J Endocrinol Invest (2014) 37:65–70 DOI 10.1007/s40618-013-0021-1
ORIGINAL ARTICLE
Mild/minimal stimulation protocol for ovarian stimulation of patients at high risk of developing ovarian hyperstimulation syndrome L. Rinaldi • F. Lisi • H. Selman
Received: 2 June 2013 / Accepted: 17 November 2013 / Published online: 8 January 2014 Ó Italian Society of Endocrinology (SIE) 2013
Abstract Background Recently, an increased scientific interest was focused on mild approaches for ovarian stimulation in clinical practice. Milder stimulation aims to develop safer and more patient-friendly protocols which are more physiological, less drug use, less expensive and the risks of treatment are highly minimized. Aim To investigate the efficacy and safety of a mild ovarian stimulation protocol in patients at high risk of developing ovarian hyperstimulation syndrome (OHSS), compared to conventional long down-regulation protocol. Subjects and methods This a prospective, open, randomized study, included 349 infertile patients considered at high risk of developing OHSS, undergoing in vitro fertilization treatment in two private assisted reproduction centers. The patients were randomized into two groups: group A (n = 148) had a mild/minimal stimulation protocol of recombinant FSH (rFSH) combined with GnRH antagonist. Group B (n = 201) (control group) had a standard long protocol of rFSH combined with GnRH agonist. Results There was no significant difference observed between the two groups regarding the mean number of oocytes retrieved per patient, mature metaphase II oocytes, fertilization rate, and embryo cleavage rate. Significantly higher implantation rate (21.5 vs 14.5 %) (p \ 0.05), pregnancy rate (37.7 vs 23.4 %) (p \ 0.05), and delivery
L. Rinaldi (&) H. Selman RISEL-One Day Medical Center, Via Attilio Ambrosini 114, 00147 Rome, Italy e-mail: [email protected] F. Lisi CERMER Clinica Villa Mafalda, Rome, Italy
rate (32.8 vs 20.1 %) (p \ 0.05) were observed in favor of groups A compared to group B. Lower proportion of patients (4.7 %), though not statistically significant, has developed OHSS in group A compared to group B (8.4 %). Conclusion Our study shows that mild stimulation regimen is highly effective for ovarian stimulation of patients who have experienced OHSS complication without increasing the risk of OHSS. Keywords Follicle-stimulating hormone GnRH antagonist GnRH agonist Ovarian stimulation Pregnancy OHSS Abbreviation OHSS Ovarian hyperstimulation syndrome rFSH Recombinant follicle-stimulating hormone IVF In vitro fertilization PCOS Polycystic ovarian syndrome
Introduction Ovarian stimulation is an integral procedure in assisted reproduction treatment. It is implemented with the aim to increase the number of oocytes yield for in vitro fertilization (IVF), thus enabling the selection of embryos for replacement [1]. For such purpose the use of gonadotropinreleasing hormone (GnRH) agonist for pituitary suppression combined with relatively high doses of exogenous follicle-stimulating hormone (FSH) is commonly employed for ovarian stimulation [2]. Such medication regimens take many weeks, are complex and expensive, and are not without risk. Problems related to ovarian stimulation include emotional stress, abdominal discomfort, short-term
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complications such as ovarian hyperstimulation syndrome (OHSS), multiple gestation, and uncertainties regarding long-term health consequences [3, 4]. Ovarian hyperstimulation syndrome is a potentially lifethreatening iatrogenic complication resulting from the use of hormonal therapy to artificially induce multiple follicular growth during IVF treatment. Extensive use of gonadotropin-releasing hormone (GnRH) down-regulation protocols for ovarian stimulation increases the risk of OHSS in infertile patients undergoing assisted fertilization treatment [5]. Although the incidence of severe forms of ovarian hyperstimulation syndrome is only 1–2 % [6, 7], OHSS remains the major significant source of morbidity and mortality in patients undergoing assisted reproduction technologies. It has been reported that the risk of OHSS is highly increased in polycystic ovarian syndrome (PCOS) or PCOS-like patients [5, 8, 9] and in women who have previously developed OHSS [10, 11]. The incidence and the duration of the syndrome are strictly related to the surge of pregnancy and the number of implanted embryos [12, 13]. A variety of preventive strategies have been adopted in order to reduce the risk of OHSS, but none of the described methods has consistently demonstrated efficacy in preventing the syndrome except for the cancelation of the treatment cycle before hCG administration [14–16]. Although the cycle cancelation is the most effective and safest approach, it is obviously frustrating and costly to the infertile couples, and a second attempt of ovarian stimulation may lead to the same risk. During last 15 years an increased scientific interest was focused on mild approaches for ovarian stimulation in clinical practice [17, 18]. Milder stimulation aims to develop safer and more patient-friendly protocols which are more physiological, less drug use, less expensive and the risks of treatment are highly minimized. Minimal or mild stimulation protocols are characterized by the administration of lower dose of gonadotrophins alone or in association with oral compounds such the antiestrogens (clomiphene citrate) following down-regulation with GnRH antagonist [19]. In this study, we report on the use of FSH in a mild ovarian stimulation of patients at high risk of OHSS downregulated either with GnRH antagonist or with GnRH agonist in order to determine any difference between protocols and to optimize the procedure.
