Terapi Progesteron pada Kehamilan, Bukti atau Tradisi?

noroyonowibowo@yahoo.com

Maintains secretory endometrium

Protects against fibrocystic breasts
Helps use fat for energy
Acts as a natural diuretic
Acts as natural antidepressant
Facilitates thyroid hormone action
Normalizes blood clotting
Increases sex drive
Normalizes blood sugar levels

Normalizes Zn & Cu levels

Restores proper oxygen cell levels
Prevents endometrial cancer
Prevents breast/prostate cancer
Stimulates osteoblastic bone building
Restores normal vascular tone
Functions as a precursor of corticosteroids
Increases sensitivity of estrogen receptors
Allows embryo to survive

is required for all aspects of female reproductive function, including :

sexual behaviour, gonadotrophin secretion, ovulation, blastocyst implantation and maintenance
of pregnancy .
Mulac-Jericevic et al. 2000, Conneely et al. 2002, Mulac-Jericevic & Conneely 2004

Kasus 1

Ny. A datang dengan perdarahan pervaginam disertai sedikit

nyeri di perut bagian bawah, saat ini terlambat 10 minggu
.
Subchorionic hematoma: 12 X 8 mm

CBC: N
APTT/PT : N
hsCRP: 8 mg/mL
P4: 12 ng/dL
.
.

Terapi:
Progesteron 400 mg
Vit. D 400 IU
Vit A 5000 IU per hari
DHA 300 mg
Vit C: 200 mg
Vit E: 200 mg
Se: 100 ug
Zn: 25 mg
Folic acid: 400 ug
B6: 15 mg
Ca: 1000 mg

The mean+ SD extractions of progesterone from 100 mg of myometrium collected at the

same timed intervals after vaginal application of progesterone

1 hour

2 hours

3 hours

4 hours

5 hours

6 hours

12 hours

0 ng
(n= 3)

31 + 5 ng
(n= 3)

267 + 84 ng
(n= 3)

254 + 305 ng
(n= 3)

299 + 87 ng
(n=3)

223 + 98 ng
(n= 3)

77 + 23 ng
(n= 3)

Humrep. 1997; 12: 10731079

Classification of progestins
Progestin

Example

Progesterone

Natural progesterone

Retroprogesterone

Dydrogesterone

Progesterone derivative

Medrogestone

17-Hydroxyprogesterone derivatives (pregnanes)

Medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate

Gestonorone caproate, nomegestrol acetate

17-Hydroxynorprogesterone derivatives (norpregnanes)

19-Norprogesterone derivatives (norpregnanes)
19-Nortestosterone derivatives (estrames)

Demegestone, promegestone, nesterone, trimegestone

Norethisterone = norethindrome, norethisterone acetate, lynestrenol, ethinodiol acetate,
norethinnodrel
Norgestrel, levonorgestrel, desogestrel, etenogestrel, gestodene, norgestimate, dienogest

19-Nortestosterone derivatives (gomanes)

Spirolactone derivative
According to reference (5-8)

Drospirenome

Table 6 Relative binding affinities of progesterone and synthetic progestins to steroid receptors and serum
binding proteins
Progestin

PR

AR

ER

GR

MR

SHBG

CBG

Progesterone
Dydrogesterone
Chlormadinone acetate
Cyproterone acetate
Medroxy-progesterone-acetate
Megestrol acetate
Nomegestrol
Promegestone (R50/20)
Drospirenome
Norethisterone
Levonorgestrel
Norgestimate
3-Keto-desogestrel
Gestodene
Dienogest

50
75
67
90
115

0
0
5
6
5

0
0
0
0

10
8
6
29

100
0
8
160

0
0
0
0

36
0
0
0

65
12
100
35
75
150
15
150
90
5

5
6
0
65
15
45
0
20
85
10

0
0
0
0
0
0
0
0
0
0

30
6
5
6
0
1
1
14
27
1

0
0
53
230
0
75
0
0
290
0

0
0
0
0
16
50
0
15
40
0

0
0
0
0
0
0
0
0
0
0

The reference steroids are listed. Taken from refernce (8,1013,15). PR: progesterone receptor (promegestone =
100%). AR: androgen receptor (metribolone = 100%). ER: estrogen receptor (estradiol-17 = 100%). GR:
glucocorticoid receptor (dexamethason = 100%). MR: mineralcorticoid receptor (aldosterone = = 100%). SHBG: sex
hormone-binding globulin (cortisol = 100%).

