The role of progestogens in threatened and idiopathic recurrent miscarriage

THE ROLE OF PROGESTOGENS IN
THREATENED AND IDIOPATHIC
RECURRENT MISCARRIAGE
DR ALKA MUKHERJEE
DR APURVA MUKHERJEE
NAGPUR M.S. INDIA

DR ALKA MUKHERJEE
MBBS DGO FICOG FICMCH PGDCR PGDMLS MA(PSY)
Director & Consultant At Mukherjee Multispecialty Hospital
MMC ACCREDITATED SPEAKER
MMC OBSERVER MMC MAO – 01017 / 2016
Present Position
 Director of Mukherjee Multispecialty Hospital
 Hon.Secretary INTERNATIONAL COUNCIL FOR HUMAN RIGHTS
 Hon.Secretary NARCHI NAGPUR CHAPTER (2018-2020)
 Hon.Secretary AMWN (2018-2021)
 Hon.Secretary ISOPARB (2019-2021)
 Life member, IMA, NOGS, NARCHI, AMWN & Menopause
Society, India, Indian medico-legal & ethics association(IMLEA),
ISOPRB, HUMAN RIGHTS
 Founder Member of South Rapid Action Group, Nagpur.
 On Board of Super Specialty, GMC, IGGMC, AIIMS Nagpur,
NKPSIMS, ESIS and Treasury, Nagpur for “ WOMEN SEXUAL
HARASSMENT COMMITTEE.”
mukherjeehospital@yahoo.com
www.mukherjeehospital.com
https://www.facebook.com/
Mukherjee Multispeciality
https://www.instagram.com/
Achievement
 Winner of NOGS GOLD MEDAL – 2017-18
 Winner of BEST COUPLE AWARD in Social
Work - 2014
 APPRECIATION Award IMA - MS
 Past Position
 Organizing joint secretary ENDO-GYN
2019
 Vice President IMA Nagpur (2017-2018)
Vice President of NOGS(2016-2017)
Organizing joint secretary ENDO-GYN
Organizing secretary AMWICON – 2019
2DR ALKA MUKHERJEE NAGPUR M.S. INDIA

INTRODUCTION
• It is estimated that about 70% of conceptions are lost
prior to live birth:
• 30% due to implantation failure,
• 30% following implantation but before a missed period,
and about
• 10% as clinical miscarriage.
• Despite considerable advances in science and
technology, preventing and managing patients at risk of
clinical miscarriage in early pregnancy continues to be a
distressing problem.
• The possible causes of miscarriage, which can be broadly
divided into two categories,

REPRODUCTIVE
ENDOCRINOLOGY

TERMINOLOGY
• The guidelines proposed by the european society of human
reproduction and embryology (ESHRE), which define recurrent
miscarriage as “the loss of two or more pregnancies”.
• A “biochemical loss” is defined as a miscarriage that occurs (usually
before 6 weeks of gestation) following a positive urinary human
chorionic gonadotropin (hcg) or a raised serum β-hcg, but prior to
ultrasound or histological verification.
• The term clinical miscarriage is used when ultrasound examination
or histological evidence has confirmed that an intrauterine
pregnancy has existed.
• Clinical miscarriages may be subdivided into early (before
gestational week 12) and late (gestational weeks 12 to 21).
• As per the expert panel, patients with a biochemical and ultrasound
confirmation of pregnancy depicting the clinical signs of threatened
miscarriage should be thoroughly investigated prior to prescribing
treatment.

THE ROLE OF HORMONES IN PREGNANCY
• Pregnancy is a hormone-mediated physiological state
that involves a decrease in uterine vascular tone and an
increase in uterine blood flow.
• Progesterone and estrogen are two key hormones that
remain elevated during pregnancy and play significant
roles in causing anatomical adjustments within the
uterus to create an environment conducive to fetal
growth.
• Progesterone - the “pregnancy hormone” / Mother
hormone

Progesterone
(Proges = to bear)

Data on the optimal window for
implantation suggests that progestogen
support should be early started in the luteal
phase.

