For many studies, the timing of biospecimen collection within a woman's menstrual cycle is important because the exposure or outcome is affected by hormone levels that change across the menstrual cycle. However, it is difficult to prospectively anticipate the timing of critical phases of the cycle without daily hormonal measurements. In the BioCycle Study, the fertility monitor was useful in scheduling clinic visits around the time of the LH surge.
Participants in the BioCycle Study did not provide daily serum or urine specimens at the clinic, so it is not possible to validate the LH peak as detected by the monitor in this study. Nevertheless, we felt confident that, with proper usage, the fertility monitor would be able to detect the LH surge on the basis of the findings of Behre et al. (13
). They compared fertility monitor data with serum hormone levels and transvaginal ultrasound scans in a study of 53 women. In that study, the monitor recorded peak fertility in 135 of 149 ovulatory cycles as determined by ultrasound (13
). Of the 149 ovulatory cycles, a serum LH surge was detected in only 139 cycles, which means that the monitor detected an LH surge when there was a detectable surge 97% of the time (13
). In addition, the monitor did not reach peak in the 1 anovulatory cycle (13
Although the work of Behre et al. (13
) suggests that the monitor can reliably detect the LH surge, the monitor is helpful only as a research tool if the women use it properly. In the BioCycle Study, the participants had high but not perfect adherence to the monitor-testing protocol. Because the LH surge occurs during a very small window, even missing a few tests could be problematic, depending on when in the cycle the tests were missed. Nevertheless, peak was observed for over 75% of the cycles, and high fertility, which is not confined to a single day and therefore is less dependent on consistent testing, was observed in approximately 85% of the cycles.
There are several factors that contribute to not observing peak fertility. The logistic factors include incomplete data because the woman did not bring her monitor in to have the data downloaded, poor compliance with testing, good compliance with testing combined with an unfortunately timed missed test, and test-stick reading errors. In some cases though, the lack of observed peak fertility may be due to anovulatory cycles or atypical hormone profiles that may or may not have resulted in ovulation. Our results are similar to those of Robinson et al. (14
), who observed peak in approximately 80% of their study cycles, which also reflects a combination of underlying cycle characteristics and compliance.
Timing blood draws at the clinic around the LH surge depended on both the monitor results and the ability of the participants to come to the clinic at the appropriate time. The study protocol instructed participants whose monitors read peak to go to the clinic that morning or to call to schedule a visit as soon as possible. Over three-quarters of the women who reached peak fertility on the monitor were able to attend the clinic for a blood draw on that day. In general, the BioCycle Study participants were an adherent group with schedules that allowed them to come to the clinic on short notice. The need for flexibility in attending the clinic was emphasized at enrollment to increase the likelihood of compliant participants. Once enrolled, participants were given individualized calendars with a projected clinic visit schedule that was revised as needed. These calendars were designed to help the women to anticipate their visit schedule as much as possible. To further encourage adherence to the visit schedule, study staff were sensitive to the time commitment of the participants and followed procedures to minimize the duration of each visit. This flexibility might not be possible in all study settings.
The standardized approaches to scheduling clinic visits (fixed-cycle days, luteal-phase method, and midpoint method) would be easier to implement logistically but would also be less likely to capture the day of peak fertility. The fact that women with longer cycles reached peak fertility later than did women with shorter cycles on average supports the concept behind the standardized methods that cycle length is correlated with the timing of ovulation. In addition, the mean cycle day of peak fertility changed across age categories, but the mean day from the end of the cycle of peak fertility did not, which provides some support specifically for the luteal-phase method. However, the day of peak fertility was farther from the end of the cycle for longer cycles and closer to the end for shorter cycles on average. Despite the compatibility of the mean peak fertility day with general expectations, use of any of the standardized methods would have missed the peak fertility day for the majority of women, even assuming perfect attendance at the clinic during the predetermined 3-day window. The luteal-phase and midpoint methods are based on cycle length, but only self-reported cycle length can be known prospectively, and it performs poorly for both algorithms. Even if the actual cycle length could be used in a prospective study, it was only marginally better than self-reported cycle length. The luteal-phase method slightly improved on the midpoint method, but only if the actual cycle length was used.
Several factors may have contributed to the poor performance of the standardized methods. Natural biologic variability in individual women is complicated by the fact that the event (LH surge) occurs in a small window (approximately 1 day), so that even modest errors in the timing of observation can miss the event completely. In addition, both we and others (9
) have found that women's self-reported cycle lengths, which are used to schedule visits in the standardized methods, do not correlate well with their actual cycle lengths. This may be due in part to the fact that women's cycle lengths vary from one cycle to the next, so that even if they correctly characterize length on average, it may be inaccurate for the study cycle. Thus, even prospectively observing a woman's cycle length prior to any clinic visits in order to appropriately schedule clinic visits during a subsequent cycle does not necessarily improve visit timing due to within-woman variability.
Using a fertility monitor is less burdensome and expensive then collecting, storing, and analyzing daily urine or blood samples. However, the fertility monitor is not suitable for use in populations with extremely short (<20 days) or long (>42 days) cycles. In the BioCycle Study, the women were fairly homogeneous and highly educated, and they were selected to have “normal” menstrual cycles. Their adherence to the fertility monitor protocol was good despite the fact they were not trying to become pregnant, one of the traditional motivating factors in reproductive studies. Nevertheless, achieving this level of protocol adherence in other study populations might be difficult. Poor compliance would undermine the utility of the monitor, but the monitor does not need to be used in isolation. In the BioCycle Study, women who did not reach peak fertility, whether because of logistic issues related to testing or because they were anovulatory, still had clinic visits that were timed on the basis of their individualized calendars. The visits for these women may not have been timed correctly, but presumably, the timing was no worse than if we had not used a monitor at all.
Although the fertility monitor does not provide as much information as collecting daily biospecimens, it does seem to be useful for timing clinic visits, particularly compared with standardized methods of scheduling based on cycle length. In fact, the monitor gives instant results, whereas daily biospecimens are generally analyzed at the end of a study, so the monitor is advantageous if other timed measurements (e.g., test of muscle strength) are desired. In addition to identifying the LH surge, the fertility monitor could be used in studies where the initial estrogen surge in the follicular phase (corresponding to the first day of high fertility on the monitor) or a specific day of the luteal phase (corresponding to a set number of days after the monitor peak) is of interest. The monitor would be most useful for researchers who have limited funds but need to time clinic visits to particular phases of the menstrual cycle, especially if the study population includes women with flexible schedules and “regular” menstrual cycles.