2. Luteal phase support (LPS)
Concept of LPS!
What causes LPD in ART?
Is LPS mandatory in ART?
What is the optimal p level in LPS?
Timing and duration of LPS
Strategies for LPS
3. Concept of LPS
Endometrial receptivity is driven by “the time of progesterone
exposure” after adequate E2 exposure
Is crucial for the trophoblast–endometrial interaction
Simon et al., 2000
4. Concept of LPS
The successful outcome of early pregnancy depends on progesterone
CL: 1st 7 weeks of pregnancy
Trophoblast: after 9th week
During ‘luteal-placental shift’ progesterone is secreted in different
ratios from both sources
Csapo et al., Am J Obstet Gynecol. 1973
5. ‘‘Luteal gap’’
Between the stimulatory effects of:
exogenous hCG—used for triggering ovulation—
&
endogenous hCG originating from the conceptus
6. ‘‘Luteal gap’’
During this luteal gap that endogenous P production may drop,
thereby causing harm to the potentially developing embryo
7. Concept of LPS
LPS is important in preventing luteal insufficiency and its negative
impact on early pregnancy
Smitz et al. RCT, Hum Reprod. 1993
Luteal function is compromised in stimulated IVF cycles
Fauser, Trends Endocrinol Metab. 2003
8. Concept of LPS.. Progesterone role
Secretory changes.. thus improves endometrial receptivity
Vascularity of the endometrium
Local vasodilatation and uterine musculature quiescence by
inducing nitric oxide synthesis in the decidua
10. LPD in ART..Controlled ovarian stimulation
Multifollicular development during COS supraphysiological E2
and P during the early LP inhibits LH release
defective luteal phase in almost all patients
van der Linden et al. Cochrane Database Syst Rev, 2015, Fatemi et al. Reprod Biomed Online, 2009
11. LPD in ART…OPU
OPU causes a LPD & affect steroid secretion..
This theory was rejected
o as aspiration of a single follicle did not lead to impaired
steroid function
Kerin 1981
12. LPD in ART…HCG
By a short-loop negative feedback mechanism after hCG trigger
Miyake et al., 1979; Garcia et al. 1981
This theory was rejected
o long-loop negative feedback by ovarian oestrogens has a greater effect
on LH levels
ohCG does not lower LH secretion in non-stimulated, normal ovulating
women
van der Linden et al., 2015
13. LPD in ART….GnRH agonist
oProlonged pituitary recovery lack of LH the CL did not
develop fully
Smitz 1992a
oSuppression for as long as 10 days after treatment with a GnRH-a
ends
14. LPD in ART….GnRH anagonist
oThought LP would be less impaired
oSignificant reduction in PR in the GnRh-an cycles as well
oSerum P levels in the early and middle LP of GnRh-an cycles are low
oLuteolysis started prematurely
LPS in GnRH antagonist protocols also remains mandatory in IVF
Tarlatzis and Kolibianakis, 2007
15. Therefore..
An adequate luteal phase support is crucial..
To counterbalance the luteal phase insufficiency after ovarian
stimulation and to maintain the secretory endometrium
HOWEVER..
The optimal start, dosage, route and the duration of
the LPS is still subject of a debate
Tomic et al., Syst Rev. 2019
16. LPS in ART.. IS IT A MUST?
In IVF cycles without LPS, luteal phase length was shortened and
early bleeding became more frequent
Albano et al., Fertil Steril. 1998
LPS has a positive effect on pregnancy outcomes, it is unethical to
not use LPS
Cochrane, 2015
LPS after ART procedures with P or hCG improves pregnancy
outcomes, but hCG increases the risk of OHSS
ASRM, 2015
17. Optimal P level in LP?
In a natural cycle:
In LPD midluteal P levels below 10 ng/ml (31.8 nmol/l)
OR
A sum of three random serum P measurements less than 30 ng/ml
(95.4 nmol/l)
Jordan et al., Fertil Steril 1994
In IVF treatments:
