FOGSI Position Statement, Dr, Ila Gupta

FOGSI Position Statement:
Progestogens in Early
Pregnancy
DR ILA GUPTA

Progesterone & its Role in Early
Pregnancy

FOGSI Position Statement 2015:
Progesterone & Early Pregnancy
• Progesterone is essential hormone needed to maintain pregnancy
• After ovulation, endogenous progesterone is produced by corpus luteum & it rises
sharply & peaks following week
• Later in pregnancy, Placenta takes over progesterone production later in pregnancy -
Regulated by hCG
http://www.fogsi.org/fogsi-gcpr/. Accessed on 12th Jan 2016

FOGSI Position Statement 2015
• Derived from plant source ie, Diosgenin (Dioscorea villosa)
• Closely related to endogenous progesterone, both in its
molecular structure as well in pharmacological effects
Both Micronized
progesterone &
Dydrogesterone

Dydrogesterone & Micronized
Progesterone
Are Synthesized From Natural Source
Progesterone
Undergoes processing Light technology bends it into
to become a curved retrosteroid structure2
Micronized Progesterone Dydrogesterone
5
Dioscorea plants
1. University of Maryland Medical Centre. Wild Yam. Available from
http://umm.edu/health/medical/altmed/herb/wild-yam (last accessed 27 April 2015).
2. Fischer M. Angew Chem Int Ed Engl 1978; 17: 16-26.
3. Schindler AE et al. Maturitas 2009; 65(Suppl 1): S3-S11.
Both progesterone and dydrogesterone are
produced from the same dioscorea plant1
Small changes can make a difference
Shaped by light, enhances the progestogenic effects
(improved bioavailability, and specificity and affinity for the progesterone receptor)3

• High specific affinity for progesterone receptors, no
affinity for androgen, mineralocorticoid, glucocorticoid,
& estrogenic receptors
Dydrogesterone

Immunomodulatory properties
• Decrease in pro–inflammatory and increase in anti-
inflammatory cytokines in early pregnancy
Dydrogesterone

Route of Progestogens in early pregnancy:
Oral, Vaginal, IM route (tablets, capsules, vaginal pessaries, injections and gels)

Progesterone Support in Recurrent
Pregnancy Loss and Threatened
Miscarriage

FOGSI Position Statement 2015:
Progesterone Support in Recurrent &
Miscarriage
• About 10% to 15% of clinically recognizable pregnancies result in spontaneous
miscarriages
• Increase in number of miscarriages would lead to increase in rate of subsequent
miscarriage (13–17% after first miscarriage & 55% after third miscarriage)

• Spontaneous loss of 3 or more consecutive pregnancies
before 20 weeks of gestation
Recurrent Miscarriage
Threatened
Miscarriage
• Pregnancy complicated by bleeding before 20 weeks
gestation
• Inadequate secretion of endogenous progesterone in
early pregnancy linked as one of etiological factors

• Endometrial maturation
• Endometrial stabilization
• Embryo implantation
• Regulation of inflammatory mediators to
create adequate positive immune
response in early pregnancy, preventing
pregnancy loss
Progesterone induces
secretory changes in
endometrium essential for

Threatened Miscarriage
Vaginal micronized progesterone & dydrogesterone
Beneficial in women presenting with clinical diagnosis of TM with relative risk reduction in
miscarriage rate of 47%

Threatened Miscarriage
• Dydrogesterone: 40 mg loading dose followed by
20–30 mg daily till 7 days after bleeding stops
Oral Route
Vaginal Route
• Micronized Progesterone: 400 mg/day vaginally till
bleeding stops

Recurrent Miscarriage
• Dydrogesterone: 10 mg BD till 20 weeks of
pregnancy
Oral Route
Vaginal Route
• Micronized Progesterone: 400 mg/day vaginally till
20 weeks of pregnancy

Safety of Progestogens
Available evidence strongly supports safety of progesterone when used in pregnancy
(based on available clinical data on vaginal progesterone & dydrogesterone)

No statistically significant difference in congenital abnormalities seen in clinical studies
between newborns of mothers who received progesterone & those who did not

Adverse Effects Reported with Progestogens
• Oral progestogens - Common adverse event: breast tenderness, bloating and
headache
• Intramuscular progesterone - Redness at injection site, pain and inflammation
• Transvaginal use of progesterone can cause discharge and vaginal irritation in some
patients

