Migraine and hormones Dr. E. - PowerPoint Presentation

Slide1

Migraine and hormones

Dr. E. JafariHeadache Department, Iranian Center of Neurological Research, Tehran University of Medical Sciences, Tehran, Iran.

Slide2

Slide3

Migraine is 3 times more prevalent in women than in

men by the age 30, with 25-30% of the female population being affected, in comparison to only 8% of the male population Lifetime prevalence of 43% for migraine in women

Slide4

Perimenopausal and peripubertal periods are associated with increased risk of migraine

Migraine incidence peaks about age 50, coinciding with fluctuations in reproductive hormone levels

Slide5

Frequency of attacks does not differ significantly

longer-lasting attacks and higher rate of relapses in womenGreater burden of disease and use of analgesic in womenPhotophobia, phonophobia, nausea and vomiting, and skin allodynia are more frequent complaints in women than in men.

Migraine in women and men

Slide6

Possible mechanisms for gender differences Hormonal effectsS

tructural and functional differences in certain brain areasBiological and psychosocial differences in pain perception and processingGenetic factorsCGRP

Slide7

CGRP CGRP system

is influenced by endogenous or exogenous ovarian steroid hormonesHigher levels of CGRP in women of reproductive age than in men and influence of cyclic hormonal fluctuations on CGRP releaseUse of combined contraceptive pills is associated with higher levels of CGRP in plasmaIn postmenopausal women, decreased estradiol serum levels are correlated with decreased plasma CGRP

Slide8

Hormonal effects: Estrogen The distribution of estrogen receptors in the trigeminovascular

system and the central nervous system’s pain control areas influences excitatory or inhibitory activity, depending on the varying levels of estrogenEstrogen modulates serotonergic neurotransmission, by increasing the expression of the tryptophan hydroxylase and decreasing the expression of the serotonin reuptake transporterActivates endogenous opioidergic systemSteady or rising concentrations of estrogen do not precipitate migraineHigh estrogen levels can trigger migraine aura by development of cortical spreading depression: pregnancy, OCP, HRT

Slide9

Hormonal effects: ProgesteroneReducing nociception in the trigeminovascular

systemInhibiting neurogenic edema, and histamine secretion from mast cells Decreasing prostaglandin productionInhibitory influence on cortical excitabilityProtective role against migraine

Slide10

20-60% association with menstruation

in women with migraineIncreased incidence of migraines in days -2 to +3 of menstruationLonger, more severe, and unresponsive attacksPure menstrual migraine:7 to 35% Menstrually related migraine: 60%A diagnosis of menstrual migraine should not be made in women with frequent migraine attacks

Menstrual Migraine

Slide11

ICHD3 criteria for menstrual migraine

ICHD 3 criteria for Menstrually related migraine(MRM)ICHD3 criteria for Pure menstrual migraine (PMM)Attacks of migraine in a menstruating woman, occurring on day 1 +/- 2 (i.e. days -2 to +3) of menstruation in at least two out of three menstrual cycles, and additionally at other times of the cycle

Attacks, in a menstruating woman occurring exclusively on day 1 +/- 2 (i.e. days -2 to +3) of menstruation in at least two out of three menstrual cycles and at no other times of the cycle

Slide12

Estrogen drop

in the late luteal phase, is the most potent trigger of migraine, esp. if it is preceded by a phase of high estrogen levels and the decrease is greater than 10μgExacerbation in migraines following ovulation in some womenPremenstrual headaches part of pre-menstrual syndrome

Slide13

Effects of estrogen withdrawalOxidative stressReduced production of serotoninImbalance

in serotonin and dopamine Increased sensitivity to prostaglandins Release of neuropeptides such as calcitonin gene-related peptide (CGRP), substance P and neurokinins Changes in calcium and magnesium concentrationsDecreased endogenous opioid activity

Slide14

Treatment of menstrual migraine

Acetaminophen, caffeine, Rizatriptan, mefenamic acidAcute treatmentNaproxen

Mefenamic acidFrovatriptanNaratriptanZolmitriptanEstradiolMagnesiumShort-term prophylaxis Standard prophylactic drugs Hormonal treatment

Long-term prevention

Slide15

Effectiveness of Triptans

2 hour pain relief2 hour pain freeSustained pain relief2 to 24 hoursSustained pain free2 to 24 hoursSumatriptan 100 mg

61% 31%Rizatriptan33-73% 63% 63% 32%Naratriptan43% 42%Zolmitriptan

28-48%

Almotriptan

48%

36%

Slide16

Preventive treatment Depends on the effectiveness of acute treatments, menstrual regularity, need for contraception, and the presence of menstrual

disordersIncludes: Perimenstrual prophylaxisStandard prophylaxisHormonal therapies

