Abstract
Are oocyte maturation rates different among 0.1, 0.2 and 0.4 mg triptorelin used for triggering final oocyte maturation in patients at high risk for ovarian hyperstimulation syndrome (OHSS) undergoing ICSI?
A dose of 0.1 mg triptorelin results in similar oocyte maturation rates compared to higher doses of 0.2 and 0.4 mg in patients at high risk for OHSS undergoing ICSI.
The GnRH agonist triptorelin is widely used instead of hCG for triggering final oocyte maturation, in order to eliminate the risk of severe OHSS in patients undergoing ovarian stimulation for IVF/ICSI. However, limited data are currently available regarding its optimal dose use for this purpose in patients at high risk for OHSS.
A retrospective study was performed between November 2015 and July 2017 in 131 infertile patients at high risk for severe OHSS undergoing ovarian stimulation for ICSI. High risk for severe OHSS was defined as the presence of at least 19 follicles ≥11 mm in diameter on the day of triggering final oocyte maturation.
Ovarian stimulation was performed with recombinant FSH and GnRH antagonists. Patients received 0.1 (n = 42), 0.2 (n = 46) or 0.4 mg (n = 43) triptorelin for triggering final oocyte maturation. Hormonal evaluation of FSH, LH, estradiol (E2) and progesterone (PRG) was carried out on the day of triggering final oocyte maturation, 8 and 36 hours post triggering and 3, 5, 7, and 10 days after triptorelin administration. During this period, all patients were assessed for symptoms and signs indicative of severe OHSS development. Primary outcome measure was oocyte maturation rate, defined as the number of metaphase II (MII) oocytes divided by the number of cumulus-oocyte-complexes retrieved per patient. Results are expressed as median (interquartile range).
No significant differences in patient baseline characteristics were observed among the 0.1 mg, the 0.2 mg and the 0.4 mg groups. Regarding the primary outcome measure, no differences were observed in oocyte maturation rate among the three groups compared [82.6% (17.8%) versus 83.3% (18.8%) versus 85.1% (17.2%), respectively, P = 0.686].
In addition, no significant differences were present among the 0.1 mg, 0.2 mg and 0.4 mg groups, regarding the number of mature (MII) oocytes [21 (13) versus 20 (6) versus 20 (11), respectively; P = 0.582], the number of oocytes retrieved [25.5 (13) versus 24.5 (11) versus 23 (12), respectively; P = 0.452], oocyte retrieval rate [81.0% (17.7%) versus 76.5% (23.5%) versus 75.0% (22.5), respectively; P = 0.088], the number of fertilized (two pronuclei) oocytes [12.5 (9) versus 14.5 (7) versus 14.0 (8), respectively; P = 0.985], fertilization rate [71.7% (22%) versus 77.1% (19.1%) versus 76.6% (23.3%), respectively; P = 0.525] and duration of luteal phase [7 (1) versus 8 (2) versus 7 (1) days, respectively; P = 0.632]. Moreover, no significant differences were present among the three triptorelin groups regarding serum levels of LH, FSH, E2 and PRG at any of the time points assessed following triggering of final oocyte maturation.
This is a retrospective study, and although there were no differences in the baseline characteristics of the three groups compared, the presence of bias cannot be excluded.
Based on the results of the current study, it appears that triggering final oocyte maturation with a lower (0.1 mg) or a higher dose (0.4 mg) of triptorelin, as compared to the most commonly used dose of 0.2 mg, does not confer any benefit in terms of oocyte maturation rate in patients at high risk for severe OHSS.
No external funding was obtained for this study. There are no conflicts of interest.
Introduction
The incidence of severe ovarian hyperstimulation syndrome (OHSS) in high-risk patients ranges from 10% to 38% (Asch et al., 1991; Kolibianakis et al., 2012; Morris et al., 1995; Swanton et al., 2010). The increased morbidity and mortality associated with the syndrome (Bowyer, 2008) renders OHSS the most serious iatrogenic complication of ovarian stimulation for IVF.
The syndrome is triggered by hCG (Aboulghar and Mansour, 2003; Rizk and Aboulghar, 1999) and is largely due to excessive ovarian secretion of angiogenic factors, such as vascular endothelial growth factor (VEGF). VEGF increases vascular permeability, causing fluid shift from the intravascular to the third space, leading to ascites formation (Rizk et al., 1997).
