Misoprostol's preoperative cervical ripening effect

Misoprostol’spreoperativecervicalripeningeffect

KevinSundeOppegaard

DepartmentofObstetricsand Gynaecology OsloUniversityHospitalUllevål

DepartmentofGynaecology KlinikkHammerfest

FacultyofMedicine UniversityofOslo

Norway Ph.D.thesis2009

© Kevin Sunde Oppegaard, 2009

Series of dissertations submitted to the Faculty of Medicine, University of Oslo No. 843

ISBN 978-82-8072-356-7

All rights reserved. No part of this publication may be

reproduced or transmitted, in any form or by any means, without permission.

Illustration page 1: Figure 1. Hieroglyphic form of the human uterus from the Third Egyptian Dynasty about 4500 BC. From Kranz and Philips (1962).

Cover: Inger Sandved Anfinsen.

Printed in Norway: AiT e-dit AS, Oslo, 2009.

Produced in co-operation with Unipub AS.

The thesis is produced by Unipub AS merely in connection with the thesis defence. Kindly direct all inquiries regarding the thesis to the copyright holder or the unit which grants the doctorate.

Unipub AS is owned by

The University Foundation for Student Life (SiO)

͵

TableofContents

ACKNOWLEDGEMENTS ...5

1.ABSTRACT ...7

2.LISTOFPAPERS ...9

3.INTRODUCTION ...11

3.1

THE

UTERINE

CERVIX ... 11

3.2

CERVICAL

RIPENING ... 12

3.3

METHODS

OF

ACHIEVING

CERVICAL

RIPENING ... 14

3.4

ROLE

OF

VARIOUS

HORMONES

IN

CERVICAL

RIPENING ... 14

3.5

ESTROGEN... 16

3.6

PROSTAGLANDINS... 16

3.7

PROSTAGLANDINS

USED

CLINICALLY

FOR

CERVICAL

RIPENING... 20

3.8

MISOPROSTOL... 23

3.9

PHARMOKOKINETICS

OF

MISOPROSTOL... 25

3.10

CERVICAL

RIPENING

BEFORE

SURGICAL

ABORTION ... 27

3.11

CERVICAL

RIPENING

IN

NONPREGNANT

WOMEN... 29

4.AIMSOFTHESTUDY ...31

5.MATERIALSANDMETHODS ...35

5.1

TRIAL

I ... 37

Ͷ

5.2

TRIAL

II ... 38

5.3

TRIAL

III ... 39

5.4

TRIAL

IV ... 40

6.RESULTS...41

6.1

TRIAL

I ... 41

6.2

TRIAL

II ... 41

6.3

TRIAL

III ... 42

6.4

TRIAL

IV ... 42

7.DISCUSSION ...45

7.1

TRIAL

I ... 45

7.2

TRIAL

II ... 47

7.3

TRIAL

III ... 48

7.4

TRIAL

IV ... 50

8.CONCLUSIONSANDRECOMMENDATIONS ...53

9.FUTURERESEARCH...55

10.BIBLIOGRAPHY...57

11.PAPERSIIV,CORRESPONDENCE ...75 12.APPENDIX ...

“Felixquipotuitrerumcognoscerecausas”

(Happyisthemanwhounderstandsthecausesofthings)

ͷ

Vergilius,Georgics29BC,book2,line490

ACKN

•–Š‡•‹•Šƒ•„‡‡ƒ››‡ƒ”•‹–Š‡ƒ‹‰ƒ†‹•„ƒ•‡†‘ˆ‘—”•–—†‹‡•…ƒ””‹‡†‘—–

–Š‡ ‡’ƒ”–‡– ‘ˆ ›ƒ‡…‘Ž‘‰›ǡ •Ž‘ ‹˜‡”•‹–› ‘•’‹–ƒŽ ŽŽ‡˜¤Žǡ ˆ”‘ ʹͲͲʹ –‘

‡‡”‘—•ˆ—†‹‰ˆ”‘‡Ž•‡ ‹ƒ”ˆ”‘ʹͲͲ͸–‘ʹͲͲͻ‡ƒ„Ž‡†‹–•…‘’Ž‡–‹‘Ǥ

•‡ƒ”…Š ‰”ƒ–• ˆ”‘ › •—’‡”˜‹•‘”•ǡ ”‹––Ǧ‰Œ‡”† ‡•Š‡‹ ƒ† ”‹ ˜‹‰•–ƒ†ǡ

OWLEDGEMENTS

Š‹

ƒ–

ʹͲͲͻǤ

Š‡ ”‡

’”‘˜‹†‡

ƒ›

›•‡Žˆ

†ˆ—”–Š‡”ˆ‹ƒ…‹ƒŽ•—’’‘”–Ǥ

”‡ƒ”ƒ„Ž‡ƒ†”‡•‘—”…‡ˆ—Ž’‡‘’Ž‡Šƒ˜‡ƒ†‡–Š‹•–Š‡•‹•’‘••‹„Ž‡Ǥ…‘—–

˜‡”›ˆ‘”–—ƒ–‡–‘Šƒ˜‡”‹––Ǧ‰Œ‡”†ƒ†”‹ƒ•›•—’‡”˜‹•‘”•ƒ†‡–‘”•Ǥ

ƒ††‹–‹‘ –‘ ˜ƒŽ—ƒ„Ž‡ …‘–”‹„—–‹‘• ˆ”‘ › …‘Ǧƒ—–Š‘”•ǡ ‡˜‡”› ’”‘Œ‡…– Šƒ• ‹˜‘Ž˜‡† ƒ

•—„•–ƒ–‹ƒŽƒ‘—–‘ˆ…‘Ǧ‘”†‹ƒ–‹‘ƒ†ƒ••‹•–ƒ…‡ˆ”‘‡„‡”•‘ˆ•–ƒˆˆƒ–‡˜‡”›Ž‡˜‡Ž‹

–Š‡‡’ƒ”–‡–‘ˆ„•–‡–”‹…•ƒ†›ƒ‡…‘Ž‘‰›ƒ–ŽŽ‡˜¤ŽǤ’‡…‹ƒŽ‡–‹‘—•–„‡ƒ†‡

‘ˆ Ž„ŒÞ”‰ ‡Ž•‡–Š ƒ† ‡Ǧ‹•‡ ‹‘Žƒ‹•‡ǡ ™Š‘ –‘‰‡–Š‡” ™‡”‡ ”‡•’‘•‹„Ž‡ ˆ‘”

”‡…”—‹–‹‰ ‡ƒ”Ž› ͳͲͲͲ •–—†› ’ƒ”–‹…‹’ƒ–• Ȃ ƒ ‡”…—Ž‡ƒ ƒ…Š‹‡˜‡‡–Ǩ ‡ ƒ”‡ †‡‡’Ž›

‹†‡„–‡†–‘ƒ”•ƒŽŽÞ‡ƒ†˜ƒ‘˜Ž—†Ǥ‹–Š‘—––Š‡‹”‹†Š‡Ž’ǡƒ•™‡ŽŽƒ•–Š‡‹”—‹“—‡

ƒ†‹‘˜ƒ–‹˜‡•‡“—‡–‹ƒŽ‡–Š‘†ǡ™‡™‘—Ž†‡˜‡”Šƒ˜‡ƒƒ‰‡†–‘…‘’Ž‡–‡–Š‡–Š‹”†

ƒ† ˆ‘—”–Š –”‹ƒŽ• ™‹–Š‹ ƒ ”‡ƒ•‘ƒ„Ž‡ –‹‡Ǧˆ”ƒ‡Ǥ ”ƒ–‡ˆ—Ž –Šƒ• –‘ ‡–‹‡ –ƒˆˆ ƒ†

ƒ”›…Š‹†–ˆ‘”•–‡”’”‘‘ˆ”‡ƒ†‹‰ǡƒ†–‘‘‡ƒ—‰ˆ‘”Š‡””‡ƒ”ƒ„Ž‡–›’‡•‡––‹‰

•‹ŽŽ• ƒ† ‡†Ž‡•• …ƒŽ ™Š‡ …‘ˆ”‘–‡† ™‹–Š ˆ”ƒ–‹… †‡ƒ†Ž‹‡• ƒ† –Š‡ Ž‹‹–ƒ–‹‘• ‘ˆ

‹…”‘•‘ˆ–‘”†Ǥ

”‡†‹– ƒ† –Šƒ• ƒ”‡ ƒŽ•‘ †—‡ –‘ › ‡’Ž‘›‡”• ƒ† …‘ŽŽ‡ƒ‰—‡• ƒ– –Š‡ –‹›

‡’ƒ”–‡– ‘ˆ ›ƒ‡…‘Ž‘‰› ‹ ƒ‡”ˆ‡•–ǡ ͹Ͳ †‡‰”‡‡• ‘”–ŠǤ Š‡› Šƒ˜‡ ƒƒ‰‡† –‘

‘”‰ƒ‹œ‡ –Š‡ †‡’ƒ”–‡– ƒ”‘—† › ’”‘–”ƒ…–‡† ƒ„•‡…‡ ƒ† Šƒ˜‡ „‡‡ —ˆƒ‹Ž‹‰Ž›

•—’’‘”–‹˜‡ƒ†’‘•‹–‹˜‡–‘™ƒ”†•›’‡”‹’Š‡”ƒŽƒ…ƒ†‡‹…’—”•—‹–•Ǥ

Šƒ– Šƒ• •—”’”‹•‡† ƒ† –‘—…Š‡† ‡ ‘•– †—”‹‰ –Š‡•‡ •‡˜‡ ›‡ƒ”• ‹• –Š‡ ™ƒ›

‘”™‡‰‹ƒ ™‘‡ •‘ •‡ŽˆŽ‡••Ž›ǡ ”‡ƒ†‹Ž› ƒ† ‰”ƒ…‹‘—•Ž› ƒ‰”‡‡ –‘ ’ƒ”–‹…‹’ƒ–‡ ‹ •…‹‡–‹ˆ‹…

͸

–”‹ƒŽ•ǤŠ‡›†‘•‘™‹–Š‘—–ƒ›”‡—‡”ƒ–‹‘ǡ’‘••‹„Ž›™‹–Š‹…‘˜‡‹‡…‡–‘–Š‡•‡Ž˜‡•

ƒ†‘Ž›„‡…ƒ—•‡–Š‡›™ƒ––‘…‘–”‹„—–‡–‘Ǯ–Š‡‰”‡ƒ–‡”‰‘‘†ǯǤŠ‡–”‹ƒŽ•Šƒ˜‡‘Ž›„‡‡

’‘••‹„Ž‡„‡…ƒ—•‡‘ˆ•—…Š’‡‘’Ž‡Ǣƒ›’‘–‡–‹ƒŽ„‡‡ˆ‹––‘‡†‹…‹‡ƒ†•‘…‹‡–›‹•–Šƒ•–‘

–Š‡Ǥ

ƒ•–Ž›ǡ„—–‘–Ž‡ƒ•–ǡ‘‡‘ˆ–Š‹•™‘—Ž†Šƒ˜‡„‡‡’‘••‹„Ž‡™‹–Š‘—–›‘–Š‡”ǤŠ‡

‡•—”‡†–Šƒ–›„”‘–Š‡”•ƒ†Šƒ†–Š‡‘’–‹‘ˆ‘”ƒ‡†—…ƒ–‹‘ƒ†ƒˆ—–—”‡‹‘”™ƒ›Ǥ

‡”—ˆƒ‹Ž‹‰—…‘†‹–‹‘ƒŽ•—’’‘”–ƒ†‡…‘—”ƒ‰‡‡–Šƒ˜‡’”‘˜‹†‡†–Š‡ˆ‘—†ƒ–‹‘ˆ‘”

›Ž‹ˆ‡Ǥ

ƒ‡”ˆ‡•–ǡ—Ž›ʹͲͲͻ KevinSundeOppegaard

͹

1.ABSTRACT

Background

‹•‘’”‘•–‘Ž‹•—•‡†ˆ‘”…‡”˜‹…ƒŽ”‹’‡‹‰„‡ˆ‘”‡ˆ‹”•––”‹‡•–‡”–‡”‹ƒ–‹‘

‘ˆ ’”‡‰ƒ…›ǡ ƒ• ™‡ŽŽ ƒ• ‹ ‘Ǧ’”‡‰ƒ– ™‘‡ „‡ˆ‘”‡ ‹–”ƒ—–‡”‹‡ ’”‘…‡†—”‡•Ǥ Š‡

‘’–‹ƒŽ†‘•‡ǡ†‘•ƒ‰‡”‘—–‡•ƒ†‘—–…‘‡•™‡”‡‘–™‡ŽŽ†‘…—‡–‡†Ǥ

Aims

Š‡ƒ‹•‘ˆ–Š‹•ŠǤǤ’”‘Œ‡…–™‡”‡–‘•–—†›–Š‡‡ˆˆ‡…–‘ˆ†‹ˆˆ‡”‡–†‘•‡•ƒ††‘•ƒ‰‡

”‘—–‡• ‘ˆ ‹•‘’”‘•–‘Ž ‘ …‡”˜‹…ƒŽ ”‹’‡‹‰ ’”‹‘” –‘ ˆ‹”•– –”‹‡•–‡” –‡”‹ƒ–‹‘ ‘ˆ

’”‡‰ƒ…›ǡ ƒ† ‘ ‘Ǧ’”‡‰ƒ– ’”‡Ǧ ƒ† ’‘•–‡‘’ƒ—•ƒŽ ™‘‡ ’”‹‘” –‘ ‘’‡”ƒ–‹˜‡

Š›•–‡”‘•…‘’›Ǥ

Patientsandmethods

‘—”’”‘•’‡…–‹˜‡”ƒ†‘‹•‡†–”‹ƒŽ•†‡•‹‰‡†ƒ†…‘†—…–‡†‹

ƒ……‘”†ƒ…‡™‹–Š–Š‡”‡…‘‡†ƒ–‹‘•‹–Š‡•–ƒ–‡‡–ǣ

Trial I

‹˜‡ Š—†”‡† ƒ† ˆ‹ˆ–›Ǧ‘‡ ™‘‡ ™‡”‡ ”ƒ†‘‹•‡† ‹ ƒ †‘—„Ž‡Ǧ„Ž‹†

’Žƒ…‡„‘Ǧ…‘–”‘ŽŽ‡†–”‹ƒŽ‡‹–Š‡”–‘ʹͲͲ‘”ͶͲͲ‹…”‘‰”ƒ•‘ˆ‘”ƒŽ‹•‘’”‘•–‘ŽͳͲǦͳ͸

Š‘—”• „‡ˆ‘”‡ ˜ƒ…—— ƒ•’‹”ƒ–‹‘Ǥ Š‡ –”‹ƒŽ ™ƒ• …‘†—…–‡† ˆ”‘ ƒ—ƒ”› –‘ —‡

ʹͲͲʹǤ

TrialII

Š”‡‡Š—†”‡†ƒ†–Š‹”–›Ǧ‡‹‰Š–™‘‡™‡”‡”ƒ†‘‹•‡†‹ƒ–”‹ƒŽ–‘ͶͲͲ

‹…”‘‰”ƒ• ‘ˆ ‘”ƒŽ ‹•‘’”‘•–‘Ž –Š‡ ‡˜‡‹‰ „‡ˆ‘”‡ ‘” ͶͲͲ ‹…”‘‰”ƒ• ‘ˆ •‡ŽˆǦ

ƒ†‹‹•–‡”‡†˜ƒ‰‹ƒŽ‹•‘’”‘•–‘Žƒ–Š‘‡–Š‡•ƒ‡†ƒ›ƒ•˜ƒ…——ƒ•’‹”ƒ–‹‘ǤŠ‡

–”‹ƒŽ™ƒ•…‘†—…–‡†ˆ”‘’”‹Ž–‘—‰—•–ʹͲͲͶǤ

Trial III

‹‰Š–›Ǧ•‹š ™‘‡ ”‡ˆ‡””‡† –‘ †ƒ›Ǧ…ƒ”‡ ‘’‡”ƒ–‹˜‡ Š›•–‡”‘•…‘’› ™‡”‡

”ƒ†‘‹•‡† –‘ ͳͲͲͲ ‹…”‘‰”ƒ• ‘ˆ ‹•‘’”‘•–‘Ž ‘” ’Žƒ…‡„‘ ‹ ‘‡ ‘ˆ –™‘

”ƒ†‘‹•‡††‘—„Ž‡Ǧ„Ž‹†ƒ†’Žƒ…‡„‘Ǧ…‘–”‘ŽŽ‡†•‡“—‡–‹ƒŽ–”‹ƒŽ•ǡ„ƒ•‡†‘–Š‡‹”

