Pharmacodynamics Specific for progesterone

Biological activities - Receptor binding

Anti-androgenic effect

Anti-mineralocorticoid effect

Tranquilizing effect

Effect on endometrium

Effects on central nervous system

Vascular effects and body weight

Action on female breast

Main indications :
Luteal Phase Support (LPS)
Sub or infertility; ART- IVF, egg donation;
threatened abortion
Irregular bleeding, secondary amenorrhea, PMS
In Hormone Replacement Therapy (HRT)
Prevention of PreTerm Delivery (PTD)

ROLE OF PHYSIOLOGICAL PROGESTERONE

1. Norwitz ER et al. N Engl J Med 2001; 345: 1400-8

2. Lovely LP et al. J Clin Endocrinol Metab 2005; 90: 2351-6

ROLE OF PHYSIOLOGICAL
PROGESTERONE

1.

Norwitz ER et al. N Engl J Med 2001; 345: 1400-8

3. Druckmann R et al. J Steroid Biochem Mol Biol 2005; 97: 389-96
4. Szekeres-Bartho J et al. Int Immunopharmacol 2001; 1: 1037-48
5. Fanchin R et al. Hum Reprod 2000; 15: 90-100
6. Perusqua M et al. Life Sci 2001; 68: 2933-44
7. Chanrachakul B et al. Am J Obstet Gynecol 2005; 192: 458-63
8. Liu J et al. Mol Hum Reprod 2007; 13: 869-74
9. Czajkowski K et al. Fertil Steril 2007; 87: 613-8
10. Schwartz N et al. Am J Obstet Gynecol 2009; 201: 211-9

PRETERM DELIVERY
BACKGROUND

Prevalence :
7 to 12% of pregnancies
Consequences :
Leading cause of neonatal morbidity and
mortality in developed countries
60 80 % of the deaths of infants without
congenital abnormality
1/3 of all health care spending on infants

Goldenberg R et al. Lancet 2008; 371: 75-84.

Simhan et al. N Engl J med 2007: 357: 477-487

Romero et al. Ultrasound Obstet Gynecol 2007; 30: 675 - 686

 30 40% association with underlying infective

process
40 50%: idiopathic !
other
genetic,
nutritional,
behavioral and other
environmental factors
Goldenberg R et al. Lancet 2008; 371: 75-84.

Pathological pathways
infection / inflammation
cervical factors
uteroplacental hypoxia /bleeding / thrombosis
uterine overdistension
mat & fetal endocrine / paracrine activation

Etiologic pathways leading to Preterm Birth

Preterm birth: pathogenesis

Before pregnancy
genetic
ethnic groups
age

During pregnancy
stress and hormones
cervical insufficiency

reproductive system
uterine overdistension
diseases
maternal medical
utero-placental ischemia
disorders
Inflammation / infection
environmental factors
and epigenetics
previous preterm
delivery

premature myometrial
activation
premature cervical
ripening
premature rupture of
membranes

Preterm birth

Efficacy in prevention
Progesterone
Antibiotics
Nutriments (fish oil)
Lamont & Jaggat Expert Opin Investig Drugs 2007; 16 (3): 33745

MECHANISM OF ACTION
Progesterone promotes myometrial relaxation
Progesterone inhibits inflammatory responses associated
with preterm parturition

Prevention in high risk women

PROGESTERONE is given
prophylactically to prevent preterm
birth among women at increased risk

Meis et al, 2003. N Engl J Med

Da Fonseca et al, 2003. Am J Obstet Gynecol
Fonseca et al, 2007. N Engl J Med
Obrien et al, 2007. Ultrasound Obstet Gynecol
DeFranco et al, 2007. Ultrasound Obstet Gynecol
Rai et al, 2009. International Journal of Gynecology and
Obstetrics
Mahji et al, 2009. J Obstet Gynecol
Cetingoz et al, 2009. Arch Gynecol Obstet

Conclusion
In women with a short cervix, treatment with
progesterone* reduces the rate of spontaneous early
preterm delivery
(ClinicalTrials.gov number, NTC00422526)

The drug and placebo were purchased from the companies, which provided no financial
support and had no involvement in study design, data collection, data handling, data
analysis, study interpretation, the drafting of the manuscript, or the decision to publish

* Vaginal micronised progesterone 200 mg/d from 24 to 33

weeks 6 days of gestation every night before going to sleep
(UTROGESTAN)

Glover publication with oral mic. P4

caps

Glover M et al. Am J Perinatal 2011: 28(5): 377-381

Vaginal Mic.P4 capsules in twins

Secondary outcomes were complications for infants including long-term

follow-up by Ages and Stages Questionnaire (ASQ) at 6 and 18 months of
age.
Risks of maternal and neonatal complications were comparable for the two
treatments. Mean ASQ score at 6 and 18 months did not differ significantly
between the progesterone and the placebo group in any of the two high-risk
Rode L et al. Ultrasound Obstet Gynecol 2011; 38: 272-280
groups.
Klein K et al. Ultrasound Obstet Gynecol 2011; 38: 281287

