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Comparison between GnRH agonist and antagonist protocols for severe endometriosis in assisted reproductive cycles
Abstract
Purpose
Endometriosis may influence different aspects of reproductive physiology including folliculogenesis, ovulation, embryo quality, and fertilization. Recent data demonstrate that patients with endometriosis-associated infertility undergoing in vitro fertilization (IVF) have a reduction of pregnancy rates compared to women with other indications for IVF. The aim of the study is to evaluate the outcomes of IVF after controlled ovarian hyperstimulation (COH) with GnRH antagonist (GnRH-ant) or GnRH agonist (GnRH-a) in severe endometriosis patients.
Methods
A total of 101 patients with severe endometriosis undergoing IVF cycles were retrospectively enrolled into two groups in relation to hypothalamic inhibition before COH, obtained respectively with leuprorelin and cetrorelix. We evaluated characteristics of COH and clinical outcomes (overall pregnancy rate, implantation rate, spontaneous miscarriages, ectopic pregnancies, and clinical pregnancy rates).
Results
The group treated with GnRH-ant presented a similar number of MII oocytes and good quality embryos while using a lower amount of gonadotropins. Outcomes of COH with both GnRH-ant and GnRH-a were similar in patients with stage III-IV endometriosis. The number of retrieved oocytes, the number of obtained embryos, the implantation rates, and the clinical pregnancy rates were similar with GnRH-ant and GnRH-a protocols.
Conclusions
Considering the pregnancy outcomes, COH with both GnRH-ant and GnRH-a protocols do not present statistical differences in patients with severe endometriosis, but the GnRH-ant protocol could be more convenient in term of gonadotropins amount and patient discomfort.
... Ultimately, eight studies were included for the final analysis with a total of Table 1). [13][14][15][16][17][18][19][20] In these studies, 1721 cycles used the long GnRHagonist protocol and 1040 cycles used the GnRHantagonist protocol. Six retrospective analyses, [13][14][15][16][17]20 one cross-sectional study 18 and one RCT 19 were identified. ...
... [13][14][15][16][17][18][19][20] In these studies, 1721 cycles used the long GnRHagonist protocol and 1040 cycles used the GnRHantagonist protocol. Six retrospective analyses, [13][14][15][16][17]20 one cross-sectional study 18 and one RCT 19 were identified. Each study was undertaken at a single centre, and all inclusion/exclusion criteria were available. ...
... For the long GnRH-agonist protocol, four studies administered triptorelin, 14,15,18,19 two studies administered leuprorelin 16,17 and one study administered decapeptyl 13 daily starting from day 20 to 21 of the previous menstrual cycle. One study 20 did not specify which GnRH agonist was used and started treatment after day 21 of the preceding cycle. ...
Background:
Endometriosis is an oestrogen-dependent disease that can cause subfertility in women who may require assisted reproductive technology (ART) to achieve their pregnancy goals.
Objectives:
The aim of this study was to compare ART outcomes in women with endometriosis following the long GnRH-agonist controlled ovarian stimulation (COS) protocol with those taking the GnRH-antagonist COS protocol.
Data Sources and Methods:
MEDLINE, Embase and Web of Science were systematically searched in June 2022. Randomized controlled trials (RCTs) and observational studies comparing the long GnRH-agonist COS protocol and the GnRH-antagonist COS protocol in women with all stages/subtypes of endometriosis were included. Data were synthesized into comprehensive tables for systematic review. The Scottish Intercollegiate Guidelines Network (SIGN) checklists were used for the risk of bias assessment of non-randomized studies and randomized studies, and all the included studies were deemed to have acceptable quality.
Main Results:
Eight studies (one RCT and seven observational) with 2695 patients (2761 cycles) were included. Most studies generally reported non-significant differences in clinical pregnancy or live birth rates regardless of the COS protocol used. However, the GnRH-agonist protocol may yield a higher total number of oocytes retrieved, especially mature oocytes. Conversely, the GnRH-antagonist protocol required a shorter COS duration and lower gonadotrophin dose. Adverse outcomes, such as rates of cycle cancellation and miscarriage, were similar between both COS protocols.