‡‘’ƒ—•ƒŽ •–ƒ–—•Ǥ ™‘ •‡’ƒ”ƒ–‡ „—– ‹†‡–‹…ƒŽ ’ƒ”ƒŽŽ‡Ž –”‹ƒŽ• ™‡”‡ …‘†—…–‡†

„‡–™‡‡—‰—•–ʹͲͲ͸ƒ†’”‹ŽʹͲͲ͹ǡ‘‡ˆ‘”’”‡‡‘’ƒ—•ƒŽ™‘‡ƒ†‘‡ˆ‘”

’‘•–‡‘’ƒ—•ƒŽ™‘‡Ǥ

ͺ

Trial IV

‡˜‡–›Ǧ–™‘ ’‘•–‡‘’ƒ—•ƒŽ ™‘‡ǡ ‘– …—””‡–Ž› —•‹‰ Š‘”‘‡

–Š‡”ƒ’›ǡ ”‡ˆ‡””‡† –‘ †ƒ›Ǧ…ƒ”‡ ‘’‡”ƒ–‹˜‡ Š›•–‡”‘•…‘’›ǡ ™‡”‡ ”ƒ†‘‹•‡† –‘ ͳͲͲͲ

‹…”‘‰”ƒ• ‘ˆ ‹•‘’”‘•–‘Ž ‘” ’Žƒ…‡„‘ ‹ ƒ †‘—„Ž‡Ǧ„Ž‹† ’Žƒ…‡„‘Ǧ…‘–”‘ŽŽ‡†

•‡“—‡–‹ƒŽ –”‹ƒŽǤ Š‡ ™‘‡ Šƒ† ƒ†‹‹•–‡”‡† ƒ ʹͷǦ‹…”‘‰”ƒ ˜ƒ‰‹ƒŽ ‡•–”ƒ†‹‘Ž

–ƒ„Ž‡– †ƒ‹Ž› ˆ‘” ͳͶ †ƒ›• „‡ˆ‘”‡ –Š‡ ‘’‡”ƒ–‹‘Ǥ  ƒ††‹–‹‘ǡ –Š‡› Šƒ† •‡ŽˆǦ

ƒ†‹‹•–‡”‡†‡‹–Š‡”ͳͲͲͲ‹…”‘‰”ƒ•˜ƒ‰‹ƒŽ‹•‘’”‘•–‘Ž‘”•‡ŽˆǦƒ†‹‹•–‡”‡†ƒ

˜ƒ‰‹ƒŽ ’Žƒ…‡„‘ –Š‡ ‡˜‡‹‰ „‡ˆ‘”‡ –Š‡ ‘’‡”ƒ–‹‘Ǥ Š‡ –”‹ƒŽ ™ƒ• …‘†—…–‡† ˆ”‘

ƒ—ƒ”›ʹͲͲͺ–‘ƒ›ʹͲͲͻǤ

Resultsandconclusions

Trial I

™‘ Š—†”‡† ‹…”‘‰”ƒ• ‘ˆ ‘”ƒŽ ‹•‘’”‘•–‘Ž …‘’ƒ”‡† ™‹–Š ͶͲͲ

‹…”‘‰”ƒ•‘”ƒŽ‹•‘’”‘•–‘Ž–ƒ‡ͳͲǦͳ͸Š‘—”•„‡ˆ‘”‡ˆ‹”•––”‹‡•–‡”–‡”‹ƒ–‹‘

‘ˆ ’”‡‰ƒ…› ”‡•—Ž–• ‹ Ž‡•• ’”‡‘’‡”ƒ–‹˜‡ ˜ƒ‰‹ƒŽ „Ž‡‡†‹‰ ƒ† ‹ ƒ •–ƒ–‹•–‹…ƒŽŽ›ǡ

ƒŽ–Š‘—‰Š‘–…Ž‹‹…ƒŽŽ›ǡ•‹‰‹ˆ‹…ƒ–”‡†—…–‹‘‹…‡”˜‹…ƒŽ†‹Žƒ–ƒ–‹‘Ǥ‡‹–Š‡”†‘•‡™ƒ•

…‘•‹†‡”‡† ‘’–‹ƒŽ ˆ‘” ƒ…Š‹‡˜‹‰ …‡”˜‹…ƒŽ ”‹’‡‹‰Ǥ —” •–—†› •—’’‘”–• •ƒŽŽ‡”

•–—†‹‡•–Šƒ–•—‰‰‡•–‡†–Šƒ–‘”ƒŽ ‹•‘’”‘•–‘Ž ‹• ‹ˆ‡”‹‘” –‘ ˜ƒ‰‹ƒŽ‹•‘’”‘•–‘Žƒ•

”‡‰ƒ”†•‡ˆˆ‹…ƒ…›ǡƒ•™‡ŽŽƒ•…ƒ—•‹‰ƒŠ‹‰Š‡”ˆ”‡“—‡…›‘ˆ•‹†‡‡ˆˆ‡…–•Ǥ

TrialII

‡ŽˆǦƒ†‹‹•–‡”‡†˜ƒ‰‹ƒŽ‹•‘’”‘•–‘Ž’”‹‘”–‘ˆ‹”•––”‹‡•–‡”–‡”‹ƒ–‹‘

‘ˆ ’”‡‰ƒ…› ‹• ‘”‡ ‡ˆˆ‡…–‹˜‡ ˆ‘” …‡”˜‹…ƒŽ ”‹’‡‹‰ …‘’ƒ”‡† ™‹–Š ‘”ƒŽ

‹•‘’”‘•–‘ŽǡŠƒ•ƒŠ‹‰Šƒ …‡’–ƒ„‹Ž‹–›”ƒ–‡ƒ†”‡•—Ž–•‹ˆ‡™‡”•‹†‡‡ˆˆ‡…–•Ǥ…

Trial III

‡ –Š‘—•ƒ† ‹…”‘‰”ƒ• ‘ˆ •‡ŽˆǦƒ†‹‹•–‡”‡† ˜ƒ‰‹ƒŽ ‹•‘’”‘•–‘Ž ͳʹ

Š‘—”• „‡ˆ‘”‡ ‘’‡”ƒ–‹˜‡ Š›•–‡”‘•…‘’› ‹• ‡ˆˆ‡…–‹˜‡ ˆ‘” …‡”˜‹…ƒŽ ”‹’‡‹‰ ‹

’”‡‡‘’ƒ—•ƒŽ„—–‘–’‘•–‡‘’ƒ—•ƒŽ™‘‡ǡ…‘’ƒ”‡†™‹–Š’Žƒ…‡„‘Ǥ

Trial IV

‡ –Š‘—•ƒ† ‹…”‘‰”ƒ• ‘ˆ •‡ŽˆǦƒ†‹‹•–‡”‡† ˜ƒ‰‹ƒŽ ‹•‘’”‘•–‘Ž ͳʹ

Š‘—”• ’”‹‘” –‘ †ƒ›Ǧ…ƒ”‡ Š›•–‡”‘•…‘’›ǡ ƒˆ–‡” ͳͶ †ƒ›• ’”‡Ǧ–”‡ƒ–‡– ™‹–Š ˜ƒ‰‹ƒŽ

‡•–”ƒ†‹‘Žǡ Šƒ• ƒ •‹‰‹ˆ‹…ƒ– …‡”˜‹…ƒŽ ”‹’‡‹‰ ‡ˆˆ‡…– …‘’ƒ”‡† ™‹–Š ’Žƒ…‡„‘ ‹

’‘•–‡‘’ƒ—•ƒŽ™‘‡Ǥ

ͻ

2.LISTOFPAPERS

Š‹•–Š‡•‹•‹•„ƒ•‡†‘–Š‡ˆ‘ŽŽ‘™‹‰’—„Ž‹…ƒ–‹‘•ǡ”‡ˆ‡””‡†–‘„›–Š‡‹”‘ƒ

—‡”ƒŽ•ǣ

I. ’’‡‰ƒƒ”† ǡ „†‡Ž‘‘” ǡ ‡•Š‡‹ ǡ ‡”˜‡ ǡ •‹Ž† Ǥ Š‡ —•‡ ‘ˆ ‘”ƒŽ

‹•‘’”‘•–‘Žˆ‘”’”‡Ǧƒ„‘”–‹‘…‡”˜‹…ƒŽ’”‹‹‰ǣƒ”ƒ†‘‹•‡†…‘–”‘ŽŽ‡†–”‹ƒŽ‘ˆͶͲͲ

‰˜‡”•—•ʹͲͲ‰‹ˆ‹”•––”‹‡•–‡”’”‡‰ƒ…‹‡•ǤBJOGʹͲͲͶǢͳͳͳǣͳͷͶȂͳͷͻǤ

II. ’’‡‰ƒƒ”† ǡ ˜‹‰•–ƒ† ǡ ‡•Š‡‹ Ǥ ”ƒŽ ˜‡”•—• •‡ŽˆǦƒ†‹‹•–‡”‡† ˜ƒ‰‹ƒŽ

‹•‘’”‘•–‘Ž ƒ– Š‘‡ „‡ˆ‘”‡ •—”‰‹…ƒŽ –‡”‹ƒ–‹‘ ‘ˆ ’”‡‰ƒ…›ǣ ƒ ”ƒ†‘‹•‡†

…‘–”‘ŽŽ‡†–”‹ƒŽǤBJOGʹͲͲ͸Ǣͳͳ͵ǣͷͺȂ͸ͶǤ

‘””‡•’‘†‡…‡ǣ œ‡™‹ Ǥ ”ƒŽ ˜‡”•—• •‡ŽˆǦƒ†‹‹•–‡”‡† ˜ƒ‰‹ƒŽ

‹•‘’”‘•–‘Ž ƒ– Š‘‡ „‡ˆ‘”‡ •—”‰‹…ƒŽ –‡”‹ƒ–‹‘ ‘ˆ ’”‡‰ƒ…› „›

’’‡‰ƒƒ”†etalǤBJOGʹͲͲ͸Ǣͳͳ͵ǣͻ͹ͻǦͻͺͲǤ

(TrialprotocolforIII)’’‡‰ƒƒ”†ǡ‡•Š‡‹Ǧǡ•–”‡ǡ˜‹‰•–ƒ†Ǥ‘’ƒ”‹•‘‘ˆ

•‡ŽˆǦƒ†‹‹•–‡”‡†˜ƒ‰‹ƒŽ‹•‘’”‘•–‘Ž˜‡”•—•’Žƒ…‡„‘ˆ‘”…‡”˜‹…ƒŽ”‹’‡‹‰’”‹‘”–‘

‘’‡”ƒ–‹˜‡ Š›•–‡”‘•…‘’› —•‹‰ ƒ •‡“—‡–‹ƒŽ –”‹ƒŽ †‡•‹‰ ȋ”‹ƒŽ ’”‘–‘…‘ŽȌǤ BJOG ʹͲͲ͹ǢͳͳͶǣ͹͸ͻǦ‡ͳʹǤ

III. ’’‡‰ƒƒ”† ǡ ‡•Š‡‹ ǡ •–”‡ ǡ ˜‹‰•–ƒ† Ǥ ‘’ƒ”‹•‘ ‘ˆ •‡ŽˆǦƒ†‹‹•–‡”‡†

˜ƒ‰‹ƒŽ‹•‘’”‘•–‘Žˆ‘”…‡”˜‹…ƒŽ”‹’‡‹‰’”‹‘”–‘‘’‡”ƒ–‹˜‡Š›•–‡”‘•…‘’›—•‹‰ƒ

•‡“—‡–‹ƒŽ–”‹ƒŽ†‡•‹‰ǤBJOGʹͲͲͺǢͳͳͷǣ͸͸͵ǡ‡ͳǦͻǤ

‘””‡•’‘†‡…‡ǣ ‹ ǡ Š‡‰ Ǥ ‘’ƒ”‹•‘ ‘ˆ •‡ŽˆǦƒ†‹‹•–‡”‡† ˜ƒ‰‹ƒŽ

‹•‘’”‘•–‘Ž ˆ‘” …‡”˜‹…ƒŽ ”‹’‡‹‰ ’”‹‘” –‘ ‘’‡”ƒ–‹˜‡ Š›•–‡”‘•…‘’› —•‹‰ ƒ

‡“—‡–‹ƒŽ–”‹ƒŽ†‡•‹‰ǤBJOGʹͲͲͺǢͳͳͷǣͳͳͺͺǤ

•

‘””‡•’‘†‡…‡ǣ•‹˜‘•ǡ‡‡Ǥ‘’ƒ”‹•‘‘ˆ•‡ŽˆǦƒ†‹‹•–‡”‡†˜ƒ‰‹ƒŽ

ͳͲ

‹•‘’”‘•–‘Ž ˆ‘” …‡”˜‹…ƒŽ ”‹’‡‹‰ ’”‹‘” –‘ ‘’‡”ƒ–‹˜‡ Š›•–‡”‘•…‘’› —•‹‰ ƒ

‡“—‡–‹ƒŽ–”‹ƒŽ†‡•‹‰ǤBJOGʹͲͲͺǢͳͳͷǣͳͳͺͺǦͳͳͺͻǤ

•

‘””‡•’‘†‡…‡ǣ —”…Š ǡ ˜ƒ•ƒ”ƒŽƒ Ǥ ‘’ƒ”‹•‘ ‘ˆ •‡ŽˆǦƒ†‹‹•–‡”‡†

˜ƒ‰‹ƒŽ ‹•‘’”‘•–‘Ž ˆ‘” …‡”˜‹…ƒŽ ”‹’‡‹‰ ’”‹‘” –‘ ‘’‡”ƒ–‹˜‡ Š›•–‡”‘•…‘’›

—•‹‰ƒ•‡“—‡–‹ƒŽ–”‹ƒŽ†‡•‹‰ǤBJOGʹͲͲͺǢͳͳͷǣͳ͹ʹͲǦͳ͹ʹͳǤ

(TrialprotocolforIV)’’‡‰ƒƒ”†ǡ‹‡‰ǡ‡”‰ǡ•–”‡ǡ˜‹‰•–ƒ†ǡ‡•Š‡‹Ǧ Ǥ ‘‡• •‡ŽˆǦƒ†‹‹•–‡”‡† ˜ƒ‰‹ƒŽ ‹•‘’”‘•–‘Ž ”‡•—Ž– ‹ …‡”˜‹…ƒŽ ”‹’‡‹‰ ‹

