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1. GDS_70000_Title_v1 1
Current Controversies and
Updates: Progestogens in
Early Pregnancy
Dr.Gauri Agarwal
MD DNB
DIRECTOR
SEEDS OF INNOCENCE IVF CENTRE

2. 2
Miscarriage

3. 3
Spontaneous Miscarriage
More than 80% of spontaneous miscarriages occur within
first 12 weeks of gestation
F. Gary Cunningham (Author), Kenneth J. Leveno (Author), Steven L. Bloom. Williams Obstetrics 24th edition, 2014

4. 4
Incidence of Pregnancy Loss
• Around 70% of conceptions are lost prior to live birth1
• Once a woman has had a positive pregnancy test, there is around a 12%
risk of having a miscarriage2,3
1. Macklon NS, et al. Hum Reprod Update 2002; 8(4): 333-343.
2. Everett C. BMJ 1997; 351(7099): 32-34.
3. Regan L, et al. BMJ 1989; 299(6698): 541-545.
Live births
Miscarriage
Early pregnancy loss
Failure of implantation
Fertilizations
Clinical pregnancy loss
Pre-clinical loss
30%
10%
30%
30%

5. 5
Impact of Miscarriage
• Miscarriage can have profound emotional impact
• Nearly 20% of women who experience miscarriage become symptomatic for
depression/anxiety
• Esp. younger women at highest risk for psychiatric morbidity following miscarriage
• Clinicians - screen women frequently for depressive symptoms beginning at 6
weeks following miscarriage
• World Health Organization recommends:
• Waiting 6 months following miscarriage before conceiving again to allow time for physical
& mental recovery
1. http://www.nhs.uk/Conditions/Miscarriage/Pages/Complications.aspx. 2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468887/

6. 6
Possible Causes of Miscarriage
1. Abnormal embryo
• Structural anomalies incompatible with life1
• Chromosomal abnormalities: trisomy, polyploidy, monosomy X, structural abnormalities
of individual chromosomes2
2. Hostile maternal environment
• Uterine abnormalities: congenital anomalies, adhesions, leiomyoma2
• Infection: bacterial vaginosis, toxoplasmosis, listeriosis, chlamydia, gonorrhea, rubella2
• Chronic maternal disease: poorly controlled diabetes, celiac disease2
• Immune dysfunction: antiphospholipid antibody syndrome2 and thyroid autoimmunity1
• Endocrine: failure of proper progesterone concentration, thyroid hormone levels3
1. Larsen EC et al. BMC Medicine 2013; 11: 154-65.
2. Griebel CP et al. Am Fam Physician 2005;1; 72(7): 1243-50.
3. Zhang HX et al. Clin Exp Obstet Gynecol 2014; 41(2): 182-5.

7. 7
Adverse Outcomes Increased in Women with
Threatened Miscarriage
Maternal
• Placenta previa
• Placental abruption
• Manual removal of placenta
• Cesarean delivery
Perinatal
• Preterm ruptured membranes
• Preterm birth
• Low-birth weight infant
• Fetal-growth restriction
• Fetal and neonatal death
F. Gary Cunningham (Author), Kenneth J. Leveno (Author), Steven L. Bloom. Williams Obstetrics 24th edition, 2014

8. 8
Etiology of Recurrent Pregnancy Loss
Ford HB et al. Rev Obstet Gynecol. 2009 Spring; 2(2): 76–83.

9. 9
Progesterone and Early Pregnancy
Female Reproductive System, Pregnancy and Childbirth. Available at http://fblt.cz/en/skripta/viii-
rozmnozovaci-soustavy/1-zenske-pohlavni-organy-tehotenstvi-a-porod/ (last accessed 24 June 2015).
• If fertilization occurs, the corpus luteum is stimulated by human chorionic
gonadotropin and continues producing progesterone
hCG, human chorionic gonadotropin

10. 10
Progestogens Effects
Pro-gestation ≈ “For Pregnancy”
• Preparation of the endometrium for implantation (secretory changes)1
• Decreases contractility of uterine smooth muscle2
• Regulation of cellular immunity1
• Mediates (i) uterine blood flow, (ii) uterine endothelial adaptation to
pregnancy [increased NO production]2
• Drop in progesterone is possibly one step that facilitates onset of labor3
1. Schindler AE. Gynecol Endocrinol 2004; 18(1): 51-57; 2. Chang K, et al. Reprod Sci 2008; 15(4):
336-348; 3. Progesterone and Progestin Therapy for Miscarriage Prevention. Available at:
http://www.naturalstandard.com/news/news200802003.asp (last accessed February 2014).

11. 11
Treatment Options in Threatened Miscarriage
• Bed rest (?)
• Uterine muscle relaxants (?)
• Human chorionic gonadotrophin [HCG] (?)
• Progestogens
Qureshi NS. Maturitas 2009; 65(Suppl 1): S35-S41.

12. 12
Bed Rest in TM

13. 13
Bed Rest in TM

14. 14
Treatment Options in Threatened Miscarriage
• Bed rest
• Most commonly prescribed intervention
• No evidence for bed rest
• May lead to physical complications such as thromboembolic events,
muscle atrophy
• May be stressful for the woman and her family
• May be costly .
Aleman A, et al. Cochrane Database Syst Rev 2005 Apr 18; (2); CD003576.

15. 15
Treatment Options in Threatened Miscarriage
• Uterine Muscle Relaxants
• e.g. beta-agonists, atropine-like antispasmodics
• Rarely used today
• Cochrane review concluded insufficient evidence to support their
use
Lede R, et al. Cochrane Database Syst Rev 2005 Jul 20; (3): CD002857.

16. 16
HCG in TM

17. 17
HCG in TM

18. 18
HCG in TM

19. 19
Treatment Options in Threatened Miscarriage
• Human Chorionic Gonadotrophin (hCG)
• Promising in two early uncontrolled studies (1973 and 1986)1,2
• Small randomized study showed it to be significantly more effective
than bed rest, but not than placebo3
• No difference to placebo in a 2005 published prospective, double blind,
randomized trial in 183 women4
• Requires weekly intramuscular injections until week 14 gestation which
may make it unacceptable to some women4
1. Baillie P, et al. S Afr Med J 1973; 47(29): 1293-1296. 2. Suvonnakote T. J Med Assoc Thai 1986;
69(11): 654-658. 3. Harrison RF. Int J Fertil Menopausal Stud 1993; 38(3): 160-165. 4. Qureshi NS, et
al. BJOG 2005; 112(11): 1536-1541.

20. 20
• Progestogens
• e.g. progesterone,
dydrogesterone
20
Treatment Options in Threatened Miscarriage
Qureshi NS. Maturitas 2009; 65(Suppl 1): S35-S41.

21. 21
Not All Progestogens
Are Suitable Options in Threatened Miscarriage
Adapted from: Benagiano G et al. Patient Prefer Adherence 2009; 3: 131-143.