Materials and methods In a prospective, open, randomized study, a total of 349 infertile patients aged 27–38 years, undergoing in vitro fertilization treatment in two private assisted reproduction
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centers from January 2008 to December 2012 were included. The patients had infertility attributable to tubal factor, moderate endometriosis, male factor, or idiopathic infertility. They exhibit serum hormonal profile within the normal range (FSH and LH \ 12 mIU/mL, estradiol \ 50 pg/mL, and prolactin \ 30 ng/mL); regular ovulatory menstrual cycles; presence of a normal uterine cavity; and body mass index (BMI) of 20–26 kg/m2. All patients were previously canceled because of a considerably high risk of developing OHSS following stimulation with a standard long GnRH agonist down-regulation protocol combined with gonadotropin. The patients were considered at high risk of developing OHSS if they had serum estradiol level C3,500 pg/mL on the day of hCG administration and [15 growing follicles ranging from intermediate size (\15 mm) to large size ([16 mm). The global incidence of OHSS risk was 2–3 % of all patients undergoing IVF treatment. The patients were randomized into two groups: group A (n = 148) had a mild/minimal stimulation protocol, 75 IU/ day of rFSH (Gonal F, Serono Italy), and 0.25 mg/day GnRH antagonist (Cetrorelix, Serono Italy) administered when the leading follicle was 14 mm. Group B (n = 201) had a standard ‘‘cautious’’ long protocol with GnRH agonist, 0.1 mg/day of triptorelin (Decapeptyl: Ipsen Milan, Italy) subcutaneously administered from the mid-luteal phase of the previous cycle for a minimum of 14 days, followed by 150 IU FSH as the lowest possible dose decided on the basis of the experience from the previous stimulation. The FSH dose was adjusted when necessary according to the follicular size and estradiol level. Final oocyte maturation was triggered by the administration of 10,000 IU of hCG (Gonasi HP, IBSA, Switzerland). Retrieved oocytes were assessed for their maturity and inseminated by standard IVF or intracytoplasmic sperm injection. Embryos were transferred on day 3 after oocyte insemination, no more than three embryos per patient were transferred. Luteal phase support was initiated on the day of oocyte retrieval using commercially available progesterone preparation (50 mg/mL i.m daily) (Prontogest, IBSA, Switzerland). Clinical pregnancy was confirmed 6 weeks after embryo transfer by ultrasonography. Randomization was performed using a computer-generated random assignment schedule for each patient. Sealed and numbered envelopes were used to conceal the treatment allocation until randomization. All patients were counseled about the nature of the study and gave their written informed consent for their participation to the randomization procedure. Participating patients were registered in our local ethical committee register that approved the study. Statistical analysis was performed using JMP software (version 4.0.4; SAS, Inc., Cary, NC, USA). For a desired
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statistical power of 90 % based on a level of 0.05, confidence intervals (CI) of 95 %, and anticipated effective size (Cohen’s D) of 0.5 (medium size), the minimum total sample size required according to two-tailed hypothesis was 172 patients—at least 86 evaluable patients per group. The parameters were compared by use of an analysis of variance (ANOVA) two-way test to analyze continuous variables. P B 0.05 was considered statistically significant. The data were analyzed using the two-tailed Student’s t test for independent data, Fisher’s exact test, and two-by-two table between groups where appropriate. All analyses were adjusted for age stratum in line with the study design.