’‘•–‡‘’ƒ—•ƒŽ ™‘‡ ƒˆ–‡” ͳͶ †ƒ›• ‘ˆ ’”‡Ǧ–”‡ƒ–‡– ™‹–Š ‡•–”ƒ†‹‘Žǫ ”‹ƒŽ

’”‘–‘…‘Žˆ‘”ƒ”ƒ†‘‹œ‡†ǡ’Žƒ…‡„‘Ǧ…‘–”‘ŽŽ‡†•‡“—‡–‹ƒŽ–”‹ƒŽǤBJOGʹͲͲͺǢͳͳͷǣͻͳ͹Ǧ

‡ͳͲǤ

IV. ’’‡‰ƒƒ”†ǡ‹‡‰ǡ‡”‰ǡ•–”‡ǡ˜‹‰•–ƒ†ǡ‡•Š‡‹ǦǤ…‘„‹ƒ–‹‘‘ˆ

‹•‘’”‘•–‘Ž ƒ† ‡•–”ƒ†‹‘Ž ˆ‘” ’”‡‘’‡”ƒ–‹˜‡ …‡”˜‹…ƒŽ ”‹’‡‹‰ ‹ ’‘•–‡‘’ƒ—•ƒŽ

™‘‡ǣƒ”ƒ†‘‹•‡†…‘–”‘ŽŽ‡†–”‹ƒŽǤ—„‹––‡†–‘BJOGʹͲͲͻǤ

Š‡ ’ƒ’‡”• ȋǦȌǡ ƒ—•…”‹’– ȋȌǡ ’”‘–‘…‘Ž• ƒ† …‘””‡•’‘†‡…‡ Ž‹•–‡† ƒ„‘˜‡ ƒ”‡

”‡’”‹–‡†‹–Š‹•–Š‡•‹•™‹–Š‹†’‡”‹••‹‘ˆ”‘‹Ž‡›ǦŽƒ…™‡ŽŽǡšˆ‘”†ǡǤ

3.INT

3.1THEUTERINECERVIX

…‡”˜‹š‹•–Š‡Ž‘™‡”’ƒ”–‘ˆ–Š‡—–‡”—•ƒ†‹•†‹˜‹†‡†ˆ”‘–Š‡—’’‡”’ƒ”–ǡ…ƒŽŽ‡†–Š‡

”’—•ǡ„›ƒˆ‹„”‘—•…—Žƒ”Œ—…–‹‘–Šƒ–‹…Ž—†‡•ƒ•’Š‹…–‡”ǤŠ‡‹–‡”ƒŽ…‡”˜‹…ƒŽ

•‡’ƒ”ƒ–‡• –Š‹• ˆ‹„”‘—• …‡”˜‹š ˆ”‘ –Š‡ —•…—Žƒ” …‘”’—•Ǥ Š‡ …‡”˜‹š ’”‘Œ‡…–•

–Š‡ƒ–‡”‹‘”˜ƒ‰‹ƒŽ™ƒŽŽƒ––Š‡˜ƒ‰‹ƒŽ˜ƒ—Ž–ǤŠ‡’ƒ••ƒ‰‡„‡–™‡‡–Š‡—–‡”‹‡

† –Š‡ ˜ƒ‰‹ƒ ‹• ˜‹ƒ –Š‡ ‡†‘…‡”˜‹…ƒŽ …ƒƒŽǡ ™Š‹…Š ‹• ˆ—•‹ˆ‘” ‹ •Šƒ’‡Ǥ Š‡

‡ˆ”‘–Š‡‡š–‡”ƒŽ–‘‹–‡”ƒŽ‘•–‹—‹•ƒ’’”‘š‹ƒ–‡Ž›–Š”‡‡…‹ƒƒ†—Ž–Ȁˆ‡”–‹Ž‡

ǡˆŽƒ––‡‡†ˆ”‘ˆ”‘––‘„ƒ…ƒ†‡ƒ•—”‹‰•‘‡•‡˜‡ƒ–‹–•™‹†‡•–’‘‹–Ǥ^ͳ

ͳͳ

RODUCTION

Š‡

…‘

‘•–‹—

–Š”‘—‰Š

…ƒ˜‹–› ƒ

†‹•–ƒ…

™‘ƒ

F : The human uterus and cervix

Š‡„ƒ•‹…•–”—…–—”‡‘ˆ–Š‡Š—ƒ…‡”˜‹š‹•ˆ‹„”‘—•…‘‡…–‹˜‡–‹••—‡ǡ™‹–Š…‘ŽŽƒ‰‡

ƒ† ‹–• ƒ••‘…‹ƒ–‡† ‰”‘—† •—„•–ƒ…‡ ƒ……‘—–‹‰ ˆ‘” ͺͲΨ ‘ˆ ‹–• †”› ™‡‹‰Š–Ǥ ‹‰Š–

‹…”‘•…‘’‹… ‡šƒ‹ƒ–‹‘• ƒ† Ǧ”ƒ› †‹ˆˆ”ƒ…–‹‘ •–—†‹‡• Šƒ˜‡ •Š‘™ –Š”‡‡ œ‘‡• ‘ˆ

…‘ŽŽƒ‰‡ǡ‡•–‹ƒ–‡†–‘”‡’”‡•‡–„‡–™‡‡͸ͶǤ͵Ψƒ†͹ʹǤͶΨ‘ˆ–Š‡ˆ‹„”‘—•–‹••—‡™‹–Š‹

–Š‡…‡”˜‹šǡ™‹–Š‡Žƒ•–‹”‡’”‡•‡–‹‰ͳǤͶΨǤŠ‡Š‹‰Š‡•–”ƒ–‹‘‘ˆ‡Žƒ•–‹–‘…‘ŽŽƒ‰‡‹•ƒ––Š‡

igure 2

‹–‡”ƒŽ ‘•Ǥ Š‡ œ‘‡• ‘ˆ …‘ŽŽƒ‰‡ „Ž‡†

•‘‘–ŠŽ› ‹–‘ ‡ƒ…Š ‘–Š‡” ‘ ’ƒ••‹‰ ”ƒ†‹ƒŽŽ›

‘—–™ƒ”† ˆ”‘ –Š‡ …ƒƒŽǤ †Œƒ…‡– –‘ –Š‡ …ƒƒŽ

ƒ† ‹ –Š‡ ‘—–‡”‘•– œ‘‡ –Š‡ ˆ‹„”‹Ž• ƒ”‡

‘”‹‡–‡† ’”‡†‘‹ƒ–Ž› Ž‘‰‹–—†‹ƒŽŽ›ǡ ‹Ǥ‡Ǥ

’ƒ”ƒŽŽ‡Ž –‘ –Š‡ …ƒƒŽǤ  –Š‡ ‹††Ž‡ œ‘‡ –Š‡

ˆ‹„”‹Ž• Šƒ˜‡ ƒ ’”‡ˆ‡””‡† ‘”‹‡–ƒ–‹‘ ‹ ƒ …‹”…—ˆ‡”‡–‹ƒŽ†‹”‡…–‹‘Ǥ

Figure 3: The collagen network in cervical tissue in a non-pregnant woman. The plane of this image is perpendicular to the longitudinal direction of the endocervical canal. (From Myers K et al.

Changes in the biochemical constituents and morphologic appearance of the human cervical stroma Sduring pregnancy. Eur J Obstet Gynecol 2009;S82- 89).

„‘—– ͺͲΨ ‘ˆ –Š‡ …‡”˜‹…ƒŽ …‘ŽŽƒ‰‡ ‹• –›’‡ …‘ŽŽƒ‰‡ ƒ† ƒŽ‘•– ʹͲΨ –›’‡ Ǥ

Š‡•‡ ’”‘’‘”–‹‘• ƒ”‡ •‹‹Žƒ” –‘ –Š‘•‡ ˆ‘—† ‹ ‘–Š‡” ˆ‹„”‘—• …‘‡…–‹˜‡ –‹••—‡•Ǥ Š‡

—•…Ž‡…‘–‡–‹•ʹͻΨ‹–Š‡—’’‡”–Š‹”†‘ˆ–Š‡…‡”˜‹šǡͳͺΨ‹–Š‡‹††Ž‡–Š‹”†ƒ†͸Ψ‹

–Š‡Ž‘™‡”–Š‹”†ǡ™Š‡”‡ƒ•‹–‹•͸ͻΨ‹–Š‡…‘”’—•Ǥ^ʹǡ͵Š‡–‡•‹Ž‡•–”‡‰–Šƒ†ˆ‹”‡••‘ˆ

–Š‡ …‡”˜‹š †‡”‹˜‡• ˆ”‘ –Š‡ …‘ŽŽƒ‰‡ •–”—…–—”‡Ȁ…‘’‘‡–Ǥ –‡”…ƒŽ…—Žƒ–‡† ƒ‘‰ –Š‡

…‘ŽŽƒ‰‡‘Ž‡…—Ž‡•ƒ”‡‰Ž›…‘•ƒ‹‘‰Ž›…ƒ•ǡ™Š‹…Šƒ”‡Žƒ”‰‡ǡ—„”ƒ…Š‡†’‘Ž›•ƒ……Šƒ”‹†‡

…Šƒ‹•ǤŠ‡”‡ƒ”‡ƒ˜ƒ”‹‡–›‘ˆ‰Ž›…‘•ƒ‹‘‰Ž›…ƒ•‹–Š‡…‡”˜‹šǡ’”‡†‘‹ƒ–Ž›†‡”ƒ–ƒ

•—Ž’Šƒ–‡ǡŠ›ƒŽ—”‘‹…ƒ…‹†ƒ†Š‡’ƒ”‹•—Ž’Šƒ–‡Ǥ^ͳ

3.2C

ͳʹ

ERVICALRIPENING

Š‡—–‡”—•Šƒ†‹–•‘™Š‹‡”‘‰Ž›’Š—†‡”–Š‡Š‹”†›ƒ•–›‹‰›’–‘˜‡”ͷͷͲͲ›‡ƒ”•

ƒ‰‘ǤŠ‡‰›’–‹ƒ•—†‡”•–‘‘†–Š‡—–‡”‹‡…‡”˜‹š–‘„‡ƒ•–”‘‰•–”—…–—”‡™‹–Š–Š‡

…ƒ’ƒ…‹–› –‘ ”‡•‹•– –Š‡ ˆ‘”…‡• ‘ˆ ’”‡‰ƒ…›Ǥ Š‡ …‡”˜‹š —•– ”‡ƒ‹ …Ž‘•‡† ƒ† ˆ‹”

ͳ͵

–Š”‘—‰Š‘—–’”‡‰ƒ…›–‘‡•—”‡–Šƒ––Š‡ˆ‡–—•‹•”‡–ƒ‹‡†—–‹Ž‹–…ƒ•—”˜‹˜‡‘—–•‹†‡–Š‡

—–‡”—•Ǥ‘‡•‘ˆ–‡‹‰‘ˆ–Š‡…‡”˜‹šȋ‘‘†‡ŽŽǯ••‹‰Ȍƒ†‡•’‡…‹ƒŽŽ›‘ˆ–Š‡‹•–Š—•ȋ‡‰ƒ”ǯ•

•‹‰Ȍ…ƒ„‡’ƒŽ’ƒ–‡†ƒ„‘—–•‹š™‡‡•ƒˆ–‡”–Š‡Žƒ•–‡•–”—ƒŽ’‡”‹‘†Ǥ^ʹ––‡”ǡŠ‘™‡˜‡”ǡ

–Š‡…‡”˜‹š…Šƒ‰‡•ˆ”‘ƒˆ‹”ǡ–‘—‰Š–‹••—‡–‘‘‡–Šƒ–‹••‘ˆ–ƒ†ƒ„Ž‡–‘†‹Žƒ–‡–‘ƒ„‘—–

ͳͲ …ǡ –‘ ƒŽŽ‘™ †‡Ž‹˜‡”› ‘ˆ –Š‡ „ƒ„›Ǥ Š‡ –”ƒ•ˆ‘”ƒ–‹‘ ’”‘…‡•• Ȃ –Š‹‹‰ǡ •‘ˆ–‡‹‰ǡ

”‡Žƒš‹‰ƒ†‘’‡‹‰‘ˆ–Š‡…‡”˜‹šǦ‹•–‡”‡†Ǯ…‡”˜‹…ƒŽ”‹’‡‹‰ǯƒ†Šƒ•„‡‡‘„•‡”˜‡†

ˆ‘”…‡–—”‹‡•Ǥ^ͶǮ”‹‹‰ǯƒ†Ǯƒ–—”ƒ–‹‘ǯ‘ˆ–Š‡…‡”˜‹šƒ”‡ƒŽ•‘…‘‘Ž›—•‡†–‡”•ˆ‘”