22. 22
Progestogens - Oral, Vaginal, or Intra-muscular Route
• Oral administration
• Easiest route of administration & most acceptable route for patient
• Vaginal administration
• Results in higher uterine concentrations, but often uncomfortable in
presence of vaginal bleeding, or may be washed out if bleeding is
severe
• Intramuscular progesterone
• Provides optimal blood levels but can induce abscesses formation &
extremely painful
Howard Carp. Gynecological Endocrinology, 2012; Early Online: 1–8

23. 23
Pitfalls of Diagnosis
• Progesterone secretion pulsatile. Blood may be drawn at pulse peak or
nadir. These may vary 10-fold (Abraham et al, 1974)
• Hormone levels may be normal, but histology abnormal due to
deficiency of progesterone receptors
• Abnormal embryo – low hCG. Low hCG leads to low progesterone
levels
• Low progesterone may be mechanism rather than cause of abortion
• Therefore diagnosis & treatment should be empirical

24. 24
Efficacy Data Supporting Use of
Progestogens in Threatened
Miscarriage

25. 25
Clinical Outcomes in Threatened Miscarriage
Dydrogesterone Is More Effective
Than Standard Care
• Omar 2005
Dydrogesterone showed significantly
higher continuing pregnancy success rate
(95.9% vs. 86.3%; p = 0.037 )1
• El-Zibdeh 2009
Dydrogesterone showed significantly lower
miscarriage rate
(17.5% vs. 25%; p < 0.05)2
• Pandian 2009
Dydrogesterone showed significantly
higher successful delivery rate
(87.5% vs. 71.6%; p < 0.05)3
No intrauterine deaths or congenital
abnormalities in either group
Dydrogesterone Seems More Effective
Than Micronized Progesterone
• Vincze 2006
Dydrogesterone (40mg then by 30mg / day) vs.
vaginal micronized progesterone (300 mg/day for
6 weeks) – No significant difference observed for
miscarriage rate4
• Czajkowski 2007
Dydrogesterone (30 mg/day) vs. vaginal
micronized progesterone (300 mg/day) in a 6
week study to evaluate spiral artery pulsatility &
resistance index - No significant difference
observed for miscarriage rate 5
• Pelinescu-Onciul 2007
Dydrogesterone (40 mg/day until 16th week) vs.
micronized progesterone - No significant
difference observed for miscarriage rate6
1. Omar MH, et al. J Steroid Biochem Mol Biol 2005; 97(5): 421-425. 2. El-Zibdeh MY, Yousef LT.
Maturitas 2009; 65(Suppl 1): S43-S46. 3. Pandian RU. Maturitas 2009; 65(Suppl 1): S47-S50. 4. Vincze E
et al. J Hungarian Gynecol. 2006; 69: 281-284; 5.Czajkowski K, et al. Fertil Steril 2007; 87(3): 613-618. 6.
Pelinescu-Onciul D. Gynecol Endocrinol 2007; 23(Suppl.1): 77-81.

26. 26
Threatened Miscarriage - Progestogens
Studies, Meta-analyses and Guidelines
Studies Length of DYD treatment
Miscarriage rate p-value
DYD Control
Omar1 Until bleeding stopped 4.1% 13.8% p=0.037
El-Zibdeh2 1 week after bleeding stopped 17.5% 25.0% p≤0.05
Pandian3 Until week 16 12.5% 28.4% p<0.05
BID, twice daily;
DYD, dydrogesterone
1. Omar MH et al. J Steroid Biochem Mol Biol 2005; 97(5): 421-425; 2. El-Zibdeh MY, Yousef LT. Maturitas 2009; 65(Suppl 1): S43-
S46; 3. Pandian RU. Maturitas 2009; 65(Suppl 1): S47-S50; 4. Wahabi HA, et al. Cochrane Database Syst Rev 2011 Dec 7; (12):
CD005943; 5.Carp H. Gynecol Endocrinol 2012; 28(12): 983-990; 6. Royal Australian and New Zealand College of Obstetricians and
Gynaecologists (RANZCOG) 2013. http://www.ranzcog.edu.au/doc/progesterone-support-of-the-luteal-phase-and-early-
pregnancy.html (Last accessed March 2014). 7. Schindler AE et al. Gynecol Endocrinol 2015. Published online 15 May 2015.
Meta-analysis Studies Included Results
Wahabi 20114 2 vag progesterone (n=84)
2 dydrogesterone(n=337)
Significant reduction of miscarriage by
progestogens vs. placebo or no treatment
0.53 (CI = 0.35–0.79)
Carp 20125 5 dydrogesterone (n=660) Significant reduction with dydrogesterone for
miscarriage compared to standard care
0.47 (CI = 0.31–0.7)
Guidelines Recommendation
2013 Australian and New Zealand Guidelines6 For women presenting with a clinical diagnosis of threatened
miscarriage, there is now preliminary evidence of a reduction in the
rate of spontaneous miscarriage with the use of progestins.
2015 European Progestin Club Guidelines for
the Treatment of Threatened Miscarriage7
For women presenting with a clinical diagnosis of threatened
miscarriage, there is a reduction in the rate of spontaneous
miscarriage with the use of dydrogesterone

27. 27
Omar et al. 2005, El-Zibdeh and Yousef 2009, Pandian
2009: Dydrogesterone in Threatened Miscarriage
Author Dydrogesterone dosing Miscarriage rate p-value
40 mg
loading
10 mg
BID Length of treatment DYD Control
Omar1 Yes Yes Until bleeding stopped 4.1% 13.8% p=0.037
El-Zibdeh2 No Yes 1 week after bleeding stopped 17.5% 25.0% p≤0.05
Pandian3 Yes Yes Until week 16 12.5% 28.4% p<0.05
BID, twice daily; DYD, dydrogesterone
1. Omar MH et al. J Steroid Biochem Mol Biol 2005; 97(5): 421-425.
2. El-Zibdeh MY, Yousef LT. Maturitas 2009; 65(Suppl 1): S43-S46.
3. Pandian RU. Maturitas 2009; 65(Suppl 1): S47-S50.

28. 28
Recurrent Miscarriage

29. 29
Treatment Options in Recurrent Miscarriage
• Anticoagulants (e.g. Heparin, Aspirin) - in women with Antiphospolipid
Syndrome1
• Heparin can cause thrombocytopenia, osteopenia and fractures, & maternal
bleeding
• Antibiotics (e.g. Clindamycin) - used in confirmed bacterial vaginosis2
• Supportive care (e.g. bed rest, vitamins, folic acid, lifestyle adaptation) –
counselling, formal emotional support, close supervision1,2
• Small number of non-randomized studies indicate decreased miscarriage rates
in woman with unexplained recurrent miscarriages2
1. Jauniaux E, et al. Hum Reprod 2006; 21(9): 2216-2222.
2. Tien JC, et al. Singapore Med J 2007; 48(12): 1074-1090.
3. Dhont M. Curr Womens Health Rep 2003; 3(5): 361-366.

30. 30
Treatment Options in Recurrent Miscarriage
• Surgery (uterine septum resection, hysteroscopic lysis of
intrauterine adhesions)3
• May be beneficial in anatomical etiology for recurrent miscarriage
• No randomized trial proves benefit
• Progestogens (e.g. dydrogesterone, progesterone)1,2
1. Jauniaux E, et al. Hum Reprod 2006; 21(9): 2216-2222.
2. Tien JC, et al. Singapore Med J 2007; 48(12): 1074-1090.
3. Dhont M. Curr Womens Health Rep 2003; 3(5): 361-366.