Results
Table 2 Embryological characteristics Group A GnRHant
Group B GnRHa
P value
No. of patients
148
201
Mean number of retrieved oocytes ± SD
7.5 ± 3.7
6.8 ± 3.4
0.42
Mean number of inseminated MII oocytes ± SD
6.4 ± 3.2
5.5 ± 3.1
0.20
Mean number of fertilized 2PN oocytes ± SD
4.1 ± 2.5
3.9 ± 2.1
0.75
Fertilization rate %
74.6
64.7
0.67
Mean number of cleaved embryos ± SD Embryo cleavage rate %
3.4 ± 2.3
2.8 ± 2.1
0.80
78
73.6
0.52
Group A GnRHant
Group B GnRHa
P value
No. of patients underwent embryo transfer
143
179
Mean number of embryos per patient ± SD
2.2 ± 0.8
2 ± 0.9
0.49
Clinical pregnancies per embryo transfer (%)
54 (37.7 %)
42 (23.4 %)
0.05
MII Metaphase II oocytes
All studied patients (n = 349) underwent oocyte retrieval, 148 patients in group A and 201 in group B. No patient had poor ovarian response to gonadotropin treatment. The two groups were comparable regarding demographic data, duration of stimulation, and endometrium thickness. Statistically lower dose of FSH administered was observed in group A compared to group B (p \ 0.03), and significantly higher estradiol level on the day of hCG in favor of group A compared to group B (p \ 0.005) (Table 1). There was no significant difference observed between the two groups regarding the mean number of oocytes retrieved per patient, mature metaphase II oocytes, fertilization rate, and embryo cleavage rate. Five patients in group A (3.3 %) and 22 patients in group B (10.8 %) had complete fertilization failure, this was statistically significant (p \ 0.05) (Table 2). Of 349 patients underwent oocyte retrieval, 322 patients had embryo transfer: 143 in group A and 179 in group B. As depicted in Table 3, although the mean number of transferred embryos was similar, significantly
Table 1 Demographic data and stimulation outcome Group A GnRHant
Group B GnRHa
P value
No. of patients
148
201
Mean age (years) ± SD
35.2 ± 4.7
35.1 ± 4.9
0.29
Mean BMI ± SD
24.6 ± 1.7
25.1 ± 1.9
0.44
Duration of stimulation (days)
13 ± 2.2
14 ± 3.2
0.68
Total FSH dose (IU)
1,334 ± 562
2,318 ± 1091
0.03
Estradiol level on hCG day (pg/mL)
1,707 ± 701
1,677 ± 749
0.005
Endometrial thickness on hCG day (mm)
10.8 ± 2.1
10.6 ± 2.4
0.51
BMI body mass index, GnRHa gonadotropin-releasing hormone agonist, GnRHant gonadotropin-releasing hormone antagonist, hCG human chorionic gonadotropin
Table 3 Clinical outcome
Implantation rate (%)
21.5
14.5
0.05
Delivery rate/embryo transfer (%)
47 (32.8)
36 (20.1)
0.05
Miscarriage rate/embryo transfer (%)
7 (13.5)
6 (13)
0.48
higher implantation rate (p \ 0.05), pregnancy rate (p \ 0.05), and delivery rate (p \ 0.05) were observed in favor of groups A compared to group B, whereas miscarriage rate was comparable between the two groups. Twenty-four patients developed OHSS without needing hospitalization: 7 (4.7 %) patients in group A and 17 (8.4 %) patients in group B, this was not statistically significant.
Discussion Prevention or elimination of OHSS would remove the most serious and potentially life-threatening side effect of ART treatment. As reported in the literature different strategies have been adopted in a variety of IVF clinic in order to decrease the incidence of OHSS, among which coasting (FSH withdrawal) [20], intravenous albumin administration [21], reduction of the hCG dose or triggering ovulation with recombinant LH or GnRH agonist [22–24], and the
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administration of a dopamine agonist from the day of hCG administration [25]. Coasting, significant reduction or total withdrawal of exogenous gonadotrophins, has been demonstrated to reduce OHSS but it negatively affects the IVF depending upon when it is initiated and its duration [21, 26, 27]. This is likely to be due to the reduction in oocyte competence and consequently embryo quality, maturation arrest, follicle atresia, or inducing apoptotic changes in the granulosa cell cohort [28]. Another possible effect related to coasting is that it might reduce the follicular fluid’s vascular endothelial growth factor, which is implicated in the pathophysiology of OHSS [20, 29]. A recent Cochrane review, however, concluded that there was no evidence to suggest a benefit of coasting for preventing OHSS compared with no coasting or other interventions [30]. Some researchers have proposed the use of GnRH agonist for triggering final oocyte maturation with the aim to reduce the risk of developing OHSS. However, although the use of GnRH agonist for ovulation induction significantly reduce the risk of OHSS, it lowers significantly the live birth rate and ongoing pregnancy rate combined with a higher miscarriage rate as compared to the use of hCG [22, 24]. In addition, other researchers approached the administration of dopamine agonist (cabergoline) or albumin from the day of hCG administration in order to prevent the onset of OHSS. Available data demonstrated that administration of dopamine agonist was more effective than albumin for preventing OHSS [31–33]. Conversely, other study has shown that dopamine agonists cannot prevent late onset of OHSS, thus limiting the usefulness of this approach for the prevention of OHSS in patients at high risk [34]. Other fluids such as albumin or hydroxyethyl starch administered at time of oocyte retrieval have been extensively tested for the prevention of OHSS; however, the data available are conflicting regarding their potential benefit to prevent OHSS and on their effect on pregnancy rates [35–37]. Recently, the introduction of GnRH antagonist into clinical practice has allowed the use of a milder stimulation approaches, which are more physiological, less drug-oriented, less expensive, more patient friendly and the risks of the treatment are highly minimized [17, 18]. It has been argued that the use of milder stimulation protocols in routine clinical use would decrease ovarian response and pregnancy rate. However, increased efficacy in IVF laboratories and the current tendency to limit the number of embryo transferred have reduced the needs to large number of oocytes. On the other hand, conventional long protocol for ovarian stimulation with GnRH agonist combined with a ‘high dose’ of gonadotrophins produces a superphysiological steroid levels which have a potential negative effect on endometrium receptivity, corpus luteum function,
