- Email: [email protected]
Basic understanding of gonadotropin-releasing hormone–agonist triggering
VIEWS AND REVIEWS
Basic understanding of gonadotropin-releasing hormone–agonist triggering Robert F. Casper, M.D. Division of Reproductive Sciences, University of Toronto, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, and Toronto Centre for Advanced Reproductive Technology Fertility Partners, Toronto, Ontario, Canada
A single bolus of human chorionic gonadotropin (hCG) at midcycle has been the gold standard for triggering final oocyte maturation and ovulation in assisted reproductive technology cycles. More recently, gonadotropin-releasing hormone (GnRH)-agonist (GnRH-a) triggering has been introduced. The GnRH-a trigger may allow a more physiologic surge of both luteinizing hormone (LH) and follicle-stimulating hormone, although whether the combined surge will result in improved oocyte and embryo quality remains to be seen. However, the short duration of the LH surge with the GnRH-a trigger (approximately 34 hours) has been shown to be beneficial for preventing ovarian hyperstimulation syndrome in GnRH antagonist in vitro fertilization (IVF) cycles when compared with the prolonged elevation of hCG (R6 days) after exposure to an hCG bolus. This review discusses the physiologic basis for the use of a GnRH-a trigger in IVF cycles. (Fertil SterilÒ 2015;-:-–-. Ó2015 by American Society for Reproductive Medicine.) Use your smartphone Key Words: Gonadotropin-releasing hormone (GnRH) agonist, human chorionic gonadotropin to scan this QR code (hCG), in vitro fertilization (IVF), ovulation induction, ovarian hyperstimulation syndrome and connect to the (OHSS) Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/casperr-gnrh-agonist-triggering/
I
n the follicular phase of natural menstrual cycles, gonadotropinreleasing hormone (GnRH) is released in hourly pulses from the mediobasal hypothalamus into the pituitary portal system, and binds to GnRH receptors on gonadotropes in the anterior pituitary. The result is the hourly release of small, discrete pulses of folliclestimulating hormone (FSH) and luteinizing hormone (LH), which are required for follicular growth and estrogen (E) secretion in the ovary. At midcycle, in the presence of rapidly rising E levels and a small rise in progesterone
(P) levels, a midcycle gonadotropin surge occurs, which triggers ovulation approximately 36–40 hours later. In reality, the midcycle surge represents a dramatic increase in the amplitude of the hourly LH and FSH pulses and lasts approximately 48 hours in humans (1). The increased amplitude of the LH and FSH pulses is thought to be facilitated by positive feedback of E on kisspeptin neurons in the anteroventral periventricular nuclei of the hypothalamus (2), and through E-mediated up-regulation of GnRH receptors on the gonadotropes in the anterior pituitary (3).
Received December 10, 2014; revised December 18, 2014; accepted December 19, 2014. R.F.C. is a board member of AbbVie, Actavis, Bayer, Ferring, EMD Serono, Merck, OvaScience, and Pfizer; is a consultant for Fertility Nutraceuticals; is employed by Insception Cord Blood Bank; has provided expert testimony for the Canadian Medical Protective Association; has received grants from Merck, EMD Serono, and Ferring; has received payment for lectures from AbbVie, Actavis, Bayer, and EMD Serono; holds patents with ZircLight and Ortho-McNeil; receives royalties from Jannsen-Ortho, Teva, and UpToDate; and holds stock in Insception, OvaScience, and Circadian-Zirclight. Reprint requests: Robert F. Casper, M.D., 150 Bloor Street West, Suite 210, Toronto, Ontario M5S2X9, Canada (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.12.129 VOL. - NO. - / - 2015
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
Assisted reproductive techniques (ART), such as in vitro fertilization (IVF) and intrauterine insemination (IUI) rely on accurate timing of ovulation for retrieving oocytes from preovulatory follicles and optimal in vivo insemination of oocytes. Luteinizing hormone itself is impractical for use as an ovulation trigger, because of its short half-life in circulation (rapid phase t1/2 is 21 minutes) (4). Because the biological activity of human chorionic gonadotropin (hCG) is similar to that of LH, since approximately the mid-1970s, a bolus of hCG (rapid phase t1/2 is 12 hours) (4) has been used to trigger the final stage of follicular and oocyte maturation, with ovulation occurring approximately 38–40 hours later, similar to the timing in natural ovulation. The hCG trigger remains the gold standard today. In 1971, the amino acid sequence of GnRH was determined independently in the laboratories of Andrew Schally and Roger Guillemin, and 1