31. 31
Prognosis
• Prognosis depends on underlying cause for pregnancy loss &
number of prior losses
• Patients and physicians can be encouraged by the overall good
prognosis, as even after 4 consecutive losses a patient has a
greater than 60% to 65% chance of carrying her next pregnancy to
term
Ford HB et al. Rev Obstet Gynecol. 2009 Spring; 2(2): 76–83.

32. 32
Efficacy Data Supporting Use of
Progestogens in Recurrent
Miscarriage

33. 33
Recurrent Miscarriage - Dydrogesterone
Studies, Meta-analyses and Guidelines
Studies Length of DYD treatment
Miscarriage rate p-value
DYD Control
El-Zibdeh1 Until week 12 13.4% 29% p=0.028
Kumar2 Until week 20 6.9% 16.8% P=0.004
BID, twice daily;
DYD, dydrogesterone
1. El-Zibdeh MY. J Steroid Biochem Mol Biol 2005; 97(5): 431-434; 2. Kumar A et al. Fertil Steril. 2014; 102:1357- 63;
3. Haas DM, Ramsey PS. Cochrane Database Syst Rev 2013; 10: CD003511; 4. Carp H. Gynecol Endocrinol. 2015
2015 Jun;31(6):422-30; 5. Schindler AE et al. Gynecol Endocrinol 2015. Published online 15 May 2015.
Meta-analysis Studies Included Results
Haas & Ramsey
20133
4 studies (n=225)
• Dydrogesterone
• Hydroxyprogesterone caproate IM
• Medroxyprogesterone acetate
• Progesterone pellets in gluteal muscle
Significant reduction of
miscarriage by progestogens
vs. placebo or no treatment
0.39(CI: 0.21–0.72)
Carp 20154 3 studies (n=509)
• Two randomized trials
• One non-randomized comparative trial
Significant reduction of
miscarriage with
dydrogesterone compared to
standard care
0.29 (CI: 0.13–0.65)
Guidelines Recommendation
2015 European Progestin Club Guidelines for
the Treatment of Threatened Miscarriage5
For women presenting with a clinical diagnosis of recurrent
miscarriage, 3 or more, there is a reduction in the rate of
miscarriage with the use of dydrogesterone

34. 34
PROMISE Trial. NEJM 2015 vs. Kumar A et al. Fertil Steril
2014

35. 35
Study Settings
Coomarasamy et al. 2015 versus Kumar et al. 2014
Coomarasamy et al. 20151 Kumar et al. 20142
Principal
investigato
r
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.

36. 36
Study Designs
Coomarasamy et al. 2015 versus Kumar et al. 2014
Coomarasamy et al. 20151 Kumar et al. 20142
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
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.

37. 37
Study Treatments
Coomarasamy et al. 2015 versus Kumar et al. 2014
Coomarasamy et al. 20151 Kumar et al. 20142
Active drug Utrogestan® (MVP) Oral dydrogesterone
Dosage 400 mg BID (800 mg daily) 10 mg BID (20 mg daily)
Formulatio
n
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
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.

38. 38
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
Live-birth rate Distribution of gestational age
Efficacy Results
Coomarasamy et al. 2015
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

39. 39
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

40. 40
Coomarasamy et al. 20151 Kumar et al. 20142
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
Coomarasamy et al. 2015 versus Kumar et al. 2014
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.
AE, adverse event; CI, confidence interval; MVP, micronized vaginal progesterone; RR, relative risk

41. 41
Choice of Progestogen and Route of Administration
• Bent structure of dydrogesterone increases its bioavailability,
specificity and affinity for the progesterone receptor3,4
Coomarasamy et al. 20151 Kumar et al. 20142
Active drug
• Utrogestan® (MVP), 400 mg BID
• Vaginal suppositories
• Oral dydrogesterone, 10 mg BID
• Tablets
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. 3. Stanczyk FZ et al. Endocr Rev 2013; 34(2):171–208. 4. Schindler AE. Maturitas
2009; 65(Suppl 1):S3–S11. 5. Dydrogesterone CCDS. 2015. 6. Bulletti C et al. Hum Reprod 1997;
12(5):1073–1079; 7. Ghosh S et al. J Obstet Gynaecol Res 2014; 40(7):1871–1876.
Women in Kumar et al. 2014 were treated with dydrogesterone, which has different types of
characteristics, compared with MVP, that translate into clinical benefits
BID, twice daily; MVP, micronized vaginal progesterone
Active drug
Enhanced
progestogenic effects
Produces long,
stable effects
Increased peak
systolic velocity
• Mean terminal half-life of dydrogesterone is 5–7 hours,5 while
MVP diffuses through the uterus in 4–5 hours6
• Dydrogesterone significantly increased peak systolic velocity
in the uteroplacental blood flow (p<0.01), while MVP showed
a non-significant increase7

42. 42
Progestogens: Differentiating
Features

43. 43
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
43
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

44. 44
Howard J.A. Carp. 2015:
Source is Natural
• Source is always natural
• All progesterone including micronized progesterone produced from plant
steroids, found in Dioscorea Mexicana, plant of yam family native to
Mexico
• Dioscorea contains sterol called diosgenin - converted to progesterone
• In order to be used therapeutically, it can be micronized, converted with
UV light to dydrogesterone, or compounded to 17-OHP
• Each progesterone is artificially manipulated
Recurrent Pregnancy Loss. Causes, Controversies, and Treatment, Second Edition. Edited by Howard J.A. Carp. 2015

45. 45
• Dydrogesterone is retroprogesterone, stereoisomer of progesterone, with
additional double bond between carbons 6 and 71
• Dydrogesterone, shaped by light, enhances progestogenic effects
(improved bioavailability, and specificity and affinity for progesterone receptor)2
Structural Modification of Progesterone
1. Kuhl H. Climacteric 2005; 8(Suppl 1): 3-63.
2. Schindler AE et al. Maturitas 2009; 65(Suppl 1): S3-S11.
Progesterone Dydrogesterone

46. 46
• Metabolites of dydrogesterone retain 4,6- diene-3-one structure
• Major metabolite of dydrogesterone retains progestational activity.
Hence, it is orally effective
• Dydrogesterone has very good oral bioavailability
• Dydrogesterone brings about 100% conversion to secretory
endometrium (identical endometrial histological appearance as
seen in natural cycles)
Dydrogesterone’ s different metabolism...
Amsterdam P H et al, European J of Drug Metabolism and Pharmacokinetics, 1980, 5 (3): 173-184; Malik S, Nagpal S, Obs & Gynae
Today, August 2000, V ( 8 ) : 497-501

47. 47
• Metabolites of progesterone do not retain 4-ene- 3-one
structure. Hence, it is not orally effective
• 95% of micronised progesterone administered orally was
converted to inactive metabolites due to first pass effect
• Incomplete secretory conversion of endometrium has
been reported with oral micronised progesterone
Oral Micronised Progesterone’s different metabolism
Amsterdam P H et al, European J of Drug Metabolism and Pharmacokinetics, 1980, 5 (3): 173-184 ; Levine H L, Watson N A,
Abstract presented at the 8th International Congress on the menopause, Sydney, Australia,November 3-7, 1996; )

