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Optimal dose of HCG for final oocyte maturation in IVF cycles: absence of evidence?
RBMOnline - Vol 19. No 1. 2009 52-58 Reproductive BioMedicine Online; www.rbmonline.com/Article/3977 on web 28 April 2009
Symposium: Update on prediction and management of OHSS Optimal dose of HCG for final oocyte maturation in IVF cycles: absence of evidence? Dr Ioanna Tsoumpou obtained her MD from the Medical School of the University of Ioannina, Greece. She is currently training as a Specialist Registrar in obstetrics and gynaecology at St Mary’s University Hospital in Manchester, UK. She has a special interest in reproductive endocrinology and in the physiology of embryo implantation.
Dr Ioanna Tsoumpou Ioanna Tsoumpou, Javaid Muglu, Tarek A Gelbaya, Luciano G Nardo1 Department of Reproductive Medicine, St Mary’s Hospital, CMMC University Hospitals, Manchester, UK 1 Correspondence: e-mail: [email protected]
Abstract There is an ongoing debate over the optimal dose of urinary HCG (u-HCG) that can trigger final oocyte maturation, leading to higher IVF success rate without increasing the risk of ovarian hyperstimulation syndrome (OHSS). A systematic review was conducted of all studies that compared the effect of at least two doses of u-HCG for final oocyte maturation on IVF outcomes and on the incidence of OHSS. The primary outcome was the live birth rate, and the secondary end-points were the number of oocytes retrieved, fertilization, implantation and pregnancy rates, and the incidence of OHSS. Only two amongst the six included studies were randomized controlled trials (RCT). Meta-analytic pool was not feasible due to insufficient number of studies assessing the same outcome and significant heterogeneity. The majority of studies concluded that the clinical outcomes were similar between women receiving 5000 or 10,000 IU of u-HCG. The incidence of OHSS was not reduced in the high-risk population even with lower dose of u-HCG. Until large scale RCT addressing the clinical effectiveness and the adverse outcomes related to various doses of u-HCG are conducted, the dose of u-HCG for final oocyte maturation for women referred for IVF needs to be individualized. Keywords: dose, IVF, OHSS, pregnancy, urinary HCG
Introduction
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Human chorionic gonadotrophin (HCG), a natural analogue of LH, is used for final oocyte maturation in assisted conception cycles. Compared with LH, it has a longer circulating half-life (>24 h versus 60 min for LH) and as a result, it persists well after ovulation for up to 6 days (Casper, 1996), unlike LH, which is rapidly cleared from the circulation after its surge (Balasch et al., 2006).
immune tolerance and may facilitate trophoblast invasion, which is known to expedite fetal development in the endometrium (Kayisli et al., 2003). Although circulating HCG is favourable for the development of a competent corpus luteum (Neulen et al., 1998), it is associated with increased incidence of ovarian hyperstimulation syndrome (OHSS) (Niederberger et al., 1995; Qasim et al., 1997; Albert et al., 2002).
The role of HCG in IVF cycles is not limited to oocyte maturation, but it is also crucial in the early stages of pregnancy. During the putative implantation period, the endometrium expresses LH/ HCG receptors (Licht et al., 2003). The HCG interacts with these receptors and promotes maintenance of the corpus luteum, which in turn allows progesterone secretion. It has also been postulated that HCG may be a link in the development of peritrophoblastic
To date, there is no consensus over the optimal dose of HCG for final oocyte maturation. Studies in animals have shown that the HCG dose required for oocyte maturation may be of lesser amplitude or duration than the one required for ovulation (Bomsel-Helmreich et al., 1989; Peluso et al., 1990; Ishikawa et al., 1992). A survey of the literature and data from various clinics indicates that the dose of urinary HCG (u-HCG)
© 2009 Published by Reproductive Healthcare Ltd, Duck End Farm, Dry Drayton, Cambridge CB23 8DB, UK
Symposium - Optimal dose of HCG for oocyte maturation - I Tsoumpou et al.
for ovulation induction could vary from 5000 to 25,000 international units (IU), although there appears to be little evidence to support the use of any one particular dose over another (Nargund et al., 2007). A systematic review was conducted in order to establish the optimal dose of u-HCG that can be administered to trigger final oocyte maturation without increasing the incidence of OHSS in women undergoing IVF.
Materials and methods Objective To compare the effect of various u-HCG doses on the live birth rate and on the incidence of OHSS in IVF cycles.
Search strategy and data extraction MEDLINE (1966 to May 2008), EMBASE (1974 to May 2008) and SCISEARCH (1974 to May 2008) databases were searched for relevant studies. The search strategy used terms such as ‘IVF’, ‘HCG’, ‘oocyte’, ‘pregnancy’ and ‘OHSS’. The Cochrane Library, the Intercollegiate Study Institute (ISI) Proceedings for conference abstracts, the International Standard Randomized Controlled Trial Number (ISRCTN) Register and the Meta-register for randomized controlled trials (mRCT) were also searched for ongoing and archived trials using the same keywords. References of retrieved articles were perused. Articles frequently cited were used in the Science Citation Index to identify additional citations. The literature search, inclusion and exclusion criteria and extraction of data were independently undertaken and verified by two investigators (JM, IT). The criteria for inclusion or exclusion of studies in the systematic review were set prior to the literature search. The results were then compared and, in case of discordance, a consensus was reached with the involvement of a third investigator (TAG). Descriptive tables for population and study characteristics for all eligible studies were generated by recording the first author, publication year, journal title, sample size, study design, the type of interventions, the ovarian stimulation protocol and all the relevant outcomes reported. The authors were contacted in an attempt to obtain missing and/or additional data. There was no language restriction.
Types of studies, inclusion and exclusion criteria All controlled studies were considered, both prospective and retrospective, that assessed the effect of at least two different doses of u-HCG administered for final oocyte maturation on the IVF outcome and on the incidence of OHSS. Agonist and antagonist cycles as well as various modes of HCG administration (intramuscular or subcutaneous) were included. Studies that compared u-HCG with other compounds to induce oocyte maturation, such as recombinant HCG (r-HCG), GnRH agonists (GnRH-a) or recombinant LH (r-LH), were excluded. In the case of duplicate studies, only the most comprehensive one was included.
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Types of outcome measures All outcomes were defined prior to the literature search. The primary outcome was the live birth rate (LBR) defined as the delivery of one live infant per patient. Other outcomes included: number of oocytes retrieved (OR), fertilization rate (FR), implantation rate (IR), pregnancy rate (PR), clinical pregnancy (CPR) and ongoing pregnancy rate (OPR). Pregnancy was defined as a positive urinary or serum β-HCG result, while clinical pregnancy was defined as the visualization of fetal heart activity on transvaginal ultrasound scan at ≥6 weeks’ gestation. Ongoing pregnancy was defined as a pregnancy continuing beyond 12 weeks of gestation. Implantation rate was defined as the number of gestational sacs seen on ultrasound scan at ≥6 weeks’ gestation divided by the number of embryos transferred per treatment cycle. The incidence of severe OHSS or OHSS requiring hospital admission was also assessed. A power analysis was performed for the live birth rate, which was the primary outcome and for the incidence of severe OHSS. Assuming a 5% difference between the studied groups, a two-group chi-squared test with an alpha of 5% would have 80% power to detect a difference between an average LBR of 25% in the control group versus an average LBR of 30% in the study group if 1251 women were recruited in each group. Furthermore, if the average incidence of OHSS in IVF cycles is 3%, in order to show that by reducing the u-HCG dose the incidence is decreased by 1%, then it would be necessary to recruit 3826 women per study group.
