Migraine in the Female Life
Cycle
Headache Forum
October 2007
Lucy Vieira MD
Objectives


Describe the changes in migraine
prevalence and characteristics throughout
the female lifecycle.
Discuss the factors to consider in the
treatment of the female migraineur.



Perimenstrual migraine
Perimenopausal migraine
Migraine and the risk of stroke
Incidence of migraine peaks in
adolescence.
Peak incidence females
Migraine
with aura:
12-13yo
(14/1000 person-years)
Migraine
without aura:
14-17yo
(19/1000 person-years)
Stewart et. al. 1993. Amer J Epidemiol 34:1111-20
– the reported age of migraine incidence in a prevalence study
Peak Incidence males
•Migraine with aura:
5yo (6.6/1000)
•Migraine without
aura:
10-11yo(10/1000)
Prevalence of Migraine
•Before puberty: prevalence higher in boys
•Until early adulthood incidence and prevalence continue to increase
•Prevalence highest from 25-55 yo. Prevalence is stable in the USA
over time.
American migraine study-I- info from 15,000 homes in 1989
AMS-II – 1999. AMPP – 2005.
prevalence mig: 18%F
6%M
Lipton Headache 38:87-96 1998. Lipton Headache 41:646-57. Lipton Headache 45:792 2005
Burden of Migraine
Individual: 25% of female migraineurs have>4 severe attacks/m
- this associated with significant disability (need bed rest)
Societal: loss of work productivity (13 billion/y)
- healthcare use: 4% of all visits for headache
-accounts for 1/3 of all OTC analgesic use.
Lipton 2001 Headache 41: 638-45. Hu 1999 Arch Intern Med 159:813-18. Holmes 2001
Neurology 56(s 1):13-19
Case Study:
Julia 27 year old Med Student
Migraine since age 13
No Phx. No meds.
Attacks are stereotypical migraine without aura.
Occur once or twice a month, usually but not exclusively
around menstruation.
Menstrual migraine
Pure menstrual migraine: migraine without aura that
occurs on day 1+2 (d-2to+3) most cycles and no migraine
at other times
10%
Menstrually-related Migraine: as above but additional
attacks with or without aura at other times of the cycle
40%
Non-menstrual migraine
50%
MacGregor EA Cephalalgia 1990 and 1996
Figure 117">
MacGregor, E. A. et al. Neurology 2006;67:2154-2158
Chance of migraine 2.5X
more
during days 1-3 of the cycle
Figure
217">
MacGregor, E. A. et al. Neurology 2006;67:2154-2158
MacGregor E.A. et al., Neurology 2004;63:351-53
Pathophysiology of this incr.
Risk of Migraine



estrogen withdrawal – incr. Neuronal
excitability
Prostaglandin release
Magnesium deficiency
Martin VT Headache 2006;46:3-23 and 365-86
Martin V et al., Headache 2006;46:365-86
Estrogen and neuronal excitability
Treatment with estradiol increases dendritic spine density in
hippocampal neurons (female rat): incr. Excitatory input
Cell membrane receptors
(progesterone metabolite)
Effects of estrogen on Purkinje cell response to glutamate
(female rats)
Smith Brain Res. 1988;475:272-282
Summary
Martin and Behbehani. Headache 2006;46:365-86
PNAS 2001: 98:4687-4692
Ann Neurol 2004;55:276-80
Hormonal treatmentspremenopausal woman
Goals:
-prevent drop in estradiol?
-produce anovulation?
-add estrogen or progesterone that may have preventative effects?
Estrogen and migraine
Medical oophorectomy alone worsened headache while add
back Estradiol improved headache.
100 mcg Estradiol patch is much better than 50 mcg
Fluctuations in serum estrogen may be very important
Martin V. Headache 2003;43:309-21
Perimenstrual Estradiol patch/gel
28 day cycle
28 day cycle
Estradiol patch/gel days –2 to +7
•100 mcg patch better than 25 mcg – need to achieve
plasma estradiol levels of 60-80 pg/ml.
•May cause spotting and irregular menses.
•Migraine shifted to when take off gel/patch.
Granella F Cephalalgia 17:35-38,1997. MacGregor A Neurology 2006; 67:2159-63
Figure 118">
MacGregor, E. A. et al. Neurology 2006;67:2159-2163
Oral contraceptives
Most composed of Ethinyl estradiol (synthetic estrogen that
inhibits gonadotropin release)
Progestins – derivatives of 10-Nortestesterone
1st gen – norethisterone
2nd gen – norgestrel, levonorgestrel
3rd gen – desogestrel, others
4th gen – drospirenone (anti-mineralocorticocoid effect)
-derivative of spironolactone
Formulations – triphasic, monophasic, extended duration
Migraine and OCPs
1. Unchanged in half, worse in 30% and improved in 6%
2. Patients with aura more likely to worsen (50% vs 25%)
3. Aura may develop for the first time with OCPs.
Martin V. Headache 2006; 46:365-86
Effect on MWA