Slide17

Slide18

Short term prophylaxis

Naproxen 550 mg Bid for 7-14 daysMefenamic acid500 mg Tid

on days -4 to +3Frovatriptan 5 mg Bid on day -2, 2.5 mg Bid on days -1 to +4Naratriptan 1 mg Bid on days -3 to +3Zolmitriptan 2.5 mg Bid on days -2 to +5Estradiol 1.5 mg transdermal starting between days -5 and -2 for 7 daysMagnesium 120 mg Tid begin on the 15th day until the next menses

Slide19

Hormonal preventive strategies

Extended-cycle regimensAdding estrogen in pill-free period:1.25 mg of conjugated equine estrogen or 10micg EEShortening the number of placebo days from 7 to 4

Slide20

The frequency or intensity of the headache may increase or its characteristics may changeAggravates headaches in 18-50%,

Improves migraine in 30-35%Causes no change in 40-65%Headaches most frequently occur in the “pill-free” week

OCP and Migraine

Slide21

Absolute risk of ischemic stroke in women aged 20 to 44 years in relation to hormonal contraception and migraine status

 No migraine Migraine without aura

Migraine with auraWithout hormonal contraception2.5/100,0004.0/100,0005.9/100,000With hormonal contraception

6.3/100,000

10.0/100,000

14.5/100,000

Active

migraine with more than 12 attacks per year are associated with increased risk of ischemic

stroke.

Very

low doses of estrogen (<

20

mcg EE)

in

non-smokers with a normal blood

pressure and migraine without aura, has

not increased

the

risk of

stroke.

The chosen progestin

does not seem to affect arterial

risks such

as stroke and myocardial

infarction.

Slide22

Consensus statement from the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESC)

Slide23

Clinical evaluation for

the presence of migraine, definition of migraine subtype and migraine frequency together with the ascertainment of conventional vascular risk factors2 - Consideration of the type of hormonal contraception :high risk products :>35 μg ethinylestradiolmedium risk products: ≤35 μg ethinylestradiol, combined contraceptive patch, and combined vaginal ringno risk products: progestogen-only contraceptives

3 - In women with migraine with aura, we suggest against prescription of combined hormonal contraceptives and suggest non-hormonal contraception or progestogen-only methods.4 - In women with migraine without aura who have additional risk factors (cigarette smoking, arterial hypertension, obesity, previous history of cardiovascular disease, previous history of deep vein thrombosis or pulmonary embolism), we suggest non-hormonal contraception or progestogen-only contraceptives.

Slide24

5 - In women with migraine without aura who have no additional risk factors, we suggest the use of combined hormonal contraceptives containing ≤35

μg dose of ethinylestradiol with monitoring of migraine frequency and characteristics.6 - In women with migraine who require hormonal treatment for polycystic ovary syndrome or endometriosis we suggest to select the hormonal treatment of choice on clinical grounds.7 - In women who start combined hormonal contraceptives and develop new onset of migraine with or without aura in a temporal relationship to starting the hormonal contraceptive, we suggest switching to non-hormonal contraception or progestogen-only

contraceptives.8 - In women with migraine with or without aura who require emergency contraception, we suggest the use of levonorgestrel 1.5 mg orally, ulipristal acetate 30 mg orally, or the copper-bearing intrauterine device.9 - In women with migraine with or without aura, we suggest against specific tests (e.g. thrombophilia screening, patent foramen ovale evaluation or neuroimaging evaluation) to decide about hormonal contraceptive prescription unless those tests are indicated by the patient’s history or by the presence of specific symptoms.

Slide25

Progesterone only pills

Can be used continuouslyNo estrogen dropNo effect on cortical spreading depression (CSD) threshold No increase the risk of vascular arterial eventsNo migraine inductionShorter half-life Less effective contraceptionIncomplete prevention of ovulation May not reduce episodes of migraine

advatage

disadvantage

Slide26

Available packs in Iran

Contraceptive pillEstrogen typeEstrogen doseProgestin typeProgestin doseHDEE50mcgLevonorgestrel250mcg

LDEE30mcgLevonorgestrel150mcgBelara/CharivaEE30mcgChlormadinone 2mgDesoceptive (Marvelon)EE30mcgDesogestrel 150mcgDianEE35mcg

