Download Progesterone - Gynae Fertility

Dr. Eeson Sinthamoney
MD (Mal), MRCOG (London), DFFP (UK)
Fellowship in Reproductive Medicine (UK/Singapore)
Consultant Obstetrician, Gynaecologist & Fertility Specialist
Pantai Hospital Kuala Lumpur
1.
2.
3.
4.
Recurrent miscarriages – definition,
causes and role of progesterone
Threatened miscarriages –
definition, prognosis and role of
progesterone
Immunological basis – progesterone
role
Summary & conclusion
Is there or isn’t there a role
for progesterone therapy in
patients with recurrent
miscarriage and threatened
miscarriage?
 Up
to 50% of them will have no identifiable
reason
 The need to be evidence-based in investigation
and management
 Evidence is a moving target!
 In the unexplained group, up to 75% have a
term live birth with TLC alone
Three or more
consecutive
pregnancy losses
occurring before 24
weeks of gestation
Royal College of Obstetricians and Gynaecologists
Guideline 17 – The investigation and treatment of couples
with recurrent miscarriage. May 2003
ASRM 2008
definition



Based on the assumption that prevalence of
possible causes will be different in those with 2
compared to those with ≥3 miscarriages
No such difference found!
However, this increases scale of the problem
from 1% to 5% of couples trying to conceive
Habayeb Om, Konje JC. The one-stop recurrent miscarriage clinic: an evaluation of its
effectiveness and outcome. Human Reproduction 2004;19:2952-8
Hogge WA et al. the clinical use of karyotyping spontaneous abortions. Am J Obstet
Gynaecol 2003;189:397-400
Jaslow CR et al. Diagnostic factors identified in 1020 women with two versus three or
more recurrent pregnancy losses. Fertil Steril. 2009
Causes
Cause
n
Prothrombotic state
54
Chromosomal anomaly
11
Uterine anomaly
53
Polycystic ovaries
13
Retarded endometrium
54
Unexplained
188
Unknown
79
Total
452
Li TC et al. Pattern of pregnancy loss in women with recurrent
miscarriages after referral, according to diagnostic criteria. Fertility and
Sterility.2002;78(5):1100-1106
Causes
1.
2.
3.
4.
5.
Genetic factors
Anatomical factors
Polycystic ovarian syndrome
Bacterial vaginosis
Antiphopholipid antibody
syndrome
✔
1.
2.
3.
4.
✖
TORCHES
Diabetes
Thyroid disorders
Autoimmune
disorders
Progestrone
Aspirin
Heparin
Steroids
hCG
?
1.
2.
3.
4.
5.
6.
Do we assess all couples for genetic
causes?
How do we prepare PCO patients preconceptually?
In patients without APL antibodies, does
empherical aspirin or heparin help?
What about other thrombophilias?
How do we assess for anatomical
defects?
Finding and treating BV
a.
b.
c.
d.
LPD was first described by Jones in
1949
as a clinical entity, it has been poorly
characterised
conflicting evidence on LPD
exogenous progesterone
supplementation remains a common
intervention for both threatened and
idiopathic recurrent miscarriages



No evidence to support the routine use of
progesterone in the first trimester to
prevent miscarriage
However, subgroup analysis of women with
RM showed a statistically significant
decrease in miscarriage rate compared to
placebo or no treatment
The route of treatment did not influence the
results
Haas DM et al. Progestogen for preventing miscarriage. Cochrane Database Syst
Rev. 2008
Give progesterone in recurrent
miss-carriers especially in
idiopathic cases
 However, no evidence to support
routine use in first trimester to
prevent miscarriage
 Role in threatened miscarriage?

