Why Indian Gynaecologist use Dydrogesterone in RPL ?

1. Role of Dydrogesterone
in
Recurrent
Pregnancy
Loss
Dr. Sharda Jain
Dr Jyoti Agarwal

2. Why Indian Gynaecologist use
Dydrogesterone in RPL ?

3. Introduction
Pregnancy loss can have a significant negative impact on the
life of couple particularly when faced with recurrent losses.
Recurrent pregnancy loss is an important reproductive
health issue, affecting 2%–5% of couples.
RPL can be challenging to the obstetricians, as even after
intensive work-up, definite cause is not always known.
Int J Womens Health. 2017; 9: 331–345
https://www.ncbi.nlm.nih.gov/books/NBK430747/

4. Progesterone is an essential hormone in the process of reproduction.
It induces secretory changes in the lining of the uterus and is essential for a successful implantation of
the embryo.
Moreover, Progesterone modulates the immune response of the mother to prevent rejection of the
embryo, and enhances uterine quiescence and suppresses uterine contractions.
Therefore it is theoretically plausible that progesterone supplementation may reduce the risk of
miscarriage in women with a history of recurrent miscarriages.
Role of progesterone
Facts Views Vis Obgyn. 2013; 5(1): 66–71

5. Natural Progesterone
 The term "natural progesterone" in reality is a
misnomer.
 "Natural Progesterone" are made from a
chemical called diosgenin that is isolated from
wild yam or soy.
All progesterone and progestin products are made in the laboratory.

6. Is there a role of Micronized
vaginal Progesterone in RPL ?

7.  Total 4153 Women Were Participated In The Trial
 Duration Of Study : 34 Weeks
Group 1
• 400 mg of Micronized Vaginal
Progesterone Twice Daily
• 2079 women
Group 2
• Placebo
• 2074 women
N Engl J Med 380;19 nejm.org May 9, 2019
PRISM
2019

8. PRISM: Primary Outcome and Secondary Outcomes
There was No significant increase in live births with progesterone in the first
trimester among women with bleeding in early pregnancy.

9. Group 1
• 400 mg of Micronized Vaginal
Progesterone Twice Daily
• 404 women
Group 2
• Placebo
• 432 Women
 Total 836 Women Were Participated In The Trial
 Duration Of Study : 24 Weeks
N Engl J Med 373;22 nejm.org November 26, 2015
PROMISE
2015

10. PROMISE: Pregnancy Outcome

11. PROMISE: Distribution of Gestational Age
Pregnancies that continued beyond
24 weeks. The hazard ratio for
miscarriage in the progesterone
group, as compared with the placebo
group, was 1.04 (95% CI, 0.91 to
1.19).
There was No significant increase in live birth rates with progesterone than placebo
in women with a history of unexplained recurrent miscarriages.

12. Limitation of Natural Progesterone
Lower
Bioavailability
Poor Oral
Absorption
High First-Pass
Mechanism
Higher Side
effects
Multiple
preparations
Patient
Compliance
Multiple Formulation
Variable Dosing

13. What Ideal Progesterone Should have?
 Higher Bioavailability and Predictable Plasma Concentration
 Lower Dosage and Dosing Convenience
 Favourable Tolerability
 Higher Compliance
Is ‘Retro’ Progesterone a solution ??

14. Dydrogesterone & Micronized Progesterone
Are Synthesized From Natural Source
Progesterone
Undergoes processing Light technology bends it into
to become a curved retrosteroid structure
Micronized Progesterone Dydrogesterone
Dioscorea plants
Both progesterone and dydrogesterone are produced from the
same dioscorea plant
Shaped by light, enhances the progestogenic effects
(improves bioavailability,specificity & affinity for the progesterone receptor potency &
side effects)
Small changes can make a difference

15. ‘Retro’ Progesterone
15
Dydrogesterone
In dydrogesterone molecule, hydrogen at
carbon 9 is in beta position & methyl group
at carbon 10 is in alpha position
- a reverse of the progesterone structure
Improved oral activity, metabolic
stability, and lack of Estrogenic,
Androgenic and Mineralocorticoid
properties.
Used to treat a variety
of conditions related
to progesterone
deficiency since the
1960s.
Ref: Reprod Biomed Online. 2019 Feb;38(2):249-259. doi: 10.1016/j.rbmo.2018.11.017

16. Receptor Binding Affinities:
Dydrogesterone Vs. Progesterone
Receptor Agonistic
Activity
Dydrogesterone Physiological
Progesterone
Progesterone
Receptor
176 100
Androgen Receptor 0.6 100
Dydrogesterone is non-androgenic, also non-estrogenic, non-corticoid and non-anabolic.
Ref: Reprod Biomed Online. 2019 Feb;38(2):249-259. doi:

17. Comparison between Dydrogesterone vs
Natural Micronized Progesterone
 Higher bioavailability than oral micronized progesterone.
 High selectivity for progesterone receptors with low anti-androgenic effects at the
pre-receptor level, thus minimizing activation of other receptors and unwanted
effects.
 Oral dydrogesterone has a good benefit–risk profile comparable to that of NMP
during luteal phase support.
Ref: Reprod Biomed Online. 2019 Feb;38(2):249-259. doi: 10.1016/j.rbmo.2018.11.017
It elicited biochemical changes consistent with secretory transformation at a dose of
10 mg, whereas oral micronized progesterone required a dose of 200 mg

18. Dydrogesterone Versus Natural Micronized Progesterone

19. Comparing Dydrogesterone with NMP
The orally-active progestogen Dydrogesterone is quite attractive from
this perspective.
In contrast to natural progesterone,
 Potent: 20-30 mg daily
 High bioavailability (28%) and half-life of 5–7 hours
 Non-androgenic, non-estrogenic, non-corticoid and non-anabolic
 Immunomodulatory role
19

20. Clinical Evidences Of Dydrogesterone In RPL

21. The Journal of Obstetrics and Gynecology of
India
https://doi.org/10.1007/s13224-021-01473-2
Oral dydrogesterone is preferred over vaginal progesterone in patients presenting with vaginal
bleeding during early pregnancy and a history of recurrent early pregnancy loss.