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oocyte, and embryo quality [38–40]. These evidences could indicate that limited ovarian stimulation and response might have a beneficial effect upon implantation and clinical outcome. Another aspect of employing mild ovarian stimulation protocol using GnRH antagonist combined with low dose of FSH that should be explored is its efficacy and safety when used to stimulate patients at high risk of developing OHSS. In the present study we attempt to use a mild/ minimal ovarian stimulation of patients at high risk of OHSS, using GnRH antagonist combined with low dose of FSH compared to conventional long down-regulation protocol with GnRH agonist. Our results show that although the stimulation duration (days) was similar between the two groups, statistically lower dose of FSH in favor of GnRH antagonist mild stimulation group compared to GnRH agonist long protocol group. This is because the dose of FSH used was lower, as defined by the mild protocol, in GnRH antagonist group compared to the GnRH agonist group where the FSH dose was practically doubled. Statistically higher estradiol level on the day of hCG administration was observed in favor of mild stimulation group compared to long protocol group. This was in contrast with other study which reports that using GnRH antagonists produce lower concentrations of peripheral oestradiol in the late follicular phase [11]. The difference in oestradiol level observed between the two studied groups may be linked to the different action between GnRH antagonist and agonist protocols. It has been shown that GnRH agonist down-regulation might result in profound suppression of peripheral LH, which may impair adequate oestradiol synthesis [41–44], whereas using GnRH antagonist the endogenous LH levels are higher enough to ensure higher circulating oestradiol levels particularly if it is not administered too early during stimulation [45]. Our results also demonstrate that GnRH antagonist mild stimulation protocol is as effective as GnRH agonist long protocol in terms of the mean number of oocytes retrieved per patient, mature metaphase II oocytes, fertilization rate and embryo cleavage rate, since that there were no significant difference observed between the two groups. Complete fertilization failure was observed in a significantly lower proportion (3.3 %) of patients stimulated with GnRH antagonist mild protocol with respect to patients stimulated with GnRH agonist protocol (10.8 %). This might be due to the fact that the majority of the cases at risk of OHSS risk are patients affected by PCOS who are more likely to exhibit either lower fertilization rate [46–48] or high incidence of unpredictable total failure of fertilization following ovarian stimulation than patients with other causes of infertility [49]. Moreover, it has been shown that profound suppression of peripheral LH, using GnRH
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agonist, as shown in group B, reduce estradiol synthesis, which negatively affect oocyte and embryo quality, resulting in a decreased fertilization rate and increasing risk of early pregnancy loss [41–44]. Further, our results show that milder stimulation protocol using GnRH antagonist achieved significantly higher implantation rate, pregnancy rate, and delivery rate compared to long stimulation protocol with GnRH agonist, although the mean number of transferred embryos was similar. This could indicate that milder stimulation regimens with GnRH antagonist may have a beneficial effect on oocyte and embryo quality, and subsequently on implantation potential and clinical outcome. Conventional long protocol using GnRH agonist and gonadotrophins increases oocyte yield but may compromise oocyte developmental competence in stimulated cycle. It is well-known that gonadotropin stimulation results in a modified steroid profile, thus altering the microenvironment of the developing follicle and their enclosed oocytes [50, 51]. There is some evidence that estradiol plays a key role in oocyte maturation as it exerts a beneficial effect on cytoplasmic maturation via a non-genomic calcium-mediated mechanism, which contribute to oocyte capacitation for fertilization and postfertilization development [52, 53]. Furthermore, profound suppression of LH has been shown to be associated with a reduced cohort of embryos and a reduced estradiol/oocyte ratio [42, 43]. Indeed, milder stimulation protocol with GnRH antagonist seems to have a positive effect on oocyte quality which is reflected in higher implantation and pregnancy rates when compared with standard long protocol with GnRH agonist. In addition, in our study a reduced incidence of patient’s who developed OHSS (4.7 %), though not statistically significant, was shown in mild stimulation group with respect to long protocol group (8.4 %). This could support previous study which demonstrated a favorable effect of GnRH antagonist in reducing the incidence of OHSS and the number of assisted fertilization cycles canceled because of the risk of OHSS in high responder patients, compared to conventional GnRH agonist protocols [11]. In conclusion, our study shows that mild/minimal stimulation regimen with GnRH antagonist is highly effective for ovarian stimulation of patients who have experienced OHSS complication and canceled during a previous IVF treatment cycle, without increasing the risk of OHSS, and it could be an attractive alternative protocol for ovarian stimulation of patients undergoing in vitro fertilization treatment.
Conflict of interest The authors L. Rinaldi, F. Lisi, and H. Selman declare that they have no conflict of interest.
