Luteal phase support

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Luteal phase support in ART
Prof. Aboubakr Elnashar
Benha University Hospital, Egypt Delta
(Mansura) Benha fertility centers Email
elnashar53_at_hotmail.com
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• There are a large number of protocols for LPS in
  ART.
• LPS has consisted of HCG P P plus HCG, E,
  ascorbic acid, aspirin or prednisolone.
• Different combinations, doses, durations
  formulations are used, but the best dose,
  duration or formulation of treatment remains
  controversial.

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Objective To review RCTs meta-analyses
concerning LPS in ART Materials methods An
electronic search of the Cochrane library, Pub
Med for RCT meta-analyses concerning LPS from
1990 to 2004.
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• Results
• Five meta-analyses,
• 41 RCT
• no Cochrane systematic review were found.
• Studies were classified into long, short,
  ultra-short direct protocol studies.

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• LPS in the long protocol using P, HCG or P plus
  HCG or E was analyzed.
• P support was reviewed as regard the type, dose,
  route of administration, when to start when to
  stop.

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I. Luteal phase support in long protocol
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1. Progesterone alone Progesterone Vs no
treatment a significantly higher PR in groups
treated with IM or oral P compared with no
treatment (8 RCTs,Soliman et al, 1994)
A. Progesterone
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• I. Route of administration
• IM Vs oral
• IM P conferred the most benefit compared with
  oral P (meta-analysis, Prittis Atwood, 2002)
• IM P (50 mg/day) resulted in significantly
  higher IR, CPR compared with oral P (600 mg/day)
  (Casini et al,2003).
• 4/30 women discontinued treatment because of
  their inability to administer IM P.

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• 2. IM Vs vaginal
• Vaginal P is as effective as the IM P is
  associated with fewer side effects greater
  patient adherence satisfaction (10 RCT,Felicia
  et al ,2003).
• Adequate tissue levels of P after vaginal P is
  attributed to uterine first-pass effect.

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• 3. Oral Vs vaginal
• The C OPR were significantly lower with the
  oral formulation (Pouly et al, 1996 Frieder et
  al, 1999, Sucedo et al, 2000). These studies
  strongly suggest the inferiority of oral P for
  LPS.
• 1. The vaginal administration of P results in a
  greater bioavailability with less relative
  variability than oral P (Levine Watson, 2000).
• 2. Oral P is subjected to first-pass
  pre-hepatic hepatic metabolism.

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II. Dose 1. Oral Micronized P at doses of 400
600 mg. No differences in CPR (Chanson et
al,1996). 2. IM 25 mg IM P was compared with
100 mg P. No difference in CPR (Check et
al,1991)..
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• III. Type (formulation)
• 1. Vaginal
• Pezino et al (2004) compared
• Gel (Crinone 8, 90 mg/day),
• Capsules (Uterogestan 200 mg twice daily)
• Suppositories (cyclogest 200 mg daily).
• No differences in CPR.
• Cost minor side effects (perineal irritation,
  leaking out, interference with coitus) may limit
  the gel in favor of capsules suppositories.

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2. IM 50 mg/d of IM P Vs 341 mg /3 days
(Costabile et al,2001) or once weekly (Abte et
al,1997) of IM 17 OH progesterone caproate No
differences in CPR or OPR.
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• IV. When to start
• Day 6 Vs day 3 after OR
• PRs are significantly decreased by starting on
  day 6 compared to day 3 (Williams et al,2001).
• Day of OR Vs day of ET
• No difference (Baruffi et al,2002).

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• V. When to stop
• At the time of pregnancy test (Stelling et al,
  1999 Penzias,2002 Jacobs Balen,2003).
• At 8 W (Costabile et al, 2001)
• At 10-12 W (Check et al, 1991).

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Most treatment protocols advocate the use of P
throughout the first trimester, based on the
findings of Shamma et al, who used 17-OH P as a
marker to demonstrate ongoing corpus luteum
activity up to week 10 of pregnancy.
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• Stelling et al (1999) found no difference in the
  CPR, OPR, spontaneous abortion between stop or
  continuing luteal support after positive
  pregnancy test.
• LPS beyond the pregnancy test may not be
  indicated (Penzias,2002 Jacobs Balen,2003).

