Luteal phase support in infertility treatment: a meta-analysis of the randomized trials

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1 Human Reproduction Vol.17, No.9 pp , 2002 Luteal phase support in infertility treatment: a meta-analysis of the randomized trials E.A.Pritts 1,3 and A.K.Atwood 2 1 Department of Obstetrics and Gynecology, University of California, San Francisco, CA 94143, USA and 2 University of Sydney School of Medicine, Sydney, Australia 3 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, University of Wisconsin, Madison, H4/630 CSC, 600 Highland Avenue, Madison, Wisconsin, 53792, USA. eapritts@wisc.edu BACKGROUND: The addition of GnRH agonist to the treatment regimen in women undergoing IVF cycles is thought to create a luteal phase defect. In an attempt to correct for this, many practitioners supplement with a variety of steroid hormones in the luteal phase. METHODS: To determine whether luteal phase support increases reproductive success in modern IVF cycles, a systematic review of the literature was performed. Meta-analyses were conducted when multiple homogeneous studies addressed a single issue. Only randomized controlled trials were included in the data analysis. The efficacy of supplementation, as well as the optimal route, formulation, dose, and length of administration were queried. RESULTS: Luteal supplementation with either i.m. hcg or i.m. progesterone significantly improved fertility outcomes compared with no treatment. When comparing i.m. progesterone with i.m. hcg, no fertility differences were found. Intramuscular progesterone conferred the most benefit compared with oral or vaginal use. Addition of oral estrogen to progesterone also improved implantation rates. CONCLUSION: Given the increased risk of ovarian hyperstimulation syndrome associated with hcg use, i.m. progesterone is favoured for luteal phase supplementation with the addition of estrogen. Key words: IVF/luteal phase/luteal phase supplementation/randomized trials/meta-analysis Introduction In 1992, a meta-analysis of all the quasi-randomized trials in the literature showed that the use of GnRH agonists increased pregnancy rates for IVF cycles by % in women who responded normally to exogenous gonadotrophins (Hughes et al., 1992). By 1995, ~85% of all IVF practitioners in the world included GnRH agonists in the stimulation protocol (de Mouzon and Lancaster, 1995). By 1997, it was apparent that protocols using the agonist for days prior to gonadotrophin stimulus were superior to shorter GnRH agonist protocols, and today, most practitioners use this long protocol for their stimulation cycles in normal responders (Gomel and Cheung, 1997). GnRH agonists work by preventing premature surges of endogenous LH during IVF cycles through pituitary suppression, allowing time for a larger number of oocytes to reach maturity prior to harvesting. They also work by increasing the time of gonadotrophin-independent follicular growth, synchronizing a larger cohort of follicles with the ability to respond to exogenous gonadotrophin. Unfortunately, although GnRH agonist use confers benefit, the use also confers detriment by inhibiting the corpora lutea in these cycles. The agonists, either by themselves, or in concert with supraphysiological hormone profiles, may create an iatrogenic luteal phase defect (Macklon and Fauser, 2000). Use of GnRH agonist causes the suppression of pituitary LH secretion for as long as 10 days after the last dose of agonist. Without this LH signal, the corpus luteum may be dysfunctional, and subsequent progesterone and estrogen secretion may be abnormal. Without proper progesterone or estrogen stimulation, endometrial receptivity may be compromised, leading to decreased implantation and decreased pregnancy rates. In an attempt to compensate for this abnormality, practitioners have employed luteal supplementation with either single or combined agents. Hormonal supplementation has consisted of estrogen, progesterone or hcg and has been used during the luteal phase and beyond for patients undergoing IVF cycles. Different doses, durations and types of treatments are used, but the best dose, duration or type of treatment remains controversial. In 1992, a meta-analysis was performed evaluating the need for luteal supplementation in IVF cycles (Soliman et al., 1994). Although this analysis was comprehensive for its time, the past 10 years have heralded a plethora of randomized trials addressing these same issues with conflicting results. Many of the more recent studies are small, leaving them underpowered to show differences in fertility outcomes even if differences do exist. The purpose of this systematic review was to extract the European Society of Human Reproduction and Embryology 2287

2 E.A.Pritts and A.K.Atwood data from the 30 randomized trials in the literature that address fertility outcomes after luteal phase supplementation, and to evaluate whether this confers any fertility benefit for women undergoing IVF cycles. The review was limited to studies with GnRH agonists in the stimulation, and only those trials that clearly stratified patient data according to length of GnRH agonist treatment. employed the short or flare protocol. Because they were too few in number, and too heterogeneous, none of the trials employing the short protocol for GnRH agonists were included in our meta-analyses. These trials are, however, still reported in this review and labelled as such. Although the length of luteal phase supplementation differed from study to study, overall homogeneity of the trials allowed for meta-analyses to be performed. Materials and methods Publications in all languages were included for evaluation. Medline and the Cochrane Library were thoroughly searched, and subsequent