Mechanisms Controlling Corpus Luteum Regression

Dr. DHIREN B. BHOI

M.V.Sc., (Gynaecology)

E. Mail:-drdhirenvet@gmail.com

The Cyclic Ovary

Corpus Luteum

Corpus Albican

Outline• Corpus luteum.

– Where it came from?– What it secretes?– Which is its function?– How it is regulated?

• Luteolysis– Why should the corpus luteum capitulate?– Who dare to kill it?– Mechanisms of murder.

• The rat corpus luteum of Pregnancy– Regulation.– Mechanisms of regression.

Corpus Luteum Formation: Luteinization

• Luteinization in the process that transforms the granulosa and theca cells into luteal cells.

• This process is triggered by the surge of LH at mid-cycle.

• The LH surge causes profound changes in the follicles that become corpora lutea.

LH surge

Primates

Structural Changes During Luteinization

A

GC

TC LC

BV

O

Steroidogenesis Before LH Surge

A

GL

BM

TI

TE

Ch P A2

Ch P A2 E2

E2

A: Antrum; GL: Granulosas; BM; Basement Memb TI: Theca Int. TE: T Ext.; C: Capillaries Ch: Cholesterol; P: Progesterone; A2: Endrogen; E2: Estradiol

17-HSD

P450scc3-HSD

Arom

LH

FSH

P450scc3-HSD

Luteal Steroidogenesis

17-HSDCh P A2 E2Arom

17-HSDCh P A2 E2Arom

Ch: Cholesterol; P: Progesterone; A2: Endrogen; E2: Estradiol

(Some Species)

Large Luteal Cells

Small Luteal Cells

P450scc3-HSD

P450scc3-HSD

Regulation of Corpus Luteum Function

Species Luteotrophic Complex

Human LH

Sheep LH & GH

Pig Estradiol

Pseudopreg. Rabbit

Estradiol, LH

Pseudopreg. Rat/Mouse

Estradiol, Prolactin & LH

Endocrine Effects of Progesterone

Contraction

and Secretion

Differentiation

and Secretion

Inhibits LH

and FSH Secretion

Lobuloalveolar

Development

For how long the corpus luteumsecrets progesterone?

For how long the corpus luteumsecrets progesterone?

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 281 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

EstrogenEstrogen

ProgesteroneProgesterone

The Corpus Luteum is a Ephemeral Gland

Duration of Luteal Function Across Species

Physiological Review 79:263

Weeks

Days/Weeks

Weeks

Weeks

Months

Luteolysis

• Luteolysis is the process by which the corpus luteum loses its capacity to synthesize and secrete progesterone.

• A luteolytic agent is any factor that can reduce luteal progesterone synthesis or secretion and/or prevent the action of a luteotrophic hormone.

Why mammals have developed mechanisms to curtail luteal function?Why mammals have developed mechanisms to curtail luteal function?

A New Beginning

Who is responsible for this decrease in CL function?Who is responsible for this decrease in CL function?

Progesterone inhibits LH and FSH Secretion

The Uterus Regulates the Life Span of the Corpus Luteum.

Luteal Phase Luteal Phase

Hysterectomy

1 10 20 1 10 20

Intact Animal Hysterectomized Animal

Pro

gest

eron

e

Pro

gest

eron

e

Effects of Hysterectomy on the Activity of the Corpus Luteum

Unilateral Effect of Hysterectomy

How can you explain these results?How can you explain these results?

There is a local transfer of a luteolytic hormone from one uterine horn and its adjacent ovary

The hormone released from one uterine horn is prevented from reaching the ovary on the contralateral side

The question is the identity of this factor?The question is the identity of this factor?

10

0

15

5

Saline PGF2

Pro

gest

eron

e C

once

ntr

atio

nu

g./g

of

Tis

sue

Effect of Prostaglandin F2 Infusion on the Concentration of Progesterone in Ovaries of

Pseudopregnant Rats

Pharris and WyngardenProc. Soc. Exp. Biol Med 1969:130:92

•It is abundant in the uterus.