48. 48
Progesterone: Safety and Tolerability
Golub MS et al. Birth Defects Res B Dev Reprod Toxicol. 2006 Oct;77(5):455-70
‘‘Natural’’ Progesterone: Information on Fetal Effects
• BACKGROUND: A variety of progestational agents have been used therapeutically and evaluated for adverse
effects over the last 50 years. However, progesterone itself has come into use as a therapeutic agent only
recently with the development of an orally bioavailable ‘‘micronized’’ preparation.
• METHODS: The current review examines progesterone adverse effects as identified in the larger literature on
the toxicity of progestational agents and pharmacokinetics.
• RESULTS: Progesterone has cytoplasmic and membrane receptors in a variety of reproductive and non
reproductive tissues including the brain and is a potent inhibitor of GnRH. Limited information is available on
progesterone receptors and actions in the fetus. Concern about exogenous progestogen effects on fetal
reproductive tract development have led to considerable human research over the years, but this literature
review demonstrates that contemporary developmental toxicology research on progesterone is lacking.
• CONCLUSIONS: Progesterone is a potent,multi-faceted endocrine agent with an expanding therapeutic profile
and a minimal scientific database for evaluating safe use during pregnancy.
“With the increased use of progesterone, safe use during pregnancy needs
to be considered. …….The micronized progesterone agent Prometrium®
currently carries an FDA Category B warning for pregnancy use.

49. 49
Facts & Comparison of Different Progestogens
Preparations: Pregnancy-related Indications
Progesterone Oral Capsules1
• Indication: “Adjunctive use with estrogen in
post-menopausal women with an intact
uterus. (HRT)”
Progesterone Vaginal Capsules2
• Indication: “Supplementation of the luteal
phase during Assisted Reproductive
Technology (ART) cycles”
1. Utrogestan 200mg oral capsules SPC. UK 16 April 2013. 2. Utrogestan 200mg vaginal capsules SPC. UK 30 April 2013;; 3. Dydroghesterone prescrbing information;
4. Crinone gel 90 mg 8% prescribing information; 5. Endometrin® (progesterone) Vaginal Insert 6. http://www.rxlist.com/progesterone-injection-drug/indications-
dosage.htm.
Dydrogesterone3
- Indication: Threatened Miscarriage,
Recurrent Miscarriage, Infertility due to LPD
Vaginal Progesterone gel4
- Indication: “IVF and ART, where luteal
phase support is indicated”
Progesterone Vaginal Insert5
• Indication: “To support embryo implantation
and early pregnancy by supplementation of
corpus luteal function as part of an Assisted
Reproductive Technology (ART) treatment
program for infertile women”
Progesterone IM6
• Indication: “indicated in amenorrhea and
abnormal uterine bleeding due to hormonal
imbalance in the absence of organic
pathology, such as submucous fibroids or
uterine cancer”

50. 50
Dydrogesterone vs. Micronized Progesterone
Dydrogesterone Compared with Micronized Progesterone
• Selective for the progesterone receptor (and thus avoiding other receptor related
side-effects)1-3
• Dydrogesterone vs oral micronized progesterone
• Better oral bioavailability1,2
• Requires a 10–20 times lower oral dose1,2
• Oral micronized progesterone is associated with a risk of cholestasis in pregnancy4
• Vaginal micronized progesterone is also metabolized in the liver5
These differences translate into clinical benefits6-8
1. Schindler AE, et al. Maturitas. 2008; 61(1-2):171-180. 2. Schindler AE. Maturitas 2009; 65S: S3-S11.
3. Rižner TL, et al. Steroids. 2011;76(6):607-615; 4. Utrogestan 200mg oral capsules. SPC. UK October 2013; 5..
Utrogestan 200mg vaginal capsules. SPC. UK October 2013; 6. Patki A, et al. Gynecol Endocrinol. 2007; 23(Suppl
1): 68-726; 7. Ganesh A, et al. Fertility and Sterility. 2011;95(6):1961-1965. 8. Chakravarty BN, et al. J Steroid
Biochem Mol Biol. 2005; 97(5):416-420.

51. 51
Dydrogesterone versus Micronized Progesterone
Receptor Selectivity
Dydrogesterone is
selective for the
progesterone receptor,
avoiding other
receptor-related
side effects1–4
1. Schindler AE, et al. Maturitas 2008; 61(1-2):171-180. 2. Schindler AE. Maturitas 2009;
65(Suppl 1):S3-S11. 3. Dydrogesterone CCDS. 23 June 2015. 4. Rižner TL, et al. Steroids
2011; 76(6):607-615.
*Dydrogesterone has less pronounced anti-androgenic effects than progesterone; + effective; ±
weakly effective; – not effective
Biological activity Dydrogesterone Progesterone
Progestogenic + +
Anti-gonadotropic – +
Anti-estrogenic + +
Estrogenic – –
Androgenic – –
Anti-androgenic ±* ±
Glucocorticoid – +
Anti-mineralocorticoid ± +

52. 52
Dydrogesterone versus Micronized Progesterone
Receptor Affinity
115%
Medroxy-
progesterone
acetate
75%
Dydrogesterone
50%
Progesterone
Affinity to
progesterone
receptor1
1. Schindler AE, et al. Maturitas 2008; 61(1-2):171-180.
2. Schindler AE. Maturitas 2009; 65(Suppl 1): S3-S11.
3. Dydrogesterone CCDS. 23 June 2015.
Dydrogesterone has ~1.5 times better affinity to
progesterone receptors than progesterone1
Dihydrodydrogesterone, the main metabolite of dydrogesterone,
also has progestogenic activity1-3

53. 53
Dydrogesterone versus Micronized Progesterone
Bioavailability and Oral Administration
1. Schindler AE, et al. Maturitas 2008; 61(1-2):171-180. 2. Schindler AE. Maturitas 2009;
65(Suppl 1):S3-S11. 3. Stanczyk FZ, et al. Endocr Rev 2013; 34(2):171-208. 4. Patki A, Pawar VC. Gynecol
Endocrinol 2007; 23(Suppl 1):68-72. 5. Ganesh A, et al. Fertil Steril 2011; 95(6):1961-1965. 6. Chakravarty
BN, et al. J Steroid Biochem Mol Biol 2005; 97(5):416-420.
28%
dydrogesterone
<5% progesterone
100–300 mg
progesterone
10 mg dydrogesterone
Oral bioavailability
Dydrogesterone requires a 10–20 times lower oral dose than
micronized progesterone,1–3 providing clear clinical benefits4–6
Dydrogesterone has ~5.6 times better oral bioavailability
than progesterone1–3
Oral dose

