Luteal phase support in assisted reproductive technology (ART)
1. EXTERNAL USE
Dr. Sunita Chandra
M.D.
ďśChairperson & Director, Rajendra Nagar Hospital & IVF Centre
ďśDirector, Morpheus Lucknow Fertility Centre
ďśFellowship IVF,Germany
2. EXTERNAL USE
Dr . Sunita Chandra , M.D.
Chairperson & Director, Rajendra Nagar Hospital & IVF Centre
Director, Morpheus Lucknow Fertility Centre
ďMember- Quality Council Of India
ďTrained with distinguished experts like Dr. B.N Chakrawarty in Kolkata, Dr. R Rajan in
Kottayam
ďFellowship - IVF,Germany
ďCo-Editor of the manual â Improving surgical skills in Obstetrics (2020)
ďAuthor of one chapter in the Bookâ âHOW I MANAGE FIBROIDSâ
ďOrganizing Committee member of AICOG 2020
ďPresently Secretary , Medico legal committee, LOGS
ďIs founder Joint Secretary UP Chapter of IFS
ďWas organizing secretary of FERTIVISION 2016, held at Lucknow , attended by more than 1000
delegates
ďHas been secretary APGL and joint secretary LOGS
ďHas been Chairperson, panellist, moderator and speaker in many National and International
Conference
ďHas attended many committee meetings at Moscow, China and Vietnam as Advisory Board
member
ďWas panellist and speaker at the UP HEALTH SUMMIT 2018 and 2019, organised by CII and
Department of Medical Health & Family Welfare, Government of Uttar Pradesh.
ďHas given many lectures in various conferences & CMEs at National and state level
ďActive participant of local bodies like LOGS, took initiative to organize many National level
Conferences & CMEs
ďAwarded âABP NEWS UP BRAND LEADERSHIP AWARDâ in Medicine & Hospital sector , handed
over by Shri Akhilesh Yadav, Chief Minister. U.P.
ďHonoured âGOMTI GAURAVâ Award by State Ministers
ďHonoured âSAMMAN CHINHâ by Lucknow Nursing Home association and LNHA Blood and
component Bank
ďHonoured with â SAMMAN PATRAâ by Dr. Neeraj Bora, MLA on Doctors Day ( July 01,2019)
5. EXTERNAL USE
⪠Luteal phase is the period between ovulation and either
establishment of pregnancy or onset of menstrual cycle 2 weeks later
⪠Following ovulation, the luteal phase of a natural cycle is
characterized by the formation of corpus luteum, which secretes
steroid hormones estrogen and mainly progesterone.
Introduction
6. EXTERNAL USE
ď Embryonic implantation occurs during
the implantation window
ď Developing blastocyst secretes human
chorionic gonadotrophin (HCG)
ď Maintain function of corpus luteum.
7. EXTERNAL USE
⢠Luteal phase insufficiency is due to inadequate production of
progesterone
⢠Progesterone is essential for secretory transformation of the
endometrium that permits implantation as well as maintenance of
early pregnancy
⢠Luteal phase defect is one of the reasons for implantation
failure, which has been responsible for many cases of
miscarriages and unsuccessful assisted reproduction
8. EXTERNAL USE
In 1949, the premature onset of menses was recognized as
indicative of a luteal phase deficiency of progesterone
production, which was shown to be correctable by exogenous
progesterone administration
(Jones, 1979)
ď§ The prevalence of a luteal phase defect in natural cycles in
normo-ovulatory patients with primary or secondary infertility
was demonstrated to be about 8.1%
(Rosenberg et al., 1980)
9. EXTERNAL USE
. Since the first formal description of LPD in
1949 as a possible cause of infertility and
recurrent miscarriage by Jones,
.Innumerable investigations have been
undertaken in an effort to verify its existence
or to characterize its pathophysiology,
diagnosis, and treatment
10. EXTERNAL USE
⢠Patients of unexplained infertility
⢠advanced maternal age
⢠recurrent abortions
⢠strenuous exercise
⢠underweight or recent sudden weight loss
sec.amenorrohoe
⢠Hyperprolactinemia/hypothroidism
11. EXTERNAL USE
⢠Diagnosis LPD is a challenge.
⢠Timed endometrial biopsy (>2->3 days out of phase) should
help in diagnosing LPD
⢠Preferred time of endometrial biopsy would be between 6-10
days post ovulation as it coincides with window of implantation
⢠In order not to over diagnose LPD two biopsies should reveal
similar picture histologically.
⢠Future would be identifying integrin molecules and
glycoprotiens may indicate uterine receptivity.
12. EXTERNAL USE
⢠Since progesterone is secreted in a pulsatile
manner, single estimation hold little value done in
luteal phase.