Results A search of the electronic databases yielded 513 available abstracts. Twenty-eight studies were found to be potentially eligible and were subsequently scrutinized in full text (Figure 1).
Excluded studies Amongst the relevant studies, 22 failed to meet the inclusion criteria. Urinary HCG was compared with GnRH-a for final follicular maturation in seven studies (Segal et al., 1992; Humaidan et al., 2005; Kolibianakis et al., 2005; Babayof et al., 2006; Orvieto et al., 2006; Griesinger et al., 2007; Engmann et al., 2008), to r-HCG in five (Driscoll et al., 2000; ERHCG Group, 2000; Chang et al., 2001; International Recombinant Human Chorionic Gonadotrophin Study Group 2001; Abdelmassih et al., 2005) and to r-LH in two studies (European Recombinant LH Study Group 2001; Manau et al., 2002). The mode of u-HCG administration was the main intervention evaluated in two studies (Elkind-Hirsch et al., 2001; Stelling et al., 2003) and four studies were not controlled (Branigan et al., 2005; Koichi et al., 2006; Nargund et al., 2007; Shapiro et al., 2008). Two doses of r-HCG were compared in one study (Chan et al., 2005). Finally, one study (Gulekli et al., 2004) assessed the effect of various u-HCG doses on in-vitro maturation (IVM) outcomes rather than on IVF.
Included studies The characteristics of the six studies included in the systematic review are presented in Table 1. Various doses of u-HCG were
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Symposium - Optimal dose of HCG for oocyte maturation - I Tsoumpou et al.
Figure 1. Flow chart of study selection. IM = intramuscular, r-LH = recombinant luteinizing hormone, r-HCG = recombinant human chorionic gonadotrophin, SC = subcutaneous, u-HCG = urinary human chorionic gonadotrophin.
compared in agonist (Abdalla et al., 1987; Wikland et al., 1995; Prien et al., 2000; Schmidt et al., 2004) and in antagonist cycles (Detti et al., 2007; Kolibianakis et al., 2007). The participants were randomized according to dose of u-HCG in two studies (Abdalla et al., 1987; Kolibianakis et al., 2007) and according to the mode of u-HCG administration [intramuscular (i.m.) versus subcutaneous (s.c.)] in one study (Wikland et al., 1995). The first randomized controlled trial conducted in order to assess the optimal dose of u-HCG for final oocyte maturation in agonist cycles (Abdalla et al., 1987) compared 2000 versus 5000 or 10,000 IU of u-HCG for ovulation induction in women who received clomiphene citrate and either purified FSH or human menopausal gonadotrophin (HMG). Women with anovulation as a primary or associated cause of subfertility were excluded from the study. The authors concluded that significantly less patients underwent oocyte retrieval if 2000 IU of u-HCG were administrated compared with 5000 or 10,000 IU (77.3 versus 95.5 and 98.1% respectively). The mean number of oocytes retrieved was not significantly different amongst the studied groups, nor was the pregnancy rate per embryo transfer (Table 2).
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The dose of u-HCG was adjusted to the oestradiol concentrations on the day of u-HCG administration in a retrospective analysis (Schmidt et al., 2004). The study group (women who had oestradiol concentrations ≥4000 pg/ml but less than 5500 pg/ ml) received 3300 IU of u-HCG and the control group (women who had oestradiol concentrations ≥2500 pg/ml but <4000 pg/ ml) received 5000 IU of u-HCG. The authors concluded that 3300 IU resulted in a higher number of oocytes retrieved from the high-responder population. However, the clinical outcomes in terms of FR, PR and CPR were similar. The researchers concluded that decreasing the u-HCG dose did not result in a reduction in the incidence of OHSS in high risk women (women with high oestradiol concentrations). There were two cases of moderate or severe OHSS amongst 47 high-responder women who received 3300 IU of u-HCG, versus none amongst 47 women who received 5000 IU of u-HCG.
Similar results for the clinical effectiveness of 5000 versus 10,000 IU of u-HCG, regardless of the route of administration (i.m. or s.c.), are reported in a prospective cohort study (Wikland et al., 1995). There was no statistical difference in the number of OR, FR or PR between the included groups (Table 2). Moreover, the LBR in women who received 5000 and in those who had 10,000 IU of u-HCG was similar (29.5 versus 33% respectively).
The effect of adjusting the u-HCG dose to the peak oestradiol concentrations and the number of follicles on the day of u-HCG administration was also assessed in a retrospective cohort study in antagonist cycles (Detti et al., 2007). The group that received 5000 IU of u-HCG had significantly higher mean oestradiol concentrations on the day of u-HCG administration (mean oestradiol concentrations 4000 ± 775 pg/ml) compared with those women who received 10,000 IU (mean oestradiol concentration 2860 ± 943 pg/ml) or 15,000 IU (mean oestradiol concentration 2046 ± 668 pg/ml). However, the number of oocytes retrieved from the group of women who received the low u-HCG dose was significantly higher (P < 0.05; Table 2).
In a retrospective cohort study in agonist cycles (Prien et al., 2000), the authors assessed the clinical outcomes of final oocyte maturation with 5000 or 10,000 IU of u-HCG. No statistically significant difference was shown on the OR and PR per patient (Table 2).
In an RCT in antagonist cycles (Kolibianakis et al., 2007), women with polycystic ovary syndrome (PCOS) were randomized to receive 2500, 5000 or 10,000 IU of u-HCG. The authors demonstrated that u-HCG dose as low as 2500 IU had similar IVF success rates in terms of OR and FR as 5000 IU. Furthermore, RBMOnline®
Symposium - Optimal dose of HCG for oocyte maturation - I Tsoumpou et al.