–Š‹•’Š›•‹‘Ž‘‰‹…ƒŽ…Šƒ‰‡Ǥ‘Ž†…‘…‡’–™ƒ•–Šƒ–…‡”˜‹…ƒŽ”‹’‡‹‰™ƒ•…ƒ—•‡†„›—–‡”‹‡

…‘–”ƒ…–‹‘•„—–‹–‹•‘™‘™–‘„‡ƒ•‡”‹‡•‘ˆ„‹‘…Š‡‹…ƒŽ’”‘…‡••‡•Ǥ^ͷŠ‡…‘’Ž‡š

„‹‘…Š‡‹…ƒŽ’”‘…‡••‡•ƒ†–Š‡‡†‹ƒ–‘”•‹˜‘Ž˜‡†ƒ”‡•–‹ŽŽŽƒ”‰‡Ž›—‘™Ǥ^͸Ǧͻ‡•‡ƒ”…Š

‹–Š‹•ƒ”‡ƒ‹•…ŠƒŽŽ‡‰‹‰ǡ’ƒ”–Ž›†—‡–‘†‹ˆˆ‹…—Ž–‹‡•‹‘„–ƒ‹‹‰…‡”˜‹…ƒŽ–‹••—‡’”‹‘”–‘ǡ

†—”‹‰ ƒ† ƒˆ–‡” †‡Ž‹˜‡”› ‹ Š‡ƒŽ–Š› ˆ‡”–‹Ž‡ ™‘‡ ™‹–Š‘—– †ƒƒ‰‹‰ –Š‡ ”‡’”‘†—…–‹˜‡

–”ƒ…–ǡ ‘” Œ‡‘’ƒ”†‹•‹‰ –Š‡ ’”‡‰ƒ…›Ǥ ‡•—Ž–• ˆ”‘ ƒ‹ƒŽ •–—†‹‡• †‘ ‘– ”‡Ž‹ƒ„Ž› …ƒ””›

‘˜‡” –‘ Š—ƒ• „‡…ƒ—•‡ ‘ˆ •–”—…–—”ƒŽ ƒ† Š‘”‘ƒŽ †‹ˆˆ‡”‡…‡• „‡–™‡‡ •’‡…‹‡•Ǥ ”‘

–Š‡„‡‰‹‹‰‘ˆ–Š‡ͳͻͺͲ•ǡ…‡”˜‹…ƒŽ–‹••—‡‹–Š‡‘’”‡‰ƒ–•–ƒ–‡„‡‰ƒ–‘„‡•–—†‹‡†ǡ^ͳͲ

„—– •‘ ˆƒ” –Š‡”‡ Šƒ˜‡ ‘– ›‡– „‡‡ ƒ› Š‹•–‘Ž‘‰‹…ƒŽ •–—†‹‡• ‘ˆ –Š‡ ”‹’‡‡† ‘’”‡‰ƒ–

…‡”˜‹šǤ

Ž–Š‘—‰Š –Š‡ —†‡”Ž›‹‰ ‡…Šƒ‹•• ‘ˆ …‡”˜‹…ƒŽ ”‹’‡‹‰ ƒ”‡ ‹…‘’Ž‡–‡Ž›

—†‡”•–‘‘†ǡ–Š‡”‡‹•‹…”‡ƒ•‹‰‡˜‹†‡…‡–‘•—‰‰‡•––Šƒ–‹–‹•ƒ‹ˆŽƒƒ–‘”›”‡ƒ…–‹‘Ǥ^ͳͳǦͳͶ

Š‡”‡ƒ’’‡ƒ”•–‘„‡ƒ…ƒ•…ƒ†‡‘ˆ•›‡”‰‹•–‹…ƒŽŽ›‹–‡”…‘‡…–‡†„‹‘…Š‡‹…ƒŽ‡˜‡–•ǡ–Šƒ–

—Ž–‹ƒ–‡Ž›Ž‡ƒ†–‘–Š‡•‘ˆ–‡‹‰‘ˆ–Š‡…‡”˜‹š‹™Š‹…Š…‘ŽŽƒ‰‡•‡‡•–‘„‡ƒ‹’‘”–ƒ–

”‡‰—Žƒ–‘”Ǥ–—†‹‡•Šƒ˜‡’”‘’‘•‡†–Šƒ–”‹’‡‹‰‘ˆ–Š‡—–‡”‹‡…‡”˜‹š”‡Žƒ–‡•–‘ƒ”‡†—…–‹‘

‹…‘ŽŽƒ‰‡†‡•‹–›–‘‰‡–Š‡”™‹–Šƒ”‡‘†‡ŽŽ‹‰‘ˆ–Š‡…‘ŽŽƒ‰‡ˆ‹„”‡ƒŽ‹‰‡–ǡ†‡…”‡ƒ•‡†

…‘ŽŽƒ‰‡ ˆ‹„”‡ •–”‡‰–Šǡ ƒ† †‹‹‹•Š‡† –‡•‹Ž‡ •–”‡‰–Š ‘ˆ –Š‡ ‡š–”ƒ…‡ŽŽ—Žƒ” ƒ–”‹š

ȋƒŽ–Š‘—‰Š –Š‡ …‘ŽŽƒ‰‡ •‡Ž‡–‘ ”‡ƒ‹•ȌǤ^ͳͷǦʹͲ ‡”˜‹…ƒŽ ”‹’‡‹‰ ‹• ƒ……‘’ƒ‹‡† „› –Š‡

‹ˆŽ—š‘ˆ‡—–”‘’Š‹Ž•Ǣ–Š‡‡—–”‘’Š‹Ž‹•ƒ”‡ƒ†›•‘—”…‡‘ˆ…‘ŽŽƒ‰‡‘Ž›–‹…‡œ›‡•ǡ•—…Šƒ•

ƒ–”‹š‡–ƒŽŽ‘’”‘–‡‹ƒ•‡•Ǥ^ͳͳƒ††‹–‹‘ǡ…Šƒ‰‡•‹–Š‡‰Ž›…‘•ƒ‹‘‰Ž›…ƒ…‘’‘•‹–‹‘

ȋ–Š‡ ‰”‘—† •—„•–ƒ…‡ „‡–™‡‡ –Š‡ …‘ŽŽƒ‰‡ ˆ‹„”‹Ž• ƒ† ‘–Š‡” •–”—…–—”ƒŽ …‘’‘‡–• ‘ˆ

–Š‡…‡”˜‹šȌƒ†ƒ…–‹˜ƒ–‹‘‘ˆ‹ˆŽƒƒ–‘”›…›–‘‹‡•ƒ”‡ƒ••‘…‹ƒ–‡†™‹–Š…‡”˜‹…ƒŽ”‹’‡‹‰Ǥ

Š‡ …‘…‡–”ƒ–‹‘ ‘ˆ …‘ŽŽƒ‰‡ †‡…”‡ƒ•‡• ™Š‹Ž‡ –Š‡ …‘…‡–”ƒ–‹‘ ‘ˆ Š›ƒŽ—”‘‹… ƒ…‹†

‹…”‡ƒ•‡• †—”‹‰ ’”‡‰ƒ…›Ǥ^ʹͳ Š‡ …‘’ƒ”‡† ™‹–Š ‘Ǧ’”‡‰ƒ– ™‘‡ǡ –Š‡

…‘…‡–”ƒ–‹‘ ‘ˆ …‘ŽŽƒ‰‡ ‹• ͹ͲΨ ƒ– –‡ ™‡‡• ‘ˆ ‰‡•–ƒ–‹‘ǡ ƒ† ͵ͲǦͷͲΨ ƒ– –‡”Ǥ Š‡

…‘ŽŽƒ‰‡‘Ž›–‹… ƒ…–‹˜‹–› ‹…”‡ƒ•‡• ™‹–Š ƒ†˜ƒ…‹‰ ‰‡•–ƒ–‹‘ƒŽ ƒ‰‡Ǥ —”‹‰ Žƒ„‘—”ǡ –Š‡

‡œ›‡…‘ŽŽƒ‰‡ƒ•‡„”‡ƒ•†‘™…‘ŽŽƒ‰‡Ǥ‡”˜‹…ƒŽ„‹‘’•‹‡•ˆ”‘™‘‡ƒˆ–‡”’”‘–”ƒ…–‡†

Žƒ„‘—”•Š‘™Š‹‰Š‡”…‘…‡–”ƒ–‹‘•‘ˆ…‘ŽŽƒ‰‡–Šƒ‹™‘‡™‹–Š‘”ƒŽŽƒ„‘—”Ǥ^ʹʹ–Šƒ•

„‡‡’”‘’‘•‡†–Šƒ–•‘‘–Š—•…Ž‡…‡ŽŽ•—†‡”‰‘’”‘‰”ƒ‡†…‡ŽŽ†‡ƒ–Šȋƒ’‘’–‘•‹•Ȍƒ†

–Šƒ––Š‹•ƒŽ•‘ƒ›’Žƒ›ƒ”‘Ž‡‹–Š‡…‡”˜‹…ƒŽ”‹’‡‹‰’”‘…‡••Ǥ^Ͷ

‘‡…–‹˜‡ –‹••—‡ „‹‘’•› •’‡…‹‡• ˆ”‘ –Š‡ Ž‘™‡” ’ƒ”– ‘ˆ –Š‡ —–‡”‹‡ …‡”˜‹š ‹

–™‘‡Šƒ˜‡„‡‡•–—†‹‡†ƒ†•Š‘™–Šƒ–’”‘•–ƒ‰Žƒ†‹ƒ’’Ž‹…ƒ–‹‘–‘…‡”˜‹…ƒŽ

‡ƒ”Ž›’”‡‰ƒ…›…ƒ—•‡••‹‹Žƒ”•–”—…–—”ƒŽƒ†’Š›•‹‘Ž‘‰‹…ƒŽ…Šƒ‰‡•–‘–Š‘•‡–Šƒ–

›‘……—”–‘™ƒ”†•–Š‡‡†‘ˆ’”‡‰ƒ…›ƒ††—”‹‰Žƒ„‘—”Ǥ^{ͳͲǡʹ͵ǡʹͶ}

ͳͶ

–Š‡ …‡”

…‡”˜‹…ƒŽ

™‡”‡ˆ‘

…‘

”‡

”‹’‡‹‰

…›–‘‹

”‹’‡‹

’”‡‰ƒ

–‹••—‡‹

ƒ–—”ƒŽŽ

‹’

‘

”‹’‡‡†

’”‘•–ƒ‰

‹’”ƒ…–

™‹–Š’”

ˆ‹”•– †‡

3.3METHODSOFACHIEVINGCERVICALRIPENING

‡‹‰‘”•‘ˆ–‡‹‰‘ˆ–Š‡…‡”˜‹…ƒŽ–‹••—‡ƒ›„‡†‡•‹”ƒ„Ž‡‡ƒ”Ž‹‡”‹’”‡‰ƒ…›‘”‹

Ǧ’”‡‰ƒ– ™‘‡ ‹ˆ ‹–”ƒ—–‡”‹‡ •—”‰‡”› ‹• ‹†‹…ƒ–‡†Ǥ^ʹͷǡʹͷ Š‡ …‡”˜ ‹š ƒ› „‡

‡…Šƒ‹…ƒŽŽ›™‹–Š‘•‘–‹…†‹Žƒ–‘”•^ʹ͹‘”„ƒŽŽ‘‘…ƒ–Š‡–‡”•ǡ^ʹͺ‘”„‹‘…Š‡‹…ƒŽŽ›™‹–Š

Žƒ†‹•ǡ^ʹͻ ƒ–‹’”‘‰‡•–‹•^͵Ͳ ‘” ‹–”‹… ‘š‹†‡ †‘‘”•Ǥ^͵ͳǦ͵͵ •‘–‹… †‹Žƒ–‘”• ƒ”‡

‹…ƒŽ–‘—•‡ƒ†ƒ”‡ƒ••‘…‹ƒ–‡†™‹–ŠƒŠ‹‰Š‡”‹…‹†‡…‡‘ˆ…‘’Ž‹…ƒ–‹‘•ǡ…‘’ƒ”‡†

‘•–ƒ‰Žƒ†‹•Ǥ^͵Ͷǡ͵ͷ‡…Šƒ‹…ƒŽ‡–Š‘†•–‘”‹’‡–Š‡…‡”˜‹š‘”–‘‹†—…‡Žƒ„‘—”™‡”‡

˜‡Ž‘’‡† ‹ –Š‡ ‡‹‰Š–‡‡–Š …‡–—”›Ǥ ‘…–‘”• —•‡† –‡–• ƒ†‡ ˆ”‘ –Š‡ •–‡• ‘ˆ

Laminariajapomica‘”Laminariadigitataȋ†”‹‡†„”‘™•‡ƒ™‡‡†Ȍ–Šƒ–™‡”‡‹•‡”–‡†‹–‘

˜‹š ƒ† •™‡ŽŽ‡† „‡…ƒ—•‡ ‘ˆ –‹••—‡ ˆŽ—‹†Ǥ ƒŽŽ‘‘ …ƒ–Š‡–‡”•ǡ ‹–”‘†—…‡† ‹–‘ –Š‡

…ƒƒŽ –‘ ’‡”‹– –Š‡ ‡š–”ƒǦƒ‹‘–‹… ‹•–‹ŽŽƒ–‹‘ ‘ˆ ‡•–”‘‰‡• ƒ† ’”‘•–ƒ‰Žƒ†‹•ǡ

—†–‘„‡‡ˆˆ‡…–‹˜‡™‹–Š‘—––Š‡’Šƒ”ƒ…‘Ž‘‰‹…ƒŽƒ‰‡–Ǥ^͵͸

3.4ROLEOFVARIOUSHORMONESINCERVICALRIPENING

’Ž‡š …ƒ•…ƒ†‡ ‘……—”• ™Š‡”‡„› ˜ƒ”‹‘—• Š‘”‘‡• •–‹—Žƒ–‡ –Š‡ …Š‡‹…ƒŽ

ƒ…–‹‘• …”‹–‹…ƒŽ ˆ‘” …‡”˜‹…ƒŽ ”‹’‡‹‰Ǥ Š‡ ‡› Š‘”‘‡• ƒ••‘…‹ƒ–‡† ™‹–Š …‡”˜‹…ƒŽ

‹ ’”‡‰ƒ…› ƒ† ’ƒ”–—”‹–‹‘ ƒ”‡ ’”‘•–ƒ‰Žƒ†‹• ƒ† ’”‘‹ˆŽƒƒ–‘”›

‡•Ǥ^{ͺǡ͵͹Ǧ͵ͻ} ‹••—‡ Ž‡˜‡Ž• ‘ˆ ’”‘•–ƒ‰Žƒ†‹ •›–Š‡–ƒ•‡• ƒ”‡ ‹…”‡ƒ•‡† †—”‹‰ …‡”˜‹…ƒŽ

‰Ǥ^ͳ͵ …”‡ƒ•‡† ˆ‘”ƒ–‹‘ ‘ˆ ’”‘•–ƒ‰Žƒ†‹• ‹ –—” •–‹—Žƒ–‡• –Š‡ …‘ŽŽƒ‰‡‘Ž›–‹…

‡œ›‡ ƒ…–‹˜‹–› ƒ† ‹†—…‡• ƒŽ–‡”ƒ–‹‘• ‘ˆ –Š‡ ‰”‘—† –‹••—‡ ‰Ž›…‘•ƒ‹‘‰Ž›…ƒ•ǡ …‘–”‹„—–‹‰ –‘ ƒ ƒŽ–‡”‡† „‹†‹‰ ƒˆˆ‹‹–› –‘ …‘ŽŽƒ‰‡ǡ –‹••—‡ Š›†”ƒ–‹‘ ƒ† …‡”˜‹…ƒŽ

‡š–‡•‹„‹Ž‹–›Ǥ^{ʹǡͶͲǡͶͳ} ‡”˜‹…ƒŽ ˆ‹„”‘„Žƒ•–• ‹†—…‡ ‰Ž›…‘•ƒ‹‘‰Ž›…ƒ ’”‘†—…–‹‘ǡ ‹…Ž—†‹‰

Š›ƒŽ—”‘‹…ƒ…‹†Ǥ^Ͷʹ

Figure 4: A simplified proposal of the inflammatory cascade in cervical tissue during the ripening

ͳͷ

process

ƒ”‡† ‹…”‡ƒ•‡ ‹ –Š‡ Ž‡˜‡Ž ‘ˆ Š›ƒŽ—”‘‹… ƒ…‹† †—”‹‰ –Š‡ Žƒ–‡– ’Šƒ•‡ ‘ˆ Žƒ„‘—”

