Progestogens in obstetrics: Which type and route????

1. Progestogens in obstetrics:
Which type and route????
Aboubakr Elnashar
Benha university, EgyptAboubakrElnashar

2. CONTENTS
1. Progestagen used during pregnancy
2. Absorption
3. Vaginal progestagen and 17 hp
4. Uses of progestagens in obstetrics
 Conclusion
4AboubakrElnashar

3. I. Progestagen used during pregnancy
Progestogen
Compound with progesterone-like action
Produces progestational changes in an oestrogen-primed
endometrium.
Transform a proliferative into a secretory endometrium to
support pregnancy.
Natural
Synthetic.
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4. Natural progestagens
Synthesized from: plant sources: soybeans and
Mexican yam roots
occasionally from: animal ovaries.
The hormone is not available from any natural source without extraction and
synthesis
Chemically and structurally identical to human
progesterone: “bioidentical” or “natural”.
Forms:
1. Oral
2. Intravaginal
3. Injectable
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5. Synthetic Progestogens= Progestins
synthetically produced and differs in structure from
progesterone.
Progesterone derivatives:
17α-oH progesterone caproate
Stereoisomers of progesterone
Dydrogesterone
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6. II. ABSORBTION
Transvaginal Progesterone.
:uterine effects with minimal systemic side effects
(Fanchin et al, 1997).
One hour after application Four hours after application
Endometrial Diffusion: Targeted delivery: Micronised Vaginal Progesterone
Progressive diffusion of progesterone from the cervix to the fundus of the uterus
(Bulletti et al. Hum Reprod. 1997)
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7. Vaginal progesterone increases endometrial tissue levels
(Fert.Steril, 2012)
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8. IM progesterone is associated with the highest
serum levels
(Fert.Steril, 2012)
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9. III. DIFFERENCE BETWEEN NATURAL
PROGESTAGEN AND 17HP
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10. Short cervix
Vaginal progesterone reduced the incidence of
PTL
(Fonseca et al, 2007; Hassan et al, 2011)
17a OH P C did not.
(Grobman et al, 2012)
Prior PTL
17a OH P C reduced the incidence of PTL
(Meis et al, 2003)
Vaginal progesterone did not.
(O’Brien et al, 2007)
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11. IV. USES IN OBSTETRICS
1.Threatened miscarriages
2.Recurrent miscarriages
3.Prevention of PTL in singleton pregnancy
4.Prevention of PTL in twin pregnancy
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12. 1. THREATENED MISCARRIAGES
 Cochrane S R. 2011:
4 studies (421)
Pandian
2009
El-Zibdeh
2009
Palagiano
2004
Gerhard
1987
(n=191)(n=146)(n=50)(n=64)
initial 40 mg
oral
dydrogesterone
followed by 10
mg twice/d
continued until
16 w
90 mg
progesterone
(Crinone
8%) vaginal
sups once
daily
for 5d
oral
dydrogesterone
10 mg twice/d
continued for
1 w after
bleeding
stopped
25mg;
progesterone;
twice/d vaginal
sups
continued for
14 d after
bleeding stopped
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13.  Progestogens is effective in the tt of threatened
miscarriage
Reduced the risk of miscarriage by 47% (with a
confidence interval consistent with a risk reduction of 21% to 65%).
Significant reduction in the mean pain score
(Palagiano 2004)
Vaginal progesterone was not statistically effective
in reducing miscarriage
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14. No statistically significant difference in between the women
who received
congenital abnormalities,
PIH
APH progestogens and those who did not.
 Limitation of MA:
1. poor methodological quality of studies
2. small number of the participants
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15.  Carp, 2012, MA
11% absolute reduction in the miscarriage rate.
significant reduction of 47% in the odds for miscarriage
when dydrogesterone is compared to standard care
Many miscarriages are caused by genetic
abnormalities in the conceptus. It is unlikely that
progestins could prevent a miscarriage of this
etiology.
controlDydrogesterone
325335Patients
24%13%Miscarriage rate
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16.  Dante et al, 2013
No evidence to support the routine use of
progesterone vaginal supp for the treatment of
threatened miscarriage.
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17. Yassaee et al, 2014
Rate of abortion was reduced in women treated
with 400 mg vaginal progesterone suppository
(Cyclogest) each day until their bleeding stopped in less
than one week.
However, the difference was not statistically
significant.
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18. 2. RECURRENT MISCARRIAGES
Mechanism:
Immmunomodulatory actions
Decreasing proinflammatory
Increasing anti-inflammatory cytokines in early
pregnancy
[Choi et al, 2000].
Duration:
Start: 3 days after the LH surge {not to inhibit
ovulation}
Continue: until 10 w
{placental progesterone production fully functional}
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19. Cochrane Database S R. 2013
4 trials, 225 women
El-Zibdeh
2005
Goldzieher 1964Le Vine
1964
Swyer
1953
1805456113
10 mg bid oral
Dydrogesterone,
5000 IU IM
hCG/4d
Duration: 12th w
10 mg/d oral
Dydrogesterone,
Duration: not
stated.
500 mg/w
IM
17 oh PC
Duration:
until 36 w
6 x 25 mg
progesterone
pellets
Duration: unclear.
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20. 3 or more consecutive miscarriages
Progestogen tt:
significant decrease in miscarriage rate compared
to placebo or no tt
(Peto OR 0.39; 95% CI 0.21 to 0.72).
2 prior miscarriages.
a trend but not a significant reduction in miscarriage
rates
(Peto OR 0.68; 95% CI 0.43 to 1.07).
Limitations of MA:
these 4 trials were of poorer methodological quality.
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21. Carp et al, 2015, SR and MA
509 women
13% absolute reduction in the miscarriage rate
significant reduction of 29% in the odds for miscarriage
when dydrogesterone is compared to
standard care
ControlDydrogesterone
23.5%10.5%Miscarriage rate
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22. AboubakrElnashar
Coomarasamy et al, 2015: NEMJ
PROMISE STUDY: 836 patients
•multicenter, double-blind, placebo-controlled,
randomized trial
Vaginal suppositories: 400 mg micronized
progesterone in 1st T did not result in a significantly
higher LBR among women with a history of un RM.

