The clinical management of menstrual migraine and headache by the herbal medicine practitioner.
Menstrual migraine affects approximately 20% of all female migraineurs and they are reported to be more severe, longer lasting, more prone to recurrence & more resistant to treatment than nonmenstrual migraine attacks. (1,2,3) Menstrual migraine, without aura, according to the International Classification of Headache Disorders (ICHD) II and III beta versions, are defined as attacks of migraine without aura (MO), which occur within 2 days before to 3 days after the onset of menses in at least two out of three menstruations. There are two subtypes; pure menstrual migraine, characterised by menstrual migraine without aura occurring exclusively in the defined perimenstrual period, and menstrually-related migraine in which non-menstrual migraine attacks occur additionally at other times of the cycle. (4,5)
The fluctuation of oestrogen levels is believed to play a role in the pathogenesis of menstrual migraine. Evidence suggests that migraine is influenced by hormonal factors, particularly by oestrogen levels, and this is supported by the observation that migraine usually starts after menarche, occurs more frequently in the days just before or during menstruation, and ameliorates during pregnancy and after menopause. (6,7) Overall, headache is generally more prevalent in women compared to men. The prevalence of migraine is more than doubled in women. However, prior to adolescence there is no difference in migraine prevalence between boys and girls. (6) A significant increase occurs in females compared to males after menarche. This also supports the hypothesis that female sex hormones play a crucial role in migraine pathophysiology. (8)
The 'oestrogen withdrawal' hypothesis was proposed more than 40 years ago and is still most commonly accepted as the mechanism describing the role of oestrogen in triggering menstrual migraine. Migraine occurs when there is a sudden decline in oestrogen levels. This can be due to: a decline in endogenous oestrogens as occurs naturally immediately before menses (in the late luteal phase of the natural menstrual cycle): the withdrawal of exogenously administered oestrogen as occurs with the hormone-free interval of the combined oral contraceptives; or the decline in endogenous oestrogens during the transition toward menopause and the early postmenopausal period. It is also known that both oestrogen addition and oestrogen withdrawal may trigger a headache with migrainous features, suggesting that migraine is sensitive to hormonal fluctuations rather than the amount of circulating hormones. (7) The fluctuation of oestrogen levels influence cellular excitability or cerebral vasculature, which results in migraine. (6)
The prevalence of migraine tends to peak during the late menopausal transition particularly in those with a past history of premenstrual stress disorder and women with a history of menstrual migraine may be more vulnerable to exacerbation of migraine perimenopausally when hormones are more unstable. (7,9)
Other mechanisms independent of oestrogen withdrawal, such as prostaglandins may have been implicated in the pathophysiology of menstrual migraine, but these are not discussed in the scope of this paper. (10)
Strategies for menstrual migraine management
The goal of hormonal treatment regimens for menstrual migraine is to minimise oestrogen fluctuations. This may be achieved by supplemental oestradiol during the perimenstrual period, continuing the administration of hormonally active pills, or the use of transdermal oestrogen during the pill-free week of the oral contraceptive pill. (7,11) However, administration of combined oral contraceptives to migraineurs with aura is cautioned due to the further increased risk for ischemic stroke. (6) It is therefore possible that supplemental dietary phytoestrogens, with weak oestrogenic action, may mitigate the premenstrual decline in oestradiol that predictably precipitates migraine attacks, in a similar way to supplemental pharmaceutical oestrogens, and reduce or prevent menstrual migraine. Further, it is possible that herbal medicines, either with a phytoestrogen component or with oestrogen-modulating effects, could work to counterbalance this oestrogen decline?
A review of literature was conducted to ascertain whether there was any evidence to support the hypotheses. Anecdotal evidence suggests beneficial effects of soy isoflavones on PMS management because of their influence on endogenous oestrogen and actions on specific tissues. (12) The search was conducted through PubMed database exclusively. The search terms that were used were menstrual migraines, phytoestrogens, soy isoflavones, herbal medicine and headaches. Three very small clinical trials were identified where phytoestrogens were prescribed for the prophylactic treatment of menstrual migraine. (12, 13, 14) Papers that addressed menstrual migraine management specifically were included. Because of the small number of papers available, all papers that discussed menstrual migraine and phytoestrogens were included. Research examining the use of herbal medicines for the treatment of menstrual migraines was limited. A trial of a phytoestrogen combination including Angelica sinensis and Actaea racemosa, (14) as well as a paper on Vitex agnus-castus, (15) were located and included in the discussion.