54. 54
1. Dydrogesterone CCDS. 23 June 2015.
2. Bulletti C, et al. Hum Reprod 1997; 12(5):1073-1079.
Dydrogesterone versus Vaginal Micronized
Progesterone Absorption and Plasma Levels
Dydrogesterone reaches peak absorption levels more rapidly than vaginal progesterone,
and these levels are maintained for a longer duration1,2
Dydrogesterone1
• Has quick-effect onset (rapidly absorbed, reaching maximal levels between 30 minutes and 2.5
hours after administration)
• Has a long, stable effect (mean terminal half-life is 5–7 hours)
Vaginal progesterone2
Progesterone diffuses through the entire
uterus by 4–5 hours, and then decreases
concentration after 5 hours
Venous blood outflow from the uterus
was highest in the first 2 hours
Vaginal route permits targeted
drug delivery for a short period of time
0
50
100
150
200
250
300
350
0
10
20
30
40
1 2 3 4 5 6 12
ng/100mgtissue
%oftotal[3H]progesterone
Hours of perfusion
Output of [3H] progesterone from the vein
Endometrial extraction of progesterone
Adapted from Bulletti C, et al. Hum Reprod 1997; 12(5):1073-1079

55. 55
BID, twice daily; ns, not significant; SD, standard deviation; TID, three times daily
Ghosh et al. 2014
• Prospective, randomized, single-blinded comparative study in women with ≥3 idiopathic miscarriages
• 4 weeks’ treatment starting after pregnancy confirmation at 7‒8 weeks, continued until 12 weeks’ gestation
Ghosh S et al. J Obstet Gynaecol Res 2014; 40(7):1871–1876.
15.7%
8%
0
2
4
6
8
10
12
14
16
18
Vaginal micronized progesterone
(100 mg TID; N=51)
Oral dydrogesterone
(10 mg BID; N=50)
Miscarriagerate,%
Uteroplacental blood flow Miscarriage rate
Peak systolic velocity significantly increased after dydrogesterone treatment,
while micronized progesterone showed a non-significant increase
0
10
20
30
40
50
60
Vaginal micronized progesterone
(100 mg TID; N=51)
Oral dydrogesterone
(10 mg BID; N=50)
Peaksystolicvelocity,±SD
Baseline (7 weeks’ gestation) After 4 weeks’ treatment
p<0.01
ns
Peak Systolic Velocity
Dydrogesterone versus Micronized Vaginal Progesterone
Active drug

56. 56
Tolerability:
Dydrogesterone vs. Vaginal Progesterone
• Women prefer to use oral formulations over vaginal ones1,2
• Application of vaginal tablets requires a private clean room whereas
tablets can be taken orally anywhere1
• In a comparative study between dydrogesterone and vaginal micronized
progesterone for luteal support3
• Vaginal discharge or irritation
• Reported by 10.5% receiving vaginal progesterone
• No complaints in dydrogesterone group
• Satisfaction with the tolerability of the treatment was significantly higher with
dydrogesterone than vaginal progesterone (p < 0.05)
1. Arvidsson C, et al. Eur J Obstet Gynecol Reprod Biol 2005; 123(1): 87-91.
2. Bingham JS. Br J Vener Dis 1984; 60(3); 175-177.
3. Chakravarty BN, et al. J Steroid Biochem Mol Biol 2005; 97(5): 416-420.

57. 57
Dydrogesterone versus Vaginal Micronized
Progesterone Safety and Tolerability
• Both oral and vaginal micronized progesterone are metabolized by the liver1,2
• Progesterone is associated with a risk of cholestasis in pregnancy, therefore it is only licensed
in the UK for use up to Week 12 of gestation in ART/IVF and only by the vaginal route
• It is estimated that more than 10 million pregnancies have been exposed to dydrogesterone.
So far, there have been no indications of a harmful effect of
dydrogesterone use during pregnancy3,4
• A randomized controlled trial in 853 infertile women compared the efficacy and tolerability of
20 mg/day oral dydrogesterone and 90 mg 8% vaginal progesterone gel used for luteal
support. Numerically more local side effects occurred in the progesterone group compared to
the dydrogesterone group5
1. Utrogestan 200 mg oral capsules. SPC UK. October 2013. 2. Utrogestan 200 mg vaginal capsules.
SPC UK. October 2013. 3. Queisser-Luft A. Early Hum Dev 2009; 85(6):375-377. 4. Dydrogesterone
CCDS. 23 June 2015. 5. Tomic V, et al. Eur J Obstet Gynecol Reprod Biol 2015; 186:49-53.
Vaginal discharge Vaginal bleeding
Perineal irritation Interference with coitusSide effects
occurring at a
greater frequency
in the
progesterone
group
ART, assisted reproductive technology; IVF, in vitro fertilization

58. 58
Dydrogesterone versus Vaginal Micronized
Progesterone Preference and Acceptability
• In studies that compared oral versus vaginal formulations of non-progestin
drugs, women prefer to use oral formulations than vaginal ones1,2
• Application of vaginal tablets requires a private, clean room;
whereas tablets can be taken orally, anywhere
1. Arvidsson C, et al. Eur J Obstet Gynecol Reprod Biol 2005; 123(1):87-91.
2. Bingham JS. Br J Vener Dis 1984; 60(3):175-177.
3. Chakravarty BN, et al. J Steroid Biochem Mol Biol 2005; 97(5):416-420.
Vaginal discharge or
irritation
Dydrogesterone
group: 0%
Progesterone group:
10.5%
Satisfaction
with tolerability
of treatment
Dydrogesterone
group: ~95%
A comparative study between dydrogesterone and vaginal
micronized progesterone for luteal support3
Progesterone group:
~73%
Statistically significant difference (p<0.05)

59. 59
1. Schindler AE et al. Maturitas 2008; 61(1-2):171–180. 2. Schindler AE. Maturitas 2009;
65(Suppl 1)S3–S11. 3. Rižner TL et al. Steroids 2011; 76(6):607–615. 4. Stanczyk FZ et al.
Endocr Rev 2013; 34(2):171–208; 5. Utrogestan 200 mg oral capsules. SPC UK 2013.
6.Utrogestan 200 mg vaginal capsules. SPC UK 2013.
Dydrogesterone is selective for the progesterone receptor, thereby
avoiding other receptor-related side effects1‒3
Oral progestogens undergo hepatic first-pass metabolism4
• Dydrogesterone puts less burden on the liver as it requires
a 10–20 times lower dose than micronized progesterone1,2
• Oral micronized progesterone is associated with a risk of
cholestasis in pregnancy5
Although administered vaginally, micronized vaginal progesterone
is also metabolized in the liver6
Safety and Tolerability
Dydrogesterone versus Micronized Progesterone
Active drug

60. 60
Pharmacokinetics Parameters of Progestogens
Oral Micronized Progesterone
(MCP/MCP SR)
Dydrogesterone
Metabolite Metabolized mainly in liver to inactive
metabolites - pregnanediols &
pregnanolones
Active metabolite -“Dihydrodydrogesterone” -
explains lack of estrogenic & androgenic effects
of dydrogesterone
Bioavailability 5-10% 28%
Half-life MCP - ~7 hrs
MCP SR – 18 hrs
Dydrogesterone – 4-5 hrs and
Dihydrodydrogesterone – 17 hrs
Peak Plasma
Concentration
MCP/MCP SR - ~3 hrs Rapidly absorbed with Tmax - 0.5 and 2.5 hrs
Use during
Pregnancy
Administration of Oral MCP during 2nd &
3rd trimester of pregnancy may result in
appearance of severe cholestasis or
hepatitis
No indication in TM / RM / LPD
Indication:
- Threatened Miscarriage
- Recurrent Miscarriage
- Infertility due to LPD

