Progesteron & Estrogen - Clinical Applications

2. Progesterone & Estrogen
Clinical Applications

3. • Progesterone is an essential hormone in the
female reproductive system.
• In conjunction with estrogen (mainly in the form
of estradiol), it controls uterine function to
facilitate reproduction.
• The central role of these hormones is reflected
in the fact that progesterone/estrogen therapy
alone is sufficient to produce a receptive uterus
capable of supporting a viable pregnancy in
post-menopausal women receiving donor
embryo transfer.

4. • Progesterone is made from pregnenolone,
which in turn comes from cholesterol.
• About 20-25 mg of progesterone is produced
per day during a woman's monthly cycle.
• Up to 300-400 mg are produced daily during
pregnancy.
• During menopause, the total amount of
progesterone produced declines to less than
one percent of the pre-menopausal level. This
drop is extreme

5. The principal uterine targets for progesterone
• Stromal and epithelial cells in the endometrium
• Smooth muscle cells in myometrium
• Stromal fibroblasts and glandular
Epithelial cells in the cervix.

6. Clinical Implications
• Infertility & LPD
• Threatened Abortion, RPL
• Preterm labour
• Menopause
The Multiple Roles of A Remarkable Hormone

7. Progesterone deficiency and abortion
• A classic series of studies conducted more than three decades ago
demonstrated that progesterone secretion by the corpus luteum is
absolutely required for the success of early human pregnancy.
• Surgical excision of corpus luteum (before 7 weeks’ gestation) uniformly
precipitated an abrupt decrease in serum progesterone concentration
followed by miscarriage.
• When luteectomy was performed 8 weeks gestation or later,
progesterone levels decreased only slightly and transiently and
pregnancy continued
Fertility and sterility. 2008 Nov; 90(3): S150-153

8. Luteal-placental shift

9. Role of progesterone in luteal phase
• Progesterone induces a
secretory transformation of
the endometrium by
inducing this change after
adequate estrogen priming,
progesterone improves
endometrial receptivity
Fatemi HM et al. Human Reproduction Update. 2007;13(6):581–590.

10. Uterine relaxant properties
• Local vasodilatation and uterine musculature
quiescence by inducing nitric oxide synthesis in the
decidua
Fanchin et al. (1998).
• A negative correlation between UC frequency and
progesterone concentrations was detected underlining
the benefits of progesterone in IVF
Fatemi HM et al. Human Reproduction Update.
2007;13(6):581–590.

11. Luteal phase defect in a natural cycle
•The prevalence of a luteal phase defect in
natural cycles in normo-ovulatory patients with
primary or secondary infertility = 8.1%
(Rosenberg et al., 1980)
ESHRE lecture handouts. The luteal phase in a natural and stimulated cycle. Accessed on 24th
May 2015. Available at
http://www.eshre.eu/~/media/emagic%20files/SIGs/Reproductive%20Endocrinology/Madrid%202010/Blockeel.pdf

12. Progesterone Deficiency and Abortion
•A 2002 meta-analysis of RCTs of IVF cycles using
GnRH agonists observed that all luteal phase
support regimens yield significantly higher pregnancy
rates compared with placebo or no treatment
•A 2004 Cochrane systematic review of 59 studies
concluded that IVF cycles involving down-regulation
with a long-acting GnRH agonist, progesterone
supplementation achieved higher ongoing pregnancy
rates per embryo transfer compared with placebo or
no treatment (Odds ratio: 2.4)
Fertility and sterility. 2008 Nov; 90(3): S150-153

13. Causes of LPD in a natural cycle
• Disordered folliculogenesis
• Defective corpus luteum function
• Abnormal luteal rescue by the early pregnancy
• A variety of clinical conditions, such as
– Hyperprolactinemia
– Hyperandrogenic states
– Weight loss
– Stress
– Athletic training may result not in oligo- or anovulation, but rather
may be manifest as LPD (Ginsburg , 1992).ESHRE lecture handouts. The luteal phase in a natural and stimulated cycle. Accessed on 24th
May 2015. Available at http://www.eshre.eu/~/media/emagic
%20files/SIGs/Reproductive%20Endocrinology/Madrid%202010/Blockeel.pdf