The most efficient strategy for OHSS prevention is the replacement of hCG with GnRH agonist for triggering final oocyte maturation and the postponement of embryo transfer by freezing of all oocytes/embryos (Devroey et al., 2011; Youssef et al., 2014). Induction of luteolysis of the developing corpora lutea, and thus OHSS elimination, is due to the very short duration of the LH peak in the absence of exogenous hCG in the luteal phase (Humaidan et al., 2012).
Several different types and doses of GnRH agonists have been used to trigger final oocyte maturation, including s.c. administration of triptorelin 0.2 mg (Bodri et al., 2009; Hernandez et al., 2009); buserelin 0.2 mg (Pirard et al., 2006), 0.5 mg (Borgbo et al., 2013) or 1 mg (Seyhan et al., 2013); leuprolide acetate 0.5 mg (Fauser et al., 2002), 1 mg (Engmann et al., 2008) or 1.5 mg (Castillo et al., 2010); nafarelin 400 μg (Parneix et al., 2001); and intranasal administration of buserelin 0.2 mg (Pirard et al., 2015).
Although the most commonly used GnRH agonist for triggering final oocyte maturation is triptorelin (Fauser et al., 2002; Humaidan et al., 2011), data on its optimal dose are currently limited. A previous study performed in IUI patients treated with urinary FSH evaluated the luteal phase after administration of different doses of triptorelin for ovulation induction with or without luteal phase support (Emperaire et al., 2004). In patients undergoing ovarian stimulation for IVF there is only one dose-finding study, performed in a group of Asian oocyte donors with normal ovarian reserve and stimulated with GnRH antagonists and corifollitropin alpha (Elonva). Using three different doses of triptorelin (0.2, 0.3 and 0.4 mg), similar oocyte maturation rates were reported. In that study, however, patients with polycystic ovary syndrome (PCOS) were excluded (Vuong et al., 2016).
It is well known that ovarian stimulation in patients with PCOS can lead to an excessive ovarian response. These patients represent a high-risk group for developing severe OHSS and are an obvious target group for triggering final oocyte maturation with GnRH agonist. This is also true when polycystic ovary morphology (PCOM) is present even without the diagnosis of the syndrome (MacDougall et al., 1992; Swanton et al., 2010), since these ovaries still respond excessively to stimulation (MacDougall et al., 1992).
The aim of the present study was to compare oocyte maturation rates following triggering with three different doses of triptorelin (0.1, 0.2 and 0.4 mg) in patients at high risk for severe OHSS.
Materials and Methods
Patient population
The current retrospective study included patients who underwent ovarian stimulation for ICSI and were at high risk for severe OHSS on the day of triggering. Patients were treated between 2015 and 2017 at Eugonia Assisted Reproduction Unit, Athens, Greece. Patients considered at high risk for severe OHSS were those with at least 19 follicles greater than 11 mm present on the day of triggering final oocyte maturation (Griesinger et al., 2016).
As a standard policy in our unit, patients at high risk for severe OHSS, following extensive consultation, are encouraged to freeze all embryos after triggering of final oocyte maturation with GnRH agonist. This is because GnRH agonist triggering in these patients has been associated with virtual elimination of severe OHSS (Devroey et al., 2011). During the study period and in the absence of a dose finding study, patients were triggered with three different doses of the GnRH agonist triptorelin. Initially, the most commonly used dose of 0.2 mg was administered (Acevedo et al., 2006; Babayof et al., 2006; Fauser et al., 2002; Melo et al., 2009) and subsequently a lower 0.1 mg and a higher dose 0.4 mg were used.
Patients could be included only once in the analysis. Patients in whom hCG was administered to trigger final oocyte maturation, those receiving GnRH agonist trigger plus aggressive luteal support aiming for fresh embryo transfer (Gurbuz et al., 2016) and those treated by conventional IVF, were not included in the analysis. Inclusion of only patients who had ICSI performed aimed to allow assessment of oocyte maturity following GnRH agonist triggering.
Initially, 150 eligible patients were included in the study. A total of 131 patients with a complete set of data were included in the final analysis, as 19 were excluded from the analysis owing to missing data or incomplete follow up.
The institutional review board of the Eugonia ART Unit provided approval for this retrospective study (approval number 01/07-01-19).
