2012 Utrogestan Natural Micronized Progesterone - From Luteal Phase Defect To Preterm Birth

From luteal phase defect to preterm birth
Utrogestan
Natural micronized progesterone
Delfin A. Tan, M.D.
Section of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology St. Lukes Medical Center Quezon City
Utrogestan Natural micronized progesterone From luteal phase defect to preterm birth
Disclosure
All the statements and opinions expressed in this presentation are those of the speaker and are not intended to reflect the views and position of the sponsor.
Delfin A. Tan, MD
Outline
Part 1 2 3 4 Utrogestan: pharmacology Luteal phase defect Recurrent early pregnancy loss Preterm birth
History of spontaneous preterm delivery Preterm labor Asymptomatic sonographically short cervix at midtrimester
Conclusions
Utrogestan: pharmacology
Part 1
Utrogestan
The only original natural micronized progesterone
Features
Exact chemical duplicate of progesterone of ovarian origin (not a progestin)
Synthesized from natural precursor (diogenin) extracted from wild yams (Dioscorea sp)
Optimal bioavailability via oral and vaginal route obtained by micronization and oil suspension
Wild yam
Micronized progesterone
Peanut oil (longchain fatty acid)
Utrogestan 100 mg
Utrogestan 200 mg
www.besins-healthcare.com
Exogenous progesterone/progestins in clinical use:

different molecules, different biological activities
Natural progesterone dydrogesterone 17-OH Progesterone caproate
Natural progesterone C21H30O2

Utrogestan, oral, vaginal
Retroprogesterone or dydrogesterone C21H28O2

Duphaston, oral
17-OH Progesterone caproate

Makena, injectable
Schindler AE, et al. Maturitas. 2003 Dec 10;46 Suppl 1:S7-S16.
Classification of progestins
Natural Synthetic
Progesterone Retroprogesterone
Dydrogesterone
Structurally related to progesterone
Pregnane derivatives
17-OH Progesterone caproate, OHprogesterone heptanoate, gestronone caproate, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, medrogestone, cyproterone acetate
Demegestone, promegestone, nomegestrol acetate, nestorone, trimegestone Lynestrenol, levonorgestrel, norethisterone/norethindrone, norethindrone acetate, ethynodiol diacetate, norgestrienone, dienogest, norethynodrel Norgestrel, desogestrel, gestodene, norgestimate Drospirenone
Norpregnane derivatives
Structurally related to testosterone
Estranes
Gonanes
Spirolactone-derived
Druckmann R. Gynecology Forum 2004;9(2).
Use of exogenous progesterone

Different routes of administration: different pharmacokinetics and dynamics
Intramuscular
Supraphysiological plasma concentrations
Oral
Rapid increase in plasma concentration followed by gradual decrease
First liver pass effect with several biological active metabolites Specific activity on different target organs (uterus, brain...)
Vaginal (preferred)
Stable plasma concentrations and consistent tissue levels
First uterine pass effect with targeted delivery into the endometrium Minimal systemic effects
Devroey P, et al. Int J Fertil. 1989 MayJun;34(3):188-93. Miles RA, et al. Fertil Steril. 1994 Sep; 62(3):485-90.
Tavaniotou A, et al. Hum Reprod Update. 2000 Mar-Apr;6(2):139-48. Perusqua M, et al. Life Sci. 2001 May 18;68(26):2933-44. Schumacher M, et al. Endocr Rev. 2007 Jun;28(4):387-439.
Devroey P, et al. Int J Fertil. 1989 MayJun;34(3):188-93. Tavaniotou A, et al. Hum Reprod Update. 2000 MarApr;6(2):139-48. Cicinelli E, et al. Obstet Gynecol. 2000 Mar;95(3):403-6.
Micronized progesterone absorption: effects of route of administration

Vaginal vs oral administration Vaginal vs intramuscular administration
Circulating P levels higher after vaginal administration

Nahoul K, et al. Maturitas. 1993 May;16(3):185-202.
Target tissue P levels higher after vaginal administration

Miles RA, et al. Fertil Steril. 1994 Sep;62(3):485-90.
10
Vaginally administered progesterone: the preferred route

