can we really treat endometriosis? johannes l.h. evers, maastricht, netherlands belek, turkey, 6...

Can we really treat endometriosis?

Johannes L.H. Evers, Maastricht, NetherlandsBelek, Turkey, 6 October 2011,

Annual Congress of the Turkish Society of Reproductive

Medicine

Objectives

To investigate the following hypotheses:

1. We understand endometriosis2. Endometriosis is a progressive

disease3. We can treat endometriosis4. We have good evidence for all of this

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Evidence-based medicineis the integration of(patho)physiologicalmechanisms and theoutcome of top-qualityclinical research

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David Sackett

Preface

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Hypothesis 1

Measles is the disease

The spots are the symptoms

Endometriosis

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You cannot cure the disease by removing the symptoms

Hypothesis 2

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2 ımportant pıtfalls

When to perform Second Look Laparoscopy?

How to deal wıth spontaneous progressıon/regressıon?

6 months drug treatment

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4

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8

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12

14

16

18

20

# implants

Danazol x 6 monthsEvers, Fertil Steril,1985

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Number of implants

FLL

SLL

SLL+2

Placebo group- better 5/17 (29%)- same 4/17 (24%)- worse 8/17 (47%)

Br Med J. 1987 January 31; 294(6567): 272–274. E J Thomas and I D Cooke

Preamble

Endometriosis is a dynamic process

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Preamble

Endometriosis is a dynamic processLesions come and lesions go

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Preamble

Endometriosis is a dynamic processLesions come and lesions goThis depends on:

Aggression: reflux menstruationDefense: peritoneal immune system

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Preamble

Endometriosis is a dynamic processLesions come and lesions goThis depends on:

Aggression: reflux menstruationDefense: peritoneal immune system

How can we modulate this process?

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Surgery Drugs

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Surgery

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HypothesisEndometriosis is a dynamic process

You can remove the implants by surgeryOccult implants will remain, and grow

You can inactivate (hide) implants by drugsThey will regrow after the end of therapy

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1Pain

Surgery Drugs

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RCT

cohort

case control

interventional

observational

validity

Hierarchy of major study designs

cross-sectional

case reports / case series

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Drugs

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Endometriosis : pelvic paindrug - placebo

0

2

4

6

8

10

12

Start 3 months 6 months follow-up

danazol

placebo

MPA

OC

GnRHa

GnRHa+

Medical treatment

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Surgery

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Endometriosis : pelvic painLUNA + ablation

0

2

4

6

8

10

12

Start 3 months 6 months

Surgery

Controls

Sutton, 1997

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Endometriosis : pelvic painLUNA + ablation

0

2

4

6

8

10

12

Start 3 months 6 months

Surgery

Controls

Sutton, 1997

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Improvement pain

Abbott et al, 2004F&S 82: 878-84

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Long term follow-up of pain surgery

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Abbott et al. 2003

VAS score

Number Needed to Treat

Pain relief surgery 36/52 = 69 %

Pain relief controls 13/50 = 26 %

ARI 43 %

NNT 3

95 % Confidence Interval 2 – 6

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Sutton, 1997Abbott, 2004

Pain conclusion Medical treatment works Surgical treatment works

Medical treatment will only suppress endometriosis temporarily

Surgical treatment will only remove visible lesions

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2 Infertility

Surgery Drugs

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Drugs

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Ovulation suppression for endometriosis

24 trials Drugs vs OR 95% CIOR pregnancy drugs versus placebo or no treatment

Placebo 0.79 0.54-1.14

No treatment

0.80 0.51-1.24Hughes et al, Cochrane 2007

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Ovulation suppression for endometriosis

24 trials Drugs vs OR 95% CIOR pregnancy drugs versus placebo or no treatment

Placebo 0.79 0.54-1.14

No treatment

0.80 0.51-1.24Hughes et al, Cochrane 2007

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AUTHORS' CONCLUSIONS: There is no evidence of benefit in the use of ovulation suppression in subfertile women with endometriosis who wish to conceive.

Surgery

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Grading endometriosis

Type Clinical findings

Complicated ImplantsAdhesionsCysts

Simple Implants

Occult ---

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Grading endometriosis

Type Clinical findings

Complicated ImplantsAdhesionsCysts

Simple Implants

Occult ---

Belek, Turkey, 6 October 2011

Grading endometriosis

Type Clinical findings

Complicated ImplantsAdhesionsCysts

Simple Implants

Occult ---

Belek, Turkey, 6 October 2011

Grading endometriosis

Type Clinical findings

Complicated ImplantsAdhesionsCysts

Simple Implants

Occult ---

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2Does endometriosis affect fertility?

