**5.2. Suppositories vs. tablets**

Another randomized trial [46] compared side effects and patient convenience of vaginal progesterone suppositories (Cyclogest) and vaginal progesterone tablets (Endometrin) used for luteal phase support in in vitro fertilization/embryo transfer cycles using pituitary. downregulation. One hundred and thirty-two infertile patients were randomized on the day of embryo transfer by a computer-generated randomization list in sealed envelopes to receive either Cyclogest 400 mg or Endometrin 100 mg twice daily for 14 days. On days 6 and 16 after ET, they rated side effects and patient convenience into four grades: none, mild, moderate and severe by completing a questionnaire.The results showed no signicant differences in perineal irritation on days 6 and 16 after embryo transfer between the two groups, although there was a trend of fewer patients with perineal irritation in the Endometrin group. Signicantly more patients in the Endometrin group had difculty of administration on day 6 after embryo transfer. There were no differences in the hormonal prole on day 6 after embryo transfer and IVF outcomes between the two groups. The study concluded that there was no difference in perineal irritation after the use of Cyclogest suppositories or Endometrin tablets for luteal phase support although more patients found administration of Endometrin tablets difficult.

### **5.3. Gel vs. capsule**

The first prospective randomized trial comparing vaginal cream Crinone 8% [47] investigated 126 patients undergoing cycles of IVF / ICSI. Patients received either Crinone 8% (n = 73) vaginally once daily or two Utrogest capsules (n=53) vaginally three times daily (600 mg). Clinical pregnancy rates were comparable (28.8 versus 18.9%), as were clinical abortion rates until 12 weeks of gestation (14.3 versus 10.0%) and clinical ongoing pregnancy rates (24.7 versus 17.0%) in the Crinone 8% and Utrogest groups, respectively. Forty-seven non-pregnant patients were randomly selected to answer questions regarding comfort during luteal phase support. Crinone 8% had a clear advantage over Utrogest as it resulted in less vaginal discharge (P < 0.01) and fewer application difficulties (P<0.05). Twenty patients familiar with the alternative preparation from a previous cycle also noted that Crinone 8% was easier to apply (P < 0.01) and less time consuming (P < 0.05) to use than Utrogest. In another prospective multicenter randomized trial [48] to study the comparative efcacy and tolerability of capsules containing 200 mg of progesterone (Utrogest 200) or Crinone 8% gel for luteal phase and early pregnancy support during assisted reproduction techniques.Four hundred thirty women who underwent their rst IVF or ICSI cycle were randomized after successful transfer of two or three embryos. Patients used vaginally applied capsules containing 200 mg of progesterone (Utrogest 200) three times per day or containing Crinone 8% gel twice per day. Therapy was started in the evening of the embryo transfer day and continued up to 10 weeks in pregnant women. If the pregnancy test proved to be negative, application was stopped. The luteal phase support in ART cycles with Utrogest™ 200 capsules (three times per day) or Crinone 8% gel (two times per day) by the vaginal route resulted in similar outcomes with respect to implantation, ongoing pregnancy, and abortion rates. The two recommended regimens of progesterone supplementation in ART proved to be equivalent and safe. A large prospective randomized study [49] compared the efficacy of intravaginal and I.M. progesterone for luteal phase support in IVF cycles. The study included women 25-44 years old with infertility necessitating treatment with IVF, 511 consecutive patients were enrolled; 474 completed participation, and 37 were excluded. Patient received luteal phase support using either Crinone 8% or natural progesterone in oil starting 2 days following oocyte retrieval. The outcome measure was pregnancy and delivery rates stratified by patient age. The study showed that overall, patients who received vaginal progesterone had higher pregnancy (70.9% vs. 64.2%) and delivery (51.7% vs. 45.4%) rates than did patients who received IM progesterone. Patients <35 who received vaginal progesterone had significantly higher delivery rates (65.7% vs. 51.1%) than did patients who received IMP. There were no differences, regardless of age, in the rates of biochemical pregnancy, miscarriage, or ectopics. The study concluded that in younger patients undergoing IVF, support of the luteal phase with Crinone produces significantly higher pregnancy rates than does IMP. Crinone and I.M. progesterone appear to be equally efficacious in the older patient. In a meta-analysis of published studies comparing vaginal progesterone gel for luteal support [50] seven randomized controlled trials, involving 2,447 patients, were included in the analysis. Studies were included where vaginal progesterone gel 90 mg once or twice daily versus any other vaginal progesterone form for luteal phase support. The endpoint was clinical pregnancy rate. No difference was observed in the overall clinical pregnancy rate when comparing vaginal progesterone gel with any other vaginal progesterone form. Moreover, clinical pregnancy rates were similar in protocols using only GnRH agonists and when comparing vaginal gel with the traditional treatment of 200 mg×3 vaginal progesterone capsules. The study concluded that no significant difference exists between vaginal gel and all other vaginal progesterone forms in terms of clinical pregnancy rates.