Patients experiencing attacks of MWA are more
likely to worsen with administration of OCPs
than those with MWoA.
case reports have demonstrated that visual,
sensory, and motor aura may develop for the first
time in those receiving OCPs.
Some patients with "new onset aura" or a
"crescendo pattern" to their migraines after the
start of OCPs have progressed to develop
cerebrovascular accidents (CVAs).
(Granella Cephalalgia 2000;20:701-7; Cupini Cephalalgia 1995;15(2):140144. Mousa Am J Optom Physiol Opt. 1982;59:821-23
).
Case#2


18 year old woman who is known to you for
migraine with aura. She would like to take
the BCP.
Aura consists of progressive bright visual
phenomena that evolve then disappear after
30 minutes. She has these about 4 times a
year. She also has migraine without aura
around the time of her period each month.




Phx: negative
Smoking: none
Neurological exam and blood tests
normal.
How would you manage this patient?
Migraine and stroke risk
•Past studies have reported an increased risk of CVAs
in patients with migraine headache
•Esp. young women and MWA.
•A recent meta-analysis reviewed 14 studies (11
case control and 3 cohort studies) to determine the
relationship between migraine and risk of ischemic
CVA. (Etminan M et al., BMJ 2005;330(7482):63)
Stang PE, et al. Neurology. 2005;64(9):1573-1577. Tzourio C, Bousser MG. Stroke. 1997;28(12):2569-2570.
Tzourio C, et al.,BMJ. 1993;307(6899):289-292. Chang CL, et al., BMJ. 1999;318(7175):13-18.
Velentgas P, Headache. 2004;44(7):642-651.
Pooled rel. risks of stroke stratified by migraine type, oral contraceptive use, and age
Relative risk (95% CI) Ri*
P value†
All studies 14
2.16 (1.89 to 2.48)
0.00
0.77
Etminan, M
Case-control studies 11
2.18 (1.86 to 2.56)
0.00
0.51
BMJ 2005;330:63
Cohort studies 3
2.10 (1.61 to 2.75) 0.00
0.96
2.27 (1.61 to 3.19) 0.49
0.08
1.83 (1.06 to 3.15)
0.60
0.04
8.72 (5.05 to 15.05) 0.26
0.28
No of studies
Migraine (any)
Migraine with aura
Case-control studies 7
Migraine without aura
Case-control studies 6
Migraine among oral contraceptive users
Case-control studies 3
Migraine among men and women <45 years
Case-control studies 9
2.36 (1.92 to 2.90) 0.07
0.38
Migraine among women <45 years
Case-control studies 7
2.76 (2.17 to 3.52) 0.00
0.82
*Proportion of the total variance due to between study variance. Large values (>0.75) indicate
large heterogeneity between studies; small values (<0.4) indicate lack of heterogeneity.7
Fig 1 Forest plot of the studies of migraine and ischaemic stroke
Etminan, M. et al. BMJ 2005;330:63
Copyright ©2005 BMJ Publishing Group Ltd.
Migraine as a risk factor for Stroke
in young women (<45)
(Absolute risk is about 2/100000/year)






Migraine without aura
Migraine with aura
No aura + BCP*
Aura + BCP*
Aura + smoking
Aura + BCP* + smoking
Bousser, MG Stroke.2004;35(suppl I):2651-56
RR
3
6
6
12
12
35
*low estrogen+progesterone
In migraineurs

No absolute contraindication for the use
of the BCP.


Should be avoided in patients who smoke
and esp. if there is aura.
Stop or switch if aura develops or
increases or if headache worsens after the
first few weeks.
In this patient



Evaluate and discuss the risks of
stroke.
Use a low estrogen or progesterone
only pill
Monitor for the development of a more
complicated or frequent aura – stop the
pill
Cardiovascular Safety of Triptans



Contraindicated in pts with
uncontrolled HTN, CAD, CVA,
complicated aura
Avoid in those with >2 risk factors
Incidence of serious cardiovascular
events is extremely low. Risk-benefit
profile favors use in the absence of
vascular risk factors.
Triptan cardiovascular safety expert panel of the American Headache society
– consensus statement. Headache 44(5):414, 2004
Management of Menstrual
Migraine


Acute therapy: NSAIDS or triptans
Mini-prophylaxis starting 48 hours before
expected headache or 10 days after ovulation
and continuing up to one week:





Increase dose of usual prophylactic
Naproxen 500 mg BID
triptans
Estradiol gel 1.5 mg Qday
Estradiol patch 100 mcg q3-4days
Acute Rx: triptans

Sumatriptan 100mg PO, 6mg s/c,
rizatriptan, zolmitriptan, Naratriptan

All effective in placebo controlled trials
Short-term MM prophylaxis
Mg
Naproxen
DHE-45 NS
Estradiol gel
Estradiol patch
Sumatriptan
Naratriptan
Zolmitriptan
360 mg/d
550 mg BID
NS q8h
1.5 mg Qday
100 mg
25 mg TID
1 mg BID
2.5 mg BID
* Refers to before expected headache
Day 15-menses
Day -7 to +6
Day -2* to +4
Day -2* to +5
same
day -2 to +3
Day -2 to +3
Day -2 to +4
Other treatments


Increase the dose of the usual prophylactic
meds
Continuous OCP: elimination of the
placebo week across 3-4 cycles
(Silberstein Headache in clinical practice 2002: 100-107)
Extended duration OCPs
Sulak Headache 2007;47:27-37
Pregnancy

Preexisting migraine most often improves with
pregnancy.