Table 1. Characteristics of the studies included in the systematic review. Study
Design
Inclusion criteria
Intervention
Ovulation HCG dose induction
Luteal support
Outcomes
Agonist cycles Abdalla et al., 1987
RCT
IVF−ET Long protocol
Pure FSH 2000 or 5000 or HMG or 10,000 IU
ND
Successful oocyte recovery, OR, PR
Wikland et al., 1995
Prospective cohort
Age: 24–43 years, normal ovulatory cycles Age: ≤39 years, BMI: ≤28 kg/m2
IVF/ SUZI−ET Long protocol
pure FSH 5000 or 10,000 P 300 mg IU (i.m. or tds for s.c.) 2 weeks (PV)
Prien et al., 2000
Retrospective Age <39 years IVF−ET, HMG cohort study long protocol
5000 or 10,000 ND IU
Schmidt et al., 2004
Retrospective High cohort study responders E2 ≥2500 pg/ml
IVF/ r-FSH ICSI−ET, long protocol
3300 or 5000 IU depending on E2 concentrations
Retrospective ND cohort study
IVF/ r-FSH ICSI−ET, long protocol
5000 or 10,000 ND or 15,000 IU depending on E2 concentrations and number of follicles 2500 or 5000 P 200mg or 10,000 IU TDS from day 1 after OR until 7 weeks of gestation
Antagonist cycles Detti et al., 2007
Kolibianakis et al., 2007
RCT
PCOS, age: IVF/ r-FSH <39 years; ICSI−ET, day 3 FSH long protocol <10 IU/l, E2 <80 pg/ml P < 1.6 ng/ml, no endometrioma
HCG serum concentration OR, cleaved oocytes, FR, PR, MR, LBR OR, PR Serum P pre- and postHCG
P 50 mg OR, FR, PR, from CPR, OHSS evening after OR until viable pregnancy HCG concentrations after HCG trigger, OR
OR, FR, IR, CPR, MR, OHSS; cancellation rate
BMI = body mass index; CPR = clinical pregnancy rate, E2 = oestradiol, ET = embryo transfer; FR = fertilization rate, HCG = human chorionic gonadotrophin, HMG = human menopausal gonadotrophin, ICSI = intracytoplasmic sperm injection, IM = intramuscular, IU = international units, LBR = live birth rate, MR = miscarriage rate, ND = not documented, OHSS = ovarian hyperstimulation syndrome, OR = oocyte retrieval, P = progesterone, PCOS = polycystic ovarian syndrome, PR = pregnancy rate, PV = per vagina, RCT = randomized controlled trial, r-FSH = recombinant FSH, SC = subcutaneous, SUZI = subzonal insemination, TDS = three times daily.
there was no significant difference between women who received 2500, 5000 or 10,000 IU of u-HCG in the ongoing pregnancy rate per patient (30.8, 30.8 and 25% respectively) or in the cycle cancellation rate due to absence of available embryos for transfer (21.7, 7.7 and 7.7% respectively). The authors also assessed the incidence of OHSS amongst the studied groups. Severe, early onset OHSS occurred in two women: one in the 5000 IU group and the other in the 10,000 IU group.
Discussion There is an ongoing debate amongst fertility physicians over the optimal dose of u-HCG leading to a higher number of mature oocytes retrieved and higher fertilization and pregnancy rates without increasing the incidence of severe OHSS. The
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argument for increasing the dose of u-HCG is that it may help increasing the number of mature oocytes and therefore the number of embryos available for transfer. However, this may theoretically increase the risk of OHSS. The present review included all controlled studies that compared various doses of u-HCG for final oocyte maturation. Metaanalysis was not feasible due to the lack of a sufficient number of studies assessing the same outcome measures. Moreover, the available studies have different population characteristics, e.g. in the RCT by Abdalla and colleagues (Abdalla et al., 1987) the authors assessed only women with regular ovulatory cycles, whereas the RCT by Kolibianakis and colleagues (Kolibianakis et al., 2007) included only patients with PCOS.
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Table 2. Comparison of clinical outcomes in women receiving 5000 versus 10,000 IU of urinary human chorionic gonadotrophin Study
Agonist cycles Abdalla et al., 1987 Wikland et al., 1995 Prien et al., 2000 Antagonist cycles Detti et al., 2007 Kolibianakis et al., 2007b
Patients
Follicles
5000 10,000 5000 IU IU IU
10,000 IU
5000 IU
10,000 IU
Fertilization rate (%) 5000 10,000 IU IU
110 44 72
104 60 34
ND ND 17 ± 2
4.4 ± 2.5 9.7 12 ± 4
4.7 ± 2.6 7.4 16 ± 3
ND 52.5 ND
ND 52.5 ND
8 15 28
21
19
17.5 ± 5a 10 ± 5
28 ± 12a
15 ± 8
ND
ND
ND
26
26
7 (6)
11.5 (10.0) 14 (9.0)
ND ND 14 ± 3
Oocytes retrieved
6 (5)
Pregnancy rate (%) 5000 10,000 IU IU
13 22 14
65.4 (24.2) 55.5 (29.0) ND
IU = international units, ND = not documented. a Significantly increased (P-value <0.05); bdata are expressed as median (interquartile range).
The LBR, which was the primary outcome of the present review, was assessed by only one study (Wikland et al., 1995). Although the LBR in women who received 5000 and in those who had 10,000 IU of u-HCG was similar (29.5 versus 33%), the number of participants was too small to reach statistical significance (44 versus 66 women respectively). The majority of included studies (Abdalla et al., 1987; Wikland et al., 1995; Prien et al., 2000; Kolibianakis et al., 2007) demonstrated clinical equivalence of 5000 compared with 10,000 IU of u-HCG in terms of OR, FR and PR. However, in two studies that adjusted the dose of HCG to the concentration of oestradiol (Schmidt et al., 2004; Detti et al., 2007), the number of oocytes retrieved was higher in women with high concentrations of oestradiol, even when lower doses of HCG were administered. Some investigators suggest that by administering 5000 rather than 10,000 IU of u-HCG, the risk of OHSS is reduced without compromising the IVF success rates in women who have high-risk factors for OHSS, but they recognize that a minimal effective dose of HCG has yet to be established (Whelan et al., 2000). The incidence of OHSS in relation to the dose of u-HCG was assessed in only two of the included studies (Schmidt et al., 2004; Kolibianakis et al., 2007). The study by Schmidt and colleagues adjusted the dose of HCG to the patient’s risk of developing OHSS, and found that for women at high risk for OHSS (oestradiol concentrations ≥4000 pg/ml but less than 5500 pg/ml), the incidence of OHSS was not reduced even when the u-HCG dose was reduced to 3300 IU compared with 5000 IU given to women with theoretically lower risk for OHSS (women who had oestradiol concentrations ≥2500 pg/ ml but <4000 pg/ml). However, their results are biased, as the study was not randomized. On the other hand, although in the RCT by Kolibianakis and colleagues (Kolibianakis et al., 2007) the same number of women with PCOS developed OHSS in either group studied, the number of participants was small (26 women in each group), and therefore the results could not reach statistical significance.