Headache prophylaxis from phytoestrogen intervention was examined as part of a small doubleblind, placebo-controlled, crossover intervention study over 7-menstrual cycles of 23 women with prospectively confirmed PMS aged 18-35 years and with a BMI 19-30 kg/m. (12) The isolated soy protein (ISP) containing 68 mg/d (aglycone equivalents) soy isoflavones was provided as a daily food supplement comprising of a powder, that could be made into a drink or sprinkled over food, and a snack bar. The placebo supplements contained milk protein. After two cycles of ISP containing the soy isoflavones intervention, total symptoms and physical symptoms were significantly reduced compared with baseline in both active and placebo groups. There was a non-significant difference between active and placebo treatment. Headache and breast tenderness were specifically reduced from baseline after soy isoflavones, but not in the milk protein placebo group.
The isoflavones genistein, daidzein, equol were measured in 24 h urine samples. Concentrations of genistein & daidzein increased following soy isoflavone consumption.
Six of the 23 participants (26%) were equol producers. This is close to representative of the third of the general population that are equol producers, who possess the colonic bacteria that convert daidzein to the more biologically active metabolite equol. (16) The symptom reports did not differ between equol and non-equol producers. However, there was a trend for a greater reduction in total and physical symptoms in the equol producers compared with the non-equol producers during the premenstrual phase of the cycle. Because equol is believed to elicit greater biological reaction than other isoflavone metabolites, it was anticipated that the clinical effectiveness of the ISP containing soy isoflavones was dependent on eqoul. However, equol production did not enhance symptom reduction in this particular study. This was be presumed to be because of the very small sample, although other unknown mechanisms may have affected results. (12)
Further research discusses the possible mechanism through which soy isoflavones may reduce symptoms of PMS, with some relevance to menstrual migraine. It is postulated that the biological actions of soy isoflavones are mediated by oestrogen or oestrogen receptors. (13) It is known that the actions of phytoestrogens depend on the target tissue, the receptor status of that tissue and the level of endogenous oestrogen. (14) When endogenous oestrogens are high, the weak oestrogenic nature of soy isoflavones results in anti-oestrogenic responses. Conversely, when endogenous oestrogens are low or limited, soy isoflavones act as weak agonists and have an oestrogenic effect. Similarly, these effects are likely to occur during the menstrual cycle, where the effect of the soy isoflavone will be contingent on the circulating concentration of oestrogen as it fluctuates during the cycle. (12)
The possibility that the effects of soy isoflavones may be mediated by other mechanisms is also discussed. It is known that soy isoflavones have a higher affinity for oestrogen [beta] receptors (ER[beta]), which are found in the brain, bone, bladder and vascular epithelia, and may be related to the reduction of symptoms. (12)
Earlier research (14) described a phytoestrogen combination that contained soy isoflavones and also the non-phytoestrogen hormone modulating herbs, Angelica sinensis (dong quai) and Actaea racemosa (black cohosh), which the authors inaccurately referred to as phytoestrogens. In this study, 49 women aged between 18-48 years, with menstrually triggered and intercurrent migraine attacks, were randomised to receive twice daily either a placebo tablet or a tablet containing 75 mg soy extract standardised to 40% isoflavones (60 mg soy isoflavones daily), 50 mg of dong quai extract standardised to 1% ligustilide, and 25 mg black cohosh extract standardized to 8% triterpenes, for 24 weeks. The average frequency of menstrually-associated migraine attacks during weeks 9-24 was reduced from 10.3 +/- 2.4 in placebo-treated patients to 4.7 +/- 1.8 (P < 0.01) in patients treated with the phytoestrogen preparation. There was no difference between the treatment group and placebo group in the mean headache severity score during weeks 1-4. However, by weeks 20-24 the mean headache severity score dropped significantly compared to placebo (P < 0.01). There was a similar pattern in the reduction of use of triptans and analgesics between phytoestrogen and placebo groups, with no difference in usage during weeks 1-4, and significant reductions in usage during weeks 20-24. About 30% of the women were taking either oral contraceptives or progestins (7/24 in placebo and 9/25 in phytoestrogen groups, respectively), and the authors concluded that their use did not affect patient response to treatment either in the intention-to-treat or protocol-correct analysis. The cohort was a mix of women with menstrually-related migraine as well as migraines not related to the menstrual cycle and the sample size was very small, detracting from the studies overall strength. However, the research provides a possible therapeutic dose of isoflavones (60mg) for future larger randomised controlled trials.