1 First uterine pass effect 2 Better bioavailability of progesterone in uterus 3 Achieves adequate endometrial secretory transformation 4 Minimal systemic undesirable effects
Tavaniotou A, et al. Hum Reprod Update. 2000 Mar-Apr;6(2):139-48.
Migration through cervical tissue and lower uterine segment up to fundus Vaginal application of progesterone
11
Luteal phase defect

Part 2
12
Definitions
Luteal phase defect
1 If serum mid-luteal phase progesterone level is <10 ng/mL; mid-luteal phase P levels do not always reflect endometrial maturation
Jordan J, et al. Fertil Steril. 1994 Jul;62(1):54-62. Batista MC, et al. Fertil Steril. 1994 Apr;61(4):637-44.
Most reasonable consensus: lag of >2 days in endometrial histological development compared to expected day of cycle
Jones GS. Curr Opin Obstet Gynecol. 1991 Oct;3(5):641-8. Dawood MY. Curr Opin Obstet Gynecol. 1994 Apr;6(2):121-7.
Luteal phase support
Administration of exogenous hormones to support implantation and early development of embryo

www.ivf-worldwide.com.
13
Luteal phase defect (luteal phase deficiency or

insufficiency)
Prevalence1-4 ~8% in natural cycles in normally ovulating women with primary or secondary infertility Almost all patients in stimulated IVF cycles Etiology5 Iatrogenic Supraphysiological steroid levels in stimulated cycles of IVF and other assisted reproductive technologies Abnormal follicle production Defective corpus luteum function Failure of uterine lining to respond to normal progesterone levels
Other mechanisms
1Rosenberg
SM, et al. Fertil Steril. 1980 Jul;34(1):17-20. 2Ubaldi F, et al. Fertil Steril. 1997 Mar;67(3):521-6. 3Kolibianakis EM, et al. Fertil Steril. 2003 Aug;80(2):464-6. 4Macklon NS, Fauser BC. J Reprod Fertil Suppl. 2000;55:101-8. 5Fatemi HM. F. V & V in ObGyn. 2009;1(1):30-46.
14
Luteal phase defect: mechanism

Luteal phase defect Inadequate ovarian progesterone production Incomplete secretory endometrium Ineffective ovum implantation
Fatemi HM. F, V & V in ObGyn. 2009;1(1):30-46.
15
Role of physiological progesterone

Prepares the endometrium for implantation
1 Promotes differentiation of endometrial stromal and epithelial cells
Norwitz ER, et al. N Engl J Med. 2001 Nov;345(19):1400-8.
2 Reduces physiological cell death occurring just before menstruation

Lovely LP, et al. J Clin Endocrinol Metab. 2005 Apr;90(4):2351-6.
16
Vaginal progesterone: fewer signs of luteal phase deficiency during stimulated cycles
Endometrial development in GnRHa/hMG stimulated cycles with or without luteal phase support
Effects of luteal phase support on endometrial development (% of cycles)
No LPS E2V + P vag 600 mg
100 80 60 40 20
Bourgain C, et al. Hum Reprod. 1994 Jan;9(1):32-40.
hCG P vag 600 mg
E2V + P im 100 mg
Delayed
In phase
Advanced
Dissynchrony
Vaginal micronized progesterone: more effective than oral dydrogesterone in creating 'in-phase' secretory endometrium
Study
6 Patients with premature ovarian failure primed with estrogen and received oral dydrogesterone or vaginal micronized progesterone in 2 subsequent cycles
With micronized progesterone
With dydrogesterone
Endometrial biopsy on day 21 after micronized progesterone: coiled glands with active secretion and minimal residual vacuoles, stromal edema and absence of mitotic activity. The maturation corresponds to day 6 of the luteal phase (HES, 200x).
Endometrial biopsy on day 21 after dydrogesterone: small glands with minimal coiling and persistent homogeneous subnuclear vacuoles and pseudostratified nuclei, no stromal edema, and focal mitotic activity. The maturation corresponds to day 2-3 of the luteal phase (HES, 200x). Continued
Vaginal micronized progesterone: more effective than oral dydrogesterone in creating 'in-phase' secretory endometrium continued
Endometrial histological dating in the luteal phase for each patient (biopsy on day 21)
Oral dydrogesterone Vaginal micronized progesterone
8 6
7 7 6 5 4 3 2 2 3 2 6 5
Endocrine profile on day 21

