Chronic Pelvic Pain / Endometriosis

Dr Cathy Burke

MSc Programme

November 2009

Chronic Pelvic PainDefinitionVarious definitionsIntermittent or chronic pain in the lower abdomen or pelvis of at least six months duration, not occurring exclusively with menstruation or intercourse and not associated with pregnancy

CPP - Prevalence

• Prevalence in primary care comparable to migraine, back pain and asthma

• Yearly prevalence 38.3/1000 Zondervan 1999

• Most common indication for referral to gynae outpatient clinics - 20% of referrals Howard 1993

• 61% of women with pelvic pain did not have a clear diagnosis Mathias 1996

Dysmenorrhea - risk factorsINCREASED RISK

• Age <30• Being thin (BMI <20)• Smoking (increased with no.

of cigs)• Early menarche• Longer cycles• Heavy / irreg bleeding• Premenstrual sxs• Clinically suspected PID• Sterilisation• Hx of sexual assaultBMJ Feb 2006

DECREASED RISK• Oral contraceptive use• Fish intake• Physical exercise• Being married or in a

stable relationship• Higher parity

Dyspareunia - risk factors

• Hx of circumcision• Clinically suspected PID• Peri-postmenopausal• Anxiety / depression• Sexual assault

BMJ Feb 2006

Non-cyclical pain - risk factors

• Previous miscarriage• Longer menstrual flow• Endometriosis• Clinically suspected PID• Caesarean section• Pelvic adhesions• Physical / sexual / other abuse• Anxiety / depression• Somatisation

BMJ Feb 2006

CPP - Causes

• Pelvic inflammatory disease• Post-surgical adhesions• Irritable bowel syndrome• Constipation• Endometriosis• Interstitial cystitis / recurrent UTI• Psychological morbidity• History of childhood / adult sexual abuse• Pelvic congestion syndrome• Adenomyosis

CPP - History takingPain details• Location • Cyclicity• Timing• Character • Duration• Intensity (score out of 10)• Aggravating / relieving factors• What has / has not worked to date

CPP - History taking

• Dysmenorrhea• Dyspareunia (superficial, deep)• Dyschezia (difficulty, pain), rectal bleeding• Urinary symptoms, haematuria• Non-cyclical pain• Periods• Associated features (bloating, nausea)• Vaginal discharge• Other pain syndromes• Family history

CPP - Examination

• General - affect, weight• Abdominal• Speculum• Pelvic• Ultrasound

CPP - Investigations

• Swabs• MSU• Pelvic ultrasound• Laparoscopy +/- hysteroscopy• Cystoscopy (glomerulations, Hunner’s ulcers

in PBS), biopsy

IBS - Treatment

• Diet - food diary and exclusion, regular meals, hydration, caffeine elimination, limit fresh fruit

• Exercise• Probiotics (not prebiotics) minimum 4 weeks• Stress reduction• Antispasmodics - mebevarine, peppermint oil• Bulk forming laxatives - increase fluid intake• Antimotility drugs - loperamide• Tricyclic antidepressants• Complementary therapies• Psychological interventions

PID - Treatment

• Chlamydia - Azithromycin 1g stat PO and refer to STI clinic

• PID, polymicrobial - Ofloxacin 400mg bd and Metronidazole 400mg bd x 14 days

Severely ill patients;Doxycycline 100mg bd and Ceftriaxone 1g iv stat andMetronidazole 400mg tds

Interstitial Cystitis (PBS) - Treatment

• Bladder distention• Bladder instillation (dimethyl sulfoxide, DMSO)• Pentosan polysulfate (Elmiron) ?repairs defects in

bladder epithelium• Aspirin, ibuprofen• TENS• Lifestyle - diet, smoking, exercise• Bladder training• Surgery - fulguration, resection, augmentation,

cystectomy

Endometriosis

Introduction

Overview

Outline current treatment modalities

Explore evidence base for treatments

Present recommendations

Definition

“The presence of endometrial glands and stroma outside the uterine cavity”