Luteal Phase Support in ART: An Update 163

**6. GnRh –agonist Luteal support** 

The first report on the place of GnRh-agonist in luteal support [51] randomized patients undergoing IVF using GnRH antagonist protocol in which triggering ovulation was done by 10 000 IU of hCG and luteal phase support was done by 600 mg of vaginal micronized progesterone as compared with triggering ovulation by 200 µg nasal GnRHa followed by different doses of intranasal GnRH-a. They found that 100 µg of buserlin intranasal three times daily is equivalent to 600 mg vaginal progesterone concerning clinical pregnancy rate. In another study [52] six hundred women about to undergo ovarian stimulation for ICSI (300 using a long GnRH agonist protocol and 300 using a GnRH antagonist protocol) were enrolled in this study. Patients treated with each of these two protocols were randomly assigned to receive a single injection of GnRH agonist or placebo 6 days after ICSI. Implantation and live birth rates were the primary outcomes.The results of the study showed that administration of 0.1 mg of GnRH agonist triptorelin on day 6 after ICSI led to a significant improvement of implantation and live birth rates after ICSI as compared with placebo. In GnRH antagonist-treated ovarian stimulation cycles, luteal-phase GnRH agonist also increased ongoing pregnancy rate. Moreover, luteal-phase GnRH agonist administration increased luteal-phase serum hCG, estradiol and progesterone concentrations in both ovarian stimulation regimens. The study concluded that luteal-phase GnRH agonist administration enhances ICSI clinical outcomes after GnRH agonist- and GnRH antagonist-treated ovarian stimulation cycles, possibly by a combination of effects on the embryo and the corpus luteum. However in a more recent study [53] five hundred and seventy women undergoing embryo transfer following controlled ovarian stimulation with a long GnRH agonist protocol were included. In addition to routine luteal phase support with progesterone, women were randomized to receive a single 0.1 mg dose of triptorelin or placebo 6 days after ICSI. Randomization was done on the day of embryo transfer according to a computer generated randomization table. Ongoing pregnancy rate beyond 20th week of gestation was the primary outcome measure. The trial was powered to detect a 12% absolute increase from an assumed 38% ongoing pregnancy rate in the placebo group, with an alpha error level of 0.05 and a beta error level of 0.2. The results showed that there were 89 (31.2%) ongoing pregnancies in the GnRH agonist group, and 84 (29.5%) in the control group (absolute difference +1.7%, 95% confidence interval −5.8% to +9.2%). Implantation, clinical pregnancy and multiple pregnancy rates were likewise similar in the GnRH agonist and placebo groups. The study concluded that single 0.1 mg triptorelin administration 6 days after ICSI following ovarian stimulation with the long GnRH agonist protocol does not seem to result in an increase ≥12% in ongoing pregnancy rates. Despite this, several independent studies reported beneficial effects of GnRh-a as luteal support. [41,42,54, 55 ,56] . In the most recent Cochrane review [15] six studies (1646 women) investigated progesterone versus progesterone + GnRH-a. The authors subgrouped the studies for single-dose GnRH agonist and multiple-dose GnRh agonist. For the live birth, clinical pregnancy and ongoing pregnancy rate the results suggested a significant effect in favor of progesterone and GnRHa. The Peto OR for the live birth rate was 2.44 (95% CI 1.62 to 3.67), for the clinical pregnancy rate was 1.36 (95% CI 1.11 to 1.66) and for the ongoing pregnancy rate was 1.31 (95% CI 1.03

### **6. GnRh –agonist Luteal support**

162 Enhancing Success of Assisted Reproduction

clinical pregnancy rates.