PROGESTERONE is given prophylactically to prevent preterm

birth in women WITH AN ASYMPTOMATIC SONOGRAPHIC
SHORT CERVIX IN THE MIDTRIMESTER Meta-analysis
With Crinone Gel
OBrien et al, 2007. Ultrasound Obstet Gynecol
Hassan et al, 2011. Ultrasound Obstet Gynecol
With Utrogestan caps
Fonseca et al, 2007. N Engl J Med
Cetingoz et al, 2009. Arch Gynecol Obstet 2009
Rode et al, 2011. Ultrasound Obstet Gynecol
Romero R et al. Am J Obstet Gynecol 2012; 206: 124. e1-19.

SAFETY AND TOLERANCE

SAFETY AND TOLERANCE

SAFETY ISSUE FOR THE FETUS

Intragastral administration of Utrogestan
at the tested dose of 55 mg/kg (10-fold
higher than the human dose) to pregnant
rats at various stages of gestation had no
embryotoxicity or teratogenicity.
Literature search: progesterone did not
affect
maternal
weight,
embryo-fetal
Christian et al
J Matern Fetal Neonatal
Med 2007;
20 (2): 89-112b
viability or causes malformation.

Tocolytic effect of P4
Progesterone is utero-relaxing*
Oral Progesterone metabolites
anxiolytic and hypnotic
tocolytic
* Fanchin
R et al. Hum Reprod 2000; 15(1): 90-100

Pharmacokinetics of Natural Progesterone

Oral and Vaginal route
Oral route:
Rapid absorption
50% to 60% of the dose is absorbed
Plasma concentration with food
Steady-state plasma concentrations are rapidly reached after
the second dose of oral micronized Pg
Vaginal route:
Lower Cmax compared with the oral administration
The mean t1/2 values were similar
More constant blood levels during nycthemera
Higher blood level at steady-state compared with oral route
of administration

Oral versus Vaginal route of

administration
Specific benefits and indications may be expected
from the 2 routes of administration:
Oral route: effect on CNS (mood and sleep disturbance)
Postmenopausal women
Stress during pregnancy
Women with anxiety in PMS
Vaginal route: endometrial secretory changes without
detectable influence on CNS

European Guidelines
1. Prior history of PTB in asymptomatic
women
(prophylaxis 200 mg vaginal P4 since
early
2nd trim)
2. Silent cervical shortening (15 mm) in
single pregnant
3. In nulliparous women in single
pregnant successfully treated for a
PTL as maintenance tocolysis,
reduced rate in PTD.
(400 mg vaginal P4)
Further studies required
4. Maternal safety of micronized
progesterone has been reported in
several trials.
Di Renzo GC et al. J Matern Fetal Neonatal Med 2011; Early Online: 19. 2011 Informa UK, Ltd.
DOI: 10.3109/14767058.2011.553694

Effect of vaginal progesterone

on preterm birth before 33 weeks of gestation

CONCLUSION: Vaginal progesterone administration to

asymptomatic women with a sonographic short cervix reduces the
risk of preterm birth and neonatal morbidity and mortality.
Romero R et al. Am J Obstet Gynecol 2012; 206: 124. e1-19.

Adverse effects of vaginal vs intramuscular

progesterone administration

Vaginal progesterone
Side effects
Vaginal discharge
Vaginal pruritus
Nausea & vomiting
Intramuscular progesterone
Bruises at site of injection
pruritus at site of injection
Nausea & vomiting
Hot flushes

Number
(n=80)
8
4
2
Number
(n=80)
12
10
6
6

El-Gharib et al. J Matern Fetal Neonatal Med 2013; 26(7): 716-719

Percentage
10,0%
8,0%
2,5%
Percentage
15,0%
10,0%
7,5%
7,5%

TOCOLYTIC EFFECT OF PROGESTERONE

Mechanism of action

Progesterone is utero-relaxing
Oral Progesterone metabolites has:
anxiolytic and hypnotic effects
tocolytic effects

Fanchin R et al. Hum Reprod 2000; 15(1): 90-100

PROGESTERONE PLASMA
& TISSUE LEVELS
400 mg of micronized progesterone
administered per os immediately prior
elective cesarean section
Measure of the levels of Pg in plasma,
placenta and myometrium
Significant in progesterone in plasma
and in myometrium 150 min after
administration
No modification in placenta concentration
F.Ferre et al. Am J Obstet Gynecol 1984; 148: 26-34

Effects of nifedipine or indomethacine

with and without P4
on myometrial contratility

P < 0.5
P < 0.5

Nifedipine

AUC = Area Under contractions Curve

Baumbach J et al. Am J Obstet Gynecol 2012; 206: 254.e1-5

Indomethacine

Dodd, JM et al. Coch Data Syst Rev.2013, Issue 7. DOI: 10.1002/14651858.CD004947.pub3.

