Triggering With Gonadotropin-Releasing Hormone Agonist in Hyperresponders
Triggering With Gonadotropin-Releasing Hormone Agonist in Hyperresponders
Humaidan P, Papanikolaou EG, Tarlatzis BC
Hum Reprod. 2009;24:2389-2394
With the recent trend of delaying childbearing, the stimulation of poor responders has become a difficult clinical challenge, and numerous publications address this issue month after month. For the clinician, however, management of the hyperresponding patient is at least as challenging as management of the poor responder. In general, we talk about a hyperresponse when a patient responds with an excessive number of follicles/oocytes to a given gonadotropin dose. If not recognized in time, this may lead to ovarian hyperstimulation syndrome (OHSS), which is the most severe and a potentially lethal complication of in vitro fertilization.
Therefore, it is important to identify patients at risk and to choose a stimulation protocol that reduces the risk for OHSS to a minimum. Typically, young and thin patients who have menstrual irregularities, polycystic ovaries, or polycystic ovary syndrome are at risk. In addition, those with elevated baseline androgen and luteinizing hormone (LH) levels are more likely to hyperrespond. Patients who respond to stimulation with high estradiol levels (> 2500-5000 pg/mL) and those who respond with many follicles/eggs (> 15-20) should be identified as being at risk. The most important risk factor is probably the history of OHSS in a previous cycle.
Several stimulation protocols have been developed for the management of these patients (eg, step-up, step-down, sequential step-up and step-down, dual suppression with oral contraceptives and gonadotropin-releasing hormone agonist [GnRHa], and replacement of follicle-stimulating hormone stimulation with low-dose human chorionic gonadotropin (hCG) from midfollicular phase). In addition to choosing the right stimulation protocol, an appropriate dose of gonadotropin and careful monitoring with ultrasound and estradiol measurements are needed.
With the availability of GnRH antagonist to prevent premature ovulation, a new option became available. Because the antagonist competitively binds to the pituitary GnRH receptor and does not lead to receptor downregulation, ovulation could be induced with GnRHa. This expert opinion discusses the benefits and risks of triggering ovulation with GnRHa in hyperresponding patients.
GnRHa in cycles where ovulation is prevented with GnRH antagonist successfully induces the midcycle LH and FSH surge, but this surge is about 50% shorter than the LH surge in a natural cycle. A similar number and quality of eggs can be retrieved following a GnRHa trigger when compared with the traditional hCG trigger. However, initial studies have shown significantly lower pregnancy and higher miscarriage rates with this approach. It was soon realized that a GnRHa trigger induces a significant luteal phase defect that cannot be effectively rescued by progesterone administration only. Three approaches to managing this problem have been tested. The first option is to add low-dose hCG at the time of the retrieval (1500 IU was tested). This approach was shown to restore the endocrine function of the luteal phase and increased pregnancy rates to those seen with an hCG trigger. An alternative is to use recombinant LH in the luteal phase or to use GnRHa to maintain luteal support. The third option is to use the combination of estradiol and progesterone for luteal support.
OHSS is potentially a very severe complication of in vitro fertilization treatment. It is therefore important to identify those patients who are at risk prior to starting the stimulation and to try to use the approach that is least likely to lead to a hyperresponse. This could be the retrieval of immature eggs with subsequent in vitro maturation or the use of a stimulation protocol that has been shown to reduce OHSS risk. In antagonist cycles, GnRHa can be used to trigger ovulation. In these cases, the luteal phase requires special attention because replacing only progesterone will not be sufficient. It appears that LH is needed as well because it induces cytokine and growth factor production that are required for successful implantation. Treatment outcomes for these cycles cannot be compared with outcomes of normal responder patients because the alternative for a hyperresponding patient is cycle cancellation or elective cryopreservation of all embryos. If, despite all measures during stimulation, the patient still shows early signs of hyperstimulation, then one has no other option but to freeze all embryos to avoid a potentially severe complication, OHSS.