14. How to define a LPD in a natural cycle?
•Serum mid-luteal progesterone levels < 10ng/ml (Jordan
et al.,1994)
•Mid-luteal progesterone levels do not always reflect the
endometrial maturation (Batista et al., 1994)
•“Most reasonable” consensus = a lag of more than two
days in endometrial histological development compared to
the expected day of the cycle (Jones, 1991; Dawood,
1994)
ESHRE lecture handouts. The luteal phase in a natural and stimulated cycle. Accessed on 24th
May 2015. Available at http://www.eshre.eu/~/media/emagic
%20files/SIGs/Reproductive%20Endocrinology/Madrid%202010/Blockeel.pdf

15. The luteal phase in stimulated cycles

16. Is luteal support necessary in GnRH
antagonist cycles?
Beckers NG et al. J Clin Endocrinol Metab. 2003 Sep;88(9):4186-92.

17. The use of progesterone in IVF
Nosarka S et al. Gynecol Obstet Invest. 2005;60(2):67-74.

18. What is the best timing of luteal support?
• The administration of progesterone before oocyte
retrieval is associated with a lower pregnancy rate
than the administration of progesterone after
oocyte retrieval. (Sohn et al., 1999)
• Decrease of preg rate 24% was seen when luteal
phase support was delayed until 6 days after or
compared to 3 days after (Williams et al., 2001)
Williams SC, et al. Fertil Steril. 2001 Dec;76(6):1140-3.Sohn SH et al. Fertil Steril. 1999 Jan;71(1):11-4.

19. Published: July 14, 2017

20. Published: May 17, 2017
Results showed that on multivariate analysis sperm motility
(p<0.01) and progesterone levels at ovulation triggering (p =
0.01) were the only two variables that significantly predicted
top quality blastocyst formation rate after adjusting for
relevant factors including female age, BMI, basal AMH and
total dose of FSH used for COS.
progesterone levels at induction showed
an inverse relation with top quality
blastocyst formation (correlation
coefficient B = -1.08, 95% CI -1.9
to -0.02) and ROC curve analysis
identified P level >1.49 ng/ml as the best
cut-off for identifi- cation of patients at risk
for the absence of top quality blastocysts
(AUC 0.55, p<0.01).
Conclusion : Increasing progesterone is associated with lower rates of top quality blastocyst. Hence, the
advantages of prolonging COS to maximize the number of collected oocytes might eventually be hindered
by a decrease in top quality blastocysts available for transfer, if increasing progesterone levels are

21. 1. LPD - Evidence

22. Embryo protective
Immunomodulation
- How is this brought about?
Normal Pregnancy
Progesterone(P) Receptor Activation
Blocks Cascade Reaction, Shift to Th type 2
Embryo Protective Immunomodulation
Protection of Embryo / Fetus
Progesterone Induced Blocking Factor(PIBF)

23. Embryo Protective
Immunomodulation – What is it?
Raghupathy et al., (2000): Cytokine production by maternal lymphocytes during normal human
pregnancy and in unexplained recurrent spontaneous abortion. Hum. Reprod. 15(3); 713-18.
3 Positive responses
T helper 2 cell response NK Activity
Asymmetric Antibodies
No binding with Antigen
No activation of
Complement Cascade
Protection of Fetus
Protective
Cytokines
IL 3
IL 4
IL 5
IL 6
IL 10
IL 13

24. Progesterone supplement in Threatened Abortion
: An immunologic therapy
• Stimulatation of the secretion of Th2 and reduces the
secretion of Th1 cytokines.
• Th2 cells are dominant within the decidua in early pregnancy
• The Th2-derived cytokines, IL-4 and IL-6, induce the release
of hCG from trophoblasts
• hCG stimulates progesterone production from corpus luteum
in pregnancy.

26. Cochrane review Results
• Four studies (421 participants) in the meta-analysis.
• Reduction in the rate of spontaneous miscarriage with the
use of progestogens compared to placebo or no treatment
(risk ratio (RR): 0.53; 95% confidence interval (CI) 0.35 to 0.79).
• No increase in the rate of antepartum haemorrhage (RR
0.76; 95% CI 0.30 to 1.94), or PIH (RR 1.00; 95% CI 0.54 to
1.88) for the mother.
• Rate of congenital abnormalities was no different between
the newborns of the mothers who received progestogens and
those who did not (RR 0.70; 95% CI 0.10 to 4.82)Wahabi HA et al. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD005943.