 A threatened miscarriage is defined as
vaginal bleeding, usually painless, that
occurs in the first 24 weeks in a viable
pregnancy without cervical dilatation.
 It is common, especially in the first
trimester, occurring in 14%–21% of all
pregnancies
 Important causes include chromosomal
abnormalities, which occur in about 70%
of the cases
 Prognosis
of threatened miscarriage with
expectant management:
-Gestational age: 29% of foetuses presenting
at 5–6 weeks, 8.2% at 7–12 weeks and 5.6% at
13–20 weeks, miscarried
-Severity of bleed: those who had active
fresh bleeding (excluding spotting), and a
viable foetus at presentation (average
gestation period was 8 weeks), the
miscarriage rate was 9.3%.
Basama FM, Crosfill F. The outcome of pregnancies in 182 women with threatened
miscarriage. Arch Gynecol Obstet 2004; 270:86-90.
Johns J, Jauniaux E. Threatened miscarriage as a predictor of obstetric outcome.
Obstet Gynecol 2006; 107:845-50
Conclusion: Corpus luteal support with dydrogesterone has
been shown to reduce the incidence of pregnancy loss in
threatened abortion during the first trimester in women
without a history of recurrent abortion.
 What
role does progesterone play in
maintaining a successful pregnancy?
 Therefore, based on sound scientific
understanding is there adequate
justification to give our threatened
miscarriage patients progesterone?
Successful mammalian pregnancy
depends upon tolerance of a
genetically incompatible fetus by
the maternal immune system.
Immunology
– back to
basics
macrophages
General responce
granulocytes
Secondary responce
Type 1/Cellular
T cells
Differentiate into Th1 and Th2
lymphocytes, which secrete different
types of IL and IFN
Type 2/ Humoral
antibodies
 Medawar’s
‘fetal allograft’ hypothesis 1953:
Fetal survival was d/t anatomical separation
of fetus, antigenic immaturity of fetus and
immunological inertness of mother (high
steroids)
 Medawar-shwartzman paradox
 Tolerance
is now
believed to depend
in part on the
interactions of
cytokines secreted
by maternal and
fetal cells at the site
of implantation.
Fetal-Maternal Interface
An inflammatory
response with
predominant proinflammatory Th1
cytokines is necessary
for initial implantation
with invasion of
trophoblasts and
induction of
angioneogenesis.
Fetal-Maternal Interface
Keleman K, Paldi A, Tinneberg H, Torok A, Szekeres-Bartho J: AJRI
1998; 39: 351-355
But thereafter the
potential detrimental
effects of the
pro-inflammatory
response are
counteracted by
anti-inflammatory
cytokines (TGF-B2)
involving a Th1 to Th2
shift.
Fetal-Maternal Interface
 Th-1
cytokines (TNF-, IFN-, IL-2, IL-12, Il18) induce several cell-mediated cytotoxic
and inflammatory reactions
 Th-2 cytokines (IL-4, IL-5, IL-6, IL-10, IL-13)
are associated with B cell antibody
production
 Th-2 cytokines downregulate Th-1-type
reactivity.
Shift towards TH-2 response, resulting in:
Anti-inflammatory cytokines > pro-inflammatory cytokines
“IMMUNOMODULATION”
Progesterone ?
 When
antigens on trophoblast are
recognized, peripheral blood lymphocytes
and CD56+ cells in decidua develop specific
progesterone receptors
 If sufficient progesterone present  these
cells produce a protein called Progesterone
Induced Blocking Factor (PIBF)
 PIBF is the pivotal mediator in progesterone
dependent immunomodulation*
DH Munn et al. Prevention of allogenic foetal rejection by tryptophan
catabolism. Science 281 (1998) 1191-93
 Induces
increased production and
predominance of Th2 cytokines.
 Downregulates expression of the
prothrombinase fgl2.
Szekeres-Bartho J, Wegmann T: J Reprod Immunol 1996; 31: 81-95.
6
5
4
3rd TRIMESTER
PRETERM DEL.
7
ABORTION
8
NON PREGNANT
RECEPTOR + CELLS %
9
1st TRIMESTER
10
2nd TRIMESTER
Progesterone Receptors
3
2
1
0
Szekeres-Bartho J et al. Lymphocytic progesterone receptors in normal and pathological human pregnancy.
J Reprod Immunol. 1989 Dec;16(3):239-47
1.Does PIBF really modulate the immunological
reaction towards a Th-2 bias in pregnancy?
Effects of PIBF on selected type 1 and type 2 cytokines
secretion from peripheral blood mononuclear cells from:
30 women with unexplained RSM
18 women undergoing PTD
11 women normal pregnancy
13 healthy non pregnant women
type 2 cytokines significantly increased in pregnant
groups, with Th-2 bias but did not effect nonpregnant women
Raghupathy R et al. Progesterone –induced blocking factor (PIBF) modulates cytokine production by
lymphocytes from women with recurrent miscarriage or preterm delivery. J reprod Immunology 80 (2009)
91-99
2. PIBF and cytokine levels in normal versus
threatened miss-carriers
30 women with threatened miscarriage
20 healthy pregnant women, 6-24 weeks
Serum + urine PIBF, IL10, IL6, TNF, IFN measured
1. PIBF concentration in urine and serum of threatened
miss-carriers significantly lower than in healthy pregnant
women
2. Threatened miss-carriers significantly lower serum levels
of anti-inflammatory cytokines and higher proinflammatory cytokines than healthy controls
Hudic I et al. Progesterone-induced blocking factor (PIBF) and Th(1)/Th(2) cytokine
in women with threatened spontaneous abortion. J Perinat Med. 2009;37(4):338-42
3. Does progesterone treatment make a
difference on hormone profile?
27 women with threatened miscarriage treated
for 10 days with dydrogesterone
16 healthy pregnant controls, no treatment
Serum P4 and E2 levels and urine PIBF measured
1. Serum progesterone in controls increased as pregnancy
progressed but not threatened cases
2. PIBF in threatened cases initially low, significantly
increased after treatment, reaching normal healthy control
levels
Kalinka J et al. The impact of dydrogesterone supplementation on hormonal profile and
progesterone-induced blocking factor concentrations in women with threatened abortion. Am J
Reprod Immunol. 2005 Apr;53(4):166-71
Does dydrogesterone change the type of
cytokines produced?
30 women with unexplained RSM
Peripheral blood mononuclear cells (PBMC) from
venous blood stimulated with
phytohaemagglutinin (PHA)
IFN-, TNF-, IL-4,IL-6,IL-10 and PIBF measured
Dydrogesterone significantly inhibited the
production of the Th1 cytokines IFN-,TNF- and
induced an increase in the levels of the Th2
cytokines IL-4 and IL-6 resulting in a substantial shift
in the ratio of Th1/Th2 cytokines
Raghupathy R et al. Modulation of cytokine production by dydrogesterone in lymphocytes from women
with recurrent miscarriage. BJOGAugust 2005, Vol. 112, pp. 1096–1101