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The evidence on alternative methods to u-HCG for final follicular maturation does not support the choice of one method
over another. The recent development of GnRH antagonist cycles permits the use of a GnRH agonist to induce the LH peak (Albano et al., 1997; Wu, 2000). An RCT that assessed GnRH agonists as a substitute for u-HCG in antagonist cycles (Babayof et al., 2006) focused mainly on the hormonal and ultrasonic parameters between the treatment protocols, showing a significant inhibition of the luteal function when triggering final oocyte maturation with GnRH agonists. There was also a reduction in the incidence of OHSS, but that was not significant as the number of participants was too small (22 women). Similarly, in another RCT (Engmann et al., 2008) that included 66 women with polycystic ovarian syndrome or polycystic ovarian morphology, the incidence of OHSS was reduced in the group of women who received GnRH agonist instead of u-HCG. However, an RCT by Humaidan and colleagues (Humaidan et al., 2005) showed that although ovulation induction with GnRH agonists, following pre-treatment with an antagonist, resulted in a significantly higher proportion of mature oocytes than ovulation induction with HCG, the implantation and clinical pregnancy rate were significantly lower and the rate of early pregnancy loss significantly higher in the GnRH agonist group. That could be due to the insufficiency of luteal phase in the GnRH agonist group as shown by Babayof and colleagues (Babayof et al., 2006). Significantly lower ongoing pregnancy rates when oocyte maturation was triggered by GnRH analogues were demonstrated in another RCT that assessed 106 women with various causes of infertility (Kolibianakis et al., 2005). Recombinant preparations of HCG derived from genetically engineered Chinese hamster ovary cells through recombinant DNA technology present another appealing method for final oocyte maturation. The main argument against the use of u-HCG versus r-HCG is that urinary preparations are associated with lack of purity and batch-to-batch variation in activity, leading to variable clinical results (Zegers-Hochschild et al., 1996). Nonetheless, a meta-analysis of RCT that compared u-HCG to r-HCG or r-LH for final oocyte maturation concluded that there is no difference in the clinical outcomes of live birth/ongoing pregnancy, pregnancy, miscarriage and OHSS between urinary and recombinant HCG (Al-Inany et al., 2005). There was, however, a significant increase in the incidence of local injection
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Symposium - Optimal dose of HCG for oocyte maturation - I Tsoumpou et al.
site adverse effects, such as skin irritation at the injection site in the group of women treated with u-HCG. Other parameters such as the cost as well as the availability of the r-HCG also need to be considered when choosing a gonadotrophin type. In terms of luteal support, progesterone was used in three of the included studies (Wikland et al., 1995; Schmidt et al., 2004; Kolibianakis et al., 2007). The remaining studies (Abdalla et al., 1987; Prien et al., 2000; Detti et al., 2007) did not document on the method adopted for luteal phase supplementation (Table 1). There is, however, evidence that luteal supplementation with HCG, using single or repeated doses, increases the risk of OHSS (Smitz et al., 1990; Navot et al., 1992; MacDougall et al., 1993; Araujo et al., 1994), whereas replacing HCG with progesterone for luteal phase support may be more important in reducing the incidence of OHSS than solely decreasing the HCG dose for oocyte maturation (Penzias, 2002). As the evidence from the included studies did not suggest a significant difference in clinical outcomes with regards to OR, FR and PR, and as there is a well recognized link between HCG and OHSS, one could assume that the lowest possible dose of HCG should be used for final oocyte maturation. However, there is some evidence to suggest that the probability of retrieving oocytes is reduced when HCG is given in a dose as low as 2000 IU (Abdalla et al., 1987). Consequently, women with previous or predicted poor response might not benefit from a decrease in the u-HCG dose. Those patients carry a higher risk of cycle cancellation due to small number of retrieved mature oocytes, low or failed fertilization or unavailable embryos for transfer. On the other hand, women at risk of OHSS, i.e. women with previous history of OHSS and high oestradiol concentrations on the day of HCG administration (Practice Committee of the American Society for Reproductive Medicine, 2003), and women with PCOS or baseline ultrasonographic findings such as high number of antral follicles, large ovarian volume and high stromal vascularity (Nargund et al., 2007), could have an adequate response even with low HCG dose. Large scale multicentre RCT that would assess the clinical effectiveness and the incidence of OHSS after various u-HCG regimes, in comparable populations, are very difficult to conduct. The initial triage of women in high and low responder groups is pivotal in the choice of the appropriate u-HCG dose. Due to lack of concrete evidence, it is believed that the dose of HCG should be individualized in the same way as the starting dose of gonadotrophins. Good responders need not receive a dose higher than 5000 IU, whereas poor responders would probably benefit from higher doses of HCG.
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human chorionic gonadotropin in inducing final follicular maturation and ovulation in in vitro fertilization procedures: results of a multicenter double-blind study. The Journal of Clinical Endocrinology and Metabolism 86, 2607–2618. Griesinger G, Kolibianakis EM, Papanikolaou EG et al. 2007 Triggering of final oocyte maturation with gonadotropinreleasing hormone agonist or human chorionic gonadotropin. Live birth after frozen−thawed embryo replacement cycles. Fertility and Sterility 88, 616–621. Gulekli B, Buckett WM, Chian RC et al. 2004 Randomized controlled trial of priming with 10,000 IU versus 20,000 IU of human chorionic gonadotrophin in women with polycystic ovarian syndrome who are undergoing in vitro maturation. Fertility and Sterility 82, 1458–1459. Humaidan P, Bredkjaer HE, Bungum L et al. 2005 GnRH agonist (buserelin) or HCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study. Human Reproduction 20, 1213–1220. International Recombinant Human Chorionic Gonadotropin Study Group 2001 Induction of ovulation in World Health Organization group II anovulatory women undergoing follicular stimulation with recombinant human follicle-stimulating hormone: a comparison of recombinant human chorionic gonadotrophin (rhCG) and urinary HCG. Fertility and Sterility 75, 1111–1118. Ishikawa J 1992 Luteinizing hormone requirements for ovulation in the rat. Biology of Reproduction 46, 1144–11450. Kayisli U, Selam B, Guzeloglu-Kayisli O et al. 2003 Human chorionic gonadotrophin contributes to maternal immunotolerance and endometrial apoptosis by regulating Fas– Fas ligand system. Journal of Immunology 171, 2305–2313. Koichi K, Yukiko N, Shima K et al. 2006 Efficacy of low-dose human chorionic gonadotropin (HCG) in a GnRH antagonist protocol. Journal of Assisted Reproduction and Genetics 23, 223–228. Kolibianakis EM, Papanikolaou EG, Tournaye H et al. 2007 Triggering final oocyte maturation using different doses of human chorionic gonadotrophin: a randomized pilot study in patients with polycystic ovary syndrome treated with gonadotropin-releasing hormone antagonists and recombinant follicle-stimulating hormone. Fertility and Sterility 88, 1382– 1388. Kolibianakis EM, Schultz-Mosgau A, Schroer A et al. 2005 A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists. Human Reproduction 20, 2887–2892. Licht P, Russu V, Lehmeyer S et al. 2003 Cycle dependency of intrauterine vascular endothelial growth factor levels is correlated with decidualization and corpus luteum function. Fertility and Sterility 80, 1228–1233. MacDougall MJ, Tan SL, Balen A et al. 1993 A controlled study comparing patients with and without polycystic ovaries undergoing in-vitro fertilization. Human Reproduction 8, 233– 237. Manau D, Fábregues F, Arroyo V et al. 2002 Hemodynamic changes induced by urinary human chorionic gonadotropin and recombinant luteinizing hormone used for inducing final follicular maturation and luteinization. Fertility and Sterility 78, 1261–1267. Nargund G, Hutchison L, Scaramuzzi R et al. 2007 Low-dose HCG is useful in preventing OHSS in high-risk women without adversely affecting the outcome of IVF cycles. Reproductive BioMedicine Online 14, 682–685. Navot D, Bergh PA, Laufer N 1992 Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertility and Sterility 58, 249–261. Neulen J, Raczek S, Pogorzelski M et al. 1998 Secretion of vascular endothelial growth factor/vascular permeability factor from human luteinized granulosa cells is human chorionic gonadotrophin dependent. Molecular Human Reproduction 4, 203–206.