27. Progestogens for Luteal Support
• Luteal function is usually compromised in ART cycles both
in GnRH agonist & antagonist protocol
• Endogenous progesterone deficiency is responsible for
implantation failure & early miscarriages
• Adequate luteal phase support is required during ART to
improve implantation and pregnancy rates, which can be
achieved by either hCG or directly by using progesterone
http://www.fogsi.org/fogsi-gcpr/. Accessed on 12th
Jan 2016
FOGSI Position Statement

28. Progestogens for Luteal Support
• Progesterone supplementation is advisable starting just
after Oocyte Retrieval/Embryo Transfer
• Duration of exogenous progesterone therapy generally
varies up to 10 – 12 weeks of gestation
http://www.fogsi.org/fogsi-gcpr/. Accessed on 12th
Jan 2016

29. FOGSI Position Statement
Progestogens for Luteal Support
• Dydrogesterone: 20-30 mg/day
http://www.fogsi.org/fogsi-gcpr/. Accessed on 12th
Jan 2016
Oral Route
Vaginal Route
• Micronized Progesterone: 600 – 800 mg/day
capsules & Gel: 8% (90 mg) OD
• Intramuscular progesterone: 50-100 mg/day
IM Route
Dydrogesterone is indicated for Infertility due to Luteal
Insufficiency and not ART as luteal phase support

30. Phase III study for Luteal Support ongoing in
several European, Middle East, Asian countries
• Dydrogesterone & Micronized Progesterone
vaginal capsules in ART (IVF)
http://www.fogsi.org/fogsi-gcpr/. Accessed on 12th
Jan 2016
LOTUS I
• Dydrogesterone & Micronized Progesterone
vaginal gel in ART (IVF)
LOTUS II
Dydrogesterone is indicated for
Infertility due to Luteal Insufficiency
and not ART as luteal phase support

31. Progesterone supplementation in recurrent pregnancy
loss
• Efficacy of progesterone supplementation in patients with unexplained
recurrent miscarriages.
• 9-year cohort study of women with otherwise unexplained recurrent
miscarriages who attended a recurrent miscarriage clinic in a tertiary care
university hospital
• Women with at least three unexplained recurrent miscarriages were included
in the study.
• For women with inadequate endogenous progesterone secretion, natural
progesterone vaginal pessaries 400 mg 12-hourly were offered until 12
weeks gestation.
Hussain M et al. J Hum Reprod Sci. 2012 Sep-Dec; 5(3): 248–251.

32. Risk of repeat miscarriage after
progesterone supplementation
Hussain M et al. J Hum Reprod Sci. 2012 Sep-Dec; 5(3): 248–251.

33. Evidence2. RPL

34. Preterm Labour..
• Preterm birth is a broad outcome measure resulting
from heterogeneous influences.
• These include infection estimated at 25% of preterm
birth, multiple gestations 3% of all pregnancies and
15% – 20% of preterm births, pre- eclampsia or
growth restriction 30% of pre- term births (Goldenberg
et al. 2008).
• The largest single category of preterm birth, however,
remains spontaneous idiopathic

35. • The inability to predict impending spontaneous
idiopathic preterm birth, or intervene to prevent
it, arises largely from the limited understanding
of the causal mechanistic pathways, which
could reflect early activation of normal
parturition mechanisms

37. Papiernik-Berkhauer Scoring matrix…
modified by Gonik-Creasy

38. Progesterone Supplementation to
Prevent Preterm Birth
Progesterone supplementation in women with a history of a
spontaneous preterm birth

39. The purpose of this study was to evaluate the effect of
prophylactic vaginal progesterone in decreasing preterm
birth rate in a high-risk population.
Study design
• A randomized, double-blind, placebo-controlled study
included 142 high-risk singleton pregnancies.
• Progesterone (100 mg) or placebo was administered
daily by vaginal suppository
• All patients underwent uterine contraction monitoring
with an external tocodynamometer once a week for 60
minutes, between 24 and 34 weeks of gestation.
• Progesterone (n = 72) and placebo (n = 70) groups were
compared for epidemiologic characteristics, uterine
contraction frequency, and incidence of preterm birth.
da Fonseca EB et al. Am J Obstet Gynecol. 2003 Feb;188(2):419-24.

