Mechanisms Controlling Corpus Luteum Regression

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 ChPA2A2 P A2A2 E2E2 E2E2 A: Antrum; GL: Granulosas; BM; Basement Memb TI: Theca Int. TE: T Ext.; C: Capillaries Ch: Cholesterol; P: Progesterone; A 2 : Endrogen; E 2 : Estradiol 17  -HSD P450scc 3  -HSD Arom LH FSH P450scc 3  -HSD

Luteal Steroidogenesis 17  -HSD Ch P A2A2 E2E2 Arom 17  -HSD Ch P A2A2 E2E2 Arom Ch: Cholesterol; P: Progesterone; A 2 : Endrogen; E 2 : Estradiol (Some Species) Large Luteal Cells Small Luteal Cells P450scc 3  -HSD P450scc 3  -HSD

Regulation of Corpus Luteum Function SpeciesLuteotrophic Complex HumanLH SheepLH & GH PigEstradiol 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 luteum secrets progesterone? For how long the corpus luteum secrets progesterone?

Estrogen Progesterone The Corpus Luteum is a Ephemeral Gland

Duration of Luteal Function Across Species Physiological Review 79:263 Weeks Days/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?

A New Beginning 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 Hysterectomy Intact AnimalHysterectomized Animal Progesterone

Effects of Hysterectomy on the Activity of the Corpus Luteum

Unilateral Effect of Hysterectomy 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?

SalinePGF 2  Progesterone Concentration ug./g of Tissue Effect of Prostaglandin F 2  Infusion on the Concentration of Progesterone in Ovaries of Pseudopregnant Rats Pharris and Wyngarden Proc. 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 F 2  Administration on the Duration of the Luteal Phase Ewe Administered In the Ovarian Artery Administered Systemically PGF 2  must be transferred from a uterine horn to its adjacent ovary. Luteal Phase Progesterone How PGF 2  is locally transported ?

Uterus-Ovary Connection Ewe Ovarian Artery

Countercurrent Transfer Mechanism Nature 1972

Does PGF 2  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 Cows Aim: 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 F 2  I’m not in the mood. Bulls, Bulls, Bulls !!!!!!! Why PGF 2  can be used to Synchronize Estrus in Cows?

PGF 2  and Estrus Synchronization of Cows PGF 2 

Mechanism of Luteolytic Action of PGF 2  Bovine Pate & Keyes 2001

The Pregnant Rat Corpus Luteum

Progesterone Day of Pregnancy PRL LH D-PRL PL A A E A E P Regulation of Rat Corpus Luteum during Pregnancy PGF 2 

Sugimoto et al. Science, 1997) Days of pregnancy Serum Progesterone (ng/ml) +/+ PGF 2  R-/- PGF 2  R Parturition Failure of Parturition in Mice Lacking the Prostaglandin F 2  Receptor Which mechanism uses PGF 2  to decrease progesterone secretion in rat at the end of pregnancy?

Days of pregnancy Steroids Levels (ng/ml) Progesterone 20  dihydro Progesterone  -HSD L19 mRNA levels PGF 2  Prostaglandin F 2  increases 20  HSD expression 20  -HSD

20  -Hydroxysteriod Dehydrogenase 20  -HSD, A New Player Progesterone 20  -dihydroprogesterone NADPHNADP H3CH3C O O H3CH3C OH 20  -HSD

Western Blot 20  -Hydroxysteriod Dehydrogenase Expression is Repressed 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  ProteinmRNA HYPOX 20  -Hydroxysteriod Dehydrogenase Expression is Inhibited by Prolactin Albarracin and Gibori. Endocrinology :1821.

PGF 2  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 :1. Luteolysis: A Neuroendocrine-Mediate Event. Physiological Reviews :263. The Corpus Luteum of Pregnancy,G Gibori. In The Ovary. Ed. EY Adashi and PCK Leung P The Corpus Luteum and Its Control in Infraprimate Species. In The Physiology of Reproduction. Ed. E Knobil and JD Neill P. 781