⢠Jordan and colleagues suggested pooling of three
progesterone values (between luteal day 5 and 9), and
values cut offs of 30 ng/ml had a sensitivity of 100%
and specificity of 80%
⢠Ultrasound can be used to trac follicle, follicular
rupture at <17 mm size could suggest LPD.
13. EXTERNAL USE
Diagnosing Luteal Phase Defects:
Neither Straightforward Nor Completely Accurate
Mesen TB, et al. Obstet GynecolClin North Am. 2015;42(1):135â151.
LPD: Luteal phase deficiency.
Approaches to diagnose LPD include:
Measuring
the luteal
phase
duration
Assessing
serum
progesterone
levels
Luteal
phase
biopsy
14. EXTERNAL USE
The consensus of the literature
is that LPD does exist and that
its cause is multifactorial â
15. EXTERNAL USE
Causes of luteal phase defect in a natural
cycle
1
5
ď§ Disordered folliculogenesis
ď§ Defective corpus luteum function
ď§ Abnormal luteal rescue by the early pregnancy
ď§ A variety of clinical conditions, such as
⢠hyperprolactinemia
⢠hyperandrogenic states
⢠weight loss
⢠stress
⢠athletic training may result not in oligo- or anovulation, but rather
may be manifest as LPD (Ginsburg , 1992).
16. EXTERNAL USE
⢠Is there any need for support in
natural cycle /IUI/IVF cycles?
⢠What to give?
⢠When to give?
⢠What dose?
⢠When to stop?
17. EXTERNAL USE
Progesterone and the Menstrual Cycle
17
⢠Post-ovulation, progesterone is secreted by the corpus luteum
⢠If no fertilization occurs, the corpus luteum degrades, progesterone levels fall
and menstrual bleeding occurs
NovĂĄkovĂĄ L, BlankovĂĄ B. VIII. Reproductive Systems. 1. Female Reproductive System, Pregnancy and Childbirth. In: Functions of Cells and HumanBody. 2016.
http://fblt.cz/en/skripta/viii-rozmnozovaci-soustavy/1-zenske-pohlavni-organy-tehotenstvi-a-porod/. Accessed 21 February 2019.
18. EXTERNAL USE
Progesterone and Early Pregnancy
18
⢠Once fertilization occurs, the corpus luteum is stimulated by human
chorionic gonadotropin and continues producing progesterone
hCG, human chorionic gonadotropin
NovĂĄkovĂĄ L, BlankovĂĄB. VIII. Reproductive Systems.1. Female Reproductive System, Pregnancyand Childbirth. In: Functionsof Cells and HumanBody. 2016.
http://fblt.cz/en/skripta/viii-rozmnozovaci-soustavy/1-zenske-pohlavni-organy-tehotenstvi-a-porod/. Accessed 21 February2019.
19. EXTERNAL USE
Progesterone Effects
Progesterone is required for several processes in
early pregnancy:
ď Preparation of the endometrium for implantation (secretory changes)
ď Decreases contractility of uterine smooth muscle
ď Regulation of cellular immunity
ď Mediates (i) uterine blood flow, (ii) uterine endothelial adaptation to
pregnancy [increased NO production]
19
20. EXTERNAL USE
What happens to luteal phase in
stimulated cycles
⢠Multiple follicles of different size might ovulate at different times,
expanding the fertilization window
⢠Thus, both oestradiol and progetsrone , after multiple ovulation is
expected to be significantly higher
(Macklon and Fauser, 2000)
⢠These high concentrations may not only influence the receptivety of
the endometrium, but may also cause luteal insufficiency and early
luteolysis
(Erdem et al., 2008)
21. EXTERNAL USE
CC- Stimulated Cycles
Some authors reported luteal phase
inadequacy in up to 50% of clomiphene
induced cycles in anovulatory women
(Cook et al., 1984,keenan et al ., 1989)
22. EXTERNAL USE
CC- Stimulated Cycles
⢠400 women analysed
⢠No difference observed on ongoing pregnancy between patients
who did, or did not , receive vaginal progesterone as luteal support
8.7% (17/196) versus 9.3% ( 19/204)
⢠Thus routine supplementation of the luteal phase with vaginal
progesterone does not seem to improve pregnancy rates in normo-
ovulatory women stimulated with Clomiphene citrate for IUI
⢠Paul devroy, Human reproduction, vol 25, issue 10. pg 2501-2506
23. EXTERNAL USE
Studies favouring the
luteal phase support
⢠Montville et al â Fertil Steril, 2010
⢠Erdem et al- â Fertil Steril, 2009
⢠Cohlem review- Reprod Biomed Online. 2009
24. EXTERNAL USE
Studies not favouring the
luteal phase support
⢠Ebrahimy M.- 12th International Congress of Gynaecology and obstetrics 2010
⢠Kyrou D- Hum Reprod 2010
⢠Bibi Shahnaz Aali , Iran J Reprod Med. Apr.2013
⢠Romero Nieto MI, Gynecol Endocrinol.2014
25. EXTERNAL USE
Luteal Phase support after IUI
Conclusion
⢠Progeterone luteal phase support may be of benefit to patients
undergoing ovulation induction with gonadotropins in IUI cycles
⢠Progeterone support did not benefit patients undergoing ovulation
induction with CC, suggesting a potential difference in endogenous
luteal phase function depending on the method of ovulation
induction.