Oral DG Mean P, g/L Mean LH, IU/L 0.3 22.5 Vaginal P 8.6 12.9 P value 0.013 0.049
4
2 0
Mean FSH, IU/L

1 2 3 4 Patients 5 6
23.9
13.0
0.047
Fatemi HM, et al. Hum Reprod. 2007 May;22(5):1260-3. Epub 2007 Jan 16.
19
Vaginal micronized progesterone for luteal phase support after assisted reproduction
Pooled results of 13 major randomized controlled studies
*Most frequent daily dosage: 600 mg Pregnancy rate, %, with micronized progesterone* as luteal phase support (n=1730 patients)
40 30 20 10 30 22.7
Clinical pregnancy rate/transfer
Ongoing pregnancy rate/transfer
Smitz J, et al. Hum Reprod. 1992 Feb;7(2):168-75. Mochtar MH, et al. Hum Reprod. 1996 Aug;11(8):1602-5. Chillik C, et al. Assisted Reprod Rev 1997; 7: 29:33. Friedler S, et al. Hum Reprod. 1999 Aug;14(8):1944-8. Lightman A, et al. Hum Reprod. 1999 Oct;14(10):2596-9. Williams SC, et al. Fertil Steril. 2001 Dec;76(6):1140-3. Ludwig M, et al. Eur J Obstet Gynecol Reprod Biol. 2002 Jun 10;103(1):48-52. Gorkemli H, et al. Gynecol Obstet Invest. 2004;58(3):140-4. Kleinstein J; Luteal Phase Study Group. Fertil Steril. 2005 Jun;83(6):1641-9. Fatemi HM, et al. Hum Reprod. 2006 Oct;21(10):2628-32. Simunic V, et al. Fertil Steril. 2007 Jan;87(1):83-7. Geber S, et al. Reprod Biomed Online. 2007 Feb;14(2):155-8. Lam PM, et al. Gynecol Endocrinol. 2008;24(12):674-80.
20
Luteal phase support: comparable outcomes with vaginal and intramuscular progesterone; vaginal route preferred
Meta-analysis of RCTs on progesterone luteal support in IVF cycles (1982-2008) Risk (OR, 95% CI) with vaginal progesterone vs intramuscular progesterone
1.4
1.2 1 0.8 0.6 0.4 0.2 0.91 0.94
Vaginal route preferred

oEasier oLess painful oLess timeconsuming oLess discomfort
0.54
Clinical Ongoing Miscarriage/clinical pregnancy/transfer, pregnancy,transfer, pregnancy, 6 trials 9 trials 6 trials

Zarutskie PW, Phillips JA. Fertil Steril. 2009 Jul;92(1):163-9.
21
For IUI cycles: luteal phase support improves pregnancy outcomes

Study
71 Infertility patients undergoing intrauterine insemination supported with vaginal progesterone once daily from day after insemination for 14 days (n=132 cycles) or not supported (n=126 cycles)
Supported cycles
80
60 40 20 0 Clinical pregnancy/patient Clinical pregnancy/cycle Live birth/patient Livebirth/cycle P=0.016
54.9 35.2
Results
Unsupported cycles
P=0.07
29.5 19.8
P=0.001
35.2 18.9
P=0.001
9.8 5.5
Maher MA. Eur J Obstet Gynecol Reprod Biol. 2011 Jul;157(1):57-62. Epub 2011 Apr 21.
22
Luteal phase support

Conclusions 1 Micronised progesterone is the standard of care for LPS.
Tavaniotou A, et al. Hum Reprod Update 2000 Mar-Apr;6(2):13948. Daya S, Gunby JL. Cochrane Database Syst Rev. 2008 Jul;(3):CD004830.
2 The vaginal route of administration of natural micronised progesterone is the treatment of choice for LPS.
Smitz J et al. Hum Reprod 1993 Jan; 8(1):40-5. Pritts EA, Atwook AK. Hum Reprod 2002 Sep;17(9):2287-99. Propst AM et al. Fertil Steril 2001 Dec;76(6):1144-9.
23
Recurrent early pregnancy loss