VIEWS AND REVIEWS synthetic GnRH was developed. Schally and Guillemin shared one-half of the Nobel Prize for Physiology or Medicine in 1977 for their work on brain peptides, especially thyrotropin-releasing hormone (TRH) and GnRH. As early as 1973, Nakano et al. (5), in Japan, showed that ovulation could be induced in the human by infusion of 600 mg of synthetic GnRH for 6 hours, followed by a subcutaneous bolus dose of 400 mg. The need for intravenous infusion made this idea impractical, and it was abandoned. During the late 1970s, the synthesis of GnRH agonists (GnRH-a) was accomplished. The GnRH-a all have a similar structure, with substitution of an inactive amino acid at position 6, to decrease degradation by endogenous peptidases, and alteration or deletion of the amino acid in position 10, which resulted in increased receptor affinity. The combination of these changes led to GnRH activity that is approximately 100–200 times greater than that of native GnRH in releasing LH and FSH from the pituitary (6). As described, a bolus of hCG has been the gold standard for simulating an LH surge and inducing ovulation. However, the increased glycosylation of hCG results in a longer biological effect when it is used as a trigger, and this may create a predisposition to ovarian hyperstimulation syndrome (OHSS) in women who are at risk for this complication of gonadotropin stimulation. In addition, in spontaneous cycles, the gonadotropin surge involves both LH and FSH. Whether FSH has a physiologic role in oocyte maturation is unknown, but recent work has suggested that it might. Lamb et al. (7) added a bolus of FSH to the hCG trigger and showed better oocyte recovery and fertilization rates in IVF, compared with use of an hCG trigger alone. As a result of both these differences between a surge triggered naturally vs. with hCG, several groups (8–11) independently proposed the use of 1 or more bolus injections of GnRH-a to simulate a midcycle gonadotropin surge. The idea behind this proposal was that such a surge might be more physiologic in the release of both LH and FSH, and because of the shorter duration of LH rise, might prevent OHSS (11). In 1989, Lanzone et al. (8) published a series of 8 cases of timed intercourse or IUI in which 3 doses of 200 mg of the GnRH-a buserelin were administered 12 hours apart, resulting in a rise of LH and FSH for approximately 48 hours. All of the women ovulated, as determined by follicle collapse on ultrasound and elevated serum P levels. The luteal-phase length was similar to that in spontaneous ovulatory cycles. Pregnancies were not reported. In 1990, Bentick et al. (9) published a case report of the use of a single nasal spray of 50-mg buserelin, resulting in a midcycle surge of LH and FSH that lasted 16 hours, in a patient undergoing an IVF cycle. Mature oocytes were retrieved 34 hours later, and three day 2 were transferred. A twin pregnancy resulted after luteal support with vaginal P. In 1990, we (10) published a randomized trial of 18 women undergoing IVF, in which we compared a single bolus of 500 mg of leuprolide acetate to 5,000 international units (IU) of hCG as the trigger for follicular and oocyte maturation. Women were stimulated with 100 mg clomiphene citrate (CC) on days 5–9, and 75–150 IU of human menopausal gonadotropins (hMG) starting on cycle day 6. The women were 2
