Terapi Progesteron pada Kehamilan, Bukti atau Tradisi?

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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 sedikitnyeri di perut bagian bawah, saat ini terlambat 10 minggu

.

.

..

CBC: NAPTT/PT : NhsCRP: 8 mg/mLP4: 12 ng/dL

Subchorionic hematoma: 12 X 8 mm

Terapi:Progesteron 400 mg Vit. D 400 IUVit A 5000 IU per hariDHA 300 mgVit C: 200 mgVit E: 200 mgSe: 100 ugZn: 25 mgFolic acid: 400 ugB6: 15 mgCa: 1000 mg

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)

The mean+ SD extractions of progesterone from 100 mg of myometrium collected at the same timed intervals after vaginal application of progesterone

Humrep. 1997; 12: 10731079

Classification of progestinsProgestin ExampleProgesterone

Retroprogesterone

Progesterone derivative

17-Hydroxyprogesterone derivatives (pregnanes)

17-Hydroxynorprogesterone derivatives (norpregnanes)

19-Norprogesterone derivatives (norpregnanes)

19-Nortestosterone derivatives (estrames)

19-Nortestosterone derivatives (gomanes)

Spirolactone derivative

Natural progesterone

Dydrogesterone

Medrogestone

Medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate

Gestonorone caproate, nomegestrol acetate

Demegestone, promegestone, nesterone, trimegestone

Norethisterone = norethindrome, norethisterone acetate, lynestrenol, ethinodiol acetate, norethinnodrel

Norgestrel, levonorgestrel, desogestrel, etenogestrel, gestodene, norgestimate, dienogest

Drospirenome

According to reference (5-8)

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

ProgesteroneDydrogesteroneChlormadinone acetateCyproterone acetateMedroxy-progesterone-acetateMegestrol acetateNomegestrolPromegestone (R50/20)DrospirenomeNorethisteroneLevonorgestrelNorgestimate3-Keto-desogestrelGestodeneDienogest

50756790115

6512100357515015150905

00565

5606515450208510

0-000

0000000000

10-8629

3065601114271

100-08160

0053230075002900

0-000

00001650015400

36-000

0000000000

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%).

Hum Reprod Up, 2009; 15: 119138

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 Frye et al (2006)

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+ influxinhibition

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

Zones of Progesterone in Pregnancy(N=109)

Zone 1

Zone 10

20

40

60

80

100

120

140

160

180

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42

Zone 1

Zone 1

National Hormone Laboratory Pope Paul VI Institute

Zone 2

Zone 2

Zone 2

Zone 2

Seru

m P

roge

ster

one

(ng/

mL)

Weeks Gestation

Zone 3

Zone 3

Zone 3

Zone 3

Zone 4

Zone 4

Zone 4

22.427.7 29.7 30.0

39.0 42.448.8 52.5

56.565.9

78.3 81.290.3

100.3

118.1

134.2

150.0164.0

172.2

Reproduction (2001) 121, 319

Progesterone increased threshold for any inflammatory response

Progesterone with cAMP induces decidualization and PGDH induction

Declining progesterone allows increasing nuclear factor expression Protective PGDH declines

Prostaglandins rise in perivascularcells NF-B events are de-repressed

Oedema and cellular ingress

MMP activation Tissue sloughing

Decidualization and pregnancy

Reversible

Irreversible

Menstruation

Progesterone concentration

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

Progesterone Withdrawal

Proteasome

Cu, Zn-SOD

Nucleus Endoplasmic reticulum

IB

NF-B NF-B

COX-2 PGF2PGF2

.O2-

Humrep.2006; 21: 25382544

J Immunol. 1995; 154: 37713378Immunology. 2000; 101:191200

Nature Immunology 2007; 8, 124 125 Nuclear Receptor Signaling (2009) 7, e003 Nature Reviews Immunology 2008; 8, 523-532

VitaminCu Se Zn Fe Es. Fatty acid Es. amino acid Prebiotic

A C E B D

Prooxidant antioxidant Balance

Cellular impact

ROS

Proliferation Apoptosis Necrosis

News Physiol Sci 2004;19: 120-123

VitaminCu Se Zn Fe DHA Cysteine Folic Ca Es. Amino acid

A C E B D

Postbinding defect in insulin action during pregnancy is probably related to increasing amounts of progesterone,cortisol, PRL, and placental lactogen.Progesterone is implicatedin 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: 341-347Am J Physiol Endocrinol Metab (January 13, 2010). doi:10.1152/ajpendo.00649.2009

Amino AcidArginine, CarnitineCysteine, GlutamineGlycine, IsoleucineLeucine, TaurineValine

MineralChromiumSeleniumZincCa

VitaminsB1, B2, B3B5, B6, B12Biotin, CholineFolic acid, InositolAscorbic acid

Lipoic acidCo Q10D-RiboseMilk thistle (81.79% silymarins

J. Clin. Invest. 118:29923002 (2008). doi:10.1172/JCI34260 http://www.progesteronetherapy.com/insulin-resistance.html , Journal of Endocrinology 2000; 166, 283291

Insulin sensitivity: modulation by nutrients and inflammation

17b-Estradiol could be responsible for the increase in insulin sensitivityduring early pregnancy when the plasma concentrations of 17b-estradioland progesterone are low.

However, during late pregnancy, when the plasma concentrations of17b-estradiol and progesterone are high, the role of 17b-estradiol couldbe to antagonize the effect of progesterone diminishing insulinsensitivity.