Part 3
24
Maintenance of early pregnancy

Implanted embryo (~14 days after conception) and the processes necessary for maintenance of an early pregnancy.
VEGF vascular endothelial growth factor hCG human chorionic gonadotropin
Norwitz ER, et al. N Engl J Med. 2001 Nov 8;345(19):1400-8.
25
Recurrent first trimester abortion: due to luteal phase defect, treated successfully with progesterone
Study Results 1988
Progesterone profiles in women with luteal phase defect vs women with normal cycles
1 Women with normal cycles vs women with LPD 2 Women with recurrent abortion
More progesterone production in luteal phase (discriminatory level of serum P: 21 nmol/L*) Incidence of LPD: 40% Successful pregnancies after treatment with P: 81%
*Provides a diagnostic test with 70% sensitivity and 71% specificity. Daya S, et al. Am J Obstet Gynecol. 1988 Feb;158(2):225-32.
26
Threatened abortion: vaginal micronized progesterone improves uteroplacental circulation

Study
53 Patients with threatened abortion and a living embryo treated with 300 mg micronized vaginal progesterone or 30 mg oral dydrogesterone daily for 6 weeks
Blood flow indices in the spiral arteries with dydrogesterone use
Resistance index Pulsatile index
Blood flow indices in the spiral arteries with micronized vaginal progesterone use
Resistance index Pulsatile index
P = 0.009
Systolic/diastolic ratio
8 7 6 5 4 3 2 1 0
7.6
Systolic/diastolic ratio
8 7 6 5 4 3 2 1 0 NS
5.6 5.3 4.05 2.09 0.75 0.81 2.48 0.77 1.65
P = 0.0059
4.9
P = 0.007
3.02 2.2 0.86 0.78 1.73 0.72 1.44
Visit 1: 12 2 days of gestation
Visit 3: 23 weeks of gestation
Visit 3: 23 weeks of gestation
Czajkowski K, et al. Fertil Steril. 2007 Mar;87(3):613-8. Epub 2006 Nov 27.
27
Progestogen reduced miscarriage rates in women with recurrent miscarriages

Study Meta-analysis of 15 trials involving 2118 women Risk (Peto OR, 95% CI) of miscarriage with progestogen treatment vs placebo/no treatment
1.4 1.2 1 0.8 0.6 0.4 0.2 0
Results 2008
0.98
0.38
All women regardless of gravidity Women with 3 miscarriages, 3 and number of previous trials miscarriages, 15 trials
Haas DM, Ramsey PS. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003511.
28
PROgesterone in recurrent MIScarriagEs (PROMISE) study

Study
Randomized, double-blind, placebo-controlled multicentre trial on first trimester progesterone therapy in women with a history of unexplained recurrent miscarriages
Principal Progesterone, 400 mg pessaries twice daily, started objective soon as possible after a positive pregnancy test (and
Status
no later than 6 weeks gestation) and continued to 12 weeks of gestation, compared to placebo, to increase live births beyond 24 completed weeks by at least 10% On-going; anticipated end date: 01/05/2012
http://www.imperial.ac.uk/
29
Preterm birth
Part 4
30
Preterm delivery, defined as birth before 37 completed weeks of gestation, is the leading cause of perinatal morbidity and mortality.
Arisoy R, Yayla M. J Pregnancy. 2012;2012:201628. Epub 2012 Feb 22.
31
Role of physiological progesterone

Maintains pregnancy
1 Modulates maternal immune responses
Druckmann R, et al. J Steroid Biochem Mol Biol. 200 Dec;97(5):389-96 4. Szekeres-Bartho J, et al. Int Immunopharmacol. 2001 Jun;1(6):1037-48.
2 3
Reduces uterine contractility

Fanchin R, et al. Hum Reprod. 2000 Jun;15 Suppl 1:90-100. Perusqua M, et al. Life Sci. 2001 May 18;68(26):2933-44. Chanrachakul B, et al. Am J Obstet Gynecol. 2005 Feb;192(2):458-63.
Improves utero-placental circulation

Liu J,et al. Mol Hum Reprod. 2007 Dec;13(12):869-74 9. Czajkowski K, et al. Fertil Steril. 2007 Mar;87(3):613-8.
Suppresses fetal inflammatory response

Schwartz N, et al. Am J Obstet Gynecol. 2009 Aug 201(2): 211.e1-9.
32
History of spontaneous preterm delivery

Preterm birth
33
Progesterone beneficial for prevention of preterm delivery in high-risk women