bibliographies cross-referenced. Hand searches of proceedings for the years were conducted for the American Society of Reproductive Medicine, European Society of Human Reproduction and Embryology, Society for Gynecologic Investigation, and Pacific Coast Reproductive Society. Some of the data were initially presented as abstracts at several of the major reproductive endocrinology conferences worldwide, then subsequently published in peer-reviewed journals. To avoid redundancy in this review, subjects who were included in multiple publications were only counted once in the analysis. Where more than one publication presented data centred upon a single question, a meta-analysis was performed. When only one publication existed for a certain question, those data were included in the results. When analysis was performed on individual studies, a χ 2 method of analysis was used. When combining data from different studies for evaluation, the Mantel Haenszel method of analysis was used. Homogeneity of trials included in all meta-analyses was assured using χ 2 analysis. Results were reported using relative risks (RR) and 95% confidence intervals (CI) (Fleiss, 1981). Criteria for inclusion and exclusion of data were established prior to the initiation of literature searches. Any disagreements between the authors extracting the data, regarding exclusion, inclusion, relevance or validity were resolved through discussion and consensus. Only randomized, prospective trials were included in this review. Control groups could consist of those patients treated with placebo, or of those receiving no treatment, as long as enrolment into either group was randomized. Trials were included only if progesterone or hcg luteal supplementation was begun within 2 days of embryo transfer. Trials included IVF embryo transfer cycles, as well as zygote intra-fallopian transfer (ZIFT), gamete intra-fallopian transfer, and ICSI, as long as proportions of each assisted reproduction type were similar in each group. A clinical pregnancy (CPR) was accepted as fetal heart activity documented by ultrasonic evaluation. Ongoing pregnancies (OPR) were defined as those achieving 24 weeks gestation. Deliveries (DR) were accepted as single events, regardless of number of children delivered. Multiple deliveries, then, were evaluated as single delivery events. Miscarriages (SAB) were defined as those pregnancies that spontaneously aborted in the first trimester of gestation. Weeks of gestation were reported as menstrual weeks of gestation. The statistics for CPR, OPR and DR were formatted to show benefits associated with these fertility outcomes, the statistics for SAB were formulated to show reduction in these events. Assumptions used in the power analyses were a 20% baseline CPR, OPR and DR. Calculations were then based upon increases of 10% (Power #1) or 20% (Power #2) above that baseline. For SAB, a 20% baseline rate was also assumed, and calculations were made for a 5% decrease (Power #1) and 10% decrease (Power #2). These data are included in Tables I VI. Most of the authors whose studies were included in this series used the long protocol of GnRH agonist treatment, but a few also 2288 Results The studies Thirty studies were found which fitted the above criteria. Although most were of high quality, they were not without flaws. A summary of the studies is presented below. For a detailed breakdown of each study, refer to the Appendix. There were 28 sets of outcomes evaluable from cycles in which the long GnRH agonist regimen was used, and five experimental sets of evaluable data in which the short protocol was used. In the majority of the studies only one cycle of treatment was evaluated for each patient. In three of the studies, however, more than one treatment cycle per patient was included in the data analysis (Check et al., 1991; Farhi et al., 2000; Costabile et al., 2001). In three other studies, the number of patients was not specified, only the number of cycles (Claman et al., 1992; Loh and Leong, 1996; Mochtar et al., 1996). In most studies, groups were statistically similar for age, indications for infertility, and number of embryos transferred. In three of the studies (Check et al., 1991; Chanson et al., 1996; Ugur et al., 2001), this information was not stated. Many of the studies did not compare each group for grade of embryos, for previous number of failed cycles, or for duration of infertility. The randomization method was confirmed as truly random in only eight studies (Claman et al., 1992; Mochtar et al., 1996; Pouly et al., 1996; Licciardi et al., 1999; Beckers et al., 2000; Anserini et al., 2001; Costabile et al., 2001; Ludwig et al., 2001), with the remaining studies using either a semirandom method or unknown methodology. The timing of randomization posed a problem in several of the studies. Because it was done at the start of a cycle, many patients were excluded post randomization, without analysis for intention to treat. In one study (Araujo et al., 1994), randomization occurred at ovulation trigger. Subsequently, the data from eight of the initial 72 patients were excluded due to either hyperstimulation or poor ovarian response. In another study, the data from 22 patients were excluded post randomization due to lack of embryos available for transfer (Smitz et al., 1993). In yet another study, randomization at the start of the IVF cycles led to loss of data from 20 of the initial 60 patients. These 20 patients did not undergo embryo transfer due either to risk of hyperstimulation or poor response, hence were not analysed (Beckers et al., 2000). Compliance was an issue in only a single study, with four patients from a single arm of the study excluded due to their inability to self-administer i.m. progesterone (Golan et al., 1993).