61. 61
Safety of Progestogens if Given in
Early Pregnancy

62. 62
Facts & Comparison of Different Progesterone
Preparations: Hepatic Safety
Progesterone Oral Capsules1
• Warnings: Prescription of
progesterone beyond 1st trimester of
pregnancy may reveal gravidic
cholestasis
• Pregnancy: Progesterone 200mg
oral capsules not indicated during
pregnancy. If pregnancy occurs during
medication, Utrogestan 200mg
Capsules should be withdrawn
immediately
Progesterone Vaginal
Capsules2
• Warnings: During pregnancy,
Progesterone Vaginal 200mg
Capsules should only be used
during first three months & only by
vaginal route. Utrogestan Vaginal
200mg Capsules are not treatment for
premature labour. Prescription of
progesterone beyond 1st trimester of
pregnancy may reveal gravidic
cholestasis
• Pregnancy: No association has been
found between maternal use of
progesterone in early pregnancy and
fetal malformations
1. Utrogestan 200mg oral capsules SPC. UK 16 April 2013.
2. Utrogestan 200mg vaginal capsules SPC. UK 30 April 2013.

63. 63
Facts & Comparison of Different Progesterone
Preparations
• Progesterone oral
Capsules 100/200mg1
– Progesterone Capsules should
not be used during pregnancy
– Pregnancy Category B
• Dydrogesterone 10mg oral
tablet:
– Can be used during pregnancy
if clearly indicated
– >10 million pregnancies
exposed to dydrogesterone
– No reports of harmful effect of
dydrogesterone use during
pregnancy
Prometrium capsule prescribing information, dated 2011
Dydrogesterone prescribing information July 2015
Category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-
controlled studies in pregnant women.

64. 64
Progesterone
Benifla JL, et al. 1997:
• Oral administration of micronized progesterone during 2nd and 3rd
trimester poses undesirable risk on liver
• N = 201 women, placebo-controlled, double-blind study that
assessed effects of oral micronized progesterone (900 -1200
mg/day) on liver
• During 3rd trimester of pregnancy, micronized progesterone is
associated with a significant risk of biological cholestasis
Benifla JL, et al. Contracept Fertil Sex. 1997; 25: 165-7

65. 65
Dydrogesterone – Safety & Tolerability
Wahabi et al. 2011RANZCOG 2013
Howard Carp 2015 Howard Carp 2012

66. 66
Dydrogesterone – Safety & Tolerability
• Royal Australian and New Zealand College of Obstetricians and Gynaecologists 2013:
• No evidence of increase in rate of antepartum hemorrhage, pregnancy-induced hypertension, or
congenital abnormalities
• Wahabi et al. 2011 in TM:
• No evidence of increased rates of pregnancy-induced hypertension or antepartum haemorrhage as
harmful effects to mother, nor increased occurrence of congenital abnormalities on newborn
• Howard Carp 2012 in TM:
• Assessment of 22 studies & follow-up data on 1380 patients suggest that side effects including birth
defects are minimal
• Howard Carp 2015 in RM:
• Assessment of 13 studies & follow-up data on 1424 patients suggests that side effects including birth
defects are minimal
1. Wahabi HA, et al. Cochrane Database Syst Rev 2011 Dec 7; (12): CD005943. 2. Carp H. Gynecol Endocrinol 2012; 28(12): 983-990. 3. Gynecol Endocrinol, Early
Online: 1–9. 2015 Informa UK Ltd. DOI: 10.3109/09513590.2015.1006618; Royal Australian and New Zealand College of Obstetricians and Gynaecologists
(RANZCOG) 2013. http://www.ranzcog.edu.au/doc/progesterone-support-of-the-luteal-phase-and-early-pregnancy.html.

67. 67
Dydrogesterone – Safety Analysis

68. 68
Dydrogesterone – Safety Analysis
Author(s) Key Findings
Queisser-Luft,
2009
• Review of birth defects from 1977 to 2005 did not find evidence
to support association of congenital malformations with
dydrogesterone
1977 - 2005:
• ~38 million women treated with dydrogesterone
• >10 million pregnancies – Fetuses exposed to dydrogesterone in
utero
Queisser-Luft A, Early Hum Dev. 2009; 85: 375-7

69. 69
Mechanism of Action of Progesterone in
Miscarriage – Immunomodulatory &
Improvement in Uterine Blood Flow (NO
Concept)

70. 70
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

71. 71
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

72. 72
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

73. 73
PIBF and Progesterone Receptor Expression are
Decreased in Women with Recurrent Miscarriage
PIBF and progesterone receptor expression in deciduas
were significantly decreased in women with recurrent miscarriage
compared to controls (p<0.001)
Wu S et al. Pathol Res Pract 2014; 210(1): 47-54.
28.1
88.6
0
20
40
60
80
100
Recurrent
miscarriage
(n=32)
Control
(n=35)
WomenwithPIBFexpression
indeciduas,%
p<0.001
18.8
88.6
0
20
40
60
80
100
Recurrent
miscarriage
(n=32)
Control
(n=35)
Womenwithprogesteronereceptor
expressionindeciduas,%
p<0.001
PIBF, progesterone-induced blocking factor
PIBF receptor expression Progesterone receptor expression

74. 74
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)

75. 75
Raj Raghupathy et al. American Journal of
Reproductive Immunology (2015)
Am J Reprod Immunol. 2015 Aug 7. doi: 10.1111/aji.12418

76. 76
Actions of Dydrogesterone & Dihydrodydrogesterone
on Cytokines
• Dihydrodydrogesterone retains immunomodulatory effects of
progestogen dydrogesterone by bringing shift in cytokine production
profiles that might conducive to success of pregnancy
• DHD suppresses production of pro-inflammatory cytokines IFN-γ
and TNF-α and upregulates production of anti-inflammatory
cytokine IL-4 (Raghupathy et al, 2015).
Am J Reprod Immunol. 2015 Aug 7. doi: 10.1111/aji.12418

77. GDS_70000_Title_v1 77
Potential Link Between
Immunomodulation & Blood Flow

78. 78
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

79. 79
• 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
Failure of Controlled Trophoblast Invasion
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

80. GDS_70000_Title_v1 80
Mechanism of Action
Blood Flow and Nitric Oxide

81. 81
Nitric Oxide Donors Increase Blood Flow
Doppler ultrasound on Days 21–23 of the cycle
• Patients with RM had
• Significantly higher uterine artery resistance and pulsation indices versus control
• Significantly lower subendometrial vascular, flow and vascular-flow index versus control
• Administration of a NO donor to women with RM significantly decreased uterine artery
indices and increased subendometrial blood flow indices (p<0.001)
Abdel-Razik M et al. J Reprod Infertil 2014; 15(3): 142-146.
NO, nitric oxide; RM, recurrent miscarriage; SD, standard deviation
*p<0.01 vs controls; **p<0.001 vs controls; †p<0.001 vs RM
0.69
2.44
1.05
0.21
0.91
2.88
0.56
0.17
0.72
1.98
0.82
0.28
0
1
2
3
4
Resistance index Pulsation index Vascular index Vascular-flow index
Index±SD
Controls (n=30)
RM (n=30)
RM + NO donor (n=30) 12.33
9.11
10.22
0
2
4
6
8
10
12
14
16
18
Flow index
Index±SD
*
**
**
**
**
†
†
†
†
†