40. Results
• Differences in uterine activity were found between the
progesterone and placebo groups (23.6% vs 54.3%,
respectively; P <.05) and in preterm birth between
progesterone and placebo (13.8% vs 28.5%,
respectively; P <.05).
• More women were delivered before 34 weeks in the
placebo group (18.5%) than in the progesterone group
(2.7%) (P <.05).
Conclusion
• Prophylactic vaginal progesterone reduced the
frequency of uterine contractions and the rate of
preterm delivery in women at high risk for
prematurity. da Fonseca EB et al. Am J Obstet Gynecol. 2003 Feb;188(2):419-24.

41. Rode L et al. Acta Obstet Gynecol Scand.
2009;88(11):1180-9.

42. • Meta-analysis of all six studies now showed that
progesterone supplementation was associated with a
significant reduction of delivery before 32 weeks and of
perinatal mortality.
• A positive effect on women with a short cervix at 23 weeks
• Reduces the risk of preterm delivery in women with preterm
labor.
Conclusions
• In women with a singleton pregnancy and previous
preterm delivery, progesterone reduces the rates of
preterm delivery before 32 weeks, perinatal death, as well
as respiratory distress syndrome and necrotizing
enterocolitis in the newborn.
• Women with a short cervix or preterm labor may also
benefit from progesterone
Rode L et al. Acta Obstet Gynecol Scand. 2009;88(11):1180-9.

43. Evidence
PTL

44. Evidence3. PTL

45. Menopausal clinical application….

46. Need of the hour..
• It was estimated that by 2010, the population of
women between the ages of 45 and 64 will reach
approximately 42 million. Among the health-related
changes and decisions these women will need to
consider include whether or not to consider the use of
hormone therapy for not just the management of
menopausal symptoms, but potentially, to help
maintain a healthy brain.
(U.S. Census Bureau. Projected population of the United States, by Age and
Sex: 200 to 2050. www.census.gov/ipc/www/usinterimproj/ Internet release
date: March 18, 2004)

47. Progesterone in Menopause
•Progesterone has been shown to exert neuroprotective
effects, both in cell models, animal models and in humans
•The classical, intracellular/nuclear PR certainly plays an
important role in mediating the effects of progesterone. For
example, our laboratory has determined that the ability of
progesterone to increase the expression (mRNA and protein
levels) of brain- derived neurotrophic factor (BDNF), a key
mediator of progesterone’s protective effects, requires the
classical PR (Jodhka et al., 2009)

48. Which progesterone?
• Progesterone is protective and that such protection can be
afforded through multiple mechanisms. In addition, the data
from several laboratories support the conclusion that not all
progestins are created equal, particularly within the context
of neuroprotection.
• Such differences may be important in considering the results
of the WHIMS studies which used MPA rather than
progesterone, and further, could provide critical insight into
the development of the most effective therapeutic
formulations for the treatment of the menopause and various
diseases whose incidence increases during the post-
menopausal period.

49. Role of progesterone?
• Medroxyprogesterone acetate (MPA), a synthetic
progestin derived from 17α- hydroxyprogesterone, is
often used in conjunction with estrogens to reduce the
risk of certain cancers (cervical cancer, for example)
resulting from unopposed estrogen therapy (Gambrell,
1986; Hirvonen, 1996).
• First, though both progesterone and MPA can bind to
the classical PR, it is important to recognize that there
are important pharmacological and pharmacokinetic
differences between MPA and progesterone.

50. • While progesterone and MPA may be equally effective
at reducing the uterotrophic effects of un-opposed
estrogen treatment, their effects on the brain are far
from identical.
• The difference in neuroprotective efficacy between
progesterone and MPA may have been attributed to their
differential regulation of BDNF
• MPA, failed to alter the glutamate-induced influx of Ca2+. And
also blocked the beneficial effect of estradiol.
• MPA has been shown to inhibit the biosynthetic enzymes associated
with the conversion of progesterone to allopregnanolone. Thus, both
the inability of MPA to be converted to neuroactive steroid
metabolites in conjunction with its effect in reducing potential
conversion of progesterone to allopregnanolone may contribute to its
lack of neuroprotection.