The lower limit of P levels to achieve and maintain a pregnancy is
not defined yet
18. Optimal p level?
Viable and ongoing pregnancy more likely with
P more than 30 ng/ml
& E2 level of more than 100 pg/ml at the day of implantation
Liu et al., 1995
Others report
mid-luteal P levels above 17 ng/ml
Aslih et al., RCT. Gynecol Endocrinol 2017
2 days after GnRH agonist trigger above 15 ng/ml
Lawrenz et al., Gynecol Endocrinol. 2018
19. Optimal p level?
Recently a Prospective multicenter study of 602 women undergoing IVF
with fresh ET & Using vaginal p found that:
The optimal chance of pregnancy with serum P4 levels of 60-100 nmol/l
in the early luteal phase
The optimal chance of Live birth with serum P4 levels of 150-250 nmol/l
during the mid-luteal phase
Below, but most distinctly above these levels, the chance of pregnancy
was consistently reduced Thomsen et al., 2018
20. Timing of LPS
Not too early Nor too late !
LPS should be initiated before endogenous P levels decrease or
become too low
However..
Starting LPS too early bears the risk of adversely affecting
endometrial receptivity
21. Timing of LPS
Summary of hCG and P levels from the time of hCG
trigger until early pregnancy during ART.
After hCG trigger (day -2), hCG levels rapidly
increase to approximately 200 IU/L at the time of
OPU (day 0) and are then cleared by approximately
day 5 after retrieval
P levels follow more slowly, peak approximately at
day 5 after retrieval and rapidly decrease
thereafter
This creates several days during which endogenous
P levels lack hCG stimulation and require
supplementation to remain at more than the
threshold of 80–100 nmol/L to maintain pregnancy
Connell. Timing ART P support. Fertil Steril 2015
22. Timing of LPS..Onset of P Supplementation
Starts several days into the LP, during the so-called luteal gap (only a
few days after OPU)
Early P harm by advancing the closure of the window of receptivity
23. Timing of LPS..Onset of P Supplementation
Routine practice in ART initiating LPS on the day of or day after OPU
Justified by:
Suppressing uterine contractions (UC) at the time of ET
This effect of early onset of LPS may be of less relevance in the case of
blastocyst transfers
* Frequency of UC on the day
of ETs was inversely related to
pregnancy
**Increased UC resulted from some degree
of resistance to the uteroquiescent effects
of P by the very high E2 levels
24. Timing of LPS.. clinical pregnancy
and day of P initiation
Markers represent the six different RCTs
results
The red shaded area represents time points
with potential lowered PRs if P is started.
The green shaded area represents the
window of P start times based on the
available RCT
a Results reported as statistically significant
in the primary studies
Connell. Timing ART P support. Fertil Steril
2015
25. Timing of LPS.. clinical pregnancy
and day of P initiation
No significant difference in CPR when commencing P on the day of OR VS
day 1–3 after OR..
Commencing P on day 6 negatively impacts the likelihood of pregnancy
Connell et al. Syst Rev. Fertil Steril 2015
26. oThere appears to be a window for P start time between the evening of
OPU and day 3 after OPU
oAlthough some studies have suggested a potential benefit in delaying
vaginal P start time to 2 days after OPU, this review could not find RCTs to
adequately assess this
Connell. Timing ART P support. Fertil Steril 2015
27. Timing of LPS.. When to stop?
Worldwide trends
In 15% of cases where the patient conceives,
P is administered until pregnancy is confirmed
In 13% P is administered until fetal heartbeat
In 44% of cases P is administered until 8-10
weeks of gestation
In 28% it is given up to 12 weeks or more
28. When Can LPS Be Stopped?
Common practice:
up to the 10th week of pregnancy
luteoplacental shift is ascertained
Mounting evidence in regular ART:
earlier than the 10th week of even the time of the 1st U/S 2–3
weeks after the positive PT
de Ziegle et al., 2018
29. When Can LPS Be Stopped?
Stopping LPS on the day of the +ve PT
because afterward the CL is supported by hCG of embryonic origin
This is different in FET cycles prepared with E2 and P regimen
no CL in principle and therefore hormonal treatment has to be pursued
until the luteoplacental shift
de Ziegle et al., 2018
30. Timing of LPS.. When Can LPS Be Stopped?
P supplementation should be administered until placental P production
is adequate, around 8–10 weeks of gestation.