Niederberger V, Rottensteiner-Grohsmann C, Turnheim K et al. 1995 Incidence of ovarian hyperstimulation syndrome in invitro fertilization treatment over a period of 11 years. Wiener Medizinische Wochenschrift 145, 642–646. Orvieto R, Zagatsky I, Yulzari-Roll V et al. 2006 Substituting human chorionic gonadotropin by gonadotropin-releasing hormone agonist to trigger final follicular maturation, during controlled ovarian hyperstimulation, results in less systemic inflammation. Gynecological Endocrinology 22, 437–440. Peluso JJ 1990 Role of the amplitude of the gonadotropin surge in the rat. Fertility and Sterility 53, 150–154. Penzias AS 2002 Luteal phase support. Fertility and Sterility 77, 318–323. Practice Committee of the American Society for Reproductive Medicine. Ovarian hyperstimulation syndrome 2003. Fertility and Sterility 80, 1309–1314. Prien SD, Canez MS, Messer RH 2000 The dosage of human chorionic gonadotrophins influences the relationship between progesterone and cycle outcome during in vitro fertilization−embryo transfer. International Journal of Fertility and Women’s Medicine 45, 258–263. Qasim SM, Karacen M, Kemmann E 1997 An eight-year review of hospitalisation for ovarian hyperstimulation syndrome. Clinical and Experimental Obstetrics and Gynaecology 24, 49–52. Schmidt DW, Maier DB, Nulsen JC et al. 2004 Reducing the dose of human chorionic gonadotropin in high responders does not affect the outcomes of in vitro fertilization. Fertility and Sterility 82, 841–846. Segal S, Casper RF 1992 Gonadotropin-releasing hormone agonist versus human chorionic gonadotropin for triggering follicular maturation in in vitro fertilization. Fertility and Sterility 57, 1254–1258. Shapiro BS, Daneshmand ST, Garner FC et al. 2008 Gonadotropinreleasing hormone agonist combined with a reduced dose of human chorionic gonadotropin for final oocyte maturation in fresh autologous cycles of in vitro fertilization. Fertility and Sterility 90, 231–233. Smitz J, Camus M, Devroey P et al. 1990 Incidence of severe ovarian hyperstimulation syndrome after GnRH agonist/HMG superovulation for in-vitro fertilization. Human Reproduction 5, 933–937. Stelling JR, Chapman ET, Frankfurter D et al. 2003 Subcutaneous versus intramuscular administration of human chorionic gonadotropin during an in vitro fertilization cycle. Fertility and Sterility 79, 881–885. Whelan JG 3rd, Vlahos NF 2000 The ovarian hyperstimulation syndrome. Fertility and Sterility 73, 883–896. Wikland M, Borg J, Forsberg AS et al. 1995 Human chorionic gonadotrophin self-administered by the subcutaneous route to induce oocyte maturation in an in-vitro fertilization and embryo transfer programme. Human Reproduction 10, 1667–1670. Wu TC 2000 Midcycle administration of single-dose GnRHa for luteal phase failure in women with ovarian hyperstimulation. A report of five cases. Journal of Reproductive. Medicine 45, 156–158. Zegers-Hochschild F, Fernandez E, Mackenna A et al. 1996 The empty follicle syndrome: a pharmaceutical industry syndrome. Human Reproduction 10, 2262–2265.
Declaration: The authors report no financial or commercial conflicts of interest. Received 6 October 2008; refereed 6 November 2008; accepted 13 February 2009.
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Symposium: Update on prediction and management of OHSS Optimal dose of HCG for final oocyte maturation in IVF cycles: absence of evidence? Dr Ioanna Tsoumpou obtained her MD from the Medical School of the University of Ioannina, Greece. She is currently training as a Specialist Registrar in obstetrics and gynaecology at St Mary’s University Hospital in Manchester, UK. She has a special interest in reproductive endocrinology and in the physiology of embryo implantation.
Dr Ioanna Tsoumpou Ioanna Tsoumpou, Javaid Muglu, Tarek A Gelbaya, Luciano G Nardo1 Department of Reproductive Medicine, St Mary’s Hospital, CMMC University Hospitals, Manchester, UK 1 Correspondence: e-mail: [email protected]
Abstract There is an ongoing debate over the optimal dose of urinary HCG (u-HCG) that can trigger final oocyte maturation, leading to higher IVF success rate without increasing the risk of ovarian hyperstimulation syndrome (OHSS). A systematic review was conducted of all studies that compared the effect of at least two doses of u-HCG for final oocyte maturation on IVF outcomes and on the incidence of OHSS. The primary outcome was the live birth rate, and the secondary end-points were the number of oocytes retrieved, fertilization, implantation and pregnancy rates, and the incidence of OHSS. Only two amongst the six included studies were randomized controlled trials (RCT). Meta-analytic pool was not feasible due to insufficient number of studies assessing the same outcome and significant heterogeneity. The majority of studies concluded that the clinical outcomes were similar between women receiving 5000 or 10,000 IU of u-HCG. The incidence of OHSS was not reduced in the high-risk population even with lower dose of u-HCG. Until large scale RCT addressing the clinical effectiveness and the adverse outcomes related to various doses of u-HCG are conducted, the dose of u-HCG for final oocyte maturation for women referred for IVF needs to be individualized. Keywords: dose, IVF, OHSS, pregnancy, urinary HCG
Introduction
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Human chorionic gonadotrophin (HCG), a natural analogue of LH, is used for final oocyte maturation in assisted conception cycles. Compared with LH, it has a longer circulating half-life (>24 h versus 60 min for LH) and as a result, it persists well after ovulation for up to 6 days (Casper, 1996), unlike LH, which is rapidly cleared from the circulation after its surge (Balasch et al., 2006).
immune tolerance and may facilitate trophoblast invasion, which is known to expedite fetal development in the endometrium (Kayisli et al., 2003). Although circulating HCG is favourable for the development of a competent corpus luteum (Neulen et al., 1998), it is associated with increased incidence of ovarian hyperstimulation syndrome (OHSS) (Niederberger et al., 1995; Qasim et al., 1997; Albert et al., 2002).
The role of HCG in IVF cycles is not limited to oocyte maturation, but it is also crucial in the early stages of pregnancy. During the putative implantation period, the endometrium expresses LH/ HCG receptors (Licht et al., 2003). The HCG interacts with these receptors and promotes maintenance of the corpus luteum, which in turn allows progesterone secretion. It has also been postulated that HCG may be a link in the development of peritrophoblastic
To date, there is no consensus over the optimal dose of HCG for final oocyte maturation. Studies in animals have shown that the HCG dose required for oocyte maturation may be of lesser amplitude or duration than the one required for ovulation (Bomsel-Helmreich et al., 1989; Peluso et al., 1990; Ishikawa et al., 1992). A survey of the literature and data from various clinics indicates that the dose of urinary HCG (u-HCG)
© 2009 Published by Reproductive Healthcare Ltd, Duck End Farm, Dry Drayton, Cambridge CB23 8DB, UK
Symposium - Optimal dose of HCG for oocyte maturation - I Tsoumpou et al.
for ovulation induction could vary from 5000 to 25,000 international units (IU), although there appears to be little evidence to support the use of any one particular dose over another (Nargund et al., 2007). A systematic review was conducted in order to establish the optimal dose of u-HCG that can be administered to trigger final oocyte maturation without increasing the incidence of OHSS in women undergoing IVF.