randomized to receive either a single hCG or GnRH-a injection when R2 follicles of 1.8-cm diameter were seen on ultrasound. We followed the women with serial blood sampling, conducted before and 1 hour after administration of GnRHa or hCG, and every 4 hours, for 24 hours. After this time period, blood samples were obtained before oocyte retrieval, and on every second day during the luteal phase until the onset of menses or determination of pregnancy. We found that serum LH and FSH levels were elevated for 34 hours after GnRH-a administration (Fig. 1). In contrast, serum hCG levels were still detectable 6 days after the administration of hCG, without any rise in serum FSH. Although luteal-phase levels of P and estradiol (E2) were lower in the GnRH-a–triggered cycles, compared with the hCG-triggered cycles, the luteal-phase length was similar in the 2 groups, and 3 women conceived and had live births without any luteal support. The results of this study provide strong evidence that the release of LH and FSH after a single administration of GnRH-a in an IVF cycle is able to complete the final stage of follicular maturation, resulting in the retrieval of fertilizable oocytes, with normal embryo development and pregnancy. In 1992, we (12) published a larger study of 179 women undergoing IVF who were randomized to receive 5,000 IU of hCG, or 500 mg of leuprolide acetate, to trigger final follicular maturation. In that study, pregnancy rates were the same with both triggers, despite the observation of luteal-phase deficiency in several of the GnRH-a–triggered cycles. Both E and P levels were significantly lower in the luteal phase. Furthermore, 16 women in the GnRH-a group (18%) had clinically short luteal phases (%10 days), despite vaginal P administration (low dose, 50 mg twice a day). The reason that luteal-phase deficiency was not seen in the early studies of GnRH-a triggering is unclear. One possibility is that the controlled ovarian stimulation in these early studies usually involved the use of CC, a selective E-receptor modulator
FIGURE 1
Mean ( standard error of the mean) serum LH concentrations (—) in the group of 9 women who were given GnRH-a, compared with hCG (o—o) and LH (D - D) concentrations in the group of 9 women who were given hCG for follicular maturation. The arrow indicates the time of GnRH-a and hCG administration. The figure is from (10), with permission. Casper. GnRH-agonist triggering. Fertil Steril 2015.
VOL. - NO. - / - 2015
Fertility and Sterility® with a half-life of up to 2 weeks (13). Another possibility is that the corpora lutea were rescued to some degree by low levels of endogenous LH that was released in response to the long-lasting estrogen receptor antagonism from residual CC activity. In our 1992 study (12), CC was not used for all the women, and many received purified FSH in the early follicular phase, along with hMG. Unfortunately, the question of whether the women with the short luteal phases received only gonadotropins cannot be answered at this point. More recently, a GnRH-a trigger has been utilized in GnRH-antagonist cycles, to induce the final stage of follicular maturation while reducing the risk of OHSS. This protocol works because GnRH-a have a greater affinity for the GnRH receptor than do GnRH antagonists. The GnRH-a thus displaces the antagonist from the receptor and results in activation of LH and FSH release. In addition, some data suggest that the GnRH antagonist may sensitize the pituitary response to GnRH (14). The GnRH-a trigger works well in antagonist IVF cycles to prevent OHSS by decreasing the duration of LH stimulation of the luteinized granulosa/theca cells. However, in the presence of a GnRH antagonist, the GnRH-a trigger results in luteal-phase deficiency that significantly lowers the implantation and pregnancy rates with fresh embryo transfers (ETs) (15). As described in the following sections of this month's Views and Reviews, the worldwide adoption of GnRH antagonist protocols has allowed the widespread use of GnRH-a for triggering final follicular maturation, especially for prevention of OHSS. Several strategies have been developed to improve the luteal phase, resulting in normal implantation and pregnancy rates with fresh ETs. In addition, the improvement of vitrification protocols for embryo cryopreservation has added the option of ‘‘segmentation’’ (16) of IVF cycles, in which all embryos are vitrified, and warmed ET occurs in subsequent nonstimulated cycles. Unquestionably, more developments will occur in the near future to optimize pregnancy rates, with GnRH-a or other more-natural triggers, for oocyte maturation and ovulation.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
REFERENCES 1. 2.