26. EXTERNAL USE
Luteal phase deficiency in ART/IVF
ď IVF is associated with luteal phase deficiency1
ď After oocyte aspiration,
supraphysiological
estradiol level caused by
ovarian stimulation has a
negative feedback on
the pituitary2
ď Promotes premature
luteolysis and low serum
progesterone levels
during the luteal phase2
26
Treatment Induced
(ART)3
Use of GnRH
analogues to
prevent
LH surge3
Aspirationof
granulosacells
during oocyte
retrieval3
ImpairCorpus
Luteumâs ability to
produce sufficient
progesterone3
1. PalombaS, Santagni S, LaSala GB. Progesterone administration for luteal phase deficiencyin human reproduction:an old or new issue? J Ovarian Res
2015;8:77:1-15;
2. BarbosaMWP,Silva LR, Navarro PA, et al. Dydrogesterone vs progesterone for luteal-phase support:systematic review and meta-analysis of randomized
controlled trials. Ultrasound Obstet Gynecol 2016;48:161â170;
3. Daya S. Luteal support:Progestogens forpregnancyprotection.Maturitas. 2009;65S:S29âS34.
27. EXTERNAL USE
Luteal phase defect in IVF
Reasons:
⢠Supra-physiological steroide concentrations secreted by multiple
corpora lutea directly inhibit LH release ( Fauser and Devroey 2003)
⢠HCG for the final oocyte maturation suppresses LH production (Miyake
er al 1979)
⢠GnRH agonist or antagonist for down regulation prevents LH rise in the
luteal phase
⢠Removal of large quantities of granulosa cells during oocyte retrieval.
28. EXTERNAL USE
PROGESTERONE PLAYS AN IMPORTANT
ROLE IN CREATING HARMONY BETWEEN
THE ENDOMETRIUM AND EMBRYOS AND
REDUCES THE ABORTION RATE IN THE
INITIAL PHASE OF PREGNANCY
Zarei Aet al. Comparisonof four protocolsforluteal phase support in frozen-thawed Embryo transfer cycles:a randomized clinical trial. ArchGynecol Obstet. 2017
Jan;295(1):239-246
30. EXTERNAL USE
Available options for
luteal support in ART
30
Treatment Use
Human chorionic gonadotropin
(hCG)
⢠Stimulation of the ovaries (or corpora lutea) to boost
production of endogenous progesterone and estradiol in
GnRH agonist/antagonist ART cycles1
Progestogens ⢠For the improvement of ART outcomes in GnRH agonist or
antagonist stimulation cycles1
⢠Available routes of administration:
⢠Vaginal1,2 (tablets, gel, suppositories)2
⢠Intramuscular1
⢠Oral1,2
Gonadotropin-releasing hormone
(GnRH) agonist
⢠For restoration of luteinizing hormone (LH) levels2
Estrogen ⢠Supplementation to progesterone; published data are
inconclusive in terms of ongoing pregnancy rate and
implantation rate3,4
1. Practice Committee of the AmericanSocietyfor Reproductive Medicine. Current clinical irrelevance of luteal phase deficiency:a committee opinion. Fertil Steril 2015;103:e27-e32;
2. van derLindenM, et al.Luteal phase supportforassisted reproductioncycles. Review. Cochrane Database Syst Rev 2015:Issue 7;CD009154;
3. Zhang X-M,et al.Estrogensupplementationto progesterone asluteal phase support in patientsundergoinginvitro fertilization:systematic review and meta-analysis. Medicine
(Baltimore). 2015;94(8):e459;
4. Kolibianakis EM, etal. Estrogenadditionto progesterone forluteal phase support in cycles stimulated withGnRH analogues and gonadotrophins forIVF:a systematic review and
meta-analysis. HumanReprod. 2008;23(6):1346â54.