3 Luteal phase support in infertility treatment Table I. IVF luteal phase support versus none or placebo: fertility outcomes Questions Outcome Author No. of No. of RR 95% CI Meta- Power Power measure studies patients analysis #2 #1 Progesterone (vaginal) versus no treatment CPR Artini et al., 1995; Abate et al., 1999b yes Progesterone (vaginal) versus no treatment DR Abate et al., 1999b no Progesterone (vaginal) versus no treatment OPR Artini et al., 1995; Abate et al., 1999b yes Progesterone (vaginal) versus no treatment SAB Artini et al., no hcg versus no treatment CPR Smith et al., 1989; Herman et al., 1990; * yes Artini et al., 1995; Beckers et al., 2000 hcg versus no treatment OPR Herman et al., 1990; Artini et al., 1995; yes Beckers et al., 2000 hcg versus no treatment SAB Herman et al., 1990; Artini et al., yes Progesterone (i.m.) versus placebo/no treatment CPR Artini et al., 1995; Abate et al., 1999a,b * yes Progesterone (i.m.) versus placebo/no treatment OPR Artini et al., 1995; Abate et al., 1999b * yes Progesterone (i.m.) versus placebo/no treatment DR Abate et al., 1999b * no Progesterone (i.m.) versus placebo/no treatment SAB Artini et al., no RR relative risk; 95% CI 95% confidence interval; Power #1 calculated with increase of 10% or for SAB decrease of 5%; Power #2 calculated with increase in 20% or for SAB decrease of 10%; CPR clinical pregnancy rate; DR delivery rate; OPR ongoing pregnancy rate; SAB miscarriage. *Significant difference between compared groups, P Table II. IVF luteal phase support doses and formulations: fertility outcomes Questions Outcome Author No. of No. of RR 95% CI Meta- Power Power measure studies patients analysis #2 #1 Progesterone dose (vaginal) 400 mg versus 600 mg each day) CPR Chanson et al., no Progesterone dose (i.m.) (25 mg versus 100 mg each day) CPR Check et al., no Progesterone dose (i.m.) (25 mg versus 100 mg each day) OPR Check et al., no Progesterone dose (i.m.) (25 mg versus 100 mg each day) SAB Check et al., no Progesterone dose (vaginal) (90 mg versus 600 mg each day) CPR Strehler et al., no Progesterone dose (vaginal) (90 mg versus 600 mg each day) SAB Strehler et al., no Progesterone dose (i.m.) (341 mg t.i.d. versus 50 mg each day) CPR Costabile et al., no Progesterone dose (i.m.) (341 mg t.i.d. versus 50 mg each day) OPR Costabile et al., no Progesterone dose (i.m.) (341 mg t.i.d. versus 50 mg each day) SAB Costabile et al., no t.i.d. three times daily; for other abbreviations, see Table I. 2289

4 E.A.Pritts and A.K.Atwood Table III. IVF luteal support comparing oral progesterone with vaginal or intramuscular progesterone or hcg: fertility outcomes Questions Outcome Author(s) No. of No. of RR 95% CI Meta- Power Power measure studies patients analysis #2 #1 Progesterone (vaginal) versus progesterone (oral) IR Pouly et al., 1996; Friedler et al., * yes Progesterone (vaginal) versus progesterone (oral) CPR Pouly et al., 1996; Friedler et al., yes Progesterone (vaginal) versus progesterone (oral) DR Pouly et al., no Progesterone (vaginal) versus progesterone (oral) SAB Pouly et al., 1996; Friedler et al., yes Progesterone (i.m.) versus progesterone (oral) CPR Licciardi et al., no hcg versus progesterone (oral) (short protocol) IR Buvat et al., * no hcg versus progesterone (oral) (long protocol) IR Buvat et al., no hcg versus progesterone (oral) (short protocol) CPR Buvat et al., * no hcg versus progesterone (oral) (long protocol) CPR Buvat et al., no hcg versus progesterone (oral) (short protocol) OPR Buvat et al., * no hcg versus progesterone (oral) (long protocol) OPR Buvat et al., no *Significant difference between compared groups, P For abbreviations, see Table I. Table IV. IVF luteal support comparing hcg with intramuscular or vaginal progesterone: fertility outcomes Questions Outcome Author(s) No. of No. of RR 95% CI Meta- Power Power measure studies patients analysis #2 #1 hcg versus progesterone (i.m.) CPR (long protocol) Albert et al., 1991; Claman et al., 1992; yes Araujo et al., 1994; Artini et al., 1995; Loh and Leong, 1996 hcg versus progesterone (i.m.) CPR (flare protocol) Golan et al., no hcg versus progesterone (i.m.) OPR (long protocol) Artini et al., no hcg versus progesterone (i.m.) DR (long protocol) Claman et al., no hcg versus progesterone (i.m.) DR (flare protocol) Golan et al., no hcg versus progesterone (i.m.) SAB (long protocol) Artini et al., no hcg versus progesterone (vaginal) CPR Artini et al., 1995; Ludwig et al., 2001; yes Martinez et al., 2001; Ugur et al., 2001 hcg versus progesterone (vaginal) OPR Artini et al., 1995; Ludwig etal., yes hcg versus progesterone (vaginal) SAB Artini et al., 1995; Ludwig et al., yes For abbreviations, see Table I. 2290