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ORIGINAL ARTICLE
Mild/minimal stimulation protocol for ovarian stimulation of patients at high risk of developing ovarian hyperstimulation syndrome L. Rinaldi • F. Lisi • H. Selman
Received: 2 June 2013 / Accepted: 17 November 2013 / Published online: 8 January 2014 Ó Italian Society of Endocrinology (SIE) 2013
Abstract Background Recently, an increased scientific interest was focused on mild approaches for ovarian stimulation in clinical practice. Milder stimulation aims to develop safer and more patient-friendly protocols which are more physiological, less drug use, less expensive and the risks of treatment are highly minimized. Aim To investigate the efficacy and safety of a mild ovarian stimulation protocol in patients at high risk of developing ovarian hyperstimulation syndrome (OHSS), compared to conventional long down-regulation protocol. Subjects and methods This a prospective, open, randomized study, included 349 infertile patients considered at high risk of developing OHSS, undergoing in vitro fertilization treatment in two private assisted reproduction centers. The patients were randomized into two groups: group A (n = 148) had a mild/minimal stimulation protocol of recombinant FSH (rFSH) combined with GnRH antagonist. Group B (n = 201) (control group) had a standard long protocol of rFSH combined with GnRH agonist. Results There was no significant difference observed between the two groups regarding the mean number of oocytes retrieved per patient, mature metaphase II oocytes, fertilization rate, and embryo cleavage rate. Significantly higher implantation rate (21.5 vs 14.5 %) (p \ 0.05), pregnancy rate (37.7 vs 23.4 %) (p \ 0.05), and delivery
L. Rinaldi (&) H. Selman RISEL-One Day Medical Center, Via Attilio Ambrosini 114, 00147 Rome, Italy e-mail: [email protected] F. Lisi CERMER Clinica Villa Mafalda, Rome, Italy
rate (32.8 vs 20.1 %) (p \ 0.05) were observed in favor of groups A compared to group B. Lower proportion of patients (4.7 %), though not statistically significant, has developed OHSS in group A compared to group B (8.4 %). Conclusion Our study shows that mild stimulation regimen is highly effective for ovarian stimulation of patients who have experienced OHSS complication without increasing the risk of OHSS. Keywords Follicle-stimulating hormone GnRH antagonist GnRH agonist Ovarian stimulation Pregnancy OHSS Abbreviation OHSS Ovarian hyperstimulation syndrome rFSH Recombinant follicle-stimulating hormone IVF In vitro fertilization PCOS Polycystic ovarian syndrome
Introduction Ovarian stimulation is an integral procedure in assisted reproduction treatment. It is implemented with the aim to increase the number of oocytes yield for in vitro fertilization (IVF), thus enabling the selection of embryos for replacement [1]. For such purpose the use of gonadotropinreleasing hormone (GnRH) agonist for pituitary suppression combined with relatively high doses of exogenous follicle-stimulating hormone (FSH) is commonly employed for ovarian stimulation [2]. Such medication regimens take many weeks, are complex and expensive, and are not without risk. Problems related to ovarian stimulation include emotional stress, abdominal discomfort, short-term
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complications such as ovarian hyperstimulation syndrome (OHSS), multiple gestation, and uncertainties regarding long-term health consequences [3, 4]. Ovarian hyperstimulation syndrome is a potentially lifethreatening iatrogenic complication resulting from the use of hormonal therapy to artificially induce multiple follicular growth during IVF treatment. Extensive use of gonadotropin-releasing hormone (GnRH) down-regulation protocols for ovarian stimulation increases the risk of OHSS in infertile patients undergoing assisted fertilization treatment [5]. Although the incidence of severe forms of ovarian hyperstimulation syndrome is only 1–2 % [6, 7], OHSS remains the major significant source of morbidity and mortality in patients undergoing assisted reproduction technologies. It has been reported that the risk of OHSS is highly increased in polycystic ovarian syndrome (PCOS) or PCOS-like patients [5, 8, 9] and in women who have previously developed OHSS [10, 11]. The incidence and the duration of the syndrome are strictly related to the surge of pregnancy and the number of implanted embryos [12, 13]. A variety of preventive strategies have been adopted in order to reduce the risk of OHSS, but none of the described methods has consistently demonstrated efficacy in preventing the syndrome except for the cancelation of the treatment cycle before hCG administration [14–16]. Although the cycle cancelation is the most effective and safest approach, it is obviously frustrating and costly to the infertile couples, and a second attempt of ovarian stimulation may lead to the same risk. During last 15 years an increased scientific interest was focused on mild approaches for ovarian stimulation in clinical practice [17, 18]. Milder stimulation aims to develop safer and more patient-friendly protocols which are more physiological, less drug use, less expensive and the risks of treatment are highly minimized. Minimal or mild stimulation protocols are characterized by the administration of lower dose of gonadotrophins alone or in association with oral compounds such the antiestrogens (clomiphene citrate) following down-regulation with GnRH antagonist [19]. In this study, we report on the use of FSH in a mild ovarian stimulation of patients at high risk of OHSS downregulated either with GnRH antagonist or with GnRH agonist in order to determine any difference between protocols and to optimize the procedure.