Patient-written informed consent was not required owing to the retrospective nature of the study.
Ovarian stimulation
Ovarian stimulation was performed with a starting dose of 150 IU/day of recombinant FSH (recFSH, Gonal-F; Merck Serono, Geneva, Switzerland). This dose was adjusted after Day 5 of stimulation, depending on the ovarian response, as assessed by estradiol (E2) levels and ultrasound (Fig. 1).
Controlled ovarian stimulation and monitoring. Schematic representation of controlled ovarian stimulation and hormonal evaluation time points.
For suppression of a premature LH surge, a flexible GnRH antagonist protocol was used, as described previously (Lainas et al., 2010). Daily s.c. administration of 0.25 mg of the GnRH antagonist Cetrorelix (Merck Serono, Geneva, Switzerland) was initiated when at least one of the following criteria were fulfilled: the presence of at least one follicle measuring 14 mm; serum E2 levels ≥600 pg/ml; and serum LH levels ≥10 IU/l (Lainas et al., 2005).
When three or more follicles with a mean diameter ≥ 17 mm were present, triggering of final oocyte maturation with GnRH agonist triptorelin was performed. Transvaginal ultrasound-guided oocyte retrieval was performed 35–36 hours later.
No luteal phase support was administered in any of the patients analyzed.
Fertilization/vitrification
Mature oocytes were fertilized by ICSI and embryos were maintained in culture until the blastocyst stage in sequential media (Origio, Malov, Denmark). All resulting blastocysts were vitrified.
Patient follow-up
Since GnRH agonist triggering for final oocyte maturation was a relatively new method and accumulation of experience was desirable, all patients at high risk for OHSS treated with GnRH agonist triggering were followed up until menstruation. During this period patients were assessed for symptoms and signs indicative of OHSS development, as well as by hormonal evaluation of FSH, LH, E2 and PRG on the day of triggering, 8 and 36 hours post triggering, and 3, 5, 7, and 10 days following triptorelin administration (Fig. 1).
Ultrasound and laboratory assessment
All ultrasound measurements were performed using a 7.5 or 6 or 5 MHz vaginal probe (Sonoline Adara, Siemens). FSH, LH, E2 and PRG levels were measured using an Immulite analyzer and commercially available kits (DPC, Los Angeles, CA, USA). Analytical sensitivity was 0.1 mIU/ml for FSH, 0.1 mIU/ml for LH, 15 pg/ml for E2 and 0.2 ng/ml for PRG. Intra- and inter-assay precision at the concentrations of most relevance to the current study (expressed as coefficients of variation) were 2.6% and 5.8% for FSH, 5.9% and 8.1% for LH, 6.3% and 6.4% for E2 and 7.9% and 10% for PRG, respectively.
Outcome measures
The primary outcome measure was oocyte maturation rate, defined as the number of metaphase II (MII) oocytes divided by the number of cumulus-oocyte-complexes (COCs) retrieved per patient. Secondary outcomes measures included number of COCs retrieved, MII oocytes, oocytes with two pronuclei (2PN), oocyte recovery rate (COCs/follicles ≥11 mm on the day of triggering final oocyte maturation), fertilization rate (2PN/MII), duration of luteal phase (number of days from oocyte retrieval until menstruation), incidence of early-onset severe OHSS, serum concentrations of LH, FSH, E2 and PRG measured at 8 and 36 hours and 3, 5, 7 and 10 days after triptorelin administration.
Statistical analysis
Continuous variables are described using median and interquartile range (IQR) due to their non-normal distribution. Dichotomous variables are expressed as proportions. Analysis of continuous variables was performed using non-parametric tests (Kruskal–Wallis). Dichotomous or categorical variables were compared using chi-square test. The time course of hormone concentrations post-triggering was analyzed using generalized estimating equations. All analyses were performed using the SPSS statistical package (Version 22; SPSS Inc., Chicago, IL, USA). The level of significance was set at P < 0.05. Values are expressed as median and IQR unless stated otherwise.