• endometrial glands

• endometrial stroma

• fibrosis

• haemorrhage

Prevalence

Women with pelvic pain have a higher incidence of endometriosis (range: 40–80%) than women with infertility without pain (20–50%) or control groups (5–20%)

Koninckx et al, 1991

Prevalence increasing over the yearsGuo et al Gynecol Obstet Invest 2006

Pathology

Peritoneal inflammation and fibrosis

Adhesions

Ovarian cysts

Deep nodules

Symptomatology

Dysmenorrhea

Dyspareunia

Dyschezia / bowel symptoms / rectal bleeding

Non-cyclical pelvic pain

Urinary symptoms / haematuria

Associations

Menorrhagia (adenomyosis)

Subfertility

IBSPID Seaman et al BJOG 2008

Chronic pain syndromes

Depression - 86% vs 38%Lorencatto et al Acta Obsstet Gynecol Scand 2006

Pathogenesis

Retrograde menstruation / transplantation Sampson

Coelomic metaplasia Meyer

Metastasis (haematogenous / lymphatic) Javert

Genetic basis (Chr 7, 10, 20) Montgomery et al Hum Reprod 08

Immunologic basis

Susceptibility

Genetic predisposition Increased exposure to menstrual debris Abnormal eutopic endometrium Altered peritoneal environment Reduced immune surveillance Increased angiogenic capacity

Healy et al 1998; Vinatier et al 2001; Treloar et al 2002; Varma et al 2004

Natural history

Largely unknown

Average sx duration 7 yrs prior to diagnosis

Remitting / recurring

Hormonally-driven

Lifetime experience

Symptom duration 16 years

Half tried three / more medical treatments

Half had surgical procedures performed at least 3 times

One in five had hysterectomy / oophorectomy - most successful for sxs

Sinaii et al Fertil Steril 2007, 1998 Endometriosis Association Survey

Symptom-to-diagnosis lag

Confusion with other conditions

Co-existence with other conditions

Lack of awareness of and enquiry into symptomatology

Un / Mis - diagnosed at laparoscopy

Mechanisms of pain

Inflammatory cytokines in the peritoneal cavity

Focal bleeding from implants

Irritation and direct infiltration of nerves

Hormonal modulation: pain threshold

Mechanisms of subfertility

Distorted adnexal anatomy

Ovarian cysts

Adverse effects on folliculogenesis

Interference with oocyte/sperm survival, fertilization and embryogenesis

Endometriosis - diagnosis

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

VESICULAR LESIONS

PERITONEAL LESION WITH NEOVASCULARISATION AND FIBROSIS

VESICULAR LESIONS

TUBAL ENDOMETRIOSIS

“KISSING OVARIES”

PERITONEAL SCARRING

SUBDIAPHRAGMATIC ENDOMETRIOSIS

SUBDIAPHRAGMATIC SCARRING

ADHESION-LIKE APPEARANCE

RECTUM ADHERENT TO POD

Endometriosis - location Ovaries 60%

Tubes 21%

POD / pelvic sidewall 83%

Ureter 13%

Bowel 51%

Bladder 13%

Grading ofendometriosis

American Society for Reproductive Medicine (ASRM)

• Peritoneal disease• Ovarian disease• POD disease• Adhesions

Stage I-IV

Endometriosis - Grade vs Symptoms

Grade not directly correlated with symptomatology

Advanced disease more frequently related to dysmenorrhea and dyspareunia compared to early disease

Milingos et al Gynaeol Obstet Invest 2006

Endometriosis - what is the impact?Quality of life (EuroQOL, Health score, EHPQ-30)

Social functioning(SF36/12)

Sexual activity(SAQ)

Medical treatment

Medical management

Non-steroidal anti-inflammatory drugs

Inhibition of ovulation OCPGnRH agonistsDepo-Provera

Atrophy of endometriotic lesions / local effectOral progestogensDepo-proveraMirena

