Endometriosis

Dr Cathy Burke MSc Programme November 2009

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: 4080%) than women with infertility without pain (20 50%) or control groups (520%)
Koninckx et al, 1991

Prevalence increasing over the years

Guo 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 IBS PID 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 a TIFF (Uncompressed) decompressor are needed to see this picture.

QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

QuickTime and a TIFF (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 Tubes POD / pelvic sidewall Ureter Bowel Bladder 60% 21% 83% 13% 51% 13%

Grading of endometriosis
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
OCP GnRH agonists Depo-Provera

Atrophy of endometriotic lesions / local effect

Oral progestogens Depo-provera Mirena

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 GnRH

Cochrane 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 sideeffects 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 months
Vercellini et al 1999

Radiographic evidence of regression of rectovaginal lesions

Fedele et al 2001

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

Mirena equivalent to GnRH for pain

Petta 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 Resection endometriosis Ureterolysis Bowel dissection Ablation of endometrioma(s) Stripping of endometrioma(s) 8% 81% 51% 57% 10% 30%

Operative time (mins) med (IQR, R) Blood loss (ml) med (IQR, R)

(90-162) (100-500)

(20-270) (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 6/12

Nardo 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 reoperation rate (x 8)
Namnoun et al Fertil Steril 1995

omplications of surgery
Complications of laparoscopy Organ injury ureter bowel bladder Bleeding

Adhesion prevention in endometriosis surgery

Suturing of ovary decreases adhesion formation
Pellicano et al Fertil Steril 2008

Adhesion prevention agents Barrier Interceed reduces adhesions

Cochrane 2008

Fluid

Limited evidence
Cochrane 2006

Icodextrin 4% (Adept) reduces adhesions

Brown et al Fertil Steril 2007

Surgery - outcomes
Mean pre-op VAS scores
Period pain Pelvis pain Sexual intercourse pain Pain opening bowels Health scores EUROQOL (Health state) SF-12 Physical Mental 46 41 52 49 6 7 0.074 <0.001 8 5 4

Mean post-op VAS scores (Med FU 6/12)

4.5 2 2

Improvement in mean scores

2.5 3 2

p-value

<0.001 <0.001 0.001

5 64 0.73

1 80 0.80

4 16 0.07

<0.001 <0.001 0.003

Evidence for surgery Pain and QOL

Improvement 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 - Fertility

Laparoscopic ablation of minimal/mild endo improves fertility
Marcoux et al NEJM 1997, Cochrane Review 2002

Endometrioma excision Ovulation rate in natural cycles reduced compared with pre-op
Horikawa 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 nonmenstrual 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 years

Abbott et al 2005

Multidisciplinary management of endometriosis

Associated with decrease in pain, anxiety, depression in CPP group
Kames et al Pain 1990

Integrated approach improved pain significantly more than standard approach with CPP
Peters et al Obstet Gynecol 1991

Complementary therapies and endometriosis

Acupuncture; Japanese-style acupuncture vs sham acupuncture
Wayne 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 levels
Lu 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 endometriosis

Presacral neurectomy Mifepristone (anti-progesterone) Aromatase inhibitors (anastrozole, letrozole) TNF alpha inhibitors Thalidomide

THANK YOU