Forty-seven non-pregnant patients were randomly selected to answer questions regarding comfort during luteal phase support. Crinone 8% had a clear advantage over Utrogest as it resulted in less vaginal discharge (P < 0.01) and fewer application difficulties (P<0.05). Twenty patients familiar with the alternative preparation from a previous cycle also noted that Crinone 8% was easier to apply (P < 0.01) and less time consuming (P < 0.05) to use than Utrogest. In another prospective multicenter randomized trial [48] to study the comparative efcacy and tolerability of capsules containing 200 mg of progesterone (Utrogest 200) or Crinone 8% gel for luteal phase and early pregnancy support during assisted reproduction techniques.Four hundred thirty women who underwent their rst IVF or ICSI cycle were randomized after successful transfer of two or three embryos. Patients used vaginally applied capsules containing 200 mg of progesterone (Utrogest 200) three times per day or containing Crinone 8% gel twice per day. Therapy was started in the evening of the embryo transfer day and continued up to 10 weeks in pregnant women. If the pregnancy test proved to be negative, application was stopped. The luteal phase support in ART cycles with Utrogest™ 200 capsules (three times per day) or Crinone 8% gel (two times per day) by the vaginal route resulted in similar outcomes with respect to implantation, ongoing pregnancy, and abortion rates. The two recommended regimens of progesterone supplementation in ART proved to be equivalent and safe. A large prospective randomized study [49] compared the efficacy of intravaginal and I.M. progesterone for luteal phase support in IVF cycles. The study included women 25-44 years old with infertility necessitating treatment with IVF, 511 consecutive patients were enrolled; 474 completed participation, and 37 were excluded. Patient received luteal phase support using either Crinone 8% or natural progesterone in oil starting 2 days following oocyte retrieval. The outcome measure was pregnancy and delivery rates stratified by patient age. The study showed that overall, patients who received vaginal progesterone had higher pregnancy (70.9% vs. 64.2%) and delivery (51.7% vs. 45.4%) rates than did patients who received IM progesterone. Patients <35 who received vaginal progesterone had significantly higher delivery rates (65.7% vs. 51.1%) than did patients who received IMP. There were no differences, regardless of age, in the rates of biochemical pregnancy, miscarriage, or ectopics. The study concluded that in younger patients undergoing IVF, support of the luteal phase with Crinone produces significantly higher pregnancy rates than does IMP. Crinone and I.M. progesterone appear to be equally efficacious in the older patient. In a meta-analysis of published studies comparing vaginal progesterone gel for luteal support [50] seven randomized controlled trials, involving 2,447 patients, were included in the analysis. Studies were included where vaginal progesterone gel 90 mg once or twice daily versus any other vaginal progesterone form for luteal phase support. The endpoint was clinical pregnancy rate. No difference was observed in the overall clinical pregnancy rate when comparing vaginal progesterone gel with any other vaginal progesterone form. Moreover, clinical pregnancy rates were similar in protocols using only GnRH agonists and when comparing vaginal gel with the traditional treatment of 200 mg×3 vaginal progesterone capsules. The study concluded that no significant difference exists between vaginal gel and all other vaginal progesterone forms in terms of

The first report on the place of GnRh-agonist in luteal support [51] randomized patients undergoing IVF using GnRH antagonist protocol in which triggering ovulation was done by 10 000 IU of hCG and luteal phase support was done by 600 mg of vaginal micronized progesterone as compared with triggering ovulation by 200 µg nasal GnRHa followed by different doses of intranasal GnRH-a. They found that 100 µg of buserlin intranasal three times daily is equivalent to 600 mg vaginal progesterone concerning clinical pregnancy rate. In another study [52] six hundred women about to undergo ovarian stimulation for ICSI (300 using a long GnRH agonist protocol and 300 using a GnRH antagonist protocol) were enrolled in this study. Patients treated with each of these two protocols were randomly assigned to receive a single injection of GnRH agonist or placebo 6 days after ICSI. Implantation and live birth rates were the primary outcomes.The results of the study showed that administration of 0.1 mg of GnRH agonist triptorelin on day 6 after ICSI led to a significant improvement of implantation and live birth rates after ICSI as compared with placebo. In GnRH antagonist-treated ovarian stimulation cycles, luteal-phase GnRH agonist also increased ongoing pregnancy rate. Moreover, luteal-phase GnRH agonist administration increased luteal-phase serum hCG, estradiol and progesterone concentrations in both ovarian stimulation regimens. The study concluded that luteal-phase GnRH agonist administration enhances ICSI clinical outcomes after GnRH agonist- and GnRH antagonist-treated ovarian stimulation cycles, possibly by a combination of effects on the embryo and the corpus luteum. However in a more recent study [53] five hundred and seventy women undergoing embryo transfer following controlled ovarian stimulation with a long GnRH agonist protocol were included. In addition to routine luteal phase support with progesterone, women were randomized to receive a single 0.1 mg dose of triptorelin or placebo 6 days after ICSI. Randomization was done on the day of embryo transfer according to a computer generated randomization table. Ongoing pregnancy rate beyond 20th week of gestation was the primary outcome measure. The trial was powered to detect a 12% absolute increase from an assumed 38% ongoing pregnancy rate in the placebo group, with an alpha error level of 0.05 and a beta error level of 0.2. The results showed that there were 89 (31.2%) ongoing pregnancies in the GnRH agonist group, and 84 (29.5%) in the control group (absolute difference +1.7%, 95% confidence interval −5.8% to +9.2%). Implantation, clinical pregnancy and multiple pregnancy rates were likewise similar in the GnRH agonist and placebo groups. The study concluded that single 0.1 mg triptorelin administration 6 days after ICSI following ovarian stimulation with the long GnRH agonist protocol does not seem to result in an increase ≥12% in ongoing pregnancy rates. Despite this, several independent studies reported beneficial effects of GnRh-a as luteal support. [41,42,54, 55 ,56] . In the most recent Cochrane review [15] six studies (1646 women) investigated progesterone versus progesterone + GnRH-a. The authors subgrouped the studies for single-dose GnRH agonist and multiple-dose GnRh agonist. For the live birth, clinical pregnancy and ongoing pregnancy rate the results suggested a significant effect in favor of progesterone and GnRHa. The Peto OR for the live birth rate was 2.44 (95% CI 1.62 to 3.67), for the clinical pregnancy rate was 1.36 (95% CI 1.11 to 1.66) and for the ongoing pregnancy rate was 1.31 (95% CI 1.03 to 1.67). The results for miscarriage and multiple pregnancy did not indicate a difference of effect. The authors concluded that there were significant results showing a benefit from addition of GnRH- a to progesterone for the outcomes of live birth, clinical pregnancy and ongoing pregnancy. In another recent systematic review and meta-analysis [57] six relevant RCTs were identified including a total of 2012 patients. The probability of live birth rate (risk difference : +16%, 95% CI: +10 to +22%) was significantly higher in patients who received GnRH agonist support compared with those who did not. The subgroup analysis according to the type of GnRH analogue used for LH suppression did not change the effect observed (studies in which GnRH agonist was used during ovarian stimulation, risk difference : +15%, 95% CI: +5 to +23%); (studies in which GnRH antagonist was used during ovarian stimulation, risk difference : +19%, 95% CI: +11 to +27%). The conclusion of the study was that the best available evidence suggests that GnRH agonist addition during the luteal phase significantly increases the probability of live birth rates.

