LUTEAL PHASE SUPPORT An evidence-based approach M. Aboulghar Cairo – Egypt IZMIR 2008

Normal luteal function is essential for maintaining pregnancy several studies have shown that removal of the corpus luteum during early pregnancy results in complete abortion (Csapo et al. 1974)

In the mid-1980s, the incorporation of GnRH agonists into ovarian stimulation regimens became associated with improved outcomes after IVF

The agonists, either by themselves, or in connection with supraphysiological hormone profiles, may create an iatrogenic luteal phase defect (Macklon and Fauser, 2000)

Luteal-phase deficiency is a common problem in current ARTs and has been described in cycles using pituitary down-regulation with a GnRH agonist as well as in those using GnRH antagonists (Macklon & Fauser, 2000; Kolibianakis et al., 2003)

Luteal phase support was considered essential to counter any luteal insufficiency that may have a negative impact on an early pregnancy (Smitz et al, 1992, 1993)

Over the years, it became clear that luteal phase support had a positive effect on outcome. A 1994 meta-analysis of randomized trials indicated that the use of hCG or progesterone led to significantly higher pregnancy rates that placebo (Soliman et al. 1994)

Progesterone has become the agent of choice for luteal supplementation, because hCG is associated with a higher risk of OHSS (MacDougall et al 1992).

In a prospective randomized study, it was found that delaying introduction or progesterone supplementation to day 6 after oocyte retrieval resulted in reduced pregnancy rate (Shaun et al 2001).

A prospective randomized trial did reveal a significant difference in implantation rates between women who received i.m. progesterone and those who received an oral micronized progesterone preparation (Licciardi et al 1999).

In a prospective randomized study of high responders, oral progesterone, chlormadinon acetate showed a comparable pregnancy rate and live birth rate with im progesterone (Iwase et al 2008).

In a prospective randomized study, luteal phase support by Crinone 8 as parental progesterone showed similar outcome (Anserini et al 2001).

Cicinelli et al. (2000) found that serum progesterone levels were higher after i.m. administration than after vaginal gel administration, although endometrial progesterone levels were significantly higher after vaginal progesterone gel.

Luteal phase support in IVF: meta- analysis of randomized trials (Nosarka et al 2005) 18 trials met the inclusion criteria. LPS is definitely indicated in IVF treatment cycles. This meta analysis favored hCG above progesterone as LPS with respect to pregnancy rate.

A metanalysis of randomized studies showed that luteal phase support with im progesterone or im hCG achieved same outcome. IM progesterone was superior to oral or vaginal routes of progesterone. Addition of oral estrogen improved implantation. hCG carries a risk of OHSS Their conclusion was im progesterone is the best LPS (Pritts and Atwood 2002).

In a Cochrane review 2004, conclusion were luteal phase support with hCG or progesterone after ART results in an increased pregnancy rate, hCG does not provide better results progesterone and it has higher risk of OHSS. The optimal route of progesterone administration has not yet been established. (Daya and Gumby 2004)

In a review by Penzias (2000), the author’s conclusion was that progesterone support is indicated though support beyond the day of BhCG may not be needed, vaginal and im progesterone are equal in outcome despite higher serum progesterone in im injections, patients prefer vaginal route.

A comparative study between vaginal and oral administration for luteal support (Friedler et al 1999) A total of 64 high responder patients requiring ICSI were prospectively randomized for oral or vaginal administration. A significantly higher implantation rate in vaginal treatment (30.7 vs. 10.7% P<0.01) but similar pregnancy rate(47 vs 33.3%) and ongoing pregnancy rate (41.1 vs 20%) was observed, compared with oral treatment.

A randomized study comparing Crinone 8% and i.m. progesterone supplementation in IVF (Propst et al 2001) In women undergoing IVF, once-a-day progesterone supplementation with Crinone 8% beginning the day after oocyte retrieval, resulted in significantly lower embryo implantation, clinical pregnancy, and live birth rates compared with women supplemented with IM progesterone.

