© Springer India 2015
Surveen Ghumman (ed.)Principles and Practice of Controlled Ovarian Stimulation in ART10.1007/978-81-322-1686-5_1717. Ovulation Trigger: HCG vs. GnRH Agonist
(1)
Department of Obstetrics and Gynaecology, ART Centre, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, Delhi, 110029, India
(2)
Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi, Delhi, India
Abstract
HCG triggering is vital for the final oocyte maturation in the in vitro fertilization cycle. In recent years, with the increase in the prevalence of polycystic ovarian disease and use of antagonist protocol for ovarian stimulation, it is possible to minimize the risk of ovarian hyperstimulation syndrome with the use of GnRH agonist in place of HCG for triggering ovulation. Some of the initial studies reported lower pregnancy rates due to defective luteal phase after GnRH trigger. But the results are encouraging with addition of rescue dose of HCG (15,000 IU) and after modified luteal phase support. It is a boon for primary prevention of ovarian hyperstimulation (OHSS) in PCOS patients.
Keywords
Ovulation triggeringGnRH agonistOvarian hyperstimulation syndrome (OHSS)17.1 Introduction
Ovulation is one of the most crucial steps in female reproduction. In natural cycles a single dominant follicle ruptures and releases a viable oocyte from the ovary; only after this process will the oocyte be made available to the sperm for fertilization. The oocyte is arrested at the prophase of first meiotic division, which resume only after preovulatory LH surge. LH receptors are present on the granulosa cells and in response to LH surge; there is expression of epidermal growth factors which act on cumulus cells, thereby triggering oocyte maturation.
It is mainly the LH surge that initiates a cascade of events including resumption of meiosis in the oocyte, expansion of cumulus, synthesis of prostaglandins responsible for follicular rupture, and luteinization of granulosa cells that produce progesterone following ovulation. Increasing concentration of progesterone causes a rise in activity of proteolytic enzymes that result in rupture of the follicular wall.
Since the endogenous LH surge is blocked in IVF cycle with the help of GnRH agonist or antagonist, some trigger agent is required for artificially inducing LH surge for scheduling oocyte retrieval.
17.2 Agents Used for Ovulation Trigger
Ever since the discovery of human-assisted reproductive techniques, there has been lots of research regarding the ideal trigger agent. Though recombinant LH has also been used, choice revolves around HCG and GnRH agonist.
17.2.1 Recombinant LH as a Trigger Agent
Study done by Aboulghar et al. to evaluate LH as ovulation trigger agent concluded significant increase in cost of treatment, as well as lower implantation rate and a higher OHSS rate (upto 12 %) with the use of LH [1].
17.2.2 HCG as a Trigger Agent
HCG has been used for decades for the final maturation of the follicle. The logic behind the use of HCG is its homology to LH. So both molecules bind to the same receptor, the LH/HCG receptor. It can be used by i.m. or s.c. route.
17.2.2.1 Dose
In an early randomized trial [2], 2,000, 5,000, and 10,000 IU HCG were administered intramuscularly. The proportion of patient with oocyte recovery was significantly lower in the 2,000 IU-dose group (77.3 %) as compared to 5,000 and 10,000 IU groups, which were comparable (99.5 % and 98.1 %). Therefore the recommended dose schedule is 5,000–10,000 IU.
17.2.2.2 Pharmacokinetics
There is difference in pharmacokinetics of LH and HCG. The half-life of HCG is more than 24 h, as compared to LH which is 60 min only [3, 4]. The longer half-life is responsible for prolonged luteotropic effect, resulting in supraphysiological level of steroid [5], increasing the risk of OHSS [6]. Its prolonged luteotropic effect is sometimes responsible for false-positive pregnancy test when HCG is given in the luteal phase.