Progesterone should be used with caution in patients with cardiovascular diseases & in
patients with impaired liver function & cholestasis

Th1-Th2 Paradigm
T helper cells = subgroup of lymphocytes1
Cytokines are the messengers of the immune system2
Th1 Th2
Cytokines
1. T Cell Immunology. Available from http://www.bdbiosciences.com/research/tcell/about/helper.jsp (last
accessed 23 April 2015); 2. Cytokines. Available from
http://www.niaid.nih.gov/topics/immunesystem/immunecells/Pages/cytokines.aspx (last accessed 23 April
2015).
Th1 cells2
Pro-inflammatory cytokines
IL-2, TNF-α, TNF-β, IFN-γ
Cell-mediated immunity
Th2 cells2
Anti-inflammatory cytokines
IL-4, IL-5, IL-6, IL-10, IL-13
Humoral immunity
IFN, interferon; IL, interleukin; Th, T helper; TNF, tumor necrosis factor

Th1-Th2 Paradigm in Pregnancy
Th1 cells4,5
Pro-inflammatory cytokines4
Cell-mediated immunity4
Rheumatoid arthritis (Th1-mediated disease)5
• Improves in pregnancy as less Th1 cytokines5
Th2 cells4,5
Anti-inflammatory cytokines4
Humoral immunity4
Systemic lupus erythematosus (Th2-mediated disease)5
• Worsens in pregnancy as more Th2 cytokines5
1. Raghupathy R et al. BJOG 2005; 112(8):1096-1101; 2. Szekeres-Bartho J, Wegmann TG. J Reprod Immunol
1996; 31(1-2): 81-95; 3. Szekeres-Bartho J. Int Rev Immunol 2002; 21(6): 471-495; 4. T Cell Immunology.
Available from http://www.bdbiosciences.com/research/tcell/about/helper.jsp (last accessed 23 April 2015); 5. Doria
A et al. Reprod Toxicol 2006; 22(2): 234-241.
Normally progressing pregnancy1–3
Th, T helper

Potential Link Between the
Endocrine and Immune Systems
Normally
progressing
pregnancy2–4
Progesterone is essential for
the maintenance of pregnancy.
It is produced by the corpus luteum
until weeks 7–9, when the placenta
takes over this function1
Progesterone
Lymphocyte
PIBF
Progesterone stimulates the production of PIBF,
which induces a Th2 response and down-regulates
NK activity, thus exerting an anti-abortive effect2–5
1. Norwitz ER et al. N Engl J Med 2001; 345(19): 1400-1408; 2. Raghupathy R et al. BJOG 2005; 112(8):1096-1101; 3.
Szekeres-Bartho J, Wegmann TG. J Reprod Immunol 1996; 31(1-2): 81-95; 4. Szekeres-Bartho J. Int Rev Immunol 2002;
21(6): 471-495; 5. Raghupathy R et al. J Reprod Immunol 2009; 80(1-2): 91-99.
Progesterone inhibits the production of the
Th1 cytokines and up-regulates the
production of the Th2 cytokines2
NK, natural killer; PIBF, progesterone-induced blocking factor; Th, T helper

PIBF
Link Between the Endocrine and
Immune System
Progestogen
PIBF
Normally
Progressing
Pregnancy
Progestogen
PIBF
Miscarriage
Mifepristone
PIBF
+anti-PIBF
Miscarriage
Adapted from: Szekeres-Bartho J, et al. Int Immunopharmacol 2001; 1(6): 1037-1048.
Progestogen

Actions of Dydrogesterone on
Cytokines
• DYD inhibits IFN (p= 0.0001) & TNF (p= 0.005) production
(Raghupathy et al, 2005)
• DYD increases levels of IL-4 (p= 0.03) & IL-6 (p= 0.017) (Raghupathy et al,
2005)
• Dydrogesterone induces production of PIBF
• Main metabolite of dydrogesterone increased nitric oxide synthesis
by endothelial cells (Simoncini T et al. 2006)

