Evidence-based management of endometriosis-associated infertility Hassan N. Sallam, MD, FRCOG, PhD...

Evidence-based management of endometriosis-associated

infertilityHassan N. Sallam,

MD, FRCOG, PhD (London)Professor in Obstetrics and Gynaecology

The University of Alexandria, andClinical and Scientific Director,

Alexandria Fertility Center, Alexandria, Egypt

3rd Congress of Society of Reproductive Medicine, 5 – 9 October

2011, Antalya / Turkey

The old Alexandria medical school

The uterus (after Soranos of Ephesus)

Karl, baron von Rokitansky (1804-1878)

http://www.boehlau.at/main/book.jsp?bookID=3-205-77205-9

Does endometriosis affect infertility?

YES

1. More commonly found in infertility patients (Mahmoud and Templeton, 1991)2. Pregnancy rates are higher in treated

patients (Marcoux et al, 1997)3. Pregnancy with AID is lower with

endometriosis (Jansen, 1986)4. Pregnancy with IVF is lower with endometriosis (Barnhart et al, 2002)

Prevalence of endometriosis (Mahmoud and Templeton, 1991) (OS)

0

5

10

15

20

25

Sterilization Infertility Pain DUB/TAH

Mahmoud and Templeton, Hum Reprod 6(4): 544-9, 1991

6%

21%

15%

25%

Laparoscopic surgery v/s no surgery (RCT) (Canadian Collaborative Group,

Marcoux et al, 1997)

Surgery (n=172)

No surgery

(n= 169)

P value

CPR30.7%17.7%0.006

Fecundity4.7%2.4%<0.05

Marcoux et al, N Engl J Med 337(4):217-22, 1997

AID in minimal endometriosis(Fecundity rates per month of

exposure)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1 3 5 7 9 11 13 15

Normal pelvis

Endometriosis

Jansen RP, Fertil Steril 46 (1): 141-3, 1986

IVF in endometriosis versus tubal infertility (CPR)

Barnhart et al, Fertil Steril 77(6): 1148-55, 2002

How does endometriosis affect infertility?

1. Tubal adhesions2. Impaired gamete

interaction3. Impaired implantation

i.e. Endometrial receptivity does not play a role in diminished pregnancy rates in

endometriosis

Oocytes from normal controls to

endometriosis patients

Oocytes from endometriosis

patients to normal controls

Reduced implantation rates

Similar implantation rates

Cross-over oocyte donation study (Pellicer et al, 2001)

Causes of diminished pregnancy and implantation rates in IVF for

endometriosis

Poor quality of oocytes (Hull et al, 1998; Norenstedt

et al, 2001)

Lower quality embryos with a reduced ability to implant

(Simon et al, 1994; Arici et al, 1996)

The poor quality of the oocytes is probably due to the altered follicular

environment:

• Increased progesterone concentration in FF (Pellicer et al,

1998)• Increased concentration of IL-6 in

FF (Pellicer et al, 1998)• Lower levels of cortisol in FF

(Smith et al, 2002) • Lower concentrations of IGFBP-1 in

FF (Cunha-Filho et al, 2003)

The poor quality of the oocytes is probably due to the altered

follicular environment (cont…)

• Increased expression of the TNF-α in the cultured granulosa cells (Carlberg

et al, 2000)• Increased rate of apoptosis (cell

death) in the granulosa cells mediated by elevated concentrations

of soluble Fas ligand in serum and peritoneal fluid (Garcia-Velasco et al,

2002)

Effect of GnRHa on the endometrium in endometriosis

(CCT)

Mohamed et al, Eur J Obstet Gynecol Reprod Biol 156(2):177-80 , 2011

Frozen cycles

Fresh cycles

P value

LBR16.9 %11.9 % <0.05

CPR18.2 %12.7 %<0.05

Management of endometriosis-associated

infertility

1. Surgical treatment 2. Medical treatment

3. Combined medical and surgical therapy

4. Controlled ovarian hyperstimulation +/- IUI

5. Assisted reproductive techniques

Evidence-based medicine

• Level A – The recommendation based on good and consistent scientific evidence

(RCT)

• Level B – The recommendation is based on limited or inconsistent scientific evidence (CT, cohort, case control)

• Level C – The recommendation is based primarily on consensus and expert opinion

Problems in the evaluation of management options

1. Any management option should be compared to expectant

management2. The monthly fecundity rate (MFR)

is more meaningful than the pregnancy rate (PR)

Expectant management in endometriosis (Prospective cohort

study PCS)Degree of

endometriosisCumulative pregnancy rate (CPR)

Monthly fecundity rate (MFR)

Mild52.9%5.7%

Moderate25%3.2%

Severe0%0%

All cases24.4%3.1%

Olive et al, Fertil Steril 44(1):35-41, 1985

Expectant management of stage I and II endometriosis (CCT)

Cumulative pregnancy

rate

Miscarriage rate

No treatment55%14.3%

MPA71%6.3%

Danazol46%11%

P valueNSNS

Hull et al, Fertil Steril 47(1):40-4, 1987


infertility1. Surgical treatment 2. Medical treatment




Problems in evaluating surgical management of

endometriosis

1. Few studies are controlled2. Few studies report the fecundity

rate3. Techniques/skills differ

4. Recognition of “atypical” lesions5. Use of adhesion prevention

agents

White endometriosis, clear endometriosis, red endometriosis and

powder burn lesions.

