Transcript Document

A review on the
luteal phase
P Devroey MD PhD
Centre for Reproductive Medicine
Dutch-speaking Brussels Free University
Brussels - Belgium
Learning objectives

Is the luteal phase defective after
ovulation induction in anovulatory women ?

Is the luteal phase defective after
“controlled” ovarian superovulation ?

If yes, which is the mechanism behind ?
Controlled ovarian superovulation for
IVF


Are the luteal phase LH concentrations
normal after controlled ovarian stimulation
with gonadotrophins alone ?
Are the luteal phase LH concentrations
normal after controlled ovarian stimulation
with the combination of GnRH agonists
and gonadotrophins ?
Controlled ovarian superovulation for IVF
(continued)


Are the luteal phase LH concentrations normal
after controlled ovarian stimulation with the
combination of GnRH antagonists and
gonadotrophins ?
Are the luteal phase LH concentrations normal
after controlled ovarian stimulation with the
combination of clomiphene citrate and
gonadotrophins ?
Endometrium


Is there any influence on endometrial
histology after the administration of
gonadotrophins before injection of human
chorionic gonadotrophins (hCG) ?
Is there any influence on endometrial
histology in GnRH agonist/antagonist gonadotrophin stimulated cycles 36 hours
after injection of hCG ?
Luteal phase supplementation or
substitution

Is luteal phase supplementation mandatory
in GnRH - agonist / antagonist -
gonadotrophin stimulated cycles ?
Is there any influence on endometrial
histology during the follicular phase in
gonadotrophin stimulated cycles before the
injection of hCG ?
YES
or
NO
Is there any influence on endometrial
histology during the follicular phase in
gonadotrophin stimulated cycles before the
injection of hCG ?
YES
or
NO
Answer : Yes
100 % secretory advancement in
preovulatory endometria ( pre - hCG ) during
ovarian stimulation
( Marchini FS 1991 )
Is there any influence on endometrial
histology in agonist / gonadotrophin
stimulated cycles 36 hours after hCG
administration ?
YES
or
NO
Is there any influence on endometrial
histology in agonist / gonadotrophin
stimulated cycles 36 hours after hCG
administration ?
YES
or
NO
Answer : Yes
100 % ( n = 40 patients )
2 - 5 days advancement
( Ubaldi FS 1997 )
Is there any influence on endometrial
histology in antagonist / gonadotrophin
stimulated cycles ?
YES
or
NO
Is there any influence on endometrial
histology in antagonist / gonadotrophin
stimulated cycles ?
YES
or
NO
Answer : Yes
100 % ( n = 55 patients )
2 - 4 days advancement
( Kolibianakis FS 2002 )
Endometrial biopsy on the day of
ovulation , natural cycle
No secretory features
Endometrial biopsy on the day of
oocyte retrieval , GnRH agonist and
gonadotrophin stimulation cycle
Clear secretory features
Is there any relation between
endometrial advancement and ongoing
pregnancy rates ?
YES
or
NO
Is there any relation between
endometrial advancement and ongoing
pregnancy rates ?
YES
or
NO
Answer : Yes
Endometrial advancement
hMG / agonist
recFSH / antagonist
TOTAL
≤ 3 days
> 3 days
10 / 32
0/7
8 / 49
0/6
18 / 81
0 / 13
P
< 0.05
Kolibianakis FS 2002
Endometrial advancement persists in
the midluteal phase
YES
or
NO
Histological regression of endometrium from oocyte
retrieval to the midluteal phase
8
6
4
2
0
-2
OP U
-4
Midluteal p hase
1
2
3
4
5
6
7
8
9
10
Patient
Kolibianakis, Bourgain, Platteau, Albano, Van Steirteghem, Devroey F S 80 2003
Describe the LH concentration during the luteal
phase ( post hCG ) in agonist gonadotrophin
stimulated cycles
LOW
or
HIGH
Describe the LH concentration during the luteal
phase ( post hCG ) in agonist gonadotrophin
stimulated cycles
LOW
or
HIGH
Answer : Low
Smitz HR 1988
Are the LH concentrations during the luteal
phase ( post hCG ) in agonist - gonadotrophin
stimulated cycles similar to the LH
concentrations in the follicular phase ?
YES
or
NO
Are the LH concentrations during the luteal
phase ( post hCG ) in agonist - gonadotrophin
stimulated cycles similar to the LH
concentrations in the follicular phase ?
Answer : No
Before hCG
1.5 mIU / ml
12 hours after hCG
0.5 mIU / ml
96 hours after hCG
0.2 mIU / ml
P < 0.0001
Demoulin FS 1991
WHY ?
Is the luteal phase LH concentration
( post hCG ) in antagonist - gonadotrophin
cycles normal or decreased ?
Is the luteal phase LH concentration
( post hCG ) in antagonist - gonadotrophin
cycles normal or decreased ?
Answer : decreased
Are the luteal phase concentrations
( post hCG ) similar in gonadotrophin
alone versus antagonist gonadotrophin
stimulated cycles ?
YES
or
NO
Are the luteal phase concentrations
( post hCG ) similar in gonadotrophin
alone versus antagonist gonadotrophin
stimulated cycles ?
YES
or
NO
Answer : Yes
Tavaniotou HR 2001
Luteinizing hormone serum concentrations
in Clomid gonadotrophin antagonist or
gonadotrophin antagonist cycles
LH level (IU /L)
15
10
5
0
-3
-2
-1
Day
0
1
2
early
mid
late
Luteal phase
Tavaniotou F S 77 2002
Is the luteal phase length normal after
gonadotrophin stimulation in non IVF ?
YES
or
NO
Is the luteal phase length normal after
gonadotrophin stimulation in non IVF ?
YES
or
NO
Answer : No
Cycles
78
Normal length
60
Shortened
18 ( 23 % )
Olson FS 1983
Statement : GnRH antagonist can be safely
administered in gonadotrophin stimulated
IUI cycles without luteal phase
supplementation
Ragni HR 2001
Is the statement in contradiction
with the lecture ?
YES
or
NO
Is the statement in contradiction
with the lecture ?
YES
or
NO
Answer : No
Stimulation
Mean no of follicles
FSH units
E2 ( ng/ml ) ( pre hCG)
LH ( U / L ) ( day 4 post hCG )
FSH + antagonist
2.7
FSH alone
3.2
1080
1054
500
900
1.8
2.5
Ragni HR 2001
Steroid serum concentrations
Natural
Patients (n)
Progesterone (g/L)
E2 (ng/L)
25
Stimulated cycles
4
8.5
50.5
92.0
549.5
Tavaniotou Master Thesis Brussels 2000
Luteal phase supplementation is
mandatory