31. EXTERNAL USE
Corpus luteum can be rescued by hCG (1080)
Advantage : hCG stimulates CL to produce progesterone & E2 Both, also
produces placental protein 14
( Anthony et al., 1993),integrin aâβ3 (Honda et al., 1997) relaxin (Ghosh et al ., 1997) to
support luteal phase and early pregnancy
Disadvantage : Risk of OHSS increases
Dose : 1500 to 2000 units on day 0/1 , 3/4 and 6/7 of oocyte retrieval
Not to be given within 7 days of pregnancy test, as may interfere with pregnancy
detection
32. EXTERNAL USE
⢠Same pregnancy rate
(meta-analysis; pritts & Atwood 2002)
⢠Higher pregnancy rate
(meta-analysis; Nosarka et al., 2005)
33. EXTERNAL USE
â˘In a recent cochrane review and meta analysis, including 15
studies invetigated progesterone Vs hCG even with subgroup
analysis of Progesterone Vs hCG and Progesterone and hCG,
no significant difference was seen accept for OHSS.
â˘Consensus opinion in favour of Progesterone
Once pregnancy is stablished supplement hCG is not beneficial
Progesterone Vs hCG
35. EXTERNAL USE
⢠Reduced implantation rates when compared with hCG, IM
and vaginal progesterone
⢠Poor bioavailability due to rapid hepatic bypass
⢠Failure to induce uniform sectretary changes in
endometrium
⢠Metabolites induce significant sedative and hypnotic
effects
( Arafat et al ., 1988)
Oral Progesterone
36. EXTERNAL USE
⢠Easy to administer
⢠Avoids liver first-pass metabolism
⢠No systemic side effects
⢠Higher endometrial tissue level despite low serum level due to âfirst
uterine pass effectâ
⢠Similar pregnancy rate as intramuscular progesterone
Vaginal Progesterone
37. EXTERNAL USE
⢠Associated with vaginal discharge and perineal irritation
. Tablets 6%
. Gelatin capsules 0-14%
. Suppositories 25-30%
. Bioadhesive gel 17%
⢠Affect patients comfort and compliance during IVF traetment
Vaginal Progesterone
38. EXTERNAL USE
⢠Uncomfortable daily injections
⢠Trained medical personnel
⢠Allergic reactions to the oil vehicle and marked
inflammation at the injection site, resulting in
redness, pain, and even sterile abscess formation
Intramuscular Progesterone
39. EXTERNAL USE
Evolution of the impact of gnadotropin â releasing hprmone agonist as
an adjuvant in luteal phase support on IVF outcome.
Conclusion:
Three 1mg doses of lupride administration 6 days after oocyte retrival
in long protocol cycles does not result in an increase in ongoing
pregnancy rates.
Inamdar and A Majumdar .J Hum Reprod. Sci. 2012
Recently studies have shown that single injection of GnRH agonist
given on luteal day 6, significantly improve the pregnancy,
implantation and delivery rate compared with placebo, especially in
antagonist protocol.
There is no increase risk of birth defects seen
GnRH agonist in luteal phase - IVF
40. EXTERNAL USE
⢠GnRH âa can collborate in the corpus luteum function, acting directly on the
endometrium via local receptors, a direct effect on the embryos or combination.
⢠GnRH âa administration can improve clinical outcomes after ICSI
⢠Premature to recommend the use of GnRH âa in the luteal phase because of
heterogeneity among trials
41. EXTERNAL USE
Conclusion:
Although there was no statistically significant difference between the two
groups, luteal phase support with single-dose GnRHa might be as efficient
as three doses of hCG. Large prospective, randomized-controlled studies
are required comparing GnRHa and hCG for luteal phase support
2019
42. EXTERNAL USE
Role of Oestrogen in IUI
for luteal support
The role of oestrogen along with progeterone
in the luteal phase appears to be only in those
cases where GnRH agonist was used instead
of hCG to trigger ovulation
43. EXTERNAL USE
Estradiol as luteal phase support - IVF
1. The use of estradiol for luteal phase support in
IVF/ICSI cycles : a systematic review and meta-
analysis.
Gelbaya TA, Fertil Steril.2008
Conclusion: the addition of E (2) to P4 for luteal
phase support in IVF/ICSI cycles has no
beneficial effect on pregnancy rates
2. Luteal phase support with estrogen in addition to
progeterone increases pregnancy rates in IVF
cycles with poor response to gonadotropins.
Kutlusoy F, Gynecol Endocrinol. 2014
44. EXTERNAL USE
Dydrogesterone Use
ď Dydrogesterone has been used worldwide since the 1960s
for a number of conditions related to progesterone
insufficiency1
ď It is estimated that the cumulative exposure for all
indications since 1960 is >113 million patients2
ď Of those, it is estimated that >20 million pregnancies
were exposed to dydrogesterone in utero2
ď Overall, clinical data support the well-established and
favorable benefitârisk profile of dydrogesterone in the
approved indications1
44
1. Mirza FG, Patki A, Pexman-Fieth C. Dydrogesterone use inearly pregnancy. Gynecol Endocrinol 2016;32(2):97â106;
2. Tournaye H, SukhikhGT, Kahler E, Griesinger G. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized
vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod 2017;32(5):1019-1027.