Luteal Phase Support in ART: An Update 165

E2 and progesterone 8 days after hCG administration for oocyte maturation. Earlier reports indicated that serum E2 concentrations severely drop at the end of the luteal phase [61]; therefore,a concern has been raised about an additional supply of E2 during luteal phase of IVF cycles. The role of E2 luteal support is still debated after more than a decade of use. Previous meta analysis [18] and an update [62] and more recent randomized trials [63, 64] reported beneficial effects of adding E2 to luteal progesterone support. In our study [63] two hundred seventy-four women undergoing first ICSI cycles were randomized after ovum pickup into three groups of luteal support . Group I received IM progesterone only, group II received progesterone plus oral E2 valerate, group III received progesterone plus hCG. Outcome measures were pregnancy rate, implantation rate, rates of multiple pregnancy and miscarriage, and midluteal serum E2 and progesterone, and midluteal E2: progesterone ratio. The results showed that the pregnancy and implantation rates were significantly higher in group II (E2 plus progesterone) compared to group I (I.M. progesterone only) and the miscarriage rate was significantly lower in group II compared with group I. Midluteal E2 was significantly higher in group II compared with group I. The decline in E2 after ovum pickup was

On the other hand two meta- analyses [65, 66] has shown that the addition of E2 to progesterone for luteal phase support in IVF/ICSI cycles has no beneficial effects on pregnancy rates. The last meta- analyses commented that the data in the literature are limited and heterogeneous, precluding the extraction of clear and definite conclusions. Therefore further studies are needed to clarify the exact role of E2 luteal support in long

In stimulated IVF/ICSI cycles, the steroid production in the first week after oocyte retrieval is likely to be well timed and more than sufficient, so the start of exogenous support is not apt to be critical within this window. It was reported that pregnancy rates were higher in IVF when progesterone was started three rather than six days after oocyte collection [67] .A randomized controlled trial [68] allocated 130 patients to start luteal support at hCG day and , 128 at egg retrieval day and 127 at day of embryo transfer. Ongoing pregnancy rate of 20.8% was found in the hCG-day group versus 22.7 and 23.6% in the other two groups, respectively. This study showed that , there is no difference between the three different

Theoretically, progesterone would be of benefit to only 'fill in the gap' between clearance of exogenously administered hCG and the increase in endogenous hCG production. As soon as endogenous hCG production increases, the corpus luteum secretes an appropriate amount of progesterone [69].However most IVF centers extend luteal support for varying durations after positive pregnancy test. A questionnaire concerning details of luteal phase

agonist vs. antagonist , normal responder vs. high responder and low responders.

lowest in group II, highest in group I.

**9. Timing of starting luteal support** 

times of start of luteal support.

**10. Duration of luteal support** 
