The Role of the foetal adrenal glands in the mechanism of initiation of parturition in the ewe

(1)

http://researchspace.auckland.ac.nz ResearchSpace@Auckland

Copyright Statement

The digital copy of this thesis is protected by the Copyright Act 1994 (New Zealand).

This thesis may be consulted by you, provided you comply with the provisions of the Act and the following conditions of use:

• Any use you make of these documents or images must be for research or private study purposes only, and you may not make them available to any other person.

• Authors control the copyright of their thesis. You will recognise the author's right to be identified as the author of this thesis, and due acknowledgement will be made to the author where appropriate.

• You will obtain the author's permission before publishing any material from their thesis.

To request permissions please use the Feedback form on our webpage.

http://researchspace.auckland.ac.nz/feedback

General copyright and disclaimer

In addition to the above conditions, authors give their consent for the digital copy of their work to be used subject to the conditions specified on the Library Thesis Consent Form.

(2)

PH'LSON LI8N,.RY, 5C'JOCL

Jvll\rUL Of y,;rlClNF

PARK _ROAD,AUCKLAND.

THE ROLE

of the

FOETAL ADRENAL GLANDS

in the

MECHANI SM

of

INITIATiON

of

PARTURITION

in the

E IUE

GRAHAM COLLINGIUOOD LIGGINs

Postgraduate SchooI of 0bstetrics and Gynaecology The University of Auckland.

Thesis submitted for the Degree of Doctor of Philosophy

September,

¹969.

PHILS . , R.o, y

S,. ~ ,

,,""I{.JJ OF f'''r~._ICfNr-

PARK ROAD, AUCK

AND .

THE ROLE

of the

FOETAL ADRENAL GLANDS

in the

mECHANIsm

of INITIATION

of

PARTURITION

in the EWE

GRAHAm COLLINGWOOD LIGGINS

Postgraduate School of Obstatrics and Gynaecology The University of Auckland.

Thesis submitted for the Degre8 of Doctor of Philosophy

September, 1969.

(3)

T A B L T O F ,C

O

II T E N'T

5

Psqs

R c rn cituu EDG E filEN,Ts

PREFACE

sufnrilARY

INTRODUCTION

taa'

aaa

aa.a

Length..

eaa ata

.ar

2

? 7 7

I

Factore Influen,c.i,ng Gastation GenEtLc Lnfluencera

Envj.sonmo,ntiI inf lueneeg The aax of thE foetus

The

ttleehanlem

of Inttiati,on of . The Pjsrgeet€aonei bloek

The Frogeet,enone-0eatrogen The 0xytocln theory

The 9erotonln tlreory Fro'etaglandLna

U'terlne volune

The foetal contrlbtrtlon

SEOPE OF THE TTIESIS

Itlumb.er

andi ei.ze o? foetuceb

. r,.

1'g 11

PErturltlon

aaa

rati,ro theoBy

taa

,laa

al.

aaa

14 14 22 26 31 55

!7

41

60 TAB LEO F .C 0 N TEN T S

ACKNOWLEDGEMENTS PREFACE

SUMMARY 2

INTRODUCTION

factors Influencing Gestation Length .•

Genetic influences

Environmental influences The sex of the foetus

Number and size of foetuses

. . .

7 7 7 9 10 1 1 The Mechanism of Initiation of Parturition

The Progesterone block

The Progesterone-Oestrogen ratio theory The Oxytocin theory

The Serotonin theory Prostaglandins

Uterine volume

The foetal contribution SCOPE OF THE THESIS

14 14 22 26 31 33 37 41 .

50

(4)

.TTIE EXP.ERItilIENTS

l,mpalnme,n,t

of FEetel Adrenal.

^Fun:c'tion

tsl.Latpral foetel. edrenaleetomy r.

^ir

lllatarl,als

a,nd

mEthods

^{,.,. .}

Paqe 62 52 52

9,2

56 59 59 63 65 65 59

Funetlon

⁷²

7Z

,12 .?4

cortl,aol,

⁷⁸

,79

.79

Rerults ...

ttimuL.at,ion ot Augma.ntatlen of

^Adranatr

EffEcte of admlnistrstl.on of

nCTll

Re,sultE

. . .