Powder burns on the right uterosacral ligament causing painful intercourse

Surgical treatment of endometriosis

1. Ablation and/or resection of laparoscopic

lesions2. Drainage +/-

excision/ablation of

endometriomas

Power sources in endoscopic surgery (Sutton, 1995)

1. Electrocautery (mono or bipolar)2. CO2 Laser

3. Fibre lasers (KTP, argon, contact Nd:YAG, tunable dye or diode

laser)4. Harmonic scalpel

5. Helica thermal coagulator

Resection or ablation for minimal or mild endometriosis - Canadian Collaborative

Group (RCT)Resection

or ablation

(n = 172)

Diagnostic laparoscop

y(n = 169)

P

value

Clinical pregnancy

rate

30.7%17.7%<0.01

Fecundity rate

4.7%2.4%<0.05

Miscarriage rate

20.6%21.6%0.91Marcoux et al, N Engl J Med 337(4):217-22, 1997

Resection or ablation for minimal or mild endometriosis (RCT)

Resection or

ablation(n = 54)

Diagnostic laparoscop

y(n = 47)

P

value

Clinical pregnancy

rate

24%29%NS

Birth rate19.6%22.2%NS

Miscarriage rate

16.7%23.1%NS

Parazzini et al, Hum Reprod 14:1332-4, 1999

Resection or ablation versus no surgery for minimal or mild

endometriosis (MA)

Clinical pregnancy rate

OR = 1.613 (95% CI = 1.04 – 2.50)*

P = 0.042

Sallam et al, submitted for publication

Resection or ablation for moderate and severe endometriosis (stages

III and IV)


rate

Fecundity rate

Luciano et al, 1992 (OS)

70%6.7%

Busacca et al, 1999 (OS)

57.5%2.4%

Surgical treatment of endometriosis

1. Ablation and/or resection of laparoscopic

lesions2. Drainage +/-

excision/ablation of

endometriomas.

leads torecurrence in 50-100%

of cases

(Nezhat et al, 1988; Vercillini et al, 1992;

Olive, 1989)

Simple drainage of endometriomas

Excision of endometriomas

Drainage + resection/ablation of cyst wall

StudynTechniqueCPR

Daniell et al, 199132Laser + stripping38%

Marrs et al, 199123KTP laser ablation

30.4%

Wood et al, 199252Cyst stripping50%

Bateman et al, 1994

21Cyst stripping42.8%

Montanino et al, 1996

11Stripping + GnRHa

45%

Donnez et al, 1996814

CO2Laser + GnRHa

51%

Drainage + resection/ablation of cyst wall (cont…)

StudynTechniqueCPR

Sutton et al, 199766CO2 Laser + KTP45%

Hemings et al, 1998

84Cyst stripping50%

Beretta et al, 1998


Busacca et al, 1999


Milingos et al, 1999

32Cyst stripping53%

Jones & Sutton, 2002

39KTP laser/diathermy

39.5%

Surgical versus non-surgical therapy

Adamson and Pasta, Am J Obstet Gynecol 171:1488-504, 1994

Laparoscopic excision versus electro-coagulation in mild endometriosis

(CCT)Electro-

coagulation(n = 48)

Excision(n = 53)

P valu

e

Pregnacy rate

57.1%53.5%NS

Miscarriage rate

12.5%17.4%NS

Duration to

pregnancy

10.7 months13.3 months

Tulandi and Al-Took, Fertil Steril 69(2):229-31, 1998

Laparoscopy versus laparotomy(Cumulative pregnancy rates –

CCT)

Laparoscopy

Laparotomy

P value

Stage I & II67.4%74.3%NS

Stage III & IV62.2%44.4%<0.05

Adamson et al, Fertil Steril 59(1): 35-44, 1993

Laparoscopy versus laparotomy in severe endometriosis – (CCT)

Laparoscopy

(n = 67)

Laparotomy

(n = 149)

P value

CPR44.9%62.7%NS

Recurrence of

dysmenorrhoa

16.4%20.3%NS

Recurrence of

dyspareunia

33.3%15.4NSCrosignani et al, Fertil Steril 66(5): 706-11,

1996


infertility





Medical treatment of endometriosis

(A) Ovarian suppression- Medroxyprogesterone (MPA)

