GnRH agonist as a luteal support in IVF cycle: mini-review—is there a role?
Middle East Fertility Society Journal volume 27, Article number: 18 (2022)
It has been established that assisted reproductive technology (ART) cycles are usually accompanied by a defective luteal phase, and that luteal phase support (LPS) is mandatory to improve reproductive outcomes. This review aims to summarize the hypothesis, safety and current evidence about GnRH agonist as a luteal phase support in ART.
There are many regimens of luteal phase support to improve ART outcomes in women undergoing fresh and thawed cycles. Luteal phase support drugs include progesterone, human chorionic gonadotropin, gonadotropin-releasing hormone agonist, estradiol, and recombinant luteinizing hormone. There is some debate about optimal drugs and timing for start of LPS in ART cycles.
Although most centers support luteal phase by vaginal progesterone, GnRH agonist is a debatable drug for luteal support cycles.
Despite improvement in several aspects of IVF, implantation rate is still low . In fact, only one-third of IVF cycles results in a live birth. Moreover, only a few numbers of all embryos transferred succeed to implant . During the luteal phase in natural cycles, the corpus luteum under the effect of LH, produce progesterone hormone which induces the secretory changes of the endometrium, to facilitate implantation by increased thickness and quality .
Currently, the luteal phase defect in ART is due to high level of steroids leading to reduced levels of LH (known as premature luteolysis) . Aspiration of the granulosa cells during ovum pickup, and the use of gonadotropin analogs (agonist or antagonist) during controlled ovarian stimulation (COS) can interfere with the production of progesterone during the luteal phase . The drawbacks of luteal phase deficiency are decreased implantation rate, pregnancy rate and an increased miscarriage rate .
Luteal phase supplement has an important and positive effect on the reproductive outcomes of IVF cycles in comparison to no treatment . The commonest forms of luteal phase supplementation is progesterone . GnRH agonist as luteal phase support in ART cycles has currently been an area of research.
Methods of luteal phase support
Progesterone is considered the preferred drug for luteal phase support in ART cycles. Cochrane meta-analysis in 2015 concluded that progesterone supplement resulted in higher live birth rates when compared to placebo or no treatment . The route and dosage of different progesterone formulations according to the European Society of Human Reproduction and Embryology (ESHRE) guidelines are 50 mg of intramuscular progesterone, 25 mg of subcutaneous progesterone and 600 mg of micronized vaginal progesterone, 90 mg daily for vaginal progesterone gel daily may have the same effect . Progesterone can be started between the evening of the day of oocyte retrieval and up to day 3 post-ovum pickup [11, 12]. There is no significant difference in live birth rate among patients who discontinued progesterone at the time of the pregnancy test and those who continued progesterone administration up to 7 weeks .
HCG is similar to LH and stimulate the corpus luteum to produce progesterone during the luteal phase. HCG injections as a LPS have no superior effect on live birth rate when compared to progesterone and compared to a combination of progesterone and estrogens . LPS with HCG injections is associated with a higher rate of ovarian hyperstimulation syndrome [9, 15].
Recently, the effect of GnRH agonist as a method of luteal phase support in ART cycles became an aspect of research in different studies [16,17,18,19]. A single dose of GnRH agonist in mid luteal phase with the routine luteal phase support significantly increased implantation rate and take-home baby in ART cycles . The benefits from GnRH agonist injection in luteal phase in ICSI cycles has been reported in many studies [20, 21].
The exact mechanisms of the effect of GnRHa as luteal phase support are unknown. GnRHa have an effect on corpus luteum, through LH , on endometrium , and on embryo . GnRH receptors are also expressed with a high levels during luteal phase in both stromal and epithelial cells of endometrium [24, 25]. LH release has a beneficial effect on endometrium by stimulation of angiogenic factors, growth factors, and cytokines increasing the chance of implantation [17, 23]. GnRH receptors are also present on embryos . GnRHa has a direct effect on embryos by regulation of the synthesis and release of human chorionic gonadotropin in embryos and placenta [17, 26].
GnRHa can be given by several regimens. Triptorelin can be added as a single bolus after 6–7 days after oocyte retrieval [26, 27] or 0.1 mg triptorelin can be offered every other day from the day of transferring embryos for total 5 days . Also, Buserelin spray 100 Mcg can be given daily for 14 days during the luteal phase .
The effect of GnRHa in the first days of pregnancy is still subject of debate in many studies [30, 31]. Animal studies did not show teratogenic effects of GnRHa on embryos . Up to 1998, more than 340 spontaneous pregnancies were exposed to GnRHa administration in the mid luteal phase. The incidence of congenital malformation and pregnancy loss were not different from general population . GnRH depots were routinely used in many ICSI long protocol . The active GnRH peptide in the depot form can be detected up to 6 and 7 weeks after their administration with no effect to the embryo . Addition of GnRH-a to luteal support is relatively safe and effective .
In a meta-analysis, administration of GnRH-a as one dose (0.1 mg of triptorelin 6 days after oocyte retrieval) increased the implantation, clinical pregnancy rate per transfer, and ongoing pregnancy rate . Another meta-analysis concluded that GnRHa administration during luteal phase increased live birth rate . According to Cochrane in 2015, GnRHa improved Live birth when added to progesterone as a luteal support. Adding a single dose of GnRHa (triptorelin acetate, 0.1 mg) on day 6 after the oocyte retrieval had a similar effect as three doses of HCG .
In a systematic review and meta-analysis of about 20 studies including thawed cycles adding GnRHa in luteal phase increased clinical pregnancy rate in fresh and frozen thawed cycles . A meta-analysis in 2020 included about 3584 cycles from 13 randomized controlled trials concluded that adding of GnRH-a for luteal support not only improved the clinical pregnancy rate, ongoing pregnancy rate, live birth rate, but also decreased the percentage of abortion . In frozen thawed transfer cycles, a single dose of 0.1 mg triptorelin at the time of implantation (3 days after embryo transfer) did not increase reproductive outcomes .
In ESHRE guidelines 2019, current evidence indicates higher live birth rate and pregnancy rates with GnRH agonist bolus, repeated doses alone, or in addition to progesterone for LPS, but still it can only be used in the research (not recommend for practical usage).
Several weak points should be documented here regarding this review. A lot of studies were retrospective and non-randomized that may have selection bias. There were no studies evaluate the effects of GnRH-a as a luteal support on the mental or behavior development of neonates and children. Evidence from most systematic reviews and meta-analysis was of low or very low quality. Despite all these limitations, most studies support the usage of GnRHa as apart from luteal phase support. GnRHa can improve reproductive outcomes. After this review, we suggest individualized LPS could improve LBR. More research should be conducted regarding safety, risks, and long-term effects of GnRH agonist on children.
Luteal phase support in ART cycles is a very dynamic field. Whereas progesterone is a mainstay in current practice. GnRH agonist for luteal support needs more assessment. Probably research should focus on obstetric and neonatal outcomes in addition to live birth.
Availability of data and materials
Assisted reproductive technology
Luteal phase support
Controlled ovarian stimulation
European Society of Human Reproduction and Embryology
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Maghraby, H., Abdelbadie, A.S., Aboali, A. et al. GnRH agonist as a luteal support in IVF cycle: mini-review—is there a role?. Middle East Fertil Soc J 27, 18 (2022). https://doi.org/10.1186/s43043-022-00109-3