Hoff JD, Quigley ME, Yen SSC. Hormonal dynamics at midcycle: a reevaluation. J Clin Endocrinol Metab 1983;57:792–6. Dumalska L, Wu M, Morozova E, Liu R, van den Pol A, Alreja M. Excitatory effects of the puberty-initiating peptide kisspeptin and group I metabo-
VOL. - NO. - / - 2015
16.
tropic glutamate receptor agonists differentiate two distinct subpopulations of gonadotropin-releasing hormone neurons. J Neurosci 2008;28: 8003–13. Nathwani PS, Kang SK, Cheng KW, Choi KC, Leung PC. Regulation of gonadotropin-releasing hormone (GnRH) and its receptor gene expression by 17b-estradiol in cultured human granulose-luteal cells. Endocrinology 2000;141:1754–63. Yen SSC, Llerena O, Little B, Pearson OH. Disappearance rates of endogenous luteinizing hormone and chorionic gonadotropin in man. J Clin Endocrinol Metab 1968;28:1763–7. Nakano R, Mizuno T, Kotsuji F, Katayama K, Wshio M, Tojo S. Triggering of ovulation after infusion of synthetic luteinizing hormone releasing factor (LRF). Acta Obstet Gynecol Scand 1973;52:269–72. Casper RF, Sheehan KL, Yen SSC. Gonadotropin-estradiol responses to a superactive luteinizing hormone-releasing hormone agonist in women. J Clin Endocrinol Metab 1980;50:179–81. Lamb JD, Shen S, McCulloch C, Jalalian L, Cedars MI, Rosen MP. Folliclestimulating hormone administered at the time of human chorionic gonadotropin trigger improves oocyte developmental competence in in vitro fertilization cycles: a randomized, double-blind, placebo-controlled trial. Fertil Steril 2011;95:1655–60. Lanzone A, Fulghesu AM, Apa R, Caruso A, Mancuso S. LH surge induction by GnRH agonist at the time of ovulation. Gynecol Endocrinol 1989;3:213–20. Bentick B, Shaw RW, Iffland CL, Burford G, Bernard A. Case report: IVF pregnancy after induction of an ovulatory endogenous gonadotrophin surge using an LHRH agonist nasal spray. Hum Reprod 1990;5:570–2. Gonen Y, Balakier H, Powell W, Casper RF. Use of GnRH agonist to trigger follicular maturation for in vitro fertilization. J Clin Endocrinol Metab 1990; 71:918–22. Itskovitz J, Boldes R, Levron J, Erlik Y, Kahana L, Brandes J. Induction of a preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist. Fertil Steril 1991;56:213–20. Segal S, Casper RF. Gonadotropin-releasing hormone agonist versus human chorionic gonadotropin for triggering follicular maturation in in vitro fertilization. Fertil Steril 1992;57:1254–8. Young SL, Opsahl MS, Fritz MA. Serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate therapy in anovulatory infertile women. Fertil Steril 1999;71:639–44. Taylor JE, Miller BT, Gray KD, Scott RT Jr, Catherino WH, Segars JH. The mechanism responsible for the supraphysiologic gonadotropin surge in females treated with gonadotropin-releasing hormone (GnRH) agonist and primed with GnRH antagonist. Fertil Steril 2010;93:1668–75. Fauser BC, de Jong D, Olivennes F, Wramsby H, Tay C, Itskovitz-Eldor J, et al. Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization. J Clin Endocrinol Metab 2002;87: 709–15. Devroey P, Polyzos NP, Blockeel C. An OHSS-free clinic by segmentation of IVF treatment. Hum Reprod 2011;26:2593–7.
