Migraine start, course and features over the cycle of combined hormonal contraceptive users with menstrual migraine— temporal relation to bleeding and hormone withdrawal: a prospective diary-based study

DOI: https://doi.org/10.1186/s10194- 020- 01150- 1

Abstract-Summary An advantage for prevention of MRM in CHC users is that the hormone withdrawal is predictable.

It is unknown, whether the attacks during the hormone-free interval are associ-

ated with the hormone withdrawal or onset of bleeding.

Prospective diary-based trial we collected migraine and bleeding data from CHC

users with MRM in at least two of three cycles.

During the hormone-free phase the relation between onset of migraine and onset

of bleeding was studied.

We compared pain intensity and identified prolonged-migraine attacks during

hormone use and the hormone-free phase.

During the hormone-free interval the number of migraine days and the pain score/migraine day were significantly higher in comparison with the mean during hormone use.

The prevalence of migraine attacks was fourfold on hormone-free days 3–6. Migraine in relation to bleeding mostly occurred on days − 1 to + 4. The day of hormone-withdrawal migraine and the first bleeding day are highly

predictable in CHC users.

Migraine onset is mostly day − 1 and 1 of the bleeding and on days 1–4 of the

hormone-free interval.

Migraine attacks of CHC users in the hormone-free interval are severe and long

lasting.

Extended: Migraine attacks of CHC users are frequently severe and long lasting

in the HFI.

Background Estrogen withdrawal is a recognised trigger for menstrual attacks in the natural cycle and in women using combined hormonal contraceptives (CHC) [709–711].

Many studies have described the features of PMM and MRM in natural cycles and the efficacy of acute therapy or short-term prevention over 5–7 days around the menstrual bleeding [712–721].

This is important for considering both type and timing of prevention, especially if symptomatic treatment of menstrual attacks in CHC users with MRM shows the same low response as it is known from MRM in the natural cycle.

The aim of this prospectively conducted diary-based study was to identify the course and features of migraines in CHC users diagnosed with menstrual migraine

2.5 Hormones

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(MRM or PMM) and to understand the temporal relationship between onset of migraine in the HFI and the first day of bleeding.

Methods Women were included if they used CHC (oral tablets, transdermal patches, or vagi- nal ring) in the standard regimen of 21 days with a 7-day HFI, reported migraine regularly occurring during the HFI in at least two out of three cycles, experienced withdrawal bleeding, planned to continue the use of their CHC for at least 3 more cycles, agreed to conduct daily diaries for 3 cycles and gave written informed consent.

The diaries collected daily information on occurrence, intensity and duration of

migraine attacks, use of pain medication, CHC use and uterine bleeding.

As for the natural cycle and in previous studies in CHC users it has been found, that the long duration of MRM is a big burden, we identified in addition to migraine days those migraine attacks with a duration of more than 24 h. Diaries of partici- pants were excluded from the final data analyses, if migraine was not reported in at least two of three cycles.

Results The mean pain score/migraine day was1.92 (range1–3). Of all migraine attacks 104 were rated as severe (pain score 3) and 45% of the latter occurred during the HFI.

During the HFI (presented as week 1) the number of migraine days, migraine attacks with a duration of more than 24 h, and consumed pain medication, were significantly higher in comparison with the weekly mean during hormone use.

In 58% of the cycles the first migraine day of the HFI occurred on days 3–7 and

in 37.8% on days 4–7.

We found that in 78% of the cycles the first migraine day occurred during bleed- ing days 1 ± 2, which is the period defined for the occurrence of menstrual migraine attacks.

Migraine attacks with a duration of more than 24 h were observed in 45% of

cycles, with 75% occurring during the HFI.

Discussion The distribution of migraine days over the HFI, the high predictability of the first bleeding day and the observation that migraine attacks start mostly on days − 1 to day + 4 in relation to the withdrawal bleed in CHC users confirm the results of our pilot study [722].

In the only trial of onset of migraine in relation to the HFI days 2–5 were identi-

fied as those with the highest prevalence of attacks in CHC users [710].

The authors report the prevalence of migraine in CHC users in intervals of sev-

eral days in relation to the withdrawal bleeding [723].

Considering the high predictability of the first bleeding day, the observation that in 50% of cycles the first migraine day is day − 1 or + 1, and typically within the range of days 1 ± 2 we suggest to start prevention on bleeding day − 2 and continue for 3–4 days depending on the typical duration of the attacks.

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2 Mechanisms

Conclusion The day of hormone-withdrawal migraine and the first bleeding day are highly pre- dictable in CHC users.

More research is needed to understand the pathophysiology of migraine during the HFI in CHC users with particular regard to estrogen withdrawal and/or uterine bleeding, and to optimize treatment.

Acknowledgement A machine generated summary based on the work of Merki-Feld, Gabriele S.; Caveng, Nina; Speiermann, Gina; MacGregor, E.  Anne. 2020  in The Journal of Headache and Pain.

Effects of estrogen and progesterone on the neurogenic inflammatory neuropeptides: implications for gender differences in migraine