Trophoblast Invasion is Strictly
Regulated by Progesterone and PIBF
• Uterine spiral arteries play a vital role in supplying nutrients to the
placenta and fetus and are remodeled by invading trophoblast cells and
NK cells into highly dilated vessels1
1. Parham P. J Exp Med 2004; 200(8): 951-955; 2. Goldman S, Shalev E. Biol Reprod 2006; 74(1): 13-22; 3.
Halasz M et al. Cell Mol Life Sci 2013; 70(23): 4617-4630.
Trophoblast invasion is strictly
regulated by progesterone2
and PIBF3
© 2004 Parham. The Journal of Experimental Medicine. 200: 951–955. doi: 10.1084/jem20041783
ENVT, endovascular trophoblast cells; EVT, extravillous trophoblast cells; NK, natural killer; PIBF, progesterone-induced blocking factor; Th, T helper

Failure of Controlled Trophoblast
Invasion
• Failure in the control of NK cells and EVT interaction results in a reduction in
the extent and depth of remodeling, which can lead to pre-eclampsia
Parham P. J Exp Med 2004; 200(8): 951-955.
© 2004 Parham. The Journal of Experimental Medicine. 200: 951–955. doi: 10.1084/jem20041783
EVT, extravillous trophoblast cells; NK, natural killer; ENVT, endovascular trophoblast cells

Dydrogesterone Increases Nitric Oxide
• Nitric oxide acts as a potent vasodilator and plays a major role in increasing uterine
blood flow during the luteal phase and early pregnancy1
Main metabolite of dydrogesterone increased nitric oxide synthesis by endothelial
cells in vitro versus control2
– Cultured human umbilical vein endothelial cells were treated with a range of
progestogens, including dydrogesterone and its main metabolite,
20-dihydrodydrogesterone (DHD)
– Assays were carried out on the endothelial cells to determine nitric oxide production
and endothelial nitric oxide synthase (eNOS) activity
1. Abdel-Razik M et al. J Reprod Infertil 2014; 15(3): 142-146.
2. Simoncini T et al. Fertil Steril 2006; 86(S3): S1235-S1242.
Endothelial cells treated with DHD or progesterone displayed:
• Increased eNOS synthesis
• Increased eNOS activity
• Increased nitric oxide production
compared to untreated cells (p<0.05 for all)

Updates from PROMISE Study
Coomarasamy A et al. N Engl J Med 2015; 373(22):2141–2148

PROMISE Trial. NEJM 2015 vs. Kumar A
et al. Fertil Steril 2014

Study Settings
Coomarasamy et al. 2015 versus Kumar et al. 2014
Coomarasamy et al. 20151 Kumar et al. 20142
Principal
investigator
Dr. Arri Coomarasamy, Birmingham, UK Dr. Ashok Kumar, Delhi, India
Location of
study
• 36 centers in the UK
• 9 centers in the Netherlands
1 site (a medical college and its associated
hospital):
Maulana Azad Medical College and
Lok Nayak Hospital, India
Sponsor • UK National Institute for Health Research
• Treatment (active and placebo) provided
by Besins Healthcare
• Indian Council of Medical Research, New
Delhi, India
• No pharma involvement
Title First Trimester PROgesterone Therapy in
Women with a History of Unexplained
Recurrent MIScarriage, A Randomized Double-
blind, Placebo-Controlled, Multi-Centre Trial
(The PROMISE Trial)
Oral dydrogesterone treatment during early
pregnancy to prevent recurrent pregnancy loss
and its role in modulation of cytokine
production: a double-blind, randomized,
parallel, placebo-controlled trial
1. Coomarasamy A et al. N Engl J Med 2015; 373(22):2141–2148.
2. Kumar A et al. Fertil Steril 2014; 102(5):1357–1363.

Study Designs
Type of study Multi-center, double-blind, randomized,
placebo-controlled
Single-center, double-blind, randomized,
placebo-controlled
Inclusion
criteria
• Unexplained recurrent miscarriage
(≥ 3 miscarriages)
• Women 18–39 years of age
• Spontaneous conception
• Unexplained recurrent miscarriage
(≥ 3 miscarriages)
• Women 18–35 years of age
• Spontaneous conception
Objectives • Live births after 24 completed weeks of
gestation (primary)
• Clinical pregnancy at 6–8 weeks
• Ongoing pregnancy at 12 weeks
• Miscarriage (before 24 weeks)
• Gestational age at delivery
• Neonatal outcomes at 28 days
• Congenital abnormalities
• Pregnancy outcome
(miscarriage rate at 20 weeks; gestational
age at delivery)
• Correlation of pregnancy outcome
with pro- and anti-inflammatory cytokine
levels