hCG versus no treatment
significantly better

Vaginal progesterone versus no treatment
significantly better
Pritts HR 17 2002
hCG versus prog IM + E2V (RCT)
hCG
Prog IM + E2V
269
252
Pregnancies (n)
81
74
%
30
29
ET (n)
Smitz unpublished
Progesterone IM + E2V versus
vaginal progesterone + E2V (RCT)
ET (n)
Prog IM
Vaginal prog
131
131
Pregnancies (n)
40
46
%
30
35
Smitz HR 1992
Vaginal progesterone versus
vaginal progesterone + E2V (RCT)
Vaginal prog
Vaginal prog + E2V
183
195
Pregnancies (n)
65
64
%
35
32
ET (n)
Smitz HR 1993
Is luteal support necessary in GnRH antagonist cycles?
Fixed dose of rec FSH 150 IU, daily antagonist by a follicle of 14mm
By a follicle of 18mm patients were randomized to receive
rec hCG, rec LH, GnRH agonist
No luteal support
When 40 patients had been included,
the study was canceled prematurely
because of observed premature luteal phase bleeding and
extremely low pregnancy rates.
Beckers et al 2004 JCEM
Is luteal support necessary in GnRH antagonist cycles?
Support of corpus luteum function remains mandatory
after ovarian stimulation for IVF with GnRH
antagonist cotreatment.
Beckers et al 2004 JCEM
Is GnRH agonist triggering an
option ?

PubMed 01.03.2011 n : 83 publications

Gonadotrophin-releasing hormone agonist
triggering : the way to eliminate ovarian
hyperstimulation syndrome - a 20 years
experience
Kol Sem Reprod Med 2010
GnRH agonist triggering
Age (years)
GnRH-a
hCG
n : 84
n : 95
33
34
Eggs (mean)
5.9
5.2
Embryos transferred
2.5
2.3
20 %
19 %
Pregnancy rates
Segal FS 1992
Reflexion
It is possible that down regulation of
pituitary receptors and reduced LH
support for the corpus luteum may
occur even after a single
administration of GnRH agonist
Segal FS 1992
Cycle outcome
Brussels
Agonist
hCG
Stimulation (in
patients)
18
24
OPU (n)
18
24
ET (n)
15
20
Ongoing pregnancy
rate / started cycle
1/18 (5.6 %)
Odds ratio (95 % CI) 0.11 (0.02 – 0.52)
P level = 0.005
10/24 (41.7 %)
Kolibianakis HR 2005
GnRH agonist triggering in a
GnRH antagonist cycle
Triggering
GnRH agonist 0.2
mg Triptorelin
hCG 10 000
Vaginal
progesterone
+
+
Estradiol
valerate
+
+
Discontinuation
-
-
Pregnancy rate
5.6 %
41.7 %
Kolibianakis HR 2005
Conclusions
1. Ovarian superovulation (IVF)
destroys luteal phase function
 Endocrinology
 Endometrium behaviour
2. Luteal phase supplementation is
mandatory
3. The degree of luteal steroid
production is the key factor