A boon for infertility patients: Ovarian stimulation with GnRH antagonist

INTRODUCTION

Ovarian stimulation is an important factor for the success of in vitro fertilization (IVF). There are two mechanisms involved in controlled ovarian stimulation (COH) − gonadotropin-releasing hormone (GnRH) agonist and antagonist protocol. GnRH agonists initially produce a stimulation of the gonadotrophs resulting in secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) and the expected gonadal response. Although continuous administration initially has the same effect, it is subsequently followed by down-regulation and inhibition of the pituitary–gonadal axis by clustering and internalization of the specific receptors. GnRH antagonists promptly suppress pituitary gonadotropin by competitive GnRH-receptor binding, thereby avoiding the initial stimulatory phase of the agonists and induce a rapid decrease in FSH and LH levels, preventing and interrupting premature LH surges and do not require desensitization period, so can be used in late follicular phase.^[1] GnRH antagonist protocol produced a comparable ovarian response, embryo development, and pregnancy rates to GnRH agonist regime requiring lesser amounts of gonadotropins. Moreover, GnRH antagonist protocol required a shorter stimulation period plus fewer side-effects.^[2] In India, the agonist protocol is time tested and still very popular. The infertility specialists are more familiar with agonist protocol and the batching is easier with this protocol. The antagonist protocol is just gaining popularity and in our center, we are using the antagonist protocol in 90% cases. The aim of the present study was to assess the clinical outcomes using GnRH antagonists in self-cycles in a private center in Delhi, India.

MATERIALS AND METHODS

A retrospective analysis was made of all GnRH antagonist cycles undergoing self-IVF-embryo transfer (IVF-ET) cycles. Between July 2014 and December 2015, 510 patients underwent ovarian stimulation using the GnRH antagonist protocol.

RESULTS

The demographic profile for the patients is summarized in Table 1. The mean age was 31.6 (range 24–40) years. All patients had normal cycle day 2 serum FSH levels (5–8 mIU/ml) and serum estradiol levels (35–50 pg/ml). Among all 510 subjects recruited, 313 (61.4%) presented with primary infertility and the rest 197 women (38.6%) were associated with secondary infertility. The mean duration of infertility was 6.3 years, ranging from 2 to 18 years.

Table 1 Demographic profile

Pregnancy rates

According to age group, higher pregnancy rates were seen in age <35 years [Table 2].

Table 2 Age distribution

The average numbers of DOS were 10.3 ranging from 10 to 12 days and the total doses used were between 2400 IU and 4500 IU. The mean number of oocytes retrieved was 13.6 ranging from 11 to 16. All ETs were done on day 2/3/5 and average number of embryos transferred was 2.9 [Table 3]. There was no cancelation of cycle due to poor response. No ovarian hyperstimulation syndrome (OHSS) case had been noted during the study period. The total pregnancy rate was 43.7% (223/510) and out of 223 pregnancies, 16 were biochemical pregnancies. Thus, the clinical pregnancy rate was 40.6%.

Table 3 IVF ET results

DISCUSSION

The present study evaluated the effectiveness of GnRH antagonist in IVF cycles. The aim of using GnRH antagonists in IVF is the inhibition of a premature LH rise which could lead to premature luteinization, follicle maturation arrest, and asynchrony of oocyte maturation. The use of GnRH antagonists in IVF is characterized by many advantages:^[3]

1. Prevention of premature LH increase is easier and takes less time. GnRH antagonists act within a few hours after their administration and thus they can be administered only when there is a risk for an LH surge. This is in contrast to GnRH agonists where pituitary down-regulation occurs only after 7–10 days.

2. The initial stimulation by GnRH agonists can induce cyst formation, which is avoided with GnRH antagonists.

3. No hot flushes are observed with GnRH antagonists, as their use does not result in profound hypo-estrogenaemia observed with GnRH agonists.

4. Inadvertent administration of the GnRH analog in early pregnancy can be avoided, as GnRH antagonist is administered in the mid-follicular phase.

5. Requirements for exogenous gonadotropins are reduced, rendering ovarian stimulation less costly.

6. Duration of ovarian stimulation protocols is shortened, improving patient comfort and compliance.

In India, most of the IVF specialists are using long protocol with agonist and are still doing batching. GnRH antagonist protocol produced a comparable ovarian response, embryo development, and pregnancy rates to GnRH agonist regime requiring lesser amounts of gonadotropins. Lainas et al.^[4] compared the flexible GnRH antagonist and the GnRH agonist long protocols in 220 polycystic ovary syndrome (PCOS) patients undergoing IVF treatment, and found that the flexible GnRH antagonist protocol was associated with a similar ongoing pregnancy rate (50.9 versus 47.3%), lower incidence of OHSS grade II, lower gonadotropin requirement, and shorter duration of stimulation, compared with GnRH agonist. Devroey et al.^[5] performed meta-analyses of various studies and stated that the treatment with antagonists was associated with similar live birth rates but reduced treatment burden (duration and side effects) and less risk of ovarian stimulation syndrome, compared with GnRH agonist long protocols. In an update of a Cochrane review, 45 randomized controlled trials (RCTs) (n = 7511) comparing the antagonist to the long agonist protocols were included and concluded that the use of antagonist compared with long GnRH agonist protocols was associated with a large reduction in OHSS [29 RCTs; odds ratio (OR) 0.43, 95% confidence interval (CI) 0.33–0.57] and there was no evidence of a difference in live-birth rate (9 RCTs; OR 0.86, 95% CI 0.69–1.08) or ongoing pregnancy (28 RCTs; OR 0.87, 95% CI 0.77–1.00).^[6] In poor responders also, GnRH antagonist had effective role. Kim et al.^[7] investigated the effectiveness of GnRH antagonist multiple-dose protocol (MDP) with oral contraceptive pill (OCP) pretreatment in 120 poor responders undergoing IVF/ICSI, compared with GnRH antagonist MDP without OCP pretreatment and GnRH agonist low-dose long protocol (LP) and concluded that GnRH antagonist MDP with OCP pretreatment was at least as effective as GnRH agonist low-dose LP in poor responders and can benefit the poor responders by reducing the amount and duration of FSH required for follicular maturation.

CONCLUSION

GnRH antagonists in ovarian stimulation for IVF is a very friendly protocol, requiring smaller dose of gonadotropins and shorter stimulation period, requiring only 2–3 times of follicular monitoring in experienced hands with good pregnancy rate.