45. EXTERNAL USE
Molecular Properties:
Structure and Formulation
ď Dydrogesterone is a retroprogesterone, a stereoisomer of progesterone, with an
additional double bond between carbons 6 and 71,2
ď Dydrogesterone, shaped by light,3 enhances the progestogenic effects2
45
1. Kuhl H. Pharmacology ofestrogens and progestogens: influence of different routes of administration. Climacteric 2005;8(Suppl 1):3â63;
2. Schindler AE, Campagnoli C, Druckmann R, et al. Classification and pharmacology ofprogestins. Maturitas 2008;61(1â2):171â180;
3. Fischer M. Industrial Applications of Photochemical Syntheses. Agnew Chem Int Ed Engl 1978;17:16-26.
Differences in the structure of dydrogesteroneand progesterone influence
the potency and potential side-effectprofilesof these progestogens1,2
46. EXTERNAL USE
Absorption and Plasma Levels
46
1. Abbott Laboratories. CompanyCore DataSheet.Dydrogesterone. 5 July2017;
2. Bulletti C, et al. Targeted drug deliveryingynaecology:the first uterine pass effect. Hum Reprod 1997;12(5):1073â1079.
Vaginal progesterone2
Progesterone diffuses through the entire
uterus by 4â5 hours, and then decreases
concentration after 5 hours
Venous blood outflow from the uterus
was highest in the first 2 hours
Vaginal route permits targeted
drug delivery for a short period of time
Dydrogesterone1
⢠Has quick-effect onset (rapidly absorbed, reaching maximal levels between 30 minutes and 2.5 hours
after administration)
⢠Has a long, stable effect (mean terminal half-life is 5â7 hours)
Dydrogesterone reaches peak absorption levels more rapidly than vaginal
progesterone, and these levels are maintained for a longer duration1,2
Adapted fromBulletti C et al. Hum Reprod 1997;12(5):1073â1079
47. EXTERNAL USE
Bioavailability
47
1. Stanczyk FZ,et al. Progestogens used in postmenopausalhormone therapy: differences in their pharmacologicalproperties,intracellular actions, and
clinical effects. Endocr Rev2013;34(2):171â208;
2. Paulson RJ,et al. Progesterone Pharmacokinetics and PharmacodynamicsWith 3 Dosagesand 2 Regimensof an Effervescent Micronized Progesterone
Vaginal Insert. J Clin Endocrinol Metab 2014;99(11):4241â4249.
3. Schindler AE, CampagnoliC,Druckmann R, et al. Classification and pharmacology of progestins. Maturitas 2008;61(1-2):171-180.
28% oral
dydrogesterone1
4â8% vaginal
progesterone2<5% oral
progesterone1
Dydrogesterone has ~5.6 times better oral bioavailability than oral progesterone1-3
48. EXTERNAL USE
Approved DAILY dosing for luteal support in ART
48
In a recent phase III RCT, the daily dose of oral dydrogesterone used was 20 times
lower than micronized vaginal progesterone capsules4,5
and showed similar clinical benefits
with a well established safety profile4
30 mg oral dydrogesterone1
1. Abbott Laboratories. CompanyCore DataSheet.Dydrogesterone. 5 July2017;
2. Merck Serono Ltd. Crinone 8% vaginal progesterone gel. SPC UK.March2015;
3. Besins Healthcare (UK) Ltd. Utrogestan vaginal 200 mg capsules. SPC UK. 29 June 2017;
4. Tournaye H,et al.APhase III randomized controlled trial comparingthe efficacy, safetyand tolerabilityof oral dydrogesterone versus micronized vaginal progesterone for
luteal support in in vitrofertilization. HumReprod 2017;32(5):1019-1027;
5. SukhikhG., etal. Lotus I:aphase III randomized controlled trial oforaldydrogesterone verses micronized vaginal progesterone forluteal supportinin vitro fertilization, withfocus on
the Russiansubpopulation.Akusherstvo I Ginekologiya/Obstetricsand Gynecology 2017;7:http://dx.doi.org/10.18565/aig.2017.7.
600 mg
vaginal
progesterone capsules3
90 mg
vaginal
progesterone gel2
49. EXTERNAL USE
Dydrogesterone versus Vaginal
Micronized Progesterone Safety and Tolerability
49
⢠Both oral and vaginal micronized progesterone are metabolized by the liver1,2
â Progesterone is associated with a risk of cholestasis in pregnancy, therefore it is only licensed in the UK for
use
up to Week 12 of gestation in ART/IVF and only by the vaginal route
⢠A randomized controlled trial in 853 infertile women compared the efficacy and tolerability of
20 mg/day oral dydrogesterone and 90 mg 8% vaginal progesterone gel used for luteal support.