Baseline and stimulation characteristics in the 0.1, 0.2 and 0.4 groups of triptorelin.
| Triptorelin 0.1 mg (n = 42) | Triptorelin 0.2 mg (n = 46) | Triptorelin 0.4 mg (n = 43) | P-value | |
|---|---|---|---|---|
| Median (interquartile range) | ||||
| Age (years) | 32.0 (6) | 32.5 (10) | 33.0 (6) | 0.495 |
| BMI (kg/m2) | 22.4 (3.3) | 22.8 (5.0) | 24.0 (5.0) | 0.133 |
| Duration of infertility (years) | 3.0 (4) | 2.0 (5) | 2.0 (3) | 0.894 |
| Previous attempts | 0 (1) | 0 (2) | 0 (1) | 0.422 |
| Basal FSH (IU/l) | 6.1 (2.3) | 6 (2.7) | 6.2 (2.2) | 0.555 |
| Basal LH (IU/l) | 5.3 (2.2) | 5.4 (3.1) | 4.8 (2.9) | 0.138 |
| Basal E2 (pg/ml) | 39.5 (18.0) | 46.8 (21.3) | 36.3 (16.2) | 0.087 |
| Basal PRG (ng/ml) | 0.53 (0.50) | 0.68 (0.40) | 0.52 (0.40) | 0.320 |
| AMH (ng/ml) | 7.7 (5.5) | 7.2 (8.0) | 7.1 (5.1) | 0.931 |
| AFC | 23.0 (4) | 23.0 (4) | 23.0 (6) | 0.774 |
| Duration of stimulation (days) | 11.0 (2) | 11.0 (2) | 11.0 (2) | 0.146 |
| Total dose of recFSH (IU/l) | 1600.0 (484) | 1612.5 (438) | 1775 (800) | 0.271 |
| Number of follicles >11 mm (day of triggering) | 30.0 (10) | 34.5 (14) | 30.0 (17) | 0.569 |
| Triptorelin 0.1 mg (n = 42) | Triptorelin 0.2 mg (n = 46) | Triptorelin 0.4 mg (n = 43) | P-value | |
|---|---|---|---|---|
| Median (interquartile range) | ||||
| Age (years) | 32.0 (6) | 32.5 (10) | 33.0 (6) | 0.495 |
| BMI (kg/m2) | 22.4 (3.3) | 22.8 (5.0) | 24.0 (5.0) | 0.133 |
| Duration of infertility (years) | 3.0 (4) | 2.0 (5) | 2.0 (3) | 0.894 |
| Previous attempts | 0 (1) | 0 (2) | 0 (1) | 0.422 |
| Basal FSH (IU/l) | 6.1 (2.3) | 6 (2.7) | 6.2 (2.2) | 0.555 |
| Basal LH (IU/l) | 5.3 (2.2) | 5.4 (3.1) | 4.8 (2.9) | 0.138 |
| Basal E2 (pg/ml) | 39.5 (18.0) | 46.8 (21.3) | 36.3 (16.2) | 0.087 |
| Basal PRG (ng/ml) | 0.53 (0.50) | 0.68 (0.40) | 0.52 (0.40) | 0.320 |
| AMH (ng/ml) | 7.7 (5.5) | 7.2 (8.0) | 7.1 (5.1) | 0.931 |
| AFC | 23.0 (4) | 23.0 (4) | 23.0 (6) | 0.774 |
| Duration of stimulation (days) | 11.0 (2) | 11.0 (2) | 11.0 (2) | 0.146 |
| Total dose of recFSH (IU/l) | 1600.0 (484) | 1612.5 (438) | 1775 (800) | 0.271 |
| Number of follicles >11 mm (day of triggering) | 30.0 (10) | 34.5 (14) | 30.0 (17) | 0.569 |
Statistical analysis was performed using non-parametric test (Kruskal–Wallis).
E2, estradiol; PRG, progesterone; AMH, anti-Mullerian hormone; AFC, antral follicle count; Rec FSH, recombinant FSH.