Progesterone, Dydrogesterone and
decidualization
• Extensive invasion of the maternal decidua by
extravillous trophoblast is considered of critical
importance for implantation and placentation in
humans. Decidual cells contribute to the highly dynamic
process at the fetal-maternal interface supporting
subsequent trophoblast invasion.
14
Gellesen et al Human Reprod. 25, 862, 2010
Proper decidualization is dependent on proper progestational support by
progesterone/progestins
DR ALKA MUKHERJEE NAGPUR M.S. INDIA

Progesterone and Dydrogesterone influence a successful
pregnancy through endocrine immune-mediated
mechanisms
• Progesterone act through nuclear and
membrane receptors and these effetcs
are mediated by the progesterone-
induced blocking factor (PIBF), which
exerts pregnancy protecting effects by
promoting a Th2-type cytokine profile.
15
Arck et al Am. J. Reprod. Immunol. 58, 268, 2007

Progesterone and endometrial progesterone receptor
synthesis in women with habitual abortion
1. Plasma progesterone was two times higher in fertile
women than in habitual aborters.
2. Plasma estradiol was not different between the
groups.
3. Endometrial tissue content of progesterone was 200
times higher in fertile women than in habitual
aborters.
4. ER and PR were at the lowest level in the cytozol and
nuclear compartment of women with recurrent
miscarriage.
19
Salazar, Catzada Gynecol. Endocrinol. 23, 222 2007

20
Progesterone
ng/ml
PR cytosol
fmol mg/protein
PR nuclear
fmol mg/protein
Fertile women
8,8 ± 1,6 21 ± 6,8 30 ± 11,8
Habitual miscarriage
4,0 ± 1,5 ˂ 3 ˂3
Significance
p˂0.005
Salazar, Cadzadar Gynecol. Endocrinol. 29, 222, 2007
Comparison of plasma progesterone and progesterone receptor
content of the endometrium in fertile women and in women with
recurrent miscarriage

Blood flow, progesterone and PRs
Blood flow in the corpus luteum phase is related to
progesterone, which is reflected in PR activity.
– Blood flow in the corpus luteum ↑
– No conception, blood flow ↓
– Conception and P ↑, blood flow ↑
and is maintained throughout pregnancy.
23
Leible et al Am. J. Obstet. Gynecol. 179, 1587, 1998
Donaghay, Lessey Semin. Reprod. Med. 25, 461, 2007

Proinflammatory cytokines lead to unreceptive
endometrium in women with recurrent (habitual)
miscarriage
A statistically significant higher level of proinflammatory
cytokines, mediators of matrix turn-over and angiogenesis
and reduced expression of antiinflammatory and angiogenic
cytokines were observed in women with recurrent
(habitual) miscarriage.
In addition, markers of endometrial receptivity were poorly
expressed.
Banerjee et al Fert. Steril. 99, 179, 2013

The window of receptivity to implantation is established by
actions of progesterone
that regulate locally produced cytokines, growth factors,
transcription factors and cyclooxygenase –derived
prostaglandins through autocrine and paracrine pathways.
Bazer et al. Mol. Human. Reprod. 16, 135, 2010

Link between endocrine and
immune systems
Szekeres-Bartho & Wegmann 1996;
Szekeres-Bartho 2002

PROGESTERONE® - Key to Embryo Survival
32
P-receptor expression at the foeto-maternal interface
Sufficient P-receptor Activation
Asymmetric ABs
Th1/Th2
NK activity
PIBF
Successful Pregnancy

Causes AN INCREASE IN HCG
Production by placenta. Hcg,cortisol & progesterone
together protect the conceptus from t-lymphocyte
med.Tissue rejection .

Progesterone / Dydrogesterone and uterine
contractions
1. Uterine contractions are related to circulating
Progesterone.
2. Removal of the corpus luteum before 8 weeks of
gestation leads to uterine contractions & widening of
cervix,thereby leads to abortion.
3. Treatment with progesterone prevents this.
36
Czapo et al Am. J. Obstet. Gynecol. 112, 1061, 1972
Czapo et al Am. J. Obstet. Gynecol. 115, 759, 1973

Progesterone is crucial in the maintenance of
pregnancy as it is involved in:
Modulation of the maternal immune response,
Suppression of inflammatory response,
Reduction of uterine contractility,
Improvement of utero-placental circulation, and
Luteal-phase support.
Particularly in early pregnancy, progesterone is
responsible for preparing the endometrium for
implantation and maintenance of the gestational
sac in the uterus

