Neurol Sci (2014) 35 (Suppl 1):S65–S69 DOI 10.1007/s10072-014-1745-1


Migraine and the menopausal transition Vincent T. Martin

Ó Springer-Verlag Italia 2014

Abstract The menopausal transition or ‘‘perimenopause’’ represents a time period of turbulent changes in ovarian hormones as middle-aged women progress into menopause. The purpose of this article is to review the literature to determine the effect of the menopausal transition on migraine headaches and to develop a rational treatment approach to these patients. The menopausal transition is divided into early and stages based upon patterns of menstruation and specific reproductive hormones. Studies would suggest that the prevalence of migraine and other climacteric symptoms tend to peak during the late menopausal transition particularly in those with a past history of premenstrual stress disorder. Treatment approaches vary by stage of the menopausal transition and include conventional daily preventatives, mini-prophylaxis and hormonal therapies. Keywords Migraine  Menopausal transition  Perimenopause  Menopause

Introduction The menopausal transition, which is also called the perimenopause, represents a time period during which middleaged women develop irregular menstrual periods and other climacteric symptoms as they evolve into menopause. The menopausal transition often represent a very turbulent time period for those with migraine leading to an increased

V. T. Martin (&) Division of General Internal Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, 260 Stetson Street, RM 4204, Cincinnati, OH 45219-0535, USA e-mail: [email protected]

frequency and disability of headache. This review will first discuss the classification, epidemiology, endocrinology, clinical symptomatology, comorbid disorders and pathophysiology related to the menopausal transition. We will then present the epidemiological studies linking migraine to the menopausal transition as well as the proposed mechanisms through which migraines might be triggered during this time period.

Classification In 2001 a workgroup of international experts in reproductive medicine was convened to define the stages of the menopausal transition and it was called the Stages of Reproductive Workshop (STRAW) criteria [1]. In 2011 a second workgroup was convened to update the original criteria and their classification was termed the STRAW?10 criteria [2]. They divided the menopausal transition and postmenopausal time periods into early and late phases. Each phase was defined not only by the characteristics of the menstrual cycles (e.g., cycle length, amenorrhea), but also by specific serum levels of reproductive hormones. The ‘‘early’’ menopausal transition was characterized by cycle length variations of C7 days while the ‘‘late’’ menopausal transition was distinguished by periods of amenorrhea lasting C2–11 months. It was proposed that the ‘‘early’’ postmenopausal time period lasted for 5–8 years and was characterized by amenorrhea lasting C1 year, low and declining estrogen levels and rising follicular stimulating hormone (FSH) levels. The ‘‘late’’ postmenopausal time period persisted for the remaining lifespan of the women and represented a time of more stable, but low serum levels of ovarian hormones.



Epidemiology The mean age of onset of the menopausal transition is 47.5 years of age while that of menopause is 50–52 years of age [3–6]. An earlier onset of menopause has been associated with lower educational level, more physical activity and smoking [7–9]. In addition, polymorphisms of genes involving steroid hormone metabolism and biosynthesis pathways have been related to age of menopause [10].

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late menopausal transition (24 vs. 36 and 32 %, respectively; p \ 0.002). Premenstrual stress disorder symptoms were strongly related to the severity of headache (odds ratio [OR] = 1.71; p = 0.001) as well as that of all other climacteric symptoms (OR’s 2.08–3.93; all p values B0.001). Therefore, the presence of PMS symptoms may indicate that a perimenopausal woman is ‘‘hormonally sensitive’’ and more vulnerable to develop ‘‘moderate to severe’’ climacteric symptoms.

Comorbid conditions Endocrinology The menopausal transition periods have a unique hormonal milieu that distinguishes them from other premenopausal times. During the ‘‘early’’ menopausal transition menstrual cycles remain ovulatory. Serum levels of estrogen are unchanged to slightly higher and progesterone levels are lower during these ovulatory cycles than those encountered in premenopausal women [11, 12]. Women may also experience aberrant menstrual cycles with luteal out-ofphase (LOOP) follicular events, which represent a second peak in estrogen that occurs during the luteal time period [13]. This second luteal peak resembles that typically seen during the late follicular phase as it is preceded by an LH surge and associated with very high serum levels of estrogen and very low levels of progesterone. Sometimes ovulation can occur with these LOOP follicular events. Anovulatory cycles predominate during ‘‘late’’ menopausal transition with the depletion of ovarian follicles. Serum levels of estrogen and progesterone are both low during these anovulatory cycles. Even if ovulation does occur serum levels of estrogen and progesterone are much lower than premenopausal time periods as these women approach menopause.