Once pregnancy is established, supplemental hCG is not beneficial
ASRM, 2012
31. Seven trials involving 1,627 participants were included
Conclusions
in fresh IVF cycles with an hCG trigger and proceeding to a fresh ET, P may
be stopped as early as the first positive hCG test
However, a substantial increase in trial size required to provide robust estimates
Watters et al., 2019
32. Strategies for LPS in ART
Progesterone
HCG
Combinations of E2, P and Hcg
Gizzo et al. RCT, Gynecol Endocrinol 2014
GnRH agonist also has been used for LPS
Fujii et al. Hum Reprod 2001; Tesarik et al. Hum Reprod 2004
33. LPS.. Drug doses
Oral P: 300–800 mg daily
Vaginal P: 8% gel (90 mg daily), cream, tablet (100–600 mg daily)
IM: 25–50 mg daily
SC: 25 mg daily
hCG generally administered every 3 days (1,500–2,500 IU)
35. Progesterone regimens…worldwide trends
oIn almost two-thirds (77%) of cycles
reported, vaginal P alone is used for
LPS
o17% of cycles, combination of
vaginal P with IM P or oral P is being
used
o IM P is used alone in 5% of cycles
ohCG as a single agent for LPS is not
being used at all
(https://ivfworldwide.com/survey/an-updated-survey-on-theuse-of-progesterone-
for-luteal-phase-support-instimulated-ivf-cycles/results-an-updated-survey-onthe-
use-of-progesterone-for-luteal-phase-support-instimulated-ivf-cycles.html).
Worldwide, the preferred route of
progesterone administration is the
vaginal route
36. LPS ..What is the optimal doses
oVery little is known about the optimal dose of natural micronized
progesterone
oDifferent reviews (Pritts and Atwood, 2002; Hubayter and Muasher, 2008)
refer to a study comparing 400 and 600 mg of micronized vaginal P,
but the original source is unverified
37. Vaginal Progesterone
Reach maximal serum levels 3-8 h after the application
Fall continuously over the next 8 h
Vaginal P: 8% gel (90 mg daily), cream, tablet (100–600 mg daily)
38. Vaginal Progesterone
Exerts a direct local effect on the endometrium before it enters the
systemic circulation known as the ‘first uterine pass’ effect
(underlying mechanism of which is not fully understood)
Bulletti et al., 1997
After One hour After Four hours
40. Vaginal Progesterone
Recent Systematic review of the clinical efficacy of vaginal P for LPS in
ART found that:
Crinone, Cyclogest, Lutigest and Utrogestan Vaginal represent equally
safe and effective choices
Child et al., 2018
41. Oral Progesterone..
Convenient way
Natural
**rapidly metabolized after oral intake
**ineffective in inducing a sufficient secretory transformation
Synthetic
*derivatives on lipids and on the psyche limit their use
42. Oral Progesterone..
Maximum serum levels in 2 to 4 hours
Remain elevated for only 6 to 7 hours, requiring more frequent dosing
In a RCTs, users of oral micronized P had a significantly decreased
implantation rate compared:
intramuscular P (18.1 vs 40.9%, P 5 .004) or
vaginal micronized P (10.7 vs 30.7%, P.01)
43. Oral Progesterone..
The recently published data, confirmed the efficacy of daily 30 mg
dydrogesterone compared to daily 600 mg micronized vaginal
progesterone as LPS
Griesinger et al., Fertil Steril 2018
44. Oral Dydrogesterone
Retroprogesteron which has higher oral bioavailability than
micronized P
Selective P agonist
Immunomodulatory
Mimics the effects of P through binding to P receptors
Benefits in LPS t outweigh the risks
45. Oral Dydrogesterone
Dose of oral dydrogesterone is 10–20-fold lower than that of oral
micronized P
Schindler et al., 2003
20-fold lower dose of oral dydrogesterone (30 mg) is non-inferior to
micronized vaginal P (600 mg) for LPS
Tournaye et al., 2017
46. Oral Dydrogesterone
Well-tolerated and efficacious
May replace micronized vaginal P as the standard of care owing to its
patient-friendly oral administration route
Tournaye et al., 2017; Griesinger et al., 2018
Dydrogesterone may induce a paradigm shift in the treatment of the
estimated 1.5 million women worldwide undergoing IVF each year
Chambers et al., 2012; Tournaye et al., 2017
47. IM Progesterone
The most inconvenient LPS approach
High plasma are reached after 2 h with peak concentrations around
8 h after injection
The doses of i.m P used for LPS vary between 25 and 100 mg per
day without any significant difference concerning the outcome
Pritts and Atwood, 2002
49. IM Progesterone vs Vaginal
A meta-analysis comparing i.m. administration of P with the
intravaginal route
Clinical pregnancy rate (OR = 0.91, 95% CI 0.74, 1.13) & Ongoing
pregnancy rate (OR = 0.94, 95% CI 0.71, 1.26) were comparable in the
two groups.