Review 4 RCTs involving 1462 high-risk women Treatment outcome, %
Progesterone
50
40 30 20 10 0 10 P=0.01 42 34 P=0.02 17 P=0.04 2
Controls
1.2 1 0.8 0.6 0.4
Treatment outcome (OR, 95% CI) with progesterone vs controls
0.6 0.49
0.5
0.2
0
Preterm delivery
Birthweight <1500 g
Neonatal death
Preterm delivery
Birthweight <1500 g
Neonatal death
Rossi AC, DAddaro V. Anatol J Obstet Gynecol. 2009;2:1.
34
Micronized progesterone prevents preterm delivery

Preterm delivery <34 weeks in major randomized controlled studies
60 50 40 30 20 10 0 Progesterone
P=0.002 18.6 2.8
Placebo
P=0.002 34.4
P=0.001 50 29.7
P=0.01
P=0.64 NS 4 6 8.8 24.3
19.2
Preterm Fonseca EB, weeks in major randomized controlled studies E, et al. 2011 Fonseca EB, et al. delivery <37 et al. Raj P, et al. 2009 Majhi P, et al. 2009 Cetingoz 2003 2007
Progesterone Placebo
P=0.002 59.5 39.2 12 Fonseca EB, et al. 2007 Raj P, et al. 2009 Majhi P, et al. 2009 Cetingoz E, et al. 2011 P=0.0027 38 P=0.036 57.2 40
80 60 40 20 0
P=0.03 28.5 13.8
Fonseca EB, et al. 2003
da Fonseca EB, et al. Am J Obstet Gynecol. 2003 Feb;188(2):419-24. Fonseca EB, et al. Fetal Medicine Foundation Second Trimester Screening Group. N Engl J Med. 2007 Aug 2;357(5):462-9. Rai P, et al. Int J Gynaecol Obstet. 2009 Jan;104(1):40-3. Majhi P, et al. J Obstet Gynaecol. 2009 Aug;29(6):493-8. Cetingoz E, et al. Arch Gynecol Obstet. 2011 Mar;283(3):423-9.
35
Micronized progesterone prevent preterm delivery

Pooled results
5 Major RCTs with micronized progesterone in preterm delivery 50 40 30 20 10 0 14.71 29.56 33.33
Preterm delivery, %, with micronized progesterone use vs placebo

Micronized progesterone Placebo
40.91
Preterm delivery <34 weeks
Preterm delivery <37 weeks
da Fonseca EB, et al. Am J Obstet Gynecol. 2003 Feb;188(2):419-24. Fonseca EB, et al. Fetal Medicine Foundation Second Trimester Screening Group. N Engl J Med. 2007 Aug 2;357(5):462-9. Rai P, et al. Int J Gynaecol Obstet. 2009 Jan;104(1):40-3. Majhi P, et al. J Obstet Gynaecol. 2009 Aug;29(6):493-8. Cetingoz E, et al. Arch Gynecol Obstet. 2011 Mar;283(3):423-9.
36
PREDICT study: vaginal progesterone did not prevent preterm delivery in twin pregnancies
Study 677 Women with twin pregnancies treated daily with progesterone
pessaries or placebo pessaries starting from 20-24 weeks until 34 weeks gestation (from 17 centers in Denmark and Austria)
Incidence of delivery before 34 weeks, %

30 25 20 15 10 5 0
18.5 15.3
Mean Ages and Stages Questionnaire (ASQ) scores of infants

Placebo Progesterone
250 230 210 190 170 150
OR 0.8, 95% CI 0.5-1.2
Pooled OR 1.06, 95% CI 0.86-1.31

P=0.45
215
218
P=0.89
193
194
Progesterone
Placebo
At 6 months
At 18 months
Rode L, et al; PREDICT Group. Ultrasound Obstet Gynecol. 2011 Sep;38(3):272-80.
37
Preterm labor
Preterm birth
38
Vaginal progesterone after successful parenteral tocolysis associated with longer latency preceding delivery
Study 70 Women with threatened preterm labor randomized, after arrest of
uterine activity, to receive progesterone suppository 400 mg daily until delivery or no treatment Gestational age at delivery, weeks
50
P = 0.037
Mean latency until delivery, days