Conclusion:
Both the long GnRH-agonist and GnRH-antagonist COS protocols generally yield similar pregnancy outcomes. However, the long GnRH-agonist protocol may be associated with a higher cumulative pregnancy rate due to the higher number of retrieved oocytes available for cryopreservation. The underlying mechanisms of the two COS protocols on the female reproductive tract remain unclear. Clinicians should consider treatment costs, stage/subtype of endometriosis and pregnancy goals of their patients when selecting a GnRH analogue for COS. A well-powered RCT is needed to minimize the risk of bias and compare the risk for ovarian hyperstimulation syndrome.
Registration:
This review was prospectively registered at PROSPERO under Registration No. CRD42022327604.
... The process of ovulation involves the rupture and release of the dominant follicle from the ovary into the fallopian tube, where fertilization may occur [49]. The regulation of ovulation is influenced by the fluctuating levels of gonadotropic hormones, especially FSH and LH, which are released by the pituitary gland [49]. ...
... The process of ovulation involves the rupture and release of the dominant follicle from the ovary into the fallopian tube, where fertilization may occur [49]. The regulation of ovulation is influenced by the fluctuating levels of gonadotropic hormones, especially FSH and LH, which are released by the pituitary gland [49]. ...
Oxidative stress (OS) is a condition that occurs as a result of an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify and neutralize them. It can play a role in a variety of reproductive system conditions, including polycystic ovary syndrome (PCOS), endometriosis, preeclampsia, and infertility. In this review, we briefly discuss the links between oxidative stress and PCOS. Mitochondrial mutations may lead to impaired oxidative phosphorylation (OXPHOS), decreased adenosine triphosphate (ATP) production, and an increased production of ROS. These functional consequences may contribute to the metabolic and hormonal dysregulation observed in PCOS. Studies have shown that OS negatively affects ovarian follicles and disrupts normal follicular development and maturation. Excessive ROS may damage oocytes and granulosa cells within the follicles, impairing their quality and compromising fertility. Impaired OXPHOS and mitochondrial dysfunction may contribute to insulin resistance (IR) by disrupting insulin signaling pathways and impairing glucose metabolism. Due to dysfunctional OXPHOS, reduced ATP production, may hinder insulin-stimulated glucose uptake, leading to IR. Hyperandrogenism promotes inflammation and IR, both of which can increase the production of ROS and lead to OS. A detrimental feedback loop ensues as IR escalates, causing elevated insulin levels that exacerbate OS. Exploring the relations between OS and PCOS is crucial to fully understand the role of OS in the pathophysiology of PCOS and to develop effective treatment strategies to improve the quality of life of women affected by this condition. The role of antioxidants as potential therapies is also discussed.
... Some recent randomized controlled trials (RCTs) and retrospective studies have compared the effectiveness of both protocols but showed inconsistent results [7][8][9][10]. So, it is necessary to focus on finding important indicator for making decisions and should be considered as a key point in defining the success of assisted reproductive technology (ART) treatment. ...
Background
A consensus has been reached on the preferred primary outcome of all infertility treatment trials, which is the cumulative live birth rate (CLBR). Some recent randomized controlled trials (RCTs) and retrospective studies have compared the effectiveness of GnRH-antagonist and GnRH-agonist protocols but showed inconsistent results. Studies commonly used conservative estimates and optimal estimates to described the CLBR of one incomplete assisted reproductive technology (ART) cycle and there are not many previous studies with data of the complete cycle to compare CLBRs in GnRH-antagonist versus GnRH-agonist protocols.
Methods
A total of 18,853 patients have completed their first IVF cycle including fresh and subsequent frozen-thawed cycles during 2016–2019, 16,827 patients were treated with GnRH-a long and 2026 patients with GnRH-ant protocol. Multivariable logistic analysis was used to evaluate the difference of GnRH-a and GnRH-ant protocol in relation to CLBR. Utilized Propensity Score Matching(PSM) for sampling by up to 1:1 nearest neighbor matching to adjust the numerical difference and balance the confounders between groups.