No differential effects in terms of route of administration, time of

commencing therapy and dose of progesterone for majority of outcomes
examined.
Further trials are required to assess the optimal timing, mode of
administration and dose of administration of progesterone therapy when
given to women considered to be at increased risk of early birth.
Dodd, JM et al. Coch Data Syst Rev.2013, Issue 7. DOI: 10.1002/14651858.CD004947.pub3.

MAIN RESULTS
N=
8523 women
N = 12,515 infants

36 RCTs included

Progesterone vs placebo for women with a past history of sPTB

6 studies

N =1453

RR 0.50

[95% CI 0.33 to 0.75)]

5 studies
10 studies

N = 602
N =1750

RR 0.31
RR 0.55

[95% CI 0.14 to 0.69)]

[95% CI 0.42 to 0.74)]

4 studies

N = 692

RR 0.58

[95% CI 0.42 to 0.79)]

Perinatal mortality
Preterm birth < 34 weeks
Preterm birth < 37 weeks
Infant birth weight < 2500 g

3 studies
N = 633
RR 0.40
[95% CI 0.18 to
3 studies
N =1170
RR 0.30
[95% CI 0.10 to
6 studies
N =1453
RR 0.45
[95% CI 0.27 to
3 studies
N = 389
RR 0.24
[95% CI 0.14 to
significant reduction
1 study
N= 148
MD** 4.47 [95% CI 2.15 to
Statistically significant increase in pregnancy prolongation weeks

Use of assisted ventilation

Necrotizing enterocolitis
Neonatal death
Admission to NICU
Statistically

0.90)]
0.89)]
0.76)]
0.40)]
6.79)]

* NICU=Neonatal Intensive Care Unit

** MD=Mean Difference

Dodd, JM et al. Coch Data Syst Rev.2013, Issue 7. DOI: 10.1002/14651858.CD004947.pub3.

MAIN RESULTS
Progesterone vs placebo for women with a short cervix identified on TUS
Preterm birth < 34 weeks
Preterm birth < 28 weeks

2 studies
2 studies

N=438
N=1115

RR 0.64
RR 0.59

[95% CI 0.45 to 0.90)]

[95% CI 0.37 to 0.93)]

Statistically significant reduction

It was not possible to assess the effect of route of progesterone administration,

gestational age at commencing therapy, or total cumulative dose of medication.

Progesterone vs no treatment/placebo for women following presentation

with threatened PTL
Infant birth weight < 2500 g
1 study
N = 70
Statistically significant reduction

RR 0.52

[95% CI 0.28 to 0.98)]

Progesterone versus placebo for women with other risk factors for
preterm birth
Infant birth weight < 2500 g
3 studies
N = 482
Statistically significant reduction

RR 0.48

[95% CI 0.25 to 0.91)]

Dodd, JM et al. Coch Data Syst Rev.2013, Issue 7. DOI: 10.1002/14651858.CD004947.pub3.

AUTHORS CONCLUSION
The use of progesterone is associated with benefits in infant
health following administration in women considered to be at
increased risk of preterm birth
due either to a prior preterm birth or
where a short cervix has been identified on ultrasound
examination.

Limited information relating to longer-term infant and

childhood outcomes, the assessment of which remains a
priority.
Further trials are required to assess the optimal timing, mode
of administration and dose of administration of progesterone
therapy when given to women considered to be at increased
risk of early birth.
Dodd, JM et al. Coch Data Syst Rev.2013, Issue 7. DOI: 10.1002/14651858.CD004947.pub3.

CONCLUSION (1)
The efficacy of progesterone in high risk patient for
preterm delivery was clearly demonstrated:
In case of single pregnancy and/or
Antecedent of spontaneous preterm delivery
and/or
A short cervix (< 25 mm at week 20th-22nd)
Vaginal Micronized Progesterone is the most used
formulation, even if optimal administration route or
daily dose are not definitively known
More studies are mandatory in other groups of high
risk patients (twins,)

CONCLUSION (2)

The role of progesterone in the physiopathology of pregnant

women is crucial from conception until delivery.
There is strong biological plausibility to support exogenous
progesterone for the management of prevention of preterm
birth in women at risk with a short cervix and/or a history of
preterm delivery.
The optimal dose, route of administration and duration
remains to be determined in symptomatic women and in
pregnancy maintenance after tocolysis.
Neonatal effects, health infant and cost-effectiveness with
vaginal micronized progesterone will be addressed in the
OPPTIMUM trial (level 1 of evidence).