Foetal hypophyeectony

lllaterlals and

methods REa,uLte .

),

Sectlon of foatatr pituitary

lllat,eriels and

metho,da

fllateriatrs and

methods

Reeu-.ltE

r

r.

Th'e effeeta of adninieteati,on ftlaterialq and

^mothode

Reeulta r..

fllaterisla and rrethsde !,

^.

aa l

raa

.lr ra

aat

stalk.

a aa aaa

fa

aa

of,

al aa

Inveatlgatlorr of the

^mode

of aet.lon of

Ogf

tleOe'teEOj,dg ,.. t

^{. .,.}

Comp,arlson sf gluc'ocortieoidg

and

mineraloeortieoid8... ...

81

8,.1

Reeults ...

82 THE EXPERIlYlENTS

Impairment of Foetal Adrenal Function Bilateral foetal adrenalectomy

lYlaterials and methods Results ••.

52 52 52 52 56 Foetal hypophysectomy

lYlaterials and methods Results

• • • 59

59 63 Section of foetal pituitary stalk.

lYlaterials and methods

65 65

Resul ts •••

· ..

⁶⁹

Stimulation or Augmentation of Adrenal Function 72 Effects of administration of ACTH 72

lYIaterials and methods 72

Results

...

⁷⁴

The effects of administration of cortisol 78

lYlaterials and methods 78

•

Results

.. . · ..

⁷⁹

Investigation of the mode of action of

corticosteroids •••

Comparison of glucocorticoids and minaralocorticoids •••

81

81 materials and methods

Resul ts •••

· ..

81 82

(5)

PaqE

Infuslons of oorti:costensne

ond

desoxycrortleo:Et€r:otte

(O0C )

Infusions of rn,ixturae of

dexamEt,haeone,

End

^DOC 85

0bseavationE on the, foetal, lunga ,..

af

lem,bE

infused uith

dexamethaBon6

The effect ,of Progesterona on t,he Action

of Dexanethaaon€ ,tr ..r

Matenials and

methods fal ao.a

The Effect of

^ACTH

on maternal progesterone trevelE and urinary oeetrogeh s'xerstisn

84

86

Re,eults

87 87 8g 91

The Effact of

Frogeete.Done

ffiechanism of

DexamE;thasone

on matsrna,l

levels ..,

Act'ion of

Dexameth,sBoFrBi . ^.

94

95

INVESTIGATtrOfiI OF hIYPOTHALIAInIC ^]CONTROI- RELEASE FRgtn THE FOETAL PITUITARY

,Ra,spsnss

tq

Hypogly,caemie

ltlaterielE and

methode

R EEUJ.

te

Respo'nae

to Fyrogan:

r r !

Illa'terial.E and

methods

OF ACTH

ta?

aaQ

ata

ftr

taa

aaq

98 9B 98 100

192 102

Beaponse to enzyme .i,nhibitose

¹⁰⁴

Infusions of corticosterone and

desoxycorticosterone (DOC) 84

Infusions of mixtures of dexamethasone and DOC 85 Observations on the foetal lungs

of lambs infused with dexamethasone

...

⁸⁶

The effect of Progesterone on the Action

of Dexamethasone 87

materials and methods 87

Results 88

The Effect of ACTH on maternal progesterone

levels and urinary oestrogen excretion 91

The Effect of Dexamethasone on maternal

Progesterone levels 94

mechanism of Action of Dexamethasone... 96

INVESTIGATION OF HYPOTHALAmIC CONTROL OF ACTH

RELEASE FRom THE FOETAL PITUITARY 98

Response to Hypoglycaemia 98

Results 100

Response to Pyrogen 102

Response to enzyme inhibitors 104

(6)

DISCUSSION

R EFERENCES PUBL I CATI ONs

APPENDIX ^A

APPENDIX B

Biochemical lflcthoda

Endocrine Evente Preeeeding Parturition in normal

^eu,es!

aaa

,,, The RoIe of the Foetal Hypothalamus and Pituitary

aaa

ata

taa

a

aaa

oa.

taa

Paoe

106 106

119

'121

12s 124

128 132 135 156 149

141 162

155 163 16s 167 168 169 170 111

The Role of the Foetal AdrEnal

115

Comparison of Glucocorticoids and fllineralocorticoids ...