Results
Before PSM, significant differences were observed in baseline characteristics and the CLBR was 50.91% in the GnRH-a and 33.42% in the GnRH-ant (OR = 2.07; 95%CI: 1.88–2.28; P < 0.001). Stratified analysis showed the CLBR of GnRH-ant was lower than GnRH-a in suboptimal responders(46.89 vs 27.42%, OR = 2.34, 95%CI = 1.99–2.74; P < 0.001) and no differences of CLBR were observed in other patients between protocols. After adjusting for potential confounders, multivariable logistic analysis found the CLBR of GnRH-ant group was lower than that of GnRH-a group (OR = 2.11, 95%CI:1.69–2.63, P < 0.001). After PSM balenced the confounders between groups, the CLBR of GnRH-a group was higher than that of GnRH-ant group in suboptimal responders((38.61 vs 28.22%, OR = 1.60, 95%CI = 1.28–1.99; P < 0.001) and the normal fertilization rate and number of available embryo in GnRH-a were higher than these of GnRH-ant groups in suboptimal responders (77.39 vs 75.22%; 2.86 ± 1.26 vs 2.61 ± 1.22; P < 0.05). No significant difference was observed in other patients between different protocols.
Conclusions
It is crucial to optimize the utilization of protocols in different ovarian response patients and reconsider the field of application of GnRH-ant protocols in China.
... The number of retrieved oocytes, the number of obtained embryos, the implantation rates and the clinical pregnancy rates were similar with GnRH-ant and GnRH-a protocols. [14] Among two recent meta-analyses, Ludwig et al. also do not report any significant difference in the pregnancy rates between GnRH antagonist and GnRH-a protocols. [15] In the present well-controlled study, women with endometriosis undergoing IVF-ET had a significantly lower oocyte yield and lower fertilization rate in comparison with tubal-factor infertility. ...
Objective:
The objective of the following study is to compare the outcome of in vitro fertilization and embryo transfer (IVF-ET) in women with endometriosis and tubal-factor infertility.
Design:
Retrospective study.
Setting:
Tertiary referral hospital, assisted reproductive technologies unit.
Materials and method:
The study group consisted of 78 women diagnosed with advanced stage endometriosis. The control group included 100 women with tubal-factor infertility. These groups were retrospectively analyzed regarding stimulation, fertilization, embryo development, implantation and pregnancy outcome.
Intervention s:
Controlled ovarian hyperstimulation and IVF-ET.
Results:
Lower oocyte yield with lower fertilization rate were found in women with endometriosis compared with tubal-factor control subjects. However, no differences were found in cleavage, implantation and clinical pregnancy rates between the endometriosis and tubal-factor groups.
Conclusions:
Our results showed that women with endometriosis have a lower oocyte yield and lower fertilization rate compared with women with tubal-factor infertility. However, once the oocyte is fertilized, it seems that the embryo has a normal chance of implantation, leading to similar pregnancy rates and adequately treated women with endometriosis have equal chances of conception as seen with tubal-factor infertility.
Background: A consensus has been reached on the preferred primary outcome of all infertility treatment trials, which is the cumulative live birth rate (CLBR). Some recent randomized controlled trials (RCTs) and retrospective studies have compared the effectiveness of GnRH-antagonist and GnRH-agonist protocols but showed inconsistent results. Studies commonly used conservative estimates and optimal estimates to described the CLBR of one incomplete ART cycle and there are not many previous studies with data of the complete cycle to compare CLBRs in GnRH-antagonist versus GnRH-agonist protocols.
Methods: A total of 18853 patients have completed their first IVF cycle including fresh and subsequent frozen-thawed cycles during 2016-2019, 16827 patients were treated with GnRH-a long and 2026 patients with GnRH-ant protocol. Multivariable logistic analysis was used to evaluate the difference of GnRH-a and GnRH-ant protocol in relation to CLBR.
Results: Before PSM, significant differences were observed in baseline characteristics and the CLBR was 50.91% in the GnRH-a and 33.42% in the GnRH-ant (OR: 2.07; 95%CI: 1.88-2.28; P<0.001). Stratified analysis showed the CLBR of GnRH-ant was lower than GnRH-a in suboptimal responders(46.89% vs 27.42%, OR=2.34, 95%CI=1.99-2.74; P<0.001) and no differences of CLBR were observed in other patients between protocols. After adjusting for potential confounders, multivariable logistic analysis found the CLBR of GnRH-ant group was lower than that of GnRH-a group (OR=2.11, 95%CI:1.69-2.63,P<0.001). After PSM to balence the baseline between groups, the CLBR of GnRH-a group was higher than that of GnRH-ant group in suboptimal responders((38.61% vs 28.22%, OR=1.60, 95%CI= 1.28-1.99; P<0.001) and the normal fertilization rate and number of available embryo in GnRH-a were higher than these of GnRH-ant groups in suboptimal responders (77.39% vs 75.22%; 2.86±1.26 vs 2.61±1.22; P<0.05). No significant difference was observed in other patients between different protocols.
