Our results show that there was a significant delay in the spontaneous LH surge in the cycle in which patients took nimodipine in comparison to both observatory cycles, with no effect on overall cycle length. Furthermore nimopidine was generally tolerable, with only mild and self-resolving side effects.
Due to MSHREB restrictions our study design focused on assessing the safety and effectiveness at the lowest therapeutic dose and duration in the minimum number of required participants. While patients took nimodipine for a period of four days, only two days of treatment occurred beyond the expected LH surge day based on the first cycle (Table 1). Therefore complete efficacy in delaying the LH surge represented a maximum two-day delay in the treatment cycle. In total, five out of eight patients had an intended delay of a spontaneous LH surge by at least one day during their nimodipine cycle. For the remainder of the patients the LH surge day was the same as the first cycle. None of the patients had an LH surge in the two day window prior to the expected LH surge day (Table 2).
Patients undergoing intra-uterine insemination (IUI) cycles, with or without ovarian stimulation, don’t routinely utilize any medical suppression of the natural LH surge. Not surprisingly, these cycles have a high prevalence of premature LH surge, commonly defined as a natural LH surge occurring before the leading ovarian follicle reaches 18 mm in diameter. In a recent study of 87 monitored IUI cycles patients were administered clomiphene citrate (CC) (60%), letrozole (16%) or no ovarian stimulation (24%), and 28.7% had a premature LH surge, with no significant difference among the three groups . In a similar study, patients were randomized to CC or recombinant follicle-stimulating hormone (rFSH) coupled with IUI. Among 153 monitored cycles 36% demonstrated a premature LH surge .
Given the prevalence of premature LH surge with ovarian stimulation, medical suppression of the physiological LH surge is routinely used in IVF cycles, which results in lower cancellation rates and improvement in routine organization. In current practice the LH surge is inhibited by GnRH agonists or antagonists, both of which ultimately suppress pituitary gonadotropin secretion . Both these treatment options increase the need for multiple injections resulting in increased patient discomfort, inconvenience and overall costs . Hence, an inexpensive oral medication, such as nimodipine, would be welcomed as a more convenient and cost effective approach if shown to be efficacious in preventing premature LH surges in ART protocols. Even in IUI cycles, where ovulation suppression is not used, there may be a pregnancy benefit to delaying the LH surge. A recent publication has demonstrated that the optimal follicle size on ultrasound to achieve pregnancy in clomiphene citrate or letrozole cycles is 2.5 cm rather than 1.8 cm . Nimodipine is a relatively lipophillic calcium channel blocker that crosses the blood brain barrier to exert its effects intracerebrally . This property makes nimodipine an ideal candidate for an oral medication to affect GnRH neurons. There is strong evidence that nimodipine can suppress GnRH release on a cellular level [8, 14, 15] and prevent ovulation in mice .
Numerous other hormones [20–23], peptides [24, 25] and endotoxins  have been explored as candidates to suppress a premature LH surge, but studies have been restricted to animal studies and clinical evidence is lacking.
Several reproductive-associated hormones, such as progesterone and mifepristone (anti-progesterone) have been investigated in human subjects. One clinical trial examined the effect of a five-day mid-cyle course of ethinyl estradiol and norethindrone on 10 volunteers with regular ovulatory cycles. None of the patients had an LH surge or evidence of ovulation, while ultrasound findings suggested appropriate follicular growth and endometrial thickening . In another small study of nine patients serving as their own controls, subjects were stimulated with rFSH in the initial cycle and with FSH and mifepristone in the subsequent cycle. An endogenous LH surge was noted in 6/9 patients in the first cycle, but none in the second. The major drawback was mifepristone’s adverse effect on folliculogenesis and decreased estradiol and progesterone levels in the luteal phase . A more recent pilot study of 15 healthy oocyte donors undergoing ovarian stimulation for IVF investigated the effectiveness of daily mifepristone in comparison to GnRH agonist to prevent premature LH surge. Although no statistical analysis was published, it was noted that none of the ten subjects treated with 40 mg mifepristone daily had a premature surge while one of the five GnRH agonist patients had premature luteinization. However, endometrial biopsies in these patients demonstrated that mifepristone had a negative impact on endometrial receptivity at the gene level, even with progesterone supplementation . The clinical utility of progesterone and mifepristone supplementation during an ovarian stimulation cycle, with the aim of inhibiting an LH surge, must be questioned as it may mimic premature luteinzation or adversely affect implantation [2, 3]. There is currently no effective alternative to GnRH analogues to inhibit the spontaneous LH surge in women undergoing ovarian stimulation.
It is imperative to keep in context the limitations of our single-arm pilot study composed of a small sample size of unblinded healthy participants. On the other hand, there does appear to be a significant temporal association between nimodipine and LH surge delay as patients served as their own controls, pre and post-intervention. Furthermore the rationale to use nimodipine to inhibit an LH surge is solidly based on both in vitro and in vivo animal research. Unlike other medications investigated in clinic settings, nimodipine is not a hormone and thus may have a more isolated effect on the LH surge, although this has yet to be proven. Furthermore it is an inexpensive oral medication with a high safety profile that could potentially be used to prevent a spontaneous LH surge.
In our study subjects received 60 mg only every eight hours for a total of four days and there were no reported cases of severe side effects. While three out of eight patients experienced a headache that was associated with nimodipine intake, conservative measures were effective in reversing symptoms, which subsided upon discontinuation of nimodipine. Without a placebo comparison arm it remains difficult to ascertain whether this is the direct effect of the medication, although it appeared to be temporally associated. In two double-blinded randomized controlled trials comparing nimodipine to placebo there was no difference in side effects  and even an increased adverse event rate in the placebo arm (RR = 1.29; CI 1.03-1.61) . Interestingly, of the three patients that experienced a headache, one had an LH surge delay of three days and another of four days.
Study participants all had a history of regular menstrual cycles, but there remains a natural intra-patient variability of LH surge day. We restricted our study design to investigate a two day delay in order to minimize drug exposure in this pilot study. It is noteworthy that nimodipine was initiated two days prior to the anticipated LH surge and no patients in the medication cycle had an LH surge in the two day window prior to the expected date. As well there was no statistical difference in the LH surge day between the two control cycles further supporting the stability of the LH surge day in our subjects.
One drawback to our study design is that if patients had an LH surge prior to initiating nimodipine (expected LH surge – 2 days), the interventional cycle was suspended and the data was used as part of a second observatory cycle, although this only occurred in one patient.
The primary outcome of this study was the LH surge day. A delayed LH surge, in essence a prolonged follicular phase, is expected accompany a longer menstrual cycle. Interestingly our results demonstrated no difference in cycle length in the nimodpine cycle. We have no explanation for this observation, but perhaps with an intentional longer LH surge delay we will be able to identify a corresponding difference in cycle length.