Study Treatments
Active drug Utrogestan® (MVP) Oral dydrogesterone
Dosage 400 mg BID (800 mg daily) 10 mg BID (20 mg daily)
Formulation Vaginal suppositories Tablets
Treatment
initiation
After a positive urinary pregnancy test and no
later than 6 weeks of gestation
Confirmation of pregnancy, preferably at
4–8 weeks of gestation (enrolled after fetal
heart activity confirmed)
End of
treatment
Treatment ended at 12 weeks of gestation Treatment ended at 20 weeks of gestation
Number of
patients
Total: 836 participants
• MVP: N=404
• Placebo: N=432
Total: 522 participants
• Dydrogesterone: N=175
• Placebo: N=173
• Healthy controls: N=174
BID, twice daily; MVP, micronized vaginal progesterone

Efficacy Results
Coomarasamy et al. 2015Live-birth rate
Secondary endpoints
No significant differences were observed
between groups in terms of:
• gestational age at delivery
• clinical pregnancy (at 6–8 weeks)
• ongoing pregnancy (at 12 weeks)
• ectopic pregnancy
• miscarriage
• stillbirth
• neonatal outcomes
Distribution of gestational age
CI, confidence interval; MVP, micronized vaginal progesterone; RR, relative rate
Live-birth rate was not significantly
different between groups
65.8% (MVP) versus 63.3% (placebo)
RR 1.04 (95% CI: 0.94, 1.15)
Progesterone did not significantly
increase gestational age at delivery compared with
placebo
Coomarasamy A et al. N Engl J Med 2015; 373(22):2141–2148.
0.01 0.1 1 10 100
Gestation outcomes among women with live births
Relative risk (95 % CI) for progesterone versus placebo
28 weeks
34 weeks
37 weeks
Live birth before:
1.03 (0.06, 16.49)
1.03 (0.44, 2.45)
1.12 (0.67, 1.87)
Favors placebo Favors progesterone

Pregnancy outcome
Gestational age at delivery
• Increased significantly with
dydrogesterone compared with placebo
(38.0 ±2.0 weeks vs 37.2 ±2.4 weeks; p=0.002)
Cytokine levels
• No correlation between serum
Th1 and Th2 cytokine concentrations
and outcome of pregnancy
3.5%
16.8%
6.9%
0
2
4
6
8
10
12
14
16
18
Healthy controls,
no RM
(N=174)
Placebo
(N=173)
Dydrogesterone
(N=175)
Risk of miscarriage was 2.4 times higher in
the placebo versus dydrogesterone group
RR: 2.4 (95% CI: 1.3, 5.9); p<0.001
Kumar A et al. Fertil Steril 2014; 102(5):1357–1363.
CI, confidence interval; Th, T helper; RM, recurrent miscarriage; RR, risk ratio
Miscarriagerate,%
Miscarriage rate
Miscarriage rate decreased significantly
with use of dydrogesterone versus placebo
6.9% versus 16.8% (p=0.004)
Efficacy Results
Kumar et al. 2014

Efficacy
results
No significant difference between MVP
and placebo for:
• live-births rate
• miscarriage rate
• median gestational age at delivery
• ectopic pregnancy
• stillbirth
Significant difference between
oral dydrogesterone and placebo for:
• miscarriage rate (p=0.004)
• mean gestational age at delivery
(p=0.002)
Safety and
tolerability
• No difference in AEs between groups
• No difference in neonatal outcomes
between groups
• In total, 3.5% of babies
‒ MVP: 3.0% (8/ 266)
‒ Placebo: 4.0% (11 /276)
‒ RR: 0.75 (95% CI: 0.31, 1.85)
• MVP: 1 hypospadias
• Placebo: 1 urachal cyst
• No significant differences between groups
in the rates of obstetrical or neonatal
adverse outcomes (exploratory analysis)
• AEs/neonatal outcomes not provided in
the publication
• Dydrogesterone showed a trend
(not significant) toward reducing
pregnancy complications, such as:
• preterm deliveries
• cesarean deliveries
• low-birth-weight babies
• small-for-date babies
Efficacy and Safety
AE, adverse event; CI, confidence interval; MVP, micronized vaginal progesterone; RR, relative risk

FOGSI Position Statement, Dr, Ila Gupta

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FOGSI Position Statement, Dr, Ila Gupta