50 40 40
Birthweight according to treatment, g

3500
P = 0.002
P = 0.041
3000
30
20 10 0
36.1
24.5
30
20 10 0
36.7
34.5
2500
2000 1500 1000
3101.5 4
2609.3 9
Progesterone
Control
Progesterone
Control
Progesterone
Control
Continued
39
Vaginal progesterone after successful parenteral tocolysis associated with longer latency preceding delivery contd
Prevalence, %, of complications of preterm labor
Progesterone
70 60 50 40
P = 0.021 36.4 27 10.8 P = 0.092 P = 0.002 57.6 51.5 35.1 24.3 18.2 5.4 P = 0.205 39.4 P = 0.136
Control
30
20 10 0
Respiratory distress syndrome
Low birthweight
Recurrent preterm labor
Admission to Neonatal sepsis intensive care unit
Borna S, Sahabi N. Aust N Z J Obstet Gynaecol. 2008 Feb;48(1):58-63.
40
Asymptomatic sonographically short cervix at midtrimester

Preterm birth
41
Midtrimester cervical length <25 mm predict preterm birth in high-risk women

Study
153 Women with prior spontaneous preterm birth 17(0)-34(6/7) weeks screened by transvaginal sonography for cervical length; 153 had CL <25 mm and 672 had CL 25 mm
Results Relationship between cervical length groups and birth <35 weeks
Owen J, et al; Vaginal Ultrasound Trial Consortium. Am J Obstet Gynecol. 2010 Oct;203(4):393.e1-5.
42
In women with short cervix, vaginal progesterone treatment reduces risk of preterm birth
Study Cervical length measured by transvaginal ultrasonography at 20 to 25
weeks of gestation in 14,620 pregnant women
413 (1.7%) had cervical length 15 mm: treated with progesterone vaginal capsule 200 mg each night or placebo from 24 to 34 weeks Risk of maternal and perinatal outcomes (RR, 95% CI) with vaginal progesterone use vs placebo
1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0
P=0.007 P=0.81 P=0.20 P=0.17 P=0.13
0.96
0.56
0.68
0.59
0.34
Spontaneous delivery <34 weeks
Birth weight <2500 g
Birth weight <1500 g
Neonatal morbidity
Neonatal death
Continued
43
Cumulative percentage of continued pregnancies In women with short cervix, vaginal progesterone treatment reduces risk of preterm birth continued
KaplanMeier plot of the probability of continued pregnancy without delivery among patients receiving vaginal progesterone as compared with placebo
Fonseca EB, et al. Fetal Medicine Foundation Second Trimester Screening Group. N Engl J Med. 2007 Aug 2;357(5):462-9.
44
Vaginal progesterone in asymptomatic women with sonographic short cervix reduces risk of preterm birth and neonatal morbidity
Meta-analysis (2011): 5 Trials of high quality with 775 women and 827 infants
Effects (RR, 95% CI) of vaginal progesterone in asymptomatic women with sonographic short cervix (25 mm) in midtrimester
1 0.8 0.75 0.6 0.58 0.4 0.2
Preterm birth <28 wk Preterm birth <33 wk Preterm birth <35 wk Respiratory distress Composite neonatal Birthweight <1500 g Preterm Preterm Preterm Respiratory Composite Birthweight syndrome morbidity/mortality Admission to NICU Admission
0.69 0.57 0.48 0.5 0.545
0.66
birth <28 wk
birth <33 wk
birth <35 wk
distress syndrome
neonatal morbidity/ mortality
<1500 g
to NICU
Requirement for Requirement mechanical for ventilation mechanical ventilation
Romero R, et a. Am J Obstet Gynecol. 2012 Feb;206(2):124.e1-124.e19. Epub 2011 Dec 11.
45
Universal cervical-length screening and vaginal progesterone prevents early preterm births, reduces neonatal morbidity and is cost saving: doing nothing is no longer an option.
Campbell S. Ultrasound Obstet Gynecol. 2011 Jul;38(1):1-9. doi: 10.1002/uog.9073.
46
Prevention of preterm birth

Review
Women with history of preterm delivery
Women with preterm labor
Level A evidence
Women with short cervical length of 15 mm on transvaginal sonography
Prophylactic use of progesterone Incidence of preterm delivery significantly reduced

da Fonseca EB, et al. Semin Perinatol. 2009 Oct;33(5):334-7. Romero R, et a. Am J Obstet Gynecol. 2012 Feb;206(2):124.e1-124.e19. Epub 2011 Dec 11. Borna S, Sahabi N. Aust N Z J Obstet Gynaecol. 2008 Feb;48(1):58-63.
47
Conclusions
Part 5
48
Utrogestan: indications and dosages