51. Progesterone support in Unexplained RPL

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

53. Progesterone support in unexplained recurrent
/spontaneous miscarriage
Evidence from studies show reduced miscarriage and
better pregnancy chances
1. http://www.isrctn.com/ISRCTN92644181 ( Accessed on 14th
January 2015)
PROgesterone in early MIScarriage (PROMISE) study
Study design
Multicentre double blind randomised placebo controlled
trial
Main Inclusion Criteria
Women with unexplained recurrent miscarriages (3 or
more first trimester miscarriages); age 18 - 39 years at
randomisation; spontaneous conception (as confirmed
by urinary pregnancy tests) ; willing and able to give
informed consent07/04/18

54. Primary objective
To test the hypothesis that in women with unexplained recurrent
miscarriages, progesterone (400mg pessaries, b.i.d), started soon
after a positive pregnancy test (at < 6 weeks gestation) and
continued to 12 weeks of gestation increases live births beyond 24
completed weeks of pregnancy by at least 10% compared to
placebo.
Secondary objectives
•Progesterone improves various pregnancy and neonatal
outcomes.
•Progesterone does not incur substantial adverse effects to the
mother or the neonate compared to placebo.
•To explore differential or subgroup effects of progesterone in
various prognostic subgroups. Three subgroup analyses are
planned: a)by maternal age (<35, =35), b) Number of previous
miscarriages (3, =4) and c) presence or absence of polycystic
ovaries.
• To evaluate economic cost-effectiveness

55. Disappointment
• Many hoped that this research would confirm progesterone
as an effective treatment that would promise an increased
chance of a ‘take-home’ baby next time. Sadly, it does not.
• The trial results will be disappointing to many health
professionals and NHS commissioners too. Those who care
for women with recurrent miscarriage want to reduce the
incidence of repeated pregnancy loss and the considerable
distress it causes. Some have prescribed progesterone
because they hoped it might help their miscarriage patients
and now, along with their patients, they are faced with
evidence that no longer supports this.

56. Positives too
• The first is that nearly two-thirds of the women in the trial had their baby,
whether they had progesterone or the placebo. So even without treatment,
the chances of a healthy pregnancy after unexplained recurrent miscarriage
are better than some might expect.
• The trial results also showed that there were no harmful effects of
progesterone treatment for women or for their babies. That is very important
information for women taking progesterone for other reasons, such as
fertility treatment or for those taking part in the
PRISM (progesterone in threatened miscarriage) trial.
• Another important finding for women who do take progesterone in early
pregnancy is that there was no sign that progesterone treatment
simply delayed the process of miscarriage. Amongst those who miscarried,
there was no difference between the treated and untreated women in the
stage at which they miscarried.

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

58. 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.

59. 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.

60. 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)
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
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.

61. 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
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
Coomarasamy A et al. N Engl J Med 2015; 373(22):2141–2148.

62. 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 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

63. 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

64. • Perhaps most important is that we finally know
the answer to a clinically important question
that has remained unanswered since
progesterone was first proposed as a treatment
for recurrent miscarriage back in 1953
• And that means that researchers can now
direct their efforts to exploring and testing other
treatments that really can reduce the risk.
07/04/18

65. Imbalances of Estrogen and
Progesterone in female
1.Progesteron deficiency This is the most common hormone
imbalance among women of all ages.
Solution: Estrogen free diet, discontinue birth control pill and use
progesterone to increase the progesterone level.
2.Estrogen deficiency: This hormone imbalance is most common in
menopausal women; especially with petite and/or slim women. Solution:
Progesterone is a biochemical precursor to
estrogen.solution Progesterone alone is sufficient to restore
estrogen balance and relief of many of the symptoms
3.Excessive estrogen This often comes about from excessive estrogen
intake as part of a hormone replacement therapy program.
Solution: Discontinue estrogen replacement therapy that uses
estrogen alone.

66. 4.Excessive androgens Excessive sugar and simple carbohydrates in
the diet often cause this. Excessive sugar stimulates androgen
receptors on the outside of the ovary
Solution: Dietary adjustment to reduce sugar and grains and proper
exercise are important.
5.Estrogen dominence Combination of absolute progesterone
deficiency and excess estrogen, resulting in a relative increase in
estrogen in comparison to progesterone.This is the result of low
estrogen but even lower progesterone. Up to 50% of western women,
especially those who are obese between the ages of 40 and 50 suffer
from estrogen dominance. Solution: Reduce Stress, Sugar and coffee
from diet.

67. Luteal-placental shift