TABLE 1 Rapid effects of progesterone in target tissues

Physiological action

Cell/tissue/organism

Signalling pathway

Reference

Acrosome reaction/capacitation

Human spermatozoa

Ca2+ influx, CI- efflux, cAMP increase

Luconi et al (2004), Blackmore et al (1991) and

Kirkman-Brown et al (2000)

Oocyte maturation

Amphibian and fish oocytes

G-protein activation and cAMP decrease, ERK 1/2 activation,

P13 kinase activation

Zhu et al (2003b), Thomas et al (2002), Maller (2001)

and Bagowski et al (2001)

Immunoregulatory function

Human T-lymphocytes

G-protein activation, K+ channel inhibition

Dosiou et al (2008) and Ehring et al (1998)

Platelet aggression

Human platelets

Ca2+ influx

Bar et al (2000) and Blackmore (1999, 2008)

Anti-apoptotic effects

Rat granulosa cells

MAPK kinase (MEK) inhibition, Ca2+ homeostatis, Protein

kinase G activation

Peluso et al (2001) and Peluso and Pappalardo (2004)

Muscle contraction

Human intestinal smooth muscle cells

Ca2+ currents reduction

Bielefeldt et al (1996)

Vasoreactivity

Rat vascular smooth muscle cells

Ca2+ influx regulation

Barbagalo et al (2001)

Steroidogenesis and LH action

Rodent Leydig cells

Na- influx

Rossato et al (1999) and El-Hefnawy and Huhtaniemi

(1998)

Lordois

Female mice

Transepithelial resistance

Human fetal membranes

Not assessed

Verikouki et al (2008)

Actin cytoskeleton remodelling/cell movement

Human umbilical vein endothelial cells,

human breast cancer cells

G-protein activation, P13 kinase and RhoA/ROCK-2 cascade

activation

Fu et al (2008a, b)

Neuroprotection

Mouse cerebral cortex, rat

hippocampal neurons

P13 kinase activation, ERK1/2 activation, Ca2+ influx

inhibition

Kaur et al (2007), Nilsen and Brinton (2003) and Cai et

al (2008)

Retinal neuronal activity

Mouse rod bipolar cells

P13 kinase activation

Koulen et al (2008

Frye et al (2006)

Hum Reprod Up, 2009; 15: 119138

Zones of Progesterone in Pregnancy

(N=109)
Zone 3

Serum Progesterone (ng/mL)

180

164.0

172.2

150.0

160

Zone 4

134.2

Zone 2

140
118.1

120

Zone 3

100.3

100

90.3
78.3 81.2

Zone 4

80

Zone 3
Zone 4

60

48.8

Zone 3 29.7 30.0 39.0

27.7

40

22.4

20

42.4

65.9

52.5 56.5

Zone 1

0
2

Zone 1

Zone 1

Zone 2
Zone 1

Zone 2

Zone 2

National Hormone Laboratory

Pope Paul VI Institute

10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42

Weeks Gestation

Decidualization and pregnancy

Progesterone increased threshold
for any inflammatory response
Progesterone with cAMP induces
decidualization and PGDH induction
Progesterone
concentration
Declining progesterone allows
increasing nuclear factor expression
Protective PGDH declines
Prostaglandins rise in perivascular
cells NF-B events are de-repressed