5 Luteal phase support in infertility treatment Table V. IVF luteal support comparing intramuscular and vaginal progesterone: fertility outcomes Questions Outcome Author(s) No. of No. of RR 95% CI Meta- Power Power measure studies patients analysis #2 #1 Progesterone (i.m.) versus progesterone (vaginal) CPR Abate et al., 1999b; Anserini et al., * yes Artini et al. 1995; Guesa et al., 2001; Perino et al., 1997 Progesterone (i.m.) versus progesterone (vaginal) OPR Artini et al., 1995; Abate et al., 1999b yes Progesterone (i.m.) versus progesterone (vaginal) DR Perino et al., 1997; Abate et al., 1999b * yes Progesterone (i.m.) versus progesterone (vaginal) SAB Artini et al., 1995; Perino et al., yes *Significant difference between compared groups, P For abbreviations, see Table I. Table VI. IVF luteal support comparing variations of additional estrogen or hcg: fertility outcomes Questions Outcome Author(s) No. of No. of RR 95% CI Meta- Power Power measure studies patients analysis #2 #1 E 2 /progesterone versus progesterone alone (long protocol) IR Farhi et al., * no E 2 /progesterone versus progesterone alone (flare protocol) IR Farhi et al., no E 2 /progesterone versus progesterone alone (long protocol) CPR Smitz et al., 1993; Lewin et yes al., 1994; Farhi, et al., 2000 E 2 /progesterone versus progesterone alone (flare protocol) CPR Farhi et al., no E 2 /progesterone versus progesterone alone (long protocol) DR Smitz et al., 1993; Lewin yes et al., 1994 E 2 /progesterone versus progesterone alone (long protocol) SAB Smitz et al., 1993; Lewin yes et al., 1994 E 2 /progesterone versus progesterone alone (flare protocol) SAB Farhi et al., no Progesterone/hCG versus progesterone alone (long protocol) CPR Ugur et al., no Progesterone/hCG versus progesterone alone (flare protocol) CPR Mochtar et al., no Progesterone/hCG versus progesterone alone (flare protocol) SAB Mochtar et al., no E 2 /progesterone versus hcg CPR Smitz et al., no E 2 /progesterone versus hcg SAB Smitz et al., no *Significant difference between compared groups, P IR implantation rate; E 2 estrogen; for other abbreviations, see Table I. 2291

6 E.A.Pritts and A.K.Atwood Is luteal supplementation of benefit for women undergoing IVF? There were no adequate studies addressing the use of oral progesterone versus placebo or no treatment for IVF luteal supplementation. In six studies, i.m. or vaginal progesterone, and i.m. hcg were compared with no treatment or placebo (Table I). Vaginal progesterone luteal support for 14 days versus no treatment did not increase CPR, OPR, DR or decrease SAB between the groups (Artini et al., 1995; Abate et al., 1999b). Four authors addressed the use of hcg supplementation versus no treatment (Smith et al., 1989; Herman et al., 1990; Artini et al., 1995; Beckers et al., 2000). In all of these studies, long protocols of GnRH agonist suppression were used, and luteal supplementation discontinued after 14 days of treatment. In these studies, the likelihood of CPR was significantly better, with a combined RR for i.m. hcg versus no treatment of 2.72 (95% CI ). There were no significant differences between OPR or SAB. Intramuscular progesterone luteal supplementation versus no treatment or placebo resulted in significant differences in CPR and OPR (Artini et al., 1995; Abate et al., 1999a,b), with combined RR of 2.38 (95% CI ) and 3.8 (95% CI ) respectively. DR were also significantly improved when comparing i.m. progesterone versus nothing, with a RR of 5.50 (95% CI ) (Abate et al., 1999b). SAB were not different between groups in a single, small, poorly powered study (Artini et al., 1995). Only the long GnRH protocol for pituitary suppression was employed in the above studies. The length of luteal supplementation varied between the studies, including supplementation only in the luteal phase, and through 10 and 12 