Administration of

^{ACTH and}

Corticosteroids to

€ruBS. r .

Experiments in Tuin Pregnanci.es

Endoerine Ehanges in Induced Parturition Effect of Progesterone on

Dexamethasone-

induced Parturition

Rsgulation of Foetal Hypothalamic Function

Parturition at Term in Normal EueE ...

Implications in other species ,..

Hypothesis ..

^. ^oa ^a

Progoeterons

Assays

Progesterone Binding Progesterone llletabolism Oarttogen Assays ...

Reprint of a publication deecribing the effects of foetal hypophysectomy on subsequent groulth

and

deveJ.opmBnt. 0bservations on gestation Iength in

this group of experiments are included in the

^body

of the thesis.

DISCUSSION

Endocrine Events Preceeding Parturition in normal ewes

The Role of the Foetal Hypothalamus and Pituitary

The Role of the Foetal Adrenal Comparison of Glucocorticoids and Mineralocorticoids

Administration of ACTH and Corticosteroids to ewes •..

106 106 111 115

119 121 Experiments in Twin Pregnancies

, , ,

¹²³

Endocrine Changes in Induced Parturition Effect of Progesterone on Dexamethasone- induced Parturition

Regulation of Foetal Hypothalamic Function

124

128 132 Parturition at Term in Normal Ewes

Implications in other species Hypothesis

REFERENCES PUBLICATIONS

APPENDIX A

Biochemical methode

Progesterone Assays Progesterone Binding Progesterone metabolism Oestrogen Assays

APPENDIX B

, ..

· ..

135 136 140

141 162

163 163

167 168 169 170 Reprint of a publication describing the effects of foetal hypophysectomy on subsequent growth and development. Observations on gestation length in this group of experiments are included in the body of the thesis.

(7)

ACKNOII'LEDGEMENTS

I ruieh to express my appreciation oF the encoutagement

of my supervLsor, Professor D.E.

^Bonham

uho resolved satisfactorily the conflictlng.demands of clinical uork, teaching and the uork of

this theeis. The faeititi€s upon uhich

many

aepecte of the

investigations have been dependent ore the result of his foreeight

and energetic admlnistration.

The colJ.aboration of Profeseor P.E. Kennedy, School of Veterinary flledlcina, University of California, Davis, in the pathological

asprprcte

of the urork ie gratef uIly acknouledged.

Profeesor Louis Holn, aleo of the School of Veterinary Medlcine,

Davis, provided the initial stimulus to an experimental

investigation of the subject of the thesis by his obeervatione on naturally oceuDring prolonged gestation in cou,s. SubEequently

he gave material aesistance in the form of surgical facilities

and

expenimental animale.

Dr.

^R.4 .5

. lllelch and lllr.

Animal Research Station, have

been

possible to ruork in their surgical arranging supplies of experimental

H. Bishop of the

Ruakura

most

^genaDoua

in making it theatre at Ruakura and in animals.

The satisfactory progress of the experiments in the

Surgical Laboratory, National lllomenrs Hospltal, is attributable to the conscientious u,ork of several people. In particular the services of

^[YlD.

Tony Mekkelholt, technician-in-charge of the

Surgical Laboratory, because of his meticulous maintenance of standards in the operating theatre, his concern for the uelfare

of the animals and hie genuine interest in the progDess of the experiments, hae been of inestimable vaIue. The continuoue

supply of urell-conditioned

BUeE

ulith accurately dated pregnancies

A C K NOW LED GEM E N T S

I wish to express my appreciation of the encouragement of my supervisor, Professor D.G. Bonham who resolved satisfactorily the conflicting .demands of clinical work, teaching and the work of this thesis. The facilities upon which many aspects of the

investigations have been dependent ore the result of his foresight and energetic administration.

