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

Belek, Turkey, 6 October 2011

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


David Sackett

Preface


Hypothesis 1

Measles is the disease

The spots are the symptoms

Endometriosis


You cannot cure the disease by removing the symptoms

Hypothesis 2


2 ımportant pıtfalls

When to perform Second Look Laparoscopy?

How to deal wıth spontaneous progressıon/regressıon?

6 months drug treatment

0

2

4

6

8

10

12

14

16

18

20

# implants

Danazol x 6 monthsEvers, Fertil Steril,1985


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


Preamble

Endometriosis is a dynamic processLesions come and lesions go


Preamble

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

Aggression: reflux menstruationDefense: peritoneal immune system


Preamble

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

Aggression: reflux menstruationDefense: peritoneal immune system

How can we modulate this process?


Surgery Drugs


Surgery


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Drugs


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surg

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drugs

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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


Surgery Drugs


RCT

cohort

case control

interventional

observational

validity

Hierarchy of major study designs

cross-sectional

case reports / case series


Drugs


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


Surgery


Endometriosis : pelvic painLUNA + ablation

0

2

4

6

8

10

12

Start 3 months 6 months

Surgery

Controls

Sutton, 1997


Improvement pain

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


Long term follow-up of pain surgery


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


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


2 Infertility

Surgery Drugs


Drugs


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


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


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

Surgery


Grading endometriosis

Type Clinical findings

Complicated ImplantsAdhesionsCysts

Simple Implants

Occult ---


2Does endometriosis affect fertility?

2 questions:


2Does endometriosis affect fertility?

If so, will treatment restore fertility?

2 questions:


RCT

cohort

case control

interventional

observational

validity


cross-sectional



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)


RCT

cohort

case control

interventional

observational

validity


cross-sectional



Prospective cohort study

20 years follow-up: live birth rates

unselectedyoungwomen


women withunexplainedsubfertility

Prospective cohort study

10 years untreated follow-up: live birth rates

? ? ??


The second best option, rephrased

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


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



Pats Pregn PR

Endocan,’97 169 29 17%

GISE,’99 45 13 29%

RCT’s surgical treatment



Pats Pregn PR

Medical 135 57 42%

Surgical 214 42 20%

2 RCT’s surgical treatment6 RCT’s medical treatment


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


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


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


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


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


Hummelshoj 01/2006www.endometriosis.ca

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

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