Oral analgaesics

NSAIDS inconclusive evidence for use Allen et al, Cochrane review 2005

Oral contraceptive pill

OCP effective for dysmenorrhea and reduced endometrioma size

Harada et al Fertil Steril 2007

OCP equivalent to GnRHCochrane Review 2007

Continuous OCP in women in whom recurrent dysmenorrhea not controlled by cyclical OCP

Vercellini et al Fertil Steril 2003

GnRH agonists

GnRH agonist use for endometriosis-related pain well-established

Dlugi et at Fertil Steril 1990, Waller et al Fertil Steil 1993, Henzl et al

NEJM 1988

GnRH agonists with or without add-back E work better than OCP for post-surgical relapse. Add-back improves QOL scores

Zupi et al Fertil Steril 2004

Progestogens

Oral progestogens poorly tolerated due to side-effects

Depo-provera equivalent to GnRH for pain scores.Less loss of bone mineral density with DMPA Schlaff et al Fertil Steril 2006

Mirena

70% symptomatic relief after 12 monthsVercellini et al 1999

Radiographic evidence of regression of rectovaginal lesionsFedele et al 2001

Improvement in severity and frequency of pain and menstrual sxs, and staging of diseaseLockhat et al Hum Reprod 2004

Mirena equivalent to GnRH for painPetta et al Hum Reprod 2005

Surgical treatment

Surgery for endometriosis

Ablation / excision of superficial peritoneal deposits

Excision of deep peritoneal deposits

Stripping / drainage and ablation of endometriomata

Hysterectomy / Oophorectomy

Extent of surgery - tertiary unit

Total laparoscopic hysterectomy 8%

Resection endometriosis 81%

Ureterolysis 51%

Bowel dissection 57%

Ablation of endometrioma(s) 10%

Stripping of endometrioma(s) 30%

Operative time (mins) med (IQR, R) (90-162) (20-270)

Blood loss (ml) med (IQR, R) (100-500) (50-2000)

Hospital stay (days) med, (IQR, R) (2-4) (1-8)

Evidence for surgical treatment

Ablation of endometriosis

Laser ablation superior to expectant mgt 62% vs 25% clinical response at 6/12

Sutton et al Fertil Steril 1994

Helica thermal coagulation - 87% response at 6/12Nardo et al Fertil Steril 2005

LUNA has no effect on endometriosis-related dysmenorrhea

Vercellini et al Fertil Steril 2003

Excision of deep endometriosis

Lap excision superior to placebo for pain and QOL Abbott et al Fertil Steril 2004

Symptoms, QOL and sexual function improved after excisional surgery

Garry et al, Anaf et al, Redwine et al, Ford et al, Lyons et al, Dubernard et al, Wykes et al

Treatment of endometriomas

Stripping vs drainage and ablation of endometriomas reduces pain symptoms and recurrence

Hart et al Fertil Steril 2005, Cochrane Review

Hysterectomy / Oophorectomy

Hysterectomy associated with high rate of symptom resolution and low re-operation rate

Shakiba et al Obstet Gynecol 2008

Ovarian conservation associated with increased risk of recurrent pain (x 6) and re-operation rate (x 8)

Namnoun et al Fertil Steril 1995

Complications of surgery

Complications of laparoscopy

Organ injury

ureter

bowel

bladder

Bleeding

Adhesion prevention in endometriosis surgerySuturing of ovary decreases adhesion formationPellicano et al Fertil Steril 2008

Adhesion prevention agentsBarrier Interceed reduces adhesions

Cochrane 2008

Fluid Limited evidence Cochrane 2006

Icodextrin 4% (Adept) reduces adhesions

Brown et al Fertil Steril 2007

Surgery - outcomesMean pre-op VAS scores

Mean post-op VAS scores

(Med FU 6/12)