Conclusions: It is crucial to optimize the utilization of protocols in different ovarian response patients and reconsider the field of application of GnRH-ant protocols in China.
Endometriosis is a frequent indication for in vitro fertilization and embryo transfer (IVF-ET). Its influence on IVF-ET cycles remains controversial. We evaluated the impact of the severity of endometriosis on IVF-ET cycles in young women.
Retrospective cohort study.
Academic tertiary referral centre.
In a retrospective cohort analysis, 164 IVF-ET cycles in 148 women with endometriosis-associated infertility were analyzed. Eighty cycles performed during the same period on 72 consecutive women with tubal infertility were considered as controls. All patients were younger than 35 years old.
Response to controlled ovarian hyperstimulation (COH), number of oocytes retrieved, fertilization, implantation and pregnancy rate (PR).
Clinical PR was lower in the group with endometriosis (all stages) in comparison with the tubal factor group. Higher total gonadotropin requirements, lower response to COH and lower oocyte yield were also found in the endometriosis group. Stage-stratified analysis showed a lower fertilization rate in stage I-II (52.6% stage I-II, 70.5% stage III-IV and 71.9% tubal factor). In stage III-IV endometriosis there was a higher cycle cancellation rate, a reduced response to COH and a lower PR compared with both the stage I-II and the tubal infertility groups (PR 9.7, 25 and 26.1%, respectively).
Stage III-IV was strongly associated with poor IVF outcome. A decreased fertilization rate in stage I-II might be a cause of subfertility in these women, owing to a hostile environment caused by the disease.
The classic, unproven dogma that ovarian endometrioma should be removed in all infertile women prior to IVF has been recently
questioned. There is currently insufficient data to clarify whether the endometrioma-related damage to ovarian responsiveness
precedes or follows surgery. Both endometrioma-related injury and surgery-mediated damage may be claimed to be involved and
the relative importance of these two insults remains to be clarified. Convincing evidence has emerged showing that responsiveness
to gonadotrophins after ovarian cystectomy is reduced. Conversely, the impact of surgery on pregnancy rates is unclear since
no deleterious effect has been reported. Of relevance here is that surgery exposes women to risk related to a demanding procedure
whereas risks associated with expectant management are mostly anecdotal or of doubtful clinical relevance. We recommend proceeding
directly to IVF to reduce time to pregnancy, to avoid potential surgical complications and to limit patient costs. Surgery
should be envisaged only in presence of large cysts (balancing the threshold to operate with the cyst location within the
ovary), or to treat concomitant pain symptoms which are refractory to medical treatments, or when malignancy cannot reliably
be ruled out.
To investigate the outcomes of intracytoplasmic sperm injection (ICSI) cycles after controlled ovarian hyperstimulation (COH) with GnRH antagonist or GnRH agonist (GnRH-a) in mild-to-moderate endometriosis and endometrioma.
Prospective randomize trial.
A private IVF center.
A total of 246 ICSI cycles in 246 patients were divided into three groups: women with mild-to-moderate endometriosis (n = 98); women who had ovarian surgery for endometrioma (n = 81); women with endometrioma and no history of previous surgery (n = 67).
Patients in each group were randomized to COH with either triptrolein or cetrorelix.
Clinical parameters, characteristics of COH, and ICSI results were analyzed.
Outcomes of COH with both GnRH antagonist and GnRH-a were similar in patients with mild-to-moderate endometriosis. Implantation rates were 15.9% vs. 22.6% and clinical pregnancy rates were 27.5% vs. 39% with GnRH antagonist and GnRH-a protocols, respectively, in patients who had ovarian surgery for endometrioma. Implantation rates were 12.5% vs. 14.8% and clinical pregnancy rates were 20.5% vs. 24.2% with GnRH antagonist and GnRH-a protocols, respectively, in patients with endometrioma and no history of ovarian surgery.