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Basic understanding of gonadotropin-releasing hormone–agonist triggering Robert F. Casper, M.D. Division of Reproductive Sciences, University of Toronto, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, and Toronto Centre for Advanced Reproductive Technology Fertility Partners, Toronto, Ontario, Canada
A single bolus of human chorionic gonadotropin (hCG) at midcycle has been the gold standard for triggering final oocyte maturation and ovulation in assisted reproductive technology cycles. More recently, gonadotropin-releasing hormone (GnRH)-agonist (GnRH-a) triggering has been introduced. The GnRH-a trigger may allow a more physiologic surge of both luteinizing hormone (LH) and follicle-stimulating hormone, although whether the combined surge will result in improved oocyte and embryo quality remains to be seen. However, the short duration of the LH surge with the GnRH-a trigger (approximately 34 hours) has been shown to be beneficial for preventing ovarian hyperstimulation syndrome in GnRH antagonist in vitro fertilization (IVF) cycles when compared with the prolonged elevation of hCG (R6 days) after exposure to an hCG bolus. This review discusses the physiologic basis for the use of a GnRH-a trigger in IVF cycles. (Fertil SterilÒ 2015;-:-–-. Ó2015 by American Society for Reproductive Medicine.) Use your smartphone Key Words: Gonadotropin-releasing hormone (GnRH) agonist, human chorionic gonadotropin to scan this QR code (hCG), in vitro fertilization (IVF), ovulation induction, ovarian hyperstimulation syndrome and connect to the (OHSS) Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/casperr-gnrh-agonist-triggering/
I
n the follicular phase of natural menstrual cycles, gonadotropinreleasing hormone (GnRH) is released in hourly pulses from the mediobasal hypothalamus into the pituitary portal system, and binds to GnRH receptors on gonadotropes in the anterior pituitary. The result is the hourly release of small, discrete pulses of folliclestimulating hormone (FSH) and luteinizing hormone (LH), which are required for follicular growth and estrogen (E) secretion in the ovary. At midcycle, in the presence of rapidly rising E levels and a small rise in progesterone
(P) levels, a midcycle gonadotropin surge occurs, which triggers ovulation approximately 36–40 hours later. In reality, the midcycle surge represents a dramatic increase in the amplitude of the hourly LH and FSH pulses and lasts approximately 48 hours in humans (1). The increased amplitude of the LH and FSH pulses is thought to be facilitated by positive feedback of E on kisspeptin neurons in the anteroventral periventricular nuclei of the hypothalamus (2), and through E-mediated up-regulation of GnRH receptors on the gonadotropes in the anterior pituitary (3).
Received December 10, 2014; revised December 18, 2014; accepted December 19, 2014. R.F.C. is a board member of AbbVie, Actavis, Bayer, Ferring, EMD Serono, Merck, OvaScience, and Pfizer; is a consultant for Fertility Nutraceuticals; is employed by Insception Cord Blood Bank; has provided expert testimony for the Canadian Medical Protective Association; has received grants from Merck, EMD Serono, and Ferring; has received payment for lectures from AbbVie, Actavis, Bayer, and EMD Serono; holds patents with ZircLight and Ortho-McNeil; receives royalties from Jannsen-Ortho, Teva, and UpToDate; and holds stock in Insception, OvaScience, and Circadian-Zirclight. Reprint requests: Robert F. Casper, M.D., 150 Bloor Street West, Suite 210, Toronto, Ontario M5S2X9, Canada (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.12.129 VOL. - NO. - / - 2015
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
Assisted reproductive techniques (ART), such as in vitro fertilization (IVF) and intrauterine insemination (IUI) rely on accurate timing of ovulation for retrieving oocytes from preovulatory follicles and optimal in vivo insemination of oocytes. Luteinizing hormone itself is impractical for use as an ovulation trigger, because of its short half-life in circulation (rapid phase t1/2 is 21 minutes) (4). Because the biological activity of human chorionic gonadotropin (hCG) is similar to that of LH, since approximately the mid-1970s, a bolus of hCG (rapid phase t1/2 is 12 hours) (4) has been used to trigger the final stage of follicular and oocyte maturation, with ovulation occurring approximately 38–40 hours later, similar to the timing in natural ovulation. The hCG trigger remains the gold standard today. In 1971, the amino acid sequence of GnRH was determined independently in the laboratories of Andrew Schally and Roger Guillemin, and 1