’”‘‘–‡•–‹••—‡Š›†”ƒ–‹‘ǡ”‡Ž‡ƒ•‡‘ˆ…‘ŽŽƒ‰‡ƒ•‡ǡŽ‡—‘…›–‡‹‰”ƒ–‹‘ƒ†‹˜‘Ž˜‡‡–‘ˆ

‹ˆŽƒƒ–‘”› ‡†‹ƒ–‘”•Ǥ^Ͷ͵ǦͶͷ‹•‹‰ …‘…‡–”ƒ–‹‘• ‘ˆ Š›ƒŽ—”‘‹… ƒ…‹† ‹ …‡”˜‹…ƒŽ –‹••—‡

…ƒ„‡ƒ’‘–‡–‹†—…‡”‘ˆ…›–‘‹‡•„›˜ƒ”‹‘—•Ž‡—‘…›–‡’‘’—Žƒ–‹‘•ǡ•—…Šƒ•‹–‡”Ž‡—‹

ȋȌǦ͸^Ͷ͸ƒ†ȋȌǦͺǤ^Ͷ͹ǡͶͺȋȌǦͺŠƒ•„‡‡‹†‡–‹ˆ‹‡†ƒ•ƒ‡›ˆƒ…–‘”‹–Š‡”‹’‡‹‰’”‘…‡••ǡ^Ͷ͹

‘–‘Ž›‹Žƒ–‡’”‡‰ƒ…›^Ͷͻ„—–ƒŽ•‘‹–Š‡ˆ‹”•––”‹‡•–‡”Ǥ^ʹ͵–‡”Ž‡—‹ȋȌǦͳEŠƒ•„‡‡

•Š‘™ –‘ ‹†—…‡ ‡š’”‡••‹‘ ‘ˆ –Š‡ ‡œ›‡ …›…Ž‘‘š›‰‡ƒ•‡Ǧʹǡ ™Š‹…Š Ž‡ƒ†• –‘ ƒ Ž‘…ƒŽ

‹…”‡ƒ•‡ ‘ˆ ’”‘•–ƒ‰Žƒ†‹ ʹ ȋʹȌ ‹ –Š‡ …‡”˜‹šǤ^ͷͲ ‹–”‹… ‘š‹†‡ ‹• Ž‹‡† –‘ ƒŽ‘•– ƒŽŽ

ˆ—…–‹‘• ‘ˆ ƒŽ‡ ƒ† ˆ‡ƒŽ‡ ”‡’”‘†—…–‹‘Ǥ – ‹• –Š‘—‰Š– –Šƒ– ’”‘•–ƒ‰Žƒ†‹• ƒ› ƒŽ•‘

•–‹—Žƒ

•›•–‡

•–”

’Ž

‘–—†

…‡”˜‹…ƒ …‡”˜‹…ƒ

ˆ—…–‹‘

‡•–”‘‰‡

–‡ –Š‡ ’”‘†—…–‹‘ ‘ˆ ‹–”‹… ‘š‹†‡ǡ ™Š‹…Š ƒ› ˆ—”–Š‡” ƒ…–‹˜ƒ–‡ –Š‡ …‘ŽŽƒ‰‡‘Ž›–‹…

Ǥ^ͷͳ

3.5ESTROG N

‘‰‡ ƒ’’‡ƒ”• –‘ „‡ ‡••‡–‹ƒŽ ˆ‘” …‡”˜‹…ƒŽ ”‹’‡‹‰ –‘ –ƒ‡ ’Žƒ…‡Ǥ ‘‡ ™‹–Š

ƒ…‡–ƒŽ•—Ž’Šƒ–ƒ•‡†‡ˆ‹…‹‡…›ȋ”‡•—Ž–‹‰‹”‡Žƒ–‹˜‡Ž›Ž‘™…‹”…—Žƒ–‹‰‡•–”‘‰‡•Ȍ†‘

‡”‰‘‘”ƒŽ”‹’‡‹‰‘ˆ–Š‡‹”…‡”˜‹šǤ^{ͷǡͷʹǦͷͶ}Š‡‹ˆŽƒƒ–‘”›…ƒ•…ƒ†‡†—”‹‰–Š‡

Ž”‹’‡‹‰’”‘…‡••‹˜‘Ž˜‡•Ž‡—‘…›–‡•ƒ†–Š‡’”‡•‡…‡‘ˆ‡•–”‘‰‡”‡…‡’–‘”•‘

Ž Ž‡—‘…›–‡•ǡ^ͷͷ ƒ† •—‰‰‡•–• –Šƒ– ‡•–”‘‰‡ ƒ› †‹”‡…–Ž› ”‡‰—Žƒ–‡ Ž‡—‘…›–‡

• ‹ –Š‡ …‡”˜‹šǤ •–”‘‰‡ …ƒ „‡ •Š‘™ –‘ –”‹‰‰‡” ‡‘•‹‘’Š‹Ž‡ ‹˜ƒ•‹‘Ǥ Š‡

 ‡ˆˆ‡…– ‹• „Ž‘…‡† „› ’”‘‰‡•–‡”‘‡ ƒ† –Š‹• ‹Š‹„‹–‹‘ ‹• ”‡˜‡”•‡† „›

‹ˆ‡’”‹•–‘‡Ǥ^ͷ͸–Šƒ•„‡‡†‡‘•–”ƒ–‡†–Šƒ–‡•–”‘‰‡‡Šƒ…‡•…‡”˜‹…ƒŽ”‹’‡‹‰^ͻƒ†

Ž‘…ƒŽƒ’’Ž‹…ƒ–‹‘‘ˆ‡•–”‘‰‡ˆ‘”‹†—…–‹‘‘ˆŽƒ„‘—”Šƒ•„‡‡–”‹‡†Ǥ^ͷ͹‹’‡‹‰†‘‡•‘……—”ǡ

„—– ‡•–”‘‰‡• ƒ’’‡ƒ” –‘ „‡ Ž‡•• ‡ˆˆ‡…–‹˜‡ –Šƒ ’”‘•–ƒ‰Žƒ†‹• ˆ‘” ‹†—…‹‰ Žƒ„‘—” ƒ†

†‡Ž‹˜‡”›Ǥ ‘™‡˜‡”ǡ –Š‡”‡ ƒ”‡ ‹•—ˆˆ‹…‹‡– †ƒ–ƒ –‘ †”ƒ™ ƒ› …‘…Ž—•‹‘•Ǥ^ͷͺ Š‡ ‡ˆˆ‡…– ‘ˆ

‡•–”‘‰‡ƒŽ‘‡‘…‡”˜‹…ƒŽ”‹’‡‹‰‘’‘•–‡‘’ƒ—•ƒŽ™‘‡Šƒ•‘–„‡‡‹˜‡•–‹‰ƒ–‡†Ǥ

Ž–Š‘—‰Š‘‡•–—†›Šƒ•‹˜‡•–‹‰ƒ–‡†–Š‡”‹’‡‹‰‡ˆˆ‡…–‘ˆ‹•‘’”‘•–‘Ž‘–Š‡‡•–”‘‰‡Ǧ

‡ƒ–‡†…‡”˜‹š‹’‘•–‡‘’ƒ—•ƒŽ™‘‡ǡ^ͷͻ–Š‡ƒ—–Š‘”•…‘…Ž—†‡†–Šƒ–‹•‘’”‘•–‘Ž‘

™ƒ•‘–‡ˆˆ‡…–‹˜‡ˆ‘”…‡”˜‹…ƒŽ”‹’‡‹‰„—––Šƒ–‹–™ƒ•‡ˆˆ‡…–‹˜‡‹ʹʹ™‘‡ƒˆ–‡”

Šƒ†ˆ‹”•–—•‡†‡•–”‹‘Ž˜ƒ‰‹ƒŽ…”‡ƒˆ‘”ͳͶ†ƒ›•Ǥ

E

ͳ͸

’”‡–”

‹–•‘™

–Š‡›



–Š

‡’ƒ

ƒ”–‹ˆ‹

”‡ƒ…– …‘–”

…‘””‘

3.6PROSTAGLANDINS

ͳͻ͵Ͳǡ–Š‡‡”‹…ƒ‰›ƒ‡…‘Ž‘‰‹•–•ƒ’Šƒ‡Ž—”œ”‘ƒ†Šƒ”Ž‡•‹‡„ˆ‹”•–†‡•…”‹„‡†

‡ •–‹—Žƒ–‘”› ‡ˆˆ‡…–• ‘ˆ •‡‹ƒŽ ˆŽ—‹† ‘ Š—ƒ —–‡”‹‡ —•…Ž‡ –‹••—‡ ƒ– –Š‡

”–‡– ‘ˆ „•–‡–”‹…• ƒ† ›‡…‘Ž‘‰› ƒ– ‘Ž—„‹ƒ ‹˜‡”•‹–›ǡ ™Š‹Ž‡ –”›‹‰ ‘—–

…‹ƒŽ ‹•‡‹ƒ–‹‘ ‹ ™‘‡Ǥ Š‡› ˆ‘—† –Šƒ– ‹ •‘‡ …ƒ•‡• –Š‡”‡ ™ƒ• ƒ ˜‹‘Ž‡–

‹‘ ‘ˆ –Š‡ —–‡”—• ƒˆ–‡” ‹•–‹ŽŽƒ–‹‘ ‘ˆ •‡‡ ƒ† ‘–‹…‡† –Šƒ– •‡‡ ™‘—Ž† ƒŽ•‘

ƒ…– Š—ƒ —–‡”‹‡ —•…Ž‡ ‹ ˜‹–”‘Ǥ^͸Ͳ Š‡•‡ ˆ‹†‹‰• ™‡”‡ ‹†‡’‡†‡–Ž›

„‘”ƒ–‡† –™‘ ›‡ƒ”• Žƒ–‡” „› ”‹–‹•Š ’Šƒ”ƒ…‘Ž‘‰‹•– ǤǤ ‘Ž†„Žƒ––^͸ͳ ƒ† ™‡†‹•Š

’Š›•‹‘Ž‘‰‹•–ƒ†‡—”‘…Š‡‹•–Žˆ˜ƒ–‡˜‘—Ž‡”Ǥ

 ͳͻ͵Ͷǡ ˜‘ —Ž‡”ǡ ™‘”‹‰ ƒ– –Š‡ ƒ”‘Ž‹•ƒ •–‹–—–‡ ‹

–‘…Š‘Žǡ ™‡†‡ǡ ˆ‘—† –Šƒ– ƒ Ž‹’‹† ‡š–”ƒ…– ˆ”‘ ‘‡›ǡ

•Š‡‡’ ƒ† ‰‘ƒ– ˜‡•‹…—Žƒ” ‰Žƒ†• †”ƒƒ–‹…ƒŽŽ› Ž‘™‡”‡† „Ž‘‘†

’”‡••—”‡™Š‡‹Œ‡…–‡†‹–‘ƒ‹ƒŽ•Ǥ^͸ʹ—ƒ•‡‹ƒŽˆŽ—‹†ƒŽ•‘

•‡‡‡†–‘…‘–ƒ‹–Š‹•—‹†‡–‹ˆ‹‡†•—„•–ƒ…‡Ǥͳͻ͵ͷǡ˜‘—Ž‡”

†—„„‡†–Š‹••—„•–ƒ…‡Dz’”‘•–ƒ‰Žƒ†‹dzǡ‹–Š‡‹•–ƒ‡„‡Ž‹‡ˆ–Šƒ–

‹–‘”‹‰‹ƒ–‡†ˆ”‘–Š‡’”‘•–ƒ–‡‰Žƒ†Ǥ^͸͵Š‡ˆ‹‡Ž†‘ˆ’”‘•–ƒ‰Žƒ†‹

”‡•‡ƒ”…Š™ƒ•–Š‡ƒ„ƒ†‘‡†ˆ‘”‘˜‡”–™‘†‡…ƒ†‡•Ǥ U

lfSvantevonEuler

 ͳͻͶͷǡ —‡ ƒ”Ž ‡”‰•–”ڏ ‡– ˜‘ —Ž‡” ƒ– ƒ ‡‡–‹‰ ‘ˆ –Š‡ Š›•‹‘Ž‘‰‹…ƒŽ

‘…‹‡–›‘ˆ–Š‡ƒ”‘Ž‹•ƒ•–‹–—–‡Ǥ‘—Ž‡”ƒ•‡†‡”‰•–”ڏ‹ˆŠ‡‹‰Š–„‡‹–‡”‡•–‡†‹

•–—†›‹‰•‘‡‘ˆŠ‹•Ž‹’‹†‡š–”ƒ…–•‘ˆ•Š‡‡’˜‡•‹…—Žƒ”‰Žƒ†•Ǥ‡”‰•–”ڏ„‡‰ƒ’—”‹ˆ›‹‰

–Š‡ ƒ…‹† ˜‘ —Ž‡” Šƒ† ‡š–”ƒ…–‡†ǡ ‹ …‘ŽŽƒ„‘”ƒ–‹‘ ™‹–Š ƒ ŒÚ˜ƒŽŽǤ  ͳͻͷ͹ –Š‡› Šƒ†

‹•‘Žƒ–‡† …”›•–ƒŽ• ‘ˆ ƒŽ’”‘•–ƒ†‹Ž ȋ’”‘•–ƒ‰Žƒ†‹ ͳȌ ˆ”‘ •Š‡‡’ ’”‘•–”ƒ–‡ ‰Žƒ†•ǡ ƒ† „›

ͳͻ͸ʹǡ–Š‡•–”—…–—”‡•‘ˆ–Š‡Dz’”‹ƒ”›dz’”‘•–ƒ‰Žƒ†‹•Šƒ†„‡‡†‡–‡”‹‡†„›‡”‰•–”ڏǡ

‡‰–ƒ—‡Ž••‘ǡŒÚ˜ƒŽŽƒ†…‘Ǧ™‘”‡”•ƒ––Š‡ƒ”‘Ž‹•ƒ•–‹–—–‡Ǥ^͸Ͷ

”‘•–ƒ‰Žƒ†‹• ™‡”‡ –Š‡ †‡†—…‡† –‘ „‡ ’”‘†—…–• ‘ˆ

’‘Ž›—•ƒ–—”ƒ–‡†ƒ…‹†‡–ƒ„‘Ž‹•ǡ’ƒ”–‹…—Žƒ”Ž›ƒ”ƒ…Š‹†‘‹…ƒ…‹†

ȋȌǤ Š‡› ƒ”‡ ˜‡”› ‡ƒ•‹Ž› ”‡Ž‡ƒ•‡† ˆ”‘ ‡„”ƒ‡

’Š‘•’Š‘Ž‹’‹†•„›–Š‡ƒ…–‹‘‘ˆ’Š‘•’Š‘Ž‹’ƒ•‡ʹ‹”‡•’‘•‡–‘

ƒ˜ƒ”‹‡–›‘ˆ’Š›•‹…ƒŽǡ…Š‡‹…ƒŽǡƒ†‡—”‘Š‘”‘ƒŽˆƒ…–‘”•Ǥ

‹•”ƒ’‹†Ž›‡–ƒ„‘Ž‹œ‡†–‘‘š›‰‡ƒ–‡†’”‘†—…–•„›–™‘†‹•–‹…–

‡œ›ƒ–‹… ’ƒ–Š™ƒ›•ǣ …›…Ž‘‘š›‰‡ƒ•‡ ƒ† Ž‹’‘š›‰‡ƒ•‡Ǥ Š‡

‹–‡”‡†‹ƒ–‡ …›…Ž‘‘š›‰‡ƒ•‡ ’”‘†—…–• ƒ”‡ …‘˜‡”–‡† –‘

’”‹ƒ”› ’”‘•–ƒ‰Žƒ†‹•ǡ ™Š‹Ž‡ –Š‡ Ž‹’‘š›‰‡ƒ•‡ ’”‘†—…–• ƒ”‡

…‘˜‡”–‡†–‘Ž‡—‘–”‹‡‡•Ǥ^͸ͷ SuneKarlBergström

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 —‡š’‡…–‡† ˆ‹†‹‰™ƒ• –Šƒ– ’”‘•–ƒ‰Žƒ†‹• …‘—Ž† „‡ ƒ†‡ ‹

