Animal Science 434

Lecture 11: The Luteal Phase of theEstrous and MenstrualCycle

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2

4

6

8

10

12

14

0 2 4 6 8 10 12 14 16 18 20 22

Day of the Estrous Cycle

Lute

olys

is

P4Production(Diestrus)

CLFormation(Metestrus)

Rela

tive

Prog

este

rone

Lev

els

(Blo

od)

Folli

cula

r Pha

se

Luteal Phase

Ovulation Ovulation

• steroid synthesis– progesterone

• collagenase– theca interna

• present 1-3 daysfollowing ovulation

• blood vessels infollicle wall rupture

• walls collapse

• cells intermix

• old basementmembrane becomesconnective tissue ofCL

• increases in size– papilla forms

• composed of cellsfrom the granulosaand theca interna

• progesteroneproductionincreases

• a small cavity maybe present wherethe folliclularantrum waspresent

Luteal Tissue

• Large cells from granulosa

• Small cells from the theca interna

Mitochondria

SecretoryGranules

- Oxytocin- Relaxin

Functional Capability of CL• the number of luteal cells– large cells undergo hypertrophy (3 fold)– small cells undergo hyperplasia (5 fold)

• vascularization of CL– Initiated by angiogenic factors from

follicle– Vascularity effects CL steroid synthesis

and delivery of hormones• Insufficient CL function– Failure to maintain pregnancy– Important in domestic animals

Progesterone TargetsAveolar

Development

Blocks EstrusNegative Feedback

Molecular Mechanism of LH on Luteal Cell

Receptor

PKA

NucleusDNA

Histones

Protein Synthesis(Enzymes) mRNA

Plasma Membrane

(cAMP second messenger)(cAMP second messenger)

Cholesterol

GAdenylate Cyclase

C

RcAMP

LH

ATP cAMP

(+ PO4)

R-ERProtein Synthesis

MitochondriaCholesterolPregnenolone

S-ERSteroid Synthesis

Progesterone

Molecular Mechanism of LH on Luteal Cell

Receptor

PKA

Protein Synthesis(Enzymes)

Plasma Membrane

(cAMP second messenger)(cAMP second messenger)

Cholesterol

GAdenylate Cyclase

C

RcAMP

LH

ATP cAMP

(+ PO4)

R-ERProtein Synthesis

MitochondriaCholesterolPregnenolone

S-ERSteroid Synthesis

Progesterone

CholChol

LDLLDL

CholChol

LDLLDL

Chol-EsterChol-Ester

LDLLDLChol

Esterase

Luteolysis

• Uterus• PGF2α• Oxytocin

Luteolysisin Cows,

Ewes,Sows

TotalHysterectomy

IpsilateralHysterectomy

ContralateralHysterectomy

NormalUterus

CLCL Normal LifespanCL Normal Lifespan

CL Normal LifespanCL Normal Lifespan CL LifespanLonger

CL LifespanLonger

CL LifespanLonger

CL LifespanLongerSimilar to

Gestation Length

>35 days

Luteolysis

• Uterus• PGF2α• Oxytocin

Prostaglandin F2α Control of LuteolysisProgesterone fromCL stimulatesproduction of uterine PGF2α afterday 15 in cow

Uterine Horn

UterineVein

Prostaglandin synthesisby uterine endometriumis released into the uterine vein.

Oviduct

Ovary

CorpusLuteum

PGF2α is picked up by ovarian artery through counter current exchangeand delivered back to theovary where it causeslysis of the CL

Uterine Artery

Ovarian Pedicle

PGF

PGF into Artery

LuteolysisMare

TotalHysterectomy

IpsilateralHysterectomy

ContralateralHysterectomy

NormalUterusCL

CL NormalLifespan

CL NormalLifespan

50% of CL’sMaintained50% of CL’sMaintained

CL MaintainedCL Maintained

50% of CL’sMaintained50% of CL’sMaintained

Blood Supply to Uterus and Ovary in the Mare

PGF Not Effective (Cow, Ewe, Mare)PGF Not Effective (Cow, Ewe, Mare)

PGF Not Effective (Sow)PGF Not Effective (Sow)

Luteolysis

• Uterus• PGF2α• Oxytocin

Relationship of Oxytocin and PGF2α

Uterus

Ovary

CL

PGF2α

AnteriorPituitary

PosteriorPituitary

Oxytocin

Luteolysis

• decreased blood flow

• cellular response– apoptosis– progesterone synthesis

• Immune response– Lymphocytes– Macrophages

Molecular Mechanism of PGF (Ca2+ Second Messenger)

Molecular Mechanism of PGF (Ca2+ Second Messenger)