On the basis of this evidence, i.m. progesterone is not
recommended as a ‘first choice’ LPS method in stimulated IVF cycles
Zarutskie and Phillips, 2009
50. SC Progesterone…
An alternative for women, who want to avoid i.m & vaginal route
Baker et al., Hum Reprod 2014
Daily dose of 25 mg s.c. P, equivalent to the physiologic amount
produced daily by the ovary in mid-luteal phase, resulted in
predecidual changes in 100% of interpretable endometrium
samples in a dose finding study
51. SC vs vaginal P
Data from two randomized phase III trials
Subcutaneous P 25 mg daily vs. either P vaginal gel 90 mg daily or 100 mg
intravaginal twice a day
Conclusion
No statistical significant or clinical significant differences exist between SC
and vaginal P for LPS Doblinger et al.,2018
52. Comparing Progesterone regimens
Cochrane Database Syst Rev, 2015
There is no evidence that any one treatment regimen is superior
Results achieved with oral P have been inconsistent
Progesterone regimens, outcome:
Clinical pregnancy rate
53. The route of progesterone administration
does not have an impact on ART outcome,
therefore also the patients’ preference can
be considered when choosing the route of
progesterone administration for LPS
Van der Linden et al. Cochrane Database Syst Rev, 2015
54. Estrogen for LPS
The CL is not only a source of P but also produces E2
It has been suggested LP S should include E2
Fatemi et al.,2007
E2 doses between 2 and 6 mg/day
55. Estrogen for LPS
The 2011 Cochrane review:
P plus E2 did not perform any better than P in terms of biochemical
pregnancy, CPR, or LBR
However, when a subgroup analysis of clinical pregnancy was performed,
P alone performed worse then P plus transdermal E2 (OR: 0.50, CI 0.31–
0.82), suggesting route of E2 administration may play a role
56. 15 RCTs that included a total of 2,406 patients
No statistical difference between E2 + P group and P-only group regarding
CPR/Per patient for different routes of administration of E2 (oral, vaginal,
and transdermal) or other relevant outcome measures
57. Estrogen for LPS
No significant effect was observed for different daily
doses of E2 (6, 4, and 2 mg), even through oral medication in CPR/PA
The best available evidence suggests that E2 addition during the LP does
not improve IVF/ICSI outcomes through oral medication, even with
different daily doses
Huang et al., 2015
58.
59. Only one study suggests the most successful embryo implantation in patients
undergoing additional of E2 + P for LPS in IVF/ICSI cycles used GnRH antagonist
However, this success is not confirmed in any of the selected studies on PR
further studies important in order to clarify the role of E2 in LPS in IVF cycles
60. hCG for LPS
Mimics the physiology
Repeatedly applied hCG in a dosage up to 2.500 IU
Risk of OHSS
Hcg for LPS avoided if:
**E2 >2500–2700 pg/ml on the day of HCG administration
** > 10 follicles
61. hCG for LPS
The early studies provided four injections of 1,500–2,500 IU hCG on top
of the hCG bolus of 10,000 IU used for inducing final oocyte maturation
But..