Baseline and stimulation characteristics in the 0.1, 0.2 and 0.4 groups of triptorelin.
| Triptorelin 0.1 mg (n = 42) | Triptorelin 0.2 mg (n = 46) | Triptorelin 0.4 mg (n = 43) | P-value | |
|---|---|---|---|---|
| Median (interquartile range) | ||||
| Age (years) | 32.0 (6) | 32.5 (10) | 33.0 (6) | 0.495 |
| BMI (kg/m2) | 22.4 (3.3) | 22.8 (5.0) | 24.0 (5.0) | 0.133 |
| Duration of infertility (years) | 3.0 (4) | 2.0 (5) | 2.0 (3) | 0.894 |
| Previous attempts | 0 (1) | 0 (2) | 0 (1) | 0.422 |
| Basal FSH (IU/l) | 6.1 (2.3) | 6 (2.7) | 6.2 (2.2) | 0.555 |
| Basal LH (IU/l) | 5.3 (2.2) | 5.4 (3.1) | 4.8 (2.9) | 0.138 |
| Basal E2 (pg/ml) | 39.5 (18.0) | 46.8 (21.3) | 36.3 (16.2) | 0.087 |
| Basal PRG (ng/ml) | 0.53 (0.50) | 0.68 (0.40) | 0.52 (0.40) | 0.320 |
| AMH (ng/ml) | 7.7 (5.5) | 7.2 (8.0) | 7.1 (5.1) | 0.931 |
| AFC | 23.0 (4) | 23.0 (4) | 23.0 (6) | 0.774 |
| Duration of stimulation (days) | 11.0 (2) | 11.0 (2) | 11.0 (2) | 0.146 |
| Total dose of recFSH (IU/l) | 1600.0 (484) | 1612.5 (438) | 1775 (800) | 0.271 |
| Number of follicles >11 mm (day of triggering) | 30.0 (10) | 34.5 (14) | 30.0 (17) | 0.569 |
| Triptorelin 0.1 mg (n = 42) | Triptorelin 0.2 mg (n = 46) | Triptorelin 0.4 mg (n = 43) | P-value | |
|---|---|---|---|---|
| Median (interquartile range) | ||||
| Age (years) | 32.0 (6) | 32.5 (10) | 33.0 (6) | 0.495 |
| BMI (kg/m2) | 22.4 (3.3) | 22.8 (5.0) | 24.0 (5.0) | 0.133 |
| Duration of infertility (years) | 3.0 (4) | 2.0 (5) | 2.0 (3) | 0.894 |
| Previous attempts | 0 (1) | 0 (2) | 0 (1) | 0.422 |
| Basal FSH (IU/l) | 6.1 (2.3) | 6 (2.7) | 6.2 (2.2) | 0.555 |
| Basal LH (IU/l) | 5.3 (2.2) | 5.4 (3.1) | 4.8 (2.9) | 0.138 |
| Basal E2 (pg/ml) | 39.5 (18.0) | 46.8 (21.3) | 36.3 (16.2) | 0.087 |
| Basal PRG (ng/ml) | 0.53 (0.50) | 0.68 (0.40) | 0.52 (0.40) | 0.320 |
| AMH (ng/ml) | 7.7 (5.5) | 7.2 (8.0) | 7.1 (5.1) | 0.931 |
| AFC | 23.0 (4) | 23.0 (4) | 23.0 (6) | 0.774 |
| Duration of stimulation (days) | 11.0 (2) | 11.0 (2) | 11.0 (2) | 0.146 |
| Total dose of recFSH (IU/l) | 1600.0 (484) | 1612.5 (438) | 1775 (800) | 0.271 |
| Number of follicles >11 mm (day of triggering) | 30.0 (10) | 34.5 (14) | 30.0 (17) | 0.569 |
Statistical analysis was performed using non-parametric test (Kruskal–Wallis).
E2, estradiol; PRG, progesterone; AMH, anti-Mullerian hormone; AFC, antral follicle count; Rec FSH, recombinant FSH.
Results
Patient population
A total of 131 patients at high risk for severe OHSS were included in the analysis. The patients were triggered with 0.1 mg (n = 42), 0.2 mg (n = 46), or 0.4 mg (n = 43) triptorelin.
Patient baseline characteristics were similar among the 0.1 mg, 0.2 mg and 0.4 mg triptorelin groups (Table I). In addition, no significant differences were observed between the triptorelin groups regarding duration of stimulation, total dose of recFSH and the number of follicles ≥11 mm present on the day of triggering (Table I).
Primary outcome
Regarding the primary outcome, no differences were observed among the 0.1 mg, 0.2 mg and 0.4 mg groups for oocyte maturation rate [82.6% (17.8%) versus 83.3% (18.8%) versus 85.1% (17.2%), respectively, P = 0.686] (Table II).