The efficacy of phytoestrogens (soy isoflavones) on the prophylactic treatment of menstrual migraine, was examined in a very small (n=11) study of a 3-month cyclic treatment with 56 mg of genisteine and 20 mg of diadzeine per day, in women with a history of menstrual migraine (i.e., attacks occurring exclusively on day 1+/-2 days of menstruation and at no other time of the cycle). The average number of days with migraine during the baseline period decreased significantly after 3 months of therapy (P < 0.005). (13)
A review of the literature for additional research on migraine management with herbal medicine revealed a trial assessing the effectiveness of Vitex agnus-castus. In a 3 month, open-label clinical observation study of 107 women, examining the effects of Vitex agnus-castus (40 mg/day) on PMS & headache, 42% of patients experienced a reduction of more than 50% in frequency of monthly migraine attacks and 57% of patients experienced a reduction of more than 50% in monthly days with headache. (15)
Based on this early research, a proposed treatment intervention for menstrual migraine management encompasses supplementation of dietary phytoestrogens, with an emphasis particularly on soy isoflavones, exclusively in the days preceding the usual onset of the migraine, for the duration of the predictable oestrogen decline. For example, the dietary manipulation is confined to times of oestrogen decline only, 2-3 days prior to the period until day 3 of the cycle inclusively. The author has recommended this regimen to patients attending the clinic for menstrual migraine over the last decade. This experimental 'prescription', prior to the literature review, had not relied on achieving a specific dose of phytoestrogens, although a dose of 50 mg of isoflavones daily was set as an arbitrary target dose. Given the evidence, this phytoestrogen target dose was close to the 60-70mg of isoflavones used as an intervention in two of the studies. (12,13) Other dietary phytoestrogen foods were also encouraged, such as linseed (which provides other classes of phytoestrogens but is not high in isoflavones) to complement the overall phytoestrogen pool. There is no evidence that lignans, found in linseeds, have any impact on menstrual migraines prophylaxis. Dietary suggestions included incorporating tempeh and tofu, soy beans, soy flour, using whole soybean-based milk in beverages and cereal; soy and linseed bread and dry biscuits, inclusion of sprouts in salads and sandwiches; freshly ground linseeds; soy grits. A list of the isoflavone content of soy dietary sources, sourced from the US Department of Agriculture Database for the Isoflavone Content of Selected Foods, (17) is provided in Table 1.
Management of menstrual migraine may also include the prescription of an herbal formula containing phytoestrogenic herbs and herbs that address the traditional naturopathic mechanisms associated with headache and/or migraine. An example of a typical formula prescribed is:
Paeonia lactiflora 30mls
Lavandula angustifolia 30mls
Humulus lupulus 15mls
Actaea racemosa 15mls
Tanacetum parthenium 10mls
Dosage: 7-8 mls BD 2-5 days pre-menstrually until day 3 of cycle. Or commenced when active oral contraceptive pill tablets ceased, until day 3 of cycle.
The rationale for the herbal prescription
The herbal formula contains oestrogen-modulating and phytoestrogen herbs that the author proposes and counterbalances the physiological decline in oestrogen that occurs premenstrually, in a similar way to the soy isoflavone counter-balancing action. There is conflicting evidence that phytoestrogen containing herbs such as Humulus lupulus and oestrogen modulating herbs such as Actaea racemosa, are used in perimenopausal women, where endogenous oestrogen is low and can alleviate symptoms associated with low oestrogen. (18) These herbs are included in the formula, in a similar way, to address the predicted oestrogen decline that occurs in the late luteal phase. Unfortunately there is no supporting evidence in the literature on utilising these herbs in this manner. A discussion of the traditional knowledge and application of the herbs for the management of menstrual migraine is presented.