Conc of LH/hCG reached levels 5- to 10 fold higher than those seen in
the normal menstrual cycle
de Ziegler et al., 2018
In today's standards, exogenous hCG used at these doses enhances the
risk of OHSS
62. hCG for LPS
Cochrane review,2015 which bluntly states;
‘‘We found that hCG, or hCG plus progesterone, was associated with a
higher risk of OHSS. The use of hCG should therefore be avoided’’
63. hCG for LPS..‘‘low-dose’’ or ‘‘microdose’’
Agonist trigger allowed abandoning the large boluses of hCG trigger
But..
required a supplementary dose of 1,500 IU hCG to sustain sufficient
endogenous P production and maintain similar PR
64. hCG for LPS..‘‘low-dose’’ or ‘‘microdose’’
This concept further developed to include:
daily microdoses of hCG of only 100–150 IU throughout the LP without
using any exogenous P preparation de Ziegler et al., 2018
65. hCG for LPS.. ‘‘low-dose’’ or ‘‘microdose’’
Microdoses of hCG led to hCG concentrations that do not exceed
physiologic levels (i.e.,5–10 IU/L)
This secures levels of P in the mid-luteal phase similar to those
achieved in standard OS protocols that use 6,500 IU hCG for
ovulation induction and vaginal P supplementation
66. hCG for LPS.. ‘‘low-dose’’ or ‘‘microdose’’
Women appear to prefer low-dose hCG to vaginal P route
Several ART programs have now switched to this microdose hCG
regimen
Difficulty of administering microdose hCG because of the lack of
widely available preparations for delivering such small doses
67. GnRH-agonist… A novel LPS
This option emerged from:
First, failed attempts at using GnRH-a to prevent implantation in a
‘‘contragestion’’ strategy
Second, inadvertent use of GnRH-a during LP of ART cycles seemed
to boost implantation
thus leading to a pilot trial of GnRH-a use in the LP of OS and E2 and P
FET cycles
Tesariket al., 2016
68. GnRH agonist for LPS
Single dose of GnRH agonist 0.1 mg triptorelin
5 to 6 days after OPU
Stimulating LH secretion for the pituitary
Effects on the endometrial GnRH receptors
Direct effects on the embryo
69. GnRH-a for LPS.. biologic mechanism
For cycles with CL:
In mid-luteal phase >> an initial flare-up ( LH ..supports CL) takes 3–4 days
before receptor down-regulation kicks in
The implanting embryo starts to secrete measurable levels of hCG shortly
after the mid-luteal phase and secures continued CL function
thus.. down-regulation becomes irrelevant for successful implantation
70. GnRH-a for LPS.. biologic mechanism
For recipients without CL:
GnRH-a may directly influence the quality of the early embryo
Direct effect on the endometrium cannot be excluded
Fatemi, 2009; Tesarik et al.,2004
71. P + GnRH-a for LPS
The addition of GnRHa to progesterone appears to improve outcomes
Cochrane, 2015
72. GnRH-a for LPS.. as the sole source
An RCT found that:
The efficacy of GnRH-a as the sole source of LPS in a GnRH-a–
triggered antagonist cycle compared with classic P-based LPS
Pirard et al., 2015
73. hCG vs GnRHa for LPS
GnRHa trigger with LH activity LPS
resulted in comparable LBRs compared
to hCG trigger
Haahr et al., 2017
74. GnRH-a for LPS..recent evidence
3,584 cycles were identified from
13 RCTs
This meta-analysis showed a
substantial efficacy of GnRH-a
addition for LPS on pregnancy
outcomes in IVF/ICSI and support
the use of GnRH-a in luteal phase
to improve the success of IVF/ICSI
Ma et al., 2019
75. This recent meta-analysis suggested that single-dose GnRH-a for LPS in IVF/ICSI was
able to increase:
ongoing pregnancy or LBR per transfer/ CPR per transfer / multiple PR per pregnancy
However, did not affect the clinical abortion rate
As multiple pregnancy increased:
GnRH-a may be a better option for LPS with single ET
Song et al., 2019
76. GnRH-a for LPS.. recent evidence
GnRH agonist treatment may be an ideal choice for LPS in IVF/ICSI
However, further RCTs or multi-center RCTs
are required prior to clinical application of GnRH agonist
Song et al., 2019
77. LPS during FET and Donor/Recipient Cycles
In earlier trials, IM and vaginal P were found to be equivalent for
priming endometrial receptivity in E2 and P
A more recent report with higher miscarriage rates reported in the
vaginal P group
78. LPS during FET and Donor/Recipient Cycles
A large retrospective cohort study comparing
