Micro-dose hCG as luteal phase support without exogenous progesterone administration: mathematical modelling of the hCG concentration in circulation and initial clinical experience

Abstract

For the last two decades, exogenous progesterone administration has been used as luteal phase support (LPS) in connection with controlled ovarian stimulation combined with use of the human chorionic gonadotropin (hCG) trigger for the final maturation of follicles. The introduction of the GnRHa trigger to induce ovulation showed that exogenous progesterone administration without hCG supplementation was insufficient to obtain satisfactory pregnancy rates. This has prompted development of alternative strategies for LPS. Augmenting the local endogenous production of progesterone by the multiple corpora lutea has been one focus with emphasis on one hand to avoid development of ovarian hyper-stimulation syndrome and, on the other hand, to provide adequate levels of progesterone to sustain implantation. The present study evaluates the use of micro-dose hCG for LPS support and examines the potential advances and disadvantages. Based on the pharmacokinetic characteristics of hCG, the mathematical modelling of the concentration profiles of hCG during the luteal phase has been evaluated in connection with several different approaches for hCG administration as LPS. It is suggested that the currently employed LPS provided in connection with the GnRHa trigger (i.e. 1.500 IU) is too strong, and that daily micro-dose hCG administration is likely to provide an optimised LPS with the current available drugs. Initial clinical results with the microdose hCG approach are presented.

Role of gonadotropin-releasing hormone agonists, human chorionic gonadotropin (hCG), progesterone, and estrogen in luteal phase support after hCG triggering, and when in pregnancy hormonal support can be stopped

“…With these regimens, the concentrations of LH/hCG achieved during the luteal phase often reached levels fiveto tenfold higher than those seen in the normal menstrual cycle. In today's standards, exogenous hCG used at these doses causes far too strong an LPS and significantly enhances the risk of OHSS (48). This has been highlighted in a Cochrane review, which bluntly states, ''We found that hCG, or hCG plus progesterone, was associated with a higher risk of OHSS.…”

“…Indeed, this approach allowed abandoning the large boluses of hCG used for triggering ovulation, but required a supplementary dose of 1,500 IU hCG to sustain sufficient endogenous P production and maintain similar pregnancy rates (49)(50)(51). This concept was further developed to include daily microdoses of hCG of only 100-150 IU throughout the luteal phase without using any exogenous P preparation (48,52). Microdoses of hCG administered to women undergoing OS with the use of agonist trigger for final maturation of oocytes led to hCG concentrations that do not exceed physiologic levels (i.e., 5-10 IU/L).…”

“…This secures levels of P in the mid-luteal phase similar to those achieved in standard OS protocols that use 6,500 IU hCG for ovulation induction and vaginal P supplementation. Preliminary data indicate that the rate of biochemical pregnancies is reduced and ongoing pregnancy increased, but proper RCTs need to confirm these results (48). Furthermore, women appear to prefer low-dose hCG administration to exogenous P administration, especially by the vaginal route.…”

“…The limiting obstacle, however, is the difficulty of administering microdose hCG because of the lack of widely available preparations for delivering such small doses. Indeed, dilution of stock solution with physiologic saline solution is required, which is cumbersome in a busy daily practice (48).…”

A Rationale for Timing of Luteal Support Post Gonadotropin-Releasing Hormone Agonist Trigger

“…Andersen et al [16,17] showed that a daily dose of hCG (125 IU) starting on the day of oocyte retrieval (without exogenous P) results in very high mid-luteal P. Daily hCG was stopped 12 days after embryo transfer.…”