Secondary outcomes
The number of mature (MII) oocytes [21 (13) versus 20 (6) versus 20 (11), P = 0.582], the number of oocytes retrieved [25.5 (13) versus 24.5 (11) versus 23 (12), P = 0.452], oocyte retrieval rate [81.0% (17.7%) versus 76.5% (23.5%) versus 75.0% (22.5%), P = 0.088], the number of fertilized (2PN) oocytes [12.5 (9) versus 14.5 (7) versus 14.0 (8), P = 0.985], fertilization rate [71.7% (22%) versus 77.1% (19.1%) versus 76.6% (23.3%), P = 0.525] and duration of the luteal phase [7 (1) versus 8 (2) versus 7 (1) days, P = 0.632] were similar among the 0.1 mg, 0.2 mg and 0.4 mg groups, respectively (Table II). No patient was diagnosed with severe early OHSS in any of the three groups of triptorelin compared.
Primary and secondary outcome measures in the 0.1, 0.2 and 0.4 mg groups of triptorelin.
| Triptorelin 0.1 mg (n = 42) | Triptorelin 0.2 mg (n = 46) | Triptorelin 0.4 mg (n = 43) | P-value | |
|---|---|---|---|---|
| Median (interquartile range) | ||||
| Oocyte maturation rate % | 82.6 (17.8) | 83.3 (18.8) | 85.1 (17.2) | 0.686 |
| COCs retrieved | 25.5 (13) | 24.5 (11) | 23.0 (12) | 0.452 |
| Metaphase II | 21.0 (13) | 20.0 (6) | 20.0 (11) | 0.582 |
| 2PN | 12.5 (9) | 14.5 (7) | 14.0 (8) | 0.985 |
| Recovery rate, % | 81.0 (17.7) | 76.5 (23.5) | 75.0 (22.5) | 0.088 |
| Fertilization rate, % | 71.7 (22.0) | 77.1 (19.1) | 76.6 (23.3) | 0.525 |
| Duration of luteal phase (days)* | 7.0 (1) | 8.0 (2) | 7.0 (1) | 0.712 |
| Triptorelin 0.1 mg (n = 42) | Triptorelin 0.2 mg (n = 46) | Triptorelin 0.4 mg (n = 43) | P-value | |
|---|---|---|---|---|
| Median (interquartile range) | ||||
| Oocyte maturation rate % | 82.6 (17.8) | 83.3 (18.8) | 85.1 (17.2) | 0.686 |
| COCs retrieved | 25.5 (13) | 24.5 (11) | 23.0 (12) | 0.452 |
| Metaphase II | 21.0 (13) | 20.0 (6) | 20.0 (11) | 0.582 |
| 2PN | 12.5 (9) | 14.5 (7) | 14.0 (8) | 0.985 |
| Recovery rate, % | 81.0 (17.7) | 76.5 (23.5) | 75.0 (22.5) | 0.088 |
| Fertilization rate, % | 71.7 (22.0) | 77.1 (19.1) | 76.6 (23.3) | 0.525 |
| Duration of luteal phase (days)* | 7.0 (1) | 8.0 (2) | 7.0 (1) | 0.712 |
Statistical analysis was performed using non-parametric tests (Kruskal-Wallis).
COC, cumulus-oocyte complex; 2PN, two pronuclei.
*Duration of luteal phase defined as the number of days from oocyte retrieval until menstruation.
Primary and secondary outcome measures in the 0.1, 0.2 and 0.4 mg groups of triptorelin.