IM progesterone with at a 50- to 100-mg daily dose
& Crinone vaginal gel 90 mg twice a day in FET with day 3 embryos
significantly higher CPR and LBR in cycles replaced with IM
progesterone
79. LPS during FET and Donor/Recipient Cycles
A review of luteal P during FET cycles was performed by Nawroth and
Ludwig and concluded cleavage-stage embryos should not be transferred
before 3 to 4 days of P treatment
Cleavage-stage embryos were transferred on the 4th day of P exposure
Blastocyst were transferred on the 6th day of P exposure
80. LPS after hCG trigger
hCG maintains corpora lutea function in the early LP for up to 5 days
because of its half-life time of more than 24 h
Damewood et al. Fertil Steril 1989;
Fatemi et al. Fertil Steril 2013
After the use of hCG trigger: exogenous P is nowadays the gold
standard
81. LPS after GnRH-a trigger
Natural LH surge is characterized by:
an ascending phase of approximately 4 h
a peak plateau of 20 h and a
descending phase of 20 h
The GnRHa-induced LH/ FSH surge has a significantly shorter ascending
phase
82. LPS after GnRH-a trigger
A shorter half-life of an LH surge induced by GnRH-agonist trigger
may not be providing sufficient luteotrophic effect necessary for
optimal endometrial receptivity in GnRH-antagonist cycles
Humaidan et al., RCT. Hum Reprod 2005;
Connell, et al., systematic review. Fertil Steril 2015
83. Indivisulaized LPS
To counterbalance LPD with GnRH-A trigger, intensive LPS is
required either by:
1. hCG administration
2. or aggressive approach of LPS, including i.m. P
Engmann et al., Fertil Steril. 2012
84. Indivisulaized LPS
To revert GnRH agonist-induced luteolysis, hCG has to be given
not later than 72 h
rescue of the corpora lutea after up to 3 days of gonadotropin
deprivation is hCG dose dependent and requires a minimum
dose of 1500 IU hCG and more
Dubourdieu et al. Fertil Steril 1991
85. Indivisulaized LPS
1.500 IU hCG, given 35 h after GnRH agonist resulted in the same PR as
compared to triggering with 10.000 IU hCG
Humaidan et al. Reprod Biomed Online 2006
However, this dosage may still lead to OHSS in the high responder
Seyhan et al. Hum Reprod 2013
Alternatively, daily dosages of 125 IU rec-hCG are also sufficient to
sustain P levels, yet still causing OHSS in some cases
Castillo et al. Reprod Biomed Online 2010
86. Indivisulaized LPS
However..
oLuteolysis after GnRH-a trigger is patient specific and not always
severe
Lawrenz et al., PLoS One 2017
o In some cases, luteolysis is not present at all..
(unprotected intercourse around the time of OPU might lead to
spontaneous pregnancies and OHSS, despite GnRH-a trigger and ‘freeze-all’
strategy)
Yarali et al., Reprod Biomed Online. 2016;
Fatemi, Fertil Steril. 2014
87. Indivisulaized LPS
NOT all patients after GnRH-a trigger need intensive LPS
and should not be treated with a ‘one-size-fits-all’ approach
The concept of ‘luteal coasting’:
based on the individual luteolysis pattern by applying hCG based on
the P4 levels measured in the early and mid-luteal phase and can be
performed with or even without the additional use of exogenous P
Kol. Reprod Biomed Online 2015
88. Indivisulaized LPS
Depending on the P level 48 h post OPU
a single hCG dosage between 375 and 1.500 IU, given in early LP,
maintain adequate P levels
may well optimize the chance of pregnancy while reducing the
risk of OHSS associated with higher doses of hCG in LP
Lawrenz et al., 2018
Disadvantage
The necessity for repeat blood tests to measure P levels
90. Take home message
In ART, LPS IS a MUST
Progesterone for LPS is necessary for optimal results
Sufficient evidence of efficacy and tolerability to make vaginal P the main
route
Patients should have a choice based on convenience and cost
LPS should be initiated from day 1 post-OR and until a positive PT
Vaginal P is best started within 24 to 48 hours after oocyte retrieval
91. Take home message
New: subcutaneous and oral DG preparations deserve careful attention
In the FET: DG and vaginal P are not effective as monotherapy
HCG for LPS is associated with increase in the risk of OHSS
Oral E2 addition to P does not improve outcomes
LPS better individualized LPS according to the patient’s specific
characteristics, needs and desires and the type of treatment performed