2012 utrogestan natural micronized progesterone - from luteal phase defect to preterm birth

Delfin A. Tan, M.D.Section of Reproductive Endocrinology and InfertilityDepartment of Obstetrics and GynecologySt. Luke’s Medical Center Quezon City

From luteal phase defect to preterm birth

Utrogestan® Natural micronized progesterone

Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth 2

DisclosureAll 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

3Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth

Outline Part 1 Utrogestan®: pharmacology

2 Luteal phase defect3 Recurrent early pregnancy loss4 Preterm birth

History of spontaneous preterm deliveryPreterm laborAsymptomatic sonographically short cervix at midtrimester

5 Conclusions


Utrogestan®: pharmacologyPart 1


Utrogestan® The only original natural micronized progesteroneFeatures 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

www.besins-healthcare.com

Wild yam Micronized progesterone

Peanut oil (long-chain fatty acid)

Utrogestan® 100 mg

Utrogestan® 200 mg


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.

Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth 7

Classification of progestinsNatural ProgesteroneSynthetic Retroprogesterone Dydrogesterone

Structurally related to progesterone

Pregnane derivatives

17-OH Progesterone caproate, OH-progesterone heptanoate, gestronone caproate, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, medrogestone, cyproterone acetate

Norpregnane derivatives

Demegestone, promegestone, nomegestrol acetate, nestorone, trimegestone

Structurally related to testosterone

Estranes Lynestrenol, levonorgestrel, norethisterone/norethindrone, norethindrone acetate, ethynodiol diacetate, norgestrienone, dienogest, norethynodrel

Gonanes Norgestrel, desogestrel, gestodene, norgestimate

Spirolactone-derived DrospirenoneDruckmann R. Gynecology Forum 2004;9(2).


Use of exogenous progesteroneDifferent routes of administration: different pharmacokinetics and dynamicsIntramuscular Oral Vaginal (preferred)Supraphysiological plasma concentrations

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...)

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 May-Jun;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. Perusquía 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 May-Jun;34(3):188-93. Tavaniotou A, et al. Hum Reprod Update. 2000 Mar-Apr;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

Target tissue P levels higher after vaginal administration

Nahoul K, et al. Maturitas. 1993 May;16(3):185-202. Miles RA, et al. Fertil Steril. 1994 Sep;62(3):485-90.


Vaginally administered progesterone: thepreferred route1 First uterine pass

effect2 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


Luteal phase defectPart 2


DefinitionsLuteal phase defect

1 If serum mid-luteal phase progesterone level is <10 ng/mL; mid-luteal phase P levels do not always reflect endometrial maturationJordan J, et al. Fertil Steril. 1994 Jul;62(1):54-62. Batista MC, et al. Fertil Steril. 1994 Apr;61(4):637-44.

2 Most reasonable consensus: lag of >2 days in endometrial histological development compared to expected day of cycleJones 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 embryowww.ivf-worldwide.com.


Luteal phase defect (luteal phase deficiency or insufficiency)Prevalence1-4 ~8% in natural cycles in normally ovulating women

with primary or secondary infertilityAlmost all patients in stimulated IVF cycles

Etiology5 Iatrogenic Supraphysiological steroid levels in stimulated cycles of IVF and other assisted reproductive technologies

Other mechanisms

Abnormal follicle productionDefective corpus luteum functionFailure of uterine lining to respond to normal progesterone levels

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.


Luteal phase defect: mechanism

Fatemi HM. F, V & V in ObGyn. 2009;1(1):30-46.


Role of physiological progesteronePrepares the endometrium for implantation

1 Promotes differentiation of endometrial stromal and epithelial cellsNorwitz ER, et al. N Engl J Med. 2001 Nov;345(19):1400-8.

2 Reduces physiological cell death occurring just before menstruationLovely LP, et al. J Clin Endocrinol Metab. 2005 Apr;90(4):2351-6.


Vaginal progesterone: fewer signs of luteal phase deficiency during stimulated cyclesEndometrial development in GnRHa/hMG stimulated cycles with or without luteal phase support

Bourgain C, et al. Hum Reprod. 1994 Jan;9(1):32-40.

Delayed In phase Advanced Dissynchrony0

20

40

60

80

100

Effects of luteal phase support on endometrial development (% of cycles)

No LPS hCG E2V + P im 100 mgE2V + P vag 600 mg P vag 600 mg

Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth

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 cyclesWith 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 →

Utrogestan® Natural micronized progesterone – From luteal phase defect to preterm birth

Vaginal micronized progesterone: more effective than oral dydrogesterone in creating 'in-phase' secretory endometrium continued →

Fatemi HM, et al. Hum Reprod. 2007 May;22(5):1260-3. Epub 2007 Jan 16.

