Luteal phase support after hCG trigger: does it support or mitigate hCG-induced potential harms?

The administration of human chorionic gonadotropin (hCG) for final oocyte maturation and ovulation has been a cornerstone of in vitro fertilization (IVF) since its inception. hCG mimics the natural mid-cycle luteinizing hormone (LH) surge due to its ability to bind and activate ovarian LH receptors. Historically introduced as a urinary extract and now predominantly in recombinant form, hCG remains the standard agent for ovulation triggering. The most recent ESHRE guidelines endorse hCG triggers, particularly for normal and low responders undergoing ovarian stimulation. ¹

Luteal phase support following hCG administration is recommended based on natural progesterone (P) or dydrogesterone. ¹ However, accumulating endocrine data indicate that hCG-induced luteal physiology deviates markedly from natural cycles, leading to a spectrum of dysregulations that are only partially ameliorated by standard progesterone supplementation. This commentary aims to delineate the gap between the recommended luteal support and the deviations in luteal phase physiology following hCG triggering.

Absence of mid-cycle FSH surge

While hCG effectively activates LH receptors, it lacks follicle stimulating hormone (FSH) activity. In natural cycles, the mid-cycle LH surge is accompanied by a concurrent FSH surge, traditionally considered superfluous but now understood to contribute critically to nuclear maturation of the oocyte ² and cumulus expansion. ³ A systematic review and meta-analysis concluded that FSH co-trigger resulted in significantly higher rates of two pronuclei (2PN) oocytes retrieved than the hCG trigger in IVF protocols, ⁴ albeit the difference seems quite small to justify the claim that FSH is globally required, indicating the superiority of gonadotropin releasing hormone agonist (GnRHa) from this perspective. Of note, a randomized controlled trial by Qiu et al. found that administering an extra FSH bolus at the time of hCG trigger did not improve IVF outcomes. ⁵

Prolonged half-life of hCG

The extended half-life of hCG results in prolonged stimulation of the corpora lutea (CL) during the early luteal phase. This excessive stimulation is associated not only with an increased risk of ovarian hyperstimulation syndrome (OHSS), but may also negatively impact pregnancy rates.^6–8

Exaggerated early luteal stimulation elevates estradiol and progesterone levels, leading to potent negative feedback at the pituitary level and consequent suppression of endogenous LH secretion. Once the pharmacological effect of hCG diminishes, insufficient LH levels are available to maintain CL function, culminating in a luteal phase defect. ⁹ This necessitates exogenous progesterone supplementation to sustain endometrial receptivity and allow endogenous hCG (in the event of embryo implantation) to support CL function.

Furthermore, excessive early luteal steroidogenesis may precipitate embryo-endometrial asynchrony by significantly advancing the window of implantation, potentially compromising implantation success.^9–11

Altered luteal phase endocrinology post-hCG trigger

Post-hCG administration, serum progesterone levels peak approximately 3–4 days following oocyte retrieval before declining.^12,13 This contrasts with the gradual progesterone rise seen in natural ovulatory cycles, where peak levels typically align with the implantation window (6–8 days post-ovulation). A decline in progesterone between days 3 and 5 post-retrieval has been correlated with reduced ongoing pregnancy rates, despite luteal support. ¹⁴

Timing of progesterone supplementation

Given the initial supraphysiologic progesterone levels due to hCG, premature exogenous progesterone supplementation may exacerbate endometrial advancement and embryo-endometrium asynchrony. Hence, careful timing of luteal support initiation is crucial.

Conclusion

Current progesterone-based luteal phase support following hCG trigger only partially addresses the complex endocrine disruptions induced by hCG.

Alternative strategies

Recombinant LH has previously been proposed as an alternative trigger; however, its clinical adoption was hindered by cost and effectiveness considerations. ¹⁵ A more viable and cost-effective approach involves the use of a gonadotropin-releasing hormone (GnRH) agonist trigger, followed by either a “freeze-all” strategy or carefully timed hCG-based luteal support in fresh transfer cycles. Since the GnRH agonist trigger leads to an increasing P levels for the first 48 h after oocyte retrieval (after which luteolysis ensues), ¹⁶ this is the perfect time to add a small hCG bolus (1.500 IU) to sustain the CL. ¹⁷ Other similar approaches have also been published: repeated hCG boluses or by daily low hCG doses.^18,19 Importantly, the risk of OHSS should be seriously considered in these cases.

This commentary underscores the need for continued evaluation and refinement of luteal phase management following hCG trigger to optimize outcomes and minimize iatrogenic risks in assisted reproductive technologies.