surgery promotes the development of...

Surgery promotes the development of endometriosis

Xishi Liu Shanghai OB/GYN Hospital

Fudan University Shanghai, China

Surgery

•  Surgery is now a well accepted treatment modality

•  Surgery is an effective treatment for – Cancer – Endometriosis

•  Women tend to receive more surgeries – Gynecological operations – Plastic surgeries – Lipo suction

The downside of surgery

•  A trauma •  Carries its own risk of mortality and

morbidity •  Risk of complications •  Blood loss, transfusion, hypothermia, and

certain anesthesia can impact negatively on – Cell-mediated immunity – Thus promoting metastasis

•  Laparotomy induces more stress hormones than laparoscopy (Muzii et al. 1996)

Documented risk of surgery •  Breast augmentation surgery increases the

risk of –  stomach (SIR = 2.65) –  cervix (SIR = 3.18) –  vulva (SIR = 2.51) –  brain (SIR = 2.16) –  leukemia (SIR = 2.19) (Brinton et al. 2001)

•  Hysterectomy increases the risk of renal cancer (OR=1.8 (1.3—2.5)) (Gago-Dominguez et al. 1999)

•  Surgical stress promotes metastasis (Sood et al. 2012)

Does surgery increase the risk of developing endometriosis?

48 fe

mal

e m

ice

-3 0 14

Induction Sacrifice

Laparotomy

Mastectomy

No surgery Lesion size, ADRB2, VEGF, MVD (CD31), PCNA

Surgery

Hotplate test

Experimental design

Control Mastectomy Laparotomy

0.05

0.10

0.15

A: Lesion weight by groups

Group

Tota

l les

ion

wei

ght (

g)

**

C

C

-5 0 5 10 15

510

1520

B: Kinetics of mean hotplate latency

Time since surgery(Day)

Hot

plat

e la

tenc

y (s

ec)

M

M

L

L

CML

ControlMastectomyLaparotomyNS

*Induction

Surgery

Representative immunostaining results


0.00

0.10

0.20

0.30

A: ADRB2

Group

Stai

ning

leve

l

*****


0.2

0.3

0.4

0.5

0.6

B: PCNA

Group

Stai

ning

leve

l

****


0.10

0.15

0.20

ADRB1

Group

Stai

ning

leve

l

**

***

NS NS


0.10

0.15

0.20

0.25

0.30

ADRA1

Group

Stai

ning

leve

l

NS

NS


0.05

0.10

0.15

0.20

ADRA2

Group

Stai

ning

leve

l

NSNS

Is intervention possible?

-7 .. -3 -2 -1 0 1 … 7 … 10 … 14

Induction

Laparotomy + Propranolol

Mastectomy + Propranolol

Propranolol

Laparotomy + PBS

Mastectomy + PBS

PBS

Surgery Sacrifice

The effect of surgery on the development of endometriosis

Day

60 f

emal

e B

lb/C

mic

e

Lesion size IHC: ADRB2, VEGF, MVD (CD31), PCNA

Hotplate test, bodyweight Randomization

Alzet pumps implanted

PBS Mast+PBS Lap+PBS Pro Mast+Pro Lap+Pro

18

19

20

21

22

23

24

A: Baseline bodyweight

Group

Bodyw

eig

ht

(g)

p=0.89


18

19

20

21

22

23

24

B: Bodyweight 2w post induction

Group

Bodyw

eig

ht

(g)

p=0.24


18

19

20

21

22

23

24

C: Bodyweight 2w after treatment

Group

Bodyw

eig

ht

(g)

p=0.01


-2-1

01

23

45

D: Change in Bodyweight post induction

Group

Change

p=0.01

CT M L P MP LP

0.05

0.10

0.15

A: Total lesion size by groups

Group

Tota

l les

ion

wei

ght (

g)

****

NSNS

NS

CC

C

-5 0 5 10 15

1520

25B: Kinetics of mean hotplate latency

Time since surgery(day)

Hot

plat

e la

tenc

y (s

ec)

M

M

M

L

L

L

P P

P

m

m

m

ll

l

CMLPml

PBSMast+PBSLap+PBSProMast+ProLap+Pro

Induction

Surgery

NS

NS

**

Representative immunostaining results

CT M L P MP LP

0.0

0.1

0.2

0.3

0.4

0.5

A: ADRB2

Group

Stai

ning

leve

l

*** ***

NS

NS

NS

CT M L P MP LP

0.0

0.1

0.2

0.3

0.4

B: PCNA

Group

Stai

ning

leve

l

******

NS

NS

NS

CT M L P MP LP

0.00

0.05

0.10

0.15

C: VEGF

Group

Stai

ning

leve

l

*NS

NS

NS

NS

CT M L P MP LP

1015

2025

D: Microvessel density (CD31)

Group

Stai

ning

leve

l

*** **

NSNS NS

CT M L P MP LP

0.05

0.10

0.15

0.20

0.25

F: ADRA1

Group

Stai

ning

leve

l

NS NS NS NS NS

CT M L P MP LP

0.05

0.10

0.15

0.20

0.25

G: ADRA2

Group

Stai

ning

leve

l

NS NS NS NS NS

How about humans?

A hospital-based case-control study Factor

Controls (n=212) (Benign gynecologic diseases)

Cases (n=208) (Ovarian endometriomas)

P-value

Age (in years) 33.3(±5.3) 34.0 (±5.2) 0.10 Parity 0 1 ≧2

57 (26.9%) 65 (30.7%) 90 (42.5%)

64 (30.8%) 53 (25.5%) 91 (43.8%)

0.46

Dysmenorrhea None Mild Moderate Severe

136 (64.2%) 66 (31.1%) 10 (4.7%) 0 (0.0%)

74 (35.6%) 77 (37.0%) 37 (17.8%) 20 (9.6%)

<0.0001

Infertility No Yes

207 (99.5%) 5 (0.5%)

190 (91.3%) 18 (8.7%)

0.005

Information collected

•  Demographic information – Education, marital status, occupation, OC use,

smoking status, •  Reproductive history

– Gravidity, # of abortions, # of C-sections •  Surgical history

–  # of abdominal surgeries, # of laparoscopic surgeries,

–  # of other surgeries – Total # of surgeries

Most interesting result Controls (n=212) Cases (n=208) P-value

Abdominal surgery (Post-menarche) None Once Twice

208 (98.1%) 4 (1.9%) 0 (0.0%)

197 (94.7%) 10 (4.8%) 1 (0.5%)

0.081

Crude OR=2.90 (0.84—12.89) Multivariate logistic regression indicates that OR=3.40 (1.08—10.70)

Post-menarche surgery is a risk factor for the development of endometriosis

Conclusions

•  Surgery accelerates the development of endometriosis in mouse – Likely through ADRB2-mediated angiogenesis

and proliferation •  Open abdominal surgery is associated

with increased risk of developing endometriosis in humans (OR=3.4 (1.08—10.70))

•  β-blockade seems to be effective in abolishing the promoting effect of surgery

surgery promotes the development of...

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