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

Aboubakr Elnashar

Benha university, Egypt

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CONTENTS

1. Progestagen used during pregnancy

2. Absorption

3. Vaginal progestagen and 17 hp

4. Uses of progestagens in obstetrics

Conclusion

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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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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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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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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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Vaginal progesterone increases endometrial tissue levels

(Fert.Steril, 2012)

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IM progesterone is associated with the highest

serum levels (Fert.Steril, 2012)

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III. DIFFERENCE BETWEEN NATURAL

PROGESTAGEN AND 17HP

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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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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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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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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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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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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.

control Dydrogesterone

325 335 Patients

24% 13% Miscarriage rate

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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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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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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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Cochrane Database S R. 2013

4 trials, 225 women

El-Zibdeh

2005

Goldzieher 1964 Le Vine

1964

Swyer

1953

180 54 56 113

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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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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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

Control Dydrogesterone

23.5% 10.5% Miscarriage rate

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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.

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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Maternal –Fetal medicine Society, 2012

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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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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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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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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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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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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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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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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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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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