Endocrine profile on day 21 Oral DG

Vaginal P

P value

Mean P, µg/L

0.3 8.6 0.013

Mean LH, IU/L

22.5 12.9 0.049

Mean FSH, IU/L

23.9 13.0 0.047

1 2 3 4 5 60

2

4

6

8

2 2

6

3

4

2

7 7

3

5

6

5

Endometrial histological dating in the luteal phase for each patient

(biopsy on day 21)

Oral dydrogesteroneVaginal micronized progesterone

Patients


Vaginal micronized progesterone for luteal phase support after assisted reproductionPooled results of 13 major randomized controlled studies

*Most frequent daily dosage: 600

mg

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.

Clinical pregnancy rate/transfer

Ongoing pregnancy rate/transfer

0

10

20

3030

22.7

Pregnancy rate, %, with micronized proges-terone* as luteal phase support (n=1730 pa-

tients)


0.2

0.6

1

1.4

0.91 0.940000000000001

0.54

Risk (OR, 95% CI) with vaginal progesterone vs intramuscular progesterone

Vaginal route preferred

oEasieroLess painfuloLess time-consumingoLess discomfort

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)

Zarutskie PW, Phillips JA. Fertil Steril. 2009 Jul;92(1):163-9.


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)

Results

Maher MA. Eur J Obstet Gynecol Reprod Biol. 2011 Jul;157(1):57-62. Epub 2011 Apr 21.Clinica

l pregn

ancy

/pati

ent

Clinica

l pregn

ancy

/cycle

Live birt

h/pati

ent

Livebirt

h/cycle

020406080

54.9

29.5 35.2

9.8

35.219.8 18.9

5.5

Supported cycles Unsupported cycles

P=0.016

P=0.07

P=0.001

P=0.001


Luteal phase supportConclusions 1 Micronised progesterone is the

standard of care for LPS.Tavaniotou A, et al. Hum Reprod Update 2000 Mar-Apr;6(2):139-48. 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.


Recurrent early pregnancy lossPart 3


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.


Recurrent first trimester abortion: due to luteal phase defect, treated successfully with progesteroneStudy Progesterone profiles in women with luteal phase defect vs women

with normal cyclesResults 1988

1 Women with normal cycles vs women with LPD

More progesterone production in luteal phase (discriminatory level of serum P: ≤21 nmol/L*)

2 Women with recurrent abortion

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.


Threatened abortion: vaginal micronized progesterone improves uteroplacental circulationStudy 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 micronized vaginal progesterone use

Blood flow indices in the spiral arteries with dydrogesterone use

Czajkowski K, et al. Fertil Steril. 2007 Mar;87(3):613-8. Epub 2006 Nov 27.

02468

0.86 0.78 0.722.2 1.73 1.44

7.6

4.9

3.02

Resistance index Pulsatile indexSystolic/diastolic ratio

02468

0.75 0.81 0.772.09 2.48

1.65

5.6 5.34.05

Resistance index Pulsatile index Systolic/diastolic ratio

P = 0.009

P = 0.0059

P = 0.007

NS


Progestogen reduced miscarriage rates in women with recurrent miscarriages

Study Meta-analysis of 15 trials involving 2118 women

Results 2008

Haas DM, Ramsey PS. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003511.

00.40.81.2

0.98 0.38

Risk (Peto OR, 95% CI) of miscarriage with progestogen treatment vs placebo/no treat-

ment


PROgesterone in recurrent MIScarriagEs (PROMISE) studyStudy Randomized, double-blind, placebo-controlled multi-

centre trial on first trimester progesterone therapy in women with a history of unexplained recurrent miscarriages

Principal objective

Progesterone, 400 mg pessaries twice daily, started soon as possible after a positive pregnancy test (and 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%

Status On-going; anticipated end date: 01/05/2012http://www.imperial.ac.uk/


Preterm birthPart 4


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.


Role of physiological progesteroneMaintains pregnancy

1 Modulates maternal immune responsesDruckmann 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 Reduces uterine contractilityFanchin R, et al. Hum Reprod. 2000 Jun;15 Suppl 1:90-100. Perusquía 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.

3 Improves utero-placental circulationLiu 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.

4 Suppresses fetal inflammatory responseSchwartz N, et al. Am J Obstet Gynecol. 2009 Aug 201(2): 211.e1-9.


History of spontaneous preterm delivery

Preterm birth


Progesterone beneficial for prevention of preterm delivery in high-risk women Review 4 RCTs involving 1462 high-risk women

Rossi AC, D’Addaro V. Anatol J Obstet Gynecol. 2009;2:1.

Preterm

delivery

Birthweigh

t <1500 g

Neonatal death

01020304050

34

102

42

17

4

Treatment outcome, %

Progesterone Controls

Preterm

delivery

Birthweigh

t <1500 g

Neonatal death

00.20.40.60.8

11.2

0.49 0.600000000000001 0.5

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

trols P=0.01

P=0.02

P=0.04


Micronized progesterone prevents preterm delivery

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.

