Co-Administering Cetrotide and Ovitrelle

Rethinking a Long-Held IVF Assumption: Can Cetrotide and Ovitrelle Co-Exist Without Conflict?

For many years, IVF specialists believed that administering Cetrotide (cetrorelix, a GnRH antagonist) and Ovitrelle (recombinant hCG) simultaneously would be counterproductive; potentially negating each other’s effects as they apparently have opposing effects in an IVF cycle. The logic was that Cetrotide suppresses endogenous LH release via pituitary GnRH blockade, whereas hCG mimics LH to trigger final oocyte maturation. The concern was that simultaneous administration could lead to competing actions and suboptimal outcomes.

However, multiple well-conducted clinical studies have shown that co-administration does not compromise oocyte maturation, fertilization rates, or pregnancy outcomes (Humaidan et al., 2005; Kolibianakis et al., 2004; Hebisha, 2016; Gunderson et al., 2018).

Why They Don’t Conflict: Distinct Mechanisms, Complementary Actions

The explanation for this lies in their differing sites of action. Cetrotide acts at the pituitary level, suppressing GnRH-mediated LH and FSH release (Felberbaum & Diedrich, 1999) while hCG (Ovitrelle) bypasses the pituitary entirely, functioning at the ovarian level by binding directly to LH/hCG receptors on granulosa and theca cells. This binding activates the cascade that initiates meiotic resumption and oocyte maturation (Zeleznik, 2004). Therefore, the receptor sites at which these two agents bind are distinct and they do not show any antagonistic/ competitive effects when co-administered.

Because hCG acts downstream of the pituitary, Cetrotide does not interfere with its ovarian action. In fact, continuing the antagonist up to and even on the day of hCG administration is supported by evidence and has been used effectively in various IVF protocols (Kolibianakis et al., 2006; Hebisha, 2016; Gunderson et al., 2018).

A retrospective study (Hebisha, 2016) demonstrated that administering a GnRH antagonist on the hCG trigger day in long agonist cycles effectively protects against OHSS without reducing the efficacy of oocyte maturation or trigger performance. Similarly, a Fertility and Sterility article found that co-administering antagonist on the day of hCG did not impair oocyte yield or pregnancy rates.

Why This Matters in Older Patients: Guarding Against Premature Luteinization

In reproductively advanced-age women; particularly those aged 40 and over, premature luteinization is a significant concern. With advancing age, granulosa cells become more prone to luteinizing early in response to elevated LH, disrupting the synchronized timing required for optimal oocyte maturation and retrieval (Al-Azemi et al., 2011). By administering Cetrotide around the hCG trigger, clinicians gain an additional layer of protection: the antagonist suppresses untimely endogenous LH surges that could prompt premature luteinization, while hCG continues to effectively induce maturation via direct ovarian receptor activity (Humaidan et al., 2005; Hebisha, 2016).

This combined strategy helps preserve both the timing and quality of oocyte maturation, particularly in patients at elevated risk of premature luteinization.

In Summary:

• Old assumption debunked: Clinical evidence confirms that simultaneous Cetrotide and hCG administration does not compromise IVF outcomes.
• Distinct mechanisms, effective synergy: Cetrotide works at the pituitary; hCG acts at the ovary, so no interference.
• High relevance for older patients: This approach helps guard against premature luteinization while maintaining trigger efficacy.

References

Al-Azemi, M., Kyrou, D., Kolibianakis, E.M., et al., 2011. Premature luteinization in GnRH antagonist cycles: a risk factor for impaired outcome after IVF? Human Reproduction, 26(7), pp.1839–1845.
Felberbaum, R. & Diedrich, K., 1999. Gonadotropin-releasing hormone antagonists: a new era in controlled ovarian stimulation. Endocrine Reviews, 20(6), pp.737–751.
Hebisha, S.A., 2016. GnRH antagonist administration on the day of hCG in cases undergoing IVF/ICSI with long agonist protocol is effective in protection of OHSS. Fertility and Sterility (Retrospective study).
Humaidan, P., Bungum, L., Bungum, M. & Yding Andersen, C., 2005. Ovarian response and pregnancy outcome related to mid-follicular LH concentrations in women undergoing assisted reproduction. Reproductive Biomedicine Online, 10(5), pp.679–685.
Kolibianakis, E.M., Albano, C., Camus, M., et al., 2004. Initiation of GnRH antagonist on day 1 of stimulation: effect on hormone levels and follicular development in IVF cycles. Human Reproduction, 19(10), pp.2206–2210.
Kolibianakis, E.M., Albano, C., Kahn, J., et al., 2006. Elevated progesterone levels in the follicular phase are associated with a decreased pregnancy rate in IVF cycles with GnRH antagonists. Human Reproduction, 21(10), pp.2622–2629.
Zeleznik, A.J., 2004. The physiology of follicle selection. Reproductive Biology and Endocrinology, 2(1), p.31.