Materials and methods Objective To compare the effect of various u-HCG doses on the live birth rate and on the incidence of OHSS in IVF cycles.
Search strategy and data extraction MEDLINE (1966 to May 2008), EMBASE (1974 to May 2008) and SCISEARCH (1974 to May 2008) databases were searched for relevant studies. The search strategy used terms such as ‘IVF’, ‘HCG’, ‘oocyte’, ‘pregnancy’ and ‘OHSS’. The Cochrane Library, the Intercollegiate Study Institute (ISI) Proceedings for conference abstracts, the International Standard Randomized Controlled Trial Number (ISRCTN) Register and the Meta-register for randomized controlled trials (mRCT) were also searched for ongoing and archived trials using the same keywords. References of retrieved articles were perused. Articles frequently cited were used in the Science Citation Index to identify additional citations. The literature search, inclusion and exclusion criteria and extraction of data were independently undertaken and verified by two investigators (JM, IT). The criteria for inclusion or exclusion of studies in the systematic review were set prior to the literature search. The results were then compared and, in case of discordance, a consensus was reached with the involvement of a third investigator (TAG). Descriptive tables for population and study characteristics for all eligible studies were generated by recording the first author, publication year, journal title, sample size, study design, the type of interventions, the ovarian stimulation protocol and all the relevant outcomes reported. The authors were contacted in an attempt to obtain missing and/or additional data. There was no language restriction.
Types of studies, inclusion and exclusion criteria All controlled studies were considered, both prospective and retrospective, that assessed the effect of at least two different doses of u-HCG administered for final oocyte maturation on the IVF outcome and on the incidence of OHSS. Agonist and antagonist cycles as well as various modes of HCG administration (intramuscular or subcutaneous) were included. Studies that compared u-HCG with other compounds to induce oocyte maturation, such as recombinant HCG (r-HCG), GnRH agonists (GnRH-a) or recombinant LH (r-LH), were excluded. In the case of duplicate studies, only the most comprehensive one was included.
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Types of outcome measures All outcomes were defined prior to the literature search. The primary outcome was the live birth rate (LBR) defined as the delivery of one live infant per patient. Other outcomes included: number of oocytes retrieved (OR), fertilization rate (FR), implantation rate (IR), pregnancy rate (PR), clinical pregnancy (CPR) and ongoing pregnancy rate (OPR). Pregnancy was defined as a positive urinary or serum β-HCG result, while clinical pregnancy was defined as the visualization of fetal heart activity on transvaginal ultrasound scan at ≥6 weeks’ gestation. Ongoing pregnancy was defined as a pregnancy continuing beyond 12 weeks of gestation. Implantation rate was defined as the number of gestational sacs seen on ultrasound scan at ≥6 weeks’ gestation divided by the number of embryos transferred per treatment cycle. The incidence of severe OHSS or OHSS requiring hospital admission was also assessed. A power analysis was performed for the live birth rate, which was the primary outcome and for the incidence of severe OHSS. Assuming a 5% difference between the studied groups, a two-group chi-squared test with an alpha of 5% would have 80% power to detect a difference between an average LBR of 25% in the control group versus an average LBR of 30% in the study group if 1251 women were recruited in each group. Furthermore, if the average incidence of OHSS in IVF cycles is 3%, in order to show that by reducing the u-HCG dose the incidence is decreased by 1%, then it would be necessary to recruit 3826 women per study group.
Results A search of the electronic databases yielded 513 available abstracts. Twenty-eight studies were found to be potentially eligible and were subsequently scrutinized in full text (Figure 1).
Excluded studies Amongst the relevant studies, 22 failed to meet the inclusion criteria. Urinary HCG was compared with GnRH-a for final follicular maturation in seven studies (Segal et al., 1992; Humaidan et al., 2005; Kolibianakis et al., 2005; Babayof et al., 2006; Orvieto et al., 2006; Griesinger et al., 2007; Engmann et al., 2008), to r-HCG in five (Driscoll et al., 2000; ERHCG Group, 2000; Chang et al., 2001; International Recombinant Human Chorionic Gonadotrophin Study Group 2001; Abdelmassih et al., 2005) and to r-LH in two studies (European Recombinant LH Study Group 2001; Manau et al., 2002). The mode of u-HCG administration was the main intervention evaluated in two studies (Elkind-Hirsch et al., 2001; Stelling et al., 2003) and four studies were not controlled (Branigan et al., 2005; Koichi et al., 2006; Nargund et al., 2007; Shapiro et al., 2008). Two doses of r-HCG were compared in one study (Chan et al., 2005). Finally, one study (Gulekli et al., 2004) assessed the effect of various u-HCG doses on in-vitro maturation (IVM) outcomes rather than on IVF.
Included studies The characteristics of the six studies included in the systematic review are presented in Table 1. Various doses of u-HCG were
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Symposium - Optimal dose of HCG for oocyte maturation - I Tsoumpou et al.
Figure 1. Flow chart of study selection. IM = intramuscular, r-LH = recombinant luteinizing hormone, r-HCG = recombinant human chorionic gonadotrophin, SC = subcutaneous, u-HCG = urinary human chorionic gonadotrophin.
compared in agonist (Abdalla et al., 1987; Wikland et al., 1995; Prien et al., 2000; Schmidt et al., 2004) and in antagonist cycles (Detti et al., 2007; Kolibianakis et al., 2007). The participants were randomized according to dose of u-HCG in two studies (Abdalla et al., 1987; Kolibianakis et al., 2007) and according to the mode of u-HCG administration [intramuscular (i.m.) versus subcutaneous (s.c.)] in one study (Wikland et al., 1995). The first randomized controlled trial conducted in order to assess the optimal dose of u-HCG for final oocyte maturation in agonist cycles (Abdalla et al., 1987) compared 2000 versus 5000 or 10,000 IU of u-HCG for ovulation induction in women who received clomiphene citrate and either purified FSH or human menopausal gonadotrophin (HMG). Women with anovulation as a primary or associated cause of subfertility were excluded from the study. The authors concluded that significantly less patients underwent oocyte retrieval if 2000 IU of u-HCG were administrated compared with 5000 or 10,000 IU (77.3 versus 95.5 and 98.1% respectively). The mean number of oocytes retrieved was not significantly different amongst the studied groups, nor was the pregnancy rate per embryo transfer (Table 2).