Materials and methods In a prospective, open, randomized study, a total of 349 infertile patients aged 27–38 years, undergoing in vitro fertilization treatment in two private assisted reproduction
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centers from January 2008 to December 2012 were included. The patients had infertility attributable to tubal factor, moderate endometriosis, male factor, or idiopathic infertility. They exhibit serum hormonal profile within the normal range (FSH and LH \ 12 mIU/mL, estradiol \ 50 pg/mL, and prolactin \ 30 ng/mL); regular ovulatory menstrual cycles; presence of a normal uterine cavity; and body mass index (BMI) of 20–26 kg/m2. All patients were previously canceled because of a considerably high risk of developing OHSS following stimulation with a standard long GnRH agonist down-regulation protocol combined with gonadotropin. The patients were considered at high risk of developing OHSS if they had serum estradiol level C3,500 pg/mL on the day of hCG administration and [15 growing follicles ranging from intermediate size (\15 mm) to large size ([16 mm). The global incidence of OHSS risk was 2–3 % of all patients undergoing IVF treatment. The patients were randomized into two groups: group A (n = 148) had a mild/minimal stimulation protocol, 75 IU/ day of rFSH (Gonal F, Serono Italy), and 0.25 mg/day GnRH antagonist (Cetrorelix, Serono Italy) administered when the leading follicle was 14 mm. Group B (n = 201) had a standard ‘‘cautious’’ long protocol with GnRH agonist, 0.1 mg/day of triptorelin (Decapeptyl: Ipsen Milan, Italy) subcutaneously administered from the mid-luteal phase of the previous cycle for a minimum of 14 days, followed by 150 IU FSH as the lowest possible dose decided on the basis of the experience from the previous stimulation. The FSH dose was adjusted when necessary according to the follicular size and estradiol level. Final oocyte maturation was triggered by the administration of 10,000 IU of hCG (Gonasi HP, IBSA, Switzerland). Retrieved oocytes were assessed for their maturity and inseminated by standard IVF or intracytoplasmic sperm injection. Embryos were transferred on day 3 after oocyte insemination, no more than three embryos per patient were transferred. Luteal phase support was initiated on the day of oocyte retrieval using commercially available progesterone preparation (50 mg/mL i.m daily) (Prontogest, IBSA, Switzerland). Clinical pregnancy was confirmed 6 weeks after embryo transfer by ultrasonography. Randomization was performed using a computer-generated random assignment schedule for each patient. Sealed and numbered envelopes were used to conceal the treatment allocation until randomization. All patients were counseled about the nature of the study and gave their written informed consent for their participation to the randomization procedure. Participating patients were registered in our local ethical committee register that approved the study. Statistical analysis was performed using JMP software (version 4.0.4; SAS, Inc., Cary, NC, USA). For a desired
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statistical power of 90 % based on a level of 0.05, confidence intervals (CI) of 95 %, and anticipated effective size (Cohen’s D) of 0.5 (medium size), the minimum total sample size required according to two-tailed hypothesis was 172 patients—at least 86 evaluable patients per group. The parameters were compared by use of an analysis of variance (ANOVA) two-way test to analyze continuous variables. P B 0.05 was considered statistically significant. The data were analyzed using the two-tailed Student’s t test for independent data, Fisher’s exact test, and two-by-two table between groups where appropriate. All analyses were adjusted for age stratum in line with the study design.