Mechanisms Involved In Miscarriage
Cytogenetics and immunogenetics - contributed to a better understanding of the
mechanisms involved in miscarriage.
The main mechanisms involved in early miscarriage include
a) Chromosomal abnormalities or aberrations,
b) Immunological and immunogenetic causes,
c) Thrombophilias, endocrinological disorders,
d) Sperm dna fragmentation,
e) Failure of embryo selection,
f) Uterine malformations,
g) Hcg gene polymorphisms and
h) Epigenetic causes, and lifestyle factors.
i) Fetal malformations were found to be responsible for 85% of early clinical
miscarriages, with chromosomal abnormalities found in one partner of 3–
6% of couples experiencing a recurrent miscarriage, which is ten times
higher than the rate in the general population.
j) Cytokine-mediated immunological reactions are estimated to be responsible
for 40–60% of all cases of idiopathic recurrent spontaneous miscarriages.

• Maternal immune tolerance of the fetus is key to
promoting fetal survival.
• Successful pregnancy is associated with downregulation
of th1-type activity and enhancement of th2-type
activity.
• Women with spontaneous recurrent miscarriages have
elevated levels of the th1 cytokines interleukin (il)-2 and
interferon-γ and decreased levels of the th2 cytokine il-
10, as assessed by antigen- and mitogen-induced
activation of peripheral blood mononuclear cells.
• Progesterone favors the development of human t-cells
producing th2 cytokines and blocks the production of
th1 cytokines, indicative of its role in pregnancy
maintenance

• What Is The Role Of Oral Progestogens In The Prevention
And Treatment Of Threatened And Idiopathic Recurrent
Miscarriage?
• Oral Micronized Progesterone
• Available data suggest that oral micronized progesterone
may have a role in preterm labor but not in threatened or
recurrent miscarriage.

• Dydrogesterone (Oral Progestogen)
• Based on data from recent systematic reviews and
meta-analyses, oral dydrogesterone effectively prevents
miscarriage in pregnant women experiencing
threatened miscarriage.
Recommendation 1: Oral progestogens, namely
dydrogesterone, are well tolerated and effectively reduce
miscarriages in women at risk of threatened or idiopathic
recurrent miscarriages.

• What Is The Role Of Vaginal Progestogens In The
Prevention And Treatment Of Threatened And Idiopathic
Recurrent Miscarriage?
• Data on the efficacy and safety of vaginal progestogens
are limited
Recommendation 2: Available evidence is insufficient to
recommend the use of vaginal progestogens (capsule,
suppository, micronized, or gel) for the treatment of
threatened or recurrent miscarriage.

• What Is The Role Of Injectable Progestogens In The
Prevention And Treatment Of Threatened And Idiopathic
Recurrent Miscarriage?
• Many studies refer to the benefit of intramuscular
progestogens for luteal-phase support and for treating
preterm birth, but not to prevent/treat threatened or
recurrent miscarriage.
Recommendation 3: There is insufficient evidence to support
the use of injectable progestogens in miscarriage prevention
and treatment.

• What Is The Role Of Combination Treatment (Oral And/Or Vaginal And/Or Injectable)
In The Prevention And Treatment Of Threatened And Idiopathic Recurrent
Miscarriage?
• There are no published articles assessing the efficacy and safety of progestogens in
combination administered through different routes.
• Furthermore, the uterus is a hormone-sensitive organ that responds to the presence
of estrogen and progesterone, each binding to their cognate receptors (ESR1 and PGR,
respectively) and working in concert to establish and maintain pregnancy.
• Disruption to this balance may increase the likelihood of miscarriage by lowering the
number of available progesterone receptors and/or estrogen receptors within the
endometrium or by the dysregulation of gene transcription and uterine biology.
Recommendation 4: There is no evidence to support the
use of combination progestogens in the prevention and
treatment of threatened and idiopathic recurrent
miscarriage. Progestogen monotherapy administered in the
appropriate dose is recommended.