The collaboration of Professor P.C. Kennedy, School of Veterinary Medicine, University of California, Davis, in the pathological asp~cts of the work is gratefully acknowledged.

Professor Louis Holm, also of the School of Veterinary Medicine, Davis, provided the initial stimulus to an experimental

investigation of the subject of the thesis by his observations on naturally occurring prolonged gestation in cows. Subsequently he gave material assistance in the form of surgical facilities and experimental animals.

Dr. R.A.S. Welch and Mr. H. Bishop of the Ruakura Animal Research Station, have been most generous in making it possible to work in their surgical theatre at Ruakura and in arranging supplies of experimental animals.

The satisfactory progress of the experiments in the Surgical Laboratory, Notional Women's Hospital, is attributable to the conscientious work of several people. In particular the services of Mr. Tony Mekkelholt, technician-in-charge of the Surgical Laboratory, because of his meticulous maintenance of standards in the operating theatre, his concern for the welfare of the animals and his genuine interest in the progress of the experiments, has been of inestimable value. The continuous supply of well-conditioned ewes with accurately dated pregnancies

(8)

is testimony to the skill and inLerest of lllr. N.G. Holruell, of Kaukapakdpar

ruho

bred the sheep, and of [Ylr. H.A. llattam of the

Epsom

Shou Grounds ulho cared for them until they reached the

Surgical Laboratory.

The biochemical uork included in the theslE is entirely the ulork of others. I uish to thank lflr. 8.5.

Knox

for urinary oestrogen assays, lYlr. R. Couch and Dr. P. Rennie

Por progesterone assays and Mr. G.Carter for investigation of progesterone metabolism and binding.

Gifts of matorial from the follouing ;ouf,cBs at€

gratefully acknouledged: The Endocrine Study Group, National Institutes of Health, Bethesda, U.5.4. for ovine pituitary

hormones; Ciba Ltd.

f

or Synacthen and llletopirone; Burroughs

tUellcome Ltd.

^f

or CI. ruelchii toxin; lllerck Sharpe and

Dohme

Ltd. for cyanoketostoroid and British Drug Houses Ltd. for

p

rogesterone.

Financi.al asgistance

u,aa

given by The LsIor Foundation,

the Medical Research Distribution Committee from the

Golden

Kimi

Lo

ltery Funds and the

tUeIJ.come

Trust.

tlly eecretary, filrs.

^N.

Jenkin, in addition to typing the thesis ala6 contributed much to it in her vatious roles

^aa

surgical assistant, autopsy assistant, animal attendant

^and

general factotum. I

^am

extremely gDateful to her for her help.

.r .r

{'

The thasis is dedicated to my ulif e.

**.*

is testimony to the skill and interest of mr. N.G. Holwell, of Kaukapakapo, who bred the sheop, 8nd of mr. H.A. Wattam of the Epsom Show Grounds who cared for thom until they reached the Surgical Laboratory.

The biochemical work included in the thesis is entirely the work of others. I wish to thank mr. 8.S.Knox for urinary oestrogen assays, mr. R. Couch and Dr. P. Rennie for progesterone assays and mr. G.Carter for investigation of progesterone metabolism and binding.

Gifts of material from the following ;ources are

gratefully acknowledged: The Endocrine Study Group, National Institutes of Health, Bethesda, U.S.A. for ovine pituitary

hormones; Ciba Ltd. for Synacthen and metopirone; Burroughs Wellcome Ltd. for Cl. welchii toxin? merck Sharpe and Dohme Ltd. for cyanoketostoroid and British Drug Houses Ltd. for progesterone.

Financial aS3istance was given by The Lalor Foundation, the medical Research Distribution Committee from the Golden

Kiwi Lottery Funds and the Wellcome Trust.

my secretary, mrs.N.Jenkin, in addition to typing the thesis a166 contributed much to it in her various roles as

surgical assistant, autopsy assistant, animal attendant and general factotum. I am extremely grateful to her for her help.

* * *

The thesis is dedicated to my wife.

* * *