In our data, recent use of oral contraceptives, extended use of oral contraceptives, and marijuana use were all associated with a longer follicular phase. Women with a history of miscarriage (among gravid women) tended to have shorter follicular phases.
One of the best documented factors affecting menstrual cycle length is women’s age. The absence of a clear age effect in our data is not so surprising, given the narrow age range of women. We also found no detectable effect of BMI, age at menarche, gravidity, caffeine intake, alcohol intake, or smoking on follicular phase length – all factors that have previously been associated with either menstrual cycle length or follicular phase length. The absence of such associations in our data may be due to the lack of variability in our sample. Also, our sample excluded women with chronic medical conditions or known reproductive problems; such conditions may be part of the causal pathway by which these variables affected cycle length in other studies.
Our results regarding longer follicular phases after recent oral contraceptive use are consistent with most previous studies. In two studies, women who discontinued oral contraceptives tended to have an increased cycle length for one to three cycles post-discontinuation 20, 21
; in another, longer cycles persisted for 8 cycles33
. In a recent study using ultrasonography, women in their first cycle after discontinuing oral contraceptives took more time to select and manifest a dominant follicle; ovulation was 5 days later than in unexposed cycles34
. In contrast, one study reported no differences in cycle length between those who recently discontinued oral contraceptives and those who had not used them within three months of the study35
. However, in this study there was a significantly longer median cycle length in one age group after discontinuation of oral contraceptives (ages 18–24), and non-significantly longer cycles in two other age groups (30–34 and 35–40). Thus, when stratified by age, there was some evidence of longer cycles. These findings are also consistent with a slightly longer time to pregnancy in women who recently discontinued oral contraceptives36–41
. The cycle length studies considered only recent use; duration of use varied widely (from 4–10 years20
, a few months to 13 years33
, to >0 to 4 years21
). However, in other studies duration of oral contraceptive use has shown no associations with such cycle-related outcomes as post-pill amenorrhea 20, 42
or inhibition of ovulation 43
. There is some evidence that among women over 45 years of age, use of oral contraceptives for at least five years is associated with lower levels of follicle stimulating hormone (FSH) in the early follicular phase. Moreover, use of oral contraceptives within the past five years was associated with lower FSH levels regardless of age, which ranged from 26–5044
. In turn, lower FSH levels were reported to be weakly associated with longer menstrual cycles in the same study sample45
. In a recent randomized trial of continuous versus conventional oral contraceptive use, researchers found that as the duration of oral contraceptive use increased (from one to three cycles), the number of developing follicles decreased34
. Thus, the authors suggest that the inhibition of follicle recruitment by oral contraceptives may compound over time, possibly through increased suppression of the hypothalamic-pituitary-ovarian axis. Whether this might have long term effects on future cycling is not known. The interpretation of our finding is complicated by the selective nature of women who choose to take oral contraceptives. For example, some women with irregular cycles may use oral contraceptives to help regulate their cycles, and such women may also have longer cycles.
We did not find any previous reports of shorter follicular phase length for women with a history of miscarriage, although short follicular phase and miscarriage might share hormonal determinants. One study has suggested that a shorter (<30 days) or longer (≥32 days) cycle length is associated with a spontaneous abortion in the following cycle 46
, and another study found long cycles associated with history of miscarriage47
. Previous analyses of our data did not find an association between usual cycle length (longer vs. other) or follicular phase length and risk of early pregnancy loss (occurring within six weeks of the last menstrual period). 48
However, early loss and clinical spontaneous abortion may be endpoints with distinct etiologies and risk factors.
Our finding of longer follicular phases with occasional marijuana use is intriguing. Animal research supports an effect of marijuana on ovulation. In rhesus monkeys, daily injections of 2.5 mg/kg Δ9
-tetra-hydrocannabinol (THC) (the equivalent of 5–6 joints) during the follicular phase delayed or prevented ovulation49
. In a longer-term study, the impact of THC on ovulation in rhesus monkeys appeared to decline over time, suggesting that tolerance may develop50
These observations have not been definitively replicated in humans. Twenty-six women who used marijuana at least three times a week over the previous six months had shorter menstrual cycles, specifically shorter luteal phases, when compared to 17 non-marijuana users 51
. We found little evidence in our study for an association between short luteal phase and marijuana-use (data not shown). The 26 marijuana users had lower prolactin levels, a slightly lower peak level of luteinizing hormone (LH), and a slower post-ovulatory rise in estrogen and progesterone 51
. Another study that included 17 female chronic marijuana users (at least weekly for more than two years) found no differences in testosterone, LH, FSH, prolactin or cortisol levels when stratified by frequency of use or when comparing users and non-users 29
. Studies of the acute effects of marijuana suggest that the timing of marijuana exposure in the menstrual cycle may modulate its effects on LH 26, 28
. Marijuana use had no acute effect on progesterone or estradiol levels 26, 28
. We do not have data on the timing of marijuana use in the menstrual cycle.
There are several possible reasons for the disparate human epidemiologic results. Marijuana users in the four previous (human) studies were, on average, heavier users than those in our study. The average frequency of marijuana use in earlier studies ranged from approximately 4 to 14 times per month26, 28, 29, 51
whereas the average among users in our sample was about 3 times per month. None of the studies, including ours, has accounted for the amount smoked at each exposure or the timing of the exposure in the menstrual cycle, which may also differ among the studies.
In the study of chronic users there was a slightly higher proportion of anovulatory cycles among marijuana users compared with non-users, but anovulation was rare and the difference was non-significant51
. We also found an excess of anovulatory cycles among marijuana smokers: three of seven (43%) confirmed anovulatory cycles were to marijuana smokers, compared with 15% marijuana smokers in the study population. In the rhesus studies, the monkeys had not been exposed to marijuana prior to the investigation, whereas in the human studies women had been marijuana smokers for an unknown (and possibly long) period of time. It could be that infrequent marijuana use (as in our study), more closely resembles the exposure pattern of the rhesus studies, and therefore that lengthening of follicular phase in our data is consistent with delayed ovulation.
All exposure information was obtained by self-report at enrollment and participants’ responses at enrollment may not represent their actual behavior after enrollment. We attempted to control this source of error by using only the first menstrual cycle under study. Our study sample was mostly white, which made it impossible to consider racial differences reported in other studies 10, 18
. Similarly, we were unable to investigate stress or physical activity as these characteristics were not included in the questionnaire. Finally, we were unable to investigate within-woman variance in follicular phase length; this would require longitudinal cycle-specific exposure data. A strength of our study is the detailed hormonal data, which allowed us to examine follicular phase length. In addition, the study participants were highly motivated and extremely careful in other aspects of their study participation, which suggests that their exposure data may also be of good quality.
In summary, we provide descriptive data on factors associated with follicular phase length, which was determined using hormonal estimates of ovulation in each menstrual cycle. Our findings suggest exposures (including oral contraceptive and marijuana use) that may lead to delayed ovulation. Future studies of follicular phase length should be more detailed in assessing marijuana exposure including measures of dose and timing of the exposure during the cycle.