Reversible

Oedema and cellular ingress

MMP activation
Tissue sloughing

Irreversible
Menstruation

Reproduction (2001) 121, 319

Progesterone Withdrawal

Proteasome

.O2-

IB
NF-B
COX-2
Nucleus

NF-B

Cu, Zn-SOD

PGF2
Endoplasmic reticulum

When pregnancy occurs, progesterone induces decidualization of ESC with increased expression of Cu,Zn-SOD
and Mn-SOD. Cu,Zn-SOD suppresses PGF2 production by scavenging superoxide radicals in the cytosol and
results in uterine quiescence. Mn-SOD protects ESC from oxidative stress by scavenging superoxide radicals
generated in the mitochondria.
On the other hand, when pregnancy does not occur, the decline of ovarian steroid levels (progesterone
withdrawal) induces the decrease in Cu,Zn-SOD expression in ESC, which in turn stimulates PGF2 production via
reactive oxygen species. PGF2 produced by ESC causes endometrial shedding
via vasoconstriction.
PlacentaVol: 28, Supplement, April, 2007

Humrep.2006; 21: 25382544

J Immunol. 1995; 154: 37713378

Immunology. 2000; 101:191200

Vitamin
Cu
A

Se

Zn

Fe

Es. Fatty acid

Es. amino acid

Prebiotic

Nature Immunology 2007; 8, 124 125

Nuclear Receptor Signaling (2009) 7, e003 Nature Reviews Immunology 2008; 8, 523-532

ROS

Prooxidant antioxidant Balance

Proliferation

Apoptosis

Necrosis

Cellular impact
News Physiol Sci 2004;19: 120-123

Vitamin
A

Cu

Se

Zn

Fe

DHA

Cysteine

Folic

Ca

Es. Amino acid

Postbinding defect in insulin action

during pregnancy is probably related to
increasing amounts of progesterone,
cortisol, PRL, and placental lactogen.
Progesterone is implicated in insulin
resistance during pregnancy by
inhibiting the PI3-kinase pathway at the
step of (I) IRS1 expression and (II)
distal to Akt, and by (III) suppressing
the PI3-kinase independent pathway of
TC10 activation by affecting Cbl
phosphorylation.
JCEM 1988;67;2: 341-347
Am J Physiol Endocrinol Metab (January 13, 2010). doi:10.1152/ajpendo.00649.2009

Insulin sensitivity:
modulation by nutrients and inflammation

Amino Acid
Arginine, Carnitine
Cysteine, Glutamine
Glycine, Isoleucine
Leucine, Taurine
Valine

Mineral
Chromium
Selenium
Zinc
Ca

Vitamins
B1, B2, B3
B5, B6, B12
Biotin, Choline
Folic acid, Inositol
Ascorbic acid

J. Clin. Invest. 118:29923002 (2008). doi:10.1172/JCI34260

http://www.progesteronetherapy.com/insulin-resistance.html , Journal of Endocrinology 2000; 166, 283291

Lipoic acid
Co Q10
D-Ribose
Milk thistle (81.79% silymarins

17b-Estradiol could be responsible for the increase in insulin sensitivity

during early pregnancy when the plasma concentrations of 17b-estradiol
and progesterone are low.
However, during late pregnancy, when the plasma concentrations of
17b-estradiol and progesterone are high, the role of 17b-estradiol could
be to antagonize the effect of progesterone diminishing insulin
sensitivity.
The effect of both hormones as proposed in this paper could appear to
be altered in the presence of high plasma concentrations of the
lactogenic hormones and growth hormone, just as occurs during normal
pregnancy.
Journal of Endocrinology (2000) 166, 283291

Kasus 2
Ny. B datang pada kehamilan 26 minggu, dengan kontraksi 2-3X/10 menit

Actions of Progesterone on the Myometrium

Decreases conduction of contractions

Increases threshold for stimulation
Decreases spontaneous activity
Decreases number of oxytocin receptors
Suppresses the inflammatory cascade

Actions of Progesterone on the Myometrium

Inhibits T lymphocyte development

Promotes expression of prostaglandin EP2 receptor
Prevents formation of gap junctions
Administration of progesterone antagonists stimulates onset of labor in
women at term

A hypothetic scheme of the mechanisms that control progesterone responsiveness in the pregnant
human myometrium

CRH, PGI2, PGE2

GPCRs
GS
AC
cAMP

Co-repressors

Co-activators

IB
+

NFB

+
+

Progesterone
Estrogen
doi: 10.1016/j.ajog.2006.09.005

Co-activators

Co-activators

pol-II
TBP

Progesterone responsive genes are active

pol-II
TBP

1/2

A hypothetic scheme of the mechanisms that control progesterone responsiveness in the pregnant
human myometrium