Results
Table 2 Embryological characteristics Group A GnRHant
Group B GnRHa
P value
No. of patients
148
201
Mean number of retrieved oocytes ± SD
7.5 ± 3.7
6.8 ± 3.4
0.42
Mean number of inseminated MII oocytes ± SD
6.4 ± 3.2
5.5 ± 3.1
0.20
Mean number of fertilized 2PN oocytes ± SD
4.1 ± 2.5
3.9 ± 2.1
0.75
Fertilization rate %
74.6
64.7
0.67
Mean number of cleaved embryos ± SD Embryo cleavage rate %
3.4 ± 2.3
2.8 ± 2.1
0.80
78
73.6
0.52
Group A GnRHant
Group B GnRHa
P value
No. of patients underwent embryo transfer
143
179
Mean number of embryos per patient ± SD
2.2 ± 0.8
2 ± 0.9
0.49
Clinical pregnancies per embryo transfer (%)
54 (37.7 %)
42 (23.4 %)
0.05
MII Metaphase II oocytes
All studied patients (n = 349) underwent oocyte retrieval, 148 patients in group A and 201 in group B. No patient had poor ovarian response to gonadotropin treatment. The two groups were comparable regarding demographic data, duration of stimulation, and endometrium thickness. Statistically lower dose of FSH administered was observed in group A compared to group B (p \ 0.03), and significantly higher estradiol level on the day of hCG in favor of group A compared to group B (p \ 0.005) (Table 1). There was no significant difference observed between the two groups regarding the mean number of oocytes retrieved per patient, mature metaphase II oocytes, fertilization rate, and embryo cleavage rate. Five patients in group A (3.3 %) and 22 patients in group B (10.8 %) had complete fertilization failure, this was statistically significant (p \ 0.05) (Table 2). Of 349 patients underwent oocyte retrieval, 322 patients had embryo transfer: 143 in group A and 179 in group B. As depicted in Table 3, although the mean number of transferred embryos was similar, significantly
Table 1 Demographic data and stimulation outcome Group A GnRHant
Group B GnRHa
P value
No. of patients
148
201
Mean age (years) ± SD
35.2 ± 4.7
35.1 ± 4.9
0.29
Mean BMI ± SD
24.6 ± 1.7
25.1 ± 1.9
0.44
Duration of stimulation (days)
13 ± 2.2
14 ± 3.2
0.68
Total FSH dose (IU)
1,334 ± 562
2,318 ± 1091
0.03
Estradiol level on hCG day (pg/mL)
1,707 ± 701
1,677 ± 749
0.005
Endometrial thickness on hCG day (mm)
10.8 ± 2.1
10.6 ± 2.4
0.51
BMI body mass index, GnRHa gonadotropin-releasing hormone agonist, GnRHant gonadotropin-releasing hormone antagonist, hCG human chorionic gonadotropin
Table 3 Clinical outcome
Implantation rate (%)
21.5
14.5
0.05
Delivery rate/embryo transfer (%)
47 (32.8)
36 (20.1)
0.05
Miscarriage rate/embryo transfer (%)
7 (13.5)
6 (13)
0.48
higher implantation rate (p \ 0.05), pregnancy rate (p \ 0.05), and delivery rate (p \ 0.05) were observed in favor of groups A compared to group B, whereas miscarriage rate was comparable between the two groups. Twenty-four patients developed OHSS without needing hospitalization: 7 (4.7 %) patients in group A and 17 (8.4 %) patients in group B, this was not statistically significant.
Discussion Prevention or elimination of OHSS would remove the most serious and potentially life-threatening side effect of ART treatment. As reported in the literature different strategies have been adopted in a variety of IVF clinic in order to decrease the incidence of OHSS, among which coasting (FSH withdrawal) [20], intravenous albumin administration [21], reduction of the hCG dose or triggering ovulation with recombinant LH or GnRH agonist [22–24], and the
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administration of a dopamine agonist from the day of hCG administration [25]. Coasting, significant reduction or total withdrawal of exogenous gonadotrophins, has been demonstrated to reduce OHSS but it negatively affects the IVF depending upon when it is initiated and its duration [21, 26, 27]. This is likely to be due to the reduction in oocyte competence and consequently embryo quality, maturation arrest, follicle atresia, or inducing apoptotic changes in the granulosa cell cohort [28]. Another possible effect related to coasting is that it might reduce the follicular fluid’s vascular endothelial growth factor, which is implicated in the pathophysiology of OHSS [20, 29]. A recent Cochrane review, however, concluded that there was no evidence to suggest a benefit of coasting for preventing OHSS compared with no coasting or other interventions [30]. Some researchers have proposed the use of GnRH agonist for triggering final oocyte maturation with the aim to reduce the risk of developing OHSS. However, although the use of GnRH agonist for ovulation induction significantly reduce the risk of OHSS, it lowers significantly the live birth rate and ongoing pregnancy rate combined with a higher miscarriage rate as compared to the use of hCG [22, 24]. In addition, other researchers approached the administration of dopamine agonist (cabergoline) or albumin from the day of hCG administration in order to prevent the onset of OHSS. Available data demonstrated that administration of dopamine agonist was more effective than albumin for preventing OHSS [31–33]. Conversely, other study has shown that dopamine agonists cannot prevent late onset of OHSS, thus limiting the usefulness of this approach for the prevention of OHSS in patients at high risk [34]. Other fluids such as albumin or hydroxyethyl starch administered at time of oocyte retrieval have been extensively tested for the prevention of OHSS; however, the data available are conflicting regarding their potential benefit to prevent OHSS and on their effect on pregnancy rates [35–37]. Recently, the introduction of GnRH antagonist into clinical practice has allowed the use of a milder stimulation approaches, which are more physiological, less drug-oriented, less expensive, more patient friendly and the risks of the treatment are highly minimized [17, 18]. It has been argued that the use of milder stimulation protocols in routine clinical use would decrease ovarian response and pregnancy rate. However, increased efficacy in IVF laboratories and the current tendency to limit the number of embryo transferred have reduced the needs to large number of oocytes. On the other hand, conventional long protocol for ovarian stimulation with GnRH agonist combined with a ‘high dose’ of gonadotrophins produces a superphysiological steroid levels which have a potential negative effect on endometrium receptivity, corpus luteum function,