ƒŽŽ –‹••—‡• ȋ‡š…‡’– ”‡† „Ž‘‘† …‡ŽŽ•Ȍǡ ‘– Œ—•– ƒŽ‡ ”‡’”‘†—…–‹˜‡

‘”‰ƒ•Ǥ^͸͸”‘•–ƒ‰Žƒ†‹•‘ˆ–Š‡•‡”‹‡•ƒ†”‘•–ƒ‰Žƒ†‹ʹƒ”‡

‰‡‡”ƒ–‡†„›–Š‡‡†‘–Š‡Ž‹—ƒ†–Š‡˜‡••‡Ž™ƒŽŽ–‘ƒ‹–ƒ‹–Š‡

‹…”‘…‹”…—Žƒ–‹‘ ƒ† –‘ …‘—–‡”ƒ…– –Š‡ ˜ƒ•‘…‘•–”‹…–‹˜‡ ƒ†

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š‘‰‡‘—•’”‘•–ƒ‰Žƒ†‹•‘ˆ–Š‡ƒ†•‡”‹‡•ƒ”‡’‘–‡–˜ƒ•‘†‹Žƒ–‘”•‹˜ƒ”‹‘—•

˜ƒ•…—Žƒ”„‡†•ǡƒ†”‡•—Ž–‹†‡…”‡ƒ•‡†•›•–‡‹…„Ž‘‘†’”‡••—”‡ƒ†”‡ˆŽ‡š•–‹—Žƒ–‹‘‘ˆ

Š‡ƒ”–”ƒ–‡Ǥ”‘•–ƒ‰Žƒ†‹•‘ˆ–Š‡•‡”‹‡•ƒ†’”‘•–ƒ‰Žƒ†‹ʹ‹…”‡ƒ•‡”‡ƒŽ„Ž‘‘†ˆŽ‘™

ƒ† ’”‘˜‘‡ †‹—”‡•‹• ƒ† ƒ–”‹—”‡•‹•ǡ ’ƒ”–Ž› „› ‘†—Žƒ–‹‰ –Š‡ ”‡‹Ǧƒ‰‹‘–‡•‹Ǧ

ƒŽ†‘•–‡”‘‡•›•–‡Ǥ”‘•–ƒ‰Žƒ†‹•‘ˆ–Š‡ •‡”‹‡•…‘–”ƒ…––Š‡„”‘…Š‹ƒŽƒ†‰—–—•…Ž‡ǡ

™Š‹Ž‡ ’”‘•–ƒ‰Žƒ†‹• ‘ˆ –Š‡ •‡”‹‡• ƒ† ’”‘•–ƒ‰Žƒ†‹ ʹ Šƒ˜‡ ‘’’‘•‹–‡ ‡ˆˆ‡…–•Ǥ

”‘•–ƒ‰Žƒ†‹•‘ˆ–Š‡ƒ† •‡”‹‡•ǡ„—–‘–’”‘•–ƒ‰Žƒ†‹ʹǡ…ƒ—•‡ƒ•–”‘‰…‘–”ƒ…–‹‘

‘ˆ –Š‡ —–‡”‹‡ —•…Ž‡Ǥ ”‘•–ƒ‰Žƒ†‹• ‘ˆ •‡”‹‡• ”‡Žƒš „”‘…Š‹ƒŽ —•…Ž‡ǡ ™Š‡”‡ƒ•

’”‘•–ƒ‰Žƒ†‹•‘ˆ–Š‡ •‡”‹‡•…ƒ—•‡„”‘…Š‘…‘•–”‹…–‹‘Ǣ–Š‡‹”‹„ƒŽƒ…‡ƒ›…‘–”‹„—–‡

–‘–Š‡Š‹‰Š„”‘…Š‹ƒŽ–‘‡‹„”‘…Š‹ƒŽƒ•–ŠƒǤ”‘•–ƒ‰Žƒ†‹•‘ˆ–Š‡ƒ†•‡”‹‡•ƒ†

ʹ ƒ”‡ ‰‡‡”ƒ–‡† „› –Š‡ ‰ƒ•–”‘‹–‡•–‹ƒŽ —…‘•ƒ ƒ† ”‡Ž‡ƒ•‡† ‹–‘ –Š‡ Ž—‡ —’‘

‡—”ƒŽ ‘” Š‘”‘ƒŽ •–‹—Žƒ–‹‘Ǣ ‹– ‹• Ž‹‡Ž› –Šƒ– –Š‡› ’ƒ”–‹…‹’ƒ–‡ ‹ –Š‡ ƒ‹–‡ƒ…‡ ‘ˆ

—…‘•ƒŽ ‹–‡‰”‹–› ƒ† ‹…”‘…‹”…—Žƒ–‹‘Ǥ š‘‰‡‘—• ’”‘•–ƒ‰Žƒ†‹• ‘ˆ –Š‡ ƒ† •‡”‹‡•

‹Š‹„‹– ‰ƒ•–”‹… ƒ…‹† •‡…”‡–‹‘ ƒ† •–‹—Žƒ–‡ ƒŽƒŽ‹‡ •‡…”‡–‹‘ ™Š‹Ž‡ ‹…”‡ƒ•‹‰ —…‘•ƒŽ

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Figure 5: Synthesis of the five principal prostaglandins from arachidonic acid. (From:

Chandrasekharan NV, Simmons DL. The cyclooxygenases. Genome Biology 2004 55:241).

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Š‡ˆ‹”•––‘–ƒŽ•›–Š‡•‹•‘ˆƒƒ–—”ƒŽ’”‘•–ƒ‰Žƒ†‹™ƒ•ƒ…Š‹‡˜‡†„›Š‹Ž‹’‡ƒŽƒ†

Š‹• …‘ŽŽ‡ƒ‰—‡• ƒ– ’Œ‘Š Žƒ„‘”ƒ–‘”‹‡• ‹ ͳͻ͸ͷǤ^͸͹ ǤǤ …Š‡‹†‡” ƒ– ’Œ‘Š ”‡’‘”–‡†

•›–Š‡•‹• ‘ˆ ”‘•–ƒ‰Žƒ†‹ ʹ ƒ† ʹƒŽ’Šƒ ‹ ͳͻ͸ͺ^͸ͺ ƒ† –Š‡ ”‡ƒ‹‹‰ ’”‹ƒ”›

’”‘•–ƒ‰Žƒ†‹• ͵ ƒ† ͵ƒŽ’Šƒ ™‡”‡ •›–Š‡•‹•‡† ™‹–Š‹ –Š‡ ‡š– ˆ‡™ ›‡ƒ”•Ǥ ‡”‰•–”ڏ

ƒ† ƒ—‡Ž••‘ǡ –‘‰‡–Š‡” ™‹–Š ‘Š ƒ‡ ƒ– –Š‡ —””‘—‰Š• ‡ŽŽ…‘‡ ‡•‡ƒ”…Š

ƒ„‘”ƒ–‘”‹‡•‹‡…‡Šƒǡǡ™‡”‡Œ‘‹–Ž›ƒ™ƒ”†‡†–Š‡‘„‡Ž”‹œ‡‹‡†‹…‹‡‹ͳͻͺʹ

ˆ‘”–Š‡‹”™‘”Ž‡ƒ†‹‰–‘–Š‡‡Ž—…‹†ƒ–‹‘‘ˆ–Š‡…Š‡‹…ƒŽ•–”—…–—”‡•‘ˆ’”‘•–ƒ‰Žƒ†‹•ƒ†

–Š‡‹” „‹‘•›–Š‡–‹… ’ƒ–Š™ƒ›•Ǥ^͸ͻ ‹Ž• ‹“—‹•– ƒ† ƒ”… ›‰†‡ƒ ƒ– –Š‡ ƒ”‘Ž‹•ƒ

•–‹–—–‡ †‡‘•–”ƒ–‡† –Š‡ ‡š–”‡‡Ž› Š‹‰Š ƒ…–‹˜‹–› ‘ˆ ‹–”ƒ˜‡‘—•Ž› ‹Œ‡…–‡†

’”‘•–ƒ‰Žƒ†‹• ‘ –Š‡ Š—ƒ ›‘‡–”‹—Ǥ^͹Ͳ ‹†‹‰• ”‡‰ƒ”†‹‰ …ƒ”†‹‘˜ƒ•…—Žƒ” ‡ˆˆ‡…–•

‹…Ž—†‡†–Š‡•–”‘‰†‹Žƒ–ƒ–‹‘‘ˆ–Š‡Ž‘…ƒŽ„Ž‘‘†˜‡••‡Ž•ƒˆ–‡”‹–”ƒǦƒ”–‡”‹ƒŽ‹Œ‡…–‹‘ƒ†

–Š‡’”‡˜‡–‹‘‘ˆ…Ž‘•—”‡‘ˆ†—…–—•ƒ”–Š‡”‹‘•—•ƒˆ–‡”„‹”–Š‹…‡”–ƒ‹–›’‡•‘ˆ„Ž—‡„ƒ„‹‡•Ǥ

 ƒ††‹–‹‘ǡ †”‡ ‘„‡”– ƒ† …‘Ǧ™‘”‡”• ƒ– ’Œ‘Š ‘’ƒ› ˆ‘—† –Š‡ Ǧ–›’‡

’”‘•–ƒ‰Žƒ†‹•‹Š‹„‹–‡†‰ƒ•–”‹…•‡…”‡–‹‘‹ͳͻ͸͹Ǥ^͹ͳ

•’”‘•–ƒ‰Žƒ†‹••‡‡–‘‘†—Žƒ–‡ƒŽ‘•–‡˜‡”›„‹‘Ž‘‰‹…ƒŽˆ—…–‹‘‹–Š‡„‘†›ǡ

–Š‡›™‡”‡‹‹–‹ƒŽŽ›…‘•‹†‡”‡†–‘Šƒ˜‡ƒ„”‘ƒ†•’‡…–”—‘ˆ–Š‡”ƒ’‡—–‹…—–‹Ž‹–›‡Ǥ‰Ǥ‹Žƒ„‘—”

‹†—…–‹‘ǡƒ•–Šƒǡƒ”–Š”‹–‹•ǡ’‡’–‹…—Ž…‡”†‹•‡ƒ•‡ǡŠ›’‡”–‡•‹‘ǡ ’Žƒ–‡Ž‡– †›•ˆ—…–‹‘ ƒ†

’‡”‹‘†‘–ƒŽ†‹•‡ƒ•‡Ǥ–‘‡’‘‹–ǡ–Š‡›™‡”‡†‡…Žƒ”‡†–Š‡Dz•–‡”‘‹†•dz‘ˆ–Š‡ͳͻ͹Ͳ•Ǥ^͹ʹˆƒ…–ǡ

–Š‡‹”—•‡Šƒ•ƒ‹Ž›„‡‡…‘ˆ‹‡†–‘–Š‡‹†—…–‹‘‘ˆŽƒ„‘—”ƒ†…‡”˜‹…ƒŽ”‹’‡‹‰ƒ†‹

–Š‡•›…Š”‘‹œƒ–‹‘‘ˆ‡•–”—•‹ˆƒ”ƒ‹ƒŽ•ǤŠ‡ƒ–—”ƒŽŽ›‘……—””‹‰’”‘•–ƒ‰Žƒ†‹•‹

–Š‡ ˆ‡ƒŽ‡ ”‡’”‘†—…–‹˜‡ –”ƒ…– ƒ”‡ ’”‘•–ƒ‰Žƒ†‹ ʹ ȋʹȌ ƒ† ’”‘•–ƒ‰Žƒ†‹ ʹƒŽˆƒ

ȋ ʹDȌǡ™Š‹…Šƒ…–„›„‹†‹‰ƒ†ƒ…–‹˜ƒ–‹‰–Š‡‹””‡•’‡…–‹˜‡”‡…‡’–‘”•Ǥ^͹͵ǡ͹ͶŠ‡›ƒ”‡„‘–Š

‡ˆˆ‹…‹‡– ‹ ’”‘†—…‹‰ …‡”˜‹…ƒŽ ”‹’‡‹‰ ƒ† Žƒ„‘—”Ǥ  ͳͻ͸ͺǡ ‹–”ƒ˜‡‘—• ‹ˆ—•‹‘ ‘ˆ

ʹD™ƒ•ˆ‘—†–‘„‡ƒ‡ˆˆ‡…–‹˜‡™ƒ›‘ˆ‹†—…‹‰Žƒ„‘—”Ǥ^͹ͷ‰”‘—’ƒ–’Œ‘Šˆ‘—†–Šƒ–

ʹD‹–‡””—’–‡†’”‡‰ƒ…›‹”ƒ–•ǤŠ‡ˆ‹”•–‡†‹…ƒŽ‹–‡””—’–‹‘‘ˆ’”‡‰ƒ…›™‹–Šƒ

’”‘•–ƒ‰Žƒ†‹ ȋ ʹDȌ ™ƒ• †‘‡ ‹ –‘…Š‘Ž ‹ ͳͻ͸ͻ ƒ† …Ž‹‹…ƒŽ –”‹ƒŽ• ‘ –Š‡ —•‡ ‘ˆ

’”‘•–ƒ‰Žƒ†‹•ˆ‘”‹†—…–‹‘‘ˆƒ„‘”–‹‘™‡”‡‹‹–‹ƒŽŽ›”‡’‘”–‡†‹ƒ—ƒ”›ͳͻ͹ͲǤ^͹͸ǡ͹͹ʹ

™ƒ• Ž‹…‡•‡† ‹ ͳͻ͹ʹ ˆ‘” –Š‡ ‹†—…–‹‘ ‘ˆ ƒ„‘”–‹‘ ƒˆ–‡” ˆ‹”•– –”‹‡•–‡” ’”‡‰ƒ…›Ǥ^͹ͺ

”‘•–ƒ‰Žƒ†‹• ƒ”‡ ‘™ ™‹†‡Ž› —•‡† ‹ –Š‡ ˆ‹‡Ž† ‘ˆ ”‡’”‘†—…–‹˜‡ Š‡ƒŽ–Šǡ ™‹–Š ͳ

‡•”‡’Žƒ…‹‰ʹƒ† ʹDƒ•–Š‡’”‘•–ƒ‰Žƒ†‹‘ˆ…Š‘‹…‡‹ƒ›Š‹‰ŠǦ‹…‘‡

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3.7PROSTAGLANDINSUSEDCLINICALLYFOR ERVICAL RIPENING

‘—‰Š …‡”˜‹…ƒŽ …Šƒ‰‡ †—”‹‰ ’”‡‰ƒ…› Šƒ• „‡‡ •–—†‹‡† –‘ †‡–‡”‹‡ –Š‡

‡…Šƒ‹• ‘ˆ …‡”˜‹…ƒŽ ”‹’‡‹‰ǡ ‹– Šƒ• ‘– ›‡– „‡‡ …‘…Ž—•‹˜‡Ž› ‡•–ƒ„Ž‹•Š‡† Š‘™

Žƒ†‹• ƒ…–—ƒŽŽ› ’”‘†—…‡ ‹–Ǥ – Šƒ• „‡‡ †‡‘•–”ƒ–‡† –Šƒ– Ž‘…ƒŽ ƒ’’Ž‹…ƒ–‹‘ ‘ˆ

Žƒ†‹ ʹ ‹†—…‡• …‡”˜‹…ƒŽ ”‹’‡‹‰ „› ‹…”‡ƒ•‡† ”‡‘†‡ŽŽ‹‰ ‘ˆ –Š‡ …‡”˜‹…ƒŽ

‹˜‡–‹••—‡Ǥ^͹’’Ž‹…ƒ–‹‘‘ˆʹ•’Ž‹–•ƒ††‹••‘Ž˜‡•–Š‡…‘ŽŽƒ‰‡ˆ‹„”‡•Ǥ^ͺͲ

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Figures 6 and 7: Electron micrographs of cervical tissue showing (left) intact well organised collagen fibrils and (right) disorganised collagen framework indicating disintegration of the collagen fibrils following treatment with misoprostol. (From Radulovic et al. Cervical priming in the first trimester: morphological and biochemical effects of misoprostol and isosorbide mononitrate. Acta Obstet Gynecol Scan 2009;88:43-51).