| Triptorelin 0.1 mg (n = 42) | Triptorelin 0.2 mg (n = 46) | Triptorelin 0.4 mg (n = 43) | P-value | |
|---|---|---|---|---|
| Median (interquartile range) | ||||
| Oocyte maturation rate % | 82.6 (17.8) | 83.3 (18.8) | 85.1 (17.2) | 0.686 |
| COCs retrieved | 25.5 (13) | 24.5 (11) | 23.0 (12) | 0.452 |
| Metaphase II | 21.0 (13) | 20.0 (6) | 20.0 (11) | 0.582 |
| 2PN | 12.5 (9) | 14.5 (7) | 14.0 (8) | 0.985 |
| Recovery rate, % | 81.0 (17.7) | 76.5 (23.5) | 75.0 (22.5) | 0.088 |
| Fertilization rate, % | 71.7 (22.0) | 77.1 (19.1) | 76.6 (23.3) | 0.525 |
| Duration of luteal phase (days)* | 7.0 (1) | 8.0 (2) | 7.0 (1) | 0.712 |
| Triptorelin 0.1 mg (n = 42) | Triptorelin 0.2 mg (n = 46) | Triptorelin 0.4 mg (n = 43) | P-value | |
|---|---|---|---|---|
| Median (interquartile range) | ||||
| Oocyte maturation rate % | 82.6 (17.8) | 83.3 (18.8) | 85.1 (17.2) | 0.686 |
| COCs retrieved | 25.5 (13) | 24.5 (11) | 23.0 (12) | 0.452 |
| Metaphase II | 21.0 (13) | 20.0 (6) | 20.0 (11) | 0.582 |
| 2PN | 12.5 (9) | 14.5 (7) | 14.0 (8) | 0.985 |
| Recovery rate, % | 81.0 (17.7) | 76.5 (23.5) | 75.0 (22.5) | 0.088 |
| Fertilization rate, % | 71.7 (22.0) | 77.1 (19.1) | 76.6 (23.3) | 0.525 |
| Duration of luteal phase (days)* | 7.0 (1) | 8.0 (2) | 7.0 (1) | 0.712 |
Statistical analysis was performed using non-parametric tests (Kruskal-Wallis).
COC, cumulus-oocyte complex; 2PN, two pronuclei.
*Duration of luteal phase defined as the number of days from oocyte retrieval until menstruation.
Hormonal profiles after triggering
No significant differences in serum levels of LH, FSH, E2 and PRG were present among the three triptorelin groups at any of the time points assessed (Fig. 2, Supplementary Table SI).
Hormonal profiles of the luteal phase. Serum levels of (a) FSH, (b) LH, (c) estradiol (E2) and (d) progesterone (PRG) on the day of triggering final oocyte maturation with 0.1, 0.2 or 0.4 mg triptorelin and during the luteal phase, 8 and 36 hours and after 3, 5, 7 and 10 days following triptorelin administration. Values are expressed as medians and error bars represent 95% CI.
A simultaneous increase in serum LH and FSH was observed 8 hours after triptorelin administration in all three groups compared. Both gonadotrophins returned to baseline by the day of oocyte retrieval and remained low for the whole period of observation. All changes in LH and FSH levels between consecutive different time points were statistically significant (P < 0.0001) (Fig. 2, Supplementary Table SI).
Regarding steroid hormones, E2 and PRG levels significantly increased 8 hours and 3 days post triggering, respectively, in all three triptorelin groups (P < 0.0001). E2 and PRG levels declined significantly (P < 0.0001) between consecutive time points until the end of the observation period (Fig. 2, Supplementary Table SI).
Discussion
In the current study, three different doses of the GnRH agonist triptorelin (0.1, 0.2 and 0.4 mg), used to trigger final oocyte maturation, were compared in patients at high risk for severe OHSS undergoing ICSI. Based on the data presented, no difference in maturation rates, in the number of COCs and of MII oocytes were observed between the doses compared.
Similar numbers of MII oocytes were also observed in a small retrospective study comparing 0.1 mg (n = 9) and 0.2 mg (n = 14) triptorelin in patients undergoing embryo transfer (Gulekli et al., 2015) and in a subsequently published randomized controlled trial evaluating use of 0.2 mg (n = 55), 0.3 mg (n = 55) and 0.4 mg (n = 55) triptorelin in Asian oocyte donors (Vuong et al., 2016). In the Vuong et al. (2016) study, and similar to the present one, the duration of the luteal phase was not associated with the dose of triptorelin used for triggering final oocyte maturation.
In the current study, there was a simultaneous increase in serum LH and FSH, peaking 8 hours after triptorelin administration in all three groups evaluated. Both gonadotrophins returned to baseline by the day of oocyte retrieval and remained low for the whole period of observation. The levels of serum E2 and PRG were highest at 8 hours and 3 days post triggering, respectively, and progressively declined. All changes in FSH, LH, E2 and PRG between consecutive time points in the luteal phase were statistically significant. However, no significant differences in serum levels of LH, FSH, E2 and PRG were present between the three triptorelin groups at any of the time points assessed.