weeks gestation. What is the best dose or formulation of drug for luteal support? Four studies were used in evaluating best doses and/or formulations of drugs for luteal support (Table II). Vaginal progesterone utilizing Utrogestan (Laboratoire Golaz, Switzerland), a micronized preparation usually used in an oral form, at doses of 400 and 600 mg was compared. Supplementation was used only for the luteal phase, and GnRH agonist was used in the long protocol (Chanson et al., 1996). No differences in CPR were noted. In another study, 600 mg of Utrogestan was compared with the use of 90 mg of the vaginal gel Crinone (Wyeth Lederle, USA) (Strehler et al., 1999). Again, there were no differences in CPR or SAB. Fifty mg each day of i.m. progesterone versus 341 mg every 3 days of i.m. 17-α hydroxyprogesterone caproate (17-OHPc) (Costabile et al., 2001) was compared. Supplementation was used through 8 weeks gestation, and GnRH agonist was used in a long protocol. No differences in CPR, OPR or SAB were found. In another study, 25 mg i.m. progesterone each day was compared with 100 mg i.m. progesterone each day (Check et al., 1991). GnRH agonist was again used in the long protocol, and luteal supplementation was used through 12 weeks gestation. No differences in CPR, OPR or SAB were found Is oral progesterone adequate for luteal supplementation? There were four trials that compared oral progesterone supplementation with vaginal or i.m. progesterone or with hcg (Table III). Implantation rates (IR) were increased in women receiving vaginal progesterone when compared with oral progesterone in the luteal phase, with combined RR of 1.5 (95% CI ). Neither CPR, DR nor SAB, however, were different in these groups (Pouly et al., 1996; Friedler et al., 1999). All of these particular patients were treated with the long GnRH protocol in their stimulation cycles, and received luteal support for either 13 or 30 days after embryo transfer. Intramuscular progesterone versus oral progesterone in the luteal phase conferred no obvious benefit upon CPR. In this study, again GnRH agonists were given in the long protocol (Licciardi et al., 1999). When comparing i.m. hcg with oral progesterone, IR, CPR and OPR were significantly increased (Buvat et al., 1990). These data were sub-analysed according to short or long GnRH protocols. The patients who were treated with the long protocol had no differences in CPR, OPR or IR when treated with either i.m. hcg or oral progesterone. The patients who were treated with short GnRH protocols had more CPR, OPR and IR when using i.m. hcg instead of oral progesterone, with RR of 8.36 (95% CI ), 7.43 (95% CI ) and (95% CI ) respectively. Is hcg in the luteal phase superior to i.m. or vaginal progesterone? There were six studies that fitted the criteria for inclusion in our analysis for women receiving either i.m. hcg or i.m. progesterone (Table IV). CPR were no different between groups (Albert and Pfeifer, 1991; Claman et al., 1992; Araujo et al., 1994; Artini et al., 1995; Loh and Leong, 1996). In these studies, the long protocol of GnRH agonist treatment was used, and luteal support lasted as little as 2 weeks and for as long as 6 weeks gestation. DR (Claman et al., 1992), OPR and SAB also were not different between the groups (Artini et al., 1995). In a single, very small study, data from women who were treated with a short GnRH agonist protocol were also reported (Golan et al., 1993). There were no significant differences in CPR or DR when comparing luteal use of i.m. hcg with i.m. progesterone, although power to detect a difference was quite low. Intramuscular hcg was compared with vaginal progesterone in four data sets (Artini et al., 1995; Martinez et al., 2000; Ludwig et al., 2001; Ugur et al., 2001). In these studies, the long GnRH agonist protocol was used, and supplementation of hcg or vaginal progesterone lasted only through the luteal phase. There were again no differences in CPR, OPR or SAB. Which route of progesterone administration confers more reproductive benefit: i.m. or vaginal? There were five studies evaluable in querying the best route for progesterone administration: i.m. or vaginal (Artini et al., 1995; Perino et al., 1997; Abate et al., 1999b; Anserini et al., 2001; Guesa et al., 2001) (Table V).