82. 82
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)

83. 83
Ghosh 2014
Dydrogesterone and Progesterone in Idiopathic RM
Aim
• To evaluate differences in uteroplacental blood flow and pregnancy outcome in women
with idiopathic recurrent spontaneous miscarriage
Design
• Prospective, randomized, single blinded comparative study
• Women with idiopathic ≥ 3 consecutive recurrent miscarriages
• Followed by a spontaneous conception
- Group A: Oral dydrogesterone 10mg BID (n= 50)
- Group B: Micronized vaginal progesterone 100mg TID (n= 51)
• Women with no history of recurrent miscarriage:
- Group C: Controls no therapy (n= 32)
• Treatment was given for 4 weeks in total starting after confirmation of pregnancy
at 7- 8 weeks and continued until 12th week.
Ghosh S et al. J Obstet Gynaecol Res. 2014; 40(7): 1871-1876.

84. 84
Ghosh 2014 – Dydrogesterone Increased Peak
Systolic Velocity and Decreased Miscarriage Rate
Results
Uteroplacental blood flow
• PSV (peak systolic velocity) increased
significantly after dydrogesterone
(p<0.001) while micronized progesterone
showed a non-significant increase
• Both treatments showed highly significant
changes while there was no change in the
control group in these parameters
• RI (resistance index) (p<0.0001)
• PI (pulsatility index) reduced (p<0.0001)
• S/D (systolic to diastolic ratio) (p<0.001)
• EDV (end diastolic velocity) (p<0.0001)
Mechanism of action:
Better blood flow to placenta
Ghosh S et al. J Obstet Gynaecol Res. 2014; 40(7): 1871-1876.
Dydrogesterone had a lower miscarriage rate
compared with vaginal micronized
progesterone (8% vs. 15.7%)
8 %
15.7 %
0
2
4
6
8
10
12
14
16
18
Oral dydrogesterone (n
= 50)
Vaginal micronized
progesterone (n= 51)
Miscarriage Rate

85. 85
Czajkowski et al. 2007
Dydrogesterone and Progesterone in TM
Aim
• To compare the influence of oral dydrogesterone or vaginal micronized progesterone
supplementation on uteroplacental circulation in early
pregnancy that is complicated by threatened abortion
Design
• Randomized, parallel-group, double-blind, double-dummy controlled study
• Women with threatened miscarriage with an intrauterine pregnancy confirmed by
ultrasound examination, and gestational age of <12 weeks
– Group A: Oral dydrogesterone 30 mg/day plus vaginal placebo (n=24)
– Group B: Vaginal micronized progesterone 300 mg/day plus oral placebo (n=29)
• Treatment was given for 6 weeks
Czajkowski K et al. Fertil Steril 2007; 87(3): 613-618.
TM, threatened miscarriage

86. 86
Czajkowski et al. 2007 – Dydrogesterone Decreased
S/D Ratio in the Uterine Arteries
Results
• Uterine arteries
• Dydrogesterone showed a statistically
significant (p≤0.043) drop in S/D (systolic
to diastolic ratio) and a gradual, but
statistically insignificant, decrease of
pulsatility index (PI)
• Spiral arteries
• Vaginal progesterone treatment was
associated with a significant decrease
(p≤0.041) in the spiral artery PI,
resistance index (RI) and S/D ratio
Czajkowski K et al. Fertil Steril 2007; 87(3): 613-618.
Dydrogesterone had a lower miscarriage rate
compared with vaginal micronized progesterone
(8.3% vs 13.8%), but the differences were not
statistically significant
8.3%
13.8%
0
2
4
6
8
10
12
14
16
Oral dydrogesterone
(n=24)
Vaginal micronized
progesterone (n=29)
Miscarriage rate

87. 87
Duration of progestogens use in miscarriages &
infertility
• Threatened miscarriage:
• Until symptoms remit
• Recurrent miscarriage:
• Until 20th week of pregnancy

88. 88
Progestogens - LPD

89. Definition: LPD
• Original definition of LPD presented by Jones in 1949:
Further investigation led to a broadening of this definition to include:
• Short luteal phase interval (<12 days between ovulation and menses) with
relatively normal progesterone concentrations
• Normal-length luteal phase with inadequate progesterone production, or
• Inadequate endometrial response to otherwise normal progesterone
concentrations
https://www.glowm.com/section_view/heading/Luteal%2520Phase%2520Deficiency%3A%2520Pathophysiology,%2520Diagnosis,%252
0and%2520Treatment/item/326
Corpus luteum defective in progesterone secretion, which in
turn cause of infertility or early spontaneous abortion

90. Prevalence & Incidence
• Jones et al.
• Reported LPD diagnosed by out-of-phase (≥3 days)
endometrial biopsy specimen in 3.5% of infertile patients &
35% of cases of recurrent miscarriage
• Balasch and Vanrell
• 13.5% of infertile patients had evidence of histologically
diagnosed LPD, with incidence of 32.5% for recurrent
miscarriage
https://www.glowm.com/section_view/heading/Luteal%2520Phase%2520Deficiency%3A%2520Pathophysiology,%2520Diagnosis,%252
0and%2520Treatment/item/326

91. Prevalence & Incidence
• Li and colleagues, in study of 227 menstrual cycles, reported
an incidence of out-of-phase (≥3 days) biopsy specimens in:
• 4.4% of fertile controls compared with a 14% incidence in
their infertile population
https://www.glowm.com/section_view/heading/Luteal%2520Phase%2520Deficiency%3A%2520Pathophysiology,%2520Diagnosis,%252
0and%2520Treatment/item/326

92. Incidence of LPD
• Incidence of LPD also may be influenced by the presence of mitigating factors,
such as:
• Dieting
• Recent childbirth
• Lactation
• Extremes of reproductive age
• Exercise
• Endometriosis
• Unexplained infertility
• Hyperprolactinemia
https://www.glowm.com/section_view/heading/Luteal%2520Phase%2520Deficiency%3A%2520Pathophysiology,%2520Diagnosis,%252
0and%2520Treatment/item/326

93. Etiology of Luteal Phase Deficiency
93
Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2015;103:e27-e32.
LPD
Treatment Induced (ART)
Use of GnRH
analogues to
prevent
LH surge
Aspiration of
granulosa cells
during oocyte
retrieval
Impair Corpus
Luteum’s ability to
produce sufficient
progesterone

94. Are There Diagnostic Criteria For
Inadequate Luteal Function?
Fertil Steril 2015;103:e27-e32. 2015 by American Society for
Reproductive Medicine