Improvement in mean scores

p-value

Period pain 8 4.5 2.5 <0.001

Pelvis pain 5 2 3 <0.001

Sexual intercourse pain

4 2 2 0.001

Pain opening bowels

5 1 4 <0.001

Health scores 64 80 16 <0.001

EUROQOL (Health state)

0.73 0.80 0.07 0.003

SF-12

Physical 46 52 6 0.074

Mental 41 49 7 <0.001

Evidence for surgery Pain and QOLImprovement in pain, SAQ and QOL scores up

to 5 years • Placebo response rate 30% • Non-responsiveness to surgery 20%

Ford et al 2004; Abbott et al 2003 & 2005

LUNA is not effective in this group Johnson et al 2005

Evidence for surgery - FertilityLaparoscopic ablation of minimal/mild endo

improves fertility Marcoux et al NEJM 1997, Cochrane Review 2002

Endometrioma excisionOvulation rate in natural cycles reduced compared with pre-opHorikawa et al, J Assist Reprod Genet 2008

Ovarian response in IVF-ET cycles reduced

Yazbeck et al, Gynecol Obstet Fertil 2006

Post-operative treatment

Post-op continuous OCP and POP useful Razzi et al Eur J Obstet Gynaecol Rep Biol 2007

Postoperative GnRH improved pain when used for 3/12 and 6/12

Parazzini et al Am J Obstet Gynecol 1994, Vercellini et al BJOG 1999

Post-op Mirena useful Abbou Setta et al Cochrane Review 2006

Post-operative treatment

Post-operative hormonal suppression (COCP or GnRH) reduces dysmenorrhea vs placebo

Dietary supplementation improves non-menstrual pain post-operatively as much as OCP

Quality of life scores better with hormonal suppression

Sesti et al Fertil Steril 2007

Endometriosis recurrence

30% recurrence of endometriomata 2 years after surgical excision

Koga et al Hum Reprod 2006

Re-operation rate 35% after 3 yearsAbbott et al 2005

Multidisciplinary management of endometriosisAssociated with decrease in pain, anxiety,

depression in CPP groupKames et al Pain 1990

Integrated approach improved pain significantly more than standard approach with CPP

Peters et al Obstet Gynecol 1991

Complementary therapies and endometriosisAcupuncture; Japanese-style acupuncture vs sham acupunctureWayne et at J Paed Adolesc Gynecol

Shu Mu vs standard vs danazol on clinical sxs and CA125

Sun et al, Zhongguo Zhen Jiu 2006

Traditional Chinese medicine; Neiyi pill / enema vs danazol x 3/12 on CA125

levelsLu et al Zhongguo Zhen Jiu, 2007

ESHRE guideline

Laparoscopy desirable for women presenting with sxs of endometriosis

Therapeutic trial of hormonal agents may be used first line

Laparoscopically-diagnosed endometriosis treated for 6/12 with ovarian suppression drug

ESHRE guideline

• Inconclusive evidence that NSAIDS (Naproxen) efffective

• Suppression of ovarian function for 6/12 reduces endometriosis-related pain. All hormonal drugs equally effective but side-effect and cost profiles differ

• LNG-IUS reduces pain

• GnRH treatment for up to 2 years with E/P addback acceptable

ESHRE guideline

• Ideal practice is to diagnose and remove endometriosis at the same time provided consent has been obtained

• Ablation of endometriosis reduces pain, less so with mild disease

• No evidence that LUNA is effective

• Excision of deeply-infiltrating lesions reduces pain

• Severe / deeply infiltrating endometriosis should be referred to a centre with expertise

ESHRE guideline

• Suppression of ovarian function not effective to enhance fertility

• Insufficient evidence that excision of moderate-severe endometriosis enhances pregnancy rates

Future treatments for endometriosisPresacral neurectomy

Mifepristone (anti-progesterone)

Aromatase inhibitors (anastrozole, letrozole)

TNF alpha inhibitors

Thalidomide

THANK YOU