7 Luteal phase support in infertility treatment In all of the trials, either vaginal gel (Crinone 8) or vaginal cream preparations were used for supplementation. The long GnRH agonist protocol was employed for suppression, and exogenous supplementation lasted through the luteal phase only, through 8 weeks gestation and through 12 weeks gestation. CPR and DR were significantly improved when i.m. progesterone was used, with combined RR of 1.33 (95% CI ) and 2.06 (95% CI ) respectively. IR, OPR and SAB were no different between the two treatment groups. Is it of benefit to add estrogen or hcg to progesterone during the luteal phase? The addition of estrogen to a standard progesterone treatment in the luteal phase was evaluated in three trials (Smitz et al., 1993; Lewin et al., 1994; Farhi et al., 2000) (Table VI). Longterm GnRH agonist suppression for pituitary down-regulation was used, and luteal support lasted 2 weeks total, 3 weeks total, and until 12 weeks gestation. The estrogen doses ranged from 2 to 6 mg oral each day, with progesterone being given both in the vaginal and i.m. routes. When estrogen was added to progesterone in the luteal phase, IR were significantly higher with a RR of 1.49 (95% CI ) (Farhi et al., 2000). There were, however, no statistically significant differences in CPR, DR or SAB between these groups. In a single study (Farhi et al., 2000) data were also included for women treated with the short GnRH agonist protocol. There were no differences in CPR or IR between women treated with an estrogen/progesterone combination versus progesterone alone, although power in these studies was low. Intramuscular hcg added to a standard dose of vaginal progesterone, compared with vaginal progesterone alone in the luteal phase, was examined in two studies. When the long GnRH agonist was used, CPR were no different between the groups (Mochtar et al., 1996). When the short GnRH agonist was utilized, there were also no differences in CPR or SAB (Ugur et al., 2001). Intramuscular progesterone with the addition of estrogen was compared with hcg as luteal supplementation in another single, small study. The long protocol was once again employed for GnRH agonist supplementation. No differences in CPR or SAB were found (Smitz et al., 1988). Discussion In summary, it seems that the need for luteal supplementation is real, with both hcg and i.m. progesterone conferring benefit to fertility in women undergoing modern IVF cycles. hcg use was superior to oral progesterone use in the luteal phase. When hcg was compared with either vaginal or i.m. progesterone, there were no differences in outcomes. However, when comparing i.m. progesterone with vaginal progesterone, there were differences. Intramuscular progesterone conferred more fertility benefit than vaginal progesterone. Addition of estrogen to progesterone in the luteal phase also seemed to confer benefit, at least in terms of implantation rates. Ever since it was first suggested that there was an iatrogenic luteal phase defect in women undergoing IVF (Edwards and Steptoe, 1980), there have been attempts at correcting it. In 1988, a meta-analysis was done which failed to show the necessity of progesterone supplementation in the luteal phase if GnRH agonists were not employed in the stimulation protocol for assisted reproductive technology (Daya, 1988). With the addition of GnRH agonists to most modern IVF cycles, it has been clearly shown that corpus luteum function is abnormal. The above analysis shows that luteal supplementation is beneficial for these women. The question of which dose or which type of drug formulation to use is presently unanswered. Vaginal doses of 400 mg seem no better or worse than 600 mg each day. Vaginal gel preparations seem no better or worse than micronized oral progesterone used in a vaginal administration. Intramuscular doses seem no better or worse if 25 or 100 mg are used, and natural progesterone appears no better or worse than 17-OHPc in increasing pregnancy rates. However, it is worth noting that most of these comparisons are from small, individual studies, and thus the power to detect clinically significant differences is low. Oral progesterone as luteal support seems appealing due to its ease of administration. However, of the many modes of progesterone administration, the oral route is associated with the lowest efficacy and largest number of side-effects. The breakdown products from metabolism of oral progesterone have been associated with sedation, drowsiness, and other hypnotic effects, as well as flushing, nausea, and fluid retention (Maxon and Hargrove, 1985; Arafat et al., 1988). Furthermore, when looking at the endometrial biopsies in women with ovarian failure, oral progesterone has been shown to be ineffective in producing