.09, 10.60)

(Jacobson, 2009)

Limitations of Surgery

• Missed lesions: false negative laparoscopy• Associated risks of surgery• Required expertise & additional surgical skills

• Ureterolysis, suturing, cystoscopy, ureteric stent placement, rigid sigmoidoscopy

• Most grads not comfortable with advanced and many basic endoscopic techniques1

• Patient’s condition• BMI• Previous multiple surgeries with suspected or known severe

adhesions• Anaesthetic risk (e.g., comorbid conditions)

1Ternamian et al. JMIG 2006; 13: 10-16. 41

Post-Surgical Medical Therapy

****key point: SURGERY IS NOT THE CURE****• Multidisciplinary approach, long term approach needed

• Conservative surgery • In patients not seeking pregnancy, CHCs should be considered

(continuous preferred over cyclic) or Progestin Therapy• Postoperative hormonal suppression associated with:

• Lower recurrence rate of ovarian endometriomas• Better management of symptoms

• Definitive surgery• Consider continuous combined CHC or Progestin Therapy

Leyland et al. JOGC 2010; 32 (Suppl 2): S1-S32. 42

CHC/Progestins Surgery or 2nd Line Meds

Long term medical treatment

CHC, combined hormonal contraceptive

• Treat the symptoms

• If the symptom is pain, alleviate the pain

• If the symptom is infertility, assist fertility

• Reduce the delay in diagnosis and medical treatment

• Preserve fertility

• Prevent the progression to chronic pain

• Reduce the # of surgeries and increase the time to surgery

SOGC Clinical Practice Guideline. Endometriosis: Diagnosis and management. J Obstet Gynecol Can 2010

Conclusion

• Until the true pathophysiologic mechanisms of endometriosis are fully understood:• Medical treatments will continue to be non-specific and

imperfect• Surgical treatment, unless definitive, will still be associated with

a high failure/recurrence rate• Until then, a tailored approach based on symptoms is the best

we can offer and new emerging treatments are welcome• References:

• www.endometriosisinfo.ca• SOGC Guidelines on:

• Abnormal uterine bleeding (adenomyosis)• Management of chronic Pelvic pain

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www.endometriosisinfo.ca

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Management of Infertility Associated With Endometriosis

Added information for your interest….

Endometriosis-Associated Infertility

• 25-50% of infertile patients have endometriosis vs. 5% in fertile population

• Medical management• Hormonal suppression such as GnRH agonists is ineffective

for infertility and should not be offered except before IVF where improved pregnancy rate can be obtained

Leyland et al. JOGC 2010; 32 (Suppl 2): S1-S32. 48

Surgical Management of Endometriosis-Associated Infertility

• If there are no pain symptoms and normal pelvic examination: is there an additional benefit of laparoscopy?• Yes, but limited efficacy: only 1 additional pregnancy will result

for every 8 laparoscopies performed in this clinical situation• Ablation and excision have equal efficacy for early stage

disease

Marcoux, Maheux et al. NEJM 1997; 337: 217-22. 49

Endometriosis-Associated Infertility

• When deep infiltrating endometriosis present:• Efficacy of laparoscopic surgery is controversial

• When endometrioma >3 cm:• Laparoscopic excision may improve fertility

• Adhesion-prevention adjuncts may help reduce adhesion formation but improvement in fertility rate is unknown

Leyland et al. JOGC 2010; 32 (Suppl 2): S1-S32. 50

Adenomyosis simplified….

• Definition: • Adeno (glands) myo (muscle) sis (condition)• Ectopic endometrial tissue within the

myometrium• Implications:

• Enlarged uterus, dysmenorrhea, heavy menstrual bleeding

• Treatments:• See Abnormal uterine bleeding guidelines

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Adenomyosis

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