A review on the luteal phase

1
A review on the luteal phase

• P Devroey MD PhD
• Centre for Reproductive Medicine
• Dutch-speaking Brussels Free University
• Brussels - Belgium

2
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 ?

3
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 ?

4
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 ?

5
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 ?

6
Luteal phase supplementation or substitution

• Is luteal phase supplementation mandatory in
  GnRH - agonist / antagonist - gonadotrophin
  stimulated cycles ?

7
Is there any influence on endometrial
histology during the follicular phase in
gonadotrophin stimulated cycles before the
injection of hCG ?

• YES or NO

8
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 )
9
Is there any influence on endometrial
histology in agonist / gonadotrophin
stimulated cycles 36 hours after hCG
administration ?

• YES or NO

10
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 )
11
Is there any influence on endometrial
histology in antagonist / gonadotrophin
stimulated cycles ?

• YES or NO

12
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 )
13
Endometrial biopsy on the day of ovulation
, natural cycle
No secretory features
14
Endometrial biopsy on the day of oocyte
retrieval , GnRH agonist and gonadotrophin
stimulation cycle
Clear secretory features
15
Is there any relation between endometrial
advancement and ongoing pregnancy rates ?

• YES or NO

16
Is there any relation between endometrial
advancement and ongoing pregnancy rates ?

• YES or NO

Answer Yes

3 days gt 3 days P
hMG / agonist 10 / 32 0 / 7
recFSH / antagonist 8 / 49 0 / 6
TOTAL 18 / 81 0 / 13 lt 0.05
Endometrial advancement
Kolibianakis FS 2002
17
Endometrial advancement persists in the
midluteal phase
YES or NO
18
Histological regression of endometrium from
oocyte retrieval to the midluteal phase
Kolibianakis, Bourgain, Platteau, Albano, Van
Steirteghem, Devroey F S 80 2003
19
Describe the LH concentration during the
luteal phase ( post hCG ) in agonist
gonadotrophin stimulated cycles

• LOW or HIGH

20
Describe the LH concentration during the
luteal phase ( post hCG ) in agonist
gonadotrophin stimulated cycles

• LOW or HIGH

Answer Low
Smitz HR 1988
21
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
22
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 lt 0.0001
Demoulin FS 1991
WHY ?
23
Is the luteal phase LH concentration
( post hCG ) in antagonist -
gonadotrophin cycles normal or decreased ?
24
Is the luteal phase LH concentration
( post hCG ) in antagonist -
gonadotrophin cycles normal or decreased ?
Answer decreased
25
Are the luteal phase concentrations
( post hCG ) similar in gonadotrophin alone
versus antagonist gonadotrophin stimulated
cycles ?
YES or NO
26
Are the luteal phase concentrations
( post hCG ) similar in gonadotrophin alone
versus antagonist gonadotrophin stimulated
cycles ?
YES or NO
Answer Yes
Tavaniotou HR 2001
27
Luteinizing hormone serum concentrations in
Clomid gonadotrophin antagonist or
gonadotrophin antagonist cycles
Tavaniotou F S 77 2002
28
Is the luteal phase length normal after
gonadotrophin stimulation in non IVF ?
YES or NO
29
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
30

• Statement GnRH antagonist can be safely
  administered in gonadotrophin stimulated IUI
  cycles without luteal phase supplementation
• Ragni HR 2001

31
Is the statement in contradiction with the
lecture ?
YES or NO
32
Is the statement in contradiction with the
lecture ?
YES or NO
Answer No
Stimulation FSH antagonist FSH alone
Mean no of follicles 2.7 3.2
FSH units 1080 1054
E2 ( ng/ml ) ( pre hCG) 500 900
LH ( U / L ) ( day 4 post hCG ) 1.8 2.5
Ragni HR 2001
33
Steroid serum concentrations
Natural Stimulated cycles
Patients (n) 25 4
Progesterone (?g/L) 8.5 50.5
E2 (ng/L) 92.0 549.5
Tavaniotou Master Thesis Brussels 2000
34
Luteal phase supplementation is mandatory

• hCG versus no treatment
  significantly better
• Vaginal progesterone versus no treatment
  significantly
  better
• Pritts HR 17 2002

35
(No Transcript)
36
hCG versus prog IM E2V (RCT)
hCG Prog IM E2V
ET (n) 269 252
Pregnancies (n) 81 74
30 29
Smitz unpublished
37
Progesterone IM E2V versus vaginal
progesterone E2V (RCT)
Prog IM Vaginal prog
ET (n) 131 131
Pregnancies (n) 40 46
30 35
Smitz HR 1992
38
Vaginal progesterone versus vaginal
progesterone E2V (RCT)
Vaginal prog Vaginal prog E2V
ET (n) 183 195
Pregnancies (n) 65 64
35 32
Smitz HR 1993
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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
40
Is luteal support necessary in GnRH antagonist
cycles?
Beckers et al 2004 JCEM
41
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

42
GnRH agonist triggering
GnRH-a hCG
n 84 n 95
Age (years) 33 34
Eggs (mean) 5.9 5.2
Embryos transferred 2.5 2.3
Pregnancy rates 20 19
Segal FS 1992
43
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

44
Cycle outcome
Brussels 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 ) 10/24 (41.7 )
Odds ratio (95 CI) 0.11 (0.02 0.52) P
level 0.005
Kolibianakis HR 2005
45
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
46
Conclusions

• Ovarian superovulation (IVF) destroys luteal
  phase function
• Endocrinology
• Endometrium behaviour
• Luteal phase supplementation is mandatory
• The degree of luteal steroid production is
  the key factor