in-phase endometrium (Bourgain et al., 1990). In this analysis, oral progesterone supplementation in the luteal phase had less benefit than vaginal progesterone or i.m. hcg. No differences were shown in oral progesterone versus i.m. progesterone support in the single, small study addressing this issue. Nonetheless, it seems that with the high side-effect profile and with the decreased fertility rates compared with other modes of treatment, oral treatment should not be recommended. It has been hypothesized that i.m. hcg might be superior to progesterone alone as luteal support. There are two rationales for this argument. First, i.m. hcg administration in the luteal phase of IVF cycles will rescue a corpus luteum and allow continuation of secretion of both estrogen and progesterone (Hutchins-Williams et al., 1990). Second, other unknown products secreted from the corpus luteum affecting implantation may be stimulated by hcg. Enhancement of corpus luteum function, therefore, might be more beneficial than replacing just estrogen or progesterone in the luteal phase (Mochtar et al., 1996). In the current analysis, no differences were observed between i.m. hcg administration in the luteal phase when comparing it with vaginal progesterone or i.m. progesterone. In fact, several studies showed significant increases in hyperstimulation rates when using i.m. hcg for luteal support compared with other treatments or no treatment at all (Buvat et al., 1990; Herman et al., 1990; Claman et al., 1992; Araujo et al., 1994; Mochtar et al., 1996). Therefore, there is no evidence that i.m. hcg as luteal support is superior to 2293

8 E.A.Pritts and A.K.Atwood progesterone alone; furthermore, it should not be recommended due to its potentially risky side-effects. The next issue addressed in this analysis was that of the best route for progesterone supplementation, i.m. or vaginal. Both treatments have side effects. Intramuscular injections are not only painful, but can also lead to inflammation and even sterile abscess formation at the injection site (Tavaniotou et al., 2000). Severe allergic reactions to the oil used as a vehicle for progesterone injections have also been reported. Vaginal application of progesterone has also led to some minor sideeffects such as vaginal discharge and irritation (Kimzey et al., 1991). Although i.m. injections lead to higher serum levels of progesterone, the vaginal formulations have been shown to have better synchronization effects upon the endometrium (Bourgain et al., 1994). This is theorized to be due to a first pass uterine effect leading to higher uterine tissue levels and lower systemic serum levels (Ludwig and Diedrich, 2001). In this meta-analysis, however, the i.m. route conferred higher CPR and DR than the vaginal route. Taken with the finding that no differences existed between vaginal progesterone as supplementation versus no treatment at all, the data suggest that vaginal progesterone is less beneficial to fertility outcomes. Intramuscular progesterone, then, seems to be the luteal phase supplement of choice. Several investigators have noted that serum estrogen levels are also low in the luteal phase of GnRH agonist IVF cycles (Smitz et al., 1988). Addition of estrogen to luteal progesterone supplementation has been addressed in the literature in varying protocols, including estrogen/progesterone versus progesterone alone, hcg/progesterone versus progesterone alone and estrogen/progesterone versus hcg. In a single trial, addition of estrogen to a standard progesterone supplementation increased IR for those patients receiving the long protocol for GnRH agonist treatment, thus there may be some value to addition of this steroid. The optimal length of treatment remains unsolved at present. It is unclear how long to treat women receiving luteal supplementation, and further trials will be needed before clear recommendations can be made. The evidence therefore suggests that luteal supplementation is beneficial. Intramuscular progesterone is no more effective than hcg, but more effective than vaginal progesterone. Because of the risks of ovarian hyperstimulation syndrome associated with hcg administration in the luteal phase, i.m. progesterone seems to be the drug of choice for luteal phase supplementation. Some evidence also exists that adding estrogen to progesterone may increase IR, hence clinicians should consider adding estrogen for luteal supplementation. 