Request PDF on ResearchGate | Antagonistas: de la fisiología a la reproducción de un fármaco relativamente nuevo antagonista de la GnRH. Peptides are provided which have improved duration of GnRH antagonistic properties and/or which can be synthesized more economically. These antagonists. GnRH Agonists & Antagonists. 1. Presented By: Dr. Manas Kr. Nath, PGT, Deptt. of Pharmacology, SMCH. Moderated By: Dr. Pinaki.
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Gonadotropin-releasing hormone GnRH antagonists, which became commercially available fromhave been used for the prevention of premature luteinizing hormone LH surges in controlled ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection.
This review focuses on the antatonistas literature on the use of GnRH antagonists and provides guidelines for optimal use in light of increasing evidence showing that GnRH antagonists are safe and effective, allowing flexibility of treatment in a wide range of patient populations.
This includes patients undergoing first-line controlled ovarian stimulation, poor responders, and women diagnosed with polycystic ovary syndrome. The GnRH antagonist offers a viable alternative to the long agonists, providing a shorter duration of treatment with fewer injections and with no adverse effects on assisted reproductive technology outcome.
This results in a significantly lower amount of gonadotropins required, which is likely to lead to improved patient antaggonistas. Gonadotropins were first introduced in the early s and have been used in ovarian stimulation anfagonistas to induce multiple follicular development, particularly during the past 3 decades, in women undergoing in vitro fertilization IVF treatment.
Preventing Natagonistas surges using GnRH analogs improves gnrn yield with more embryos, allowing better selection and, therefore, leading to an increase in antavonistas rates [ 3 ]. Since the early s, the use of GnRH agonists in ovarian stimulation has greatly improved the success rate of IVF [ 4 ]. GnRH agonists reduce the incidence of premature LH surges [ 56 ] by suppressing gonadotropin release via pituitary desensitization following an initial short period of gonadotropin hypersecretion.
More recently, GnRH antagonists with high potency and fewer side effects have been introduced into Antagonistaw and have emerged as an alternative in preventing premature LH surges. Furthermore, GnRH antagonist suppression of gonadotropin secretion can be quickly reversed [ 7 – 9 ].
This different pharmacologic mechanism of action makes GnRH antagonists a more logical choice to use in IVF for the prevention of premature LH surges [ 5 ]. Clinically, stimulation with urinary FSH or recombinant human FSH rFSHeither alone or in antahonistas with urinary-derived human menopausal gonadotropin hMGis started on day 2 or 3 of the menstrual cycle and the GnRH antagonist is antagonistzs in the late follicular phase, from day 5 or 6 of stimulation onward. The dose of gonadotropins may be adjusted according to individual response.
This review focuses on literature concerning the use of Abtagonistas antagonists in ovarian stimulation for IVF and provides guidelines for optimal use. There are a number of theoretical advantages of GnRH antagonists versus GnRH agonists [ 1213 ], including a shorter duration of injectable drug treatment, absence of vasomotor symptoms, less risk of inadvertent administration during early pregnancy, avoidance of ovarian cyst formation, and a significantly smaller dose of gonadotropin per cycle, which translate to improved patient convenience [ 914 ].
The literature regarding the cost effectiveness of GnRH antagonist protocols is currently contradictory. In a randomized trial by Badrawi et al. Current evidence suggests that GnRH antagonists and agonists are similarly effective in the context of oocyte donation [ 17 ].
Análogos de la GnRh: agonistas y antagonistas | Progresos de Obstetricia y Ginecología
However, due to their increased convenience, GnRH antagonist protocols are often the regimen of choice for oocyte donors. More recently, it has been recommended that treatment guidelines for the prevention of ovarian hyperstimulation syndrome OHSS [ 18 ] should be updated to incorporate findings from the literature over the past 5 years. Potential disadvantages of GnRH antagonist protocols over GnRH agonist protocols include less flexible options in terms of cycle programming and early studies suggesting a minor reduction in pregnancy rates per cycle [ 2021 ].
Increasing flexibility of GnRH antagonist protocols can be achieved with oral contraceptives [ 20 ]. Pretreatment with oral contraceptives allows programming of cycles, whereby stimulation can be started during a 5-day interval following withdrawal of the oral contraceptive [ 22 ].
Use of oral contraceptives with a GnRH antagonist protocol and the pregnancy outcomes of GnRH antagonist gnr are discussed below. Despite an initial trend toward a lower pregnancy rate with GnRH antagonists compared with agonists in a number of early randomized controlled studies, a meta-analysis by Kolibianakis et al.