Numerically more local side effects occurred in the progesterone group compared to the
dydrogesterone group3
ART, assisted reproductive technology;IVF, in vitro fertilization
1. Besins Healthcare (UK) Ltd. Utrogestan oral 100 mgcapsules.SPC UK. 14 July2017;
2. Besins Healthcare (UK) Ltd. Utrogestan vaginal 200 mg capsules. SPC UK. 29 June 2017;
3. Tomic V, et al. Oral dydrogesterone versus vaginal progesterone gel inthe luteal phase support:randomized controlled trial. Eur J Obstet Gynecol Reprod
Biol 2015;186:49â53
Vaginal discharge Vaginal bleeding
Perineal irritation
Interference with
coitus
Side effects occurring at
a greater frequency in the
progesterone group
50. EXTERNAL USE
Dydrogesterone versus Vaginal Micronized
Progesterone Preference and Acceptability
50
⢠In studies that compared oral versus vaginal formulations of
non-progestin drugs,
women prefer to use oral formulations than vaginal ones1,2
⢠Application of vaginal tablets requires a private, clean room; whereas
tablets can be taken orally, anywhere
1. Arvidsson C, et al. Preference and acceptability oforal versus vaginal administrationof misoprostol in medical abortion withmifepristone Eur J Obstet Gynecol Reprod Biol
2005;123(1):87â91;
2. Bingham JS. Single blind comparisonofketoconazole 200 mg oral tablets and clotrimazole 100 mg vaginal tablets and 1% cream in treating acute vaginal candidosis. Br J Vener
Dis1984;60(3):175â177;
3. Chakravarty BN, et al. Oral dydrogesterone versus intravaginal micronized progesterone as luteal phase support inassisted reproductive technology (ART) cycles: results of a
randomised study J Steroid Biochem Mol Biol 2005;97(5):416â420.
Vaginal discharge
or irritation
Dydrogesteronegroup:
0%
Progesteronegroup:
10.5%
Satisfaction
with tolerability
of treatment
Dydrogesteronegroup:
~95%
A comparative study between dydrogesterone and
vaginal micronized progesterone for luteal support3
Progesteronegroup:
~73%
Statisticallysignificant difference (p<0.05)
51. EXTERNAL USE
LOTUS I STUDY
A double-blind, double-dummy, randomized,
multicenter, multinational study comparing the
efficacy, safety and tolerability of oral
dydrogesterone 30 mg versus MVP capsules 600
mg daily for luteal support in IVF
51
52. EXTERNAL USE
Clinical evidence in ART
Data Supporting the Design of the Lotus I Study
52
DYD, dydrogesterone;IVF, in vitro fertilization;MVP, micronized vaginal progesterone;RCT,randomized controlled trial
1. ChakravartyBN, Shirazee HH, DamP, et al. Oral dydrogesterone versusintravaginal micronized progesterone as luteal phase supportinassisted reproductive technology(ART) cycles:
results ofarandomised study. JSteroid Biochem Mol Biol 2005;97(5):416â420;2. Patki A, PawarVC. Modulating fertilityoutcome in assisted reproductive technologiesbythe use of
dydrogesterone.Gynecol Endocrinol 2007;23(Suppl 1):68â72;3. GaneshA, Chakravorty N, Mukherjee R, et al. Comparison of oral dydrogestrone withprogesterone gel and
micronized progesterone for luteal support in1,373 womenundergoing in vitro fertilization:a randomized clinical study. Fertil Steril 2011;95(6):1961â1965;4. Fatemi HM, Bourgain
C, Donoso P, et al. Effect of oral administrationof dydrogestrone versus vaginal administrationof natural micronized progesterone on the secretorytransformationof endometrium
and luteal endocrine profile inpatients withpremature ovarianfailure:a proof of concept. Hum Reprod 2007;22(5):1260â1263;5. Tournaye H, Sukhikh GT,KahlerE, Griesinger G.
APhase III randomized controlled trial comparingthe efficacy, safetyand tolerabilityof oral dydrogesterone versusmicronized vaginal progesterone forluteal support in in vitro
fertilization. HumReprod 2017;32(5):1019â1027.