•It has a short half-life in

circulation.

•It decreases progesterone.

Effect of Prostaglandin F2Administration on the Duration of the Luteal Phase

Ewe

AdministeredIn the Ovarian Artery

AdministeredSystemically

PGF2must be transferred from a uterine horn to its adjacent ovary.PGF2must be transferred from a uterine horn to its adjacent ovary.

Luteal PhaseLuteal Phase

Pro

gest

eron

e

Pro

gest

eron

eHow PGF2 is locally transported ?How PGF2 is locally transported ?

Uterus-Ovary Connection

Ewe

Ovarian

Artery

Countercurrent Transfer Mechanism

Nature 1972

Does PGF2 Fulfill the Role of Uterine Luteolytic Factor?

• It is produced by the uterus at the moment of luteolysis.

• Its administration causes premature luteolysis.

• It is transported from the uterus to the ovary by a countercurrent mechanism (not in all species).

Estrus Synchronization of CowsAim: To breed a high percentage of females in a short period of time

using artificial or natural insemination.

A Practical Application of the Luteolytic Effect of Prostaglandin F2

I’m not in the mood.

Bulls, Bulls, Bulls !!!!!!!

Why PGF2 can be used to Synchronize Estrus in Cows?

Why PGF2 can be used to Synchronize Estrus in Cows?

PGF2 and Estrus Synchronization of Cows

PGF2

Mechanism of Luteolytic Action of PGF2

BovinePate & Keyes 2001

The Pregnant Rat Corpus Luteum

1 6 12 21

Progesterone

Day of Pregnancy

PRL LH

D-PRL PL A

AE

A

E

P

Regulation of Rat Corpus Luteum during Pregnancy

PGF2

Sugimoto et al. Science, 1997)

0

10

20

30

40

50

Days of pregnancy17 19 2117 19 21

Ser

um

Pro

gest

eron

e(n

g/m

l)

+/+ PGF2R -/- PGF2R

Par

turi

tion

Failure of Parturition in Mice Lacking theProstaglandin F2 Receptor

Which mechanism uses PGF2 to decrease progesterone secretion in rat at the end of pregnancy?

Which mechanism uses PGF2 to decrease progesterone secretion in rat at the end of pregnancy?

0

50

100

150

200

250

Days of pregnancy

Steroids Levels(ng/ml)

Progesterone

20dihydroProgesterone

18 19 20 21 22

20-HSD

L19mRNA levels

PGF2

Prostaglandin F2 increases 20HSD expression

20-HSD

20-Hydroxysteriod Dehydrogenase20-HSD, A New Player

Progesterone 20-dihydroprogesterone

NADPH NADP

H3C

O

O

H3C

OH

20-HSD

Western Blot

20-Hydroxysteriod DehydrogenaseExpression is Repressed During Pregnancy

Now, who is responsible for this repression in the expression of 20-HSD during pregnancy?

Now, who is responsible for this repression in the expression of 20-HSD during pregnancy?

Wiest, et al and Gibori et al.

PRL

20

Protein mRNA

HYPOX

20-Hydroxysteriod DehydrogenaseExpression is Inhibited by Prolactin

Albarracin and Gibori. Endocrinology 1991 129:1821.

PGF2

20-HSD mRNA

Regulation of 20-HSD Expression in Rat Corpus Luteum

?

PRL

Recommended Reading

• Mechanisms Controlling the Function and Life Span of the Corpus Luteum. Physiological Reviews. 2000 80:1.

• Luteolysis: A Neuroendocrine-Mediate Event. Physiological Reviews. 1999 79:263.

• The Corpus Luteum of Pregnancy,G Gibori. In The Ovary. Ed. EY Adashi and PCK Leung. 1994 P. 261.

• The Corpus Luteum and Its Control in Infraprimate Species. In The Physiology of Reproduction. Ed. E Knobil and JD Neill. 1993. P. 781