17.2.2.3 Timing of Oocyte Retrieval After HCG Injection
Timing of oocyte retrieval after HCG administration is very important as if it is given too early, this will lead to greater number of metaphase II oocyte, whereas a delayed retrieval might result in premature ovulation, resulting in decreased number of oocyte retrieved. Based on the available evidences [7, 8], oocyte retrieval should be timed between 34 and 38 h.
17.2.2.4 Disadvantage of HCG
Increased risk of ovarian hyperstimulation syndrome (OHSS) is the main disadvantage when using HCG as the trigger. This is the most feared complication of ART with incidence of 0.7 % in all the stimulated cycles [9]. Moreover, in some cases, it can even be life threatening. According to the UK-based Confidential Enquiry into Maternal and Child Health 7th report, 2007, there have been three deaths due to OHSS in the year 2003–2005 [10]. Ovarian hyperstimulation syndrome is still underreported in many parts of world. It is often the prime cause for cycle cancellation.
Another problem is requirement of large quantities of urine for their extraction. This leads to its unreliable pharmaceutical activity and possibility of allergic reaction [11]. This issue has been sorted out with the use of recombinant HCG, 250 μg s.c., which is considered equally effective, and the incidence of local reaction at injection site is significantly lower [12, 13].
17.2.2.5 Advantages of hCG
hCG can be used in both GnRH agonist as well as antagonist cycle. The biggest advantage of hCG is the vast experience of its use which is obviously lacking with GnRH agonists.
17.2.3 GnRH Agonist as a Trigger Agent
In the recent years, there has been a shift of interest toward the use of GnRH agonist as an ovulation trigger agent to avoid OHSS in stimulated cycles, particularly in patients with polycystic ovarian syndrome (PCOS).
17.2.3.1 Indication for Use
In the long agonist protocol in which GnRH agonist are used for downregulation, GnRH agonist cannot be used as a trigger agent. But in the short protocol involving GnRH antagonist, GnRH agonist has got its role. As demonstrated by several studies, a single bolus of GnRH agonist causes LH surge and triggers ovulation.
17.2.3.2 Pharmacokinetics and Dose
Chillik et al. [14] in their studies on monkeys has stated that tonic gonadotropins remain suppressed under the effect of GnRH antagonist treatment, but acute LH release can be elicited in a GnRH bolus. In humans, Felberbaum et al. [15] has demonstrated that the pituitary retains its responsiveness to GnRH agonist under GnRH antagonist treatment. Similar reports were demonstrated by Olivennes et al. [16]. The extent of pituitary suppression by use of GnRH antagonist is somewhat dose dependent [17].
With the minimal effective dose of GnRh antagonist (0.25 mg daily; Gainerelix Dose Finding group, 1998), it is suggested that ovulation can be safely and effectively triggered by a single dose of GnRH agonist (triptorelin 0.2 mg s.c., buserelin 0.5 mg s.c., or leuprolide acetate 1 mg) [15, 17, 18].
There exists a difference between the natural LH surge and that which is GnRH agonist induced. The LH surge of natural cycle is characterized by three phases, with a total duration of 48 h [19], whereas that induced by GnRH agonist is of two phases only, with duration of 24–36 h [6]. Thus the response elicited by GnRH agonist is not that pronounced in contrast to that produced by HCG which is exaggerated due to its prolonged luteotropic effect [20]. Because of this, the risk of OHSS is almost abolished by use of GnRH as reported in various studies [5, 20–26].
17.2.3.3 Advantage of GnRH Agonist as Ovulation Trigger
OHSS is prevented to a great extent when GnRH agonist is used for ovulation trigger. It becomes especially important in those patients who are more prone to develop OHSS. This has been recently confirmed in a Cochrane meta-analysis [26]. The same concept was used by Sismanoglu et al. [27] in their study, which they designed to evaluate GnRH agonist in the donor population. Egg donors are usually selected from the young, normally fertile women and thus more prone to develop ovarian hyperstimulation.
The retrieval of more number of mature oocyte [metaphase 2] has been reported with GnRH agonist triggering [28].
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