Fonseca EB, et al. 2003


Raj P, et al. 2009 Majhi P, et al. 2009 Cetingoz E, et al. 2011

0102030405060

2.8

19.2

29.7

48.8

18.6

34.4

50

6

24.3

Preterm delivery <34 weeks in major randomized controlled studiesProgesterone Placebo



Raj P, et al. 2009 Majhi P, et al. 2009 Cetingoz E, et al. 2011

010203040506070

13.8

39.2

12

4028.5

59.5

38

57.2

Preterm delivery <37 weeks in major randomized controlled studies

Progesterone Placebo

NS

P=0.002

P=0.002

P=0.001

P=0.64P=0.01

P=0.03

P=0.002

P=0.0027

P=0.036


Micronized progesterone prevent preterm deliveryPooled results

5 Major RCTs with

micronized progesterone

in preterm delivery

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.

Preterm delivery <34 weeks Preterm delivery <37 weeks05

1015202530354045

14.71

33.3329.56

40.91

Preterm delivery, %, with micronized progesterone use vs placebo

Micronized progesterone Placebo


PREDICT study: vaginal progesterone did not prevent preterm delivery in twin pregnanciesStudy 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)

Rode L, et al; PREDICT Group. Ultrasound Obstet Gynecol. 2011 Sep;38(3):272-80. Progesterone Placebo0

5

10

15

20

25

30

15.318.5

Incidence of delivery before 34 weeks, %

At 6 months At 18 months150

170

190

210

230

250

215

193

218

194

Mean Ages and Stages Ques-tionnaire (ASQ) scores of infants

Placebo Progesterone

OR 0.8, 95% CI 0.5-1.2Pooled OR 1.06, 95% CI 0.86-1.31P=0.45

P=0.89


Preterm labor Preterm birth


Progesterone Control0

10

20

30

40

50

36.1

24.5

Mean latency until delivery, days

P = 0.037


10

20

30

40

50

36.7 34.5

Gestational age at delivery, weeks

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

Continued →

P = 0.041


1500

2000

2500

3000

3500

3101.54

2609.39

Birthweight according to treatment, g

P = 0.002


Vaginal progesterone after successful parenteral tocolysis associated with longer latency preceding delivery cont’d

Borna S, Sahabi N. Aust N Z J Obstet Gynaecol. 2008 Feb;48(1):58-63.

Respira

tory

distre

ss sy

ndrome

Low birt

hweight

Recurre

nt pre

term la

bor

Admission to

intensiv

e care

unit

Neonatal sepsis

0

20

40

60

10.8

2735.1

24.3

5.4

36.451.5 57.6

39.4

18.2

Prevalence, %, of complications of preterm labor

Progesterone Control

P = 0.021 P = 0.205

P = 0.136

P = 0.002P = 0.092


Asymptomatic sonographically short cervix at midtrimester

Preterm birth


Midtrimester cervical length <25 mm predict preterm birth in high-risk womenStudy 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.


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 women413 (1.7%) had cervical length ≤15 mm: treated with progesterone vaginal capsule 200 mg each night or placebo from 24 to 34 weeks

Continued →

Spontaneous de-livery <34

weeks

Birth weight <2500 g

Birth weight <1500 g

Neonatal morbidity

Neonatal death 0

0.4

0.8

1.2

1.6

0.56

0.960.68 0.59

0.34

Risk of maternal and perinatal outcomes (RR, 95% CI) with vaginal progesterone use vs placebo

P=0.007 P=0.81 P=0.20 P=0.17P=0.13


In women with short cervix, vaginal progesterone treatment reduces risk of preterm birth continued →

Kaplan–Meier 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.

Cumulative percentage of continued pregnancies


Vaginal progesterone in asymptomatic women with sonographic short cervix reduces risk of preterm birth and neonatal morbidityMeta-analysis (2011): 5 Trials of high quality with 775 women and 827 infants

Romero R, et a. Am J Obstet Gynecol. 2012 Feb;206(2):124.e1-124.e19. Epub 2011 Dec 11.

0.2

0.4

0.6

0.8

1

0.50.58

0.69

0.48

0.57 0.545

0.75

0.66

Effects (RR, 95% CI) of vaginal progesterone in asymptomatic women with sonographic short cervix (≤25 mm) in midtrimester

Preterm birth <28 wk



Respiratory distress

syndrome

Composite neonatal

morbidity/ mortality

Birthweight <1500 g

Admission to NICU

Requirement for

mechanical ventilation


‘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.


Prevention of preterm birthReview

Level A evidence

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.


ConclusionsPart 5


Utrogestan: indications and dosages 1 Luteal phase

defect/supportIVF cycles: 400 mg to 600 mg/day in 2 or 3 divided doses from hCG injection until 12th week of pregnancyCOH-IUI: 200 mg at bedtime daily for 14 days or until 12th weeks of pregnancy

2 Recurrent early pregnancy loss

200 mg to 400 mg until 12th week of pregnancy800 mg/day (PROMISE study)

3 History of preterm birth 200 mg/day from 24 weeks to 34 weeks of pregnancy

4 Preterm labor During tocolysis: 400 mg every 6-8 hoursMaintenance phase: 200 mg 3x daily until 36th week of pregnancy

5 Asymptomatic sono-graphically 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

Documents

administered progesterone

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natural precursor diogenin

vaginal route

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