Medroxyprogesterone
Has androgenic and anabolic effects
Early case report linking first trimester use to CAH in a male
neonate (1969)
Later and larger studies showed no association
FDA – category X – contraindicated if are / may become pregnant

17-hydroxyprogesterone caproate
Reports of fetal genital abnormalities and virilization (Cochrane
2003)
Recent evidence – reduces PTD risk when given from 16 weeks
onwards (NEJM 2003)

Dydrogesterone
No androgenic effects
No reports of fetal abnormalities except one when used together
with 17OHPC (1977)
Summary
-Inhibition of
NK cell
activity
-Asymmetric,
pregnancy
protecting
a/b
-Th2 bias
Immunological recognition of pregnancy
Up-regulation of progesterone receptors on NK cells in
decidua / lymphocytes amongst placental cells
In presence of sufficient progesterone, activated lympocytes
and decidual CD56+ cells synthesise Progesterone induced
Blocking Factor (PIBF)
Effect on humoral (B cell) and cellular (T cell) immune system
and reduced NK cell activity*
substantial anti-abortive effects
*J Szekeres-Bartho et al. The role of g/d T cells in progesterone-mediated
immunomodulation during pregnancy: a review. Am J Reprod Immunolo 42(1999)
44-8
1.
2.
3.
4.
5.
Recurrent miscarriage especially
idiopathic– give progesterone
Important ‘immunomodulatory’ role of
progesterone via PIBF in immunology of
pregnancy
Good evidence to support concept of
progesterone deficiency in threatened /
recurrent miscarriage
Threatened miscarriage – consider
progesterone despite lack of RCT evidence
Routine use to prevent miscarriage – NO!