Sam Mesiano, Phd

Anti-Inflammatory Actions of Progesterone

Sam Mesiano, PhD

Department of Reproductive Biology Case Western Reserve University I have NO conflicts of interest

Department of Ob/Gyn related to the presented material MacDonald Women’s Hospital University Hospitals of Cleveland

Progesterone: Historical Perspective Progesterone Actions

Progesterone Implantation - secretory endometrium Pregnancy - establishment, maintenance HOW? Lactation - preparation of lactation

Born: Secretions from the Behavior - reproduction PROGESTERONE ACTIONS PROGESTIN THERAPY CL protect the early embryo and promote pregnancy Ovary - ovulation Amenorrhea Progestins Corner & Allen: Isolated Cyproterone acetate Norethisterone Uterus - pregnancy Infertility/Pregnancy loss “progestin” from rabbit CL Demegestone Medroxyprogesterone acetate Prenant: CL is an organ Endometriosis Desogestrel Mifepristone Breast - lactation of internal secretion Butenandt: progestin is a Dienogest Nesterone Drospirenone Nomegestrol acetate Fibrocystic mastopathy Δ4-keto-steroid - named it Brain - reproductive behavior “progesterone” Dydrogesterone Norgestimate Ethynodiol diacetate Norgestrinone Leiomyoma Gestodene Promegestone Immune system - suppression Levonorgestrel Trimegestone Premenstrual syndrome De Graff: CL is Schering AG: associated with the P4 derivatives Endometrium protection 17OHPC presence of a fetus Micronized Progesterone Menopausal symptoms

1672 1898 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020 Progesterone/PR Signaling ProgesteroneWorking Model Blocks Labor

Progesterone Progesterone

PR PR

PPR R

mRNA Protein Phenotype

PPR R Pro-Labor PRE Stimuli

ProgesteroneWorking Model Withdrawal Triggers Labor Progesterone/PR Signaling in Pregnancy

Progesterone Progesterone

PRP R

QUIESCENT Pro-Labor PRP Stimuli R Pro-Inflammatory Drivers of Parturition Progesterone/PR Signaling in Pregnancy

Pro-labor/Pro-inflammatory Pro-labor/Pro-inflammatory Stimuli Stimuli Progesterone

PRP R NFκB NFκB LABOR

PGs QUIESCENT P4 Block

Tissue-Level PRP NFκB Inflammation NFκB R

κB Site IL-8 κB Site IL-8 PTGS2 PTGS2 IL-6 IL-6

Functional P4/PR Withdrawal Systemic Progesterone Withdrawal

Mifepristone 500.0 Birth Pro-labor/Pro-inflammatory RU486 Human Rat Birth Stimuli Progesterone Progesterone Progesterone

100.0 Estradiol Functional Progesterone Withdrawal 50.0 • During most of pregnancy the uterus is 0 4 8 12 16 20 24

PR Birth responsive to progesterone.

Progesterone Sheep 10.0• At parturition(non -thepregnant) uterus becomes refractory

PRP 5.0 to progesterone. R NFκB LABOR Estradiol

0 20 40 60 80 100 120 140 (ng/mL) UnconjugatedSteroid 1.0

PGs Birth 0.5 ER/PR Kd

Tissue-Level NFκB Estradiol Inflammation (non-pregnant) 0.1 κB Site IL-8 Rabbit PTGS2 0 4 8 12 16 20 24 28 32 36 40 IL-6 0 5 10 15 20 25 30 35 Gestational Age (weeks) Functional P4/PR Withdrawal Nuclear PRs

Pro-labor/Pro-inflammatory Parturition Stimuli Progesterone Trigger

PRP 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 Stimulus Progesterone Stimuli Progesterone Parturition Trigger

NFκB PR-A PR-B PR-B PR-A

PR-A PRP-B R PRP-B PR-A R NFκB PR-A-mediated functional P4 withdrawal

PR-A PRP-B R

IL-8 NFκB PTGS2 LABOR NFkB PRP-B IL-6 R κB Site IL-8 PTGS2 IL-6 Inflammation-Induced P4 Withdrawal HormonalWorking ControlModel of Parturition

Pro-inflammatory Stimulus Progesterone Progesterone

NFκB Kinase PR-A PR-B PRs

P PR-A PRP-B P R Anti- Inflammatory

P PR-A PRP-B P R

IL-8 PTGS2 Stress/Inflammation NFkB PRP-B IL-6 R

HormonalWorking ControlModel of Parturition Working Model - Pro-Labor Inflammatory Load

Progesterone

Threshold Limited PRs

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

Anti-inflammatory SPRMs SPRM Therapy to Prevent Preterm Birth

LPS-Induced Mouse Parturition F - F F - - Birth

pa pe an SPRM Cl - - - -

Vehicle P4 RU486 A A A 3 5 3, 4 3, 3,4,5 or LPS LPS Vehicle (30 µg) pSer345-PR SPRM: A-pa (2 mg) PR-B PR-A Vehicle 8 7 PR 6 PR-B Progesterone 5 PR-A 4 3 # of Births

2 2/5 GAPDH Estradiol 1

0 3/10 6/10 7/10 4/10 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 specific SPRMs Aberrant PR Demegestone Phosphorylation? Desogestrel Dienogest Progesterone Pathologies Drospirenone Physiology/ Amenorrhea Dydrogesterone Ser Pathology Infertility/Pregnancy loss Ethynodiol diacetate Kinase Endometriosis Gestodene P Levonorgestrel Fibrocystic mastopathy Norethisterone Ser Leiomyoma Medroxyprogesterone acetate Premenstrual syndrome Highest frequency of aa Micronized progesterone Endometrium protection divergence Mifepristone Nesterone Phenotype Menopausal symptoms Nomegestrol acetate Norgestimate Norgestrinone Promegestone Trimegestone

Acknowledgements

Lab Team (present) Collaborators Rachel Wilson CWRU Carlos Padilla Charles Malemud Callista Pascarella Greg Tochtrop Jessica Thorpe Focco van den Akker Angela DeTomasso Wendy Goodman

Alumni Other Zack Stanfield Louis Muglia (Cincinatti) Peyvand Amini Mark Johnson (London) Huiqing Tan Steven Yellon (Loma Linda) Lijuan Yi Yelenna Skomorovska-Prokvolit Greg Peters Junye Wang

Ohio Collaborative