PLC

PIP2

Endoplasmic Reticulum

Ca2+

Protein Kinase C

Plasma Membrane

PGFR

ecep

tor

G-proteinDAG

IP3

R Ca2+

PlasmaMembrane

Ca2+

R

PIP2

CholesterolCholesterol

ProgesteroneProgesteroneApoptosis

Luteolysis

• decreased blood flow

• cellular response– apoptosis– progesterone synthesis

• Immune response– Lymphocytes– Macrophages

Menstrual Cycle FSHLH

Estradiol

Progesterone

FollicleOvulation

Corpus LuteumCorpus

Albicans

2 4 6 8 10 14 16 18 20 22 24 26 28 212

AnteriorPituitary

Hormones

OvarianHormones

Ovary

UterineEndo-

metrium

RecruitmentSelection DominanceRecruitment

Luteolysis in the Primate• Does not require the uterus• CL lifespan in the human is 12-14 days

unless pregnancy occurs– In the absence of pregnancy, CL self destructs– Possible intra-ovarian oxytocin receptors and

PGF2α production• Menstruation– Drop in P4 and E2– Endometrial PGF2α, vasoconstriction, necrosis– Endometrial inflammation and tissue

degeneration

Manipulating Ovulation

• Hormonal induction of ovulation– PGF2α– GnRH– Progestins

• Superovulation– FSH– eCG

Principle of PGF2α UsePrinciple of PGF2α Use

• Regress active corpus luteum– Only effective on a day 5 - 17 CL– Not effective on days:

1 - 4 (CL not responsive)18 - 21 (CL already regressed)

Induction of Ovulation with PGF2α

Ovulation

Folli

cula

r Siz

e

Day After Ovulation9 16 21

Dominance

Recruitment

Selection

OvulationProgesterone

Induction of Ovulation with PGF2α

Ovulation

Folli

cula

r Siz

e

Day After Ovulation9 16 21

ProgesteroneInduction of Ovulation with PGF2α

Ovulation

Folli

cula

r Siz

e

Day After Ovulation9 16 21

Progesterone

PGF2α

Induction of Ovulation with PGF2α

Ovulation

Folli

cula

r Siz

e

Day After Ovulation9 16 21

Progesterone

PGF2α

7Days

36 - 48hours

GnRH PGF2α

8 - 18 hoursTimed AITimed AI

GnRH

Eliminatecurrentfollicular

wave

Ovsynch

Luteolysis Ovulates dominantfollicle

Induction of Ovulation with PGF2α

Ovulation

Folli

cula

r Siz

e

Day After Ovulation9 16 21

Dominance

Recruitment

Selection

OvulationProgesterone

Induction of Ovulation with PGF2α

Ovulation

Folli

cula

r Siz

e

Day After Ovulation9 16 21

Progesterone

GnRH

Induction of Ovulation with PGF2α

Ovulation

Folli

cula

r Siz

e

Day After Ovulation9 16 21

Progesterone

GnRH

Induction of Ovulation with PGF2α

Ovulation

Folli

cula

r Siz

e

Day After Ovulation9 16 21

Progesterone

GnRH

PGF2α

Induction of Ovulation with PGF2α

Ovulation

Folli

cula

r Siz

e

Day After Ovulation9 16 21

Progesterone

GnRH

PGF2α

GnRH

AI

7Days

36 - 48hours

GnRH PGF2α

8 - 18 hoursTimed AITimed AI

GnRH

Eliminatecurrentfollicular

wave

Ovsynch

Luteolysis Ovulates dominantfollicle

Principle:

Maintain the cow under the influence of progesterone untilcorpus luteum regresses, remove progesterone -animal respond to progesterone with estrus and ovulation2-5 days later.

Administration:

• Injection

• Feed

• Implant

• Pessary or Control Internal Drug Release (CIDR)

Use of Progestogens

This does not regress the CL!!!!

Progestens Effect on OvulationOvulationOvulation

Estru

s

ProgesteroneFrom C.L.

ProgesteroneFrom C.L.

Estru

s

17 210

OvulationOvulation

Follicular WaveFollicular Wave Follicular WaveFollicular Wave Follicular WaveFollicular Wave

Progestens Effect on OvulationOvulationOvulation

Estru

s

ProgesteroneFrom C.L.

ProgesteroneFrom C.L.

Estru

s

17 210

OvulationOvulation

Follicular WaveFollicular Wave Follicular WaveFollicular Wave Follicular WaveFollicular Wave

Estru

s

Estru

s

17 210 FollicularWave

FollicularWave

FollicularWave

FollicularWave

FollicularWave

FollicularWave

P4 from CLP4 from CLP4 from CIDR

Remove CIDR

Ov.Ov.

Stimulating FollicularDevelopment

OvulationOvulationEs

trus

ProgesteroneFrom C.L.

ProgesteroneFrom C.L.

eCGor

FSH

eCGor

FSH

Estru

s

MultipleOvulations

MultipleOvulations

17

Estru

s

Estru

s

eCG orFSH

eCG orFSH

First FollicularWave

First FollicularWave

10-12

PGF2α