Considering the implantation and clinical pregnancy rates, COH with both GnRH antagonist and GnRH-a protocols may be equally effective in patients with mild-to-moderate endometriosis and endometrioma who did and did not undergo ovarian surgery.
This review aims to evaluate whether severe endometriosis has an impact on the outcome of in vitro fertilisation (IVF), whether IVF is associated with specific complications in this context, whether a specific ovarian stimulation protocol is most appropriate, whether the endometrial condition progresses following ovarian stimulation, and whether endometrial cysts pose a specific problem for IVF. In patients with severe endometriosis, IVF represents an effective treatment option for infertility, as a complement to surgery. The prognostic parameters of IVF are identical to those of other patients. However, the risks related to the severity of endometriosis, particularly the risk of ovarian deficiency, need to be considered. Because of this issue, to which endometriosis-related pain often adds, IVF treatment should be initiated as early as possible, using appropriate protocols and after having fully informed the patient about the specific oocytes retrieval-related risks.
Endometriosis has a wide range of severity but molecular factors associated with variable extension of the disease have not been widely investigated. The present study compares the peritoneal fluid (PF) proteome of 109 women with endometriosis and different disease stage as defined by the American Society for Reproductive Medicine (ASRM).
PF samples were subjected to two-dimensional gel electrophoresis; protein spots of interest were identified by liquid chromatography tandem mass spectrometry.
Over 470 protein spots were analyzed. One isoform of haptoglobin alpha chain, alpha-1b-glycoprotein and one unknown protein had higher expression in PF of women with ASRM stage I-II endometriosis. Four isoforms of alpha1-antitrypsin, three isoforms of alpha-1b-glycoprotein, one isoform of S100-A8 and serotransferrin had higher expression in PF of women with ASRM stage III-IV disease.
Several protein isoforms have different expression in PF of women with ASRM stage I-II endometriosis than in those with ASRM stage III-IV disease; most of these molecules are involved in inflammation and immune response.
Thirty-nine cycles were studied in patients with a history of endometriosis who went through in vitro fertilization. In 15 cycles, there was no evidence of endometriosis; in 10 cycles, the patients had mild or moderate disease; in 14 cycles, severe or extensive endometriosis was found. The pregnancy rates per cycle were 33%, 60%, and 7%, respectively (groups I and II, no significant difference; groups II and III, P less than 0.01). The difference was due to the different number of oocytes aspirated at laparoscopy because of technical problems in the cases with severe and extensive disease. There was also a significant difference in the number of pregnancies per transferred cycles. There was no difference in the luteal phase in the three groups. The reproductive potential, which seemed to be similar in groups I and II, was severely impaired in the group with severe endometriosis.
The literature suggests that the results of in-vitro fertilization (IVF) for patients with endometriosis depend on the stage of the disease, and that patients with severe endometriosis have a higher failure rate. Miscarriage is said to be more prevalent in women treated for endometriosis. In the study reported here, 140 patients with endometriosis underwent 182 cycles of IVF using gonadotrophin-releasing hormone analogues (GnRHa). Patients with endometriosis only were allocated to one group (group 4). The results were compared with those of three other groups of patients undergoing the same treatment within the same period. Group 1 consisted of couples with male factor only (45 cycles), group 2, couples with unexplained infertility (196 cycles) and group 3, couples with a tubal factor only (1139 cycles). The mean age of the patients, mean number of human menopausal gonadotrophin (HMG) ampoules administered, oestradiol concentration on the day of human chorionic gonadotrophin administration, number of days of HMG, mean number of oocytes retrieved and retrieval rate were not significantly different. The fertilization rate was significantly lower in group 1; no difference was observed in the other three groups. The mean number of normally fertilized embryos was not significantly different. The number of transferred embryos in each cycle and the implantation rates were similar in the four groups. The overall pregnancy rate per transfer was 39% in group 1, 48% in group 2, 45% in group 3 and 40% in group 4.(ABSTRACT TRUNCATED AT 250 WORDS)