48% to 79% of women with a history of
preexisting migraine improve during pregnancy,
particularly during the second and third trimesters

Aura symptoms occur frequently during
pregnancy in those with a past history of
migraine.

Several studies have reported "new onset" visual,
sensory, and motor aura during pregnancy.

the "high estrogen milieu" of pregnancy could
play a role in initiating attacks of MWA.

pts with "exclusively" MWA were less likely to
have an improvement in migraine during
pregnancy.
Perimenopause:
time period 2 to 8 yrs prior to menopause +1 year (WHO)




menstrual cycles var., heavier menstrual bleeding,
anovulation, and intermittent amenorrhea during
this time.
Levels of ovarian hormones may differ: lower
progesterone
No longitudinal diary studies
Cross-sectional studies suggest: prevalence of
migraine higher during perimenopause in pts
with MWoA and premenstrual syndrome.
(Mattsson Headache 003;43:27-35)
Exogenous hormones:
Postmenopausal women
50 year old woman with a past history of migraine without aura.
Attacks were well controlled with Ibuprofen until last 12 months.
Now occur 5-6 times per month.
She thinks it’s due to the fact that her sleep is disturbed by hot
flushes. She had one menstrual period in the last 6 months.
She is constantly tired and feels sleep deprived.
Her gynecologist does not want to give her hormone therapy
because of her migraines.
Hormone replacement therapy
Effect on migraine depends on:
1. Preparation used and route of delivery
2. Dose used
3. Constancy of dosing
4. Concomitant use of a progestin
Menopause


no longitudinal cohort studies
retrospective questionnaires of the effect of menopause on
headaches:



migraine improves in 8% to 36%, worsens in 9% to 42%, and remains
unchanged in 27% to 64% at the time of menopause
8 to 13% develop migraine denovo
Patients with a surgical menopause may do worse: 38% to 87%
worsening of existing migraine.

abrupt withdrawal of estrogen (surgical oophorectomy may be more
provocative) Another potential explanation may be that the dose of
estrogen replacement therapy used in surgically oophorectomized
patients was too low to prevent migraine ( Martin 2006)
Hodson J, Climacteric. 2000;3(2):119-124. Granella F,. Headache. 1993;33(7):385-389
HRT

HORMONE REPLACEMENT THERAPY: natural, conjugated, and
synthetic estrogens.(lower potency than those generally found in OCPs.)

Natural estrogen preparations contain estrogens normally found with women
(eg, β-estradiol).

Conjugated estrogens are produced from animal and/or plant sources

synthetic estrogens are synthesized estrogen derivatives (eg, ethinyl estradiol).

The oral progestins include natural progesterone (eg, micronized progesterone)
as well as synthetic progestins (eg, medroxyprogesterone).

Oral progestins may be administered daily or for 10 to 12 days each month to
prevent endometrial hyperplasia.

routes of delivery of HRT include pills, transdermal patches/gels, subcutaneous
implants or injections, and vaginal suppositories.



HRT can improve migraine in 22% to 23%, worsen
migraine in 21%, and leave it unchanged in 57%
In a cross-sectional study of 17,107 postmenopausal
women from the Women's Health Study: diagnosis of
migraine was 1.44 times more likely in HRT users
aura symptoms can develop secondary to estrogen
replacement therapy in some patients.

lowering the dosage of estrogen or changing to another type of
estrogen replacement may lead to an abatement of aura
symptoms.
Hodson J Climacteric. 2000;3(2):119-124. Greendale GA, Obstet Gynecol. 1998;92(6):982-988.
MacGregor A. Headache. 1999;39(9):674-678.
HRT



Dose: women who had a medical menopause only the 100-mcg patch was preventative
of migraine.
Type and Route of Administration: headache outcome worsened in patients receiving
an oral conjugated estrogen and medroxyprogesterone, while they did not change as
compared to baseline in those receiving a 50-mcg transdermal estradiol patch and
medroxyprogesterone.

HRTs containing conjugated estrogens are provocative for migraine, while those containing
natural estrogens have less effect on migraine.

transdermal routes of delivery may be superior to oral routes, since they maintain a more
constant serum estradiol level
HRT regimens using the same dosage of estrogens and progestins on a daily basis are
superior to those using intermittent dosing of HRT.
Nappi RE, Maturitas. 2001;38(2):157-163.
Facchinetti F Headache.2002;42(9):924-929.