95. TREATMENT: LPD
• Supplemental progesterone,
• Progesterone plus estrogen,
• hCG in the luteal phase, or ovulation induction with
clomiphene or gonadotropins
Fertil Steril 2015;103:e27-e32. 2015 by American Society for Reproductive Medicine

96. Luteal Phase Dysfunction – Progesterone
Supplementation
• Progestogen supplementation is most commonly used
treatment when luteal phase dysfunction can reasonably be
assumed
• Majority of clinical studies focused on luteal phase support
during assisted reproduction
• Much less is known about role of progestogens in women with
infertility due to luteal phase dysfunction
Daya S. Luteal support: Progestogens for pregnancy protection. Maturitas 65S (2009) S29–S34

97. Balasch J et al. (1982): Infertility due to LPD
• 44 infertile women with LPD (diagnosed by histological assessment) confirmed in at least 2
consecutive cycles
• Dydrogesterone (20 mg/day) or Progesterone suppositories 25mg BD for at least 3 months &
no treatment
• Success rate significantly higher with dydrogesterone (68.7%) & progesterone (62.5%) than
in control group (16.6%) (p < 0.001)
• Equivalent to absolute treatment effect (ATE) of 45.9%, which translates into number
needed-to-treat (NNT) of 2
• Pregnancy rate - 31% in both active treatment groups, compared with 17% in group that
received no treatment
Balasch J, Vanrell JA, Márquez M, Burzaco I, González-Merlo J. Dehydrogesterone versus vaginal progesterone in the
treatment of the endometrial luteal phase deficiency. Fertil Steril 1982;37:751–4.
Success rate, defined as correction of the endometrial defect (i.e. normal secretory pattern in the endometrial biopsy) during
the fourth treatment cycle if pregnancy was not achieved, or term pregnancy

98. Author(s) • Key Findings
Malik et al. (2000)1 • 25 patients suffering from LPD; Duration - 3 months; Dose –
Duphaston 10 mg BD from day of ovulation for 14 days for 3 cycles
• Dydrogesterone treatment results in 100% secretory conversion of
endometrium
• Pregnancy rate - 37.5% with no side effects observed with
dydrogesterone therapy in this study
• Of 20.83% achieved pregnancy within first month
Malik S et al. Obs & Gynae. 2000(8):497-501
Malik et al. (2000): Infertility due to LPD

99. Why Luteal Phase Support required in IVF?
• Removal of granulosa cells at oocyte retrieval ?
• hCG suppressing LH activity ?
• High E2 suppressing LH activity ?
• Use of GnRH agonist or GnRH antagonist ?
• Combination of these factors ?
Oocyte retrieval
Damages granulosa cells
Fertil Steril 1981;36:5565–72.; Hum Reprod Update 2007;13:581–90.; Indian J Endocrinol Metab. 2013 JanFeb;17(1):
44–49

100. Cochrane 2011
Van der Linden et al. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD009154.

101. Luteal Phase Support in ART
Cochrane Review 2011
Meta-analysis of 69 randomized controlled trials with a total of 16,327 women
Total number of subjects from dydrogesterone studies = 2,360
• Belaisch-Allart (1987) dydrogesterone (D) vs. placebo
• Kupferminc (1990) D vs. placebo vs. hCG
• Chakravarty (2005) D vs. micronized vaginal progesterone (MVP) capsule
• Patki (2007) D vs. MVP capsule
• Ganesh (2011) D vs. MVP gel vs. MVP capsule
The results suggested a significant effect in favour of synthetic progesterone compared to
micronized progesterone. The only synthetic progesterone used was oral
dydrogesterone.
The route of progesterone administration does not seem to matter, although synthetic
progesterone seems to give better results, which in most cases was oral
dydrogesterone.
101
van der Linden M et al. Database of Systematic Reviews 2011, Issue 10. Art. No.: CD009154
(Note: These are experimental data. Dydrogesterone is not labeled in ART/IVF)
.

102. Cochrane 2011: Vaginal versus Oral Progesterone
Treatment
• Six studies with 801 events in 2735 participants
• No evidence of significant difference between the groups
• Outcome-Clinical pregnancy rates
Van der Linden et al. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD009154.
Treatment A- Vaginal; Treatment B - oral

103. Cochrane 2011: Micronized Vaginal versus
Dydrogesterone
• Four studies with 698 events in 2388 participants reported
• Significantly better outcome of pregnancy is seen with dydrogesterone
• Outcome: Pregnancy outcome rates
Van der Linden et al. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD009154.
Treatment A- Micronized Treatment B – dydrogesterone
Label indication of Dydrogesterone
is Infertility due to Luteal
Insufficiency and not ART as luteal
phase support

104. Luteal Phase Support for Assisted Reproduction
• Author’s Conclusion:
• Significant effect in favour of progesterone for luteal phase support,
favouring dydrogesterone over micronized progesterone
• Overall, addition of other substances such as estrogen or hCG did not
seem to improve outcomes
• Average duration of dydrogesterone given – 12 weeks of gestation*
• No evidence favouring specific route or duration of administration of
progesterone
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0016228/
*Chakravarty 2005 – up to 12 weeks; Ganesh 2011- until 12 weeks
gestation; Tomic V et al. 2015 – up to 12 weeks gestation
Label indication of Dydrogesterone
is Infertility due to Luteal
Insufficiency and not ART as luteal
phase support

105. Luteal Phase Support for Assisted Reproduction
• Author’s Conclusion:
• hCG, or hCG plus progesterone associated with a higher risk of OHSS
• Use of hCG should be avoided
• Significant results showing benefit from addition of GnRH agonist to
progesterone for outcomes of live birth, clinical pregnancy and ongoing
pregnancy
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0016228/
Label indication of Dydrogesterone
is Infertility due to Luteal
Insufficiency and not ART as luteal
phase support

106. Experimental Data with Dydrogesterone in ART*
Chakravarty 2005, Patki 2007, Ganesh 2011
4 prospective, randomized and controlled clinical trials concluded that
dydrogesterone is effective in luteal phase support in IVF
N
Oral
Dydro
Vaginal
Prog Cap
Vaginal
Prog Gel Efficacy Tolerability
Chakravarty 2005 430 20 mg/d 600 mg/d _ All similar
Vag. irritation &
discharge
Patki 2007 675 30 mg/d 600 mg/d _
Dydro
significantly
better
Ganesh 2011 1363 20 mg/d 600 mg/d 90 mg/d All similar
Vag. irritation &
discharge
Tomic 2015 831 20 mg/d _ 90 mg/d All similar
Vag. discharge
& irritation,
Dydro = dydrogesterone, Prog = progesterone
Chakravarty BM et al. J Steroid Biochem Mol Biol. 2005 ;97(5):416-20; Patki A, et al. Gynecol
Endocrinol. 2007; Suppl 1:68-72; Ganesh A et al. Fertil Steril. 2011;95(6):1961-5; Tomic V et al. Eur J
Obstet Gynecol Reprod Biol. 2015;186:49-53.
Label indication of Dydrogesterone
is Infertility due to Luteal
Insufficiency and not ART as luteal
phase support

107. Thank You