Journal of Clinical Medicine Review Acute and Preventive Management of Migraine during Menstruation and Menopause Raffaele Ornello , Eleonora De Matteis, Chiara Di Felice , Valeria Caponnetto, Francesca Pistoia and Simona Sacco * Neuroscience Section, Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, 67100 L’Aquila, Italy; [email protected] (R.O.); [email protected] (E.D.M.); [email protected] (C.D.F.); [email protected] (V.C.); [email protected] (F.P.) * Correspondence: [email protected]; Tel.: +39-0862433561 Abstract: Migraine course is influenced by female reproductive milestones, including menstrua- tion and perimenopause; menstrual migraine (MM) represents a distinct clinical entity. Increased susceptibility to migraine during menstruation and in perimenopause is probably due to fluctu- ations in estrogen levels. The present review provides suggestions for the treatment of MM and perimenopausal migraine. MM is characterized by long, severe, and poorly treatable headaches, for which the use of long-acting triptans and/or combined treatment with triptans and common anal- gesics is advisable. Short-term prophylaxis with triptans and/or estrogen treatment is another viable option in women with regular menstrual cycles or treated with combined hormonal contraceptives; conventional prevention may also be considered depending on the attack-related disability and the presence of attacks unrelated to menstruation. In women with perimenopausal migraine, hormonal treatments should aim at avoiding estrogen fluctuations. Future research on migraine treatments will benefit from the ascertainment of the interplay between female sex hormones and the mechanisms of Citation: Ornello, R.; De Matteis, E.; migraine pathogenesis, including the calcitonin gene-related peptide pathway. Di Felice, C.; Caponnetto, V.; Pistoia, F.; Sacco, S. Acute and Preventive Keywords: migraine; menstruation; menopause; migraine treatment; triptans; hormonal treatments Management of Migraine during Menstruation and Menopause. J. Clin. Med. 2021, 10, 2263. https://doi.org/ 10.3390/jcm10112263 1. Introduction Migraine is a common headache disorder affecting 14% of people worldwide [1]. Academic Editor: Antonio Russo Migraine commonly affects young people and especially women; indeed, the prevalence of migraine is three to four times higher in women compared with men [1–3]. Different Received: 29 April 2021 mechanisms might explain the female predominance of migraine, including the migraine- Accepted: 19 May 2021 Published: 24 May 2021 enhancing role of female sex hormones and a higher genetic heritability in women com- pared with men [4]. Of note, migraine prevalence is the same in women and in men Publisher’s Note: MDPI stays neutral during childhood, while a higher prevalence of migraine in women than in men is found with regard to jurisdictional claims in only after puberty, when women start menstruating [5]. According to the so-called “es- published maps and institutional affil- trogen withdrawal hypothesis”, the cycles of rise and fall in estrogen levels typical of the iations. female fertile period are deemed responsible for an increased susceptibility to migraine in women [6]. Estrogen levels undergo a sudden fall during the days immediately preceding menstruation [7,8]. Hence, the highest susceptibility to migraine is in the perimenstrual period. The years immediately preceding and following the menopause also pose women at an increased risk of having severe migraine [9] due to the rapid fluctuations in estrogen Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. levels that accompany this phase of the female reproductive cycle. This article is an open access article Estrogen withdrawal can partly explain the effect of female sex hormones on migraine; distributed under the terms and however, the influence of sex hormones on migraine mechanisms is complex and not fully conditions of the Creative Commons elucidated. Sex hormones influence nociceptive processing, acting on both central and Attribution (CC BY) license (https:// peripheral pathways [10]. Animal studies have found a broad localization of estrogen creativecommons.org/licenses/by/ receptors in brain structures involved in migraine generation, including the trigeminal 4.0/). ganglion [11] and pain-processing structures within the brain [12]. At a central level, J. Clin. Med. 2021, 10, 2263. https://doi.org/10.3390/jcm10112263 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 16 trogen receptors in brain structures involved in migraine generation, including the tri- J. Clin. Med. 2021geminal, 10, 2263 ganglion [11] and pain-processing structures within the brain [12]. At a central2 of 16 level, estrogens can activate