2 questions:

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2Does endometriosis affect fertility?

If so, will treatment restore fertility?

2 questions:

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RCT

cohort

case control

interventional

observational

validity

Hierarchy of major study designs

cross-sectional

case reports / case series

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The best option: RCTSow - at random - endometrium in

peritoneal cavity of one group of healthy female volunteers and not in the other, and compare fertility

(cf. Ridley JH, Edwards IK: Experimental endometriosis in the human Am J Obstet Gynecol 76: 783-790, 1958)

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RCT

cohort

case control

interventional

observational

validity

Hierarchy of major study designs

cross-sectional

case reports / case series

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Prospective cohort study

20 years follow-up: live birth rates

unselectedyoungwomen

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women withunexplainedsubfertility

Prospective cohort study

10 years untreated follow-up: live birth rates

? ? ??

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The second best option, rephrased

Study spontaneous PR in untreated controls of RCT’s Compare to PR in women with unexplained subfertility

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Spontaneous PR in RCT Controls

Pats Pregn PR

Thomas,’87 17 4 24%

Bayer,’88 36 17 47%

Telimaa,’88a 14 6 43%

Telimaa,’88b 14 6 43%

Fedele,’92 36 17 47%

Overton,’94 18 7 39%

RCT’s medical treatment

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Spontaneous PR in RCT Controls

Pats Pregn PR

Endocan,’97 169 29 17%

GISE,’99 45 13 29%

RCT’s surgical treatment

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Spontaneous PR in RCT Controls

Pats Pregn PR

Medical 135 57 42%

Surgical 214 42 20%

2 RCT’s surgical treatment6 RCT’s medical treatment

Spontaneous PR in RCT Controls

Pats Pregn PR

Medical 135 57 42%

Surgical 214 42 20%

weighted average 28%

95%CI 24-34%

2 RCT’s surgical treatment6 RCT’s medical treatment

Spontaneous pregnancy rates

Pats

Pregn

PR

Present review Endometriosis 349 99 28%

Adamson,1996 Endometriosis 1063 360 34%

Taylor & Collins,1992

Unexplained subfertility

2026 669 33%

Adamson, WCE Yokohama, 1996Taylor & Collins, Unexplained Infertility, 1992

surgery

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ENDOCAN – 1997 Canada172 surgery169 controls29% PR surgery17% PR controls

Removal of lesions + lysis of adhesions

GISE – 1999 Italy51 surgery49 controls20% PR surgery22% PR controls

Removal of lesions + lysis of adhesions

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Jacobson TZ, Barlow DH, Koninckx PR, Olive D, Farquhar C. Laparoscopic surgery for subfertility associated with endometriosis (Cochrane Review). In: The Cochrane Library, Issue 2, 2003. Oxford: Update Software.

Jacobson et al. 2003

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Number Needed to Treat

PR surgery 60/223 = 26.9 %

PR controls 39/214 = 18.2 %

ARI 8.7 %

NNT 12

95 % Confidence Interval 6 - 111

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Can we treat Endometriosis?

Evidence for drug effect Pain: ovulation suppression works Subfertility: no effect

Evidence for surgery effect Pain: NNT 3 (95% CI 2 – 6)

Subfertility: NNT 12 (95% CI 6 – 111)

Control & treated pats

0

5

10

15

20

25

30

35

40

45

50

FedeleBayerTelimaa aTelimaa bOvertonGISEThomas-Endocan CEndocan EC E

Untreated controls, 7 RCTs Endocan

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Control & treated pats

0

5

10

15

20

25

30

35

40

45

50

FedeleBayerTelimaa aTelimaa bOvertonGISEThomas-Endocan CEndocan EC E

Untreated controls, 7 RCTs Endocan

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Control & treated pats

0

5

10

15

20

25

30

35

40

45

50

FedeleBayerTelimaa aTelimaa bOvertonGISEThomas-Endocan CEndocan EC E

Untreated controls, 7 RCTs Endocan

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Hummelshoj 01/2006www.endometriosis.ca