Prostaglandins and Luteolysis

ANSC 631

EP1

Ca2+/IP3

EP2

cAMP

EP3a

cAMP

EP3b

cAMP

EP3c

cAMP

EP3d

cAMP/

EP4

cAMP

DP receptor

cAMP

IP receptor

cAMP

FPA,B receptor

Ca2+ + IP3

TP receptor

Ca2+ + IP3

Relaxant Receptors Constrictor Receptors

Ca2+ / IP3 or cAMP

Nuclear receptor

PPARPPARPPAR

IP3

cAMP

COOH

COOH

COOH

OH

PGI2

PGD2 PGE2 PGF2

PGH2 TxA2

PGG2

PGI Synthase TX Synthase

PGD Synthase PGE Synthase PGF Synthase

COOH

Arachidonic Acid(5, 8, 11, 14-eicosatetraenoic acid)

COOHO

O

Cox-1 Cox-2

9-keto-PGEreductase

OH

O

O

OH

OHOH

OH

COOH

OHOH

O

COOH

OHO

OH

O

O

COOHO

O

OH

20

1917131211

1415 16 1810

98

7 4 2

356

Cox-1 Cox-2

PhospholipidscPLA2

PGDHPGFMPGEM

PGDH

Pregnancy inhibits endometrial production of

luteolytic PGF2 pulses in ewes

Subluteolytic

Luteolytic

Temporal and tissue-specific expression of prostaglandin

receptors

PGE: EP2, EP3, EP4 (not expressed in cow)

PGF: FP

Cyclooxygenases 1 and 2 in uterus and fetal membranes

Corpus Luteum of Ewes

Small Luteal Cells

• No secretory granules

• Little RER

• P4, pg/cell/min – 2+1

• cAMP stimulates P4- 551%

• LHCGR/cell – 33,260

• FP/cell – 2115

• FP Kd – 409 X 10

Large Luteal Cells

• Secretory granules

• Abundant RER

• P4, pg/cell/min – 42+30

• cAMP stimulates P4 -68%

• LHCGR/cell – 3,074

• FP/cell – 68,143

• FP Kd 17 X 10

Corporal Lutea of Pigs

• FP/cell

– Days 6-11: Mean of 740,000

– Days 12-16: Mean of 2,850,000

EP/cell: Days 6-11: Mean of 900

Days 12-16: Mean of 11,000

Luteotrophic Agents: Stimulate

Secretion of Progesterone

• Prolactin:

– Increases P4, Pregnenolone (P5) and 3 beta HSD,

but decreases 20 alpha hydroxylase

• LH:

– Increases P4, 20 alpha hydroxylase, P5, 3B HSD

• Beta 2 Adrenergic Receptor Agonist

(Epinephrine)

– Increases P4, P5 and 3B HSD, but decreases 20

alpha hydroxylase

CHOLESTEROL TO PREGNENOLONE: PROLACTIN, LH AND BETA

AGONIST ARE STIMULATORY

PREGNENOLONE TO PROGESTERONE: PROLACTIN, LH AND BETA

AGONIST ARE STIMULATORY

P4 TO 20 ALPHA HYDROXY P4: LH AND GnRH ARE STIMULATORY,

BUT PROLACTIN AND BETA AGONISTS ARE INHIBITORY

CHOLESTEROL PREGNENOLONE P4

20 ALPHA

HYDROXY P4

Meidan R, Levy N. Endothelin-1 receptors and biosynthesis

in the corpus luteum: molecular and physiological

implications. Domest Anim Endocrinol. 2002;23:287-298

Endothelin-1 (ET-1)

21-amino acid peptide identified as a potent vasoconstrictor

inhibits steroidogenesis in vitro and in vivo

compliments luteolytic effects of PGF2 alpha

ET-1 receptors type A (ETA

ET-1 gene is transcribed as prepro ET-1 (ppET-1)

Active form of ET-1 derived from inactive intermediate big ET-

1 by endothelin-converting enzyme-1 (ECE-1)

CL responsive to PGF2 alpha only when both ppET-1 and ECE-

1 genes are expressed for uninterrupted ET-1 biosynthesis.

Luteolytic Effects of PGF2alpha

Vasocontriction of blood vessels to CL

Inhibition of LHCGR and STAR Expression and Steroidogenesis

Recruitment of Immune Cells and Cytokines that Induce Cell Death

Endothelin Compliments PGF by Inhibiting Steroidogenesis and Acting as Vasoconstrictor