23. 3. PREVENTION OF PTL IN SINGLETON
PREGNANCY
Mechanisms of action
1. Stimulate transcription of ZEB1 and ZEB2: inhibit connexin
43 (gap-junction protein that helps synchronize contractile
activity) and oxytocin-receptor gene
2. Decrease prostaglandin synthesis, infection-mediated
cytokine production (antiinflammatory effects) by fetal
membranes/placenta
3. Changes in PR-A and PR-B expression (decreased PR-
A/PR-B ratio keeps uterus quiescent)
4. Membrane-bound PR in myometrium
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24. Maternal –Fetal medicine Society, 2012
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25. AboubakrElnashar

26. Cochrane Syst Rev.2013
Progesterone vs placebo for women with a
past history of PTB
statistically significant reduction in the risk of
Perinatal mortality
PTB less than 34 w
PTB less than 37 w
No differential effects in terms of:
Route of administration
time of commencing therapy
dose of progesterone
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27. Progesterone vs placebo for women with a
short cervix identified on US
statistically significant reduction in the risk of
PTB less than 34 w
PTB at less than 28 w
It was not possible to assess the effect of
Route of administration
gestational age at commencing therapy, or
total cumulative dose of medication.
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28. NICE, 2015
Offer prophylactic vaginal progesterone to women
with
no history of PTB or mid-trimester loss
in whom
TVS has been carried out between 16+0 and
24+0 w that reveals a cervical length of less than
25 mm.
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29. Norman et al, 2016: Lancet.
OPPTIMUM study
1,228 women
Double blind, RCT, placebo trial
vaginal progesterone, 200 mg daily taken from 22-
24 to 34 w
women at risk of PTB
previous spontaneous birth at ≤34 w
cervical length ≤25 mm
Vaginal progesterone
not associated with reduced risk of PTB or
composite neonatal adverse outcomes
no longterm benefit or harm on outcomes in children at 2
y of age.
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30. 4. PREVENTION OF PTL IN TWIN PREGNANCY
Maternal –Fetal medicine Society, 2012
No evidence of effectiveness
Cochrane Syst Rev.2013
Progesterone vs placebo for women with a
multiple pregnancy
no statistically significant differences
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31.  Schuit et al, 2014, MA
13 trials included 3768 women
Neither 17Pc (250 mg/w) nor
vaginal progesterone **
reduced the incidence of PTL
**Pessary: 200-400 mg
Gel: 90 mg
Sups: 100 -400 mg
Caps: 200 mg
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32. In a subgroup of women with a cervical length of
≤25 mm:
vaginal progesterone reduced PTL when cervical
length was measured
at randomisation (15/56 vs 22/60; RR 0.57; 95% CI 0.47–0.70) or
before 24 w of gestation (14/52 vs 21/56; RR 0.56;95% CI
0.42–0.75).
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33. Brubaker et al, 2015
vaginal progesterone therapy in twin pregnancies
with a CL ≤2.5 cm: an increased risk of PTB
Brizot et al, 2015
In nonselected twin pregnancies,
vaginal progesterone administration:
No prevent and does not reduce neonatal
morbidity and death.
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34. CONCLUSION
1. T M and RM: Oral
2. PTL in Singleton:
Short cx: vaginal (NICE, 2015)
Previous PTL: IM
4. PTL in Twin:
Short cx: vaginal (Schuit et al, 2014, MA)
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