The effect of both hormones as proposed in this paper could appear tobe altered in the presence of high plasma concentrations of thelactogenic hormones and growth hormone, just as occurs during normalpregnancy.

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

1/2

ACGS

CRH, PGI2, PGE2GPCRs

cAMP

Co-repressors

Co-activators

++

+

IB

NFB+

+

+

TBPpol-II

Co-activators

TBPpol-II

Co-activators

Progesterone responsive genes are active

+

doi: 10.1016/j.ajog.2006.09.005

Progesterone

Estrogen

A

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

2/2

doi: 10.1016/j.ajog.2006.09.005

ACGS

cAMP

Co-repressors

Co-activators +

NFB+

+

+

TBPpol-II

Co-repressors

TBPpol-II

Co-repressors

Progesterone responsive genes are repressed

Progesterone

Estrogen

B

+

IB

GS

CRH, PGI2, PGE2GPCRs

IL-1b, TNF

PKC

CRH, PGI2, PGE2GPCRs

Estrogen responsive genes are stimulated

+ + +

mPR, mPR

The Use of Progesterone for Prevention of Preterm BirthRecommendations

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

2. Women should be informed about the lack of available data for may neonatal outcome variables and about thelack of comparative data on dosing and route of administration. Women with short cervix should be informed ofthe 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 22-26weeks gestation) on transvaginal ultrasound could be used as an indication for progesterone therapy. The therapyshould 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 andthe 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

Fetal Diagn Ther 2011;29:197200

Maternal serum concentration of progesterone-inducedblocking factor at 1113 weeks in pregnancies delivering spontaneously before 34 weeks (closed circles) and those delivering at term (open circles).

In women who have a spontaneous early preterm delivery, the maternal serum levels of PIBF are not altered at 1113 weeks of gestation

Am J Reprod Immunol. 2010 Aug 1;64(2):77-86

PIBF: the double edged sword. Pregnancy and tumor

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.

Szekeres-Bartho J, Polgar B

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

Karakteristikkelahiran preterm

< 37 minggukelahiran aterm 37 minggu P

Panjang serviks 2,5 cmPanjang serviks > 2,5 cm

144

015

< 0.001b

Lahir < 7 hari Lahir 7 hari

Panjang serviks 2,5 cmPanjang serviks > 2,5 cm

133

116

< 0.001a

Lahir < 48 jam Lahir > 48 jam

Panjang serviks 2,5 cmPanjang serviks > 2,5 cm

70

719

0.001b

aUji Chi-square; bUji Fisher

Progesterone Generally considered an anti-inflammatory steroid:

IntImmunopharmacol 2001;1:10371048

It opposes prostaglandin production in the uterus of pregnancy, partiallyby inhibiting cyclooxygenase (COX-2) expression, and by up-regulating15-prostaglandin dehydrogenase, aprostaglandin catabolizing enzyme

Endocr Rev 1997;18:502519.Endocrinology 2000;141:581597.Mol Endocrinol 2006;20:27242733

Preventing Premature Cervical RipeningAm J Obstet Gynecol 2008;198:314 e311318

Am J ObstetGynecol 2008;199:391.e1-391.e7.

P4 significantly inhibited spontaneous contractility dose dependently. The inhibition was not blockedby RU486 but was reversible after washing. Surprisingly, 17P dose dependently stimulatedcontractility.

Comparison of 17P to P4 on contractility Reversibility of P4 inhibition after washing

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

(J Soc Gynecol Investig 2005; 12: 466-78)

Four Strategies for Targeting the PG synthesis-receptor cascade to delay preterm delivery and prolong pregnancy

Membrane-bound Arachidonate

Arachidonic Acid

PGH2

PGs

PG Receptors

PLA2

PGHS-2

PG Synthases

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

2. Block receptor action (THG 113.31)

NFB

3. Antagonize NFBactivity (Sulfasalazine) Bay 11-0782)

? 4. Combination of 1, 2 and/or 3

P4

Placebo Progesterone RR CI P value

N 153 306

Am J Obstet ,Gynecol (2006) 194, 123442

Study Progestational Agent n/N Placebo n/N RR (95% CI Random) Weight % RR (95 % CI Random)

Johnson, 197518 1/19 11/25 5.0 0.12 (0.02, 0.85)

Meis, 200319 111/306 84/153 64.6 0.66 (0.54, 0.81)

DaFonseca, 200371 12/74 21/71 30.5 0.55 (0,29, 1.03)

Total (95% CI) 124/399 116/249 100.0 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

Comparison : 01 Progestational agents vs placeboOutcames : 01 Delivery before 37 weeks

1 5 10-1 -2

Favours Treatment Favours Control

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) Progesterone (ng/ml)

Mean 95% CI* Mean 95% CI Mean 95% CI Mean 95% CIBirth weight (g)

Anatol J Obstet Gynecol 2009; 2: 1

Obstet Gynecol Clin N Am 39 (2012) 116

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

Deficiency In primate placenta

P450c17-hydroxylase

cholesterol

pregnenolone progesterone

17-hydroxy-pregnenolone

17-hydroxy-pregnenolone

3b-HSD

3b-HSD

P450c17 lyase

DHEA androstenedione3b-HSD

DHEA sulfate DHEA

3b-HSD

16-OH DHEA sulfate 16-OH DHEASulfatase

Sulfatase

Fetal liver

estriol

estradiolestronearomatase 17b-HSD

aromatase

PLACENTAFetal a

dren

al g

land

s

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

The synthetic pathway utilized by human placenta for estrogen synthesis