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9 Luteal phase support in infertility treatment Friedler, S., Raziel, A., Schachter, M., Strassburger, D., Bukovsky, I. and Ron-El, R. (1999) Luteal support with micronized progesterone following in-vitro fertilization using a down-regulation protocol with gonadotropinreleasing hormone agonist: a comparative study between vaginal and oral administration. Hum. Reprod., 14, Golan, A., Herman, A., Soffer, Y., Bukovsky, I., Caspi, E. and Ron-El, R. (1993) Human chorionic gonadotrophin is a better luteal support than progesterone in ultrashort gonadotrophin-releasing hormone agonist/ menotrophin in-vitro fertilization cycles. Hum. Reprod., 8, Gomel, V. and Cheung, P.C.K. (eds) (1997) In Vitro Fertilization and Assisted Reproduction. Monsuzzi Editore, Bologna, pp Guesa, S., Causio, F., Marinaccio, M., Stanziano, A. and Sarcina, E. (2001) Luteal phase support with progesterone in IVF/ET cycles: a prospective, randomized study comparing vaginal and intramuscular administration. 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Scand., 80, Ludwig, M., Finas, A., Katalinic, A., Strik, D., Kowalcek, I., Schwartz, P., Felderbaum, R., Kupker, W., Schopper, B., Al-Hasani, S. et al. (2001) Prospective, randomized study to evaluate the success rates using hcg, vaginal progesterone or a combination of both for luteal phase support. Acta Obstet. Gynecol. Scand., 80, Macklon, N.S. and Fauser, B.C.J.M. (2000) Impact of ovarian hyperstimulation on the luteal phase. J. Reprod. Fertil., 55 (Suppl.), Martinez, F., Coroleu, B., Parera, N., Alvarez, M., Traver, J.M., Boada, M. and Barri, P.N. (2001) Human chorionic gonadotropin and intravaginal natural progesterone are equally effective for luteal phase support in IVF. Gynecol. Endocrinol., 14, Maxon, W. and Hargrove, J. (1985) Bioavailability of oral micronized progesterone. Fertil. Steril., 44, Mochtar, M.H., Hogerzeil, H.V. and Mol, B.W. (1996) Progesterone alone versus progesterone combined with hcg as luteal support in GnRHa/ HMG induced IVF cycles; a randomized clinical trial. Hum. Reprod., 11, Perino, M., Brigandi, F.G., Abate, F.G., Costabile, L., Balzano, E. and Abate, A. (1997) Intramuscular versus vaginal progesterone in assisted reproduction: a comparative study. Clin. Exp. Obstet. Gynecol., 24, Pouly, J.L., Bassil, S., Frydman, R., Hedon, B., Nicollet, B., Prada, Y., Antoine, J.M., Zambrano, R. and Donnez, J. (1996) Luteal support after in-vitro fertilization: Crinone 8%, a sustained release vaginal progesterone gel, versus Utrogestan, an oral micronized progesterone. Hum. Reprod., 11, Smith, E.M., Anthony, F.W., Gadd, S.C. and Masson, G.M. (1989) Trial of support treatment with human chorionic gonadotropin in the luteal phase after treatment with buserelin and human menopausal gonadotrophin in women taking part in an in vitro fertilisation programme. Br. Med. J., 298, Smitz, J., Devroey, P., Camus, M., Deschact, J., Khan, I., Staessen, C., Van Waesberghe, L., Wisanto, A. and Van Steirteghem, A.C. (1988) The luteal phase and early pregnancy after combined GnRH-agonist/HMG treatment for superovulation in IVF or GIFT. Hum. Reprod., 3, Smitz, J., Bourgain, C., Van Waesberghe, L., Camus, M., Devroey, P. and Van Steirteghem, A.C. (1993) A prospective randomized study on oestradiol valerate supplementation in addition to intravaginal micronized progesterone in buserelin and HMG induced superovulation. Hum. Reprod., 8, Soliman, S., Daya, S., Collins, J. and Hughes, E.G. (1994) The role of luteal phase support in infertility treatment: a meta-analysis of randomized trials. Fertil. Steril., 61, Strehler, E., Abt, M., El-Danasouri, I. and Sterzik, K. (1999) Transvaginal administration of micronized progesterone does not differ to progesterone gel application in the efficacy of luteal phase support in IVF cycles. Abstracts of 11th World Congress on In vitro Fertilization and Human Reproductive Genetics, Australia, Abstract, P-243. Tavaniotou, A., Smitz, J., Bourgain, C. and Devroey, P. (2000) Comparison between different routes of progesterone administration as luteal phase support in infertility treatments. Hum. Reprod. Update, 6, Ugur, M., Yenicesu, O., Ozcan, S., Keles, G. and Gokmen, O. (2001) A prospective randomized study comparing hcg, vaginal micronized progesterone and a combination regimen for luteal phase support in an in-vitro fertilization programme. Fertil. Steril., 76, S118, Abstract, P-19. Submitted on January 10, 2002; accepted on April 22,

10 E.A.Pritts and A.K.Atwood Appendix. Studies included in the meta-analysis ART assisted reproductive technology; PRP prospective randomized placebo controlled; 17-OHPc 17α-hydroxyprogesterone caproate; I inclusion criteria; PRC prospective randomized comparison; P progesterone; TVA transvaginal aspiration of oocytes; BMI body mass index; ZIFT zygote intra-fallopian transfer; OT ovulation trigger; E exclusion criteria; E 2 estradiol; GIFT gamete intra-fallopian transfer. 2296

11 Luteal phase support in infertility treatment 2297

12 E.A.Pritts and A.K.Atwood 2298

13 Luteal phase support in infertility treatment 2299