- Gestrinone- GnRH agonists

- Danazol(B) Aromatase inhibitors

- Letrozole(C) Novel approaches

Ovarian suppression for endometriosis (CPR)

No therapy

Ovarian suppressio

n

P value

Thomas et al, 1987 (RCT) (Gestrinone)

24%25%NS

Bayer et al, 1988 (RCT) (Danazol)

57.4%37.2%NS

Telimaa et al, 1988 (RCT) (Danazol)

46%33%NS

Telimaa et al, 1988 (RCT) (MPA)

46%42%NS

Fedele et al, 1992 (RCT) (Buserelin)

61%37%NS

Ovarian suppression for endometriosis

(Hughes et al, 2007) (Odds ratio for pregnancy)

Ovarian suppression v/s no treatment or placebo

OR = 0.79 (95% CI = 0.54 – 1.14)

Ovarian suppression v/s danazolOR = 1.37 (95% CI = 0.94 – 1.99)

Hughes et al, Cochrane Database Syst Rev. 2007 Jul 18;(3):CD000155

Effect of letrozole on the ASRM score (OS)

Ailawadi et al, Fertil Steril 81(2): 290-6, 2004

Letrozole for the treatment of endometriosis (RCT)

Letrozole

(n = 47)

Triptorelin

(n = 40)

Controls(n = 57)

P value

CPR after 12 months

23.4%27.5%28.1%NS

Recur-rence

6.4%5%5.3%NS

Alborzi et al, Arch Gynecol Obstet 284: 105-10, 2011

Novel medical therapies

1. Antiangiogenic agents (Dabrosin et al, 2002)

2. SPRMs (e.g. J867) (Chwalisz et al, 2002)

3. GnRH antagonists (e.g. ganirelix and cetrorelix) (Kupker et al, 2002)4. Mifepristone (Murphy et al, 2002)5. Local therapy (e.g. methotrexate)

(Mesogitsis et al, 2000)


infertility


3. Combined medical and surgical therapy 4. Controlled ovarian hyperstimulation +/-

IUI5. Assisted reproductive techniques

Pre-operative medical treatment for endometriosis (CCT)

Danazol Gestrinone Buserelin

Regression of endometriosi

s

30%34% 73% *


rate

45%47%58% *

Donnez et al, Int J Fertil 35(5): 297-301, 1990

Post-operative GnRHa for endometriosis

(Cumulative pregnancy rates - CPR)

Surgery with

GnRHa

Surgery without GnRHa

P valu

e

Parazzini et al, 1994

(RCT)

19%18%NS

Vercellini et al, 1999

(RCT)

11.6%18.4%NS

Pre and post operative medical therapy for endometriosis surgery

(Cochrane review)

• Pre-surgical medical therapy showed a significant improvement in AFS

scores• Post-surgical hormonal suppression showed no benefit for the outcomes

of pain or pregnancy rates but a significant improvement in disease

recurrenceYap et al, Cochrane Database Syst 2004;

(3):CD003678


infertility





COH in stages I & II endometriosis

Intervention

No therapy

COHP value

Simpson et al, 1992 (CCT)

Clomiphene citrate

9%22%<0.05

Fedele et al, 1992

(RCT)

HMG24%37.4%

NS

COH + IUI in stages I & II endometriosis

No therapy

COH + IUIP value

Deaton et al, 1990 (RCT)

3.3%9.5%<0.05

Tummon et al, 1997 (RCT)

2%11%<0.005

Serta et al, 1992 (CCT)

32%32%NS

Peterson et al, 1994 (CCT)

1.4%15%<0.005

COH + IUI in endometriosis (Meta-analysis)

Number of studies

Number of cycles

Mean cycle fecundity (SD)

Stage I & II57830.14 *

Stage III & IV

31790.08

Peterson et al, Fertil Steril 62(3):535-44, 1994


infertility





Intracytoplasmic sperm injection (ICSI)

IVF in endometriosis versus tubal infertility (CPR)

Barnhart et al, Fertil Steril 77(6): 1148-55, 2002

Surgical approaches to treat endometriosis before IVF and

ICSI

1. Surgical removal of endometriomas appears to diminish the success rate of

IVF/ICSI (Aboulghar et al, 2003)2. Laparoscopic cystectomy has no

effect (Canis et al, 2001; Marconi 2002)

Surgical approaches to treat endometriosis before IVF and ICSI

(cont…)3. LASER vaporization of the internal

wall of endometriomas did not affect the outcome (Donnez et al,

2001; Wyns et al, 2003)4. Ultrasound-directed cyst

aspiration is associated with mixed results (Dicker et al, 1991;

