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
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
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
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.
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
Editor's Notes
We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data.
RESULTS
A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P=0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P=0.08). The incidence of adverse events did not differ significantly between the groups.
We conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation.
RESULTS
A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, −4.0 to 9.0). There were no significant between-group differences in the rate of adverse events.
There were no significant between-group differences in the rates of clinical pregnancy (at 6 to 8 weeks), ongoing pregnancy (at 12 weeks), ectopic pregnancy, miscarriage, stillbirth, and neonatal outcomes, as well as in the median gestational age at miscarriage (Table 2). A total of 533 pregnancies in the two study groups progressed to live birth after 24 weeks; the babies were delivered before 34 weeks in 10 of 262 pregnancies (3.8%) in the progesterone group and in 10 of 271 pregnancies (3.7%) in the placebo group (relative risk, 1.03; 95% CI, 0.44 to 2.45). The distributions of gestational age at the time of live-birth delivery were similar in the two study groups
Progesterone acts via its own receptor to produce a mediator protein known as progesterone-induced blocking factor (PIBF). It favors the development of human T helper (Th) cells producing Th2-type cytokines and promotes the production of interleukin (IL)-4, while inhibiting embryotoxic Th1 cytokine production.
In women with recurrent spontaneous abortion, dydrogesterone inhibits the production of the Th1 cytokines, interferon-gama, and tumor necrosis factor-alpha (TNFα) from lymphocytes and upregulates production of the Th2 cytokines IL-4 and IL-6, thereby inducing a Th1 to Th2 cytokine shift.
Reference
Patki A, Pawar VC. Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone. Gynecol Endocrinol. 2007;23 (Suppl 1):68–72.
Dydrogesterone also induces progesterone-induced blocking factor (PIBF) production. Thus, apart from progestogenic properties, dydrogesterone has been shown to have immunomodulating effects, which favor a successful pregnancy.
Reference
Patki A, Pawar VC. Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone. Gynecol Endocrinol. 2007;23 (Suppl 1):68–72.