Clinical symptoms A variety of climacteric symptoms develop during the menopausal transition including hot flashes, night sweats, irritability, insomnia, joint aches, vaginal dryness, decreased libido and headache [14]. Women with a past history of premenstrual stress disorder (PMS), migraine, depression or atopy are at increased risk for the development of climacteric symptoms [14, 15]. Freeman and colleagues [14] reported that the severity of headache symptoms rated on a 0–3 scale (0 = none, 1 = mild, 2 = moderate, 3 = severe) varied with the stage of the menopausal transition. The proportion of patients with ‘‘moderate to severe’’ headache was lowest during postmenopausal time periods and highest during the early and


Depression, anxiety and sleep disturbances are all more prevalent during the menopausal transition and postmenopausal time period. Bromberger and colleagues [16] found that depression was 2.2–3.69 more common during the menopausal transition and postmenopause as compared with the premenopause. Another study [17] found that with low anxiety at baseline was 1.5–1.69 more likely to develop severe anxiety during the menopausal transition and postmenopause. Sleep disturbances (e.g., frequent awakenings, trouble falling asleep, waking up early) were most prevalent during the late menopausal transition [18].

Pathophysiology It has long been assumed that the symptoms of the climacteric period are solely related to low serum levels of estradiol. However, more recent studies challenge this hypothesis and in some instances implicate other reproductive hormones. Randolph and colleagues [19] reported that higher serum levels of FSH and lower estrogen levels were both associated with hot flashes in univariate analyses. However, only FSH was independently predictive in multivariate analyses that included both variables. A greater risk of depression has been reported in perimenopausal women with higher serum levels of testosterone as well as fluctuations in estrogen and FSH [20– 22]. Sleep disturbances were greatest on those days with higher urinary levels of FSH and progesterone metabolites in menstruating perimenopausal women [23]. Thus, there may be several different patterns of reproductive hormonal hormones that may predispose to climacteric symptoms.

Migraine during the menopausal transition There has only been one past study to date to ascertain the effect of the menopausal transition on the prevalence of migraine headache. Wang and colleagues [24] conducted a

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cross-sectional study of 1,436 Chinese women to determine if the prevalence of migraine differs during the various climacteric time periods. Migraine was least prevalent in individuals after a spontaneous menopause (OR = 0.6 [0.4, 0.9; 95 % CI]) when compared to those in the early and late menopausal transition for the population as a whole. Migraine was significantly more common in the hysterectomy/oophorectomy group (hysterectomy alone [n = 63], hysterectomy ? unilateral oophorectomy [=22] or hysterectomy ? bilateral oophorectomy [n = 19]) as compared to those with a spontaneous menopause occurring in 27 and 7 %, respectively (p \ 0.001). There was an increase in the proportion of individuals with migraine during the late menopausal transition as compared to the premenopause and early menopausal transition only in those with PMS (31 vs. 21–22 %).

Mechanisms The ‘‘estrogen withdrawal’’ hypothesis is the most commonly advanced theory to explain the mechanism through which migraine is triggered by ovarian hormones. This theory is supported by the fact that menstrual migraine occurs in 35–51 % of female migraineurs and can be prevented by perimenstrual administration of estrogen [25– 27]. In the past ‘‘estrogen withdrawal’’ has been considered a transient event that only occurs for several days around menstruation. However, ‘‘estrogen withdrawal’’ may trigger migraine for weeks to months if estrogen deprivation is prolonged as may occur from the amenorrhea that occurs during the late menopausal transition or early postmenopausal time periods. This is supported by the results of the Medical Oophorectomy in Migraine (MOM) study [28] in which headache outcome measures tended to worsen or remain unchanged during a 2-month treatment phase with placebo while they improved in those receiving add-back estrogen therapy. The hormone changes in the menstrual cycle that are encountered during the menopausal transition could theoretically provoke migraine. Greater mid-cycle fluctuations in estrogen as occur during the early menopausal transition may be more likely to trigger mid-cycle attacks of migraine. Past studies [26, 29] had not identified a midcycle pattern of migraine, but a more recent study [30] clearly demonstrated the existence of mid-cycle peak of headache that was related to PMS symptoms. Likewise, the bifid peaks in estrogen that occur with LOOP follicular events might trigger attacks of migraine in susceptible patients. Extremely high or low serum levels of progesterone during the mid-luteal time period as seen during the early and late menopausal transition might be provocative for headache [31].