Suganuma et al, 2002) and an increased incidence of infection (Nargund and Parsons, 1995)

Medical approaches to treat endometriosis before IVF and ICSI

1. Corticosteroids (Kim et al, 1997) (RCT but small and not repeated)

2. Danazol (Tei et al, 1998) (RCT but small and not repeated)

3. GnRH agonists (Oehninger et al, 1989; Dicker et al, 1990; Dale et al, 1990; Nakamura et al, 1992; Curtis et al, 1993; Marcus et al, 1994; Chedid et al, 1995; Ruiz-

Velasco and Allende, 1998)

Corticosteroids before IVF in endometriosis (RCT)

Corticosteroids

(n = 54)

Controls

(n = 57)

P value

CPR42.6%22.8%<0.05

Miscarriage rate

21.7%15.4%NS

Multiple pregnancy

rate

17.4%15.4%NS

Kim et al, J Obstet Gynaecol Res 23(5): 463-70, 1997

Danazol before IVF in repeated IVF failures (RCT)

Danazol (400 mg/d for 12

wks)

Controls

P value

Number4141

CPR40%19.5%<0.05

Tei et al, J Reprod Med 43(6): 541-6, 1998

Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006

GnRH agonist v/s no agonist before IVF

(Clinical pregnancy rate per woman)


GnRH agonist v/s no agonist before IVF

(Ongoing pregnancy rate per woman)


GnRH agonist v/s no agonist before IVF (Number of oocytes

retrieved)


GnRH agonist v/s no agonist before IVF (Dose of HMG or FSH

required)


Effect of GnRHa on adenomyosis (CCT)

Mijatovic et al, Eur J Obstet Gynecol Reprod Biol 151(1):62-5 , 2010

Adenomyosis cycles (n=20)

Control cycles (n=54)

P valu

e

Fertilization48.0 %42.0 %NS

Implantation

31.0 %28.2 %NS

Miscarriage19.0 %26.1 %NS

Preg >12 wks

35.0 %30.0 %NS

Conclusions

1. In endometriosis-associated infertility, expectant management is associated

with ~ 50% CPR in stages I and II, while patients with stages III and IV rarely

become pregnant (B)2. In general, surgical management is associated with a significantly higher

pregnancy rate compared to medical or no treatment (B)

3. Simple cyst aspiration results in recurrence in ~ 50% of instances (B)

Conclusions (cont…)4. Drainage of endometriomas + ablation or resection of their walls results in a higher pregnancy rate

compared to no therapy (B)5. Laparoscopic ablation and/or

resection in stages I & II is associated with a significantly higher pregnancy

rate compared to diagnostic laparoscopy (A)

6. Danazol, gestrinone, MPA, letrozole and GnRH agonists do not improve pregnancy rates over placebo or no

therapy (A)

Conclusions (cont…)

7. Combining laparoscopic surgery and medical therapy does not improve

pregnancy rates over surgery alone (A)8. COH+IUI improves the pregnancy rates

significantly compared to no therapy in stages I and II endometriosis (A)

9. Women with endometriosis treated with IVF have significantly lower

pregnancy rates compared to tubal infertility (B)

10. Long-term GnRHa before IVF improves the pregnancy rates

significantly (A)

Bibliotheca Alexandrina

Evidence-based management of endometriosis-associated

infertilityHassan N. Sallam,

MD, FRCOG, PhD (London)Professor in Obstetrics and Gynaecology

The University of Alexandria, andClinical and Scientific Director,

Alexandria Fertility Center, Alexandria, Egypt

3rd Congress of Society of Reproductive Medicine, 5 – 9 October

2011, Antalya / Turkey

GIFT versus COH+IUI in endometriosis (CCT) (Delivery rate

per cycle)GIFTCOH+IUIP value

Stages I & II28.1%14.7% <0.05

Stages III & IV40.9%12.5% NS

Lodhi et al, Gynecol Endocrinol 19(3):152-9, 2004

Effect of GnRHa on stage III and IV endometriosis

Ma et al, Int J Gynaecol Obstet 100(2):167-70, 2008

Long term GnRH

agonist

Control cycles

P value

-Mohamed et al, Eur J Obstet Gynecol Reprod Biol. 2011 Jun;156)2(:177-80

- Mijatovic et al, Eur J Obstet Gynecol Reprod Biol. 2010 Jul;151)1(:62-5

- Tavmergen et al, Curr Opin Obstet Gynecol. 2007 Jun;19)3(:284-8

- Gong et al, Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2009 Mar;34)3(:185-9

- Ma et al, Int J Gynaecol Obstet. 2008 Feb;100)2(:167-70

- Tokushige et al. Discovery of a novel biomarker in the urine in women with endometriosis Fertility

and Sterility 95)1(: 46-49, 2011

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