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oocyte, and embryo quality [38–40]. These evidences could indicate that limited ovarian stimulation and response might have a beneficial effect upon implantation and clinical outcome. Another aspect of employing mild ovarian stimulation protocol using GnRH antagonist combined with low dose of FSH that should be explored is its efficacy and safety when used to stimulate patients at high risk of developing OHSS. In the present study we attempt to use a mild/ minimal ovarian stimulation of patients at high risk of OHSS, using GnRH antagonist combined with low dose of FSH compared to conventional long down-regulation protocol with GnRH agonist. Our results show that although the stimulation duration (days) was similar between the two groups, statistically lower dose of FSH in favor of GnRH antagonist mild stimulation group compared to GnRH agonist long protocol group. This is because the dose of FSH used was lower, as defined by the mild protocol, in GnRH antagonist group compared to the GnRH agonist group where the FSH dose was practically doubled. Statistically higher estradiol level on the day of hCG administration was observed in favor of mild stimulation group compared to long protocol group. This was in contrast with other study which reports that using GnRH antagonists produce lower concentrations of peripheral oestradiol in the late follicular phase [11]. The difference in oestradiol level observed between the two studied groups may be linked to the different action between GnRH antagonist and agonist protocols. It has been shown that GnRH agonist down-regulation might result in profound suppression of peripheral LH, which may impair adequate oestradiol synthesis [41–44], whereas using GnRH antagonist the endogenous LH levels are higher enough to ensure higher circulating oestradiol levels particularly if it is not administered too early during stimulation [45]. Our results also demonstrate that GnRH antagonist mild stimulation protocol is as effective as GnRH agonist long protocol in terms of the mean number of oocytes retrieved per patient, mature metaphase II oocytes, fertilization rate and embryo cleavage rate, since that there were no significant difference observed between the two groups. Complete fertilization failure was observed in a significantly lower proportion (3.3 %) of patients stimulated with GnRH antagonist mild protocol with respect to patients stimulated with GnRH agonist protocol (10.8 %). This might be due to the fact that the majority of the cases at risk of OHSS risk are patients affected by PCOS who are more likely to exhibit either lower fertilization rate [46–48] or high incidence of unpredictable total failure of fertilization following ovarian stimulation than patients with other causes of infertility [49]. Moreover, it has been shown that profound suppression of peripheral LH, using GnRH
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agonist, as shown in group B, reduce estradiol synthesis, which negatively affect oocyte and embryo quality, resulting in a decreased fertilization rate and increasing risk of early pregnancy loss [41–44]. Further, our results show that milder stimulation protocol using GnRH antagonist achieved significantly higher implantation rate, pregnancy rate, and delivery rate compared to long stimulation protocol with GnRH agonist, although the mean number of transferred embryos was similar. This could indicate that milder stimulation regimens with GnRH antagonist may have a beneficial effect on oocyte and embryo quality, and subsequently on implantation potential and clinical outcome. Conventional long protocol using GnRH agonist and gonadotrophins increases oocyte yield but may compromise oocyte developmental competence in stimulated cycle. It is well-known that gonadotropin stimulation results in a modified steroid profile, thus altering the microenvironment of the developing follicle and their enclosed oocytes [50, 51]. There is some evidence that estradiol plays a key role in oocyte maturation as it exerts a beneficial effect on cytoplasmic maturation via a non-genomic calcium-mediated mechanism, which contribute to oocyte capacitation for fertilization and postfertilization development [52, 53]. Furthermore, profound suppression of LH has been shown to be associated with a reduced cohort of embryos and a reduced estradiol/oocyte ratio [42, 43]. Indeed, milder stimulation protocol with GnRH antagonist seems to have a positive effect on oocyte quality which is reflected in higher implantation and pregnancy rates when compared with standard long protocol with GnRH agonist. In addition, in our study a reduced incidence of patient’s who developed OHSS (4.7 %), though not statistically significant, was shown in mild stimulation group with respect to long protocol group (8.4 %). This could support previous study which demonstrated a favorable effect of GnRH antagonist in reducing the incidence of OHSS and the number of assisted fertilization cycles canceled because of the risk of OHSS in high responder patients, compared to conventional GnRH agonist protocols [11]. In conclusion, our study shows that mild/minimal stimulation regimen with GnRH antagonist is highly effective for ovarian stimulation of patients who have experienced OHSS complication and canceled during a previous IVF treatment cycle, without increasing the risk of OHSS, and it could be an attractive alternative protocol for ovarian stimulation of patients undergoing in vitro fertilization treatment.
Conflict of interest The authors L. Rinaldi, F. Lisi, and H. Selman declare that they have no conflict of interest.
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