Adapted from Kolibianakis [ 23 ] and Al-Inany [ 45 ]. In normal responders, the use of GnRH antagonist versus long GnRH agonist protocols was associated with a statistically significant reduction of OHSS, with no evidence of a difference in live birth rates [ 45 ]. GnRH antagonist protocols have been shown to result in better outcomes than GnRH agonists in patients with poor prognosis [ 5253 ].
In oocyte donation [ 55 ] and embryo transfer [ 56 ] cycles, the replacement of GnRH agonist with a GnRH antagonist had no gnrhh on the pregnancy and implantation rates. Higher pregnancy rates were also shown in a gonadotropin intrauterine insemination cycle than antagonixtas a cycle where no intervention took place [ 57 ].
Gonadotropin-releasing hormone antagonist
In a prospective randomized trial, Prapas et al. GnRH antagonists have been shown to be an effective treatment in women undergoing controlled ovarian stimulation for IVF in multiple meta-analyses and clinical studies. In the systematic review and meta-analyses by Kolibianakis et al. In a more recent systematic review, Al-Inany et al. Borm and Mannaerts [ 8 ] evaluated the efficacy and safety of ganirelix in women undergoing ovarian stimulation with rFSH.
The patients were randomized in a 2: Ganirelix in comparison with buserelin resulted in a shorter duration of treatment 5 vs 26 days. Comparison of the number and size of follicles indicated that in the ganirelix group, the final number of follicles on the day of hCG administration, was smaller The ganirelix regimen resulted in the recovery of good-quality oocytes, as reflected by the high fertilization rate The clinical outcome defined as the ongoing pregnancy rate per attempt was good This suggests that the slightly lower pregnancy rates observed in early trials may have been related to lack of experience with the use of antagonist protocols.
With regard to safety, ganirelix was found to be safe and well tolerated with a two-fold lower 2.
GnRH antagonists have been used effectively in patients who have a poor prognosis or who have shown a diminished ovarian response to controlled ovarian stimulation. The microdose flare protocol has been proven to increase both clinical and ongoing pregnancy rates in poor responders.
The authors concluded that the ganirelix protocol may be preferable because it requires significantly fewer injections and a shorter treatment course, resulting in cost savings and improved convenience for the patient. An earlier review by Copperman [ 60 ] also noted that the use of a GnRH antagonist for the suppression of premature LH surges in poor responders is at least as good as the microdose flare and provides better cycle outcomes than the long luteal leuprolide acetate downregulation protocols.
The use of GnRH antagonists among patients with poor prognosis was also evaluated by Shapiro et al. Overall, the pregnancy rates per initiated cycle and per embryo transfer were The patients with poor prognosis had a pregnancy rate of 8. While this retrospective analysis supports the use of GnRH antagonist protocols as an alternative to agonist protocols in normal responders, the use of GnRH antagonists in patients with poor IVF prognosis resulted in predictably poor outcomes.
In a recent meta-analysis comparing the efficacy of GnRH antagonists versus agonists in poor responders, Pu et al.
The ability to offer patients who have suffered numerous failed cycle attempts a choice of effective alternatives may improve outcomes for these women.
This protocol involves administration of transdermal estradiol patches and a GnRH antagonist in the luteal phase of the preceding menstrual cycle, followed by high-dose follicular phase gonadotropin stimulation with adjunctive GnRH antagonist.
All clinical outcomes, including ongoing pregnancy rates, were comparable between the two groups, suggesting that the use of an LPG protocol is at least as effective as a microdose agonist protocol. Similar findings were obtained by the same group of investigators in a subsequent prospective randomized controlled trial RCT [ 64 ]. Cetrorelix acetate, a US Food and Drug Administration-approved GnRH antagonist, has been shown to be effective and safe as a single-dose 3 mg or multiple-dose regimen 0.
In a prospective randomized trial, Vlaisvljevic et al. However, multiple-dose protocols are now the standard and single-dose protocols are rarely used. Ganirelix is only available as a multiple-dose regimen.
The multiple-dose protocol for ganirelix involves the administration of 0. The Ganirelix Dose-Finding Study [ 69 ] was the first multicenter, double-blind, randomized dose-finding study to establish the minimal effective dose of ganirelix to prevent premature LH surges in women undergoing ovarian stimulation with rFSH.
