Anti-Inflammatory Actions of Progesterone Sam Mesiano, PhD I have - - PowerPoint PPT Presentation

Department of Reproductive Biology Case Western Reserve University Department of Ob/Gyn MacDonald Women’s Hospital University Hospitals of Cleveland

Anti-Inflammatory Actions of Progesterone

Sam Mesiano, PhD

I have NO conflicts of interest related to the presented material

1672 1898 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010

De Graff: CL is associated with the presence of a fetus Prenant: CL is an organ

• f internal secretion

Born: Secretions from the CL protect the early embryo and promote pregnancy Corner & Allen: Isolated “progestin” from rabbit CL Butenandt: progestin is a Δ4-keto-steroid - named it “progesterone” Schering AG: P4 derivatives 17OHPC

Progesterone: Historical Perspective

2020

Implantation - secretory endometrium Pregnancy - establishment, maintenance Lactation - preparation of lactation Behavior - reproduction

Progesterone

Micronized Progesterone

Cyproterone acetate Demegestone Desogestrel Dienogest Drospirenone Dydrogesterone Ethynodiol diacetate Gestodene Levonorgestrel Norethisterone Medroxyprogesterone acetate Mifepristone Nesterone Nomegestrol acetate Norgestimate Norgestrinone Promegestone Trimegestone

Progestins PROGESTERONE ACTIONS Ovary - ovulation Uterus - pregnancy Breast - lactation Brain - reproductive behavior Immune system - suppression

Progesterone Actions

PROGESTIN THERAPY Amenorrhea Infertility/Pregnancy loss Endometriosis Fibrocystic mastopathy Leiomyoma Premenstrual syndrome Endometrium protection Menopausal symptoms

HOW?

PR

P R

PR

P R

PR PR

mRNA

Progesterone

PRE

Progesterone/PR Signaling

Protein Phenotype

Progesterone Pro-Labor Stimuli

Working Model

Progesterone Blocks Labor

Progesterone Pro-Labor Stimuli

Working Model

Progesterone Withdrawal Triggers Labor

Progesterone

PR P R PR P R PR

QUIESCENT

Progesterone/PR Signaling in Pregnancy

NFκB

κB Site IL-8 PTGS2 IL-6

PGs Tissue-Level Inflammation

LABOR Pro-Inflammatory Drivers of Parturition

Pro-labor/Pro-inflammatory Stimuli

NFκB

κB Site IL-8 PTGS2 IL-6

Progesterone

PR P R PR P R PR

QUIESCENT

P4 Block

Progesterone/PR Signaling in Pregnancy

Pro-labor/Pro-inflammatory Stimuli

NFκB NFκB

κB Site IL-8 PTGS2 IL-6

Progesterone

PR P R PR

Pro-labor/Pro-inflammatory Stimuli Mifepristone RU486 PGs Tissue-Level Inflammation

LABOR Functional P4/PR Withdrawal

NFκB NFκB

Rat

20 24 20 4 8 12 16 24 Birth Progesterone Estradiol

Sheep

20 40 60 80 100 120 140 Birth

Rabbit

5 10 15 20 25 30 35 Birth

Systemic Progesterone Withdrawal

100.0 50.0 10.0 5.0 1.0 0.5 0.1 500.0 4 8 12 16 20 24 28 32 36 40

Gestational Age (weeks) Unconjugated Steroid (ng/mL) Estradiol Progesterone Birth

Estradiol (non-pregnant) Progesterone (non-pregnant) ER/PR Kd

Human

• During most of pregnancy the uterus is

responsive to progesterone.

• At parturition the uterus becomes refractory

to progesterone.

Functional Progesterone Withdrawal

κB Site IL-8 PTGS2 IL-6

Progesterone

PR P R PR

Pro-labor/Pro-inflammatory Stimuli Parturition Trigger PGs Tissue-Level Inflammation

LABOR Functional P4/PR Withdrawal

NFκB NFκB

Nuclear PRs

Transrepression

κB Site IL-8 PTGS2 IL-6

Progesterone

PR-B P R PR-B

Pro-labor/Pro-inflammatory Stimuli

PR-A PR-A

PR-A Trans-Repression Hypothesis

Parturition Trigger PR-A-mediated functional P4 withdrawal

NFκB NFκB

LABOR

Pro-inflammatory Stimulus

Progesterone

P R PR-B

NFκB IL-8 PTGS2 IL-6

P R PR-B PR-A PR-B PR-A PR-A P R PR-B NFkB

Inflammation-Induced P4 Withdrawal

Pro-inflammatory Stimulus

Progesterone

P R PR-B

NFκB IL-8 PTGS2 IL-6

P R PR-B PR-A PR-B PR-A PR-A P R PR-B NFkB

Inflammation-Induced P4 Withdrawal

P P P P

Kinase

Anti- Inflammatory

Progesterone Stress/Inflammation

Working Model

Hormonal Control of Parturition

PRs

Anti- Inflammatory

Progesterone Stress/Inflammation

Working Model

Hormonal Control of Parturition

PRs

Threshold Limited

Working Model - Pro-Labor Inflammatory Load

SPRMs

Selective PR Modulators (SPRMs)

P4 PR

Ser Ser P Ser P Physiology/ Pathology Kinase

Phenotype A

Control of pSer-PR by SPRMs

SPRM

Ser Ser

Phenotype B

P Physiology/ Pathology Kinase A-pa A-pe A-an 3-Cl 3, 5-F 3, 4-F 3,4,5-F RU486 P4 Vehicle pSer345-PR PR PR-B PR-A PR-B GAPDH PR-A

Anti-inflammatory SPRMs

2/5

1 2 3 4 5 6 7 8 13.5 14.5 15.5 16.5 17.5 18.5 19.5 # of Births Day of Pregnancy SPRM: A-pa (2 mg) Vehicle

3/10 6/10 7/10 4/10 LPS (30 µg) SPRM

• r

Vehicle

SPRM Therapy to Prevent Preterm Birth

LPS Birth Progesterone Estradiol

LPS-Induced Mouse Parturition

TERM

Highest frequency of aa divergence

PR Evolutionary Biology Progestin-Based Therapies

Progesterone Pathologies Amenorrhea Infertility/Pregnancy loss Endometriosis Fibrocystic mastopathy Leiomyoma Premenstrual syndrome Endometrium protection Menopausal symptoms

SPRMs

Cyproterone acetate Demegestone Desogestrel Dienogest Drospirenone Dydrogesterone Ethynodiol diacetate Gestodene Levonorgestrel Norethisterone Medroxyprogesterone acetate Micronized progesterone Mifepristone Nesterone Nomegestrol acetate Norgestimate Norgestrinone Promegestone Trimegestone Phospho-PR specific SPRMs

Ser Ser

Phenotype

P Physiology/ Pathology Kinase

Aberrant PR Phosphorylation? Lab Team (present) Rachel Wilson Carlos Padilla Callista Pascarella Jessica Thorpe Angela DeTomasso Alumni Zack Stanfield Peyvand Amini Huiqing Tan Lijuan Yi Yelenna Skomorovska-Prokvolit Greg Peters Junye Wang Collaborators CWRU Charles Malemud Greg Tochtrop Focco van den Akker Wendy Goodman Other Louis Muglia (Cincinatti) Mark Johnson (London) Steven Yellon (Loma Linda)

Ohio Collaborative

Acknowledgements