In contrast to the present study, Vuong et al. (2016) showed significantly higher LH levels at 24 and 36 hours after trigger, as well as higher PRG levels at 6 days after oocyte retrieval in the 0.4 mg triptorelin group compared with the 0.2 mg and 0.3 mg groups. In addition, one case of severe early OHSS was observed in the 0.3 mg triptorelin group. No clear explanation can be given regarding the origin of the above differences compared to the present study. However, it should be noted that the study by Vuong et al. (2016) was performed exclusively in an Asian population. Ethnicity has been shown to affect IVF/ICSI treatment outcome (Maalouf et al., 2017) as well as the incidence of OHSS (Luke et al., 2010). Furthermore, ethnic differences in response to gonadotrophins and GnRH analogues may exist due to the presence of receptor polymorphisms (Fatemi et al., 2014).
Whether the reported case of OHSS following triggering with 0.3 mg triptorelin in the study by Vuong et al. (2016) was associated with the decision of the authors of that study to stimulate patients with long-acting gonadotrophin is not clear. Although long acting gonadotrophin can be used in patients without PCOS, as in the study by Vuong et al. (2016), the number of COCs retrieved in the 0.3 mg group (18.7 ± 8.9), where the OHSS case was observed, indicates that a proportion of these patients may have been at high risk for OHSS (Fensore et al., 2015; Mahmoud Youssef et al., 2012).
The maximum gonadotrophin levels observed in the present study following agonist triggering in all GnRH agonists groups evaluated were comparable to circulating midcycle LH and FSH levels described in natural cycles (Hoff et al., 1983). However, an LH surge of shorter duration compared to a natural LH surge (Hoff et al., 1983; Itskovitz et al., 1991) was observed in all GnRH agonist doses evaluated, similar to previous observations (Fauser et al., 2002; Vuong et al., 2016). The shorter duration of the LH surge reflects the luteolytic effect of the GnRH agonists, which results in corpus luteum demise. While the GnRH agonist-induced luteolysis is beneficial for eliminating OHSS development, at the same time it leads to a clearly defective luteal phase (Fig. 2) for all GnRH agonist triggering doses evaluated. Despite standard luteal phase support after agonist triggering, low pregnancy rates have been observed following fresh embryo transfer (Youssef et al., 2014).
It has to be noted that although no differences were observed in the current study regarding baseline characteristics in the three groups compared, the presence of bias cannot be excluded, as in any retrospective study. Acknowledging this limitation, the results of the present study suggest that the lower dose of triptorelin 0.1 mg is as effective as the higher doses of 0.2 and 0.4 mg in patients at high risk for OHSS.
Whether these results are valid in patients with normal or low ovarian response cannot be deducted from the present study. Future research could focus on the potential association of BMI with oocyte recovery rate or maturation rate in patients triggered with the GnRH-agonist triptorelin for final oocyte maturation.
If an effect of BMI on maturation rate is shown, research on higher doses of triptorelin could potentially be justified.
Further evaluation of lower doses of triptorelin probably does not appear to be justified, as it would not be expected to result in important cost savings.
In conclusion, a dose of 0.1 mg triptorelin results in similar maturation rates compared to the higher doses of 0.2 or 0.4 mg for triggering final oocyte maturation in patients at high risk for OHSS undergoing ICSI.
Acknowledgements
The authors wish to thank Dr G.K. Petsas and Dr I.Z. Zorzovilis for assisting with clinical work, G. Stavropoulou for patient coordination and M. Panagopoulou, E. Giouvani, S. Ntovolou, E. Lamprou and G. Kalogeropoulou for data entry.
Authors’ roles
G.T.L. had the original conception of the study; participated in study design, acquisition and interpretation of data, writing and revision of the manuscript; and performed clinical work. T.G.L. participated in study design, acquisition and interpretation of data and writing and revision of the manuscript and performed clinical work. I.A.S. participated in the acquisition and interpretation of data and writing and revision of the manuscript and performed embryology work. C.A.V. contributed in the statistical analysis and interpretation of data and participated in the revision of the manuscript. B.C.T., G.F.G., K.C. and J.K.B. participated in the interpretation of data and revision of the manuscript. E.M.K. had the original conception and general supervision of the study, participated in study design, acquisition and interpretation of data and writing and revision of the manuscript and performed the statistical analysis.
Funding
No external funding was obtained for this study.
Conflict of interest
None.