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The dose of u-HCG was adjusted to the oestradiol concentrations on the day of u-HCG administration in a retrospective analysis (Schmidt et al., 2004). The study group (women who had oestradiol concentrations ≥4000 pg/ml but less than 5500 pg/ ml) received 3300 IU of u-HCG and the control group (women who had oestradiol concentrations ≥2500 pg/ml but <4000 pg/ ml) received 5000 IU of u-HCG. The authors concluded that 3300 IU resulted in a higher number of oocytes retrieved from the high-responder population. However, the clinical outcomes in terms of FR, PR and CPR were similar. The researchers concluded that decreasing the u-HCG dose did not result in a reduction in the incidence of OHSS in high risk women (women with high oestradiol concentrations). There were two cases of moderate or severe OHSS amongst 47 high-responder women who received 3300 IU of u-HCG, versus none amongst 47 women who received 5000 IU of u-HCG.
Similar results for the clinical effectiveness of 5000 versus 10,000 IU of u-HCG, regardless of the route of administration (i.m. or s.c.), are reported in a prospective cohort study (Wikland et al., 1995). There was no statistical difference in the number of OR, FR or PR between the included groups (Table 2). Moreover, the LBR in women who received 5000 and in those who had 10,000 IU of u-HCG was similar (29.5 versus 33% respectively).
The effect of adjusting the u-HCG dose to the peak oestradiol concentrations and the number of follicles on the day of u-HCG administration was also assessed in a retrospective cohort study in antagonist cycles (Detti et al., 2007). The group that received 5000 IU of u-HCG had significantly higher mean oestradiol concentrations on the day of u-HCG administration (mean oestradiol concentrations 4000 ± 775 pg/ml) compared with those women who received 10,000 IU (mean oestradiol concentration 2860 ± 943 pg/ml) or 15,000 IU (mean oestradiol concentration 2046 ± 668 pg/ml). However, the number of oocytes retrieved from the group of women who received the low u-HCG dose was significantly higher (P < 0.05; Table 2).
In a retrospective cohort study in agonist cycles (Prien et al., 2000), the authors assessed the clinical outcomes of final oocyte maturation with 5000 or 10,000 IU of u-HCG. No statistically significant difference was shown on the OR and PR per patient (Table 2).
In an RCT in antagonist cycles (Kolibianakis et al., 2007), women with polycystic ovary syndrome (PCOS) were randomized to receive 2500, 5000 or 10,000 IU of u-HCG. The authors demonstrated that u-HCG dose as low as 2500 IU had similar IVF success rates in terms of OR and FR as 5000 IU. Furthermore, RBMOnline®
Symposium - Optimal dose of HCG for oocyte maturation - I Tsoumpou et al.
Table 1. Characteristics of the studies included in the systematic review. Study
Design
Inclusion criteria
Intervention
Ovulation HCG dose induction
Luteal support
Outcomes
Agonist cycles Abdalla et al., 1987
RCT
IVF−ET Long protocol
Pure FSH 2000 or 5000 or HMG or 10,000 IU
ND
Successful oocyte recovery, OR, PR
Wikland et al., 1995
Prospective cohort
Age: 24–43 years, normal ovulatory cycles Age: ≤39 years, BMI: ≤28 kg/m2
IVF/ SUZI−ET Long protocol
pure FSH 5000 or 10,000 P 300 mg IU (i.m. or tds for s.c.) 2 weeks (PV)
Prien et al., 2000
Retrospective Age <39 years IVF−ET, HMG cohort study long protocol
5000 or 10,000 ND IU
Schmidt et al., 2004
Retrospective High cohort study responders E2 ≥2500 pg/ml
IVF/ r-FSH ICSI−ET, long protocol
3300 or 5000 IU depending on E2 concentrations
Retrospective ND cohort study
IVF/ r-FSH ICSI−ET, long protocol
5000 or 10,000 ND or 15,000 IU depending on E2 concentrations and number of follicles 2500 or 5000 P 200mg or 10,000 IU TDS from day 1 after OR until 7 weeks of gestation
Antagonist cycles Detti et al., 2007
Kolibianakis et al., 2007
RCT
PCOS, age: IVF/ r-FSH <39 years; ICSI−ET, day 3 FSH long protocol <10 IU/l, E2 <80 pg/ml P < 1.6 ng/ml, no endometrioma
HCG serum concentration OR, cleaved oocytes, FR, PR, MR, LBR OR, PR Serum P pre- and postHCG
P 50 mg OR, FR, PR, from CPR, OHSS evening after OR until viable pregnancy HCG concentrations after HCG trigger, OR
OR, FR, IR, CPR, MR, OHSS; cancellation rate
BMI = body mass index; CPR = clinical pregnancy rate, E2 = oestradiol, ET = embryo transfer; FR = fertilization rate, HCG = human chorionic gonadotrophin, HMG = human menopausal gonadotrophin, ICSI = intracytoplasmic sperm injection, IM = intramuscular, IU = international units, LBR = live birth rate, MR = miscarriage rate, ND = not documented, OHSS = ovarian hyperstimulation syndrome, OR = oocyte retrieval, P = progesterone, PCOS = polycystic ovarian syndrome, PR = pregnancy rate, PV = per vagina, RCT = randomized controlled trial, r-FSH = recombinant FSH, SC = subcutaneous, SUZI = subzonal insemination, TDS = three times daily.
there was no significant difference between women who received 2500, 5000 or 10,000 IU of u-HCG in the ongoing pregnancy rate per patient (30.8, 30.8 and 25% respectively) or in the cycle cancellation rate due to absence of available embryos for transfer (21.7, 7.7 and 7.7% respectively). The authors also assessed the incidence of OHSS amongst the studied groups. Severe, early onset OHSS occurred in two women: one in the 5000 IU group and the other in the 10,000 IU group.
Discussion There is an ongoing debate amongst fertility physicians over the optimal dose of u-HCG leading to a higher number of mature oocytes retrieved and higher fertilization and pregnancy rates without increasing the incidence of severe OHSS. The
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argument for increasing the dose of u-HCG is that it may help increasing the number of mature oocytes and therefore the number of embryos available for transfer. However, this may theoretically increase the risk of OHSS. The present review included all controlled studies that compared various doses of u-HCG for final oocyte maturation. Metaanalysis was not feasible due to the lack of a sufficient number of studies assessing the same outcome measures. Moreover, the available studies have different population characteristics, e.g. in the RCT by Abdalla and colleagues (Abdalla et al., 1987) the authors assessed only women with regular ovulatory cycles, whereas the RCT by Kolibianakis and colleagues (Kolibianakis et al., 2007) included only patients with PCOS.
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Table 2. Comparison of clinical outcomes in women receiving 5000 versus 10,000 IU of urinary human chorionic gonadotrophin Study
Agonist cycles Abdalla et al., 1987 Wikland et al., 1995 Prien et al., 2000 Antagonist cycles Detti et al., 2007 Kolibianakis et al., 2007b
Patients
Follicles
5000 10,000 5000 IU IU IU
10,000 IU
5000 IU
10,000 IU
Fertilization rate (%) 5000 10,000 IU IU
110 44 72
104 60 34
ND ND 17 ± 2
4.4 ± 2.5 9.7 12 ± 4
4.7 ± 2.6 7.4 16 ± 3
ND 52.5 ND
ND 52.5 ND
8 15 28
21
19
17.5 ± 5a 10 ± 5
28 ± 12a
15 ± 8
ND
ND
ND
26
26
7 (6)
11.5 (10.0) 14 (9.0)
ND ND 14 ± 3
Oocytes retrieved
6 (5)
Pregnancy rate (%) 5000 10,000 IU IU
13 22 14
65.4 (24.2) 55.5 (29.0) ND
IU = international units, ND = not documented. a Significantly increased (P-value <0.05); bdata are expressed as median (interquartile range).