In a randomized study, investigators compared a vaginal progesterone gel (Crinone 8%), 90 mg once daily, with an oral progesteron preparation (Utrogestan, 400 mg once daily, and i.m. progesterone in oil, 50 mg once daily. The clinical and ongoing pregnancy rates were comparable between the vaginal gel and i.m. groups, but significantly (P<.05) lower with the oral formulation (Saucedo et al 2000)

Addition of estradiol to progesterone for luteal supplementation in patients stimulated with GnRH antagonist/rFSH for IVF: a randomized controlled trial (Fatemi et al 2006) In the progesterone grome ongoing PR was 26% versus 29.7% in progesteroen E2 group (Difference 3.7 and 95%, CI: to 8.6%). Addition of E2 to progestrone in the luteal phase after stimulation with rFSH and GnRH antagonist does not enhance the probability of pregnancy.

Timing LPS in GnRH agonist down-regulated IVF cycles (Mochtar et al 2006) After hCG administration (hCG group), at the day of oocyte retrieval (OR group), or at the day of ET (ET group). Ongoing PR of 20.8% was found in the hCG group versus 22.7 and 23.6% in the OR group and ET group, respectively.

A retrospective study of 2000 IVF patients with positive BHCG received progesterone 600 mg vaginal suppositories for three weeks as compared to 200 women who did not receive progesterone after positive BhCG. Delivery rate was the same in both groups. Progesterone supplementation after positive BhCG did not yield any benefit. (Schmidt 2001).

In a prospective study on 303 pregnant patients after IVF, patients were randomized into a group which stopped progesterone on day of positive pregnancy test and another group which received progesterone for 3 more weeks. There was no difference in miscarriage rate between the two groups. Progesterone can be safely withdrawn at time of positive BhCG (Andersen et al 2002).

Luteal phase GnRH administration enhances ICSI clinical outcome after protocols by agonist and antagonist, possibly by a combination of effects on the embryo and corpus luteum (Tesarik et al. 2006)

Prospective randomized study comparing LPS for ICSI patients up to first ultrasound versus three weeks more (Aboulghar et al. 2008) Patients were divided in two groups. Group A = 132 continued LPS for 3 weeks after first ultrasound, Group B = 125 stopped LPS on day of first ultrasound. Miscarriage rate after confirming pulsations up to 20 weeks gestation was 4.6% (6/132) in group A and 4.8% (6/125) in group B (OR=0.94; 95% CI = ). Bleeding episodes were 15.9% in Group A as compared to 20.8% in group B (OR = 0.72; 95% CI = ). This single centre randomized trial did not support extending the LPS beyond the day of first ultrasound demonstrating echoes and pulsations.

The Egyptian IVF-ET Center Clinical directors: M. Aboulghar, M. D. G. Serour, M. D. - Clinical associates: Y. Amin, M. D. M. Sattar, M. D. A. Ramzy, M. D. L. Mansour, M. D. M. Metwally, M. D. H. Aboulghar, M. D. M. Aboulghar, M. D. H. Al Inany, M. D. A. Abou-Setta, M. D. - Andrology: I. Fahmy, M. D. A. El-Gindy Scientific director & Program manager: Ragaa Mansour, M. D., Ph. D. - Embryology and micromanipulation S. Mansour, M. D. A. Kamal, M. D. A. Mostafa, M. D. N. Tawab, B.Sc. M. Serour, B.Sc. G. Afifi, B.Sc. M. Hammam, B.A. - Cytogenetics H. Fayek, Ph. D. A. Abdel-Razek, M. D. A. Amer, B.Sc. A. Khalil, Ph. D. A. Naser, Ph. D. O. Kamal, B.S. S. Mostafa - Cryobiology & andrrology D. Saad, B.Sc. Y. Demery, B.Sc. A. Barakat, B.Sc. M. Serour, B.Sc. N. Salah, B.Sc. H. Fanous, B.Sc. A. Mohamed, B.Sc.