The menopausal transition may be associated with a worsening of migraine secondary to an increase in the prevalence of comorbid disorders (e.g., depression, insomnia). The American Migraine and Prevention (AMPP) study found that depression conferred a 65 % excess risk of transitioning from episodic to chronic migraine. Another study [32] found that insomnia was related to an increased frequency of migraine headache.

Management There are three potential approaches to prevent ‘‘hormonally triggered’’ migraines during the menopausal transition. These include conventional daily preventative medications, mini-prophylaxis of menstrual migraine and hormonal therapies. Their use might vary depending upon the stage of the menopausal transition. Conventional daily preventatives can be used during any stage of the menopausal transition. Topiramate has the best evidence in the prevention of menstrually related migraines and could be particularly effective during the early menopausal transition. Allais and colleagues [33] reported that topiramate was equally effective in reducing the frequency of migraine during perimenstrual and non-perimenstrual time periods in patients with menstrually related migraine. Gabapentin, fluoxetine and venlafaxine might also be considered since they have been shown to prevent both migraine and climacteric symptoms [34–36]. Mini-prophylaxis of menstrual migraine might be employed during the early menopausal transition if menses are regular and migraines predictably occur during perimenstrual time periods. Perimenstrual administration of triptans or estrogen gels/patches has been shown to reduce the frequency of menstrual migraine in past studies [25, 37, 38]. Contraceptive therapies such as estrogen-containing oral contraceptive pills (OCPs) or patches might be used to prevent migraine if patients have no contraindications (e.g., breast cancer, thromboembolic disease, cardiovascular risk factors). Generally these therapies are given continuously for extended durations only administering a placebo week every 3 months or not at all. Such approaches have been shown to reduce the frequency of menstrual migraine by decreasing time periods of ‘‘estrogen withdrawal’’ [39, 40]. These therapies could be employed during the early and late menopausal transition to prevent headache. Hormone replacement therapy (HRT) is most commonly used during the late menopausal transition and early menopausal time periods to relieve climacteric symptoms. Transdermal estradiol patches or estradiol gels are preferred over oral therapies as they maintain more constant levels of estrogen. Estrogen preparations should be



administered daily as interruptions in therapy will create ‘‘estrogen withdrawal’’ and precipitate headache. Progestins must be used in women with an intact uterus to prevent endometrial hyperplasia. Daily progestin regimens are preferred as opposed to those that administer cyclic progestins for 10–12 days each month [41]. An important question is whether HRT can be used to prevent migraine headache in perimenopausal migraineurs. Cross-sectional studies [42, 43] suggest that HRT is associated with a greater prevalence of migraine headache. It is tempting to conclude that HRT increases the prevalence of migraine, but it is equally plausible that migraineurs receive HRT as a therapy to prevent worsening headaches during perimenopausal times. Studies [44, 45] have reported that daily oral conjugated estrogens ? cyclic or daily progestins increase the frequency of migraine while daily transdermal estrogen ? cyclic progestins do not change the frequency. A 100 mg transdermal estradiol patch by itself was found to decrease headache outcome measures by 34 % in premenopausal women after induction of a medical menopause [28]. Therefore, HRT regimens consisting of oral estrogen ? progestins worsen migraine while transdermal formulations of estradiol ± oral progestins leave migraine unchanged or provide a modest preventative benefit. See a manuscript by Nappi [46] for a more comprehensive review of hormonal therapies during the menopause. There have been rare instances in which attacks of migraine with aura have been triggered by estrogen-containing OCPs and estrogen replacement therapy [47, 48]. If this occurs then it may be necessary to discontinue these medications altogether or use lower dosages or potencies of estrogen preparations. Another option for perimenopausal women is tibolone, which is a steroid hormone used to treat climacteric symptoms that binds to estrogen, progesterone and androgen receptors. It has been shown to reduce the number of hours of headache-related disability per month as compared to baseline in postmenopausal women with headache and climacteric symptoms [45].

Conclusion The menopausal transition represents a time of great change in ovarian hormones and the characteristics of the menstrual cycle. It is divided into early and late stages based on the patterns of menstrual bleeding as well as specific changes in reproductive hormones. The prevalence of migraine is greatest during the late menopausal transition, but only in those experiencing symptoms of PMS. The mechanisms through which the perimenopause might trigger migraine include ‘‘estrogen withdrawal’’,


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fluctuations in ovarian hormones, or secondarily through an increase in comorbid disorders. An understanding of these mechanisms may guide therapy for these women during their transition into menopause. Conflict of interest I certify that there is no actual or potential conflict of interest in relation to this article.

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Migraine and the menopausal transition.

The menopausal transition or "perimenopause" represents a time period of turbulent changes in ovarian hormones as middle-aged women progress into meno...
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