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 During pregnancy

genetic
stress and hormones premature myometrial
ethnic groups
activation
age cervical insufficiency

reproductive system premature cervical

uterine overdistension ripening
diseases
maternal medical utero-placental ischemia premature rupture of
disorders
membranes
environmental factors
Inflammation / infection Preterm birth
and epigenetics
previous preterm
delivery
Efficacy in prevention
Progesterone

Antibiotics

Nutriments (fish oil)

Lamont & Jaggat Expert Opin Investig Drugs 2007; 16 (3): 337-
45
 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
groups. Rode L et al. Ultrasound Obstet Gynecol 2011; 38: 272-280
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
Christian et al weight,
J Matern Fetal Neonatal embryo-fetal
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 Number

Side effects (n=80) Percentage
Vaginal discharge 8 10,0%
Vaginal pruritus 4 8,0%
Nausea & vomiting 2 2,5%
Number
Intramuscular progesterone (n=80) Percentage
Bruises at site of injection 12 15,0%
pruritus at site of injection 10 10,0%
Nausea & vomiting 6 7,5%
Hot flushes 6 7,5%

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

 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 Indomethacine

AUC = Area Under contractions Curve

Baumbach J et al. Am J Obstet Gynecol 2012; 206: 254.e1-5
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 36 RCTs included
N = 12,515 infants

Progesterone vs placebo for women with a past history of sPTB

Perinatal mortality 6 studies N =1453 RR 0.50 [95% CI 0.33 to 0.75)]

Preterm birth < 34 weeks 5 studies N = 602 RR 0.31 [95% CI 0.14 to 0.69)]
Preterm birth < 37 weeks 10 studies N =1750 RR 0.55 [95% CI 0.42 to 0.74)]

Infant birth weight < 2500 g 4 studies N = 692 RR 0.58 [95% CI 0.42 to 0.79)]

Use of assisted ventilation 3 studies N = 633 RR 0.40 [95% CI 0.18 to 0.90)]

Necrotizing enterocolitis 3 studies N =1170 RR 0.30 [95% CI 0.10 to 0.89)]
Neonatal death 6 studies N =1453 RR 0.45 [95% CI 0.27 to 0.76)]
Admission to NICU 3 studies N = 389 RR 0.24 [95% CI 0.14 to 0.40)]
Statistically significant reduction
1 study N= 148 MD** 4.47 [95% CI 2.15 to 6.79)]
Statistically significant increase in pregnancy prolongation weeks

* 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 2 studies N=438 RR 0.64 [95% CI 0.45 to 0.90)]
Preterm birth < 28 weeks 2 studies N=1115 RR 0.59 [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 RR 0.52 [95% CI 0.28 to 0.98)]
Statistically significant reduction

Progesterone versus placebo for women with other risk factors for
preterm birth
Infant birth weight < 2500 g 3 studies N = 482 RR 0.48 [95% CI 0.25 to 0.91)]
Statistically significant reduction

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).