• Are The Available Progestogens Safe In Early Pregnancy?
• Clinical studies of oral and vaginal routes of
administration are associated with acceptable and
minimal side effects, with fatigue, fluid retention,
lipid level alterations, dysphoria, hypercoagulant
states, and increased androgenicity reported most
commonly.
• Natural progestogens are reported to have milder side
effects, with oral micronized natural progestogens
having fewer side effects than natural progesterones.
• The poor bioavailability of oral micronized
progesterone - high doses required, which may result
in drowsiness and liver toxicity

• Dydrogesterone, a progestogen that is highly selective
for the progesterone receptor, lacks estrogenic,
androgenic, anabolic, and corticoid properties;
• Most studies report no significant side effects including
no masculinization of the female fetus
• No congenital abnormalities.
• In comparison with micronized progesterone,
dydrogesterone found to cause significantly fewer cases
of drowsiness with no differences in nausea, vomiting,
giddiness, bloating, diarrhea, or headache
• Dydrogesterone is very unlikely to be teratogenic.

• Intramuscular progestogen is commonly associated with
injection-site reactions, including soreness, swelling,
itching, and bruising, with daily injections associated
with pain at injection site and local abscess formation.
• Recommendation 5: Progestogens are generally well
tolerated, with minimal side effects. Although progestogen
administration during the first trimester was linked to
hypospadias risk, recent and more thorough reports have not
shown an increase in the rate of hypospadias.

POSITION STATEMENTS
• Threatened Miscarriage
• For women presenting with a clinical diagnosis of threatened
miscarriage, dydrogesterone may reduce the rate of
miscarriage.
• Oral dydrogesterone should be offered.
• Dosage: 40 mg loading, then 30 mg once daily until symptoms
(bleeding) remit.
• If symptoms persist/recur, increase dose by 10 mg three
times a day.
• Maintain effective dose for 1 week after symptoms have
ceased and then gradually reduce dose.
• Immediately resume treatment at effective dose, if symptoms
recur.

• Recurrent Miscarriage
• Thorough investigations are warranted to rule out other causes of
miscarriage. Once ruled out, a diagnosis of idiopathic recurrent
miscarriage is confirmed.
• For women presenting with a clinical diagnosis of idiopathic
recurrent miscarriage (having experienced two or more), there is a
reduction in the rate of miscarriage with the use of dydrogesterone.
• Dydrogesterone should be administered as early as possible, at the
diagnosis of pregnancy or during the luteal phase, in stimulated
cycles.
• Oral dydrogesterone should be offered.
• Dosage: 10–20 mg daily, until the 20th week of pregnancy.
Treatment should preferably start before conception. If symptoms
of threatened miscarriage occur during treatment, continue
treatment as stated for that indication.
POSITION STATEMENTS

RCOG
• RCOG
• Progesterone could prevent 8,450 miscarriages a year, finds
new research
• News 31 January 2020
• Giving progesterone to women with early pregnancy bleeding
and a history of miscarriage could lead to 8,450 more babies
being born each year, finds new research published today.
• Two new studies evidence both the scientific and economic
advantages of giving a course of self-administered twice daily
progesterone pessaries to women from when they first
present with early pregnancy bleeding up until 16 weeks of
pregnancy to prevent miscarriage.

• The first of the new studies, published in the American Journal of Obstetrics
and Gynecology, examines the findings of two major clinical trials –
PROMISE and PRISM - led by the University of Birmingham and Tommy’s
National Centre for Miscarriage Research.
• PROMISE studied 836 women with unexplained recurrent miscarriages at
45 hospitals in the UK and the Netherlands, and found a 3% higher live
birth rate with progesterone.
• PRISM studied 4,153 women with early pregnancy bleeding at 48 hospitals
in the UK and found there was a 5% increase in the number of babies born
to those who were given progesterone who had previously had one or
more miscarriages, compared to those given a placebo.
• The benefit was even greater for the women who had previous ‘recurrent
miscarriages’ (i.e., three or more miscarriages) – with a 15% increase in the
live birth rate in the progesterone group compared to the placebo group.
• The second of the new studies, published in BJOG: an international Journal
of Obstetrics & Gynaecology, evaluates the economics of the PRISM trial
and concludes that progesterone is cost-effective, costing on average £204
per pregnancy.

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