Six different ganirelix doses 0. In this study, patients were treated with a fixed dose of IU rFSH for 5 days before starting ganirelix. The study revealed that 0. Patients received one controlled ovarian hyperstimulation cycle with ganirelix or a long protocol of leuprolide acetate in conjunction with rFSH [ 27 ].
From day 6 of rFSH treatment, ganirelix 0. The mean number of oocytes retrieved per attempt was Fertilization rates were Clinical and ongoing pregnancy rates per attempt, respectively, were Fewer moderate and severe injection-site reactions were reported with ganirelix Overall, the results showed that ganirelix achieved similar clinical efficacy with a shorter duration of treatment compared with the GnRH agonist. The ganirelix regimen was 17 days shorter 9 vs 26 days than the triptorelin regimen with a median reduction in the total dose of rFSH utilized of IU vs IU.
The fertilization rates and the number of good-quality embryos were similar in both treatment groups. The implantation rates of the two treatment arms were identical Furthermore, local tolerance of ganirelix appeared to be better than that of triptorelin, as the percentage of subjects with at least one local skin reaction was two-fold lower when using the ganirelix regimen In a prospective randomized trial in patients undergoing assisted reproductive technologies Wilcox et al.
Cetrorelix is also available as a multiple-dose regimen 0. Similar efficacy and safety results were shown in a cetrorelix 0.
Optimal usage of the GnRH antagonists: a review of the literature
Flexible dosing was introduced to reduce the number of antagonist injections and the duration of stimulation. It has been suggested that development of flexible dosing regimens, that is, individualizing or tailoring GnRH antagonist administration, might lead to better clinical outcomes in GnRH antagonist-treated patients [ 77 ].
Results from several clinical studies support the efficacy and safety of flexible-dosing regimens with ganirelix, though some show no significant advantage over the standard fixed-dose regimen [ 78 – 80 ].
Nevertheless, there is evidence that flexible dosing regimens lead to improvement in the outcomes of ovarian stimulation cycles.
In a prospective, randomized, single-center study comparing fixed multiple-dose antagonist with a flexible ganirelix regimen, Ludwig et al. There were, however, no differences in pregnancy rates among the three groups. The benefits of flexible GnRH antagonist administration according to follicular size versus starting dosing on a fixed day were also highlighted by Al-Inany et al.
Although no statistically significant difference in pregnancy rate was observed between flexible and fixed protocols, there was a significant reduction in the amount of rFSH with antagonistax flexible protocol. As an effective alternative to hCG-induced ovulation, GnRH agonists induce a sustained release of Anyagonistas and FSH from the pituitary that effectively induces oocyte maturation and ovulation.
A possible advantage of a GnRH agonist for trigger in comparison with hCG is the simultaneous induction of a FSH surge comparable to the surge of a natural cycle [ 82 ]. GnRH agonist triggering, however, results in a shorter endogenous LH surge that leads to a defective corpus luteum formation and an inadequate luteal phase [ 8384 ].
The profound luteolysis observed after GnRH agonist triggering in contrast to the prolonged luteotropic effect often seen after triggering with hCG has been shown to almost completely eliminate the risk of OHSS in high responders, avoiding the need for cycle cancellation [ 8285 ]. Because of the inadequate luteal phase after GnRH agonist trigger, the use of standard luteal phase support is inadequate and results in lower conception and higher miscarriage rates [ 86 ]. Therefore, luteal support strategies including one bolus of low-dose hCG, repeated boluses of hCG, recombinant LH add-back, and more intensive estradiol and progesterone supplementation were proposed to achieve optimal conception rates [ 8287 – 89 ].
The study also found no significant differences in the rates of implantation In concluding, the authors suggested that a protocol consisting of a GnRH agonist trigger after GnRH antagonist co-treatment combined with luteal phase and early pregnancy estradiol and progesterone supplementation should be given strong consideration for patients at high risk of developing OHSS. In a more recent publication reviewing the predictive factors of successful outcome after GnRH agonist trigger and intensive luteal support, Kummer et al.
The ongoing pregnancy rate was No patients developed moderate or severe OHSS [ 92 ]. Zntagonistas the advantages of GnRH antagonists—that is, much shorter treatment regimens, fewer injections, and the need for less gonadotropin—the more general acceptance of antagonist regimens has been hampered by their perceived association with slightly lower pregnancy and implantation rates compared with GnRH agonist protocols.