22. WHY

23. Immunomodulatory Action
 Progestogens prevent myometrial contractility and prevent cervical dilatation.
 Activation of progesterone receptors on lymphocytes results in the synthesis of a protein known as
progesterone-induced blocking factor (PIBF). PIBF favors the production of asymmetric, pregnancy-
protecting antibodies.
Enhances
Implantation
Affect Cytokine
Balance
Inhibit Natural
Killer Cell
Activity
Inhibit Release of
Arachidonic Acid
Immunomodulatory
Action
Gynecological Endocrinology, 2012; 28(12): 983–990

24. Immunomodulating Effects of Dydrogesterone
and Positive Outcomes
Patki A, et al. Gynecol Endocrinol. 2007;23 (Suppl 1):68–72.
Th: T helper; IFNγ: Interferon gama; TNFα: Tumor necrosis factor-alpha.
Dydrogesterone
inhibits Th1
cytokines, IFN-γ and
TNFα production.
Harmful cytokine
Embryo/fetus
T-helper 1 cell response activated
Tumor necrosis factor- , interleukin-2
Abortion of fetus
Natural killer cells
Immunological reactions during recurrent pregnancy loss
Lymphokine-activated killer cells
…Caring hearts, healing hands

25. Dydrogesterone Induces PIBF Production
Patki A, et al. Gynecol Endocrinol. 2007;23 (Suppl 1):68–72.
PIBF: Progesterone induced blocking factor.
Immunological reactions during successful pregnancy
Dydrogesterone
induces PIBF
production.
Progesterone receptor activation
 Progesterone-induced blocking factor
Blocks cascade reaction, shift to T-helper type 2
Embryo-protective immunomodulation
Protection of embryo/fetus
…Caring hearts, healing hands

26. Dydrogesterone and Nitric Oxide
 Dydrogesterone Increases Nitric Oxide.
 Nitric Oxide acts as a potent vasodilator and plays a major role in Increasing Uterine
Blood Flow and Endometrial Blood Flow during luteal phase and early pregnancy.
Increased e NOS activity
Increased e NOS synthesis
Increased NO Production
Patients with unexplained recurrent abortion had significantly higher uterine
artery resistance and pulsation indices and lower sub-endometrial vascular,
flow and vascular-flow index.
J Reprod Infertil. 2014;15(3):142-146

27. FOGSI Position Statement 2015: Micronized
progesterone and Dydrogesterone
• When taken orally, exogenous progesterone is absorbed rapidly, but almost the
entire dose is expected to be metabolized completely in one pass through the gut
and liver. Hence, the vaginal route or injectable route is preferred for
administration of exogenous progesterone.
• Dydrogesterone, a progestogen that has high specific affinity for progesterone
receptors, no affinity for androgen, mineralocorticoid, glucocorticoid, and
estrogenic receptors.

28. FOGSI Position Statement: Progesterone
Support in Recurrent Pregnancy Loss
• Dydrogesterone is known for immunomodulatory properties:
• decreasing pro-inflammatory
• increasing anti-inflammatory cytokines
• Argument for use of progesterone; no evidence of harm & some
evidence of benefit. Decision should be based on clinician's discretion
• Recurrent Miscarriage:
• Oral Dydrogesterone 10 mg BD till 20 weeks of pregnancy
• Micronized Progesterone : 400 mg /day vaginally till 20 weeks of pregnancy

29. FOGSI Position Statement: Safety of Progesterone
• There is no statistically significant difference in the congenital
abnormalities seen in the clinical studies between the newborns of
the mothers who received progesterone and those who did not.
• Progesterone should be used with caution in patients with
cardiovascular diseases and in patients with impaired liver function
and cholestasis.

30. Key Results of the KAP survey conducted by
Emcure pharmaceuticals Ltd.PAN INDIA
 Survey sites: Pan-India; 1168 sites
 Data collection period: December 2020 to Feb 2021
 Objectives: To assess attitudes and perception/practices of
obstetrician and gynecologists towards use of dydrogesterone in
daily clinical practice.
Current Place of Dydrogesterone: Insights from Daily Clinical Practice

31. • Indian doctors mostly prefer to use dydrogesterone along with micronized progesterone.
• The most common indication reported for co-administration of dydrogesterone and micronized
progesterone was recurrent miscarriage followed by threatened abortion and luteal phase support.
Key Results from KAP Survey
Current Place of Dydrogesterone: Insights from Daily Clinical Practice

32. To conclude... • Recent studies, Meta analysis supports
superiority of oral dydrogesterones over
NMP
• Oral dydrogesterone can effectively prevent
miscarriage in pregnant women
experiencing unexplained Recurrent
Pregnancy Loss
• Possess immunomodulatory property

33. Take home points
As compared to natural micronized progesterone,
Dydrogesterone has:
High oral bioavailability
Is Non-androgenic, non-estrogenic, non-corticoid and non-anabolic
Offers Patient-friendly oral administration which improves patient compliance
Provides better safety and patient tolerability