⢠Clinical Data: Up to 2012, three prospective RCTs concluded that dydrogesterone was equally as
effective or more effective than MVP for luteal support in IVF1â3
⢠Histological data: Oral dydrogesterone 20 mg daily was shown to have reduced endometrial
development compared with MVP 600 mg daily4
⢠Empirical data: Recommendations by IVF specialists
⢠Thus, the dose of 30 mg dydrogesterone daily for the Lotus I Study was chosen based on
recommendations by IVF specialists and previous studies5
Oral DYD
(mg/day)
MVP capsules
(mg/day)
Efficacy
Chakravarty 20051
20 600 Similar
Patki 20072
30 600 DYD better than MVP (p<0.01)
Ganesh 20113
20 600 Similar
53. EXTERNAL USE
Study Schedule
53
OR, oocyte retrieval;hCG, human chorionic gonadotropin;MVP, micronized vaginal progesterone
Tournaye H, Sukhikh GT, KahlerE, GriesingerG. APhase III randomized controlled trial comparingthe efficacy, safetyand tolerabilityof oral dydrogesterone versusmicronized
vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod 2017;32(5):1019â1027.
Screening
and
enrolment
Dayâ14
Day 1
Days 2â7
Embryo transfer
Post-treatment
safety
evaluation every
2months
Follow-up
30 days or 6
months
after
deliverya
Oral dydrogesterone 30 mg (n=520)
MVP 600 mg (n=511)
Day â1
Week 4 Week 8
Week 12 of gestation
End of treatment
Pregnancy test
(serum β hCG and urine strip test)
OR and
treatment start
Week 10 of treatment
Ultrasound performed
Weeks of Gestation
Weeks ofTreatment
54. EXTERNAL USE
Conclusions
54
DYD, dydrogesterone;IVF, in vitro fertilization;MVP, micronized vaginal progesterone
Tournaye H, Sukhikh GT, KahlerE, GriesingerG. APhase III randomized controlled trial comparingthe efficacy, safetyand tolerabilityof oral dydrogesterone versusmicronized
vaginal progesterone for luteal support ininvitro fertilization. Hum Reprod 2017;32(5):1019â1027.
Primary objective
Lotus I demonstrated that oral DYD
was non-inferior to MVP for the
presence of fetal heartbeats at
12 weeks of gestation
Safety and tolerability
Secondary objectives
Rates of positive pregnancy test,
clinical pregnancy, live births and
newborn assessments were similar
between the two treatment groups
OralDYD treatment had a similar
safety profile to MVP, with no new
safety concerns identified in this
study
Implications
Oral DYD may replace MVP as the
standard of care for luteal support in
IVF, owing to the ease of oral
administration
55. EXTERNAL USE
LOTUS II STUDY
A Randomized, Open-label, Two-arm,
Multicenter Study Comparing the Efficacy,
Safety and Tolerability of Oral
Dydrogesterone 30 mg daily versus Crinone 8%
intravaginal progesterone gel 90 mg daily for
Luteal Support in In-Vitro Fertilization
55
56. EXTERNAL USE
Study Design
56
Phase III
Study Design Dydrogesterone vs. Micronised
Progesterone
Open label, 2-arms, randomized
Primary Objective Non-inferiority
Primary Endpoint Presence of fetal heart beats at 12 weeksâ
gestation (10 weeks´ pregnancy)
determined by transvaginal ultrasound
Patients Included Women undergoing IVF
Treatment Duration 12 weeksâ gestation (10 weeks´ pregnancy)
Arms/Daily Dose Dydrogesterone 10 mg tid versus
Micronized Progesterone 8% intravaginal
gel once
Observation/Follow-up
Period
30 days after delivery
57. EXTERNAL USE
Conclusions
57
Primary objective
Lotus II demonstrated that oral DYD
was non-inferior to MVP gel for the
presence of fetal heartbeats at
12 weeks of gestation
Safety and tolerability
Secondary objectives
Rates of positive pregnancy test,
clinical pregnancy, live births and
newborn assessments were similar
between the two treatment groups
OralDYD treatment had a similar
safety profile to MVP gel, with no new
safety concerns identified in this
study
Implications
Oral DYD may replace MVP as the
standard of care for luteal support in
IVF, owing to the ease of oral
administration
DYD, dydrogesterone; MVP, micronized vaginalprogesterone;
GriesingerG, BlockeelC, Sukhikh G, et al. Oral dydrogesterone versusintravaginal micronized progesterone gelfor lutealphase support in in vitro fertilization (LOTUSII): a
randomized, open-label, multicenter, phase III, non-inferiority study. In preparation
58. EXTERNAL USE
Systematic review and
meta-analysis Barbosa et al, 2016
58
Design
⢠Eight RCTs comparing oral dydrogesterone with progesterone by any route
of administration (oral, intramuscular, vaginal capsules or vaginal gel) for
luteal support (LPS) in women undergoing ART were considered eligible and
included in the review and meta-analyses
1. BarbosaMWP,Silva LR, Navarro PAet al.Dydrogesterone vs progesterone for luteal-phase support:systematic review and meta-analysis of randomized controlled trials.
Ultrasound Obstet Gynecol 2016;48:161â170.