ƒ‰‹ƒŽ –”‡ƒ–‡– ™‹–Š ‹•‘’”‘•–‘Ž Šƒ• „‡‡ •Š‘™ –‘ ‹…”‡ƒ•‡ …‡”˜‹…ƒŽ …‘…‡–”ƒ–‹‘

Ž‡˜‡Ž• ‘ˆ –Š‡ ƒ–”‹š ‡–ƒŽŽ‘’”‘–‡‹ƒ•‡• Ǧͺ ƒ† Ǧͻ ‹ –Š‡ ˆ‹”•– –”‹‡•–‡”ǡ

•‹‰‹ˆ›‹‰ ‹†—…–‹‘ ‘ˆ …‘ŽŽƒ‰‡‘Ž›•‹•Ǥ^ͳͶǡʹͶ – Šƒ• „‡‡ •—‰‰‡•–‡† –Šƒ– –Š‡ ‹ˆŽƒƒ–‘”›

…ƒ•…ƒ†‡ǡ^͵ͺ Ž‡—‘…›–‡ ‹ˆ‹Ž–”ƒ–‹‘ǡ^ͺͳ ƒ† …‘ŽŽƒ‰‡ ”‡‘†‡ŽŽ‹‰^ͺʹ ‘„•‡”˜‡† ‹ –Š‡ …‡”˜‹…ƒŽ

–‹••—‡ƒ›„‡†—‡–‘–Š‡‹…”‡ƒ•‡‹Ž‘…ƒŽ’”‘•–ƒ‰Žƒ†‹•Ǥ‡”˜‹…ƒŽ’”‘•–ƒ‰Žƒ†‹”‡…‡’–‘”•

Šƒ˜‡„‡‡†‡‘•–”ƒ–‡†ǡ^ͺ͵ƒ†–Š‡…‡”˜‹š…ƒ’”‘†—…‡ƒ˜ƒ”‹‡–›‘ˆ’”‘•–ƒ‰Žƒ†‹•^ͺͶ–Šƒ–

ƒ›ƒˆˆ‡…–ˆ‹„”‘„Žƒ•–ƒ…–‹˜‹–›–Š”‘—‰Š–Š‡‹”’”‘†—…–‹‘‘ˆ‰Ž›…‘’”‘–‡‹•Ǥ^ͷ”‘•–ƒ‰Žƒ†‹•

ƒ”‡…ƒ’ƒ„Ž‡‘ˆ‹†—…‹‰–Š‡’”‘†—…–‹‘‘ˆŠ›ƒŽ—”‘‹…ƒ…‹†„›…‡”˜‹…ƒŽˆ‹„”‘„Žƒ•–•ǡ…ƒ—•‹‰

‹…”‡ƒ•‡† Š›†”ƒ–‹‘ ƒ† ƒŽ–‡”ƒ–‹‘ ‘ˆ –Š‡ …‘’‘•‹–‹‘ ‘ˆ

‰Ž›…‘•ƒ‹‘‰Ž›…ƒ•Ȁ’”‘–‡‘‰Ž›…ƒ•Ǥ^ͺͷ ”‘•–ƒ‰Žƒ†‹• ƒ› ƒ…– ƒ• …Š‡‘–ƒ…–‹… ƒ‰‡–•ǡ

’”‘‘–‹‰–Š‡‹ˆ‹Ž–”ƒ–‹‘‘ˆŽ‡—‘…›–‡•ƒ†ƒ…”‘’Šƒ‰‡•‹–‘–Š‡…‡”˜‹…ƒŽ•–”‘ƒǤŠ‡•‡

‹ˆŽƒƒ–‘”› …‡ŽŽ• …‘—Ž† „‡ –Š‡ •‘—”…‡ ‘ˆ –Š‡ •’‡…‹ˆ‹… †‡‰”ƒ†‹‰ ‡œ›‡• …ƒ—•‹‰ –Š‡

…‹ƒ–‡†™‹

…Šƒ‰‡•‹–Š‡‡š–”ƒ…‡ŽŽ—Žƒ”ƒ–”‹š–Šƒ–ƒ”‡ƒ••‘ –Š…‡”˜‹…ƒŽ”‹’‡‹‰Ǥ^ͷ

Š‡”‡ ‹• ‡˜‹†‡…‡ ˆ‘” –Š‡ ‡š‹•–‡…‡ ‘ˆ ƒ ‹–”‹… ‘š‹†‡ •›•–‡ ™‹–Š‹ –Š‡ Š—ƒ

—–‡”‹‡…‡”˜‹šƒ†ƒ”‘Ž‡ˆ‘”‹–”‹…‘š‹†‡‹–Š‡…‘–”‘Ž‘ˆ…‡”˜‹…ƒŽˆ—…–‹‘ƒ†”‡Žƒšƒ–‹‘

‘ˆ…‡”˜‹…ƒŽ•‘‘–Š—•…Ž‡Ǥ^ͺ͸‹–”‹…‘š‹†‡ƒ›”‡‰—Žƒ–‡–Š‡ƒ…–‹˜‹–›‘ˆ‡–ƒŽŽ‘’”‘–‡‹ƒ•‡•

ʹʹ

”‡•’‘•‹„Ž‡ˆ‘”…‘ŽŽƒ‰‡†‡‰”ƒ†ƒ–‹‘ƒ†‹†—…‡’”‘•–ƒ‰Žƒ†‹’”‘†—…–‹‘„›•–‹—Žƒ–‹‰

…›…Ž‘‘š›‰‡ƒ•‡ ƒ…–‹˜‹–›Ǥ^ͺ͹ ‹’‡‹‰ †—‡ –‘ ‹–”‹… ‘š‹†‡ ƒ› „‡ ‡†‹ƒ–‡† ‹ ’ƒ”– ˜‹ƒ

‹…”‡ƒ•‡†’”‘•–ƒ‰Žƒ†‹ ʹƒŽˆƒȋ ʹDȌ•›–Š‡•‹•ǡ^ͺͺǡͺͻ’”‘•–ƒ‰Žƒ†‹ʹȋʹȌƒ†…›…Ž‹…

‰—ƒ‘•‹‡‘‘’Š‘•’Šƒ–‡Ǥ^ͻͲ‹–”‹…‘š‹†‡ƒ…–••›‡”‰‹•–‹…ƒŽŽ›™‹–Š’”‘•–ƒ‰Žƒ†‹ǡ’‘••‹„Ž›

‹†—…‹‰ …‡”˜‹…ƒŽ ”‹’‡‹‰ „› …ƒ—•‹‰ …Šƒ‰‡• ‹ –Š‡ ‡š–”ƒ…‡ŽŽ—Žƒ” ƒ–”‹š –Šƒ– ƒ”‡

ƒ••‘…‹ƒ–‡† ™‹–Š ”‹’‡‹‰ ‘ˆ –Š‡ …‡”˜‹šǤ^ͻͳ ‘†‹— ‹–”‘’”—••‹†‡ ƒ’’Ž‹‡† ‹–‘ –Š‡ …‡”˜‹…ƒŽ

…ƒƒŽ‹†—…‡•ƒ”ƒ’‹†ƒ†•‹‰‹ˆ‹…ƒ–•‘ˆ–‡‹‰‘ˆ–Š‡…‡”˜‹šƒ†‹•‘•‘”„‹†‡‘‘‹–”ƒ–‡

ƒ†‰Ž›…‡”›Ž–”‹‹–”ƒ–‡…ƒ‡ˆˆ‡…–…‡”˜‹…ƒŽ”‹’‡‹‰•‹‹Žƒ”–‘–Š‡’”‘•–ƒ‰Žƒ†‹ƒƒŽ‘‰—‡

‰‡‡’”‘•–Ǥ^͵ʹ

Š‡ ’‘–‡– —–‡”‘–‘‹… ƒ…–‹˜‹–› …ƒ—•‡† „› ’”‘•–ƒ‰Žƒ†‹• ‹• †—‡ –‘ ‹…”‡ƒ•‡†

‹–”ƒ…‡ŽŽ—Žƒ” …ƒŽ…‹— ƒ† –Š‡ ƒ…–‹˜ƒ–‹‰ ‘ˆ ›‘•‹ Ž‹‰Š– …Šƒ‹ ‹ƒ•‡ ȋȌǤ …–‹ ƒ†

›‘•‹—•…Ž‡ˆ‹„”‡•–Š‡—†‡”‰‘…‘ˆ‘”ƒ–‹‘ƒŽ…Šƒ‰‡•–Šƒ–ƒŽŽ‘™–Š‡–‘•Ž‹†‡‘˜‡”

‡ƒ…Š‘–Š‡”…ƒ—•‹‰•Š‘”–‡‹‰‘ˆ–Š‡—•…Ž‡…‡ŽŽƒ†–Š‡”‡„›—–‡”‹‡…‘–”ƒ…–‹‘Ǥ^ͷǡ͹͵

Ž‹‹…ƒŽŽ›ǡ –Š‡ Ž‹…‡•‡† ʹ ’”‡’ƒ”ƒ–‹‘• —•‡† ˆ‘” …‡”˜‹…ƒŽ ”‹’‡‹‰ ƒ† Žƒ„‘—”

‹†—…–‹‘ ƒ”‡ †‹‘’”‘•–‘‡ ƒ† •—Ž’”‘•–‘‡Ǥ Š‡•‡ ’”‡’ƒ”ƒ–‹‘• Šƒ˜‡ •‡˜‡”ƒŽ

†‹•ƒ†˜ƒ–ƒ‰‡•Ǥ ‹‘’”‘•–‘‡ ȋ‹’”‘•–‹“ǡ ‡”˜‹†‹Ž“ǡ ”‘•–‹ ʹ“ǡ ƒ† ”‘’‡••“Ȍ ‹•

‡š’‡•‹˜‡ǡ‹–‹•—•–ƒ„Ž‡ƒ–”‘‘–‡’‡”ƒ–—”‡Ȃƒ‹‰•–‘”ƒ‰‡ƒ†–”ƒ•’‘”–†‹ˆˆ‹…—Ž–Ǧ

ƒ†‹–‹•‘Ž›ƒ˜ƒ‹Žƒ„Ž‡‹ƒŽ‹‹–‡†—„‡”‘ˆ…‘—–”‹‡•ǡ†—‡–‘’‘Ž‹–‹…ƒŽŠ‡ƒŽ–Š‹••—‡•ǤŠ‡

ʹ†‡”‹˜ƒ–‹˜‡•—Ž’”‘•–‘‡Šƒ•„‡‡ƒ••‘…‹ƒ–‡†™‹–Šƒƒ—‰‡–‡†”‹•‘ˆ›‘…ƒ”†‹ƒŽ

‹ˆƒ”…–‹‘Ǥ^ͻʹ Š‡ ʹD ’”‡’ƒ”ƒ–‹‘ ‹‘’”‘•–“ ‹• ‘Ž› ƒ˜ƒ‹Žƒ„Ž‡ ƒ• ƒ ‹Œ‡…–ƒ„Ž‡

’”‡’ƒ”ƒ–‹‘ƒ†‹•ƒ••‘…‹ƒ–‡†™‹–ŠƒŠ‹‰Š‹…‹†‡…‡‘ˆ‰ƒ•–”‘Ǧ‹–‡•–‹ƒŽ•‹†‡‡ˆˆ‡…–•Ǥ^ͻ͵

Š‡ͳƒƒŽ‘‰—‡•—•‡†ˆ‘”…‡”˜‹…ƒŽ”‹’‡‹‰ƒ†Žƒ„‘—”‹†—…–‹‘ƒ”‡‰‡‡’”‘•–

ȋ‡‡’”‘•–“Ȍ ƒ† ‹•‘’”‘•–‘Ž ȋ›–‘–‡…“ȌǤ ‡‡’”‘•– Šƒ• „‡‡ ™‹†‡Ž› —•‡† ‹ ‡ƒ”Ž›

‡†‹…ƒŽƒ„‘”–‹‘Ǥ–‹•‡ƒ•‹Ž›ƒ˜ƒ‹Žƒ„Ž‡ƒ†‰›ƒ‡…‘Ž‘‰‹•–•Šƒ˜‡ƒŽ‘‰‡š’‡”‹‡…‡™‹–Š–Š‡

†”—‰ ƒ• ‹– ‹• Ž‹…‡•‡† ˆ‘” ˜ƒ‰‹ƒŽ ƒ’’Ž‹…ƒ–‹‘ ‹ •‡…‘† –”‹‡•–‡” ƒ„‘”–‹‘Ǥ – Šƒ• „‡‡

•—’‡”•‡†‡† „› ‹•‘’”‘•–‘Ž^ͻͶ ƒ• ‰‡‡’”‘•– Šƒ• •‡˜‡”ƒŽ †‹•ƒ†˜ƒ–ƒ‰‡• …‘’ƒ”‡† ™‹–Š

‹•‘’”‘•–‘Žǣ ‹– ‹• ‘Ž› ƒ˜ƒ‹Žƒ„Ž‡ ƒ• ͳ ‰ ’‡••ƒ”› ˆ‘” ˜ƒ‰‹ƒŽ —•‡ǡ –Š‡ ƒ˜ƒ‹Žƒ„Ž‡ ’‡••ƒ”›

…‘–ƒ‹• ƒ —‡…‡••ƒ”‹Ž› Š‹‰Š †‘•‡ ‘ˆ ’”‘•–ƒ‰Žƒ†‹ ˆ‘” ˜‡”› ‡ƒ”Ž› ‡†‹…ƒŽ ƒ„‘”–‹‘

ȋ™Š‹…Š…ƒ”‡•—Ž–‹†‘•‡Ǧ”‡Žƒ–‡†•‹†‡‡ˆˆ‡…–•Ȍǡƒ†‹–‹•‡š’‡•‹˜‡ƒ†—•–ƒ„Ž‡ƒ–”‘‘

–‡’‡”ƒ–—”‡Ǥ

ƒ—

™‘

3.8MISOPROSTOL

ŽǤ‘ŽŽ‹•†‹•…‘˜‡”‡†‹•‘’”‘•–‘ŽȋͳͷǦ†‡‘š›Ǧͳ͸ǦŠ›†”‘š›Ǧͳ͸Ǧ‡–Š›ŽͳȌ™Š‹Ž‡

”‹‰ ƒ– –Š‡ ’Šƒ”ƒ…‡—–‹…ƒŽ …‘’ƒ› ǤǤ ‡ƒ”Ž‡ ȋ‘‹‡ǡ ŽŽ‹‘‹•ǡ Ȍ ‹ –Š‡

ͳ͹Ͳ•Ǥ^͹ʹ‹•‘’”‘•–‘Ž™ƒ•†‡˜‡Ž‘’‡†ƒ•ƒƒ–‹Ǧ‰ƒ•–”‹…—Ž…‡”†”—‰•‹…‡

‹–Šƒ†„‡‡•Š‘™‹ͳͻ͸͹–Šƒ–ƒ–—”ƒŽŽ›‘……—””‹‰’”‘•–ƒ‰Žƒ†‹•‘ˆ

–Š‡ •‡”‹‡• ‹Š‹„‹– ‰ƒ•–”‹… ƒ…‹† •‡…”‡–‹‘Ǥ^͹ͳ – ™ƒ• ˆ‹”•– ƒ’’”‘˜‡† ‹

ͳͻͺͺ „› –Š‡ ˆ‘” –Š‡ ’”‡˜‡–‹‘ ƒ† –”‡ƒ–‡– ‘ˆ ‰ƒ•–”‹… —Ž…‡”•

‹†—…‡† „› • ȋ‘•–‡”‘‹†ƒŽ ƒ–‹Ǧ‹ˆŽƒƒ–‘”› †”—‰•Ȍ ƒˆ–‡”