CRH, PGI2, PGE2

IL-1b, TNF

GPCRs

CRH, PGI2, PGE2

GPCRs
GS

mPR, mPR
GS
AC

PKC

IB

Co-activators

cAMP

+
Co-repressors

NFB

Estrogen responsive genes

are stimulated

Progesterone
Estrogen
doi: 10.1016/j.ajog.2006.09.005

Co-repressors

pol-II
TBP

Co-repressors

pol-II
TBP

Progesterone responsive genes are repressed

2/2

The Use of Progesterone for Prevention of Preterm Birth

Recommendations
1.

Women at risk for PTL should be encouraged to participate in studies on the role of progesterone in reducing the
risks of preterm labour. (I-A)

2.

Women should be informed about the lack of available data for may neonatal outcome variables and about the
lack of comparative data on dosing and route of administration. Women with short cervix should be informed of
the single large RCT showing the benefit of progesterone in preventing PTL. (I-A)

3.

Women and their caregivers should be aware that a previous preterm labour and/or short cervix (< 15 mm at 22-26
weeks gestation) on transvaginal ultrasound could be used as an indication for progesterone therapy. The therapy
should be started after 20 weeks gestation and stopped when the risk of prematurity is low. (I-A)

4.

On the basic of the data from the RCTs and meta-analysis, it is recommended that in cases where the clinician and
the patient have opted for the use of progesterone the following dosages should be used:
For prevention of PTL in women with history of previous PTL: 17 alpha-hydroxyprogesterone 250 mg IM weekly
(IB) or progesterone 100 mg daily vaginally. (I-A)
For prevention of PTL in women with short cervix < 15 mm detected on transvaginal ultrasound at 22-26 weeks
progesterone 200mg daily vaginally. (I-A)

J Obstet Gynaecol Can 2008:30(1):67-71

In women who have a

spontaneous early preterm
delivery, the maternal serum
levels of PIBF are not altered
at 1113 weeks of gestation
Maternal serum concentration of progesterone-induced
blocking factor at 1113 weeks in pregnancies delivering
spontaneously before 34 weeks (closed circles) and those
delivering at term (open circles).

Fetal Diagn Ther 2011;29:197200

PIBF: the double edged sword. Pregnancy and tumor

Szekeres-Bartho J, Polgar B

Progesterone-induced blocking factor is produced by

pregnancy lymphocytes and also by malignant
tumors. The PIBF-induced Th2-dominant immune
response is favorable during pregnancy but might
facilitate tumor growth by suppressing local
antitumor immune responses.
Am J Reprod Immunol. 2010 Aug 1;64(2):77-86

Progesterone rapidly suppresses the fetal inflammatory response,

possibly via nongenomic activation of the cAMP cascade.

Am J Obstet Gynecol 2009;201:211.e1-9.

Panjang serviks 2,5 cm dan Saat Kelahiran

Karakteristik
Panjang serviks 2,5 cm
Panjang serviks > 2,5 cm

Panjang serviks 2,5 cm

Panjang serviks > 2,5 cm

Panjang serviks 2,5 cm

Panjang serviks > 2,5 cm
aUji

Chi-square; bUji Fisher

kelahiran preterm
< 37 minggu

kelahiran aterm
37 minggu

14
4

0
15

< 0.001b

Lahir < 7 hari

Lahir 7 hari

13
3

1
16

Lahir < 48 jam

Lahir > 48 jam

7
0

7
19

< 0.001a

0.001b

Progesterone

Generally considered an anti-inflammatory steroid:

IntImmunopharmacol 2001;1:10371048

It opposes prostaglandin production in the uterus of pregnancy, partially

by inhibiting cyclooxygenase (COX-2) expression, and by up-regulating
15-prostaglandin dehydrogenase, aprostaglandin catabolizing enzyme
Endocr Rev 1997;18:502519.
Endocrinology 2000;141:581597.
Mol Endocrinol 2006;20:27242733

Preventing Premature Cervical Ripening

Am J Obstet Gynecol 2008;198:314 e311318

Comparison of 17P to P4 on contractility

Reversibility of P4 inhibition after washing

P4 significantly inhibited spontaneous contractility dose dependently. The inhibition was not blocked
by RU486 but was reversible after washing. Surprisingly, 17P dose dependently stimulated
contractility.
Am J ObstetGynecol 2008;199:391.e1-391.e7.

