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

Anti-Inflammatory Actions of Progesterone Sam Mesiano, PhD I have NO conflicts of interest Department of Reproductive Biology Case Western Reserve University related to the presented material Department of Ob/Gyn MacDonald Women’s Hospital University Hospitals of Cleveland Progesterone: Historical Perspective Progesterone Actions Implantation - secretory endometrium Progesterone HOW? Pregnancy - establishment, maintenance Lactation - preparation of lactation Behavior - reproduction PROGESTERONE ACTIONS PROGESTIN THERAPY Born: Secretions from the CL protect the early embryo Ovary - ovulation Amenorrhea and promote pregnancy Progestins Infertility/Pregnancy loss Corner & Allen: Isolated Uterus - pregnancy Cyproterone acetate Norethisterone “progestin” from rabbit CL Demegestone Medroxyprogesterone acetate Prenant: CL is an organ Endometriosis Desogestrel Mifepristone Breast - lactation of internal secretion Dienogest Nesterone Butenandt: progestin is a Fibrocystic mastopathy Drospirenone Nomegestrol acetate Δ4-keto-steroid - named it Brain - reproductive behavior Dydrogesterone Norgestimate “ progesterone ” Leiomyoma Ethynodiol diacetate Norgestrinone Gestodene Promegestone Immune system - suppression Levonorgestrel Trimegestone Premenstrual syndrome Schering AG: De Graff: CL is P4 derivatives Endometrium protection associated with the 17OHPC presence of a fetus Micronized Progesterone Menopausal symptoms 1672 1898 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020

Working Model Progesterone/PR Signaling Progesterone Blocks Labor Progesterone Progesterone PR PR P PR R mRNA Protein Phenotype P Pro-Labor PR R Stimuli PRE Working Model Progesterone Withdrawal Triggers Labor Progesterone/PR Signaling in Pregnancy Progesterone Progesterone PR P PR R QUIESCENT Pro-Labor P PR Stimuli R

Pro-Inflammatory Drivers of Parturition Progesterone/PR Signaling in Pregnancy Pro-labor/Pro-inflammatory Pro-labor/Pro-inflammatory Progesterone Stimuli Stimuli PR P PR R NFκB NFκB LABOR PGs QUIESCENT P4 Block Tissue-Level PR P NFκB NFκB Inflammation R κB Site κB Site IL-8 IL-8 PTGS2 PTGS2 IL-6 IL-6 Functional P4/PR Withdrawal Systemic Progesterone Withdrawal Mifepristone Birth 500.0 Human Pro-labor/Pro-inflammatory RU486 Rat Progesterone Birth Stimuli Progesterone Progesterone 100.0 Functional Progesterone Withdrawal Estradiol 50.0 • During most of pregnancy the uterus is Unconjugated Steroid (ng/mL) 0 4 8 12 16 20 20 24 24 responsive to progesterone. PR Birth Progesterone • At parturition the uterus becomes refractory Sheep 10.0 (non-pregnant) to progesterone. P PR 5.0 R NFκB LABOR Estradiol 0 20 40 60 80 100 120 140 1.0 PGs Birth ER/PR Kd 0.5 Tissue-Level NFκB Estradiol Inflammation (non-pregnant) 0.1 Rabbit κB Site IL-8 PTGS2 0 4 8 12 16 20 24 28 32 36 40 IL-6 Gestational Age (weeks) 0 5 10 15 20 25 30 35

Functional P4/PR Withdrawal Nuclear PRs Pro-labor/Pro-inflammatory Parturition Progesterone Stimuli Trigger PR P PR R NFκB LABOR PGs Transrepression Tissue-Level NFκB Inflammation κB Site IL-8 PTGS2 IL-6 PR-A Trans-Repression Hypothesis Inflammation-Induced P4 Withdrawal Pro-inflammatory Pro-labor/Pro-inflammatory Progesterone Stimulus Progesterone Parturition Stimuli Trigger NFκB PR-A PR-B PR-B PR-A PR-A P PR-B R P PR-B PR-A R PR-A-mediated NFκB functional P4 withdrawal PR-A P PR-B R IL-8 PTGS2 NFκB LABOR IL-6 NFkB PR-B P R κB Site IL-8 PTGS2 IL-6

Working Model Inflammation-Induced P4 Withdrawal Hormonal Control of Parturition Pro-inflammatory Progesterone Stimulus Progesterone PRs NFκB Kinase PR-A PR-B P PR-A P PR-B P Anti- R Inflammatory P PR-A P PR-B P R Stress/Inflammation IL-8 PTGS2 IL-6 NFkB PR-B P R Working Model Hormonal Control of Parturition Working Model - Pro-Labor Inflammatory Load Progesterone Threshold PRs Limited Anti- Inflammatory Stress/Inflammation

Selective PR Modulators (SPRMs) Control of pSer-PR by SPRMs P4 SPRM SPRMs PR Physiology/ Physiology/ Ser Pathology Ser Pathology Kinase Kinase P P Ser Ser P Ser Phenotype A Phenotype B SPRM Therapy to Prevent Preterm Birth Anti-inflammatory SPRMs LPS-Induced Mouse Parturition Vehicle RU486 3,4,5-F Birth 3, 5-F 3, 4-F A-pa A-pe A-an SPRM 3-Cl P4 or LPS LPS Vehicle (30 µg) SPRM: A-pa (2 mg) pSer345-PR PR-B Vehicle PR-A 8 7 PR 6 Progesterone PR-B # of Births 5 PR-A 4 3 2/5 2 Estradiol GAPDH 1 3/10 6/10 7/10 4/10 0 13.5 14.5 15.5 16.5 17.5 18.5 19.5 Day of Pregnancy TERM

PR Evolutionary Biology Progestin-Based Therapies SPRMs Phospho-PR Cyproterone acetate Aberrant PR specific SPRMs Demegestone Phosphorylation? Desogestrel Progesterone Pathologies Dienogest Drospirenone Physiology/ Amenorrhea Ser Pathology Dydrogesterone Infertility/Pregnancy loss Ethynodiol diacetate Kinase Endometriosis Gestodene P Fibrocystic mastopathy Levonorgestrel Norethisterone Ser Leiomyoma Medroxyprogesterone acetate Premenstrual syndrome Micronized progesterone Highest frequency of aa Endometrium protection divergence Mifepristone Menopausal symptoms Nesterone Phenotype Nomegestrol acetate Norgestimate Norgestrinone Promegestone Trimegestone Acknowledgements Collaborators Lab Team (present) Rachel Wilson CWRU Carlos Padilla Charles Malemud Callista Pascarella Greg Tochtrop Focco van den Akker Jessica Thorpe Wendy Goodman Angela DeTomasso Alumni Other Louis Muglia (Cincinatti) Zack Stanfield Mark Johnson (London) Peyvand Amini Huiqing Tan Steven Yellon (Loma Linda) Lijuan Yi Yelenna Skomorovska-Prokvolit Greg Peters Junye Wang Ohio Collaborative