1 Luteal phase defect/support IVF cycles: 400 mg to 600 mg/day in 2 or 3 divided doses from hCG injection until 12th week of pregnancy COH-IUI: 200 mg at bedtime daily for 14 days or until 12th weeks of pregnancy 2 3 4 Recurrent early pregnancy loss History of preterm birth Preterm labor 200 mg to 400 mg until 12th week of pregnancy 800 mg/day (PROMISE study) 200 mg/day from 24 weeks to 34 weeks of pregnancy During tocolysis: 400 mg every 6-8 hours
Maintenance phase: 200 mg 3x daily until 36th week of pregnancy

5 Asymptomatic sonographically short cervix 200 mg/day from 24 weeks to 34 weeks of pregnancy
Based on current review and modified from www.besins-healthcare.com.

2012 Utrogestan Natural Micronized Progesterone - From Luteal Phase Defect To Preterm Birth

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2012 Utrogestan Natural Micronized Progesterone - From Luteal Phase Defect To Preterm Birth

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Drepturi de autor:

Formate disponibile

From luteal phase defect to preterm birth

Peanut oil (longchain fatty acid)

Exogenous progesterone/progestins in clinical use:

Natural progesterone C21H30O2

Retroprogesterone or dydrogesterone C21H28O2

17-OH Progesterone caproate

Schindler AE, et al. Maturitas. 2003 Dec 10;46 Suppl 1:S7-S16.

Structurally related to progesterone

Structurally related to testosterone

Use of exogenous progesterone

Micronized progesterone absorption: effects of route of administration

Circulating P levels higher after vaginal administration

Target tissue P levels higher after vaginal administration

Vaginally administered progesterone: the preferred route

Luteal phase defect

Luteal phase support

Administration of exogenous hormones to support implantation and early development of embryo

Luteal phase defect (luteal phase deficiency or

Luteal phase defect: mechanism

Role of physiological progesterone

2 Reduces physiological cell death occurring just before menstruation

hCG P vag 600 mg

With micronized progesterone

Endocrine profile on day 21

Mean FSH, IU/L

Clinical pregnancy rate/transfer

Ongoing pregnancy rate/transfer

Vaginal route preferred

Clinical Ongoing Miscarriage/clinical pregnancy/transfer, pregnancy,transfer, pregnancy, 6 trials 9 trials 6 trials

For IUI cycles: luteal phase support improves pregnancy outcomes

Luteal phase support

Recurrent early pregnancy loss

Maintenance of early pregnancy

Norwitz ER, et al. N Engl J Med. 2001 Nov 8;345(19):1400-8.

Threatened abortion: vaginal micronized progesterone improves uteroplacental circulation

Visit 1: 12 2 days of gestation

Visit 2: 24 2 days of gestation

Visit 3: 23 weeks of gestation

Visit 1: 12 2 days of gestation

Visit 2: 24 2 days of gestation

Visit 3: 23 weeks of gestation

Progestogen reduced miscarriage rates in women with recurrent miscarriages

PROgesterone in recurrent MIScarriagEs (PROMISE) study

Role of physiological progesterone

Reduces uterine contractility

Improves utero-placental circulation

Suppresses fetal inflammatory response

History of spontaneous preterm delivery

Progesterone beneficial for prevention of preterm delivery in high-risk women

Treatment outcome (OR, 95% CI) with progesterone vs controls

Rossi AC, DAddaro V. Anatol J Obstet Gynecol. 2009;2:1.

Micronized progesterone prevents preterm delivery

P=0.03 28.5 13.8

Fonseca EB, et al. 2003

Micronized progesterone prevent preterm delivery

Preterm delivery, %, with micronized progesterone use vs placebo

Preterm delivery <34 weeks

Preterm delivery <37 weeks

Incidence of delivery before 34 weeks, %

Mean Ages and Stages Questionnaire (ASQ) scores of infants

OR 0.8, 95% CI 0.5-1.2

Pooled OR 1.06, 95% CI 0.86-1.31