the endogenous opioid system that controls pain sensations [13] and modulate the levels of oxytocin, a neurohormone released by the hypothalamus, which can exertestrogens an anti-migraine can activate effect the endogenous [14]. Notably, opioid both system estrogens that controls [15] pain and sensations oxytocin [13 ] and modulate the levels of oxytocin, a neurohormone released by the hypothalamus, [16] might act onwhich the cantrigeminal exert an anti-migraine ganglion and effect modulate [14]. Notably, the both release estrogens of [calcitonin15] and oxytocin gene- [16] related peptide (CGRP),might act onwhich the trigeminal is implied ganglion in the and generation modulate theof releasemigraine of calcitonin pain. Progestins gene-related might also attenuatepeptide pain (CGRP), responses which via is implied conversion in the generationto the neurosteroid of migraine pain.allopregnanolone, Progestins might as suggested by alsoanimal attenuate evidence pain responses[17]. Taken via all conversion together, to thefemale neurosteroid sex hormones allopregnanolone, influence as suggested by animal evidence [17]. Taken all together, female sex hormones influence the the susceptibilitysusceptibility to migraine, to migraine,acting through acting through a complex a complex interplay interplay of ofcentral central and and peripheralperiph- eral pathways (Figurepathways 1). (Figure 1). Figure 1. Female sex hormones and pathogenesis of menstrual migraine. Figure 1. Female sex hormones and pathogenesis of menstrual migraine. The influence of female hormonal fluctuations on migraine is so remarkable that The influencemenstrual of female migraine hormonal (MM) is fluctuations recognized by on the currentmigraine international is so remarkable classification that as a menstrual migrainedistinct (MM) headache is recognized disorder [18 by]. the In detail, current pure international menstrual migraine classification occurs exclusively as a dis- on day 1 ± 2 of menstruation in at least two out of three menstrual cycles and at no other tinct headache disordertimes of the[18]. cycle, In detail, while menstrual-relatedpure menstrual migrainemigraine occurs occurs on dayexclusively 1 ± 2 of menstrua-on day 1 ± 2 of menstruationtion in in at at least least two two out out of three of th menstrualree menstrual cycles, andcycles additionally and at no at other times times of of the the cycle, while menstrual-relatcycle [18](Figure2ed). Differently migraine from occurs MM, on perimenopausal day 1 ± 2 of menstruation migraine is not recognized in at least as two out of three anmenstrual independent cycles, clinical and entity. additionally at other times of the cycle [18] (Figure The treatment of MM and perimenopausal migraine generally follows the indications 2). Differently from MM, perimenopausal migraine is not recognized as an independent for the acute and preventive treatment of any other form of migraine, in the absence clinical entity. of specific indications. Nevertheless, some additional considerations are needed when migraine occurrence is influenced by female sex hormones. In the present paper, we narratively reviewed the current concepts on the treatment of menstrual and perimenopausal migraine and the possible lines of future treatments, with a focus on practical suggestions. J. Clin. Med. 2021, 10, x FOR PEER REVIEW 3 of 16 J. Clin. Med. 2021, 10, 2263 3 of 16 Figure 2. Example of headache diary of patient with pure menstrual and menstrual-related migraine. Figure 2. Example of headache diary of patient with pure menstrual and menstrual-related mi- graine. TheThe Xs Xs represent represent headache headache days; days; Ms Ms represent represent reported reported menstruation menstruation days. days. 2. Methods The treatment of MM and perimenopausal migraine generally follows the indications We searched PubMed and Scopus for articles containing the terms “migraine”, “men- for the acute and preventive treatment of any other form of migraine, in the absence of strual”, “menopause”, and “treatment”, up to February 2021. We included reviews and specific indications. Nevertheless, some additional considerations are needed when mi- original articles. Due to the broadness of the topic and the inclusion of the authors’ personal graine occurrence is influenced by female sex hormones. views, we did not perform a systematic review. In the present paper, we narratively reviewed the current concepts on the treatment of menstrual3. The and Burden perimenopaus and Unmetal migraine Needs of and Women the possible with Menstrual lines of andfuture treatments, with a focusPerimenopausal on practical suggestions. Migraine MM affects 3% of young women [19], with a peak of 22% in women