Progesterone as a Tocolytic

6 trials have been reported

Various progesterone compounds used
Design of studies varied
None of the trials found a significant prolongation of pregnancy with the
use of the progesterone treatment
Progesterone treatment of women with active uterine contractions
should be discouraged outside of research protocols

Membrane-bound
Arachidonate
PLA2

3. Antagonize NFB
activity (Sulfasalazine)
Bay 11-0782)

Arachidonic Acid
1. Inhibit PGHS-2 (Nimesulide,
Meloxicam, Roficoxib)

PGHS-2

NFB

PGH2
PG
Synthases
PGs

2. Block receptor action

(THG 113.31)

PG
Receptors

P4

4. Combination of 1, 2
and/or 3

Four Strategies for Targeting the PG synthesis-receptor cascade to delay preterm

delivery and prolong pregnancy
(J Soc Gynecol Investig 2005; 12: 466-78)

Placebo

Progesterone

RR

CI

P value

153

306

<34 weeks

54%

36.3%

0.66

0.54 0.93

0.0001

<35 weeks

30.7%

20.6%

0.67

0.48 0.93

0.0165

<32 weeks

19.6%

11.4%

0.58

0.37 0.92

0.0180

N Engl J Med 2003;348:23792385 [erratum in N Engl J Med 2003; 349:1299

Comparison
Outcames
Study

: 01 Progestational agents vs placebo

: 01 Delivery before 37 weeks
Progestational Agent
n/N

Placebo n/N

1/19

Weight %

RR (95 % CI Random)

11/25

5.0

0.12 (0.02, 0.85)

111/306

84/153

64.6

0.66 (0.54, 0.81)

12/74

21/71

30.5

0.55 (0,29, 1.03)

Johnson, 197518
Meis, 200319
DaFonseca, 200371

Total (95% CI)

124/399

RR (95% CI Random)

116/249

100.0

1.57 (0.36, 0.90)

Test for heterogenely chi-square = 3.38df=2 p= 0.18

Test for overall effect z=2.41 P = .02

-1 -2
Favours Treatment

10

Favours Control
Am J Obstet ,Gynecol (2006) 194, 123442

No.

Estriol

Estrone

Estradiol

Progesterone

Birth weight (g)

567

0.32***

0.13**

0.17***

0.17***

Birth length (cm)

566

0.21***

0.06

0.08

0.12**

Ponderal index (kg/cm3)

566

0.16**

0.11*

0.13**

0.08

Placental weight (decagram)

480

0.18***

0.07

0.09*

0.24***

* p < 0.05; **p < 0.01; ***p < 0.0001.

Sample size varies because of missing values of fetal growth indicators.
Am J Epidemiol 2003; 157:258-266

No.

Estriol (ng/ml)

Estrone (ng/ml)

Estradiol (ng/ml)