VIEWS AND REVIEWS synthetic GnRH was developed. Schally and Guillemin shared one-half of the Nobel Prize for Physiology or Medicine in 1977 for their work on brain peptides, especially thyrotropin-releasing hormone (TRH) and GnRH. As early as 1973, Nakano et al. (5), in Japan, showed that ovulation could be induced in the human by infusion of 600 mg of synthetic GnRH for 6 hours, followed by a subcutaneous bolus dose of 400 mg. The need for intravenous infusion made this idea impractical, and it was abandoned. During the late 1970s, the synthesis of GnRH agonists (GnRH-a) was accomplished. The GnRH-a all have a similar structure, with substitution of an inactive amino acid at position 6, to decrease degradation by endogenous peptidases, and alteration or deletion of the amino acid in position 10, which resulted in increased receptor affinity. The combination of these changes led to GnRH activity that is approximately 100–200 times greater than that of native GnRH in releasing LH and FSH from the pituitary (6). As described, a bolus of hCG has been the gold standard for simulating an LH surge and inducing ovulation. However, the increased glycosylation of hCG results in a longer biological effect when it is used as a trigger, and this may create a predisposition to ovarian hyperstimulation syndrome (OHSS) in women who are at risk for this complication of gonadotropin stimulation. In addition, in spontaneous cycles, the gonadotropin surge involves both LH and FSH. Whether FSH has a physiologic role in oocyte maturation is unknown, but recent work has suggested that it might. Lamb et al. (7) added a bolus of FSH to the hCG trigger and showed better oocyte recovery and fertilization rates in IVF, compared with use of an hCG trigger alone. As a result of both these differences between a surge triggered naturally vs. with hCG, several groups (8–11) independently proposed the use of 1 or more bolus injections of GnRH-a to simulate a midcycle gonadotropin surge. The idea behind this proposal was that such a surge might be more physiologic in the release of both LH and FSH, and because of the shorter duration of LH rise, might prevent OHSS (11). In 1989, Lanzone et al. (8) published a series of 8 cases of timed intercourse or IUI in which 3 doses of 200 mg of the GnRH-a buserelin were administered 12 hours apart, resulting in a rise of LH and FSH for approximately 48 hours. All of the women ovulated, as determined by follicle collapse on ultrasound and elevated serum P levels. The luteal-phase length was similar to that in spontaneous ovulatory cycles. Pregnancies were not reported. In 1990, Bentick et al. (9) published a case report of the use of a single nasal spray of 50-mg buserelin, resulting in a midcycle surge of LH and FSH that lasted 16 hours, in a patient undergoing an IVF cycle. Mature oocytes were retrieved 34 hours later, and three day 2 were transferred. A twin pregnancy resulted after luteal support with vaginal P. In 1990, we (10) published a randomized trial of 18 women undergoing IVF, in which we compared a single bolus of 500 mg of leuprolide acetate to 5,000 international units (IU) of hCG as the trigger for follicular and oocyte maturation. Women were stimulated with 100 mg clomiphene citrate (CC) on days 5–9, and 75–150 IU of human menopausal gonadotropins (hMG) starting on cycle day 6. The women were 2
randomized to receive either a single hCG or GnRH-a injection when R2 follicles of 1.8-cm diameter were seen on ultrasound. We followed the women with serial blood sampling, conducted before and 1 hour after administration of GnRHa or hCG, and every 4 hours, for 24 hours. After this time period, blood samples were obtained before oocyte retrieval, and on every second day during the luteal phase until the onset of menses or determination of pregnancy. We found that serum LH and FSH levels were elevated for 34 hours after GnRH-a administration (Fig. 1). In contrast, serum hCG levels were still detectable 6 days after the administration of hCG, without any rise in serum FSH. Although