Progesterone

1
Progesterone Prevention of Preterm Delivery

• Michael Paidas, M.D.
• Associate Professor
• Co-Director, The Yale Blood Center for Women and
  Children
• Department of Obstetrics, Gynecology
  Reproductive Sciences
• Yale University School of Medicine
• Food and Drug Administration
• Advisory Committee for Reproductive Health Drugs
• August 29, 2006

2
Preterm Delivery

• PTD and Low birth weight represent the leading
  cause of infant mortality
• PTD Rate Over 12 in USA, and rising
• Cost 13.6 billion dollars in 2001
• No effective Treatment, but antenatal steroids
  will reduce prematurity complications
• Progesterone as a prevention

3
17- alpha-Hydroxyprogesterone (250mg) IM Weekly
from 16-206 wk reduces recurrent PTD (RCT Double
blind, 21 ratio)Progesterone Group N
310 Placebo N 153Meis PJ et al, NEJM 2003
348 2379-85
Outcome Progesterone N 306 Placebo N 153 Relative Risk (95 CI)
Del lt 37 wks 111 (36.3) 84 (54.9) 0.66 (0.54- 0.81)
lt37w, Black 64 (35.4) 47 (52.2) 0.68 (0.51-0.90)
lt37w, non-B 47 (37.6) 37 (58.7) 0.64 (0.47-0.87)
Del lt35 wks 63 (20.6) 47 (30.7) 0.67 (0.48-0.93)
Del lt 32 wks 35 (11.4) 30 (19.6) 0.58 (0.37- 0.91)
4
Meis et al, New England Journal of Medicine, 2003
Outcome 17P Placebo RR 95 CI
BW lt2500 27.2 44.1 0.66 0.51-0.87
BW lt1500 8.6 13.9 0.62 0.36-1.07
NN death 2.6 5.9 0.44 0.17-1.13
IVH 1.3 5.2 0.25 0.8-0.82
NEC 0 2.6 NA NA
Suppl O2 14.9 23.8 0.62 0.42-0.92
RDS 9.5 15.1 0.63 0.38-1.05
5
Progestational Agents meta- analysis and
systematic reviewSanchez- Ramos et al. Obstet
Gynecol 2005 105 273-9
10 trials N 1,339 subjects PTD rate Prog v placebo Odds Ratio
PTD (lt37wks) ( need to Rx 10) 26.2 vs 35.9 OR 0.45 (95 CI 0.25-0.80)
17 P specifically 29.3 vs 40.9 OR 0.45 (95 CI 0.22-0.93)
BW lt2500g 20.3 vs 28.4 OR 0.50 (95 CI 0.36-0.71)
CONCLUSION The use of progestational agents and
17 alpha hydroxyprogesterone caproate reduced the
incidence of preterm birth and low birthweight
newborns.
6
ACOG Committee Opinion, Number 291 November,
2003

• Use of Progesterone to Reduce Preterm Birth
• Progesterone supplementation greatly reduces
  preterm birth in a select group of women
• Progesterone has been studied only as a
  prophylactic measure in asymptomatic women, not
  as a tocolytic
• More research needed for patients with other high
  risk factors
• Although a small study of vaginal suppositories
  supports its use, a larger study is needed.

7
Progesterone Actions

• Relaxation of myometrial smooth muscle
• Blocking action of oxytocin
• Inhibits formation of gap junctions
• Inhibits uterine prostaglandin production
• Inhibits T-Lymphocyte mediated processes
• Creates barrier to entry of pathogens into uterus
• Influences decidual cell hemostasis
• Blunts the increase in Interleukin -11 by
  Interleukin -I beta and thrombin.
• J Clin Endocrinol 2005 90(9) 5279

8

• PTD Pathogenesis
• Stress
• Infection
• Decidual hemorrhage
• Uterine distension

Decidual Hemorrhage
Extravasation of clotting factors
FVIIa/TF
CTX
FXa
Thrombin
uPA tPA
plasmin
2o infection (?)
Active MMPs
clot
ECM Degradation
contractions
rupture of membranes
cervical change
9
Thrombin induces decidual cell IL-8 expression
Thrombin has a role in neutrophil trafficking
Preterm

• IL-8 promotes infiltration of neutrophils into
  the decidua.
• Neutrophils are a rich source of proteases that
  degrade the extracellular matrix

Abruption
10
17-P Therapy Candidates

• At risk for spontaneous preterm delivery, i.e.,
  documented history of a previous spontaneous
  birth at less than 37 weeks GA
• Current pregnancy between 16-20 completed weeks
• Therapy continued until 36 completed weeks
  gestation

11
17P Safety

• 17P naturally occurring metabolite of
  progesterone
• Produced naturally in large quantities by
  placenta during pregnancy
• No androgenic activity
• Side effects Pain or irritation at the injection
  site, headache, dizziness, fatigue, depression,
  water retention, breakthrough bleeding.
  Precaution can affect carbohydrate metabolism
• Fetus Safe, according to extensive reviews

12
Limited Product Availability

• Currently no commercial mass-produced brand name
  or generic 17P (250 mg/ml) available on the
  market.
• Extensive experience with 17P
• Delalutin, Hylutin, Prolutinib Depot,
  Prodorox, Hydrogest
• Corporate availability will increase physician
  access to 17P

13

• Michael J. Paidas, M.D.
• Associate Professor
• Co-Director
• The Yale Blood Center for Women and Children
• Yale University School of Medicine
• 333 Cedar Street
• New Haven, Ct 06520-8063
• 203 785-7894
• Email michael.paidas_at_yale.edu