Paeonia lactiflora, in animal studies, has demonstrated relaxation of vascular smooth muscle. (19) In traditional Chinese medicine it 'nourishes the blood' and is used for blood deficiency. (20) Lavandula angustifolia is a relaxing nervine incorporated as part of the management of menstrual migraines (21) and traditionally used to treat migraine. (22) Humulus lupulus is included in the prescription because it contains as one of its active constituents the flavonoid 8-prenylnaringen, which has been identified, in vitro, as one of the most potent phytoestrogens. (23) It is the primary herb in this formula that serves to counterbalance the decline in oestrogen. Humulus lupulus is also a bitter tonic with relaxant and sedative actions. (22) Improving liver function and addressing muscular tension are therapeutic objectives of herbal medicine management of headache and migraine. (24) Tanacetum parthenium is well known for the prophylactic treatment of migraine. (25) Actaea racemosa is an oestrogen modulating herb and does not bind to oestrogen receptors or exhibit oestrogenic effects in vitro. (21,26) The effective compounds in this herb are most likely neurotransmitter-mimetic (serotonergic and dopaminergic) in nature. A variation of the formula with the omission of Actaea racemosa is sometimes prescribed, as higher doses are reported to cause headaches and it is an observation of this author that this is the case particularly in the hormonally sensitive migrainous female patient. (22) Additional herbs added to tailor the formula to the individual may include hepatics and nervines when indicated.
Anecdotal observations in clinical practice show that hormonal manipulation with dietary phytoestrogens may reduce severity of menstrual migraines or prevent their occurrence of, apparently as a result of their weak oestrogenic effect mitigating the premenstrual decline in oestrogen. The preliminary research on phytoestrogen supplementation for migraine prophylaxis has been reviewed, but is limited by the small sample sizes. The precise 'dose' of dietary phytoestrogens has not been established, but based on the interventions in the reviewed literature a dose of 60-70 mg of soy isoflavones may be an appropriate target dose. Further research is required to examine if dietary phytoestrogens, specifically soy isoflavones, taken in the perimenstrual period, can reduce the frequency or severity of menstrual migraine.
The efficacy of the implementation of a phytoestrogen herb as a single remedy has not been examined, and may be the focus for further research. Humulus lupulus is a prospective herb to consider as it contains a potent phytoestrogenic constituent. Other classes of phytoestrogens, other than isoflavones, have not been the focus of this review, and it appears that there is no research investigating their use in the treatment of menstrual migraine. Hefbal medicine practitioners often also include herbs with muscle relaxant, tonic, hepatic and nervine actions to complete the holistic management of menstrual migraine.
(1.) Vetvik KG, Macgregor EA, Lundqvist, C, Russell, MB 2014. 'Prevalence of menstrual migraine: a population based study.' Cephalalgia 34(4):280-8.
(2.) Calhoun AH, 2012. Menstrual migraine: update on pathophysiology and approach to therapy and management. Curr Treat Options Neurol 14(1):1-14.
(3.) Nierenburg HDC, Ailani J, Malloy M, Siavoshi S, Hu NN, Yusuf N. 2015. Systemic Review of Preventive and Acute Treatment of Menstrual Migraine. Headache 55(8):1052-71.
(4.) Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia, 2013, vol. 33, pp 629-808.
(5.) Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004, vol.24 (suppl 1), pp. 9-160.
(6.) Sacco S, Ricci S, Degan, D, Carolei A, 2012. Migraine in women: the role of hormones and their impact on vascular diseases. J Headache Pain 13(3):177-189.
(7.) Ripa P, Ornello R, Degan D, Tieso C, Stewart J, Pistoia F, Sacco S. 2015. Migraine in menopausal women: a systemic review/ Int J Womens Health 7:773-782. Published online August 20. DOI: 10.2147/IJwH.S70073.
(8.) Karli N, Baykan B, Ertas M, Zarfoglu M, Siva A, Saip S, Ozkaya G, 2012. Impact of sex hormonal changes on tension-type headaches and migraine: a cross-sectional population-based survey in 2,600 women. J Headache Pain 13(7):557-65.