luteal-phase levels of P and estradiol (E2) were lower in the GnRH-a–triggered cycles, compared with the hCG-triggered cycles, the luteal-phase length was similar in the 2 groups, and 3 women conceived and had live births without any luteal support. The results of this study provide strong evidence that the release of LH and FSH after a single administration of GnRH-a in an IVF cycle is able to complete the final stage of follicular maturation, resulting in the retrieval of fertilizable oocytes, with normal embryo development and pregnancy. In 1992, we (12) published a larger study of 179 women undergoing IVF who were randomized to receive 5,000 IU of hCG, or 500 mg of leuprolide acetate, to trigger final follicular maturation. In that study, pregnancy rates were the same with both triggers, despite the observation of luteal-phase deficiency in several of the GnRH-a–triggered cycles. Both E and P levels were significantly lower in the luteal phase. Furthermore, 16 women in the GnRH-a group (18%) had clinically short luteal phases (%10 days), despite vaginal P administration (low dose, 50 mg twice a day). The reason that luteal-phase deficiency was not seen in the early studies of GnRH-a triggering is unclear. One possibility is that the controlled ovarian stimulation in these early studies usually involved the use of CC, a selective E-receptor modulator
FIGURE 1
Mean ( standard error of the mean) serum LH concentrations (—) in the group of 9 women who were given GnRH-a, compared with hCG (o—o) and LH (D - D) concentrations in the group of 9 women who were given hCG for follicular maturation. The arrow indicates the time of GnRH-a and hCG administration. The figure is from (10), with permission. Casper. GnRH-agonist triggering. Fertil Steril 2015.
VOL. - NO. - / - 2015
Fertility and Sterility® with a half-life of up to 2 weeks (13). Another possibility is that the corpora lutea were rescued to some degree by low levels of endogenous LH that was released in response to the long-lasting estrogen receptor antagonism from residual CC activity. In our 1992 study (12), CC was not used for all the women, and many received purified FSH in the early follicular phase, along with hMG. Unfortunately, the question of whether the women with the short luteal phases received only gonadotropins cannot be answered at this point. More recently, a GnRH-a trigger has been utilized in GnRH-antagonist cycles, to induce the final stage of follicular maturation while reducing the risk of OHSS. This protocol works because GnRH-a have a greater affinity for the GnRH receptor than do GnRH antagonists. The GnRH-a thus displaces the antagonist from the receptor and results in activation of LH and FSH release. In addition, some data suggest that the GnRH antagonist may sensitize the pituitary response to GnRH (14). The GnRH-a trigger works well in antagonist IVF cycles to prevent OHSS by decreasing the duration of LH stimulation of the luteinized granulosa/theca cells. However, in the presence of a GnRH antagonist, the GnRH-a trigger results in luteal-phase deficiency that significantly lowers the implantation and pregnancy rates with fresh embryo transfers (ETs) (15). As described in the following sections of this month's Views and Reviews, the worldwide adoption of GnRH antagonist protocols has allowed the widespread use of GnRH-a for triggering final follicular maturation, especially for prevention of OHSS. Several strategies have been developed to improve the luteal phase, resulting in normal implantation and pregnancy rates with fresh ETs. In addition, the improvement of vitrification protocols for embryo cryopreservation has added the option of ‘‘segmentation’’ (16) of IVF cycles, in which all embryos are vitrified, and warmed ET occurs in subsequent nonstimulated cycles. Unquestionably, more developments will occur in the near future to optimize pregnancy rates, with GnRH-a or other more-natural triggers, for oocyte maturation and ovulation.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
REFERENCES 1. 2.
Hoff JD, Quigley ME, Yen SSC. Hormonal dynamics at midcycle: a reevaluation. J Clin Endocrinol Metab 1983;57:792–6. Dumalska L, Wu M, Morozova E, Liu R, van den Pol A, Alreja M. Excitatory effects of the puberty-initiating peptide kisspeptin and group I metabo-
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