•–—†‹‡•†‡‘•–”ƒ–‡†‹–•‡ˆˆ‹…ƒ…›^ͻͷǡͻ͸ƒ†‹–‹•‘™ƒ’’”‘˜‡†‹‘”‡

–Šƒ ͺͲ …‘—–”‹‡•ǡ ‘•–Ž› —†‡” –Š‡ „”ƒ† ƒ‡ ‘ˆ ›–‘–‡…“Ǥ – ‹•

•—’’Ž‹‡†‹–ƒ„Ž‡–•…‘–ƒ‹‹‰ʹͲͲ‹…”‘‰”ƒ•‘ˆ‹•‘’”‘•–‘Žˆ‘”‘”ƒŽ

—•‡Ǥ ͳͲͲ ‹…”‘‰”ƒ ˆ‘” ‹• ƒ˜ƒ‹Žƒ„Ž‡ ‹ •‘‡ …‘—–”‹‡•Ǥ ‡ˆ‘”‡

ƒ””› ƒ”•ŠƒŽŽ ƒ† ‘„‹ ƒ””‡ •Š‘™‡† ƒ …ƒ—•ƒŽ …‘‡…–‹‘ „‡–™‡‡ –Š‡ „ƒ…–‡”‹—

helicobacter pyloriǡ ‰ƒ•–”‹–‹•ǡ ƒ† ’‡’–‹… —Ž…‡” †‹•‡ƒ•‡ ‹ ͳͻͺͶǡ^ͻ͹ǡͻͺ –Š‡ ’”‡˜ƒ‹Ž‹‰ –Š‡‘”›

–‘™ƒ”†ƒ…—”‡ˆ‘”–Š‹•†‹•‡ƒ•‡™ƒ•Dz‘ƒ…‹†Ǧ‘—Ž…‡”dzƒ†‹•‘’”‘•–‘Ž™ƒ•ƒ‹‡†‹ƒ–‡

…ƒ†‹†ƒ–‡ˆ‘” —Ž…‡” –Š‡”ƒ’›ǤŠ‡—–‡”‘–‘‹…’”‘’‡”–‹‡•™‡”‡‘–‡† ƒ• ƒ ™‘””‹•‘‡ •‹†‡

‡ˆˆ‡…– ‘ˆ ƒ–—”ƒŽ ’”‘•–ƒ‰Žƒ†‹• ƒ† ƒ …ƒ—•‡ ˆ‘” ’‘–‡–‹ƒŽ …‘…‡” ™‹–Š •›–Š‡–‹…

ƒƒŽ‘‰—‡•Ǥ‘ŽŽ‹•ƒ†Š‹•…‘Ǧ™‘”‡”•™‡”‡—ƒ„Ž‡–‘‡Ž‹‹ƒ–‡–Š‡•–‹—Žƒ–‘”›ƒ…–‹˜‹–›‘ˆ

‹•‘’”‘•–‘Ž ‘ —–‡”‹‡ •‘‘–Š —•…Ž‡Ǥ –—†‹‡• †‡‘•–”ƒ–‡† –Šƒ– ‹•‘’”‘•–‘Ž …‘—Ž†

‹…”‡ƒ•‡ —–‡”‹‡ …‘–”ƒ…–‹Ž‡ ƒ…–‹˜‹–› ƒ† ‡†ƒ‰‡” ’”‡‰ƒ…›Ǥ Š‡ —–‡”‹‡ ‡ˆˆ‡…–• ‘ˆ

‹•‘’”‘•–‘Ž™‡”‡‘–•‡‡‹ƒ‹ƒŽ•–—†‹‡•ǡ„—––™‘•–—†‹‡•…‘†—…–‡†—•‹‰™‘‡‹

–Š‡ ˆ‹”•– –”‹‡•–‡” ‘ˆ ’”‡‰ƒ…›ǡ •‡‡‹‰ Ž‡‰ƒŽ ƒ„‘”–‹‘ǡ •Š‘™‡† –Šƒ– ‹•‘’”‘•–‘Ž ™ƒ•

ƒ••‘…‹ƒ–‡† ™‹–Š —–‡”‹‡ „Ž‡‡†‹‰ ƒ† ’ƒ”–‹ƒŽ ‘” …‘’Ž‡–‡ ‡š’—Ž•‹‘ ‘ˆ –Š‡ —–‡”‹‡

…‘–‡–•Ǥ^ͻͻ ”‡ƒ–‡– ƒ† ’”‡˜‡–‹‘ ‘ˆ ‰ƒ•–”‹… —Ž…‡”• ƒ”‡ •–‹ŽŽ –Š‡ ‘Ž› Ž‹…‡•‡†

‹†‹…ƒ–‹‘•ˆ‘”‹•‘’”‘•–‘Žǡ™‹–Š–Š‡‡š…‡’–‹‘‘ˆ›‹•‘“‹ ”ƒ…‡ƒ†ƒʹͷP‰˜ƒ‰‹ƒŽ

•—’’‘•‹–‘”› ˆ‘” ‹†—…–‹‘ ‘ˆ Žƒ„‘—” ƒ˜ƒ‹Žƒ„Ž‡ ‹ ”ƒœ‹Ž ƒ† ‰›’–Ǥ^ͳͲͲ  –Š‡ ǡ ƒ

‹•‘’”‘•–‘Ž –ƒ„Ž‡– ˆ‘” Žƒ„‘—” ‹†—…–‹‘ ȋ•’”‡Ž‘”̻ Ǧ ʹͷρ‰ ˜ƒ‰‹ƒŽ –ƒ„Ž‡–•Ȍ ‹• …—””‡–Ž›

—†‡”‰

Figure 8: Discovery of misoprostol

ʹ͵

‘‹‰’Šƒ•‡–”‹ƒŽ•Ǥ

‘’ƒ”‡†™‹–Š‘–Š‡”’”‘•–ƒ‰Žƒ†‹•Ȃƒ–—”ƒŽ‘”•›–Š‡•‹•‡†Ȃ‹•‘’”‘•–‘Ž‹•˜‡”›

•–ƒ„Ž‡ƒ†…ƒ„‡’”‡’ƒ”‡†ˆ”‘ƒ•‘Ž‹††‹•’‡”•‹‘‘Š›†”‘š›’”‘’›Ž‡–Š›Ž…‡ŽŽ—Ž‘•‡ƒ•

ʹͶ

•‘Ž‹†–ƒ„Ž‡–•™‹–Šƒ•Š‡ŽˆŽ‹ˆ‡‘ˆ•‡˜‡”ƒŽ›‡ƒ”•ƒ–”‘‘–‡’‡”ƒ–—”‡Ǥ–Šƒ•ˆ‡™‡”•‹†‡‡ˆˆ‡…–•

–Šƒ ʹ^ͳͲʹ ƒ† ‹• ƒ •ƒˆ‡ ƒ† ™‡ŽŽǦ–‘Ž‡”ƒ–‡† †”—‰Ǥ – Šƒ• •Š‘™ ‡‹–Š‡” ‡•–”‘‰‡‹…ǡ

’”‘‰‡•–‘‰‡‹…ǡ‘”ƒ†”‘‰‡‹…ƒ‰‘‹•‘”ƒ–ƒ‰‘‹•Ǥ‹•‘’”‘•–‘Ž‹•‡‹–Š‡”ˆ‡–‘–‘š‹…

‘”…ƒ”…‹‘‰‡‹…Ǥ‘…Ž‹‹…ƒŽŽ›•‹‰‹ˆ‹…ƒ–ƒ†˜‡”•‡Šƒ‡ƒ–‘Ž‘‰‹…ƒŽǡ‡†‘…”‹‡ǡ„‹‘…Š‡‹…ƒŽǡ

‹—‘Ž‘‰‹…ǡ”‡•’‹”ƒ–‘”›ǡ‘’Š–ŠƒŽ‹…ǡ’Žƒ–‡Ž‡–ǡ‡–ƒŽ‘”…ƒ”†‹‘˜ƒ•…—Žƒ”‡ˆˆ‡…–•Šƒ˜‡„‡‡

”‡’‘”–‡†Ǥ – ‹• ˜‡”› ‹‡š’‡•‹˜‡ǡ …‘•–‹‰ ƒ’’”‘š‹ƒ–‡Ž› ͳͲͲ –‹‡• Ž‡•• –Šƒ ‘–Š‡”

’”‘•–ƒ‰Žƒ†‹•Ǥ^ͳͲʹ Š‡ ‘”ƒŽ –ƒ„Ž‡–• ƒ”‡ ‡ˆˆ‡…–‹˜‡ ™Š‡ ƒ†‹‹•–‡”‡† ‘”ƒŽŽ›ǡ ˜ƒ‰‹ƒŽŽ›ǡ

•—„Ž‹‰—ƒŽŽ›ǡ„—……ƒŽŽ›‘””‡…–ƒŽŽ›Ǥ^{ͳͲ͵ǦͳͲͺ}

Š‡ ƒ—ˆƒ…–—”‡” ƒ† Š‘Ž†‡” ‘ˆ –Š‡ ’ƒ–‡– ˆ‘” ‹•‘’”‘•–‘Žǡ ‡ƒ”Ž‡ ȋ‘™

‹…‘”’‘”ƒ–‡† ‹–‘ ˆ‹œ‡”Ȍǡ Šƒ• ‡˜‡” ƒ’’Ž‹‡† ˆ‘” Ž‹…‡…‡• ˆ‘” ƒ› ‰›ƒ‡…‘Ž‘‰‹…ƒŽ ‘”

‘„•–‡–”‹…‹†‹…ƒ–‹‘ǡ†‡•’‹–‡–Š‡ƒ„—†ƒ–Ž‹–‡”ƒ–—”‡‘‹–••ƒˆ‡ƒ†‡ˆˆ‡…–‹˜‡—•‡‹–Š‡•‡

ˆ‹‡Ž†•Ǥ Š‡ ”‡ƒ•‘ ‹• ’”‘„ƒ„Ž› –‘ ƒ˜‘‹† ’‘–‡–‹ƒŽŽ› †ƒƒ‰‹‰ ’—„Ž‹…‹–› …‘…‡”‹‰ –Š‡

†”—‰ǯ• ’”‘’‡”–‹‡• ƒ• ƒ ƒ„‘”–‹‘Ǧ‹†—…‹‰ †”—‰Ǥ^ͳͲͻ ‹•‘’”‘•–‘Ž ‹• …‘–”ƒ‹†‹…ƒ–‡† ‹

’”‡‰ƒ–™‘‡ǡ‘”–Š‘•‡™‹•Š‹‰–‘„‡…‘‡’”‡‰ƒ–ǤŠ‡ƒ„•‡…‡‘ˆ”‡‰‹•–”ƒ–‹‘ˆ‘”‹–•

‘„•–‡–”‹…ƒŽƒ†‰›ƒ‡…‘Ž‘‰‹…ƒŽƒ’’Ž‹…ƒ–‹‘•‹•ƒ‹’‘”–ƒ–’”‘„Ž‡ǤŠ‡’Šƒ”ƒ…‡—–‹…ƒŽ

‹†—•–”› ‹• ‘”ƒŽŽ› ”‡•’‘•‹„Ž‡ ˆ‘” ‹ˆ‘”‹‰ ’Š›•‹…‹ƒ• ƒ„‘—– †”—‰•ǯ ‹†‹…ƒ–‹‘•ǡ

‡ˆˆ‡…–‹˜‡‡••ǡ ƒ† …‘””‡…– †‘•ƒ‰‡•ǡ ”‘—–‡ ‘ˆ ƒ†‹‹•–”ƒ–‹‘ǡ †‘•ƒ‰‡ ‹–‡”˜ƒŽǡ …‘–”ƒ‹†‹…ƒ–‹‘•ǡ’”‡…ƒ—–‹‘•ǡ•‹†‡‡ˆˆ‡…–•ƒ†ƒƒ‰‡‡–‘ˆ…‘’Ž‹…ƒ–‹‘•Ǥ‘™‡˜‡”ǡ

ƒ•‹•‘’”‘•–‘Ž‹•‰‡‡”ƒŽŽ›‘–”‡‰‹•–‡”‡†ˆ‘””‡’”‘†—…–‹˜‡Š‡ƒŽ–Š‹†‹…ƒ–‹‘•ǡ–Š‡‹†—•–”›

Šƒ•‡‹–Š‡”’”‘˜‹†‡†–Š‹•‹ˆ‘”ƒ–‹‘ˆ‘”’Š›•‹…‹ƒ•‘”’ƒ…ƒ‰‡†–Š‡†”—‰‹ƒ’’”‘’”‹ƒ–‡

†‘•‡•ǤŠ‡”‡•—Ž–‹•–Šƒ––Š‹•†”—‰‹•—•‡†‹ƒ›†‹ˆˆ‡”‡–™ƒ›•ƒ……‘”†‹‰–‘‹ˆ‘”ƒŽ

Ž‘…ƒŽ’”‘–‘…‘Ž•Ǥ^ͳͳͲ

ƒ—ƒ”›ʹͲͲ͸ǡˆ‹œ‡”•–‘’’‡†•‡ŽŽ‹‰›–‘–‡…“‹‡”ƒ›™‹–Š‘—–’”‹‘”‘–‹…‡Ǥ

Š‡‘ˆˆ‹…‹ƒŽ”‡ƒ•‘‰‹˜‡„›–Š‡…‘’ƒ›™ƒ•–Šƒ–‹•‘’”‘•–‘Ž™ƒ•ƒ‘—–†ƒ–‡†–”‡ƒ–‡–

”‡‰‹‡ƒ†‘Ž‘‰‡”Dz•–ƒ–‡‘ˆ–Š‡ƒ”–dzǤŠ‡…‘’ƒ›ƒŽ•‘•–ƒ–‡†–Šƒ––Š‹•†‡…‹•‹‘™ƒ•

Ž‹‹–‡†–‘‡”ƒ›Ǥ‘™‡˜‡”‹–‹•‘™–Šƒ–ˆ‹œ‡”ȋƒ†ˆ‘”‡”Ž›Šƒ”ƒ…‹ƒƒ†‡ƒ”Ž‡Ȍ

™‡”‡—Šƒ’’›™‹–Š–Š‡—•‡‘ˆ›–‘–‡…“‹Ȁ›Ǥ–‹•‘’‡–‘•’‡…—Žƒ–‹‘Š‘™—…Š

–Š‹•™‹–Š†”ƒ™ƒŽ‹•ƒ™ƒ›–‘‰‡–”‹†‘ˆ–Š‡’”‘†—…–ƒ†™Š‡–Š‡”‘”‘–‘–Š‡”…‘—–”‹‡•™‹ŽŽ

ˆ‘ŽŽ‘™Ǥ^ͳͳͳ