Using Nimodipine, a Calcium Channel Blocker, to Prevent the LH Surge and Ovulation in Women Undergoing Assisted Reproduction

In reproductive aged women regular ovulatory cycles generate 1-2 mature ovarian follicles every month. Approximately mid-cycle a natural LH surge is observed and predictably induces ovulation within 24-36 hours. LH is a hormone produced by the anterior pituitary gland and is released in response to GnRH. Concurrently GnRH is synthesized and released in a pulsatile manner from GnRH neurons within the hypothalamus.

One of the essential steps of successful IVF is to ensure the properly timed aspiration of mature follicles from the ovaries prior to ovulation. If ovulation were to precede aspiration then the oocytes would have already been released and become unobtainable. Therefore inhibiting spontaneous ovulation is a crucial component of successful oocyte retrieval. In the clinical setting of IUI no oocyte retrieval is required, but appropriate timing of insemination with respect to ovulation is critical.

A premature LH surge and subsequent premature luteinization may occur in up to a third of ovarian stimulation cycles using gonadotropins (applicable to both IUI and IVF cycles), making it a major cause of treatment cancellation and having a negative impact on pregnancy outcomes 2-5. The most commonly used medications to prevent a premature LH surge are GnRH agonists and more recently GnRH antagonists. They are both commonly administered subcutaneously on a daily basis and act on the anterior pituitary gland (through different mechanisms) to inhibit the release of LH. Besides the additional patient cost and burden, these medications are associated with prolonged treatment protocols and decreased ovarian response to stimulation.

Nimodipine is a unique calcium channel blocker with lipophilic properties and a greater affinity for cerebral vasculature, and therefore has the ability to cross the blood-brain barrier. In a study on mice with induced intracerebral hemorrhage, nimodipine treatment improved cerebral bloodflow and displayed anti-ischemic effects. Nimodipine has obtained FDA approval to reduce the severity of neurological deficits in patients who have had a recent subarachnoid hemorrhage.

On a cellular level nimodipine has been shown to inhibit the pulsatile activity of GnRH gene expression, an intrinsic property of GnRH neurons that is necessary for proper initiation of the LH surge. Specifically, nimodipine blocks L-type voltage gated calcium channels which prevent the influx of extracellular calcium and subsequently the stimulation of GnRH release. The intrinsic pulsatile secretion of GnRH has been directly associated with the rhythmic changes in intracellular calcium concentration in GnRH neurons.