The LBR, which was the primary outcome of the present review, was assessed by only one study (Wikland et al., 1995). Although the LBR in women who received 5000 and in those who had 10,000 IU of u-HCG was similar (29.5 versus 33%), the number of participants was too small to reach statistical significance (44 versus 66 women respectively). The majority of included studies (Abdalla et al., 1987; Wikland et al., 1995; Prien et al., 2000; Kolibianakis et al., 2007) demonstrated clinical equivalence of 5000 compared with 10,000 IU of u-HCG in terms of OR, FR and PR. However, in two studies that adjusted the dose of HCG to the concentration of oestradiol (Schmidt et al., 2004; Detti et al., 2007), the number of oocytes retrieved was higher in women with high concentrations of oestradiol, even when lower doses of HCG were administered. Some investigators suggest that by administering 5000 rather than 10,000 IU of u-HCG, the risk of OHSS is reduced without compromising the IVF success rates in women who have high-risk factors for OHSS, but they recognize that a minimal effective dose of HCG has yet to be established (Whelan et al., 2000). The incidence of OHSS in relation to the dose of u-HCG was assessed in only two of the included studies (Schmidt et al., 2004; Kolibianakis et al., 2007). The study by Schmidt and colleagues adjusted the dose of HCG to the patient’s risk of developing OHSS, and found that for women at high risk for OHSS (oestradiol concentrations ≥4000 pg/ml but less than 5500 pg/ml), the incidence of OHSS was not reduced even when the u-HCG dose was reduced to 3300 IU compared with 5000 IU given to women with theoretically lower risk for OHSS (women who had oestradiol concentrations ≥2500 pg/ ml but <4000 pg/ml). However, their results are biased, as the study was not randomized. On the other hand, although in the RCT by Kolibianakis and colleagues (Kolibianakis et al., 2007) the same number of women with PCOS developed OHSS in either group studied, the number of participants was small (26 women in each group), and therefore the results could not reach statistical significance.
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The evidence on alternative methods to u-HCG for final follicular maturation does not support the choice of one method
over another. The recent development of GnRH antagonist cycles permits the use of a GnRH agonist to induce the LH peak (Albano et al., 1997; Wu, 2000). An RCT that assessed GnRH agonists as a substitute for u-HCG in antagonist cycles (Babayof et al., 2006) focused mainly on the hormonal and ultrasonic parameters between the treatment protocols, showing a significant inhibition of the luteal function when triggering final oocyte maturation with GnRH agonists. There was also a reduction in the incidence of OHSS, but that was not significant as the number of participants was too small (22 women). Similarly, in another RCT (Engmann et al., 2008) that included 66 women with polycystic ovarian syndrome or polycystic ovarian morphology, the incidence of OHSS was reduced in the group of women who received GnRH agonist instead of u-HCG. However, an RCT by Humaidan and colleagues (Humaidan et al., 2005) showed that although ovulation induction with GnRH agonists, following pre-treatment with an antagonist, resulted in a significantly higher proportion of mature oocytes than ovulation induction with HCG, the implantation and clinical pregnancy rate were significantly lower and the rate of early pregnancy loss significantly higher in the GnRH agonist group. That could be due to the insufficiency of luteal phase in the GnRH agonist group as shown by Babayof and colleagues (Babayof et al., 2006). Significantly lower ongoing pregnancy rates when oocyte maturation was triggered by GnRH analogues were demonstrated in another RCT that assessed 106 women with various causes of infertility (Kolibianakis et al., 2005). Recombinant preparations of HCG derived from genetically engineered Chinese hamster ovary cells through recombinant DNA technology present another appealing method for final oocyte maturation. The main argument against the use of u-HCG versus r-HCG is that urinary preparations are associated with lack of purity and batch-to-batch variation in activity, leading to variable clinical results (Zegers-Hochschild et al., 1996). Nonetheless, a meta-analysis of RCT that compared u-HCG to r-HCG or r-LH for final oocyte maturation concluded that there is no difference in the clinical outcomes of live birth/ongoing pregnancy, pregnancy, miscarriage and OHSS between urinary and recombinant HCG (Al-Inany et al., 2005). There was, however, a significant increase in the incidence of local injection
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Symposium - Optimal dose of HCG for oocyte maturation - I Tsoumpou et al.
site adverse effects, such as skin irritation at the injection site in the group of women treated with u-HCG. Other parameters such as the cost as well as the availability of the r-HCG also need to be considered when choosing a gonadotrophin type. In terms of luteal support, progesterone was used in three of the included studies (Wikland et al., 1995; Schmidt et al., 2004; Kolibianakis et al., 2007). The remaining studies (Abdalla et al., 1987; Prien et al., 2000; Detti et al., 2007) did not document on the method adopted for luteal phase supplementation (Table 1). There is, however, evidence that luteal supplementation with HCG, using single or repeated doses, increases the risk of OHSS (Smitz et al., 1990; Navot et al., 1992; MacDougall et al., 1993; Araujo et al., 1994), whereas replacing HCG with progesterone for luteal phase support may be more important in reducing the incidence of OHSS than solely decreasing the HCG dose for oocyte maturation (Penzias, 2002). As the evidence from the included studies did not suggest a significant difference in clinical outcomes with regards to OR, FR and PR, and as there is a well recognized link between HCG and OHSS, one could assume that the lowest possible dose of HCG should be used for final oocyte maturation. However, there is some evidence to suggest that the probability of retrieving oocytes is reduced when HCG is given in a dose as low as 2000 IU (Abdalla et al., 1987). Consequently, women with previous or predicted poor response might not benefit from a decrease in the u-HCG dose. Those patients carry a higher risk of cycle cancellation due to small number of retrieved mature oocytes, low or failed fertilization or unavailable embryos for transfer. On the other hand, women at risk of OHSS, i.e. women with previous history of OHSS and high oestradiol concentrations on the day of HCG administration (Practice Committee of the American Society for Reproductive Medicine, 2003), and women with PCOS or baseline ultrasonographic findings such as high number of antral follicles, large ovarian volume and high stromal vascularity (Nargund et al., 2007), could have an adequate response even with low HCG dose. Large scale multicentre RCT that would assess the clinical effectiveness and the incidence of OHSS after various u-HCG regimes, in comparable populations, are very difficult to conduct. The initial triage of women in high and low responder groups is pivotal in the choice of the appropriate u-HCG dose. Due to lack of concrete evidence, it is believed that the dose of HCG should be individualized in the same way as the starting dose of gonadotrophins. Good responders need not receive a dose higher than 5000 IU, whereas poor responders would probably benefit from higher doses of HCG.
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Declaration: The authors report no financial or commercial conflicts of interest. Received 6 October 2008; refereed 6 November 2008; accepted 13 February 2009.
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