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• The optimal length of treatment remains unsolved
  at present further trials are needed before
  clear recommended.
• The assumption that high serum P levels are
  required to achieve biological efficacy in the
  endometrium appears to be incorrect
  (Penzias,2000)

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2. Progesterone plus estrogen The oral estrogen
doses 2 to 6 mg /d 1. No advantage (Lewin et
al, 1994 Smitz et al,1993Tay Lenton, 2003
Rashidi et al,2004).
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2. Beneficial effect on IR PR (Farhi et
al,2000 Gorkemli et al,2003). 3. Beneficial
effect on PR in patients with profound E2 decline
(E2 on day of HCG/ E2 of ET gt50) (Lakkis et
al,2002 Gleicher et al,2000).
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• 3. Progesterone plus HCG
• HCG
• 5000 IU/3d no statistically significant
  differences in CPR (Ludwig et al,2001).
• 2500 IU midluteal. No affect on PR, but it helps
  to preserve corpus luteum function avoids the
  need for further supplementation during early
  pregnancy (Herman et al,1996)

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4. Progesterone plus ascorbic acid No benefit
(Griesinger et al, 2002)
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5. Progesterone plus Prednisolone Prednisolone
(15 mg daily following ET) does not improve the
clinical pregnancy or implantation rates
(Ezzeldin et al, 2003). The sample size of this
study was small.
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6. Progesterone plus Prednisolone Low dose
aspirin No benefit on PR , but it may reduce the
rate of spontaneous pregnancy loss (Mollo et
al,2003)
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1. HCG Vs no treatment HCG 1000-5000 s.c.
every 2-5 days A significantly higher PR
(Meta-analysis of 5 RCTs, Soliman et al,
1994) Many clinics have now stopped giving HCG
because OHSS is not always easy to predict
(Jacobs Balen,2003).
B. HCG
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2. HCG Vs IM P CPR OPR were not different
(Albert Pfeifer, 1991, Claman et al,1992
Araujo et al,1994 Artini et al,1995 Loh
Leong,1996 Claman et al,1992 Artni et al,1995).
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3. HCG Vs vaginal P No differences in CPR, OPR
or SAB (Artini et al,1995 Martinez et al,2000
Ludwig et al,2001 Ugur et al,2001).
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4. HCG Vs oral P CPR OPR were not
significantly different (Buvat et al,1990). 5.
HCG Vs IM P plus oestrogen There were no
significant differences (Pritts Atwood,2002)
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II. Luteal phase support in short Protocol
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• 1. Oral Progesterone VS HCG
• When using IM HCG the CPR, OPR IR were
  significantly higher (Buvat et al,1990).
• The poor results obtained with oral P is related
  to its poor bioavailability

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2. Vaginal Progesterone Vs P plus estrogen No
differences in CPR or IR (Farhi et al, 2000). The
power of this study was low. 3. Vaginal
Progesterone Vs P plus HCG No differences in
CPR or SAB (Ugur et al,2001).
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III. Luteal phase support in ultrashort Protocol
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1. IM progesterone Vs HCG In a single very
small study, there were no significant
differences in CPR or DR (Golan et al,1993). 2.
Vag Progesterone VS P plus HCG Vaginal P alone
provides sufficient luteal phase support (Mochtar
et al,1996).
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IV. Luteal phase support in direct protocol
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• Progesterone
• 1. Vaginal P Vs placebo
• No difference in PR (Polson et al,1992)
• 2. IM P Vs no treatment
• PR was similar (Steirteghem et al,1988 Leeton et
  al,1985).
• P LPS is unlikely to have a significant effect on
  increasing PR.

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• B. HCG
• HCG Vs no treatment
• HCG support of the luteal phase is not routinely
  warranted in hMG-stimulated cycles (Keenan
  Moghissi,1992)
• 2. Oral P, HCG or placebo
• No differences (Kupfemrminc et al,1990).
• No necessity of P supplementation in the luteal
  phase if GnRH agonists were not used (Daya,1988).

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Conclusions
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• I. In long protocol
• IM P is more effective than oral P.
• Vag P is more effective than oral P.
• Addition of oral E to P improves IRPR in
  patients with profound E2 decline.

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• No significant differences in fertility outcomes
  when comparing
• 1. IM P with vag P
• 2. different doses of P
• 3. different forms of vag or IM P 4. start of P
  at oocyte retrieval with start at ET

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• Addition of ascorbic acid, prednisolone, aspirin
  to P has no benefit.

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II. In direct protocol No need of P
supplementation in the luteal phase
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Thank you
Prof. Aboubakr Elnashar
Benha University Hospital Delta (Mansura) Benha
fertility centers Email elnashar53_at_hotmail.com