Cyproterone Acetate2mg

Yasmin

/

Rokin

EE

30mcg

Drospirenone

3mg

Yaz

EE

20mcg

Drospirenone

3mg

Drosbela

EE

20mcg

Drospirenone

3mg

Slide27

Ethinyl estradiol 20mcg

Slide28

Perimenopause is a 2-8 year

phase ending 12 months after the last menstrual period Women enter perimenopause in their mid-forties, or earlier, and tend to reach menopause by age 55significant fluctuations in hormone levels, iron deficiency caused by increased menstrual bleeding, depression and sleep disturbances Risk of medication overuse

Menopause

Slide29

Menopause Hormonal headaches have a higher chance of worsening around menopauseMigraine with aura appears to be unaffected by either natural or surgical

menopausePhysiologic menopause has been associated with a lower incidence of migraine than surgical menopause

Slide30

There is not enough evidence in favor of increased risk of stroke in women with migraine headaches above 45 years of ageHRT should be administered according to its common indications and

contraindicationsMigraine aura is not a contraindication to HRT, when administered topical with low dose natural estrogen

HRT

Slide31

HRT Depending on the duration, type, dose, and route

of administration of estrogen, migraine can be exacerbated, unchanged, or improvedElevated doses can induce new migraine with aura or exacerbate attack frequency and intensityInitial exacerbation of migraine in the first few weeks of treatment can occur; therefore, it is important not to stop treatment too earlyTransdermal combinations provide more stable serum levels and do not increase the risk of strokeContinuous HRT with low dose transdermal estrogen with or without progesterone

Slide32

HRTTreatment strategies for worsening of migraine with HRT:

dose reduction non-cyclic estrogen use switching from conjugated estrogens to pure estradiol or from synthetic to bioidentical estrogen

Slide33

References Delaruelle

Z, Ivanova TA, Khan S, Negro A, Ornello R, Raffaelli B, et al. Male and female sex hormones in primary headaches. J Headache Pain. 2018;19(1):117Todd C, Lagman-Bartolome AM, Lay C. Women and Migraine: the Role of Hormones. Current neurology and neuroscience reports. 2018;18(7):42.Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, et al. Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache. 2013;53(8):1278-99.Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia : an international journal of headache. 2018;38(1):1-211.Calhoun AH. Understanding Menstrual Migraine. Headache. 2018;58(4):626-30.MacGregor EA. Migraine, menopause and hormone replacement therapy. Post reproductive health. 2018;24(1):11-8.

Calhoun AH, Batur P. Combined hormonal contraceptives and migraine: An update on the evidence. Cleveland Clinic journal of medicine. 2017;84(8):631-8.Labastida-Ramirez A, Rubio-Beltran E, Villalon CM, MaassenVanDenBrink A. Gender aspects of CGRP in migraine. Cephalalgia : an international journal of headache. 2019;39(3):435-44.Allais G, Chiarle G, Sinigaglia S, Benedetto C. Menstrual migraine: a review of current and developing pharmacotherapies for women. Expert opinion on pharmacotherapy. 2018;19(2):123-36.Maasumi K, Tepper SJ, Kriegler JS. Menstrual Migraine and Treatment Options: Review. Headache. 2017;57(2):194-208.Sacco S, Merki-Feld GS, KL AE, Bitzer J, Canonico M, Kurth T, et al. Hormonal contraceptives and risk of ischemic stroke in women with migraine: a consensus statement from the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESC). J Headache Pain. 2017;18(1):108.Sacco S, Merki-Feld GS, KL AE, Bitzer J, Canonico M, Gantenbein AR, et al. Effect of exogenous estrogens and

progestogens on the course of migraine during reproductive age: a consensus statement by the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESCRH). J Headache Pain. 2018;19(1):

76

Allais G,

Chiarle

G,

Sinigaglia

S,

Airola

G,

Schiapparelli

P, Benedetto C. Estrogen, migraine, and vascular risk. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2018;39(

Suppl

1):11-20

.

Martin VT,

Pavlovic

J, Fanning KM,

Buse

DC, Reed ML, Lipton RB.

Perimenopause

and Menopause Are Associated With High Frequency Headache in Women With Migraine: Results of the American Migraine Prevalence and Prevention Study. Headache. 2016;56(2):292-305.

Slide34

See the IHS website for more information

and to join online

Belong to the

International Headache Society (IHS)

Headache/neurology specialists from Iran can join

free of charge

as an Associate Member

Online access to

Cephalalgia

Online access to

The Neuroscientist

Access to the IHS Online Learning Centre

Early access to IHS International Guidelines

Benefit from key Exchange Programmes and Awards

Fellowships / Scholarships

Travel Grants

Visiting Professors

Headache Master Schools

www.ihs-headache.org

To advance headache science, education and management, and promote headache awareness worldwide

.

Free of charge

Associate Membership