Results
⢠There was no relevant difference between oral dydrogesterone and vaginal
progesterone for LPS with respect to rate of:
⢠Ongoing pregnancy (risk ratio (RR), 1.04 (95% CI, 0.92â1.18); seven RCTs,
n=3134)
⢠Clinical pregnancy (RR, 1.07 (95% CI, 0.93â1.23); eight RCTs, n=3809)
⢠Miscarriage (RR, 0.77 (95% CI, 0.53â1.10); seven RCTs, 906 clinical
pregnancies)
59. EXTERNAL USE
Clinical pregnancy and live birth were the primary outcome measures of the present study.
Dydrogesterone was used in 233 participants (54%) and 337 cycles, while 199 participants (46%) and
233 cycles received vaginal micronized progesterone capsule treatment. The proportion of clinical
pregnancies (7.4% vs. 10.2%, pâ=â.213), live births (68% vs. 73%, pâ=â.286) were similar in the two
groups. Oral dydrogesterone and vaginal micronized progesterone provide similar pregnancy outcomes
in terms of clinical pregnancy and live birth rates in women undergoing IUI in conjunction with ovarian
stimulation with rFSH. Given the simple and easy administration, lack of safety concerns and better
patient tolerability,
we suggest that oral dydrogesterone might be preferred for luteal phase support in IUI.
2019
61. EXTERNAL USE
Role of PROGESTOGENS as
Luteal Support in ART/IVF
ď Progestogens improve outcomes in women undergoing
ART procedures1
61
ART, assisted reproduction technology;D, day;ET, embryo transfer;GnRH, gonadotropin-releasing hormone;hCG, human chorionic gonadotropin;
IVF, in vitro fertilization;OR, ovumretrieval.
1.The Practice Committee of the ASRM incollaborationwith the Societyfor Reproductive Endocrinologyand Infertility. Progesterone supplementation during the luteal phase and in
earlypregnancyinthe treatment ofinfertility:an educational bulletin. Fertility and Sterility 2008;90(3):S150-S153;
2.PalombaS, Santagni S, LaSala GB. Progesterone administration for luteal phase deficiencyin human reproduction:an old or new issue? J Ovarian Res 2015;8:77:1-15;
3.DepaloR, JayakrishanK, Garruti G, Totaro I, et al. GnRH agonist versus GnRHantagonist in in vitrofertilization and embryo transfer(IVF/ET). ReprodBiol Endocrinol 2012;10:26:1-
8.
12 weeks
of gestation
D1Dâ21
Start stimulation
ET
Pregnancytest
Long-agonist protocol2,3
Short-agonist protocol2,3
Antagonist protocol2,3
Antagonist
Agonist
Stimulation
Agonist
Stimulation
Stimulation
hCG
Luteal support
Luteal support
Luteal support
OR
62. EXTERNAL USE
600 mg of progesterone starting on the day of ET for 14 days after ET
+ve hCG
150 women did NOT receive
P for another 3 weeks ( study Group)
150 women received
P for another 3 weeks ( control Group)
Delivery rate
63. EXTERNAL USE
⢠Prolongation of P in the early pregnancy
( upto 7 weeks of gestation) has no effect on
the miscarriage and delivery rates P can be
safely withdrawn after a positive hCG test
Study group Control group
Delivery 118 ( 78.7) 126 ( 82.4)
65. EXTERNAL USE
Duration of LPS in IVF
Authors Protocol Study group Control group
Andersen 2002 Vaginal P
Live birth
LPS till 7 weeks
78.7%
LPS till PT +ve ( 4
weeks)
82.4%
Aboulghar 2008 Vaginal or IM P
Miscarriage
LPS till 10 weeks
4.6%
LPS till USS (7 weeks)
4.8%
Goudge 2010 IM P
Livebirth
LPS till 8 weeks
52.0%
LPS till PT +ve ( 4
weeks)
49.0%
Kyrou 2011 Vaginal P
Ongoing
LPS till 7 weeks
82.0%
LPS till PT +ve ( 4
weeks)
73.0%
Kohls 2012 Vaginal P
ongoing
LPS till 8 weeks
73.0%
LPS till USS (5 weeks)
75.0%
66. EXTERNAL USE
Summary
ď Luteal support is necessary in patients undergoing ART procedures due
to low progesterone levels resulting from disrupted luteal phase
physiology
ď It is important to look at patient convenience in luteal phase supportâas
physical and/or psychological treatment burden are the primary reasons
for dropout in IVF cycles
ď The most important factors that affect pregnancy rate are quality of
embryo and endometrial receptivity
ď Progesterone plays an important role in creating harmony between the
endometrium and embryos and reduces the abortion rate in the initial
phase of pregnancy
ď Clinical data from the Lotus I and II study demonstrates that
dydrogesterone is at least as effective as vaginal micronized
progesterone and results in comparable pregnancy outcomes
66