(9.) Martin VT, 2014. Migraine and the menopausal transition. Neurol Sci 35 Suppl 1:6-9.
(10.) MacGregor, EA, 2015. Migraine Management During Menstruation and Menopause. Continuum (MinneapMinn) 21(4):990-1003.
(11.) Loder E, Rizzoli P, Golub J. 2007. Hormonal management of migraine with menses and the menopause: a clinical review. Headache 47(2):329-40.
(12.) Bryant M, Cassidy A, Hill C, Powell J, Talbot D, Dye L. 2005. Effect of consumption of soy Isoflavones on behavioural, somatic and affective symptoms in women with premenstrual syndrome. Br JNutr 93(5):731-9.
(13.) Ferrante F, Fusco E, Calabresi P, Cupini LM. 2004. Phytooestrogens in the prophylaxis of menstrual migraine. Clin Neuropharmacol 27(3):137-40.
(14.) Burke BE, Olson RD, Cusack BJ, 2002. Randomized, controlled trial of phytoestrogen in the prophylactic treatment of menstrual migraine. Biomed Pharmacother 56(6):283-8.
(15.) Ambrosini A, Di Lorenzo C, Coppola G, Pierelli F. 2013. Use of Vitex agnus-castus in migrainous women with premenstrual syndrome: an open-label clinical observation. Acta Neurol Belg 113(1):25-9.
(16.) Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of The North American Menopause Society' Menopause: The Journal of The North American Menopause Society, 22(11).
(17.) http://www.ars.usda.gov/SP2UserFiles/Place/80400525/Data/ isoflavAsoflav_R2.pdf
(18.) Depypere HT, Comhaire, FH. 2014. Herbal preparations for the menopause: Beyond Isoflavones & Black Cohosh. Maturitas 77(2):191-194.
(19.) Jin SN, Wen JF, Wang TT, Kang DG, Lee HS, Cho KW. 2012. Vasodilatory effects of ethanol extract of Radix Paeoniae Rubra and its mechanism of action in the rat aorta. J Ethnopharmacol 142(1):188-93. See comment in PubMed Commons below
(20.) Bensky D, Gamble A. Chinese Herbal Medicine Materia Medica. Revised edition 1993. Seattle, Washington, USA. Eastland Press, Inc. pg. 332.
(21.) Trickey, R. Women, Hormones & the Menstrual Cycle. Third edition. Fairfield, Victoria, Australia. Trickey Enterprises (Victoria) Pty Ltd. Pg. 201
(22.) Braun L, Cohen M. 2010. Herbs & Natural Supplements. An evidence-based guide. 3 rd Edition. Chatswood, NSW, Australia. Churchill Livingstone.
(23.) Nikolic D, Li Y, Chadwick LR, van Breemen RB. 2006. In vitro studies of intestinal permeability and hepatic and intestinal metabolism of 8-prenylnargenin, a potent phytoestrogen from hops (Humulus lupulis L). Pharm Res 23(5):864-72.
(24.) Hechtman L. 2012. Clinical Naturopathic Medicine. Chatswood, NSW. Churchill Livingstone. Pg. 1230.
(25.) Pfaffenrath V, Diener HC, Fischer M, Friede M, Henneickevon Zepelin HH. 2002. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis- a double-blind, Multicentre, randomized placebo-controlled dose-response study. Cephalgia 22(7):523-32.
(26.) Wuttke W, Jarry H, Haunschild J, Stecher G, Schuh M, Seidlova-Wuttke D. 2014. The non-estrogenic alternative for the treatment of Climacteric complaints: Black cohosh (Cimicifuga or Actaea racemosa). J Steroid Biochem Mol Biol 139:302-10.
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Table 1: Dietary sources of high isoflavone containing soy foods Dietary source Total isoflavones mg/100g Soy beans dry roasted 148 Soy beans boiled 65 Soybeans canned 52.8 Miso 41.5 Tempeh 35-72 Tofu 22-34 Silken tofu 18 Edamame (cooked) 17.9 Soy and linseed bread 14.7 Smoked tofu 13.1 Soy milk 7-10
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|Publication:||Australian Journal of Herbal Medicine|
|Date:||Sep 1, 2016|
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