Mean

95% CI*

Mean

95% CI

Mean

95% CI

22
317
216
12

7.7
11.8
13.9
15.8

6.5, 9.0
11.4, 12.3
13.2, 14.5
13.1, 19.0

6.2
8.3
8.9
10.0

4.8, 7.9
7.7, 8.9
8.1, 9.8
5.7, 17.6

18.7
22.1
24.3
24.7

135
143
200
88

11.0
12.1
13.0
14.1

10.3, 11.8
11.4, 12.8
12.4, 13.7
13.1, 15.2

7.5
9.2
8.7
8.5

6.7, 8.4
8.3, 10.1
7.9, 9.5
7.3, 9.8

11.2
12.5
13.0
13.6

10.4, 12.0
11.9, 13.1
12.2, 13.7
12.3, 15.1

7.9
8.2
9.1
9.2

10.4, 12.0
11.4, 12.6
12.1, 13.9
12.1, 15.1

8.2
8.2
8.2
7.8

Progesterone (ng/ml)
Mean

95% CI

16.1, 21.6
21.2, 23.1
22.9, 25.8
17.4, 35.1

145
175
187
222

128, 165
169, 181
179, 195
186, 265

21.1
23.6
23.2
23.5

19.7, 22.7
22.1, 25.1
21.8, 24.7
21.4, 25.9

174
173
179
195

164, 185
165, 182
172, 187
183, 207

7.0, 8.9
7.5, 8.9
8.2, 10.1
7.8, 10.8

21.9
22.7
22.8
25.2

20.5, 23.5
21.4, 24.0
21.3, 24.3
22.4, 28.3

178
178
175
192

169, 187
171, 186
166, 184
177, 208

7.3, 9.2
7.5, 8.9
7.3, 9.2
6.2, 9.8

21.3
22.7
22.5
22.4

19.8, 23.0
21.5, 24.1
21.0, 24.2
19.1, 26.3

164
172
191
199

154, 175
165, 180
181, 201
183, 216

Birth weight (g)

<2,500
2,5003,499
3,5004,499
4,500

Birth length (cm)

<50
50<52
52<54
54

Ponderal index (kg/cm3)

<2.25
2.25<2.50
2.50<2.75
2.75

123
226
150
67

Placental weight (decagram = 10 g)

<40
4049
5059
60

109
210
117
44

11.2
12.0
13.0
13.5

Am J Epidemiol 2003; 157:258-266

Anatol J Obstet Gynecol 2009; 2: 1

Recent randomized trials of progesterone

Author

Date, Site

Subjects

Primary
Outcome

Intervention

Results

Da Fonseca et al33

2003, Brazil

157 women at high

risk for preterm birth

Preterm birth
<37 weeks

Intravaginal progesterone (100 mg) or

placebo, 24-28 weeks

RR 0.49 (95% CI
0.25-0.96)

Meis et al32

2003, USA

463 women with prior

spontaneous PTB

Preterm birth
<37 weeks

17-hydroxy-progesterone caproate (250

mg weekly) or placebo, 16-20 to 36
weeks

RR 0.66 (95% CI
0.54-0.81)

OBrien et al34

2007,
Multinational

659 women with prior

SPTB

Preterm birth
<32 weeks

Daily vaginal progesterone gel (90 mg)

or placebo

RR 1.08 (95% CI
0.76-1.52)

Fonseca et al46

2007, UK, Brazil,

Greece

250 women with

cervical length 15
mm

Preterm birth
<34 weeks

Nightly intravaginal pessary (200 mg

micronized progesterone) or placebo,
24-33 + 6 weeks

RR 0.56 (95% CI
0.36-0.86)

Rouse et al39

2007, USA

661 twin pregnancies

Composite of
delivery or death
prior to 35
weeks

Weekly IM injection of 250 mg 17hydroxy-progesterone caproate or

placebo (castor oil) from 16 to 20 + 3
weeks until 34 completed weeks

RR 1.1 (95% CI 0.91.3)

Hassan et al47

2011, USA

458 singleton
pregnancies

Preterm birth
before 33 weeks

Daily vaginal progesterone gel or

placebo from 20 to 23 6/7 until 36 6/7
weeks

RR 0.55 (95% CI
0.33-0.92)

Obstet Gynecol Clin N Am 39 (2012) 116

The synthetic pathway utilized by human placenta for

estrogen synthesis
cholesterol

pregnenolone

3b-HSD

progesterone

P450c17-hydroxylase

17-hydroxypregnenolone

3b-HSD

17-hydroxypregnenolone

Deficiency In primate placenta

Fetal adrenal glands

P450c17 lyase

DHEA

3b-HSD

androstenedione

aromatase

estrone

17b-HSD

estradiol

3b-HSD

DHEA sulfate

Sulfatase

DHEA

PLACENTA

Fetal liver

16-OH DHEA sulfate

XQ Li et al. / placenta 35 (2014) 291-296

Sulfatase

16-OH DHEA

aromatase

estriol