Abstract
GnRHa to Trigger Final Oocyte Maturation: A Time to Reconsider
Humaidan P, Papanikolaou EG, Tarlatzis BC
Hum Reprod. 2009;24:2389-2394
Background
With the recent trend of delaying childbearing, the stimulation of poor responders has become a difficult clinical challenge, and numerous publications address this issue month after month. For the clinician, however, management of the hyperresponding patient is at least as challenging as management of the poor responder. In general, we talk about a hyperresponse when a patient responds with an excessive number of follicles/oocytes to a given gonadotropin dose. If not recognized in time, this may lead to ovarian hyperstimulation syndrome (OHSS), which is the most severe and a potentially lethal complication of in vitro fertilization.
Therefore, it is important to identify patients at risk and to choose a stimulation protocol that reduces the risk for OHSS to a minimum. Typically, young and thin patients who have menstrual irregularities, polycystic ovaries, or polycystic ovary syndrome are at risk. In addition, those with elevated baseline androgen and luteinizing hormone (LH) levels are more likely to hyperrespond. Patients who respond to stimulation with high estradiol levels (> 2500-5000 pg/mL) and those who respond with many follicles/eggs (> 15-20) should be identified as being at risk. The most important risk factor is probably the history of OHSS in a previous cycle.
Several stimulation protocols have been developed for the management of these patients (eg, step-up, step-down, sequential step-up and step-down, dual suppression with oral contraceptives and gonadotropin-releasing hormone agonist [GnRHa], and replacement of follicle-stimulating hormone stimulation with low-dose human chorionic gonadotropin (hCG) from midfollicular phase). In addition to choosing the right stimulation protocol, an appropriate dose of gonadotropin and careful monitoring with ultrasound and estradiol measurements are needed.
With the availability of GnRH antagonist to prevent premature ovulation, a new option became available. Because the antagonist competitively binds to the pituitary GnRH receptor and does not lead to receptor downregulation, ovulation could be induced with GnRHa. This expert opinion discusses the benefits and risks of triggering ovulation with GnRHa in hyperresponding patients.
Summary
GnRHa in cycles where ovulation is prevented with GnRH antagonist successfully induces the midcycle LH and FSH surge, but this surge is about 50% shorter than the LH surge in a natural cycle. A similar number and quality of eggs can be retrieved following a GnRHa trigger when compared with the traditional hCG trigger. However, initial studies have shown significantly lower pregnancy and higher miscarriage rates with this approach. It was soon realized that a GnRHa trigger induces a significant luteal phase defect that cannot be effectively rescued by progesterone administration only. Three approaches to managing this problem have been tested. The first option is to add low-dose hCG at the time of the retrieval (1500 IU was tested). This approach was shown to restore the endocrine function of the luteal phase and increased pregnancy rates to those seen with an hCG trigger. An alternative is to use recombinant LH in the luteal phase or to use GnRHa to maintain luteal support. The third option is to use the combination of estradiol and progesterone for luteal support.
Viewpoint
OHSS is potentially a very severe complication of in vitro fertilization treatment. It is therefore important to identify those patients who are at risk prior to starting the stimulation and to try to use the approach that is least likely to lead to a hyperresponse. This could be the retrieval of immature eggs with subsequent in vitro maturation or the use of a stimulation protocol that has been shown to reduce OHSS risk. In antagonist cycles, GnRHa can be used to trigger ovulation. In these cases, the luteal phase requires special attention because replacing only progesterone will not be sufficient. It appears that LH is needed as well because it induces cytokine and growth factor production that are required for successful implantation. Treatment outcomes for these cycles cannot be compared with outcomes of normal responder patients because the alternative for a hyperresponding patient is cycle cancellation or elective cryopreservation of all embryos. If, despite all measures during stimulation, the patient still shows early signs of hyperstimulation, then one has no other option but to freeze all embryos to avoid a potentially severe complication, OHSS.
Abstract